CS Company Law MCA 21 And Filling In XBRL Question and Answers

An Introduction To MCA – 21 And Filling In XBRL

E-form

An e-form is a re-engineered conventional form, represents a document in electronic format.

Feature of E-governance

Director Identification Number (DIN), Corporate Identity Number (CIN) and Digital Signature Certificate (DSC) are the important features under e-governance mode (MCA-21).

MCA-21

MCA-21 system provides for the facility of payment of statutory fees through multiple modes i.e. (i) Off-line payment through a challan generated by the system and payment of fees at the counter of the notified bank branches through DDs/ Cash; (ii) on-line payments through Internet Banking and Credit Cards [Master Card/VISA].

SRN

Each transaction under e-filing is uniquely identified by a Service Request Number (SRN). On filing of an e-form, the system will generate and provide a Service Request Number (SRN). A user can check the status of the document/ transaction, by entering the SRN.

Stamp duty on documents

If the stamp duty on documents which are required to be filed on non-judicial stamp paper is paid electronically through Ministry of Corporate Affairs portal www.mca.gov.in, in such case, the company. shall not be required to make physical submission of such documents, in addition to their submission in the electronic form.

MCA Services

  • LLP Services
  • LLP Services for Business User
  • E-Filing
  • Company Services
  • Complaints
  • Document Related Services
  • Fee and Payment Services
  • Public Search of Trademark
  • Investor Services

Corporate Identity Number(CIN)/ Foreign Company Registration Number (FCRN)

Every company is allocated a Corporate Identity Number (CIN). CIN can be found from the MCA-21 portal through search based on:

  • ROC Registration No.
  • Existing Company Name
  • Old Name of Company (in case of change of name, user is required to enter old name and the system displays corresponding current name).
  • Inactive CIN [In case of change of CIN, the user is required to enter previous (inactive) CIN Number]

Foreign Company Registration Number (FCRN)

Every foreign company has been allocated a Foreign Company Registration Number (FCRN).

Director Identification Number (DIN)

DIN is an identification number which the Central Government may allot to any individual, intending to be appointed as director or to any existing directors of a company, for the purpose of his identification

All existing and any person intending to be appointed as a director are required to obtain the Director Identification Number (DIN). DIN is also mandatory for directors of Indian Companies who are not citizens of India. However, DIN is not mandatory for directors of foreign company having branch offices in India.

Every individual, who is intending to be appointed as Director of a company or designated partner of a limited liability partnership is required to make an application electronically in Form DIR -3 to Central Government for obtaining Director Identification Number (DIN) or in case the company is being incorporated through Form SPICE, a maximum of three directors can apply for DIN. DIN is a unique, identification number and once obtained is valid for life time of a director. A single DIN is required to be obtained irrespective of the number of directorships.

MCA 21 And Filling In XBRL

Mca 21 Company Law

Digital Signature Certificate (DSC)

For MCA-21, the following four types of users are identified as users of Digital Signatures and are required to obtain digital signature certificate:

  • MCA (Government) Employees.
  • Professionals (Company Secretaries, Chartered Accountants, Cost Accountants, and Lawyers) who interact with MCA and companies in the context of Companies Act.
  • Authorized signatories of the Company including Managing Director, Directors, Manager or Secretary.
  • Representatives of Banks and Financial Institutions.

e-forms

An e-form is only a re-engineered conventional form notified and represents a document in electronic format for filing with MCA authorities through the Internet. This may be either a form filed for compliance or information purpose or an application seeking approval from the MCA. Due to technical updates, these forms updates regularly, even though their user interface may not change. User always use latest e- forms from the MCA Portal.

XBRL Extensive Business Reporting Language

XBRL Filing

XBRL (Extensible Business Reporting Language) is a language for the electronic communication of business and financial data which is revolutionizing business reporting around the world. It helps in the preparation, analysis and communication of business information. It offers cost savings, greater efficiency and improved accuracy and reliability to all those involved in supplying or using financial data.

The Ministry of Corporate Affairs has mandated the following select class of companies mentioned below to file financial statements in XBRL (extensible Business Reporting Language) mode and by using the XBRL taxonomy:

  • all companies listed with any Stock Exchange(s) in India and their Indian subsidiaries; or
  • all companies having paid-up capital of Rupees five crore and above; or
  • all companies having turnover of Rupees one hundred crore and above; or
  • all companies who were required to file their financial statements for FY 2010-11, using XBRL mode.

However, the companies in banking, insurance, power sector, non-banking financial companies and housing finance companies are exempted from XBRL filing till further orders.

MCA 21 And Filling In XBRL Short Notes

Question 1. Write notes on the following:

XBRL

Answer:

Extensible Business Reporting Language (XBRL) is a language for the electronic communication of business and financial data revolutionizing business reporting around the world. It provides major benefits in the preparation, analysis and communication of business information. It offers cost savings, greater efficiency and improved accuracy and reliability to all those involved in supplying or using financial data.

The Ministry of Corporate Affairs has mandated for selected class of companies to file their Balance Sheet and Profit and Loss Account and other documents as required under Section 137 of Companies Act, 2013 with the Registrar of Companies in XBRL (Extensible Business Reporting Language) mode and by using the XBRL taxonomy.

Question 2. Write notes on the following:

XBRL filing.

Answer:

The applicability of e-form AOC-4 XBRL on classes of companies has been amended.

Filing of financial statements with Registrar. The following class of companies shall file their financial statements and other documents under Section 137 of the Act with the Registrar in e-form AOC-4 XBRL as per Annexure-1:

  • companies listed with stock exchanges in India and their Indian subsidiaries;
  • companies having paid up capital of five crore rupees or above;
  • companies having turnover of one hundred crore rupees or above;
  • all companies which are required to prepare their financial statements in accordance with Companies (Indian Accounting Standards) Rules, 2015:

Provided that the companies preparing their financial statements under the Companies (Accounting Standards) Rules, 2006 shall file the statements using the Taxonomy provided in Annexure-Il and companies preparing their financial statements under Companies (Indian Accounting Standards) Rules, 2015, shall file the statements using the Taxonomy provided in Annexure-II A:

Provided further that non-banking financial companies, housing finance companies and companies engaged in the business of banking and insurance sector are exempted from filing of financial statements under these rules.

Key benefits of XBRL filing are as under:

Relevant data has tags and selective information can be fetched for specific purposes by various government and regulatory agencies.

It is in conformity with Global Reporting Standards, which helps in improved data mining and relevant information search.

Question 3. Write notes on the following:

Keeping documents, records, registers, minutes, etc., of the company in electronic form

Answer:

According to Section 120, the documents, records, registers, minutes etc. may be kept and inspected in electronic form.

Rule 27 of Companies (Management and Administration) Rules, 2014 initially mandated every listed company or a company having not less than one thousand shareholders, debenture holders and other security holders may maintain its records, as required to be maintained under the Act or Rules made thereunder in electronic form.

According to Rule 27(2) the records in electronic form shall be maintained in such manner as the Board of Directors of the company may think fit, provided that:

  • the records are maintained in the same formats and in accordance with all other requirements as provided in the Act or the rules made thereunder;
  • the information as required under the provisions of the Act or the rules made thereunder should be adequately recorded for future reference;
  • the records must be capable of being readable, retrievable and reproducible in printed form;
  • the records are capable of being dated and signed digitally wherever it is required under the provisions of the Act or the rules made thereunder;
  • the records, once dated and signed digitally shall not be capable of being edited or altered:
  • the records shall be capable of being updated, according to the provisions of the Act.or the rules made thereunder and the date of DISTINGUISH BETWEEN updating shall be capable of being recorded on every updating. Space to write important points for revision

Question 4. Write notes on the following:

Pre-certification of e-forms

Answer:

Pre-certification of e-forms

Apart from authentication of e-forms by authorized signatories using digital signatures, certain e-forms are also required to be pre-certified by practicing professionals who are members of professional bodies namely ICAI, ICSI or ICWAI with the responsibility of ensuring correctness, completeness and integrity of documents filed by them with MCA in electronic mode including filing of financial statements in XBRL mode. Pre-certification is not required in the case of one person companies and small companies.

Once an e-form has been pre-certified by a professional towards its authenticity based on the particulars contained in the books of accounts and records of the company, MCA21 system takes that e-form on file by way of straight through process. Professionals are responsible for certifying documents through digital signature and the system would accept the documents online without approval by ROC.

This process of taking the forms on record by way of straight through process requires professionals to be extra cautious and vigilant towards the information, he/she certifies in the forms. If a professional certifies incorrect information or omits any material information, which later on proves that the same was done knowingly, he/she will be liable for the punishment under Section 448 read with Section 447 of the Companies Act, 2013, besides disciplinary action by the respective Institute, which issued the certificate of practice to the professionals.

Xbrl Filing Process

MCA 21 And Filling In XBRL Distinguish Between

Question 1. Distinguish between the following:

‘Pre-scrutiny’ and ‘check form’.

Answer:

Company Law An Introduction To MCA And Filling In XBRL Pre Scrutiny and check form

Question 2. Distinguish between the following:

‘Informational services’ and ‘approval services (Registrar of Companies)’ for categories of e-forms.

Answer:

Company Law An Introduction To MCA And Filling In XBRL Approval Services

Informational Services:

Company Law An Introduction To MCA And Filling In XBRL Informational Services

Question 3. Distinguish between the following:

XBRL tags and XBRL taxonomies.

Answer:

In XBRL, information is not treated as a static block of text or set of numbers. Instead, information is broken down into unique items of data (e.g. total liabilities = 100). These data items are then assigned mark-up tags that make them computer-readable. For example, the tag<Liabilities>100</Liabilities> enables a computer to understand that the item is liabilities, and it has a value of 100.

Computers can treat information that has been tagged using XBRL ‘intelligently’; they can recognize, process, store, exchange and analyze it automatically using software.

Because XBRL tags are formed in a universally-accepted way, they can be read and processed by any computer that has XBRL software XBRL tags are defined and organized using categorization schemes called taxonomies.

XBRL Taxonomies:

Different countries use different accounting standards. Reporting under each standard reflects differing definitions. The XBRL language uses different dictionaries, known as ‘taxonomies’, to define the specific tags used for each standard. Different dictionaries may be defined for different purposes and types of reporting.

Taxonomies are the computer-readable ‘dictionaries’ of XBRL. Taxonomies provide definitions for XBRL tags, they provide information about the tags, and they organize the tags so that they have a meaningful structure.

As a result, taxonomies enable computers with XBRL software to:

  • understand what the tag is (e.g. whether it is a monetary item, a percentage or text);
  • In tagging Section, “N” refers to navigation, “A” refers to attaching the disclosures “T” refers to text entry etc.
  • what characteristics the tag has (e.g. if it has a negative value);
  • its relationship to other items (e.g. if it is part of a calculation).

Taxonomies differ according to reporting purposes, the type of information being reported and reporting presentation requirements.

MCA 21 And Filling In XBRL Descriptive Questions

Question 1. In relation to e-form CRA-2, state the:

  1. Reasons for filing this form
  2. Particulars required to be filled in the form
  3. Documents required to be enclosed with the form
  4. Person who is to sign and certify the form.

Answer:

  • Reasons for filling this form
    • This is a form of application to the Central Government for appointment of cost auditor.
  • Particulars required to be filled in the form
    • Corporate Identity Number (CIN) or Foreign Company Registration Number (FCRN) of the company;
    • Name of the company;
    • Category of cost audit order;
    • Details of the cost auditor proposed to be appointed;
    • Proposed remuneration of the cost auditor; and
    • Date of Board Meeting of Directors proposing the name of the cost auditor.
  • Documents required to be enclosed with the form
    • Copy of the board resolution of the company sanctioning the proposal for which the Government approval has been sought.
    • Copy of the certificate obtained from cost auditor.
  • Person who is to sign and certify the form
    • The form is required to be digitally signed by Managing Director or Director or Manager or Secretary of the company (in case of Indian Company) or an authorized representative (in case of a Foreign Company).

Question 2. Who are the persons required/obliged to use digital signature for filing/certifying e-forms? 

Answer:

Digital signature certificate is essential for every users who is required to sign in e-form for submission with MCA. For MCA – 21 there are four types of users that is given below are identifies as user of digital signature and are. required to obtain digital signature certificate:

  • MCA (Government) Employee.
  • Professional (Company Secretaries, Chartered Accountants, Cost Accountants).
  • Authorised signatories of the company including managing director, directors, manager or secretary.
  • Representatives of Banks and Financial Institutions.

Question 3. When a Director Identification Number (DIN) application is rejected by the Ministry of Corporate Affairs portal, does the applicant necessarily need to apply for a fresh DIN? Discuss.

Is online viewing of public documents of a company open to any member of the public? How one (who is eligible) can view online public documents of a company? Is a copy of a public document available to the public? Give two examples of company documents filed online with the Registrar of Companies.

Answer:

  • Common causes of Rejection for Director Identification Number (DIN)
    • The applicant details are not as per the PAN.
    • The particulars filed in form DIR 3 do not match with the details given in the supporting documents submitted along with DIN application.
    • Residence proof like :
      • Bank statement
      • Electricity bill
      • Telephone bill
      • Utility bill etc.
        Submitted are older than 2 months of submitting the application for verification.
    • The supporting document are not duly attested that is:
      • Name
      • Designation
      • Membership
      • Practicing certificate number etc. are not clearly indicated
    • Passport/Driving License/Identity proofs etc. attached are expired only such documents which are currently valid should be attached..

Viewing public documents is open to any member of public because the very term ‘public document’ means a document to which a member of public has access. There is no issue on eligibility to view public document. Any member of public or citizen can access MCA portal for viewing public documents of any company registered with ROC.

The feature of viewing is available after login. One who wishes to view will select the company concerned after login. Then the documents under each category will come on the screen. Contents of the documents can be seen only after payment of requisite fee. Once payment is made the person can view the documents during the next 7 days and once the view is started then it is available for a maximum of 3 hours.

The documents can be viewed from anywhere i.e. from any online facility available without visiting Registrar of Companies’ office, using the ‘My documents’ tab available after logging into the portal. Apart from viewing public documents, a person can also obtain certified copies of documents of payment. In this regard, an application is to be made to the concerned ROC within whose jurisdiction the company’s registered office is situated. Examples of public documents are:

Documents relating to incorporation of a company

Annual returns and balance sheets

Note: Examples of public documents are given below:

  • Documents relating to incorporation of company.
  • Annual returns and financial statement. Space to write important points for revision

Mca 21 And Xbrl Questions

Question 4. What is the general structure of e-filing process under MCA-21?

Answer:

Company Law An Introduction To MCA And Filling In XBRL Features of E-filling

Question 5. “XBRL offers major benefits at all stages of business reporting and analysis”. Discuss.

Answer:

Benefits of XBRL

XBRL offers major benefits at all stages of business XBRL reporting and analysis. The benefits are seen in automation, cost saving, faster, more reliable and more accurate handling of data, improved analysis and in better quality of information and decision- making.

  • It saves costs and improves efficiency in handling business and financial information.
  • It is extensible and flexible which can adapt any changes according to the requirements.
  • It enables producers and consumers of financial data to switch resources away from costly manual processes, typically involving time-consuming comparison, assembly and re-entry of data.
  • The users of financial data are able to make more effort on analysis.

Question 6. List out the resolutions which require filing of e- Form MGT-14 with the Registrar of Companies.

Answer:

Section 117 of the Companies Act, 2013 provides that a copy of every resolution and an agreement in respect of matters specified therein together with a explanatory statement shall be filed in Form No. MGT-14 with the Registrar within thirty days of its passing.

Resolutions and agreements to be filed with the Registrar are as under:

  • special resolutions;
  • resolutions which have been agreed to by all, the members of a company, but which if not so agreed to, would not have been effective for their purpose unless they had been passed as special resolutions;
  • any resolution of the Board of Directors of a company or agreement executed by a company, relating to the appointment, re-appointment or renewal of the appointment or variation of the terms of appointment, of a managing director;
  • resolutions or agreements which have been agreed to by any class of members but which, if not so agreed to, would not have been effective for their purpose unless they had been passed by a specified majority or otherwise in some particular manner and all resolutions or agreements which effectively bind such class of members though not agreed to by all those members;
  • resolutions passed by a company according consent to be exercised by its Board of Directors of any of the powers under clause (a) and clause (c) of Sub-Section (1) of Section 180;
  • resolutions requiring a company to be wound up voluntarily passed in pursuance of Section 304;
  • resolutions passed in pursuance of Sub-Section (3) of Section 179, and
  • any other resolution or agreement as may be prescribed and placed in the public domain.

Question 7. “The e-forms are required to be authenticated by the authorised signatories using digital signatures.” With reference to e-filing of documents with the Registrar of Companies, identify the users of digital signature who are required to obtain Digital Signature Certificate (DSC) and enlist the requirements of obtaining DSC in the case of foreign directors.

Answer.

The following four types of users are identified as users of Digital Signatures and are required to obtain digital signature certificate:

  • MCA (Government) Employees.
  • Professionals (Company Secretaries, Chartered Accountants, Cost Accountants and Lawyers) who interact with MCA and companies in the context of Companies Act.
  • Authorized signatories of the Company including Managing Director, Directors, Manager or Secretary.
  • Representatives of Banks and Financial Institutions.

Requirements for obtaining DSC in case of foreign directors: Foreign directors are required to obtain Digital Signature Certificate from an Indian Certifying Authority (List of Certifying Authorities is available on the MCA portal). The process of registration of DSC is same as applicable to others.

In case of Foreign Director, the DSC application is to be made to one of the Indian Certifying Authorities which is licensed u/s 24 of the Information Technology Act, 2000 and mentioned in the list available on the MCA portal. The said application should be duly filled by such applicant with the relevant enclosures.

Such DSC application then to be physically submitted with the necessary documents. Further, the said documents be attested and notarized by the Notary Public by the Foreign Ambassador/Diplomatic. In this manner, the Foreign Director can obtain the DSC from C.A. on the successful verification of the Application along with the documents and information.

Question 8. CIN, issued by MCA, the unique identifier, provides the key profile of companies – Explain.

Answer:

Every company incorporated on or after Nov 1, 2000 is allotted a 21.digit Corporate Identity Number (CIN) by the ROC, which indicates the listing status, economic activity (industry), State, Year of incorporation, ownership and sequential number assigned by the ROC. This number is to be quoted in all e-forms and once the number is typed, MCA site automatically pre-fills the essential particulars.

CIN is structured as under to indicate the profile of the company:

1st digit Listing Status

Next 5 digits: Economic activity (industry to which the company belongs) Next 2 digits: State in which Company is registered

Next 4 digits: Year of incorporation

Next 3 digits: Ownership

Next 6 digits: Sequential number assigned by the ROC (Registration Number)

CIN can also be searched in MCA site based on ROC registration number, existing company name or old name, if any. Keeping in view the said specifications, CIN can be considered the unique identifier.

Cs Company Law Mca 21

Question 9. Filing of financial statements in XBRL mode and by using XBRL taxonomy is mandatory to certain companies. Discuss, referring to the provisions of the Companies Act, 2013. 

Answer:

As per Rule 3 of the Companies (Filling of Documents and Forms in Extensive Business Reporting Language) Rules, 2018 mandates the following select class of companies mentioned below to file financial statements in XBRL (extensible Business Reporting Language) mode and by using the XBRL taxonomy:

  • All companies listed with any Stock Exchange(s) in India and their Indian subsidiaries; or
  • All companies having paid-up capital of Rupees five crore and above; or
  • All companies having turnover of Rupees one hundred crore and above; or
  • All companies who were required to file their financial statements for F.Y. 2010-11, using XBRL mode.

But, the companies in banking, insurance, power sector, non-banking financial companies and housing finance companies are exempted from XBRL filing till further orders.

Question 10. Shalini, practicing Company Secretary, has disclosed information acquired in the course of her professional engagement to a person other than the client, without the consent of such client. Can she do so? Can she retain the digital signature of her client for uploading e-forms on MCA portal?

Answer:

Clause 1 of Part I of Second Schedule to the Company Secretaries Act, 1980 provides that a Company Secretary in Practice shall be deemed to be guilty of professional misconduct, if he discloses information acquired in the course of his professional engagement to any person other than the client so engaging him, without the consent of such client, or otherwise than as required by any law for the time being in force. This clause indicates the position of trust and confidence reposed by the client in a Company Secretary in practice. Therefore, Shalini is guilty under the above mentioned clause.

It is suggested that Shalini may retain digital signature of client after obtaining a formal letter signed by his client authorising PCS to make use of his Digital signature..

Question 11. Who are all the persons required to obtain Digital Signature Certificates?

Answer:

The e-forms are required to be authenticated by the authorized signatories using Digital Signature Certificate (DSC) as defined under the Information Technology Act, 2000. A digital signature is the electronic signature duly issued by a certifying authority that shows the authority of the person signing the same.

It is an electronic equivalent of a written signature. Every user who is required to sign an e-form for submission with MCA is required to obtain a Digital Signature Certificate. For MCA-21, the following four types of users are identified as users of Digital Signatures and are required to obtain digital signature certificate:

  • MCA (Government) Employees.
  • Professionals (Company Secretaries, Chartered Accountants, Cost Accountants and Lawyers) who interact with MCA and companies in the context of Companies Act.
  • Authorized signatories of the Company including Managing Director, Directors, Manager or Secretary.
  • Representatives of Banks and Financial Institutions.

All companies (Public Company, Private Company, Company not having share capital, Company limited by share or guarantee, Unlimited Company) must comply with this requirement of registration of DSC by the director, manager and secretary. Foreign directors are required to obtain Digital Signature Certificate from an Indian Certifying Authority (List of Certifying Authorities is available on the MCA portal). The process of registration of DSC is same as applicable to others.

Xbrl Filing In Companies Act

Question 12. Every company is required to get pre-scrutiny and pre- certification of e-forms by a practising professional before filing with the Registrar of Companies (ROC). Is this true? Explain the relevant legal provisions.

Answer:

Pre-Scrutiny: Pre-scrutiny is a functionality that is used checking whether certain core aspects are properly filled in the e-form. It can be done by the company itself and no professional is required. Pre scrutiny function is available for all forms and is to be done by all class of companies.

Pre-Certification: Apart from authentication of e-forms by authorized signatories using digital signatures, some e-forms are also required to be pre-certified by practicing professionals. Pre-certification means certification of correctness of any document by a professional before the same is filed with the Registrar of Companies. E-forms mentioned in Rule 8(12) of the Companies (Registration Offices and Fees) Rules, 2014 such as INC-22, AOC-4, MGT-14, DIR-12 etc., are required to be pre-certified by Company Secretaries or Chartered Accountants or Cost Accountants who are in whole-time practice by all class of companies except One Person Company and Small Companies.

Consequently, every company is required to do pre-scrutiny of e-forms but pre-certification of certain forms is not mandatory for every class of company. Space to write important points for revision

Question 13. Assistant Company Secretary of JKL Ltd. has made excess payment of 1 lakh to MCA for filing of e-forms. What is the procedure of refund of MCA-21 fees?

Answer:

In order to claim refund of multiple payments or incorrect payment or excess payment of MCA-21 fees, while using MCA services, following procedure is required to be followed:

  • The Person is required to file the ‘Refund Form’ available on MCA21 portal for claiming refund.
  • The refund of MCA21 fees is available in the following cases:
    • Multiple Payments This includes cases where service seeker does multiple filings such as in e-Form No. SH-7 and makes payments more than once (multiple times) for the same service. Although, refund shall not be allowed in respect of approved e-Forms.
    • Incorrect Payments This includes cases where the service seeker has made payment in respect of an e-Form or Stamp duty through an incorrect option under Pay miscellaneous fee facility.
    • Excess Payments- This includes cases where any excess fee has been paid by the service seeker due to some incorrect data entered in the e-Form or incorrect data in MCA-21 system due to migration of data from legacy system.
  • The refund form is to be filed within the stipulated time period. Also, there shall be deduction in the amount to be refunded based on time period within which refund e-form is filed. Space to write important points for revision-

MCA 21 And Filling In XBRL Practical Questions

Question 1. Prudent General Insurance Company Ltd. is engaged in the general insurance business. The company is not listed in any stock exchange in India but is a subsidiary of Reliable General Insurance Company Ltd., listed at Bombay Stock Exchange. The turnover of Prudent General Insurance Company Ltd. is 330 crore. Examining the provisions of the Companies Act, 2013, state whether the company is required to file XBRL enabled balance sheet.

Answer:

Company Law An Introduction To MCA And Filling In XBRL XBRL Filling

Question 2. In relation to filing of financial statements of a company in XBRL mode and by using the XBRL taxonomy, decide whether the following companies are required to file the financial statements in the said mode:

  1. Grand Ltd., the subsidiary company of Tiny Ltd. which is listed at Kolkata Stock Exchange.
  2. Prime Ltd., a company which has paid-up share capital of 100 crore.
  3. Crafty Ltd., a company which has a turnover of 400 crore.
  4. Comfort Ltd., a non-banking financial company.

Answer:

XBRL Filing: The Ministry of Corporate Affairs has mandated the following select class of companies mentioned below to file financial statements in XBRL (Extensible Business Reporting Language) mode and by using the XBRL taxonomy:

  • all companies listed with any Stock Exchange(s) in India and their Indian subsidiaries; or
  • all companies having paid-up share capital of rupees five crore and above; or
  • all companies having turnover of rupees one hundred crore and above; or
  • all companies who were required to file their financial statements for F.Y. 2010-11; using XBRL mode.

However, banking companies, insurance companies, power companies and Non-Banking Financial Companies are exempted from XBRL filing till further orders.

  • Yes, Company is required to file financial statements through XBRL mode.
  • Yes, Company is required to file financial statements through XBRL mode.
  • Since in this case the turnover is more than 100 crore, the company is required to file the financial statements through XBRL mode.
  • This company is exempted from filing the financial statements through XBRL mode.

How To File Xbrl With Mca

Question 3. ABC Ltd. has not satisfied any conditions specified as per section 137 of the Companies Act for current financial year.. The company has filed financial statement as per XBRL Taxanomy for the previous financial year. Is ABC Ltd. still required to file financial statements as per XBRL. Taxanomy for the current financial year?

Answer:

Rule 3 of the Companies (Filing of Documents and Forms in XBRL) Rules, 2015

  • The following class of companies shall file their financial statements and other documents under section 137 of the Act with the Registrar in e-Form AOC-4 XBRL:
    • companies listed with stock exchanges in India and their Indian subsidiaries
    • companies having paid up capital of five crore rupees or above;
    • companies having turnover of one hundred crore rupees or above;
    • all companies which are required to prepare their financial statements in accordance with Companies (Indian Accounting Standards) Rules, 2015.
  • Provided that the Companies preparing their financial statements under the Companies (Accounting Standards) Rules, 2006 shall file the statements using the Taxonomy provided in Annexure-Il and companies preparing their financial statements under Companies (Indian Accounting Standards) Rules, 2015, shall file the statements using the Taxonomy provided in Annexure-II A of the Companies (Filing of Documents and Forms in XBRL) Rules, 2015
  • Further non-banking financial companies, housing finance companies and companies engaged in the business of banking and insurance sector are exempted from filing of financial statements under these rules.
  • The companies which have filed their financial statements under sub-rule (1) of Rule 3 of XBRL Rules, shall continue to file their financial statements and other documents though they may not fall under the class of companies specified therein in succeeding years. The companies which have filed their financial statements under the erstwhile rules, namely the Companies (Filing of Documents and Forms in Extensible Business Reporting Language) Rules, 2011, shall continue to file their financial statements and other documents as prescribed in Rule 3(1) of XBRL Rules though they do not fall under the class of companies specified therein.

Therefore, as per the above provisions ABC Ltd. though has not satisfied any conditions specified as per Section 137 of the Companies Act, 2013 for current financial year, yet the company is required to file financial statements as per XBRL Taxonomy for the current financial year as it has filed the financial statements as per XBRL Taxonomy for the previous financial year.

CS Company Law Merger And Amalgamation Of Companies Question and Answers

An Overview Of Corporate Re-organisation Merger And Amalgamation Of Companies Chapter At A Glance

Compromise in Companies Act, 2013

A compromise means settlement or adjustment of claims in dispute by mutual concessions.

Arrangement in Companies Act, 2013

Arrangement includes a reorganization of the share capital of the Company by consolidation of shares of different classes or division of shares into shares of different classes or by both of these methods.

Reconstruction in Companies Act, 2013

Reconstruction’, inter alia, indicates the process that involves

  • the transfer of undertakings of an existing company to another company, usually incorporated for the purpose. The old company ceases to exist. However, all the assets might not be passed to the new company;
  • the carrying on of substantially the same business by the same persons;
  • the rights of the shareholders in the old company are satisfied by their being allotted shares in the new company.

Amalgamation in Companies Act, 2013

Amalgamation is the blending of two or more undertakings (companies) into one undertaking, the shareholders of each blending undertaking becoming substantially the shareholders of the other company that holds blended undertakings.

Merger in Companies Act, 2013

Merger is a form of amalgamation where all the properties and liabilities of the transferor company get merged with the properties and liabilities of the transferee company leaving behind nothing with the transferor company except its name, which also gets removed through the process of law. In reality, companies do not merge; only the assets and liability merge.

Reverse Merger in Companies Act, 2013

Reverse Merger is the opposite of Merger. No clear definition of reverse merger has been given in the Companies Act nor the term has been precisely defined by the Indian Courts. Reverse Merger represents a case where the loss-making company or less profit-earning company extends its embracing arms to the profitable company and, in turn, absorbs it into its fold.

Binding in Companies Act, 2013

The sanctioned scheme would be binding on all the concerned parties. However, in certain circumstances, the Tribunal shall not sanction a scheme of compromise and arrangement.

No Objection Certificate in Companies Act, 2013

In a scheme of compromise or arrangement, the Tribunal is bound to seek a report from the Registrar of Companies as well as a no objection certificate from the Income Tax Authority to ensure that the affairs of the Company have not been conducted in a prejudicial manner.

Explanatory Statement in Companies Act, 2013

An explanatory statement, as provided for in the act, would be attached to every notice calling the meeting.

Supervise the Scheme in Companies Act, 2013

The Tribunal has the power to supervise the implementation of the scheme and to sanction modification of the terms of the scheme. While sanctioning the scheme; the Tribunal also has the power to order winding up.

Merger And Amalgamation In Company Law

Cross Border Mergers in Companies Act, 2013

Section 234(2) states that subject to the provisions of any other law for the time being in force, a foreign company, may with the prior approval of the Reserve Bank of India, merge into a company registered under this Act or vice versa and the terms and conditions of the scheme of merger may provide, among other things, for the payment of consideration to the shareholders of the merging company in cash or Depository Receipts or partly in cash and partly in Depository Receipts, as the case may be, as per the scheme to be drawn up for the purpose.

Merger And Amalgamation Of Companies

Merger And Amalgamation Of Companies Descriptive Questions

Question 1. Examining the provisions of the Companies Act, 2013, explain the powers of the Central Government to order the amalgamation of companies in the public interest.

Answer:

Section 237(1) states that when the Central Government is satisfied that it is essential in the public interest that two or more companies should amalgamate, the Central Government may, by order notified in the Official Gazette, provide for the amalgamation of those companies into a single company with such constitution, with such property, powers, rights, interests, authorities, and privileges, and with such liabilities, duties, and obligations, as may be specified in the order.

Question 2. Comment on the following:

The merger of a ‘Subsidiary’ Company into a ‘Holding’ Company.

Answer:

The merger of a ‘Subsidiary’ Company into a ‘Holding’ Company

  • As per Section 233 of the Companies Act, 2013, a scheme of merger or amalgamation may be entered into between two or more small companies or between a holding company and its wholly-owned subsidiary company or such other class or classes of companies as may be prescribed, subject to the following, namely:
    • a notice of the proposed scheme inviting objections or suggestions, if any, from the Registrar and Official Liquidators where the registered office of the respective companies are situated or persons affected by the scheme within thirty days is issued by the transferor company or companies and the transferee company
    • the objections and suggestions received are considered by the companies in their respective general meetings and the scheme is approved by the respective members or class of members at a general meeting holding at least ninety percent. Of the total number of shares
    • each of the companies involved in the merger files a declaration of solvency, in the prescribed form, with the Registrar of the place where the registered office of the company is situated and
    • the scheme is approved by a majority representing nine-tenths in value of the creditors or class of creditors of respective companies indicated in a meeting convened by the company by giving a notice of twenty-one days along with the scheme to its creditors for the purpose or otherwise approved in writing.
    • The transferee company shall file a copy of the scheme so approved in the manner as may be prescribed, by the Central Government, Registrar, and the Official Liquidator where the registered office of the company is situated.
    • On the receipt of the scheme, if the Registrar or the Official Liquidator has no objections or suggestions to the scheme, the Central Government shall register the same and issue a confirmation thereof to the companies.
    • If the Registrar or Official Liquidator has any objections or suggestions, he may communicate the same in writing to the Central Government within thirty days:
    • Provided that if no such communication is made, it shall be presumed that he has no objection to the scheme.
    • If the Central Government after receiving the objections or suggestions or for any reason thinks that such a scheme is not in the public interest or the interest of the creditors, it may apply to the Tribunal within sixty days of the receipt of the scheme under sub-Section (2) stating its objections and requesting that the Tribunal may consider the scheme under Section 232.
    • On receipt of an application from the Central Government or any person, if the Tribunal, for reasons to be recorded in writing, thinks that the scheme should be considered as per the procedure laid down in Section 232, the Tribunal may direct accordingly or it may confirm the scheme by passing such order as it deems fit:
    • Provided that if the Central Government does not have any objection to the scheme or it does not file any application under this section before the Tribunal, it shall be deemed that it has no objection to the scheme.

Types Of Mergers And Amalgamations

Question 3. Serious Ltd. has three factories in Chennai. The company wants to sell one of the factories. Can the company sell its factory? Further, assuming that the company has also borrowed credit facilities from the bank, explain the statutory provisions under the Companies Act, 2013.

Answer:

According to Sub-Section (1)(a) of Section 180 of the Companies Act, 2013, the Board of Directors of a company may sell, lease or otherwise dispose of the whole or substantially the whole of the undertaking of the company or where the company owns more than one undertaking, of the whole or substantially the whole of any of such undertakings only with the consent of the company by a special resolution.

Accordingly, the company may sell any of its factories with the consent of the company by a special resolution.

Where the company has a credit facility on creating a charge on such undertaking, the company, may be required to obtain a no-objection- certificate from the bank as per contractual obligation and shall also modify the charge accordingly.

CS Company Law Merger And Amalgamation Of Companies

Question 4. Comment on the following:

The provisions of the Companies Act, 2013 relating to compromises and arrangements are uniformly applicable to all companies. 

Answer:

Sections 230 to 240 of the Companies Act, 2013 provide for the Compromise, Arrangements, and Amalgamation of Companies. The said provisions are uniformly applicable to all companies except Section 233 which specifies the simplified procedure for merger or amalgamation of –

  • Two or more small companies, or
  • Between a holding company and its wholly-owned subsidiary company,
    or
  • Such other classes or classes of companies as may be prescribed.

Section 233 (1) of the Companies Act, 2013 Provides that notwithstanding the provisions of Section 230 and Section 232 of the Companies Act, 2013, a scheme of merger or amalgamation may be entered into between two or more small companies or between a holding company and its wholly-owned subsidiary company or such other class or classes of companies as may be specified, subject to the following, namely:-

  • a notice of the proposed scheme inviting objections or suggestions, if any, from the Registrar and Official Liquidators where the registered office of the respective companies are situated or persons affected by the scheme within 30 days is issued by the transferor company or companies and the transferee company;
  • the objections and suggestions received are considered by the. companies in their respective general meetings and the scheme is approved by the respective members or class of members at a general meeting holding at least ninety percent of the total number of shares;
  • each of the companies involved in the merger files a declaration of solvency, in the prescribed form, with the Registrar of the place where the registered office of the company is situated; and
  • the scheme is approved by a majority representing nine-tenths in value of the creditors or class of creditors of respective companies indicated in a meeting convened by the company by giving a notice of twenty-one days along with the scheme to its creditors for the purpose or otherwise approved in writing.

Question 5. The appointed date and Effective date are very important in any merger or amalgamation through a scheme of arrangement. Do you agree?

Answer:

The appointed date and Effective date are two significant dates in any scheme of Merger and Amalgamation.

Mention of an appointed date is compulsory for the schemes falling under Section 232 of the Companies Act, 2013. Schemes involving Merger Amalgamation or division of undertaking are required to fix an appointed date.

In Marshall Sons & Co. India Ltd. vs. ITO, it was held by the Hon’ble Supreme Court that every scheme of amalgamation has to necessarily provide a date with effect from which the amalgamation/transfer shall take place and that such date may precede the date of sanctioning of the scheme by the Court, the date of filing of certified copies of the orders of the Court before the Registrar of Companies, and the date of allotment of shares, etc. Although, would be given effect from the transfer date (appointed date) itself.

  • Section 232(6) of the Companies Act, 2013 states that the scheme shall be deemed to be effective from the ‘appointed date’ and not a date after the ‘appointed date’.
  • This is an enabling provision to allow the companies to decide and agree upon an ‘appointed date’ from which the scheme shall come into force.

The “Effective date” is the date when the amalgamation/merger is completed in all respects after having gone through the formalities involved, and the transferor company is dissolved by the Registrar of Companies and a certified copy of the order for the scheme of compromise and arrangement is filed with ROC and all other required statutory authorities, if any.

Merger And Amalgamation Of Companies Practical Questions

Question 1. A transferor company got approval for a scheme of amalgamation with the transferee company. An amount of 5 lakh was deposited by the transferor company on the direction of the Tribunal for settling the dues of employees. An ex-employee of the transferor company objected to the amalgamation citing that he is also entitled to the claim in the amount deposited. Will he succeed? Give reasons.

Answer:

Company Law An Overview of Corporate Re-organisation Merger Facts of the Case

Companies Act Merger And Amalgamation Process

Question 2. SUP Ltd. is a public company incorporated in India. It wants to propose a scheme of arrangement (merger) with another company in the same line of business in India. Help the company in preparing such a scheme of arrangement first. Secondly, help the company in getting approval from NCLT. Advise how the company should approach NCLT for its approval of the scheme and discuss grounds based on which NCLT will accord its approval.

Answer:

Preparation of Scheme of Amalgamation

The scheme of amalgamation to be prepared by the company should contain the following information:

  • Brief details of transferor and transferee companies.
  • Appointed date.
  • Main terms of transfer of assets and liabilities from the transferor to the transferee.
  • Effective date of the scheme.
  • The terms of carrying on the business activities by transferor between ‘appointed date’ and ‘effective date’.
  • Details of Share Capital of Transferor and Transferee Company.

No Companies or arrangement shall be sanctioned by the Tribunal unless a certificate by the company’s auditor has been filed with the Tribunal to the effect that the accounting treatment, if any, proposed in the scheme of compromise or arrangement conforms with the accounting standards prescribed under Section 133.

Approach the Tribunal

In terms of provisions of Section 232(1), an application is required to be made to the Tribunal for sanctioning a scheme of an arrangement (merger) proposed between a company and another company.

On receiving the application, the Tribunal may order a meeting of the creditors or class of creditors or the members or class of members, as the case may be, to be called, held, and conducted in such manner as the Tribunal may direct and the provisions of sub-sections (3) to (6) of Section 230 shall apply mutatis mutandis.

The company, after receiving such an order must circulate the required documents for members’/creditors’ meetings as stated under the provisions of Section 232(2).

Merger And Amalgamation Of Companies Short Notes

Question 1. Write short notes on the merger of small companies.

Answer:

Accordingly, sub-section (1) of Section 233 states that notwithstanding the provisions of Section 230 and 232, a scheme of merger or amalgamation may be entered into between two or more small companies or between a holding company and its wholly-owned subsidiary company or such other class or classes of companies as may be prescribed, subject to the following, namely:

  • a notice of the proposed scheme inviting objections or suggestions, if any, from the Registrar and Official Liquidators where the registered office of the respective companies are situated or persons affected by the scheme within thirty days is issued by the transferor company or companies and the transferee company;
  • the objections and suggestions received are considered by the companies in their respective general meetings and the scheme is approved by the respective members or class of members at a general meeting holding at least ninety percent of the total number of shares;
  • each of the companies involved in the merger files a declaration of solvency, in the prescribed form, with the Registrar of the place where the registered office of the company is situated; and
  • the scheme is approved by a majority representing nine-tenths in value of the creditors or class of creditors of respective companies indicated in a meeting convened by the company by giving a notice of twenty-one days along with the scheme to its creditors for the purpose or otherwise approved in writing.

Merger And Amalgamation Of Companies Descriptive Questions

Question 2. Describe the powers of the Central Government to provide for the amalgamation of companies in the public interest.

Answer:

  • If the Central Government is satisfied that it is essential in the public interest that two or more companies should amalgamate, the Central Government may, by order notified in the Official Gazette, provide for the amalgamation of those companies into a single company with such constitution, with such property, powers, rights, interests, authorities, and privileges, and with such liabilities, duties, and obligations, as may be specified in the order.
  • The order under sub-section (1) may also provide for the continuation by or against the transferee company of any legal proceedings pending by or against any transferor company and such consequential, incidental, and supplemental provisions as may, in the opinion of the Central Government, be necessary to give effect to the amalgamation.
  • Every member or creditor, including a debenture holder, of each of the transferor companies before the amalgamation shall have, as nearly as may be, the same interest in or rights against the transferee company as he had in the company of which he was originally a member or creditor, and in case the interest or rights of such member or creditor in or against the transferee company are less than his interest in or rights against the original company, he shall be entitled to compensation to that extent, which shall be assessed by such authority as may be prescribed and every such assessment shall be published in the Official Gazette, and the compensation so assessed shall be paid to the member or creditor concerned by the transferee company.
  • Any person aggrieved by any assessment of compensation made by the prescribed authority under sub-section (3) may, within thirty days from the date of publication of such assessment in the Official Gazette, prefer an appeal to the Tribunal and thereupon the assessment of the compensation shall be made by the Tribunal. No order shall be made under this section unless-
    • a copy of the proposed order has been sent in draft to each of the companies concerned;
    • the time for preferring an appeal under sub-section (4) has expired, or where any such appeal has been preferred, the appeal has been finally disposed of; and
    • the Central Government has considered and made such modifications, if any, in the draft order as it may deem fit in the light of suggestions and objections which may be received by it from any such company within such period as the Central Government may fix in that behalf, not being less than two months from the date on which the copy aforesaid is received by that company, or from any class of shareholders therein, or any creditors or any class of creditors thereof.

The copies of every order made under this section shall, as soon as may be after it has been made, be laid before each House of Parliament.

Cs Company Law Merger Questions

Question 3. Describe the provisions relating to cross-border mergers in Companies Act, 2013.

Answer:

Section 234(2) states that subject to the provisions of any other law for the time being in force, a foreign company, may with the prior approval of the Reserve Bank of India, merge into a company registered under this Act or vice versa and the terms and conditions of the scheme of merger may provide, among other things, for the payment of consideration to the shareholders of the merging company in cash, or Depository Receipts, or partly in cash and partly in Depository Receipts, as the case may be, as per the scheme to be drawn up for the purpose.

For subsection (2), the expression “foreign company” means any company or body corporate incorporated outside India whether having a place of business in India or not.

Section 234(1) states that the provisions of this Chapter unless otherwise provided under any other law for the time being in force, shall apply mutatis mutandis to schemes of mergers and amalgamations between companies registered under this Act and companies incorporated in the jurisdictions of such countries as may be notified from time to time by the Central Government. The Central Government may make rules, in consultation with the Reserve Bank of India, in connection with mergers and amalgamations provided under this section.

Question 4. What are the requirements relating to notice required under Section 230 of the Companies Act, 2013?

Answer:

Section 230(3) states that when a meeting is proposed to be called in pursuance of an order of the Tribunal under sub-section (1), a notice of such meeting shall be sent to all the creditors or class of creditors and all the members or class of members and the debenture-holders of the company, individually at the address registered with the company which shall be accompanied by

  • a statement disclosing the details of the compromise or arrangement,
  • a copy of the valuation report, if any, and
  • explaining their effect on creditors, key managerial personnel, promoters and non-promoter members, and the debenture-holders, and
  • the effect of the compromise or arrangement on any material interests of the directors of the company or the debenture trustees, and
  • such other matters as may be prescribed;

Such notice and other documents shall also be placed on the website of the company, if any, and in the case of a listed company, these documents shall be sent to the Securities and Exchange Board and stock exchange where the securities of the companies are listed, for placing on their website and shall also be published in newspapers in such manner as may be prescribed. -Space to write important points for revision

 An Overview Of Corporate Reorganisation Majority Rule And Minority Rights

Powers

Under the Companies Act, the powers have been divided between two segments; one is the Board of Directors and the other is of shareholders. The directors exercise their powers through meetings of the Board of Directors and shareholders exercise their power through Annual General Meetings/Extra-ordinary General Meetings.

Principle of company law

The general principle of company law is that every member holds equal rights with other members of the company in the same class. The scale of rights of members of the same class must be held evenly for the smooth functioning of the company. In case of difference(s) amongst the members, the issue is decided by a vote of the majority.

Protection for the minority shareholders

Since the majority of the members are in an advantageous position to run the company according to their command, the minority shareholders are often oppressed. The company law provides for adequate protection for the minority shareholders when their rights are trampled by the majority.

Prejudicial to the public interest

Any member of a company who complains that the affairs of the company are being conducted in a manner prejudicial to the public interest or in a manner oppressive to any member(s) (including any one or more of themselves) may make an application to the NCLT by way of petition for relief.

Relief

Relief under the Act will also be available if the affairs of the company are being conducted in a manner prejudicial to the public interest. ‘Public interest’ is a very broad term involving the welfare not only of the individual shareholders but also of the country according to the economic and social policies of the State.

Violation of the Regulations

If there is a persistent violation of the regulations and statutes and an appeal to the general body is not likely to put an end to the matters complained of because those responsible for the violations control the affairs of the company, then it will be just and equitable to wind up the company.

Right to Apply

The following members of a company shall have the right to apply u/s 241, namely:

  • In the case of a company having a share capital of not less than 100 members of the company or not less than one-tenth of the total number of members, whichever is less or any member or members holding not less than one-tenth of the issued share capital of the company, subject to the condition that the applicant or applicants have or have paid all calls and other sums due on his or their shares;
  • In the case of a company not having a share capital: Not less than one-fifth of the total number of members. However, the Tribunal may, on an application, waive all or any of the above requirements to enable the members to apply u/s 241.

Exceptions to the Rule in Foss v. Harbottle or Protection of Minority Rights and share-holders remedies

  • Ultra Vires Act
  • Fraud on Minority
  • Wrongdoers in Control
  • A resolution requiring a Special Majority but is passed by a simple majority
  • Personal Actions
  • Breach of Duty
  • Prevention of Oppression and Mismanagement

Under the Provision of Companies Act, 2013:

The first remedy in the hands of an oppressed minority is to move the NCLT. Section 241 provides that any member of a company who complains that the affairs of the company are being conducted in a manner prejudicial to the public interest or in a manner oppressive to any member(s) (including any one or more of themselves) may make an application to the NCLT by way of petition for relief.

The following requirements must be satisfied to seek relief under Section 241:

  • That the affairs of the company are being conducted: (a) in a manner prejudicial to public interest; or (b) oppressive to any members.
  • The fact justified the compulsory winding up order because it is just and equitable that the company should be wound up.
  • That to wind up the company would unfairly prejudice the petitioners [Ramji Lal Baiswala v. Britain Cable Ltd., (1964) 14 Raj. 135].

On being satisfied with the above requirements, the NCLT may make the necessary orders for ending the matters complained of. The first requirement relates to public interest or oppression. First, we analyze and discover the precise connotation of the word “oppression” with the help of judicial decisions.

Class Action Suits

A class action suit is a lawsuit where a group of people representing a common interest may approach the Tribunal to sue or be sued. It is a procedural instrument that enables one or more plaintiffs to file and prosecute litigation on behalf of a larger group or class having common rights and grievances.

Application of Class Action and Relief

  • to restrain the company from committing an ultra act vires the articles or memorandum of the company;
  • to restrain the company from committing a breach of any provision of the company’s memorandum or articles;
  • to declare a resolution altering the memorandum or articles of the company as void if the resolution was passed by suppression of material facts or obtained by misstatement to the members or depositors;
  • to restrain the company and its directors from acting on such a resolution;
  • to restrain the company from doing an act which is contrary to the provisions of this Act or any other law for the time being in force;
  • to restrain the company from taking action contrary to any resolution passed by the members;

Difference Between Merger And Amalgamation

Corporate Reorganisation Majority Rule And Minority Rights

Distinguish Between

Question 1. Distinguish between the following:

‘Oppression’ and ‘mismanagement’.

Answer:

Company Law An Overview of Corporate Re-organisation Merger Oppression

Question 2. Distinguish between the following:

Oppression and mismanagement application and Class action suits.

Answer:

Oppression and Mismanagement Application:

Section 244 of the Companies Act, 2013 provides that the following members of a company have the right to apply in case of oppression and management referred to under Section 241 to the tribunal:

  • in the case of a company having a share capital, not less than one hundred members of the company or not less than one-tenth of the total number of its members, whichever is less, or any member or members holding not less than one-tenth of the issued share capital of the company, subject to the condition that the applicant or applicants have or have paid all calls and other sums due on his or their shares;
  • in the case of a company not having a share capital, not less than one-fifth of the total number of its members:
    The Tribunal has the power that on an application made to it on this behalf, waive all or any of the above-mentioned requirements to enable the members to apply under Section 241.

Class Action Suits:

Section 245 of the Companies Act, 2013, dea! with Class action suits. It is provided that members, depositors. or any class of them, may, if they think that the management or conduct of the affairs of the company is being conducted in a manner prejudicial to the interests of the company or its members or depositors, apply to the Tribunal on behalf of the members or depositors.

The requisite number of members is as under:

  • in the case of a company having a share capital, not less than one hundred members of the company or not less than such percentage of the total number of its members as may be prescribed, whichever is less, or any member or members holding not less than such percentage of the issued share capital of the company as may be prescribed, subject to the condition that the applicant or applicants have or have paid all calls and other sums due on his or their shares;
  • in the case of a company not having a share capital, nor less than one-fifth of the total number of its members.

Further, the requisite number of depositors shall not be less than one hundred depositors or not less than such percentage of the total number of depositors as may be prescribed, whichever is less, or any depositor or depositors to whom the company owes such percentage of total deposits of the company as may be prescribed.

Corporate Reorganisation Majority Rule And Minority Rights

Descriptive Questions

Question 1. Comment on the following:

The NCLT law will not interfere with the internal management of companies acting within their powers. 

Answer:

Company Law An Overview of Corporate Re-organisation Merger The Principle of Majority Rule

Company Law An Overview of Corporate Re-organisation Merger Act illegal or ultra vires

Approval Process For Mergers In India

Question 2. Explain the following:

A mere lack of confidence between the majority shareholders and minority shareholders would not be enough to order relief under Section 241. 

Answer:

  • The scope of Section 241 was very succinctly enunciated by the Supreme Court in Shanti Prasad Jain v. Kalinga Tubes Ltd. where it observed that “It is not enough to show that there is just and equitable cause for winding up of the company though that must be shown as a preliminary to the application under Section 241.
  • It must further be shown that the conduct of majority shareholders was oppressive to the minority as members and this requires that events have to be considered not in isolation but as a part of a consecutive story.
  • There must be continuous acts on the part of the majority shareholders continuing to the date of the petition, showing that the affairs of the company were being conducted in a manner oppressive to some members. the conduct must be burdensome, harsh, and wrongful.
  • Mere lack of confidence between the majority shareholders and the minority shareholders would not be enough unless the lack of confidence springs from the oppression of the minority by the majority in the management of the company’s affairs and such oppression must involve at least an element of lack of probity or fair dealing to a member in the matter of his proprietary rights as a shareholder.”

Question 3. A petition signed by 100 members of a company has been moved to NCLT for prevention of mismanagement. Later on, half of the members (signatories) withdrew their consent after filing the petition. Examine whether the remaining applicants (petitioners/signatories) to the petition would be successful in their complaint to NCLT.

Answer:

  • Right to apply under Section 241 [Section 244]
    • The following members of a company shall have the right to apply u/s 241, namely:
      • In the case of a company having a share capital of not less than 100 members of the company or not less than one-tenth of the total number of members, whichever is less or any member or members holding not less than one-tenth of the issued share capital of the company, subject to the condition that the applicant or applicants have or have paid all calls and other sums due on his or their shares;
      • In the case of a company not having a share capital: Not less than one-fifth of the total number of members.
  • Rajahmundry Electric Supply Co. v. A. Nageshwara Rao, AIR 1956 SC 213
    • However, the Tribunal may, on an application, waive all or any of the above requirements to enable the members to apply u/s 241. Once the consent has been given by the requisite number of members by signing the application, the application may be made by one or more of them on behalf of and for the benefit of all of them.
    • It has been held by the Supreme Court in Rajahmundry Electric Supply Co. v. A. Nageshwara Rao, AIR 1956 SC 213, that if some of the consenting members have, after the presentation of the application, withdraw their consent, it would not affect the right of the applicant to proceed with the application.
    • Obtaining consent is a condition precedent to the making of the application and hence consent obtained after the application is ineffective. Makhan Lal Jain Vs. The Amrit Banaspati Co. Ltd., I. L. R. (1954) I All. 131.
  • Chandramurthy V. K. L. Kapsi (2005) 48 SCL | 294 CLB
    • In L. Chandramurthy V. K. L. Kapsi (2005) 48 SCL 294 CLB, a person who had disposed of his shares was not allowed to apply. Therefore, in the above case, the withdrawal of consent by some of the members shall not affect the success of the remaining applicants.

Question 4. What do you mean by Class Action Suit? Discuss concerning eligibility criteria for class action, the nature of relief, and the effect of the Tribunal’s order. 

Answer:

Section 245 of the Companies Act, 2013 makes provision for class action by investors. The term ‘investors’ includes shareholders, deposit holders, and any class of security holders of the company.

Section 245 permits a representative of any class of investors to file a suit before the National Company Law Tribunal for relief.

In terms of Section 245 (1), Such number of members or members, depositor or depositors or any class of them, as the case may be, as is indicated in sub-section (2) of the section may if they think that the management or conduct of the affairs of the company is being conducted in a manner prejudicial to the interests of the company or its members or depositors, apply to the Tribunal on behalf of the members or depositors for seeking all or any of the relief specified. Eligibility criteria for class action

Sub-section (3) (i) of Section 245 of the Companies Act, 2013 provides the requisite number of members provided in Sub-Section (1) shall be as under:

  • in the case of a company having a share capital, not less than one hundred members of the company or not less than such percentage of the total number of its members as may be prescribed, whichever is less, or any member or members holding not less than such percentage of the issued share capital of the company as may be prescribed, subject to the condition that the applicant or applicants have or have paid all calls and other sums due on his or their shares;
  • in the case of a company not having a share capital, not less than one-fifth of the total number of its members.

The requisite number of depositors provided in sub-section (1) shall not be less than one hundred depositors or not less than such percentage of the total number of depositors as may be prescribed, whichever is less, or any depositor or depositors to whom the company owes such percentage of total deposits of the company as may be prescribed.

Nature of Relief

The order by Tribunal may relate:

  • to restrain the company from committing an ultra act vires the articles or memorandum of the company;
  • to restrain the company from committing a breach of any provision of the company’s memorandum or articles;
  • to declare a resolution altering the memorandum or articles of the company as void if the resolution was passed by suppression of material facts or obtained by misstatement to the members or depositors;
  • to restrain the company and its directors from acting on such a resolution;
  • to restrain the company from doing an act which is contrary to the provisions of this Act or any other law for the time being in force;
  • to restrain the company from taking action contrary to any resolution passed by the members;
  • to claim damages or compensation or demand any other suitable action from or against:
    • the company or its directors for any fraudulent, unlawful, or wrongful act or omission or conduct or any likely act or omission or conduct on its or their part;
    • the auditor including the audit firm of the company for any improper or misleading statement of particulars made in his audit report or for any fraudulent, unlawful, or wrongful act or conduct; or
    • any expert advisor consultant or any other person for any incorrect or misleading statement made to the company or for any fraudulent, unlawful, or wrongful act or conduct or any likely act or conduct on his part;
  • to seek any other remedy as the Tribunal may deem fit.

Effect

Any order passed by NCLT shall be binding on the company and all its members, depositors, auditors, consultants advisors, or any other person associated with the company. Non-compliance with the order by the company shall be punishable with a fine which shall not be less than 5 Lakhs but which may extend to 25 Lakhs and every officer of the company who is in default shall be punishable with imprisonment for a term upto 3 years and with a fine ranging from 25,000 to 1 lakh.

Merger And Amalgamation In Company Law

Question 5. What do you understand by ‘class action suit’ as introduced by the Companies Act, 2013? Explain the objective behind introducing this provision in the Companies Act and the persons who can initiate such a class action suit.

Answer:

A class action suit is a lawsuit where a group of people representing a common interest may approach the Tribunal to sue or be sued. It is a procedural instrument that enables one or more plaintiffs to file and prosecute litigation on behalf of a larger group or class having common rights and grievances.

The major objective behind the provision of class action suits is to safeguard the interests of the minority shareholders. So, class action suits are expected to play an important role in addressing numerous prejudicial and abusive acts committed by the Board of Directors and other managerial personnel.

Person to initiate Class Action Suit:

  • Members:
    The requisite number of members provided in sub-section (1) shall be as under:-
    • in the case of a company having a share capital, not less than one hundred members of the company or not less than such percentage of the total number of its members as may be prescribed, whichever is less, or any member or members holding not less than such percentage of the issued share capital of the company as may be prescribed, subject to the condition that the applicant or applicants have or have paid all calls and other sums due on his or their shares;
    • in the case of a company not having a share capital, not less than one-fifth of the total number of its members.
  • Depositors:
    • According to Section 245(3)(ii) the requisite number of depositors provided in Section 245(1) shall not be less than one hundred depositors or not less than such percentage of the total number of depositors as may be prescribed, whichever is less, or any depositor or depositors to whom the company owes such percentage of total deposits of the company as may be prescribed. Space to write important points for revision

Question 6. In a scheme of amalgamation, it was proposed that the name of the transferor company shall be deemed to be the name of the transferee company. The Regional Director (RD), of the Ministry of Company Affairs, objected to the because the proposed name is undesirable if it is identical with or too nearly resembling the name of an existing company. Decide if the stand taken by the RD is valid under the Companies Act, 2013. Reference may be made to decided case laws.

Answer:

It has been held in earlier judgment PMP Auto Industries Ltd. that in case of amalgamation Chapter XV of the Companies Act, 2013 is a complete code like a “single window clearance” system, the object of which is to eliminate frequent applications being made to the Court in order effectively to implement a scheme of amalgamation which the Court sanctions in the exercise of its powers.

Further, in this case, Michelin India Private Limited High Court held that a complete code by itself on the subject of arrangement/compromise and reconstruction is comprehensive enough to include a change in the name consequent on the amalgamation or arrangement.

Thus considering the above, in the present case the objection of RD is invalid.

Question 7. “The Companies Act, 2013 attempts to maintain a balance between the rights of majority and minority shareholders.” Discuss.

Answer:

  • In India, the Companies Act, 2013 attempts to maintain a balance between the rights of majority and minority shareholders by admitting, the rule of the majority but limiting it at the same time by several well-defined minority rights, thus protecting the minority shareholders as well.
  • The rule of Foss V. Harbottle establishes the rule of the majority but it is not absolute but subject to certain exceptions and the minority shareholders are protected by
    • the common law; and
    • the provisions of the Companies Act, 2013.
  • Section 241 to Section 245 of Chapter XVI of the Companies Act, 2013 deals with the provisions relating to the prevention of oppression and mismanagement of a company.
  • Oppression and mismanagement of a company mean that the affairs of the company are being conducted in a manner that is oppressive and biased against the minority shareholders or any member or members of the company.
  • To prevent the same, there are provisions for the prevention and mismanagement of a company.

Corporate Reorganisation Majority Rule And Minority Rights Practical Questions

Question 1. In a case about oppression and mismanagement, the respondents pleaded that the legal heirs of a deceased member whose name is still on the register of members are not entitled to apply before the Tribunal, as only members of the company can complain about oppression and mismanagement. Thus, legal heirs have no locus standi. Examine this argument in the light of decided cases.

Answer:

According to Section 241 of the Companies Act, 2013 any member of the company may make an application to the Tribunal for relief in cases of oppression or mismanagement under given circumstances. In Worldwide Agencies (P) Ltd. v. Margaret T. Decor (1990), it was decided that the legal representatives of a deceased member whose name is still on the register of members are entitled to file a petition, for relief against oppression or mismanagement.

In the above case, the above-mentioned case is applicable, where the member has died and his name still exists in the register of members, the legal heirs are entitled to maintain the petition.

Question 2. XYZ Ltd. sold a mine, owned by it for 28.20 crore. A minority shareholder brought an action for damages against their directors and against the company itself stating that the real value of the mine was 100.00 crore. Concerning provisions of the Companies Act, 2013 state whether the action for damages is maintainable.

Answer:

In the case of Pavlides v. Jensen (1956) Ch. 565, a minority shareholder brought an action for damages against three directors and against the company it because that they had been negligent in selling a mine owned by the company for £ 82,000, whereas its real value was about £ 10,00,000. It was held that the action was not maintainable.

The judge observed, “It was open to the company, on the resolution of a majority of the shareholders to sell the mine at a price decided by the company in that manner, and it was open to the company by a vote of majority to decide that if the directors by their negligence or error of judgment have sold the company’s mine at an undervalue, proceedings should not be taken against the directors”.

Applying the above interpretation, the action for damages undertaken by the minority shareholders of XYZ Ltd. is not maintainable. Hence an action for damages neither against the company nor against the directors is valid. Space to write important points for revision-

Types Of Mergers And Amalgamations

Corporate Reorganisation Majority Rule And Minority Rights Short Notes

Question 1. Write short notes on Class Action Suits.

Answer:

A class action suit is a lawsuit where a group of people representing a common interest may approach the Tribunal to sue or be sued. It is a procedural instrument that enables one or more plaintiffs to file and prosecute litigation on behalf of a larger group or class having common rights and grievances.

Application of Class Action and Reliefs [Section 245(1)]

Subsection (1) of Section 245 states that such number of members, depositors, or any class of them, as the case may be, may, file an application before the Tribunal for seeking all or any of the following orders, namely:

  • to restrain the company from committing an ultra act vires the articles or memorandum of the company;
  • to restrain the company from committing a breach of any provision of the company’s memorandum or articles;
  • to declare a resolution altering the memorandum or articles of the company as void if the resolution was passed by suppression of material facts or obtained by misstatement to the members or depositors;
  • to restrain the company and its directors from acting on such a resolution;
  • to restrain the company from doing an act which is contrary to the provisions of this Act or any other law for the time being in force;
  • to restrain the company from taking action contrary to any resolution passed by the members;
  • to claim damages or compensation or demand any other suitable action from or against-
    • the company or its directors for any fraudulent, unlawful, or wrongful act or omission or conduct or any likely act or omission or conduct on its or their part;
    • the auditor including the audit firm of the company for any improper or misleading statement of particulars made in his audit report or for any fraudulent, unlawful, or wrongful act or conduct; or
    • any expert advisor consultant or any other person for any incorrect or misleading statement made to the company or for any fraudulent, unlawful, or wrongful act or conduct or any likely act or conduct on his part;
  • to seek any other remedy as the Tribunal may deem fit.

Question 2. Write short notes on the Effect of Order.

Answer:

Order shall The ordering: Any order passed by the Tribunal shall be binding on the company and all its members, depositors, and auditor including the audit firm expert consultants advisor, or any other person associated with the company. [Section 245(6)]

Punishment for non-compliance: Any company which fails to comply with an order passed by the Tribunal under this section shall be punishable with fine which shall not be less than five lakh rupees but which may extend to twenty-five lakh rupees and every officer of the company who is in default shall be punishable with imprisonment for a term which may extend to three years and with fine which shall not be less than twenty-five thousand rupees but which may extend to one lakh rupees. [Section 245(7)]

Companies Act Merger And Amalgamation Process

An Overview Of Corporate Re-organisation Winding-up

Winding-up of a Company

  • Winding-up of a Company is defined as a process by which the life of a Company is brought to an end and its property administered for the benefit of its members and creditors.
  • An administrator called the liquidator is appointed and he takes control of the Company, collects its assets, pays debts, and finally distributes any surplus among the members by their rights.
  • At the end of winding up, the Company will have no assets or liabilities. When the affairs of a company are completely wound up, the dissolution of the Company takes place.
  • On dissolution, the company’s name is struck off from the Register of Companies, and its legal personality as a corporation comes to an end.

Modes of Winding-up

There are two modes of winding up:

Winding up by Tribunal i.e. Compulsory Winding-up, and Voluntary Winding-up;

Compulsory Winding-up

Section 271 of the Companies Act, 2013 provides that a company may, on a petition under Section 272, be wound up by the Tribunal under the following circumstances-

  • if the company has, by special resolution, resolved that the company be wound up by the Tribunal;
  • if the company has acted against the interests of the sovereignty and integrity of India, the security of the State, friendly relations with foreign States, public order, decency, or morality;
  • if on an application made by the Registrar or any other person authorized by the Central Government by notification under this Act, the Tribunal thinks that the affairs of the company have been conducted fraudulently or the company was formed for a fraudulent and unlawful purpose or the persons concerned in the formation or management of its affairs have been guilty of fraud, misfeasance or misconduct in connection therewith and that it is proper that the company be wound up;
  • if the company has made a default in filing with the Registrar its financial statements or annual returns for immediately preceding five consecutive financial years; or
  • if the Tribunal thinks that it is just and equitable that the company should be wound up.”.

Petition for the Winding up (Section 272 of Companies Act, 2013)

Who may file a Petition for the Winding up?

  • the company; or
  • any creditor or creditors, including any contingent or prospective creditor or creditors; or
  • any contributory or contributories; or
  • all or any of the parties specified above in clauses (a), (b), (c) whether together or separately; or
  • the Registrar; or
  • any person authorized by the Central Government.
  • by the Central government or State Govt., in a case falling under clause (c) of Section 271(1).

Voluntary Winding-up

  • A corporate person who intends to liquidate itself voluntarily and has not committed any default may initiate voluntary liquidation proceedings under the provisions of this Chapter.
  • The voluntary liquidation of a corporate person under sub-section (1) shall meet such conditions (3) and procedural requirements as may be specified by the Board.
  • Without prejudice to sub-section (2), voluntary liquidation proceedings of a corporate person registered as a company shall meet the following conditions, namely:
    • a declaration from the majority of the directors of the company verified by an affidavit stating that-
      • they have made a full inquiry into the affairs of the company and they have formed an opinion that either the company has no debt or that it will be able to pay its debts in full from the proceeds of assets to be sold in the voluntary liquidation; and
      • the company is not being liquidated to defraud any person;
    • the declaration under sub-clause (a) shall be accompanied by the following documents, namely:
      • audited financial statements and records of business operations of the company for the previous two years or for the period since its incorporation, whichever is later;
      • a report of the valuation of the assets of the company, if any prepared by a registered valuer;
    • within four weeks of a declaration under sub-clause (a), there shall be
      • a special resolution of the members of the company in a general meeting.
      • a resolution of the members of the company in a general meeting requiring the company to be liquidated voluntarily as a result of the expiry of the period of its duration, if any, fixed by its articles or on the occurrence of any event in respect of which the articles provide that the company shall be dissolved.

Registered Valuer

Section 247(1) of the Companies Act, 2013 states that where a valuation is required to be made in respect of any property, stocks, shares, debentures, securities or goodwill, or any other assets or net worth of a company or its liabilities under the provision of the Companies Act, 2013, it shall be valued by a person having such qualifications and experience and registered as a valuer in such manner, on such terms and conditions as may be prescribed and appointed by the audit committee or in its absence by the Board of Directors of that company.

ICSI- RVO

As specified above, Section 247 of the Companies Act, 2013 provides that where a valuation is required to be made in respect of any assets it shall be valued by a person who, having the necessary qualifications and experience, and being a valuer member of a recognized valuer organization, is registered as a valuer with the Authority. Accordingly, to enable the members of the Institute/others to practice as Registered Valuers, the Institute incorporated ICSI-RVO.

ICSI-RVO is a Section 8 company that has been formed with the intent to enroll, register, educate, train, promote, develop, and regulate Registered Valuers Rules while establishing and promoting high standards of practice and professional conduct and to promote good professionalism, ethical conduct and competency of Registered Valuers for ensuring the quality of valuation work.

Difference Between Merger And Amalgamation

Corporate Re-organisation Winding-up Distinguish Between

Question 1. Distinguish between the following: (a) ‘Winding-up’ and ‘dissolution’.

Answer:

The terms winding up and dissolution are sometimes erroneously used to mean the same thing. But there is a subtle difference between the two terms.

Company Law An Overview of Corporate Re-organisation Merger Winding up and dissolution

Corporate Re-organisation Winding-up Descriptive Questions

Question 1. Comment on the following:

Winding-up is only a process while dissolution puts an end to the existence of a company. 

Answer:

In the process of winding up the assets of the company are disposed of and the debts of the company are paid off out of the realized assets by a liquidator. If any balance remains in the hands of the liquidator, it is distributed among the members of the company by their rights under the articles.

According to Professor Gower, “winding up of a company is the process whereby its life is ended and its property administered for the benefit of its creditors and members.”

  • An administrator, called a liquidator, is appointed and he takes control of the company, collects its assets, pays its debts, and finally distributes any surplus among the members by their rights. At the end of the winding up there will not be type remained any of assets and liabilities in the company, and it will therefore be simply a formal step for it to be dissolved that is for its legal personality as a corporation to be brought to an end.
  • In between winding up and dissolution, the legal entity of the company remains and it may be sued in a Tribunal.
  • A company that has been dissolved no longer exists as a separate entity capable of holding property or of being sued in a Tribunal of law, but a company in liquidation though the administration of its affairs has passed the liquidator retains its complete existence.
  • If the liquidation should be annulled, the company will resume its powers.
  • On dissolution, the company’s name is struck off the register of companies, and its legal personality as a corporation comes to an end. Space to write important points for revision

Question 2. Mahesh is a creditor of an unlimited company. The company was wound up. Mahesh, therefore, wants to sue the members of the company to recover the dues. Advise Mahesh regarding the remedy available to him.

Answer.

Company Law An Overview of Corporate Re-organisation Merger Meaning of Unlimited Company

Question 3. Referring to the provisions of the Companies Act, 2013, state the grounds on which the Registrar of Companies can file a petition for the winding-up of a company.

Answer:

The Registrar shall be entitled to present a petition for winding up under Section 271, except on the grounds specified in clause (a) or clause (e) of that sub-section:

Provided that the Registrar shall obtain the previous sanction of the Central Government for the presentation of a petition:

Provided further that the Central Government shall not accord its sanction unless the company has been given a reasonable opportunity to make representations.

Question 4. The Mumbai Bench of the National Company Law Tribunal has received a petition for the winding up of Presentable Commodities Ltd. Pramod, Manager (Human Resources) of the company wants to know from you, the Secretary of the company, what orders can be passed by the Tribunal in this regard. Advise Pramod, under the relevant provisions of the Companies Act, 2013.

Answer:

According to Section 273(1) of the Companies Act, 2013, the Tribunal may, on receipt of a petition for winding up pass any of the following orders:

  • dismiss it, with or without costs;
  • make any interim order as it thinks fit;
  • appoint a provisional liquidator of the company till the making of a winding-up order;
  • make an order for the winding up of the company with or without costs;
    or
  • any other order as it thinks fit.

Difference Between Merger And Amalgamation

Question 5. Can a contributory file a petition for the winding up of the company? Discuss.

Answer:

Section 272(1) of the Companies Act, 2013 provides that subject to the provisions of this section, a petition to the Tribunal for the winding up of a company shall be presented by, inter-alia, any contributory or contributory.

As per Section 272(2) of the Companies Act, 2013, a contributory shall be entitled to present a petition for the winding up of a company, notwithstanding that he may be the holder of fully paid-up shares, or that the company may have no assets at all or may have no surplus assets left for distribution among the shareholders after the satisfaction of its liabilities, and shares in respect of which he is a contributory or some of them were either originally allotted to him or have been held by him, and registered in his name, for at least six months during the eighteen months immediately before the commencement of the winding up or have devolved on him through the death of a former holder.

Question 6. Govt. of West Bengal applied winding up of KTC Ltd. in the Tribunal citing sec. 271 of the Companies Act, 2013 in the interest of the sovereignty and integrity of India which was opposed by the company stating that the state government cannot file a petition for winding up. Is the claim of the company sustainable and why?

Answer:

Section 271(b) of the Companies Act, 2013 provides that a company may, on a petition under section 272, be wound up by the Tribunal if the company has acted against the interests of the sovereignty and integrity of India, the security of the State, friendly relations with foreign States, public order, decency or morality.

Section 272(1) of the Companies Act, 2013 provides that subject to the provisions of this section, a petition to the Tribunal for the winding up of a company shall be presented by

  • the company;
  • any contributory or contributors;
  • all or any of the persons specified in clauses (a) and (b);
  • the Registrar;
  • any person authorized by the Central Government on that behalf; or
  • in a case falling under clause (b) of sub-section (1) of section 271, by the Central Government or a State Government.

Given the above provisions, the claim of the company is not sustainable. -Space to write important points for revision

Corporate Re-organisation Winding-up Practical Questions

Question 1. On 3rd December 2018, the Registrar of Companies applied to the Regional Director for seeking sanction to file a winding up application against a company. On the next day i.e. on 4th December, 2018, the Regional Director granted its sanction. Examine the validity of the Regional Director’s action.

Answer:

Section 272(1) of the Companies Act, 2013, provides that a petition to the Tribunal for the winding up of a company can be presented by the Registrar of Companies. However, the Registrar shall obtain the previous sanction of the Central Government for the presentation of a petition. The section also provides that the Central Government shall not accord its sanction unless the company has been given a reasonable opportunity to make representations. The Power of Central Government in this context has been assigned to Regional Directors.

In the above case, the Regional Director granted its sanction on the very next day of filing the petition without giving a reasonable opportunity to the company to be heard. Here the action of the Regional Director is invalid. – Space to write important points for revision-

Question 2. Amitabh is a director at PQR Overseas Trading Ltd. The company’s name has recently been struck off from the register of companies by the Registrar. He does not hold a directorship in any other company. Therefore, Amitabh applied to the Registrar for cancellation of his DIN. However, the application was rejected by the Registrar. Is the rejection of the application correct in your opinion? 

Answer:

Rule 11 of the Companies (Appointment and Qualification of Directors) Rules, 2014 allows cancellation surrender, or deactivation of DIN under the following cases-

  • If DIN is found to be duplicated in respect of the same person provided the data related to both the DIN shall be merged with the validly retained number;
  • If it is obtained in a wrongful manner or by fraudulent means
  • Death of the concerned individual
  • A concerned individual has been declared as a person of unsound mind by a competent court
  • A concerned individual has been adjudicated an insolvent
  • On application made in Form DIR-5 by the DIN holder to surrender DIN along with a declaration that he has never been appointed as a director in any company and said DIN has never been used for filing of any document with any authority.

The issue raised in question is not covered in any of the above conditions. As Amitabh was appointed as a director using his DIN (and presumably filed e-forms using the DIN), such DIN shall not be deactivated and DIR-5 cannot be filled even though the name of the company has been struck off and he does not hold directorship in any other Company. Therefore, the action of the Registrar is correct.

Question 3. Sunita sold her flat to NOP Televisions Ltd. on 1 April 2016. The company appointed Prakash (a registered valuer and also husband of Sunita) on 1st May 2019 to determine the value of the flat purchased from Sunita. Can Prakash validly undertake this assignment? Would your answer differ if the appointment had been made on 1 March 2019?

Answer:

According to Section 247(2)(d) of the Companies Act, 2013, the valuer shall not undertake the valuation of any assets in which he has a direct or indirect interest or becomes so interested at any time during three years before his appointment as a valuer or three years after the valuation of assets was conducted by him.

In the instant case, Prakash had an indirect interest in the property because it was owned by his wife (Sunita). However, he was appointed on May 01, 2019, as valuer of the property, since a period of three years has already elapsed after the sale of the property, Prakash can validly take up the assignment of valuation of the property.

However, if the appointment had been made on March 01, 2019, the period of three years would not have elapsed and he could not have taken up the assignment.

Approval Process For Mergers In India

Corporate Re-organisation Winding-up Short Notes

Question 1. Write short notes on Registration Offices and Fees.

Answer:

Section 403 states that any document, required to be submitted, filed, registered, or recorded, or any fact or information required or authorized to be registered under the Companies Act, 2013, shall be submitted, filed, registered, or recorded within the time specified in the relevant provision on payment of such fee as may be prescribed. The fees are prescribed under the Companies (Registration Offices and Fees) Rules, 2014.

However, in case of failure to submit, file register, or record the above-stated documents, within the period provided in the relevant section, it may, without prejudice to any other legal action or liability under the Companies Act, 2013, be submitted, filed, registered or recorded as the case may be:-

  • In case of documents provided under Section 92 or 137 [First proviso to Section 403]
    • alter expiry of the period so provided under Section 92 or 137,
    • on payment of such additional fee as may be prescribed –
      • which shall not be less than one hundred rupees per day, and
      • different amounts may be prescribed for different classes of companies.
  • In case of any other documents [Second proviso to Section 403]:
    • after the expiry of the period so provided under the relevant Section,
    • on payment of such additional fees as may be prescribed and different fees may be prescribed for different classes of companies.

Corporate Re-organisation Winding-up Descriptive Question

Question 2. Who shall Conduct the valuation?

Answer:

Section 247(1) of the Companies Act, 2013 states that where a valuation is required to be made in respect of any property, stocks, shares, debentures, securities or goodwill, or any other assets or net worth of a company or its liabilities under the provision of the Companies Act, 2013, it shall be valued by a person having such qualifications and experience and registered as a valuer in such manner, on such terms and conditions as may be prescribed and appointed by the audit committee or in its absence by the Board of Directors of that company.

The valuer appointed under sub-section (1) shall,-

  • make an impartial, true, and fair valuation of any assets which may be required to be valued;
  • exercise due diligence while performing the functions as a valuer;
  • make the valuation by such rules as may be prescribed; and
  • not undertake valuation of any assets in which he has a direct or indirect interest or becomes so interested at any time during three years before his appointment as valuer or three years after the valuation of assets was conducted by him.

Question 3. What is ICSI-RVO?

Answer:

As specified above, Section 247 of the Companies Act, 2013 provides that where a valuation is required to be made in respect of any assets it shall be valued by a person who, having the necessary qualifications and experience, and being a valuer member of a recognized valuer organization, is registered as a valuer with the Authority. Accordingly, to enable the members of the Institute/others to practice as Registered Valuers, the Institute incorporated

ICSI-RVO.

ICSI-RVO is a Section 8 company that has been formed with the intent to enroll, register, educate, train, promote, develop, and regulate Registered Valuers Rules while establishing and promoting high standards of practice and professional conduct and promoting good professionalism, ethical conduct and competency of Registered Valuers for ensuring the quality of valuation work.

The IBBI vide Registered Valuers Organisation Recognition No. IBBI/RVO/2018/003 recognized ICSI RVO. as a Registered Valuers Organisation for the Asset Class(es):-

  • Land and Building
  • Plant and Machinery
  • Securities or Financial Assets

Companies Act Merger And Amalgamation Process

Question 4. Who can offer valuation services?

Answer:

For conducting valuations required under the Companies Act, 2013, and the Insolvency and Bankruptcy Code, 2016, a person is to be registered with the IBBI as a registered valuer. To register with IBBI, a person must have the necessary qualifications and experience, haves to be enrolled as a valuer member with a Registered Valuer Organisation (RVO), complete a recognized educational course conducted by the RVO and pass a value,tion examination conducted by IBBI.

IBBI, being the Authority, in pursuance of the first proviso to Rule 5 (1) of the Companies (Registered Valuers and Valuation) Rules, 2017 specified the details of the educational course for the Asset Class of ‘Securities or Financial Assets’. These courses shall be delivered by the RVOS in not less than 50 hours.

A person, who is rendering valuation services under the Companies Act, 2013, may continue to do so without a certificate of registration up to 31st March, 2018, thereafter with effect from 1st April, 2018 for conducting valuations required under the Companies Act, 2013 and the Insolvency and Bankruptcy Code, 2016, a person is to be registered with the IBBI as a registered value.

CS Company Law Registers And Records Question and Answers

Registers And Records Introduction

The Companies Act, 2013 lays down that every company incorporated under this Act must maintain and keep at its registered office certain books, registers and copies of certain returns, documents etc. and to give certain notices, file certain returns, forms, reports, documents etc. with the Registrar of Companies within certain specified time limits and with the prescribed filing fees. These books are known as Statutory Books.

Statutory books and registers

Every company incorporated under the Act is required to keep at its registered office, inter alia, the following statutory books and registers:

  • Register of securities bought back. (Section 68 Rule 17(12) of Companies (Share Capital and Debenture) Rules, 2014.
  • Register of deposits. [Section 73, Rule 14 Companies (Acceptance of Deposits) Rules, 2014.
  • Register of charges (Section 81 Rule 7 of Company’s Registration of Charges, Rules, 2014).
  • Register of sweat equity shares [Section 54 and Rule 8 (14) of Companies (Share Capital and Debenture) Rules, 2014]
  • Annual Return (Section 92) Rule 11 of The Companies (Management and Administration (Rules 2014)).
  • Register of Postal Ballot [Section 110 and Rule 22 of the Companies (Management and Administration) Rules, 2014]
  • Books containing minutes of general meeting and of Board and of committees of Directors. [Section 118] Books of Accounts. [Section 128]
  • Register of Directors/ key managerial personnel. (Section 170 (1)).
  • Register of investments in securities not held in company’s name. [Section 187, Rule 14 of Companies (Meetings and Board Powers) 2014].
  • Register of loans, guarantees given and security provided or acquiring securities (Section 186/9 rule 12 Companies Meetings of Boards and its Powers Rules, 2014).
  • Register of contracts with companies/firms in which directors are interested. [Section 189(5) Rule 16 of Companies (Meetings of Boards and its Powers) Rules, 2014].

Law Registers And Records

Registers And Records In Company Law

Registers And Records List of Important Forms

Company Law Registers And Records List of Important Forms

Registers And Records Distinguish Between

Question 1. Distinguish between the following:

‘Statutory books’ and ‘statistical books’.

Answer:

Company Law Registers And Records Statutory Books

Statutory Registers Under Companies Act

Registers And Records Descriptive Questions

Question 2. Chairman of your company wants to know the procedure of condonation of delay by Central Government in filing the document with the Registrar of Companies. As a Company Secretary, prepare a note for consideration of the Chairman.

Answer:

Company Law Registers And Records Condonation of Delay in filling any document

Question 3. Minutes of the meetings of the company shall be preserved for a period of not less than eight years. Comment with reference to the provisions of the Companies Act, 2013.

Answer:

Section 118 of Companies Act, 2013, read with Secretarial Standards on Board Meetings (SS-1) and Secretarial Standards on General Meetings (SS-2), Minutes of all Board Meetings and shareholders meetings shall be preserved permanently in physical or in electronic form with Timestamp. Space to write important points for revision-

Question 4. What are the requirements as to the maintenance of Register of Postal Ballot?

Answer:

Section 110 of the Companies Act, 2013 and Rule 22(10) of the Companies (Management and Administration) Rules, 2014 states that every company which is required to or which proposes to get any resolution passed through postal ballot should maintain a separate register for each postal ballot to record the assent or dissent received through postal ballot.

The scrutinizer shall maintain a register either manually or electronically to record their assent or dissent received, mentioning the particulars of name, address, folio number or client ID of the shareholder, number of shares held by them, nominal value of such shares, whether the shares have differential voting rights, if any, details of postal ballots which are received in defaced or mutilated form and postal ballot forms which are invalid.

Entries in the register should be made immediately after the opening of postal ballots. Separate folios should be maintained for each resolution passed through postal ballot. The register should be kept at the registered office of the company after the Scrutinizer has submitted his report.

The postal ballot and all other papers relating to postal ballot including voting by electronic means, shall be under the safe custody of the scrutinizer till the chairman considers, approves and signs the minutes and thereafter, the scrutinizer shall return the ballot papers and other related papers or register to the company who shall preserve such ballot papers and other related papers or register safely.

Question 5. You are a company secretary in a company. The Board of Directors want to know the details that should be entered in the Register of Renewed and Duplicate share certificates and the period for which such register should be maintained. Clarify the Board in this regard.

Answer:

  • In terms of Section 46 of the Companies Act, 2013 read with Rule 6 of the Companies (Share Capital and Debentures) Rules, 2014, every company with a share capital should, from the date of its registration, maintain a register of renewed and duplicate certificates.
  • The word ‘renewed’ includes consolidation and sub-division of shares and issue of certificate in lieu thereof.
  • Particulars of every share certificate issued shall be recorded in a Register of Renewed and Duplicate Share Certificates. Such register shall be maintained in Form No. SH-2 indicating against the name(s) of the person(s) to whom the certificate is issued, the number and date of issue of the share certificate in lieu of which the new certificate is issued, and the necessary changes indicated in the Register of Members by suitable cross-references in the “Remarks” column. Such register shall be kept at the registered office of the company or at such other place where the Register of Members is kept.
  • The register shall be preserved permanently and shall be kept in the custody of the Company Secretary of the company or any other person authorized by the Board for the purpose.
  • All entries made in the Register of Renewed and Duplicate Share Certificates shall be authenticated by the company secretary or such other person as may be authorised by the Board for purposes of sealing and signing the share certificate. The register is not open for inspection. -Space to write important points for revision

Types Of Records Maintained By Companies

Question 6. Mention the requirements in relation to maintenance of minutes, as prescribed by the Secretarial Standards Board. 

Answer:

Secretarial Standard-2 (SS-2) on “General Meetings”:

  • Secretarial Standard-2 (SS-2) on “General Meetings”, is issued by the Council of the Institute of Company Secretaries of India and approved by the Central Government.
  • Minutes’ are the official recording of the proceedings of the Meeting and the business transacted at the Meeting. Every company shall keep Minutes of all Meetings. Minutes kept by the provisions of the Act evidence the proceedings recorded therein. Minutes help in understanding the deliberations and decisions taken at the Meeting.
  • Minutes of Board Meeting:
    • Minutes shall be recorded in books maintained for that purpose.
    • A distinct Minutes Book shall be maintained for Meetings of the Members of the company, creditors and others as may be required under the Act.
    • A company may maintain its Minutes in physical or electronic form.
    • The pages of the Minutes Books shall be consecutively numbered. Minutes shall not be pasted or attached to the Minutes Book, or tampered with in any manner.
    • Minutes of Meetings, if maintained in loose-leaf form, shall be bound periodically at least once in every three years.
    • Minutes Books shall be kept at the Registered Office of the company.
  • Contents of Minutes:
    • Minutes shall state, at the beginning the Meeting, name of the company, day, date, venue and time of commencement of the Meeting
    • Minutes shall record the names of the Directors and the Company Secretary present at the Meeting
    • Minutes shall, inter alia, contain, (a) The Record of election, if any, of the Chairman of the Meeting. (b) The fact that certain registers, documents, the Auditor’s Report and Secretarial Audit Report, as prescribed under the Act were available for inspection. (c) The Record of presence of Quorum. (d) The number of Members present in person including representatives. (e) The number of Proxies and the number of shares represented by them. (f) The presence of the Chairmen of the Audit Committee, Nomination and Remuneration Committee and Stakeholders Relationship Committee or their authorised representatives. (g) The time of commencement and conclusion of the Meeting.
  • In respect of Resolutions passed by e-voting or postal ballot, a brief report on the e-voting or postal ballot conducted including the Resolution proposed, the result of the voting thereon and the summary of the scrutiniser’s report shall be recorded in the Minutes Book and signed by the Chairman or in the event of death or inability of the Chairman, by any Director duly authorised by the Board for the purpose, within thirty days from the date of passing of Resolution by e-voting or postal ballot.
  • Recording of Minutes:
    • Minutes shall contain a fair and correct summary of the proceedings of the Meeting.
    • Minutes shall be written in clear, concise and plain language
    • Each item of business taken up at the Meeting shall be numbered. Minutes shall be entered in the Minutes Book within thirty days from the date of conclusion of the Meeting
    • The date of entry of the Minutes in the Minutes Book shall be recorded by the Company Secretary
    • Minutes, once entered in the Minutes Book, shall not be altered Minutes of a General Meeting shall be signed and dated by the Chairman of the Meeting or in the event of death or inability of that Chairman, by any Director who was present in the Meeting and duly authorised by the Board for the purpose, within thirty days of the General Meeting
    • The Chairman shall initial each page of the Minutes, sign the last page and append to such signature the date on which and the place where he has signed the Minutes.

Statutory Registers Maintenance In India

  • Inspection and Extracts of Minutes:
    • Directors and Members are entitled to inspect the Minutes of all General Meetings including Resolutions passed by postal ballot.
    • Extract of the Minutes shall be given only after the Minutes have been duly signed. However, any Resolution passed at a Meeting may be issued even pending signing of the Minutes, provided the same is certified by the Chairman or any Director or the Company Secretary.
  • Preservation of Minutes and Other Records:
    • Minutes of all Meetings shall be preserved permanently in physical or in electronic form with Timestamp
    • Office copies of Notices, scrutiniser’s report and related papers shall be preserved in good order in physical or in electronic form for as long as they remain current or for eight financial years, whichever is later and may be destroyed thereafter with the approval of the Board.
    • Minutes Books shall be kept in the custody of the Company Secretary.

CS Company Law Transparency And Disclosures Question and Answers

Transparency And Disclosures

The annual report is a comprehensive report provided by most public companies to disclose their corporate activities over the past year. The report is typically issued to shareholders and other stakeholders who use it to evaluate the firm’s performance including both operating and financial highlights.

Such annual report shall contain the following:

  • audited financial statements i.e. balance sheets, profit and loss accounts etc, and Statement on Impact of Audit Qualifications, if applicable;
  • consolidated financial statements audited by its statutory auditors;
  • cash flow statement presented only under the indirect method as prescribed in Accounting Standard-3 or Indian Accounting Standard 7, as applicable, specified in Section 133 of the Companies Act, 2013
  • directors report;
  • management discussion and analysis report – either as a part of directors report or addition thereto;
  • for the top five hundred listed entities based on market capitalization

Board’s Report in Companies Act, 2013

The Board’s Report is the most important means of communication by the Board of Directors of a company with its shareholders. It is a comprehensive document which serves to inform the shareholders about the performance and various other aspects of the company, its major policies, relevant changes in management, future programmes of expansion, modernization and diversification, capitalization or reserves, etc.

It is mandatory for the Board of Directors of every company to present financial statement to the shareholders along with its report, known as the “Board’s Report” at every annual general meeting.

Disclosure in Board’s Report pursuant to the Companies Act, 2013

  • Disclosures under Section 134(3)
  • Details of Employees Stock Option Scheme – section 62(1)(b)
  • Voluntary revision of Financial Statements or Board’s Report- Section 131(1)
  • Resignation of Director – Section 168(1)
  • Issue of Equity Shares with differential rights
  • Restrictions on purchase by company or giving of loans by it for
  • Corporate Social Responsibility – Section 135
  • Composition of Audit Committee – Section 177(8)
  • Issue of Sweat Equity Shares
  • Disclosures pertaining to Consolidated Financial Statements
  • Re-Appointments of an Independent Director – Section 149(10)
  • Details of Vigil Mechanism – Section 177(10)
  • Disclosures pertaining to remuneration of directors and employees – Section 197(12)
  • Policy relating to the remuneration for the directors, key managerial personnel and other employees – Section 178(4)
  • Remuneration received by MD and WTD from holding or subsidiary companies-Section 197(14)
  • Related party transactions – Section 188(2) (xvii) Secretarial Audit Report – Section 204(1)
  • Additional Disclosures by Producer Company

Signing of Board’s Report [Section 134(6)]

Company Law Transparency And Disclosures Board's Report

Transparency And Disclosure In Corporate Governance

Annual Return in Companies Act, 2013

As per Section 92 of the Companies Act, 2013, every company is required to prepare the Annual Return in Form No. MGT-7 containing the particulars as they stood on the close of the financial year. Annual Return is to be filed with the Registrar within 60 days from the date on which Annual General Meeting (AGM) is actually held or from the last day on which AGM should have been held.

  • As provided in sub-Section (2) of Section 384, the provisions of Section 92 regarding filing of annual return apply to a foreign company subject to such exceptions, modifications and adoptions as may be provided for in the Rules.
  • Rule 7 of the Companies (Registration of Foreign Companies) Rules, 2014 provides that every foreign company shall prepare and file, within a period of sixty days from the last day of its financial year, to the Registrar annual return in Form FC-4 along with fee, containing the particulars as they stood on the close of the financial year.

Signing of Annual Return in Companies Act, 2013

Under section 92(1) of the Act, the Annual Return is required to be signed both by a director and the Company Secretary, or where there is no Company Secretary, by a Company Secretary in Practice.

The Annual Return of One Person Company and Small Company shall be signed by the Company Secretary or where there is no company- secretary, by the director of the company. The Act authorises the Central Government.

CS Company Law Transparency And Disclosures

Website Disclosures in Companies Act, 2013

Companies Act, 2013 does not mandate companies to have an active website, but SEBI (LODR), 2015 requires all the listed entities shall maintain a functional website containing the following information about the listed entity:

  • details of its business;
  • financial information including complete copy of the annual report including balance sheet, profit and loss account, directors report etc;
  • email address for grievance redressal and other relevant details;
  • name of the debenture trustees with full contact details;
  • the information, report, notices, call letters, circulars, proceedings, etc. concerning non-convertible redeemable preference shares or non convertible debt securities;
  • all information and reports including compliance reports filed by the listed entity;

Transparency And Disclosures Short Notes

Question 1. Write a note on the following:

Directors’ responsibility statement in Companies Act, 2013

Answer:

Company Law Transparency And Disclosures Provisions of Section 134

Transparency And Disclosures Descriptive Questions

Question 1. The Directors’ Report of Ayush Ltd. for the financial year ended 31st March, 2012 has been dated 15th May, 2012, whereas the Auditors’ Report for the same period is dated 16th May, 2012. Is this in order? Explain.

Answer:

Company Law Transparency And Disclosures Date of Directors report and auditors report

Disclosures Under Companies Act 2013

Question 2. Narrate briefly the importance of Corporate Governance Report and also state who can certify such report.

Answer:

Company Law Transparency And Disclosures Companies that Required to submit Quarterly CGR

Question 3. The Board of directors of Charming Ltd. seek your advice on the matters to be included in the directors’ responsibility statement forming part of the company’s annual report to shareholders. As the Company Secretary of Charming Ltd., advise the Board.

Answer:

Company Law Transparency And Disclosures Provsions of Section 134 of Companies

Question 4. Comment on the following:

Every company is required to disclose the details of vigil mechanism in the Board Report.

Answer:

According to Section 177(9) of Companies Act, 2013, read with Rule 7 of Companies (Meetings of Board and its Powers) Rules, 2014 the following companies are required to establish a vigil mechanism for their directors and employees to report their genuine concerns or grievances.

  • Every listed company;
  • The Companies which accept deposits from the public;
  • The Companies which have borrowed money from banks and public financial institutions in excess of fifty crore rupees.

Further the sub-section (10) provides that the details of establishment of such mechanism shall be disclosed by the company on its website, if any, and in the Board’s report.

Corporate Transparency And Accountability

Question 5. What are the ‘related party disclosures’ required to be made by listed entities as per SEBI Regulations?

Answer:

According to SEBI (LODR) Regulations, 2015, the Annual Report shall make certain provisions of Related Party Disclosures. Further as per Regulation 27(2) of SEBI (LODR) Regulations, 2015 details of all material transactions with related parties shall be disclosed along with the quarterly compliance report on corporate governance in the format as prescribed by the Board from time to time to the recognised Stock Exchange(s) within fifteen days from end of the quarter.

  • The listed entity shall make disclosures in compliance with the Accounting Standard on “Related Party Disclosures”.
  • The disclosure requirements shall be given below:-

Disclosures of amounts at the year end and the maximum amount of loans/advances/ investments outstanding during the year, in the books of accounts of:

  • Holding Company:-
    • Loans and advances in the nature of loans to subsidiaries by name and amount.
    • Loans and advances in the nature of loans to associates by name and amount.
    • Loans and advances in the nature of loans to firms/companies in which directors are interested by name and amount.
  • Subsidiary:-Same disclosures as applicable to the parent company in the accounts of subsidiary company.
  • Holding Company:- Investments by the loanee in the shares of parent company and subsidiary company, when the company has made a loan or advance in the nature of loan.

For the purpose of above disclosures directors’ interest shall have the same meaning as given in Section 184 of the Companies Act, 2013. Disclosures of transactions of the listed entity with any person or entity belonging to the promoter/promoter group which holds 10% or more shareholding in the listed entity, in the format specified in the relevant accounting standards for annual results.

Question 6. Comment on the following:

Annual Return is a significant document in relation to the company.

Answer:

Annual Return is an important document in relation to the company Annual Return is an important document for the stakeholders of a company as it provides a very exhaustively information about the different aspects of a company. It is perhaps the most significant document required’ to be filed by every company with the Registrar of Companies.

Apart from the Financial Statements, this is the only document to be mandatory filed with the Registrar of Companies, every year irrespective of any events/happenings in the company.

While the Financial Statements give information on the financial performance of a company, it is the Annual Return which gives substantial disclosure and greater insight into the non-financial matters of the company and the people entrusted with the management of the company.

Under Section 92(1) of the Companies Act, 2013 Annual Return contains the following information:

  • its registered office, principal business activities, particulars of its holding, subsidiary and associate companies;
  • its shares, debentures and other securities and shareholding pattern;
  • its indebtedness [omitted by the Companies (Amendment) Act, 2017)];
  • its members and debenture-holders along with changes therein since the close of the previous financial year;
  • its promoters, directors, key managerial personnel along with changes therein since the close of the previous financial year;
  • meetings of members or a class thereof, Board and its various committees along with attendance details;
  • remuneration of directors and key managerial personnel;
  • penalty or punishment imposed on the company, its directors or officers and details of compounding of offences and appeals made against such penalty or punishment;
  • matters relating to certification of compliances, disclosures as may be prescribed;
  • such other matters as may be prescribed.

Cs Company Law Disclosure Requirements

Question 7. Comment on the following:

Every Company is required to comply the disclosure requirements under the Sexual Harassment of Women at Workplace (Prevention, Prohibition and Redressal) Act, 2013 in their Board Report.

Answer:

Under Section 134 read with Rule 8(5) (x) of the Companies (Accounts) Rules, 2014, every company except (Small Companies and One Person Companies) is required to include the following in its Director’s Report:

Statement that the company has complied with provisions relating to the constitution of Internal Complaints Committee under the Sexual Harassment of Women at Workplace (Prevention, Prohibition and Redressal) Act, 2013

Disclosure Requirements under the Sexual Harassment of Women at Workplace (Prevention, Prohibition & Redressal) Act, 2013

  • The Sexual Harassment of Women at Workplace (Prevention, Prohibition and Redressal) Act, 2013 is applicable to every workplace, establishment, company or organisation employing 10 or more employees irrespective of its location or nature of industry.
  • The said Sexual Harassment of Women at Workplace (Prevention, Prohibition and Redressal Act,) 2013 provides for constitution of a Committee to be known as the “Internal Complaints Committee”.
  • Section 21 of the Sexual Harassment of Women at Workplace (Prevention, Prohibition and Redressal) Act, 2013 mandates that Internal Committee shall prepare an Annual Report
  • Section 22 of the said Act provides that the employer shall include in its report the number of cases filed, if any, and their disposal under this Act in the Annual Report.

As Per Rule 14 of Sexual Harassment of Women at Workplace (Prevention, Prohibition & Redressal) Rules, 2013 provides that the annual report which the Complaints Committee is required to prepare under Section 21 of the Sexual Harassment of Women at Workplace (Prevention, Prohibition & Redressal) Act, 2013 shall contain the following details:

  • Number of complaints of sexual harassment received in the year;
  • Number of complaints disposed off during the year;
  • Number of case’s pending for more than 90 days;
  • Number of workshops or awareness programme against sexual harassment carried out;
  • Nature of action taken by the employer or District Officer.

Question 8. Every company is required to have active website. Comment.

Answer:

The Companies Act, 2013 does not mandate companies to have an active website, but the SEBI (LODR) Regulations, 2015 requires that all listed entities shall maintain a functional website containing the basic information about the listed entity:

As per the provisions of the SEBI (LODR) Regulation, 2015, the listed entity shall disseminate the prescribed informations under a separate section on its website, including:

  • details of its business;
  • terms and conditions of appointment of independent directors;
  • composition of various committees of board of directors;
  • code of conduct of board of directors and senior management personnel;
  • details of establishment of vigil mechanism/ Whistle Blower policy;
  • criteria of making payments to non-executive directors, if the same has not been disclosed in annual report;
  • policy on dealing with related party transactions;
  • policy for determining ‘material’ subsidiaries;
  • details of familiarization programmes imparted to independent directors including the following details:-
    • number of programmes attended by independent directors (during the year and on a cumulative basis till date),
    • number of hours spent by independent directors in such programmes (during the year and on cumulative basis till date), and
    • other relevant details.
  • the email address for grievance redressal and other relevant details;
  • contact information of the designated officials of the listed entity who are responsible for assisting and handling investor grievances;
  • financial information including:
    • notice of meeting of the board of directors where financial results shall be discussed;
    • financial results, on conclusion of the meeting of the board of directors where the financial results were approved;
    • complete copy of the annual report including balance sheet, profit and loss account, directors report, corporate governance report etc.
  • shareholding pattern;
  • details of agreements entered into with the media companies and/or their associates, etc.;
  • the information, report, notices, call letters, circulars, proceedings, etc. concerning non- convertible redeemable preference shares or non-convertible debt securities;
  • all information and reports including compliance reports filed by the listed entity;
  • information with respect to the following events:
    • default by issuer to pay interest on or redemption amount;
    • failure to create a charge on the assets;
    • revision of rating assigned to the non-convertible debt securities.

It is important that the listed entity ensures the contents of the website are correct and updated at any given point of time.

Types Of Disclosures In Company Law

Question 9. Comment on the following:

Signing of the Board’s Report can be done by any one of the directors and be filed within 60 days of AGM.

Answer:

As per Section 134(6) of the Companies Act, 2013, the Board’s report and any annexures thereto, shall be signed by the Chairperson of the company if he is authorised by the Board and where he is not so authorised, shall be signed by at least two directors, one of whom shall be a managing director, or by the director where there is one director.

As per Section 137(1) of the Companies Act, 2013 states that a copy of financial statements, including consolidated financial statement, if any, along with all documents required to be attached to such financial statements under the Companies Act, 2013, duly adopted at the annual general meeting (AGM) or adjourned annual general meeting of the company shall be filed with the Registrar of Companies (ROC) within 30 days of annual general meeting or adjourned annual general meeting along with the prescribed fees.

The Board’s Report has to be attached to the financial statements. Although, where the financial statements are not adopted at annual general meeting (AGM) or adjourned annual general meeting, such unadopted financial statements along with the required documents shall be filed with the Registrar within thirty days of the date of annual general meeting.

In case of a One Person Company (OPC) a copy of the financial statements duly adopted by its member, along with all the documents which are required to be attached to such financial statements, shall be filed within one hundred eighty days from the closure of the financial year.

Transparency And Disclosures Practical Questions

Question 1. Pioneer Fisheries Ltd. has borrowed an amount of * 50 crore from a financial institution. The annual general meeting of the company was held on 1st September, 2015. Examining the provisions of the Companies Act, 2013, state as to who will sign and certify the annual return while filing the same with the Registrar of Companies after the annual general meeting. 

Answer:

Company Law Transparency And Disclosures Section 92

Question 2. Amendment made by Companies (Amendment) Act, 2017

Revised Section 92(1)-

“Every company shall prepare a return (hereinafter referred to as the annual return) in the prescribed form containing the particulars as they stood on the close of the financial year regarding:

  • its registered office, principal business activities, particulars of its holding, subsidiary and associate companies;
  • its shares, debentures and other securities and shareholding pattern;
  • its members and debenture-holders along with changes therein since the close of the previous financial year;
  • its promoters, directors, key managerial personnel along with changes therein since the close of the previous financial year;
  • meetings of members or a class thereof, Board and its various committees along with attendance details;
  • remuneration of directors and key managerial personnel;
  • penalty or punishment imposed on the company. its directors or officers and details of compounding of offences and appeals made against such penalty or punishment;
  • matters relating to certification of compliances, disclosures as may be prescribed;
  • details, as may be prescribed, in respect of shares held by or on behalf of the Foreign Institutional Investors; and
  • such other matters as may be prescribed, and signed by a director and the company secretary. or where there is no company secretary, by a company secretary in practice:

Provided that in relation to One Person Company, small company and such other class or classes of companies as may be prescribed, the annual return shall be signed by the company secretary, or where there is no company secretary, by the director of the company.

Provided further that the Central Government may prescribe abridged form of annual return for One Person Company, small company and such other class or classes of companies as may be prescribed.”

Question 3. Priya, a nominee director on the Board of Aroma Ltd., a listed company, informed the Board of directors during a Board meeting that the next annual report of the company shall contain a ‘Management Discussion and Analysis Report’. You being the Company Secretary have been asked by the Board to prepare the said report. State the matters you would include in the report.

Answer:

A Management Discussion and Analysis Report (MDAR) should form part of the Annual Report to the shareholders. This Management Discussion and Analysis should include discussion on the following matters within the limits set by the company’s competitive position:

  • Industry structure and developments.
  • Opportunities and Threats.
  • Segment-wise or product-wise performance.
  • Outlook.
  • Risks and concerns.
  • Internal control systems and their adequacy.
  • Discussion on financial performance with respect to operational performance.
  • Material developments in Human Resources/Industrial Relations front, including number of people employed.

Transparency In Financial Reporting

Question 4. Fabulous Ltd. is in the process of finalisation of its annual return. It is a listed company with paid-up capital 1 crore. The company seeks your advice on the following:

  1. Who will sign the return on behalf of the company?
  2. What are the requirements of certification of annual return by a practising Company Secretary. 

Answer:

  • As per Section 92 of the Companies Act, 2013, every company shall prepare its annual return containing the required particulars as they stood on the close of the financial year and shall be signed by a director and the Company Secretary, or where there is no Company Secretary, by a Company Secretary in practice.
  • Whereas in case of One Person Company and small company, the annual return shall be signed by the Company Secretary, or where there is no Company Secretary, by the director of the company.
  • Every listed company, or a company with paid up share capital of 10 crore or more or a company with turnover of 50 crore or more, shall be required to get a certificate by the Practicing Company Secretary (PCS) stating the facts that the requirements of the Companies Act, 2013 and rules thereto have been complied with and Annual Return discloses the facts correctly and adequately.

Question 5. Phosphate Ltd. has suffered a major loss of * 100 crore in May, 2018 on the dealing of commodity exchange. The annual accounts and Board’s report for the year 2017-18 are under finalization.

The Chief Financial Officer (CFO) of the company does not want to disclose this loss in the Board’s report for year 2017-18 because this loss does not pertain to said financial year. Is the view of CFO correct? The Board of Directors seek your advice in this matter.

Answer:

According to Section 134(3)(k) all material changes and commitments, if any, affecting the financial position of the company which have occurred between the end of the financial year of the company to which the financial statements relate and the date of the report should form part of the Board’s Report.

The Director’s Report shall, therefore, contain material changes pertaining to post-financial statement events impacting the operations and performance of the Company. Thus, in present case view of Chief Financial Officer is incorrect. Loss of 100 Crore incurred during May, 2018, i.e. post financial year, shall be included in the Board’s Report for the year 2017-18. -Space to write important points for revision

Transparency And Disclosures Short Notes

Question 1. Write short note on Certification of Annual Return.

Answer:

Certification of Annual Return:

Certification of Annual Return under sub-section (2) of Section 92 of the Act read with Rule 11(2) of the Companies (Management and Administration) Rules, 2014, the Annual Return of a listed company or of a company having a paid up share capital of 10 Crores or more or turnover of 50 Crores or more shall be certified by a Company Secretary in Practice in the Form No. MGT-8. The certificate shall state that the annual return discloses the facts correctly and adequately and that the company has complied with all the provisions of this Act.

The Companies (Management and Administration) Amendment Rules, 2021:

The MCA has notified the Companies (Management and Administration) Amendment Rules, 2021 to further amend the Companies (Management and Administration) Rules, 2014.

In Section 92 of the Principal Act, for sub-Section (5), the following sub- Section shall be substituted, namely:

Amendment made by Companies (Amendment) Act, 2020

If any company fails to file its annual return under Section 92(4) of the Companies Act, 2013, before the expiry of the period specified therein, such company and its every officer who is in default shall be liable to a penalty of ₹10,000 and in case of continuing failure, with further penalty of ₹100 for each day during which such failure continues, subject to a maximum of 2 lakhs in case of a company and 50,000 in case of an officer who is in default.

Disclosures Under Companies Act 2013

Question 2. Write short note on website disclosure.

Answer:

Website Disclosure:

  • details of its business;
  • financial information including complete copy of the annual report including balance sheet, profit and loss account, directors report etc;
  • contact information of the designated officials of the listed entity who are responsible for assisting and handling investor grievances;
  • email address for grievance redressal and other relevant details;
  • name of the debenture trustees with full contact details;
  • the information, report, notices, call letters, circulars, proceedings, etc concerning non-convertible redeemable preference shares or non convertible debt securities;
  • all information and reports including compliance reports filed by the listed entity:
  • information with respect to the following events:
    • default by issuer to pay interest on or redemption amount;
    • failure to create a charge on the assets;
    • revision of rating assigned to the non convertible debt securities:

It is important that the listed entity ensures the contents of the website are correct and updated at any given point of time. Space to write important points for revision

Transparency And Disclosures Descriptive Questions

Question 3. What information is required to be disclosed in Annual Report.

Answer:

Annual Report:

The annual report is a comprehensive report provided by most public companies to disclose their corporate activities over the past year. The report is typically issued to shareholders and other stakeholders who use it to evaluate the firm’s performance including both operating and financial highlights.

Such annual report shall contain the following:

  • audited financial statements i.e. balance sheets, profit and loss accounts otc, and Statement on Impact of Audit Qualifications, if applicable;
  • consolidated financial statements audited by its statutory auditors;
  • cash flow statement presented only under the indirect method as prescribed in Accounting Standard-3 or Indian Accounting Standard 7, as applicable, specified in Section 133 of the Companies Act, 2013
  • directors report;
  • management discussion and analysis report – either as a part of directors report or addition thereto;
  • for the top five hundred listed entities based on market capitalization Further it is provided that the annual report shall contain any other disclosures specified in Companies Act, 2013 along with other requirements as specified in Schedule V of above mentioned regulations.

As per SEBI (LODR), the annual report shall contain the following additional disclosures:

  • Related Party Disclosure:
  • Management Discussion and Analysis:
  • Corporate Governance Report
    • A brief statement on listed entity’s philosophy on code of governance.
    • Board of directors:
    • Audit committee
    • Nomination and Remuneration Committee:
    • Remuneration of Directors:
    • Stakeholders’ grievance committee:
    • General body meetings:
    • Means of communication:
    • General shareholder information:
  • Declaration signed by the chief executive officer stating that the members of board of directors and senior management personnel have, affirmed compliance with the code of conduct of board of directors and senior management.
  • Compliance certificate from either the auditors or practicing company secretaries regarding compliance of conditions of corporate governance shall be annexed with the directors’ report.
  • Disclosures with respect to demat suspense account/ unclaimed suspense account

Corporate Transparency And Accountability

Question 4. Describe the contents and signing of Annual Return.

Answer:

Annual Return:

  • As per Section 92 of the Companies Act, 2013, every company is required to prepare the Annual Return in Form No. MGT-7 containing the particulars as they stood on the close of the financial year.
  • Annual Return is to be filed with the Registrar within 60 days from the date on which Annual General Meeting (AGM) is actually held or from the last day on which AGM should have been held.
  • As provided in sub-Section (2) of Section 384, the provisions of Section 92 regarding filing of annual return apply to a foreign company subject to such exceptions, modifications and adoptions as may be provided for in the Rules.
  • Rule 7 of the Companies (Registration of Foreign Companies) Rules, 2014 provides that every foreign company shall prepare and file, within a period of sixty days from the last day of its financial year, to the Registrar annual return in Form FC-4 along with fee, containing the particulars as they stood on the close of the financial.year.

Contents of Annual Return

Annual Return shall contain the following particulars in consonance with the Section 92(1) of the Act:

  • its registered office, principal business activities, particulars of its holding, subsidiary and associate companies;
  • its shares, debentures and other securities and shareholding pattern;
  • its members and debenture-holders along with changes therein since the close of the previous financial year;
  • its promoters, directors, key managerial personnel along with changes therein since the close of the previous financial year;
  • meetings of members or a class thereof, Board and its various committees along with attendance details;
  • remuneration of directors and key managerial personnel;
  • penalty or punishment imposed on the company, its directors or officers and details of compounding of offences and appeals made against such penalty or punishment;
  • matters relating to certification of compliances, disclosures as may be prescribed;
  • details, as may be prescribed, in respect of shares held by or on behalf of the Foreign Institutional Investors and such other matters as may be prescribed.

Signing of Annual Return

Under section 92(1) of the Act, the Annual Return is required to be signed both by a director and the Company Secretary, or where there is no Company Secretary, by a Company Secretary in Practice.

The Annual Return of One Person Company and Small Company shall be signed by the Company Secretary or where there is no company secretary, by the director of the company. The Act authorises the Central Government.

CS Company Law Distribution Of Profits Question and Answers

Distribution Of Profits

Section 2(35)

Under section 2(35) of the Companies Act, 2013, ‘dividend’ includes any interim dividend.

Dividend in Companies Act, 2013

The dividend is the share of the company’s profit distributed among the members.

Declare Interim Dividend in Companies Act, 2013

The Board may declare an interim dividend during any financial year out of the surplus in the Profit and Loss Account at any time between two AGMs of the company.

Final Dividend in Companies Act, 2013

Final Dividend means a Dividend which was declared at the Annual General Meeting of the company.

Inadequacy of Profits in Companies Act, 2013

In case of inadequacy of profits, the company can declare the dividend under Rule 3 of Companies (Declaration and Payment of Dividend) Rules 2014.

Amount of Dividend in Companies Act, 2013

The amount of the dividend shall be deposited in a scheduled bank in a separate account within 5 days from the date of declaration.

Unpaid Dividend Account in Companies Act, 2013

Where the dividend is not paid or claimed within 30 days, the company shall, within 7 days transfer the amount to the Unpaid Dividend Account which shall be opened in a scheduled bank.

Investor Education and Protection Fund in Companies Act, 2013

The amount remaining unpaid along with interest accrued thereon for 7 years shall be transferred to the Investor Education and Protection Fund.

Utilization of Investor Education and Protection Fund in Companies Act, 2013

Section 125 (3) provides the Fund shall be utilized for

  • The refund in respect of unclaimed dividends, matured deposits, matured debentures, the application money due for refund, and interest thereon;
  • Promotion of investors’ education, awareness, and protection;
  • Reimbursement of legal expenses incurred in pursuing class action suits under sections 37 and 245 by members, debenture-holders, or depositors as may be sanctioned by the Tribunal.

Distribution Of Profits

Distribution Of Profits Under Companies Act

Punishment for Failure to Distribute Dividends in Companies Act, 2013

Section 127 of the Companies Act, 2013 provides that when a dividend has been declared by a company but has not been paid or the warrant in respect thereof has not been posted within thirty days from the date of declaration to any shareholder entitled to the payment of the dividend, every director of the company shall, if he is knowingly a party to the default, be punishable with imprisonment which may extend to two years and with fine which shall not be less than one thousand rupees for every day during which such default continues and the company shall be liable to pay simple interest at the rate of eighteen percent. per annum during the period for which such default continues.

List of Important Forms in Companies Act, 2013

Company Law Distribution Of Profits List Of Important Forms

Distribution Of Profits Short Notes

Question 1. Write a note on the following:

Investor Education and Protection Fund (IEPF) in Companies Act, 2013

Answer:

Company Law Distribution Of Profits What shall be credited to IEPF

Question 2. Write a note on the following: Punishment for failure to distribute dividends and exceptions in the Companies Act, 2013
Answer:

Company Law Distribution Of Profits Punishment for Failure

Distribution Of Profits Distinguish Between

Question 3. Distinguish between the following:

‘Interim dividend’ and ‘final dividend’ in Companies Act, 2013

Answer:

Company Law Distribution Of Profits Basis Meaning

Dividend Distribution Policy In India

Distribution Of Profits Descriptive Questions

Question 1. Comment on the following:

Dividends can be paid out of capital only if the articles of association of a company authorize such payment. 

Answer:

Company Law Distribution Of Profits Authenticity of statement

Question 2. The Board of Directors of a company in a meeting held on 30th April 2013 declared an interim dividend. In another meeting held on 18th May 2013, the Board revoked the interim dividend declared without assigning any reason. Advise the company in the matter.

Answer:

Company Law Distribution Of Profits Interim Dividend

Question 3. Due to the inadequacy of profits, the Board of Directors of Rise Ltd. decided not to recommend any dividend for the financial year ending 31st March 2015.

Certain shareholders of the company complained to the NCLT regarding mismanagement of the affairs of the company, since the Board of the company did not recommend any dividend. Explaining the provisions of the Companies Act, 2013, examine whether the contention of the shareholders is tenable.

Answer:

Company Law Distribution Of Profits Basis of Petition

Question 4. Referring to the provisions of the Companies Act, 2013 advise a public company that declared a dividend on 30th September 2018 as to the procedures to be followed in this regard for payment of dividend. Whether any intervening holidays in October 2018 shall be taken into account in calculating the time limit?

Answer:

  • Section 123(4) of the Companies Act, 2013 provides that the amount of the dividend, including interim dividend shall be deposited in a scheduled bank in a separate account within five days from the date of declaration of the dividend.
  • However, in the case of a Government Company sub Section 4 of Section 123 shall not apply in which the entire paid-up share capital is held by the Central Government, or by any State Government or Governments by the Central Government and one or more State Governments or by one or more Government Company.
  • Inferring from Section 124(1) dividend must be paid to any shareholder entitled to the payment of the dividend, within 30 days from the date of declaration of dividend.
  • Secretarial Standard-3(SS-3) hereby clarifies that the Dividend shall be deposited in a separate bank account within five days from the date of declaration and shall be paid within 30 days of declaration. The intervening holidays, if any, falling during ‘such a period shall be included.
  • Therefore in the given illustration, the dividend shall be deposited into a separate bank account of a scheduled bank on or before 05.10.2018 and the same must be paid to the registered shareholder or his order or his banker on or before 30.10.2018.

Cs Company Law Profit Distribution Questions

Question 5. Manish, a shareholder of a company has not claimed his dividends from the company for the last 10 years due to different reasons. He wants to know whether he will be able to recover the dividends declared by the company for all these years. Explain to him, the relevant legal provisions.

Answer:

  • According to Section 124 of the Companies Act, 2013 dividends must be paid within 30 days from the date of declaration and if any amount remains unpaid or unclaimed then the company is required to transfer the unpaid dividend to a special account, known as Unpaid Dividend Account opened by the company in any scheduled bank within seven days from the date of expiry of thirty days.
  • If any money transferred to this account remains unpaid or unclaimed for seven years from the date of transfer to such account it shall be transferred by the company to the Investor Education and Protection Fund established under Section 125 (1) of the Companies Act, 2013 maintained and administered by the Central Government.
  • In the present case, the amount of the dividend for the first 3 years must have been transferred to the Investor Education and Protection Fund. The amount for the remaining period must be in the Unpaid Dividend Account of the Company.
  • According, to Section 125 of the Companies Act, 2013 read with Rule 7 of the IEPF(Accounting, Audit, Transfer and Refund) Rules, 2016, the person whose amounts have been transferred to Investor Education and Protection Fund, shall be entitled to get a refund out of the fund in respect of such claims by submitting an online application in Form IEPF-5.
  • Manish should approach the company for the amount of dividends for the last 7 years.

Question 6. Comment on the following:

Dealing with dividends is the prerogative of the Board of Directors. However, there are certain parameters included in the dividend distribution policy of a company. Answer:

Regulation 43A of the SEBI (LODR) Regulations, 2015 provides for the formulation of policy for dividend distribution which broadly specifies the external and internal factors including parameters that may be considered while declaring dividends and the circumstances under which the shareholders of the company may or may not expect a dividend. The dividend distribution policy shall include the following parameters:

  • the circumstances under which the shareholders of the listed entities may or may not expect dividends;
  • the financial parameters that shall be considered while declaring dividends;
  • internal and external factors that shall be considered for the declaration of dividend;
  • policy as to how the retained earnings shall be utilized; and
  • parameters that shall be adopted about various classes of shares.

Hence, the top 500 listed entities based on market capitalization (calculated as of March 31 of every financial year) are required to formulate a dividend distribution policy which shall be disclosed in their annual reports and as well as on their websites.

The listed entities other than the top five hundred listed entities based on market capitalization may also disclose their dividend distribution policies voluntarily in their annual reports and on their website.

Distribution Of Profits Practical Questions

Question 1. A company for the financial year 2011-12 declared a dividend on 19th September 2012 but failed to distribute the same within the prescribed period. A case was filed against a director in this regard. The director has contended that he had resigned before the declaration of the dividend. Decide the fate of the director in light of the relevant provisions of the Companies Act, 2013.

Answer:

Company Law Distribution Of Profits Punishment for Failure to distribute dividends

Question 2. In Evergreen Ltd., the Board of Directors declared an interim dividend but could not distribute the dividend due to objections of the audit committee that the accounts considered by the Board were false; and true financial results were inflated by not incorporating outstanding liabilities and over-valuation of inventories.

A shareholder filed a suit for non-payment of dividends. One of the directors contended that he never attended the Board meeting where the issue relating to the payment of the interim dividend was declared based on false accounts. Discuss the validity of the contention of the director.

Answer:

The contention of the absentee director is correct and he is not liable for the payment of dividends on false accounts declared in a meeting where the director to become liable was absent. The facts of the case are similar to the case law of Nagendra Prabhu v. the Popular Bank ZLR (1961) 1 Ker 340.

Company Profits And Dividends Rules

Question 3. Rise Ltd., a company with diversified interests, has constituted an Investor Education and Protection Fund as required under the provisions of the Companies Act, 2013. The company has so far not deposited any amount to the fund. The President (Finance) has asked you, the Company Secretary, to submit a note on amounts payable to the credit of the fund and the period within which the amount shall be paid. Prepare the said note.

Answer:

  Rise Limited

The President (Finance)                                                             Date ________

Sir,

Sub: Details on the amount payable to the Investor Education and Protection Fund constituted under the Companies Act, 2013.

According to Section 125(1) of the Companies Act, 2013, the Central Government shall establish a Fund to be called the Investor Education and Protection Fund. Therefore, the company is not required to constitute such a fund.

According to Section 125(2) of the Companies Act, 2013 the following amounts shall be credited to the Fund established by the Government by the company:

  • the amount is given by the Central Government by way of grants after due appropriation made by Parliament by law on this behalf for being utilized for the Fund;
  • donations given to the Fund by the Central Government, State Governments, Companies, or any other institution for the Fund;
  • the amount in the Unpaid Dividend Account of companies transferred to the Fund under sub-section (5) of Section 124;
  • the amount lying in the Investor Education and Protection Fund.
  • the interest or other income received out of investments made from the Fund;
  • the amount received under sub-section (4) of Section 38;
  • the application money received by companies for allotment of any securities and due for refund;
  • matured deposits with companies other than banking companies;
  • matured debentures with companies;
  • interest accrued on the amounts referred to in clauses (h) to (i);
  • sale proceeds of fractional shares arising out of issuance of bonus shares, merger, and amalgamation for seven or more years;
  • redemption amount of preference shares remaining unpaid or unclaimed for seven or more years; and
  • such other amount as may be prescribed:
    Provided that no such amount referred to in clauses (h) to (j) shall form part of the Fund unless such amount has remained unclaimed and unpaid for seven years from the date it became due for payment.

This is for your information and record, please.

Best Regards

Company Secretary

Question 4. The Board of Directors of AVB Limited wants to declare a dividend. 15 lakhs out of capital profits for the year ended 31st March 2017, without making provisions for depreciation. Referring to the provisions of the Companies Act, 2013, you being the Secretary of the Company advise the board whether it can go ahead with its proposal.

Answer:

  • By the provisions of the Companies Act, 2013, as contained in the third proviso to Section 123(1), no dividend shall be declared or paid by a company from its reserves other than free reserves. As per Section 2(43) of the Companies Act, 2013, “free reserves” means such reserves which, as per the latest audited balance sheet of a company, are available for distribution as dividends.
  • Further according to Section 123(2), for declaration of dividend by a company as per Section 123(1) (a), depreciation shall be provided by the provisions of Schedule II.
  • Therefore, in the given case, AVB Limited can neither declare dividends from capital profit nor it can declare dividends without making provision for depreciation.

Question 5. The Board of Directors of American Express Ltd. declared an interim dividend third time during the financial year 2015-16. After the declaration, the Board of Directors decided to revoke the third interim dividend as they noticed that the company’s financial position did not permit payment of such an interim dividend. The Board of Directors seeks your advice in this matter. Please advise the Board as a company secretary. Would your advice be different in case it was a regular dividend instead of an interim dividend?

Answer:

  • The Board of Directors may declare an interim dividend and the amount of the dividend including the interim dividend shall be deposited in a separate bank account within 5 days from the date of declaration of such dividend.
  • A dividend when declared becomes debt and a shareholder is entitled to sue for recovery of the same after the expiry of the 30 days prescribed under Section 127.
  • Section 2(35) defines ‘Dividend’ to include interim dividend. Therefore, the interim dividend once declared cannot be revoked except with the consent of the shareholders.
  • Based on the aforesaid facts, the Board of Directors of American Express Limited cannot revoke the interim dividend and should pay the same.
  • No, Regular dividends also cannot be revoked even by the shareholders. It’s a statutory debt against the company once it is declared.

Retained Earnings Vs Distributed Profits

Question 6. The Board of Directors of Peculiar Ltd. proposes to recommend a final dividend of 25 each to all the equity shareholders of the company. The company seeks your opinion on the following:

  1. The company wants to deposit the dividend amount to a cooperative bank.
  2. The company is a defaulter in the repayment of deposits and proposes to repay all deposits after the payment of the dividend within 10 days.
  3. Dividends will be declared out of the capital reserves of the company.
  4. The company wants to pay such dividends through the cash counter by way of a cash voucher.

Answer:

Peculiar Ltd. has to follow the below procedure for recommending the final dividend:

  • Referring to Section 123(4) of the Companies Act, 2013, the amount of the dividend has to be deposited in a scheduled bank. The company should first ensure that said Co-operative bank is a scheduled bank from the list of scheduled banks available on the RBI website, and then it may deposit the dividend amount in the scheduled Co-operative Bank.
  • Referring to Section 123(6) of the Companies Act, 2013 a company that fails to comply with the provisions relating to acceptance and repayment of deposits shall not, so long as such failure continues, declare any dividend on its equity shares. Hence Peculiar Ltd. cannot declare dividends till the failure persists.
  • Referring to the third proviso to Section 123(1), no dividend shall be declared or paid by a company from its reserves other than free reserves.
    Free reserves, as per Section 2(43), means such reserves which, as per the latest audited balance sheet of a company, are available for distribution as dividends: Provided that:

    • Any amount representing unrealized gains, notional gains, or revaluation of assets, whether shown as a reserve or otherwise, or
    • Any change in the carrying amount of an asset or of a liability recognized in equity, including surplus in profit and loss account on measurement of the asset or the liability at fair value, shall not be treated as free reserves;
    • Hence dividends cannot be declared out of the capital reserves of the company.
  • Referring to Section 123(5) dividends shall not be payable in cash. Hence company’s proposal to pay dividends through the cash counter by way of a cash voucher is not permitted under law.

Question 7. A company declared a dividend on 21st November 2018. It reported on 22nd December 2018 that it could not pay dividends to 46 members as they have not been traceable for the last three years. Advise the company about unpaid dividends under the provisions of the Companies Act, 2013.

Answer:

Company Law Distribution Of Profits Provisions of Section 126

Distribution Of Profits Under Companies Act

Question 8. While adopting accounts for the year, the Board of Directors of Prima Ltd. decided to consider the interim dividend @ 12% as the final dividend and did not consider the transfer of profit to reserves. Explain whether the decisions of the Board were justified by referring to relevant provisions.

Answer:

  • Section 123 of the Companies Act, 2013 provides that for the provisions relating to the declaration of dividends.
  • Since an interim dividend is also a dividend, companies should provide for depreciation under Section 123 of the Companies Act, 2013. before the declaration of the interim dividend.
  • However, the first proviso to Section 123(1) of the Companies Act, 2013 provides that a company may, before the declaration of any dividend in any financial year, transfer such percentage of its profits for that financial year as it considers appropriate to the reserves of the company irrespective of the size of declared dividend i.e. company is not compulsory required to transfer the profit to reserves, and it is only an option made available to the company to transfer such percentage of profit to reserves.
  • In the above case, the Board has decided to pay an interim dividend of @12% of the paid-up capital. Assuming the company has complied with the depreciation requirement and other applicable provisions, the interim or final dividend can be declared without transferring such percentage of its profits as it may consider appropriate to the reserve of the company.
  • Hence, it may be end that Prima Ltd. is under no contravention of law by not transferring i.e. the company is free to transfer any amount of its profit to the reserves, without any compulsion or restriction before the declaration of any dividend.
  • Section 123(3) of the Companies Act, 2013 states that the Board of Directors of a company may declare an interim dividend during any financial year or at any time during the period from the closure of the financial year till the holding of the annual general meeting out of the surplus in the profit and loss account or out of profits of the financial year for which such interim dividend is sought to be declared or out of profits generated in the financial year till the quarter preceding the date of declaration of the interim dividend.
  • The amount of dividend including interim dividend should be deposited in a separate bank account within five days from the declaration of such dividend for compliance with Section 123(4) of the Companies Act, 2013.

Question 9. The following summarized information is available in respect of a company for the year ended 31st March 2019:

Company Law Distribution Of Profits Lakhs

The company has paid dividends to the equity shareholders @ 8%, 10%, and 12% during the immediately preceding three financial years. Advise the Board of Directors on the maximum amount they can pay this year by way of dividends.

Answer:

As per Section 123 (1) of the Companies Act, 2013, a company can distribute dividends out of profits of the current year or from profits of previous financial years.

In the event of inadequacy or absence of profits in any financial year, if the company wants to propose a declaration of dividend, it can pay it out of accumulated profits earned by it in previous years and transferred by the company to the free reserves, according to the conditions prescribed under Rule 3 of the Companies (Declaration and Payment of Dividend) Rules, 2014.

In the above case, the net loss for the year 2018-19 is 25000. According to Rule 3 of the Companies (Declaration and Payment of Dividend) Rules, 2014 the following conditions must be fulfilled:

  • The rate of dividend cannot exceed the average of the rates at which the dividend was declared in the three years immediately preceding that year i.e. (8%+10% +12%) / 3 = 10%, so in this case, the amount of dividend should not exceed 1 Lakh.
  • The total amount to be drawn from such accumulated profits shall not exceed one-tenth of the sum of its paid-up share capital and free reserves as appearing in the latest audited financial statement. Thus the company can draw only upto 1.2 lakh.
  • The balance of reserves after such withdrawal shall not fall below 15% of its paid-up capital as appearing in the latest audited balance sheet. Accordingly, the maximum that may be withdrawn cannot exceed 50000.
  • However, the amount so withdrawn must be used to set off losses of the current year i.e. ₹ 25000.

Hence, the maximum amount in this instant case that can be paid by way of dividend is ₹ 25000.

Question 10. Examine the validity of the following:

  1. XYZ Ltd. wants to declare the dividend out of the current year’s profit without adjusting the previous year’s carry-forward losses and depreciation.
  2. The Board of Directors of XYZ Ltd. wants to declare an interim dividend after the end of the financial year.

Answer:

Declaration of Dividend:

  • Section 123(1) of the Companies Act, 2013 states that the dividend shall be declared or paid by a company for any financial year out of the profits of the company for that year arrived at after providing for depreciation or out of the profits of the company for any previous financial year or years arrived at after providing for depreciation and remaining undistributed, or out of both.
    Proviso to this section provides that a company shall not declare dividends unless carried over previous losses and depreciation not provided in the previous year or years are set off against profits of the company for the current year.
    Hence, XYZ Ltd has to set off the previous year’s carry-forward loss and depreciation from the current year’s profit before the declaration of the dividend.
  • As per section 123(3), the board of directors of a company may declare an interim dividend during any financial year or at any time during the period from the closure of the financial year till the holding of the annual general meeting out of surplus in the profit and loss account or out of profits of the financial year for which such interim dividend is sought to be declared or out of profits generated in the financial year till quarter preceding the date of declaration of the interim dividend.

Dividend Distribution Policy In India

Short Notes

Question 1. Write a short note on Punishment for failure to distribute dividends.

Answer:

Section 127 of the Companies Act, 2013 provides that when a dividend has been declared by a company but has not been paid or the warrant in respect thereof has not been posted within thirty days from the date of declaration to any shareholder entitled to the payment of the dividend, every director of the company shall, if he is knowingly a party to the default, be punishable with imprisonment which may extend to two years and with fine which shall not be less than one thousand rupees for every day during which such default continues and the company shall be liable to pay simple interest at the rate of eighteen percent. per annum during the period for which such default continues.

Distribution Of Profits Descriptive Questions

Question 2. State the procedure for the transfer of unpaid or unclaimed dividends to the Investor Education and Protection Fund.

Answer:

Any money transferred to the Unpaid Dividend Account of a company in pursuance of Section 124 which remains unpaid or unclaimed for seven years from the date of such transfer shall be transferred by the company along with interest accrued if any, thereon to the Investor Education and Protection Fund and the company shall send a statement in the prescribed form of the details of such transfer to the Investor Education and Protection Fund Authority and it shall issue a receipt to the company as evidence of such transfer.

  • Every company shall within ninety days after holding the Annual General Meeting or the date on which it should have been held as per the provisions of section 96 of the Act and every year thereafter till completion of the seven years, identify the unclaimed dividend, as on the date of holding of Annual General Meeting or the date on which it should have been held as per the provisions of section 96 of the Act, separately furnish and upload on its website and also on website of Authority or any other website as may be specified by the Government, a statement or information through Form No. IEPF-2, separately for each year, contains the following information, namely:
    • the names and last known addresses of the persons entitled to receive the sum;
    • the nature of the amount;
    • the amount to which each person is entitled;
    • the due date for transfer into the Invest or Education and Protection Fund; and
    • such other information as may be considered relevant for the purposes.
  • The amount of unclaimed or unpaid dividend required to be credited by the companies to the Fund shall be remitted into the specified branches of Punjab National Bank, which is the accredited Bank of the Pay and Accounts Office, Ministry of Corporate Affairs, and other authorized banks engaged by the MCA-21 system, within thirty days of such amounts becoming due to be credited to the Fund.
  • The amount shall be tendered by the companies along with challan (in triplicate) to the specified Bank Branches of Punjab National Bank and other authorized banks under the MCA-21 system who will return two copies of the challan, duly stamped in token of having received the amount, to the Company. The third copy of the challan will be forwarded along with the daily credit scroll by the receiving branch to its Focal Point Branch of the Bank for onward transmission to the Pay and Accounts Office, Ministry of Corporate Affairs.
  • Every company shall file with the concerned Authority one copy of the challan referred to in point (3) indicating the deposit of the amount to the Fund and shall fill in the full particulars of the amount tendered, including the head of the account to which it has been credited.
  • The company shall, along with the copy of the challan as required under point(4), furnish a Statement in Form No. IEPF 1 contains details of such transfer to the Authority within thirty days of submission of challan.
  • The amount may also be remitted by Electronic Fund Transfer in such manner, as may be specified by the Central Government.
  • On receipt of the statement, the Authority shall enter the details of such receipt in a Register maintained physically or electronically by it in respect of each company every year, and reconcile the amount so remitted and collected, with the concerned designated bank every month.
  • Each designated bank shall furnish an abstract of such receipts during the month to the Authority within seven days after the close of every month.
  • The company shall maintain a record consisting of the name, last known address, amount, folio number or client ID, certificate number, beneficiary details, etc. of the persons in respect of whom unpaid or unclaimed amount has remained unpaid or unclaimed for seven years and has been transferred to the Fund and the Authority shall have the powers to inspect such records. Space to write important points for revision

Company Profits And Dividends Rules

Question 3. Enumerate the procedure for declaration of dividend out of Reserve.

Answer:

  • Give notice to all the directors of the company for holding a Board meeting. In the meeting, decide to declare dividends out of the company’s reserves because of inadequacy or absence of profits and also fix the date, time, and place of the Annual General Meeting. Authorize the Company Secretary or any competent person if the company does not have a company secretary to issue the notice of the AGM on behalf of the Board of Directors of the company to all the members, directors, and auditors of the company and other persons entitled to receive the same.
  • Ensure that the Companies (Declaration and Payment of Dividend), Rules, 2014 are complied with.
  • While calculating the profits of the previous years, take only the net profit after tax.
  • Ensure that while computing the amount of profits, the amount transferred from the Development Rebate Reserve is included and all items of capital reserves including reserves created by revaluation of assets are excluded.
  • In the case of listed companies, inform the Stock Exchange with which the shares of the company are listed within 30 minutes of the closure of the Board meeting about the decision to recommend the declaration of dividend out of the Company’s Reserves. [Regulation 30 of SEBI (LODR) Regulations, 2015].
  • Issue notices in writing at least 21 days before the date of the Annual General Meeting hold the meeting and pass the necessary resolution.
  • In the case of listed companies, forward copies of the notice and a copy of the proceeding of the general meeting to the Stock Exchange.
  • Open a separate bank account for making dividend payments and credit. the said bank account with the total amount of dividend payable within five days of declaration of dividend.
  • Issue dividend warrants within 30 days from the date of declaration of dividend. The rest of the procedural steps are the same as in the case of payment of the final dividend.

Drugs Acting On Autonomic Nervous System Adrenergic Drugs Notes

Drugs Acting On Autonomic Nervous System Introduction

The human nervous system consists of the Central Nervous System (CNS) and the Peripheral Nervous System (PNS). CNS is composed of the brain (located in the cranial cavity) and the spinal cord (located in the vertebral cavity), which serve as the main control centers. for all body activities.

PNS is composed of nerves derived from the brain and spinal cord (12 pairs of cranial nerves and 31 pairs of spinal nerves) which serve as a linkage between the CNS and the body.

PNS can be subdivided into sensory (afferent) nerves and motor (efferent) nerves. Sensory nerves send nerve impulses from the body to the CNS to effector organs.

Motor nerves are divided into the Somatic Nervous System (SNS) which regulates the voluntary contraction of the skeletal muscles and the Autonomic Nervous System (ANS) which regulates the involuntary control of smooth, cardiac muscles and glands.

The Autonomic Nervous System (ANS) can be divided into sympathetic and parasympathetic branches where in general sympathetic nerves stimulate activities of the effect or organs (except digestive organs) and parasympathetic nerves inhibit activities of the effect or organs (except digestive organs).

Medical Chemistry Drugs Acting On Autonomic Nervous System Central Nervous System

The Autonomic Nervous System (ANS) controls a variety of involuntary and reflexive regulatory responses, e.g. the beating of the heart, expansion or contraction of blood vessels or pupils, etc.

It is responsible for both the “fight or flight” response that represents the body’s physiological response to crisis or stress and for the less crisis-driven functions of resting, repairing, digesting, and reproductive activities. Many of the drugs used to treat common conditions of the heart, circulation, and blood pressure by altering the functioning of the ANS.

Read and Learn More Medicinal Chemistry III Notes

There are three main components of ANS, viz., Sympathetic Nervous System (SNS), Parasympathetic Nervous System (PNS), and Enteric Nervous System (ENS).

ENS is intrinsic to the digestive system; it carries the key functions in support of systemic neurologic and immunologic well-being and is highly responsible for both physical and emotional stimuli. Comparison chart between Sympathetic Nervous System (SNS) and Parasympathetic Nervous System (PNS):

Adrenergic Drugs

The sympathetic system activates and prepares the body for vigorous muscular activity, stress, and emergencies. Adrenergic drugs are chemical agents that exert their principal pharmacological and therapeutic effects by either enhancing or reducing the activity of the various components of the sympathetic division of the Autonomic Nervous System.

Adrenergic drugs act by stimulation of the peripheral nerve endings of the sympathetic or adrenergic nerves, the action being exerted on the effector cells supplied by postganglionic endings.

As these drugs stimulate the adrenergic nerves directly by mimicking the action of norepinephrine or indirectly by stimulating the release of norepinephrine, they are also called adrenomimetic or sympathomimetic agents.

A sympathomimetic drug plays a vital role in various life-threatening disorders, like acute attacks of bronchial asthma, cardiac arrest, shock and allergic reactions. As most of adrenergic agents contain an intact or partially substituted amino group, they are also called as sympathomimetic amines.

Adrenergic Neurotransmitters

Adrenergic neurons release nor-epinephrine (nor-adrenaline) as the primary neurotransmitter. These neurons are found in the Central Nervous System and also in the Sympathetic Nervous System, where they serve as links between the ganglia and the effector organs.

The adrenergic neurons and receptors located either pre-synaptically on the neuron or post-synaptically on the effector organ, are the sites of action of the adrenergic drugs.

Catecholamines

The catecholamines are so named because they contain a catechol group and an amine group. A catechol group is simply a benzene ring with hydroxyl groups on two adjacent carbons. The amine component of the catecholamines is ethylamine.

Because of their chemistry, all catecholamines have three properties in common: (1) They cannot be used orally. (2) They have a long duration of action. (3) They cannot cross the blood-brain barrier.

Catechol is highly susceptible to oxidation in the presence of oxygen to produce an ortho- quinone-like compound, which undergoes further reaction to give a mixture of colored products. Hence solution of catechol amines is stabilized by the addition of antioxidants (reducing agents) such as ascorbic acid or sodium bisulfite.

Synthesis, Storage, and Release of Catecholamine

Catecholamine biosynthesis takes place in adrenergic and dopaminergic neurons in the CNS, in sympathetic neurons in the ANS, and in the adrenal medulla. Epinephrine and norepinephrine each possess chiral carbon atoms, and thus exist an enantiomeric pair of isomers.

The enantiomer with R-configuration is biosynthesized by the body and possesses biological activity. Neurotransmission in adrenergic neurons is a process that involves five steps: synthesis, storage, release, and receptor binding of norepinephrine, followed by removal of the neurotransmitter from the synaptic gap.

  • Synthesis Of Nor-Epinephrine (Nor-Adrenaline): Hydroxylation of tyrosine is rate rate-limiting step.
  • Uptake Into Storage Vesicles: Dopamine enters a vesicle and is converted to norepinephrine. Norepinephrine is protected from degradation in the vesicle.
  • Release Of Neurotransmitter: Influx of the calcium causes fusion of the vesicle with the cell membrane in a process known as exocytosis.
  • Binding To Receptor: The post synaptic receptor is activated by the binding of neurotransmitters.
  • Removal Of Norepinephrine: Released norepinephrine is rapidly taken into the neuron.
  • Metabolism: Norepinephrine is methylated by COMT and oxidized by MAO.

Medical Chemistry Drugs Acting On Autonomic Nervous System Neurotransmitters from adrenergic nerves

All five enzymes that are involved in the pathway of the biosynthesis of norepinephrine are synthesized within the cell bodies of the adrenergic neurons and transported to their nerve terminals. Phenylalanine-hydroxylase also called phenylalanine-4-monooxygenase coverts phenylalanine to tyrosine.

Conversion of tyrosine to L-B-(3,4-dihydroxy phenyl)-α- alanine (DOPA) is a rate-limiting step catalyzed by the enzyme, tyrosine-hydroxylase. Decarboxylation of DOPA to dopamine takes place by the enzyme aromatic amino-acid decarboxylase. Dopamine formation takes place in the cytoplasm.

In synaptic vesicles, dopamine is hydroxylated stereospecifically by the enzyme dopamine B-monooxygenase (dopamine-ß- hydroxylase) to give noradrenaline (norepinephrine). Norepinephrine undergoes methylation in the presence of the enzyme phenylethanolamine-N-methyl transferase to give adrenaline (epinephrine).

The norepinephrine formed is stored in vesicles as its adenosine triphosphate complex until the depolarization of neuron initiates the process of vesicle fusion with the plasma membrane and extrusion of norepinephrine into the synaptic cleft. Synthesis of norepinephrine and epinephrine also takes place in adrenal medulla.

The release of neurotransmitters occurs when an action potential opens voltage-sensitive calcium channels and increases intracellular calcium. Influx of calcium triggers the fusion of the vesicle with the surface membrane. This causes the release of neurotransmitter (norepinephrine) from the synaptic vesicle through exocytosis.

It then binds to the adrenoreceptor on the effector cells and produces effects by various mechanisms. The excess norepinephrine that are not bound to the postsynaptic receptor, binds to presynaptic receptors to decrease its own release. It then diffuses out, either by metabolism by COMT or is taken back up by the presynaptic neuron.

Medical Chemistry Drugs Acting On Autonomic Nervous System Biosynthesis of Catecholamines

Uptake And Metabolism Of Catecholamines

The actions of norepinephrine at adrenergic receptors are terminated by a combination of processes, such as

  • Uptake into the neuron and into extraneuronal tissues,
  • Diffusion away from the synapse and uptake at non-neuronal sites, and
  • Metabolism.

The two principal enzymes involved in catecholamine metabolism are namely monoamine oxidase (MAO) and catechol-o-methyl transferase (COMT).

Both of these enzymes are distributed widely throughout the body, with high concentrations found in the liver and kidney. Catecholamines that are administered orally become inactivated before they can reach to the systemic circulation.

Hence, catecholamines are ineffective if given by mouth. Both enzymes are very active and quickly destroy catecholamines, therefore, three catecholamines viz., norepinephrine, dopamine, and dobutamine are effective only if administered by continuous infusion (by IV route in an emergency), whereas other parenteral routes like subcutaneous and intramuscular will not yield adequate blood levels.

Because of the hydroxyl groups on the catechol portion of the catecholamines, they cannot cross the blood-brain barrier; therefore catecholamines have minimal effects on the CNS.

Norepinephrine (NE) is deaminated oxidatively by MAO to give 3,4-dihydroxy- phenylglycoaldehyde which is then reduced by aldehyde reductase to 3,4-dihydroxy- phenylethylene glycol. This glycol metabolite is primarily released into the circulation, where it undergoes methylation by the COMT to give 3-methoxy-4-hydroxyphenylethylene glycol.

3,4-dihydroxyphenylglycolaldehyde undergoes dehydrogenation in the presence of aldehyde dehydrogenase to give 3,4-dihydroxy-mandelic acid, which is then by the action of COMT convert to 3-methoxy-4-hydroxy mandelic acid. This metabolite is commonly referred to as vanillylmandelic acid. It is the end product of several pathways of norepinephrine metabolism.

Medical Chemistry Drugs Acting On Autonomic Nervous System Metabolism of Catecholamines

Non-Catecholamines

The non-catecholamines have ethylamine in their structure but do not contain the catechol moiety that characterizes the catecholamines. The non-catecholamines differ from the catecholamines in three important respects:

  • As they do not have a catechol group, non-catecholamines are not substrates for COMT and are metabolized slowly by MAO. As a result, the half-lives of non-catecholamines are much longer than those of catecholamines.
  • As they do not undergo rapid degradation by MAO and COMT, non-catecholamines can be administered orally, whereas catecholamines cannot.
  • Non-catecholamines are considerably less polar than catecholamines, and hence are more able to cross the blood-brain barrier.

Medical Chemistry Drugs Acting On Autonomic Nervous System Structures of catecholamines and non-catecholamines

Adrenergic Receptors

Catecholamines bind to specific receptors known as adrenergic receptors. There are two basic types of receptors: a-adrenergic receptors and B-adrenergic receptors. a-adrenergic receptors have subtypes such as a and α2, whereas ẞ-adrenergic receptors have subtypes such as B1 B2, and B3.

The action of neurotransmitters adrenergic drugs or sympathomimetic drugs upon these receptors is an important means of alternate ANS functions for the therapy of different disease states.

Receptor Distribution:

  • α-Adrenergic Receptors: They are found in the smooth muscles of the iris, arteries, arterioles, and veins.
  • a-Adrenergic Receptors: They mediate the inhibition of adrenergic neurotransmitter release.
  • B1-Adrenergic Receptors: They are found in the myocardium where their stimulation increases the force and rate of myocardial contraction.
  • B2-Adrenergic Receptors: They are found in bronchial and vascular smooth muscles where their stimulation causes smooth muscle dilation or relaxation.
  • B3-Adrenergic Receptors: These receptors are expressed on fat cells and their stimulation causes lipolysis.

Medical Chemistry Drugs Acting On Autonomic Nervous System Catecholamines

Norepinephrine activates primarily a-receptors and epinephrine activates primarily B-receptors, although it may also activate a-receptors. Stimulation of a-receptors is associated with constriction of small blood vessels in the bronchial mucosa and relaxation of smooth muscles of the intestinal tract. B-receptor activation relaxes bronchial smooth muscles which cause the bronchi of the lungs to dilate.

In addition, B-receptor stimulatory effects cause an increase in the rate and force of heart contractions. As a result, an increased amount of blood leaves the heart and is diverted from non-active organs to areas that actively participate in the body’s reaction to stress such as skeletal muscles, brain, and liver.

Fight Or Flight Response: The changes experienced by the body during emergencies have been referred to as the fight or flight response. These reactions are triggered both by direct sympathetic activation of the effector organs and by stimulation of the adrenal medulla to release epinephrine and lesser amounts of norepinephrine. These hormones enter the bloodstream and promote responses in effector organs that contain adrenergic receptors.

Effects of stimulation of the sympathetic division:

  • To increase heart rate and blood pressure.
  • To mobilize energy stores of the body.
  • To increase blood flow to skeletal muscles and the heart while diverting flow from the skin and internal organs.
  • Dilation of the pupils and the bronchioles.
  • Affects gastrointestinal motility and the function of the bladder and sexual organs.

Selected Tissue Responses to Stimulation of Adrenoceptor Subtypes

Medical Chemistry Drugs Acting On Autonomic Nervous System Adrenoceptor subtypes

Classification Of Sympathomimetic Agents

Sympathomimetic agents are subdivided into three classes: direct-acting, indirect-acting and dual (mixed) acting sympathomimetic agents.

Direct-Acting Sympathomimetics

Direct-acting agents elicit a sympathomimetic response by interacting directly with adrenergic receptors. They bind to and activate α1, α2, B1, and B2 receptors.

Naturally occurring molecules that bind to these receptors include,

Norepinephrine: A neurotransmitter which binds to a1, a2, and ẞ1 receptors. It is non-selective sympathomimetic.

Epinephrine: A hormone produced and secreted from the adrenal medulla that binds α1, α2, B1, and B2 receptors. It is non-selective sympathomimetic.

Dopamine: A neurotransmitter that binds to D1 or D2 receptors as well as α1, α2, and ẞ1 receptors.

a-receptor stimulation:

α-agonists act by G-protein activation of the enzyme phospholipase C, resulting eventually in the release of calcium, thereby increasing the intracellular calcium concentration. 2-agonists act by inhibiting adenylyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). This leads to decreased intracellular cAMP levels.

Alpha receptors are further subdivided into α1A, 1B, αic and α1D as well as α2A, 2B and

Medical Chemistry Drugs Acting On Autonomic Nervous System Alpha receptors

B-receptor stimulation:

B-agonists are selective to a subtype (B1, B2, and ẞ3) or nonselective- stimulate adenylyl cyclase, causing increased intracellular cAMP levels.

Medical Chemistry Drugs Acting On Autonomic Nervous System Beta receptors

Dopamine-receptor stimulation:

Dopamine receptor agonists can act on D1 or D2 receptors. D1-receptors activate adenylyl cyclase and increase intracellular cAMP mainly in neurons and vascular smooth muscle. D2- receptors reduce intracellular cAMP and are found in the brain and as pre-synaptic receptors. Receptor Drug

Medical Chemistry Drugs Acting On Autonomic Nervous System Dopamine receptor stimulation

Indirect Acting Sympathomimetics

Indirect-acting sympathomimetic agents produce effects, primarily by causing the release of NE (e.g., amphetamine) from adrenergic nerve terminals and preventing its re-uptake (e.g., cocaine and tricyclic antidepressants). The NE that is released by the indirect-acting agent activates the receptors to produce the response.

Mixed-acting Sympathomimetics

Mixed-acting drugs employ both mechanisms i.e., direct and indirect (e.g., ephedrine, metaraminol). They bind directly with adrenergic receptors and cause the release of NE. Ephedrine is used to treat nasal congestion.

Mechanisms For Activation Of Adrenergic Receptor

Drugs can activate adrenergic receptors by four basic mechanisms:

  • Direct Receptor Binding: Direct interaction with receptors is the most common mechanism by which drugs activate peripheral adrenergic receptors. The direct-acting receptor stimulants produce their effects by binding to adrenergic receptors and mimicking the actions of natural transmitters (norepinephrine, epinephrine, and dopamine).
  • Promotion of Norepinephrine Release: By acting on terminals of sympathetic nerves to cause norepinephrine release, drugs can bring about activation of adrenergic receptors.
    Example: Amphetamines and ephedrine.
  • Inhibition of Norepinephrine Reuptake: Recall that reuptake of norepinephrine into terminals of sympathetic nerves is the major mechanism by which adrenergic transmission is terminated. By blocking norepinephrine reuptake, drugs can cause norepinephrine to accumulate within the synaptic gap, and can thereby increase receptor activation.
    Example: Cocaine and tricyclic antidepressants (imipramine).
  • Inhibition of Norepinephrine Inactivation: Some of the norepinephrine in terminals of adrenergic neurons is subject to inactivation by monoamine oxidase (MAO). Hence, drugs that inhibit MAO can increase the amount of NE available for release, and can thereby enhance receptor activation.

Direct Acting Sympathomimetics

Structure-Activity Relationship:

  • The sympathomimetic drugs may be divided into catechol and non-catechol amines.
  • All catecholamines possess the catechol nucleus (o-dihydroxybenzene). Catechol-amines have only a brief duration of action, and are ineffective orally, due to degradation by COMT.

Medical Chemistry Drugs Acting On Autonomic Nervous System Catechol

Non-catecholamines consist of a benzene ring and an ethylamine side chain (i.e. B-phenylethylamine). Substitution on the meta and para positions of the aromatic ring and, on a and B-positions of the ethylamine side chain influences not only the mechanism of sympathomimetic action but also the receptor selectivity of the drug.

Medical Chemistry Drugs Acting On Autonomic Nervous System Phenylethylamine

Substitution on the aromatic nucleus, specifically -OH groups at the 3 (meta) and 4 (para) positions of the ring and a B-OH group are required for maximal a and B activity.

Examples: Adrenaline And Noradrenaline.

Medical Chemistry Drugs Acting On Autonomic Nervous System Adrenaline

B-hydroxyl (B-OH) Group:

  • Due to chirality, they exhibit high stereo selectivity in producing their agonistic effect. The more potent enantiomer i.e. R-configuration is 100 times more potent than S-configuration.
  • All direct-acting B-phenylethylamine-derived agonists have the arrangement in space of the catechol group, the amino group, and the B-OH group in the fashion resembling that of R-norepinephrine stereo selectively acts as three critical pharmacophoric groups which bind with three complementary binding areas on the receptor and called as Easson-Stedman Hypothesis (Three point attachment theory).

Medical Chemistry Drugs Acting On Autonomic Nervous System Beta hydroxyl group

Amino (-NH2) Group:

  • The presence of the amino group in phenylethylamines is important for direct agonist activity.
  • The amino group should be separated from the aromatic ring by two carbon atoms for optimal activity.
  • Both primary and secondary amines are found among the potent direct-acting agonists, but tertiary or quaternary amines tend to be poor direct agonists.
  • Substitution of the bulkier group at the nitrogen decreases a-receptor agonist activity and increases B-receptor activity. Thus, norepinephrine is an effective ẞ-receptor agonist as well as a potent a-receptor agonist, while epinephrine is a potent a, ẞ1 and B2-receptor agonist. Isoproterenol is a potent and ẞ2-receptor agonist, but has little affinity for a-receptors.

Example: Isoproterenol

Medical Chemistry Drugs Acting On Autonomic Nervous System Isoproterenol

Large substituents on the amino group also protect the amino group front undergoing oxidative deamination by MAO as well as increase ẞ2 selectivity.

Examples: N-tert-butyl norepinephrine (Colterol)

Medical Chemistry Drugs Acting On Autonomic Nervous System N-tert-Butylnorepinephrine

α-Carbon Atom:

  • Substitution of CH3 or C2Hs at a-carbon atom reduces direct receptor agonist activity at both a and ẞ receptors.
  • a-alkyl group increases the duration of action by making the compound resistant to metabolic deamination by MAO. It also increases oral effectiveness and greater CNS activity.
  • Another effect of a-substitution is the introduction of a chiral center i.e. a-methyl norepinephrine, is the erythro isomer that possesses significant activity at a-receptor.

Catechol Moiety:

  • Catechol moiety is important for maximal agonist activity. It can be replaced with other substituted phenyl moieties to provide selective adrenergic agonist activity. This approach can be used in the design of selective ẞ2-receptor agonists.
  • Replacement of the meta-OH of the catechol structure with a hydroxymethyl group shows B2 selectivity.

Examples: Albuterol (Salbutamol)

Medical Chemistry Drugs Acting On Autonomic Nervous System Albuterol

Hydroxyl (-OH) groups at the 3 and 5 positions of the aromatic ring (Resorcinol ring), in compounds with large amino substituents, show ẞ2 selective activity. As the resorcinol ring is not a substrate for COMT, it tends to have better absorption and longer duration of action.

Examples: Metaproterenol, Terbutaline

Medical Chemistry Drugs Acting On Autonomic Nervous System Metaproterenol

Modification at the catechol ring can also bring about a-selectivity at receptors. Removal of the p-OH group from epinephrine gives phenylephrine, which, in contrast to epinephrine, is selective for the a-adrenergic receptor with B-activity almost entirely absent.

Examples: Phenylephrine

Medical Chemistry Drugs Acting On Autonomic Nervous System Phenylephrine

Optical isomerism is conferred by substitution on either of the ethyl carbon atoms.

Laevorotatory: Substitution at the B-carbon atom produces naturally occurring epinephrine and norepinephrine, both of which are over 10 times as potent as their isomers.

Dextrorotatory: Substitution at the a-carbon atom generally confers greater potency in CNS stimulation, e.g. d-amphetamine.

Medical Chemistry Drugs Acting On Autonomic Nervous System Amphetamine

  • Agents lacking -OH substitution, especially the compounds with 3-OH, are resistant to COMT and have a longer duration of action and oral effectiveness.
  • Lacking of both, aromatic -OH groups and the B-OH on the ethyl chain produce almost all of their effects by NE release, thus their effects are mainly on a and ẞ1.

Examples: Ephedrine

Medical Chemistry Drugs Acting On Autonomic Nervous System Ephedrine

Substitution on the B-C atom generally decreases central stimulant action, due to the lower lipid solubility of these agents. However, this also greatly enhances both a and ẞ potency. Thus, ephedrine is less potent than methamphetamine as a CNS stimulant but is more potent vasoconstrictor and bronchodilator.

Medical Chemistry Drugs Acting On Autonomic Nervous System Methamphetamine

Absence of the benzene ring reduces the CNS stimulant action, without reducing peripheral effects. e.g. Cyclopentamine, and many of these agents are used as nasal decongestants.

Medical Chemistry Drugs Acting On Autonomic Nervous System Cyclopentamine

Endogenous Catecholamines

Adrenaline (Epinephrine)

Medical Chemistry Drugs Acting On Autonomic Nervous System Adrenaline 1

  • Adrenaline is chemically 1-(3,4-dihydroxyphenyl)-2-methylaminoethanol and available as adrenaline acid tartarate.
  • Adrenaline is a potent stimulator of both a and ẞ receptors.
  • It is light sensitive and easily oxidized on exposure to air because of the catechol ring system and turns to brown colour.
  • It is ineffective by the oral route because of poor absorption and rapid metabolism by MAO and COMT.
  • Adrenaline is rapidly inactivated in the body, despite its stability in blood.
  • It shows prominent actions on the heart and vascular smooth muscle.
  • Adrenaline is one of the most potent vasopressors known, given by IV route, it evokes a characteristic rise in blood pressure.
  • Increase in blood pressure is due to direct myocardial stimulation (positive inotropic effect), an increased heart rate (positive chronotropic effect) and peripheral vasoconstriction.

Adrenaline Uses:

  • As it activates ẞ1 receptors, epinephrine is used to overcome AV heart block and restore cardiac function in patients experiencing cardiac arrest.
  • Activation of ẞ2 receptors in the lung promotes bronchodilation, which can be useful in patients with asthma.
  • Used to prevent bleeding during surgery or in the case of inner organ bleeding.
  • It can cause. α-mediated vasoconstriction; it is administered in combination with local anaesthetics which leads to longer lasting effect of local anaesthetics in smaller doses.
  • Used in the treatment of open-angle glaucoma, where it apparently reduces intraocular pressure increasing the rate of outflow of aqueous humour from its anterior chamber of the eye.
  • Used to produce mydriasis during ophthalmologic procedures.
  • It activates a combination of a and ẞ receptors, epinephrine used as treatment of choice for anaphylactic shock.

Noradrenaline (Norepinephrine):

Medical Chemistry Drugs Acting On Autonomic Nervous System Noradrenaline

  • Noradrenaline is chemically 1-(3,4-dihydroxyphenyl) amino ethanol, available as acid tartarate salt.
  • Both adrenaline and noradrenaline are approximately equipotent at cardiac ẞ1 receptors. Noradrenaline is a potent agonist for a-receptors but has little action on B2 receptors.
  • Noradrenaline should be protected from air and light as it darkens on exposure to air and light.
  • Like the other. endogenous catecholamines, it is a substrate for both MAO and COMT and thus is not effective by the oral route of administration. It is given by intravenous injection.
  • Levo-isomer is pharmacologically active.

Noradrenaline Uses:

  • Noradrenaline is used to maintain blood pressure in acute hypotensive states resulting from surgical or non-surgical trauma, central vasomotor depression and haemorrhage.

Dopamine:

Medical Chemistry Drugs Acting On Autonomic Nervous System Dopamine

  • Dopamine is chemically 3,4-dihydroxyphenylethylamine, is a central neurotransmitter. It differs from the other naturally occurring catecholamines, lacking the B-OH group on the ethylamine side chain.
  • It is the metabolic precursor of noradrenaline and adrenaline..
  • It is a substrate for both MAO and COMT and is thus ineffective orally.
  • As it cannot cross blood brain barrier, it has minimal effects on the CNS.
  • It stimulates ẞ1-receptors of heart and exerts a positive inotropic effect on the heart.
  • It increases blood flow to the kidney in doses that have no chronotropic effect on the heart or that cause no increase in blood pressure.

Dopamine Uses:

  • Dopamine is used in acute congestive cardiac failure with imminent renal failure, septic shock, cardiogenic shock, surgical shock and acute pancreatitis.

α-adrenergic Receptor Agonists

Phenylephrine:

Medical Chemistry Drugs Acting On Autonomic Nervous System Phenylephrine

  • Phenylephrine is chemically 1-(3-hydroxyphenyl)-2-methylaminoethanol and available as hydrochloride salt.
  • It should be stored in airtight container to protect from light because it is decomposed by light.
  • Phenylephrine differs from adrenaline only by lacking the 4-OH group on the benzene ring and subsequently is resistant to COMT and has predominantly α-agonist effects.
  • It gets metabolized by MAO.
  • Phenylephrine is a selective α1-receptor agonist.
  • Oral absorption is not reliable, and so it is given parenterally or topically as eye or nasal drops.

Phenylephrine Uses:

  • Phenylephrine is potent vasoconstrictor, but is less potent than epinephrine and norepinephrine.
  • It is used as a nasal decongestant, mydriatric and as a vasopressor agent.
  • It is used to dilate the pupil and to treat open-angle glaucoma.
  • It is used in spinal anesthesia, to prolong the anesthesia and to prevent a drop in blood pressure.
  • It is used in the treatment of severe hypotension resulting from either shock or drug administration.

Methoxamine:

Medical Chemistry Drugs Acting On Autonomic Nervous System Methoxamine

  • Methoxamine is chemically, 2-amino-1-(2,5-dimethoxyphenyl)propan-1-ol.
  • It is a selective direct acting a1-receptor agonist.
  • It is less potent than phenylephrine as a vasoconstrictor that has no stimulant action on the heart.
  • It is not substrate for COMT, its duration of action is significantly longer than that of norepinephrine.

Methoxamine Uses:

  • It is used primarily during surgery or shock to maintain adequate arterial blood- pressure.

Imidazolines:

Medical Chemistry Drugs Acting On Autonomic Nervous System Imidazole

Structure-Activity Relationship:

  • These compounds interact differently with receptors to that of B-phenylethylamine. The heterocyclic imidazoline ring is linked to a substituted aromatic moiety.
  • Modification in imidazoline ring decreases the activity.
  • Open ring imidazoline are highly active i.e. Guanabenz and Guanfacine.
  • Aromatic substitution is flexible. Agonist activity increases on substitution of aromatic ring with halogen (CI) or small alkyl group (CH3), particularly when placed at two ortho positions.
    • Naphazoline: (2-(1-naphthylmethyl)-2-imidazoline}
    • Tetrahydrozoline: 2-(1,2,3,4-tetrahydronaphthalen-1-yl)-4,5-dihydro-1H-imidazole}
    • Xylometazoline: (2-(4-tert-butyl)2, 6-dimethylbenzyl)-2-imid ‘ine}
    • Oxymetazoline: (6-tert-butyl-3-(2-imidazoline-2-ylmethyl)-2,4-dimethylphenol}

Medical Chemistry Drugs Acting On Autonomic Nervous System Imidazoline

  • These drugs are agonists at both α, and a2-adrenergic receptors.
  • Because of the basic nature of the imidazoline ring, these drugs essentially exist in an ionized form at physiological pH.

Imidazolines Uses:

  • These agents are used for their vasoconstrictive effects as nasal decongestants and ophthalmic decongestants.
    • (e) Guanabenz: (2-[(2,6-dichlorophenyl) methylideneamino] guanidine}
    • (f) Guanfacine: (2-[(2,6-dichlorophenyl) acetamido] guanidine}

Medical Chemistry Drugs Acting On Autonomic Nervous System Guanfacine

  • Structurally, these two compounds can be considered “open-ring imidazolidines.
  • 2,6-dichlorophenyl moiety is connected to a guanidino group by a two-atom bridge.
  • In guanabenz the bridge is -CH-N- group and in guanfacine the bridge is -CH2CO-group.
  • Conjugation of the guanidine moiety with the bridging moiety helps to decrease the pka, therefore because of basic group these drugs exist in their non-ionized form at physiological pH.

Imidazolines Uses:

  • Guanabenz and guanfacine are used as antihypertensive drugs.

Clonidine:

Medical Chemistry Drugs Acting On Autonomic Nervous System Clonidine

  • Clonidine is chemically, 2-(2,6-dichloroanilino)-2-imidazoline.
  • It has selective action on α2 receptor.
  • It exhibits vasoconstrictive activity by stimulation of peripheral a-adrenergic receptors.
  • It enters into the CNS and stimulates 2 receptors located in regions of the brain leads to decrease in sympathetic outflow from the CNS, which in turn, decreases in peripheral vascular resistance and blood pressure.
  • It produces bradycardia due to stimulation of cardiac a2-adrenergic receptor.

Clonidine Uses:

  • Clonidine is useful in the treatment of hypertension.

Methyldopa:

Medical Chemistry Drugs Acting On Autonomic Nervous System Methyldopa

  • Methyldopa is 3-(3,4-dihydroxyphenyl)-2-methyl-L-alanine.
  • Methyldopa is used only by oral administration since its zwitter ionic character limits its solubility.
  • a-methyl norepinephrine is the metabolic product of the drug methyldopa. It shows selectivity towards the α1 receptor.
  • a-methyl norepinephrine acts on a2 receptors in the CNS in the same manner as clonidine to decrease sympathetic outflow and to lower blood pressure.

Methyldopa Uses:

  • Methyldopa is useful in the treatment of hypertension.

α and ẞ-adrenergic Receptor Agonists

Dobutamine:

Medical Chemistry Drugs Acting On Autonomic Nervous System Dobutamine

  • Dobutamine is chemically 3,4-dihydroxy-N-[3-(4-hydroxyphenyl)-1-methylpropyl]-b- phenylethylamine.
  • Dobutamine is a synthetic catecholamine derivative.
  • Dobutamine is given by intravenous infusion since it is not effective orally.
  • Dobutamine gets metabolized by COMT and conjugation, but not by MAO.
  • Dobutamine resembles dopamine chemically but possesses a bulky aromatic residue on the amino group i.e. 1-(methyl)-3-(4-hydroxyphenyl) propyl and the absence of a B-OH group.
  • Dobutamine is a selective ẞ1 receptor agonist and has only slight indirect actions.
  • Dobutamine increases cardiac output without any effect on heart rate and blood pressure.
  • Dobutamine is a racemic mixture of two enantiomeric forms. The (+) isomer has potent B-agonistic actions. The (-) isomer has potent agonistic and poor ẞ-agonistic actions.
  • Racemic dobutamine increases the inotropic activity of the heart to a much greater extent than chronotropic activity.
  • Dobutamine does not act as an agonist at the dopaminergic receptors that mediate renal vasodilation.

Dobutamine Uses:

  • Dobutamine is used in patients with heart failure associated with myocardial infarction, open heart surgery and cardiomyopathy.

B-adrenergic Receptor Agonists

Isoproterenol:

Medical Chemistry Drugs Acting On Autonomic Nervous System Isoproterenol receptor agents

  • Isoproterenol is chemically, 4-[1-hydroxy-2-[isopropylaminoethyl]-1,2-benzenediol. It acts on both ẞ1 and B2 receptors.
  • As it contains an isopropyl substitution on the nitrogen atom, it has virtually no effect on a-receptors.
  • Isoproterenol increases cardiac output by stimulating cardiac ẞ1 receptors and can bring about bronchodilation through stimulation of B2 receptors in the respiratory tract.
  • Isoproterenol is available for use by inhalation and injection.
  • Isoproterenol is metabolized by COMT.

Isoproterenol Uses:

  • Isoproterenol is clinically used for the relief of bronchospasms associated with bronchial asthma.
  • It produces adverse effect as cardiac stimulation which leads to use it sometimes in the treatment of heart block.

Selective ẞ2-adrenergic Receptor Agonists:

  • Modification of the catechol portion of a ẞ-agonist (isoproterenol) has resulted in the development of selective ẞ2 receptor agonists.
  • Further the shift of the OH group produces resistance to MAO and prolongs the duration of action.
  • Increased ẞ2 agonist activity is also conferred by the substitution of increasing bulky lipophilic groups on the amino group of isoproterenol.
  • Because of their relative selectivity, these agents relax the smooth muscle of the bronchi, uterus and blood vessels.
  • They have far less action on the heart than Isoproterenol and other agents.

Metaproterenol:

Medical Chemistry Drugs Acting On Autonomic Nervous System Metaproterenol Receptor Agonists

  • Metaproterenol is chemically,1-(3,5-dihydroxy phenyl)-2-isopropylaminoethanol.
  • Metaproterenol is a photosensitive compound and, hence should be protected from light and air.
  • Metaproterenol is less ẞ2 selective than terbutaline.
  • Metaproterenol is not metabolized by either COMT or MAO, therefore more effective when given orally, and have a longer duration of action.

Terbutaline:

Medical Chemistry Drugs Acting On Autonomic Nervous System Terbutaline

  • Terbutaline is chemically, N-tert-butyl-N-[2-(3,5-dihydroxyphenyl)-2-hydroxy-methyl]amine or 1-(3,5-dihydroxyphenyl)-2-(tert-butyl amino) ethanol.
  • It is a non-catecholamine, therefore is resistant to COMT.

Salbutamol (Albuterol):

Medical Chemistry Drugs Acting On Autonomic Nervous System Salbutamol

  • Salbutamol is chemically, 1-(4-hydroxy-3-hydroxymethylphenyl)-2-(tert-butylamino) ethanol.
  • It is a selective ẞ2 receptor agonist whose selectivity results from the replacement of the meta-hydroxyl group of the catechol ring with a hydroxyl methyl moiety.
  • It is not metabolized by either COMT or MAO.
  • It is active orally and they exhibit a longer duration of action.

Salbutamol Uses:

  • Metaproterenol, Terbutaline, and Salbutamol (albuterol) possess strong ẞ2 agonistic properties.
  • They are used in the treatment of bronchial asthma.

Bitolterol:

Medical Chemistry Drugs Acting On Autonomic Nervous System Bitolterol

  • Bitolterol is a prodrug of the ẞ2 selective adrenergic agonist colterol.
  • It is chemically, [4-[2-(tert-butylamino)-1-hydroxyethyl]-2-(4-methylbenzoyl)-oxyphenyl] 4-methylbenzoate.
  • The presence of the two p-toluic acid esters in bitolterol makes it considerably more lipophilic than colterol.
  • It is. hydrolyzed by esterases in the lung and other tissues to produce the active agent, colterol.
  • It has a longer duration of action and is metabolized by COMT and conjugation after hydrolysis of the esters.

Bitolterol Uses:

  • Bitolterol is administered by inhalation for bronchial asthma and reversible bronchospasm.

Selective ẞ3 adrenergic receptor agonists

Selective ẞ3 receptor agonists have been developed, but not approved for therapeutic use. B3 receptor stimulation promotes lipolysis. These agents act as anti-obesity drugs and are used for the treatment of non-insulin-dependent diabetes.

Indirect Acting Sympathomimetics

Indirect-acting sympathomimetics act by releasing endogenous NE. They enter the nerve endings by way of the active uptake process and displace NE from its storage granules. This class is comprised of non-catecholamines.

These compounds are resistant to COMT and MAO enzymes due to the lack of phenolic hydroxyl groups and the presence of a-methyl groups. These compounds pass more readily through blood blood-brain barrier because of increased lipophilicity.

Medical Chemistry Drugs Acting On Autonomic Nervous System Heterocyclic ring

Structure-Activity Relationship:

  • Most of these drugs retain phenyl ethylamine skeleton.
  • The presence of a B-OH group decreases, and an α-CH3 group increases the effectiveness of indirect-acting agents.
  • The presence of nitrogen substituents decreases indirect activity,
  • Substituent larger than the methyl group at nitrogen renders the compound virtually inactive.
  • Tertiary amino group substitution is ineffective as an NE-releasing agent.

Amphetamine:

Medical Chemistry Drugs Acting On Autonomic Nervous System Amphetamine synpathomimetics

  • Amphetamine is chemically, 1-phenylpropan-2-amine.
  • It is one of the most potent sympathomimetic.
  • It is an indirect-acting sympathomimetic amine and its action depends on the release of norepinephrine from adrenergic nerves.
  • CNS stimulant effects are thought to be due to stimulation of the cortex.
  • The d-isomer of amphetamine is 3-4 times more potent than the I-isomer.

Amphetamine Uses:

  • Amphetamine causes increased wakefulness, elevated mood, increased initiative, self- confidence and ability to concentrate.
  • It has an anorexic action and can be used in the treatment of obesity.

Hydroxyamphetamine:

Medical Chemistry Drugs Acting On Autonomic Nervous System Hydroxyamphetamine

  • Hydroxyamphetamine is chemically, 4-(2-aminopropyl)phenol or 1-(4-hydroxy- phenyl)-propan-2-amine.
  • It possesses a-receptor stimulant activity, but lacks CNS activity.
  • It is a powerful vasoconstrictor.

Hydroxyamphetamine Uses:

  • Hydroxyamphetamine is used as an anorexiant in the treatment of obesity.
  • It is used to dilate the pupil for diagnostic eye examinations and for surgical procedures on the eye.
  • It is used sometimes with cholinergic blocking drugs like atropine to produce a mydriatic effect.
  • It is used in hyperkinetic syndrome in children.
  • It is used in narcolepsy (sudden attack of sleep in completely inappropriate situations).

Pseudoephedrine:

Medical Chemistry Drugs Acting On Autonomic Nervous System Pseudoephedrine

  • L-(+)-Pseudoephedrine is chemically, (15,25)-2-(methylamino)-1-phenylpropan-1-ol. It is the (S,S) diastereoisomer of ephedrine in which B-OH group is having S-configuration.
  • It is a naturally occurring alkaloid from the Ephedra species.
  • Ephedrine has a mixed mechanism of action whereas pseudoephedrine acts predominantly by an indirect mechanism.

Pseudoephedrine Uses:

  • Pseudoephedrine is used as a nasal decongestant and in the treatment of cold.
  • Pseudoephedrine can also be used in the treatment of hypertension.

Propylhexedrine:

Medical Chemistry Drugs Acting On Autonomic Nervous System Propylhexedrine

  • Propylhexedrine is an analogue of amphetamine in which the aromatic ring has been replaced with a cyclohexane ring.
  • It is chemically, 1-cyclohexyl-2-methylaminopropane.

Propylhexedrine Uses:

  • Propylhexedrine is used as nasal decongestant.
  • It has local vasoconstrictor effect on nasal mucosa in the symptomatic relief of nasal congestion caused by the common cold, allergic rhinitis or sinusitis.

Sympathomimetics With Mixed Action

These drugs act both, directly with the receptor sites and partly by the release of endogeneous norepinephrine. These agents have no -OH on the aromatic ring, but do have 6-OH group.

Ephedrine:

Medical Chemistry Drugs Acting On Autonomic Nervous System Ephedrine Mixed Action

  • Ephedrine is chemically, (1R, 25)-2-(methylamino)-1-phenylpropan-1-ol.
  • It occurs naturally in many plants, being the principal alkaloid obtained from various species of Ephedra.
  • Ma Huang, the plant containing ephedrine, has been used in China for over 2000 years.
  • It contains two asymmetric carbon atoms, thus there are four optically active forms. The erythro racemate is called as ephedrine, whereas threo racemate is known as pseudoephedrine.
  • Among four compounds available, D(-) isomer is clinically most active.
  • It has agonist activity at both a. and B-receptors.
  • Ephedrine decomposes gradually and darkens when exposed to light.
  • It is not metabolized by either MAO or COMT.

Ephedrine Uses:

  • The pharmacological activity of ephedrine resembles with epinephrine. Ephedrine differs from adrenaline mainly by its
    • effectiveness after oral administration,
    • longer duration of action,
    • more pronounced central actions,
    • much lower potency.
  • It produces a sharp rise in systolic, diastolic and pulse pressures, with a reflex bradycardia, similar to adrenaline, but lasting for 10 times as long.
  • Ephedrine is mainly used as a bronchodilator in asthma.
  • It is used to treat narcolepsy and depressive state.
  • It is also used as nasal decongestant, mydriatic and in certain allergic disorders. • It is also used to treat hay fever and urticaria.

Phenylpropanolamine:

Medical Chemistry Drugs Acting On Autonomic Nervous System Phenylpropanolamine

  • Phenylpropanolamine is similar in structure to ephedrine except that, it possesses primary amine instead of a secondary amine.
  • It is chemically, (1S 2R)-2-amino-1-phenyl propan-1-ol.
  • This structural difference makes Phenylpropanolamine to slightly higher vassopressive and lower central stimulatory action than ephedrine.

Phenylpropanolamine Uses:

  • Phenylpropanolamine is used as nasal decongestant with prolonged action than that of ephedrine.
  • Earlier it was used as appetite suppressant and also used in the treatment of cough and cold. But because of increased risk of hemorrhagic stroke in young women, FDA recommended its removal from such medication.

Metaraminol:

Medical Chemistry Drugs Acting On Autonomic Nervous System Metaraminol

  • Metaraminol is chemically, 3-[(1R,25)-2-amino-1-hydroxypropyl]phenol.
  • It is an isomer of phenylephrine.
  • It possesses a mixed mechanism of action.
  • It’s direct-acting effects mainly on a-adrenergic receptor.

Metaraminol Uses:

  • Metaraminol is used for its vasopressor action for maintaining blood pressure during spinal anesthesia and hemorrhage.
  • It has also been used to treat severe hypotension brought on by other traumas that induce shock.

Adrenergic Receptor Antagonists

Adrenergic receptor antagonists are also called as adrenergic blocking agents or adrenergic receptor blockers or sympatholytic agents.

α-Adrenergic Receptor Antagonists

Drugs that attach to a-adrenergic receptors and block the effect of norepinephrine and epinephrine are categorized as a- adrenergic antagonists.

These drugs consist of a number of compounds of diverse chemical structure that bear little obvious resemblance to the a-adrenergic receptor agonist. a-adrenergic receptor antagonists may be non-selective or selective for α1 receptor.

Non-selective a-adrenergic receptor antagonists block both a1 and α2 adrenergic receptors resulting in reducing blood pressure as a major cardiovascular effect.

Generally, a-adrenergic receptor antagonists are useful in the management of hypertension, prostatic hypertrophy (prostate enlargement) and heart failure.

Non-selective a-Receptor Antagonists:

Reversible a-Receptor Antagonists:

Example: Tolazoline and Phentolamine

Medical Chemistry Drugs Acting On Autonomic Nervous System Tolazoline

  • Tolazoline and phentolamine are imidazoline a-antagonists that also have antihypertensive activity.
  • They have structural similarities to the imidazoline α-agonists, such as naphazoline and xylometazoline, but does not have the lipophilic substituents required for agonist activity.
  • They are potent non-selective competitive (reversible) a-adrenergic receptor antagonists.
  • They have both α1- and a2- antagonistic activity and produce tachycardia.
  • Tolazoline is chemically, 2-benzyl-4,5-dihydro-1H-imidazole.
  • Tolazoline is relatively weak a-antagonist, its histamine like and acetylcholine like action contributes to its vasodilatory activity.
  • Tolazoline stimulates stimulation of gastric acid secretion, render its use in patients who have gastric or peptic ulcer.
  • Phentolamine is chemically, 3-[N-(4,5-dihydro-1H-imidazol-2-ylmethyl)-4- methylanilino] phenol.
  • Phentolamine is the more effective a-antagonist. The vasodilatory effect of phentolamine is used in the management of hypertension.

Reversible a-Receptor Antagonists Uses:

  • Tolazoline is a vasodilator that is used to treat spasms of peripheral blood vessels.
  • Tolazoline is used in treatment of persistent pulmonary hypertension of the newborn. Tolazoline is used to treat Raynaud’s syndrome and other conditions involving peripheral vasospasm.
  • Tolazoline is also used to treat thrombophlebitis.
  • Phentolamine is used to prevent or control hypertensive episodes that occur in patients with pheochromocytoma.
  • Phentolamine can be used as an aid in the diagnosis of pheochromocytoma (Tumor of the adrenal medulla).
  • Phentolamine is used in combination with papaverine to treat impotence.

Irreversible a-Receptor Antagonists:

Example: Phenoxybenzamine

Medical Chemistry Drugs Acting On Autonomic Nervous System Phenoxybenzamine

  • Phenoxybenzamine is chemically, N-benzyl-N-(2-chloroethyl)-1-phenoxypropan-2-amine.
  • It is non-competitive, non-selective and irreversible a-adrenergic receptor antagonist. It is a B-haloalkylamine that alkylates a-receptors.
  • It is non-selectively and irreversibly blocks the postsynaptic a-adrenergic receptor in smooth muscle, leading to a muscle relaxation and a widening of the blood vessels.
  • It has small onset of action, but long duration of action which may last for 3-4 days.
  • As phenoxybenzamine forms covalent bonds with the receptors is irreversible, new receptors must be synthesized before the effects can be overcome, therefore, the a-receptor blocking action is long-lasting.

Irreversible a-Receptor Antagonists Uses:

  • Phenoxybenzamine is used to treat hypertension and as a peripheral vasodilator.
  • It is used in alleviating the sympathetic effects of pheochromocytoma.

Selective α-receptor Antagonists:

Example: Prazosin, Terazosin, Doxazosin

Medical Chemistry Drugs Acting On Autonomic Nervous System Prazosin

  • These agents contain quinazoline ring, the piperazine ring, and the acyl moiety.
  • The 4-amino group on the quinazoline ring is very important for α-rcceptor affinity. Replacement of piperazine ring with other heterocyclic ring like piperidine does not lose the activity.
  • The pharmacokinetic activity of these agents is significantly affected by nature of acyl group.
  • These drugs produce peripheral vasodilation without an increase in heart rate or cardiac output.
  • Prazosin is chemically, [4-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperazin-1-yl]- (furan-2-yl)methanone.
  • Terazosin is chemically, [4-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperazin-1-yl]- (oxolan-2-yl)methanone.
  • Doxazosin is chemically, [4-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperazin-1-yl]- (2,3-dihydro-1,4-benzodioxin-3-yl)methanone.
  • They are selective adrenergic α- antagonist.

Selective α-receptor Antagonists Uses:

  • Prazosin is used in the treatment of heart failure; hypertension; pheochromocytoma; Raynaud’s syndrome; prostatic hypertrophy and urinary retention.
  • Terazosin is used for treatment of symptoms of an enlarged prostate. It also acts to lower the blood pressure, and is therefore a drug of choice for men with hypertension and prostate enlargement.
  • Doxazosin is used to treat high blood pressure and urinary retention associated with prostate enlargement.

Selective α2-receptor Antagonists:

Example: Yohimbine

Medical Chemistry Drugs Acting On Autonomic Nervous System Yohimbine

  • Yohimbine, an indole alkaloid is isolated from Pausinystalia yohimbe bark and Rauwolfia roots.
  • It is an α2-antagonist with greater selectivity for a2- than for α1-adrenoceptors.
  • It is also used as a serotonin antagonist.
  • It has actions both in the CNS and in the periphery, inducing hypertension and increase in heart rate.

Selective α2-receptor Antagonists Uses:

  • Yohimbine is used to treat male erectile impotence and postural hypotension.
  • It increases heart rate and blood pressure as a result of its blockade of a2-receptors in the CNS.
  • It is also used in research to induce anxiety.

Other α-receptor antagonists:

Dihydroergotamine:

Medical Chemistry Drugs Acting On Autonomic Nervous System Dihydroergotamine

  • Dihydroergotamine is an ergot derivative with agonistic activity for alpha- adrenergic, serotonergic, and dopaminergic receptors.
  • It acts by stimulating the 5-HT1D receptor subtype and causes constriction of cerebral blood vessels.
  • It is administered as a nasal spray or injection. Nausea is a common side effect.

Dihydroergotamine Uses:

  • Dihydroergotamine is used to treat migraine headaches and cluster headaches.

Methysergide:

Medical Chemistry Drugs Acting On Autonomic Nervous System Methysergide

  • Methysergide is an ergot derivative.
  • It is chemically, (6aR,9R)-N-[(2S)-1-hydroxybutan-2-yl]-4,7-dimethyl-6,6a,8,9- tetrahydro-indolo[4,3-fg]quinoline-9-carboxamide.
  • It antagonizes the effects of serotonin in blood vessels and gastrointestinal smooth muscle.

Methysergide Uses:

  • Methysergide is used prophylactically in migraine and other vascular headaches.

B-Adrenergic Receptor Antagonists

B-adrenergic receptor antagonists are drugs that attach to B-adrenergic receptors and block the effect of agonists (e.g. Norepinephrine and epinephrine) at those B-receptor sites. B-antagonists are classified as non-selective and cardioselective.

Non-selective ẞ- antagonist blocks both B1 and B2-receptors; whereas cardio-selective ẞ-antagonist preferentially blocks B1-receptors and decreases heart rate and myocardial contraction. ẞ2-receptor antagonistic effects include inhibition of vascular dilation and inhibition of bronchodilation.

B-adrenergic receptor antagonists are useful in the management of hypertension, arrhythmia, ischemic heart disease, chronic open-angle glaucoma, migraine, and thyrotoxicosis. It is also useful in the management of chronic but not acute heart failure.

The common side effects of B-adrenergic receptor antagonists are bradycardia, bronchospasm, fatigue, sleep disturbance, impotence in men, and attenuated responses to hypoglycemia. Non-selective ẞ-antagonists are generally avoided in patients with asthma, as it may lead to progressive heart block, bronchoconstriction, and heart failure.

Sudden discontinuation of ẞ-antagonist may result in “rebound” increases in heart rate and blood pressure, which may lead to myocardial ischemia, infarction, or sudden death in susceptible individuals, therefore for termination of ẞ-antagonist therapy gradual reduction of the dose is recommended.

Structure-Activity Relationships:

  • Structural modification by replacing the aromatic hydroxyl groups of Isoproterenol by chlorines leads to the formation of dichloro isoproterenol, which is a ẞ-antagonist that blocks the effects of sympathomimetic amines on bronchodilation, uterine relaxation, and heart stimulation.

Medical Chemistry Drugs Acting On Autonomic Nervous System Dichlorolsoproterenol

  • Dichloroisoproterenol is a partial agonist, it has no clinical utility, therefore it is not used as a clinically useful drug.
  • Pronethalol, 3,4-dichloro substitutes with a carbon bridge to form a naphthyl-ethanolamine derivative which is a clinically useful drug. It has less intrinsic sympathomimetic activity than dichloro isoproterenol, but it was withdrawn from clinical testing because of tumor induction in animal tests.

Medical Chemistry Drugs Acting On Autonomic Nervous System Pronethalol

  • Introduction of an oxymethylene bridge, (-OCH2-) between the aromatic ring and the ethylamino side chain and changing the side chain from C2 to C position of the naphthyl group of pronethalol (arylethanolamines) increases the B-blocker activity, i.e. propranolol (an aryloxypropanolamine).

Medical Chemistry Drugs Acting On Autonomic Nervous System Propranolol

  • Oxymethylene bridge (-OCH2-) is responsible for the antagonistic properties of the molecules which depend on the nature of the aromatic ring and its substituents.
  • Lengthening the side chain would prevent the appropriate binding of the required functional groups to the same receptor site.
  • The nature of the aromatic ring is also a determinant in the ẞ1-selectivity of the antagonists.
  • Substitution of sufficient size on the para and absence at the meta position of an aromatic ring is a common structural feature of cardio-selective antagonist (B) i.e., practolol.

Medical Chemistry Drugs Acting On Autonomic Nervous System Practolol

  • Bulky aliphatic groups, such as the tert-butyl and isopropyl groups are essential for B-receptor antagonist activity.
  • Secondary amine is essential for optimal activity. N, N-disubstituted compounds are inactive.
  • B-blocking agent exhibits its effect based on stereoselectivity.
  • The -OH-bearing C-atom possesses S-configuration for optimal activity to ẞ-receptor. The enantiomer with the R-configuration is typically 100 times less potent.
  • Although most of the B-antagonistic activity resides in one enantiomer, propranolol, and most other B-blockers are used clinically as racemic mixtures. The only exceptions are levobunolol, timolol, and penbutolol with which the S-enantiomer is used.

Non-Selective ẞ-Blockers:

Example: Propranolol

Medical Chemistry Drugs Acting On Autonomic Nervous System Propranolol

  • Propranolol is chemically, 1-naphthalen-1-yloxy-3-(propan-2-ylamino)propan-2-ol.
  • Non-Selective ẞ-Blockers is a non-selective ẞ-adrenergic receptor antagonist, which blocks both B1 and B2 receptors.
  • Non-Selective ẞ-Blockers act by blocking the B-receptor in the heart. It slows down the heart rate, reduces the force of contraction, and reduces cardiac output.
  • Its antihypertensive action is due to its ability to reduce cardiac output and suppress renin release from the kidney.
  • Non-selective ẞ-Blockers is contraindicated in the presence of conditions such as asthma and bronchitis.
  • Its receptor blocking action can be reversed with a sufficient quantity of B-agonist.
  • Non-selective ẞ-Blockers is well absorbed after oral administration, but undergo extensive first-pass metabolism before it reach the systemic circulation.

Non-Selective ẞ-Blockers Uses:

  • Propranolol is used in the treatment of hypertension, cardiac arrhythmias, angina pectoris, myocardial infarction, hypertrophic cardiomyopathy, pheochromocytoma, and migraine prophylaxis.
  • Non-Selective ẞ-Blockers have high lipophilicity and the ability to penetrate the CNS and found to be useful in treating diseases of the CNS, such as anxiety.
  • Non-Selective ẞ-Blockers is under investigation for the treatment of schizophrenia, alcohol withdrawal syndrome, and aggressive behavior.

Other Non-selective ẞ-blockers:

Several other nonselective ẞ-blockers, such as pindolol, nadolol, penbutolol, carteolol, timolol, levobunolol, sotalol, and metipranolol are found to be clinically useful agents.

Medical Chemistry Drugs Acting On Autonomic Nervous System Metipranolol

These drugs are chemically,

  • Pindolol: 1-(1H-indol-4-yloxy)-3-(propan-2-ylamino)propan-2-ol.
  • Nadolol: (2R,3S)-5-(3-(tert-butylamino)-2-hydroxypropoxy]-1,2,3,4-tetrahydro naphthalene-2,3-diol.
  • Penbutolol: (25)-1-(tert-butylamino)-3-(2-cyclopentylphenoxy)propan-2-ol.
  • Carteolol: 5-[3-(tert-butylamino)-2-hydroxypropoxy]-3,4-dihydro-1H-quinolin-2-one.
  • Timolol: (25)-1-(tert-butylamino)-3-[(4-morpholin-4-yl-1,2,5-thiadiazol-3-yl)oxy] propan-2-ol.
  • Levobunolol: 5-[(25)-3-(tert-butylamino)-2-hydroxypropoxy]-3,4-dihydro-2H-naphthalen-1-one.
  • Sotalol: N-[4-[1-hydroxy-2-(propan-2-ylamino)ethyl]phenyl]methanesulfonamide.
  • Metipranolol: [4-[2-hydroxy-3-(propan-2-ylamino)propoxy]-2,3,6-trimethylphenyl] acetate.

Other Non-selective ẞ-blockers Uses:

  • Pindolol, nadolol, penbutolol, carteolol and timolol are used to treat hypertension.
  • Nadolol is found to be useful in the long-term management of angina pectoris.
  • Timolol is used in the prophylaxis of migraine headaches and in myocardial infarction.
  • In addition to its ẞ-adrenergic blocking activity, sotalol also blocks the inward K* current which delays cardiac repolarization and leads to be a useful agent in the treatment of ventricular arrhythmias and atrial fibrillation.
  • Carteolol, timolol, levobunolol and metipranolol are used topically to treat open-angle glaucoma. This agent lowers intraocular pressure by decreasing the amount of aqueous humour fluid produced in the eye by the ciliary body.

B1-Selective Blockers:

Cardioselective ẞ-antagonist drugs have a greater affinity for the ẞ1-receptors of the heart than for B2-receptors in other tissues. These agents are useful in the treatment of cardiovascular diseases, such as hypertension. These drugs do not possess ẞ2-receptor antagonistic properties and, therefore can be used safely in patients who have bronchitis or bronchial asthma.

Because of the absence of vascular ẞ2-receptor antagonistic activity, these agents reduce the increase in peripheral resistance that sometimes occurs after the administration of non-selective ẞ-antagonists. These drugs show its ẞi-receptors blocking cardio selectivity at relatively low doses only. At normal therapeutic doses, most of the selective activity is lost.

Medical Chemistry Drugs Acting On Autonomic Nervous System Metoprolol

These drugs are chemically,

  • Acebutolol: N-[3-acetyl-4-[2-hydroxy-3-(propan-2-ylamino) propoxy]phenyl]butanamide. Atenolol: 2-[4-[2-hydroxy-3-(propan-2-ylamino)propoxy]phenyl]acetamide.
  • Betaxolol: 1-[4-[2-(cyclopropylmethoxy)ethyl]phenoxy]-3-(propan-2-ylamino) propan-2-ol.
  • Bisoprolol: 1-(propan-2-ylamino)-3-[4-(2-propan-2-yloxyethoxymethyl)phenoxy] propan-2-ol. Esmolol: Methyl 3-[4-[2-hydroxy-3-(propan-2-ylamino)propoxy]phenyl]propanoate.
  • Metoprolol: 1-[4-(2-methoxyethyl)phenoxy]-3-(propan-2-ylamino)propan-2-ol.

B1-Selective Blockers Uses:

  • All drugs except esmolol are used in the treatment of hypertension. Acebutolol and esmolol are used for treating certain cardiac arrhythmias.
  • Atenolol and metoprolol are useful in treating angina pectoris and in myocardial infarction. Atenolol has low lipid solubility and does not readily cross the blood brain barrier.
  • Betaxolol is used in the treatment of glaucoma.
  • Esmolol possesses a rapid onset of action and a very short duration of action. Its effects disappear within 20 to 30 minutes after the infusion is discontinued. Therefore it is used in controlling heart rate during surgery after operation.

Mixed α / ẞ-Adrenergic Receptor Antagonists

These drugs possess both ẞ- and a-receptor blocking within the same molecule. Labetalol and carvedilol are anti-hypertensives with α1, B1 and B2-blocking activity.

Labetalol:

Medical Chemistry Drugs Acting On Autonomic Nervous System Labetalol

  • Labetalol is chemically, 2-hydroxy-5-(1-hydroxy-2-(4-phenylbutan-2-ylamino)ethyl] benzamide.
  • It is a phenyl ethanolamine derivative that is a competitive inhibitor of both ẞ1 and B2-adrenergic receptors as well as adrenergic receptors.
  • It is a more potent ẞ-antagonist than a-antagonist.
  • It has two asymmetric carbon atoms, therefore it exists as a mixture of four isomers. The different isomers possess different a and ẞ antagonistic activities. The ẞ-blocking activity is seen only in the (1R, 1’R) isomer, whereas α-antagonistic activity is seen in the (15, 1’R) isomer.
  • It is very well absorbed and it undergoes extensive first-pass metabolism.

Labetalol Uses:

  • Labetalol is a clinically useful as an antihypertensive drug.
  • Due to its a-receptor blocking effect, it produces vasodilation and because of the B-receptor blocking effect, it prevents the reflex tachycardia usually associated with vasodilation.

Carvedilol:

Medical Chemistry Drugs Acting On Autonomic Nervous System Carvedilol

  • Carvedilol is chemically, 1-(9H-carbazol-4-yloxy)-3-[2-(2-methoxyphenoxy)-ethyl- amino] propan-2-ol.
  • It is a B-blocker that also possesses α- adrenergic receptor blocking activity.
  • Its only S-enantiomer possesses the ẞ-blocking activity, whereas both enantiomers possess α1-receptor antagonistic activity.
  • It also possesses antioxidant activity and an anti-proliferative effect on vascular smooth muscle cells.

Carvedilol Uses:

  • It is used in the treatment of hypertension and congestive cardiac failure.
  • It has neuro-protective effect and the ability to provide major cardiovascular protection.

Synthesis

Phenylephrine

Medical Chemistry Drugs Acting On Autonomic Nervous System Phenylephrine 1

Salbutamol

Medical Chemistry Drugs Acting On Autonomic Nervous System Salbutamol Synthesis

Tolazoline

Medical Chemistry Drugs Acting On Autonomic Nervous System Tolazoline Synthesis

Propranolol

Medical Chemistry Drugs Acting On Autonomic Nervous System Propranolol Synthesis

Multiple Choice Questions

Question 1. Sympathetic stimulation is mediated by:

  1. release of norepinephrine from nerve terminals
  2. activation of adrenoreceptors on postsynaptic sites
  3. release of epinephrine from the adrenal medulla
  4. all of the above

Answer. 4. all of the above

Question 2. Clonidine hydrochloride IP is:

  1. monoamine oxidase inhibitor which contains an imidazoline ring system
  2. arterial and venous vasodilator which contains an imidazoline ring system
  3. monoamine oxidase inhibitor which contains a pyrimidine ring system
  4. monoamine oxidase inhibitor which contains a phthalazine ring system

Answer. 2. arterial and venous vasodilator which contains an imidazoline ring system

Question 3. DOPA is an important natural amino acid and a precursor in the biosynthesis of

  1. Dopamine
  2. Adrenaline
  3. Nor-adrenaline
  4. Methyldopa

Answer. 3. Nor-adrenaline

Question 4. Characteristics of epinephrine include all of the following EXCEPT:

  1. It is synthesized into the adrenal medulla.
  2. It is mainly synthesized into the nerve ending.
  3. It is transported in the blood to target tissues.
  4. It directly interacts with and activates adrenoreceptors.

Answer. 2. It is mainly synthesized into the nerve ending.

Question 5. Chemically a-methyldopa is:

  1. 2-methyl-3-hydroxy-2-tyrosine
  2. 3-methyl-2-hydroxy-2-tyrosine
  3. 6-methyl-4-hydroxy-2-tyrosine
  4. 3-hydroxy-a-methyl-2-tyrosine

Answer. 4. 3-hydroxy-a-methyl-2-tyrosine

Question 6. Which of the following sympathomimetics acts indirectly?

  1. Epinephrine
  2. Norepinephrine
  3. Ephedrine
  4. Methoxamine

Answer. 3. Ephedrine

Question 7. The raw material for the synthesis of Propranolol is

  1. a-Naphthylamine
  2. B-Naphthol
  3. α-Naphthol
  4. a-Naphtholdehyde

Answer. 3. α-Naphthol

Question 8. Indirect action includes all of the following properties EXCEPT:

  1. Displacement of stored catecholamines from the adrenergic nerve ending.
  2. Inhibition of reuptake of catecholamines already released.
  3. Interaction with adrenoreceptors.
  4. Inhibition of the metabolism of endogenous catecholamines from peripheral adrenergic neurons.

Answer. 3. Interaction with adrenoreceptors.

Question 9. Tyrosine is a p-hydroxy derivative of phenylalanine. It loses carbon dioxide on heating with formation of:

  1. Dopamine
  2. 2-p-Hydroxypropionic acid
  3. 2-p-Hydroxy benzoic acid
  4. 2-p-Hydroxyphenylethylamine

Answer. 4. 2-p-Hydroxyphenylethylamine

Question 10. Catecholamine includes the following EXCEPT:

  1. Ephedrine
  2. Epinephrine
  3. Isoproterenol
  4. Norepinephrine

Answer. 1. Ephedrine

Question 11. Identify the biologically active isomer of adrenaline:

  1. R (+) enatiomer
  2. R (-) enatiomer
  3. S (+) enatiomer
  4. S (-) enatiomer

Answer. 2. R (-) enatiomer

Question 12. Epinephrine decreases intracellular cAMP levels by acting on:

  1. a receptor
  2. a2 receptor
  3. B1 receptor
  4. B2 receptor

Answer. 2. a2 receptor

Question 13. IUPAC name of terbutaline is:

  1. 5-[2-[(1,1-dimethyl ethyl)amino]-1-hydroxy ethyl]-1,3-benzenediol
  2. 5-[2-[(2,2-dimethyl ethyl)amino]-1-hydroxy ethyl]-1,3-benzenediol
  3. 5-[3-[(1,1-dimethyl ethyl)amino]-1-hydroxy ethyl]-1,3-benzenediol
  4. None of above

Answer. 1. 5-[2-[(1,1-dimethyl ethyl)amino]-1-hydroxy ethyl]-1,3-benzenediol

Question 14. Direct effects on the heart are determined largely by:

  1. α1 receptor
  2. a2 receptor
  3. B1 receptor
  4. B2 receptor

Answer. 3. B1 receptor

Question 15. Which isomer of the Propranolol is more active?

  1. Dextro isomer
  2. Levo isomer
  3. Meso isomer
  4. Racemic isomer

Answer. 1. Dextro isomer

Question 16. Which of the following effects is related to direct ẞ1-adrenoreceptor stimulation?

  1. Bronchodilation
  2. Vasodilation
  3. Tachycardia
  4. Bradycardia

Answer. 3. Tachycardia

Question 17. The aromatic nucleus present in Propranolol is

  1. Benzene
  2. Naphthalene
  3. Anthracene
  4. Pyridine

Answer. 2. Naphthalene

Question 18. The most appropriate starting material for propranolol is

  1. a-naphthol, epichlorohydrin, and isopropyl amine
  2. B-naphthol, epichlorohydrin, and isopropyl amine
  3. a-naphthol, epichlorhydrine and butyl amine
  4. a-naphthol, epichlorohydrin and dimethyl amine

Answer. 1. a-naphthol, epichlorohydrin and isopropyl amine

Question 19. Distribution of a-adrenoreceptor subtypes is associated with all of the following tissues except those of:

  1. Heart
  2. Blood vessels
  3. Prostate
  4. Pupillary dilator muscle

Answer. 1. Heart

Question 20. B-adrenoreceptor subtypes are contained in all of the following tissues EXCEPT:

  1. Bronchial muscles
  2. Heart
  3. Pupillary dilator muscle
  4. Fat cells

Answer. 3. Pupillary dilator muscle

Question 21. In which of the following tissues both a and ẞ1 adrenergic stimulation produce the same effect?

  1. Blood vessels
  2. Intestine
  3. Uterus
  4. Bronchial muscles

Answer. 1. Blood vessels

Question 22. The effects of sympathomimetics on blood pressure are associated with their effects on:

  1. The heart rate
  2. The peripheral resistance
  3. The cardiac output
  4. All of the above

Answer. 4. All of the above

Question 23. A relatively pure a-agonist causes all of the following effects EXCEPT:

  1. Increase in peripheral arterial resistance
  2. Increase in venous return
  3. Has no effect on blood vessels
  4. Reflex bradycardia

Answer. 3. Has no effect on blood vessels

Question 24. A non-selective ẞ-receptor agonist causes all of the following effects EXCEPT:

  1. Increase in cardiac output
  2. Increase in peripheral arterial resistance
  3. Decrease in peripheral arterial resistance
  4. Decrease in mean pressure

Answer. 2. Increase in peripheral arterial resistance

Question 25. Which of the following statements is not correct?

  1. a-agonists cause miosis.
  2. a-agonists cause mydriasis.
  3. B-antagonists decrease the production of aqueous humor.
  4. a-agonists increase the outflow of aqueous humor from the eye.

Answer. 1. a-agonists cause miosis.

Question 26. A bronchial smooth muscle contains:

  1. a1-receptor
  2. α2-receptor
  3. B1-receptor
  4. B2-receptor

Answer. 4. B2-receptor

Question 27. All of the following agents are ẞ-receptor agonists EXCEPT:

  1. Epinephrine
  2. Isoproterenol
  3. oxymetazoline
  4. Dobutamine

Answer. 3. oxymetazoline

Question 28. Which of the following drugs causes bronchodilation without significant cardiac stimulation?

  1. Isoproterenol
  2. Terbutaline
  3. Xylometazoline
  4. Clonidine

Answer. 2. Terbutaline

Question 29. B1-receptor stimulation includes all of the following effects EXCEPT:

  1. Increase in heart contractility
  2. Bronchodilation
  3. Tachycardia
  4. Increase in conduction velocity in the atrioventricular node

Answer. 2. Bronchodilation

Question 30. B2-receptor stimulation includes all of the following effects EXCEPT:

  1. Stimulation of renin secretion
  2. Fall of potassium concentration in plasma
  3. Relaxation of bladder, uterus
  4. Tachycardia

Answer. 1. Stimulation of renin secretion

Question 31. Hyperglycemia induced by epinephrine can be due to:

  1. Gluconeogenesis (B2)
  2. Inhibition of insulin secretion (α2)
  3. Stimulation of glycogenolysis (B2)
  4. All of the above

Answer. 4. All of the above

Question 32. Which of the following effects is associated with ẞ3-receptor stimulation?

  1. Lipolysis
  2. Decrease in platelet aggregation
  3. Bronchodilation
  4. Tachycardia

Answer. 1. Lipolysis

Question 33. Which of the following statements is not correct?

  1. Epinephrine acts on both a- and ẞ-receptors.
  2. Norepinephrine has a predominantly ẞ-action.
  3. Phenylephrine has a predominantly a-action.
  4. Isoproterenol has a predominantly ẞ-action.

Answer. 2. Norepinephrine has a predominantly ẞ-action.

Question 34. Indicate the drug, which is a direct-acting both a- and B-receptor agonist:

  1. Norepinephrine
  2. Methoxamine
  3. Isoproterenol
  4. Ephedrine

Answer. 1. Norepinephrine

Question 35. Which of the following agents is an a2-selective agonist?

  1. Norepinephrine
  2. Clonidine
  3. Ritodrine
  4. Ephedrine

Answer. 2. Clonidine

Question 36. Which of the following agents is a non-selective ẞ-receptor agonist?

  1. Norepinephrine
  2. Terbutaline
  3. Isoproterenol
  4. Dobutamine

Answer. 3. Isoproterenol

Question 37. Indicate the ẞ1-selective agonist:

  1. Isoproterenol
  2. Dobutamine
  3. Metaproterenol
  4. Epinephrine

Answer. 2. Dobutamine

Question 38. Which of the following sympathomimetics is a ẞ2-selective agonist?

  1. Terbutaline
  2. Xylometazoline
  3. Isoproterenol
  4. Dobutamine

Answer. 1. Terbutaline

Question 39. Indicate the indirect-acting sympathomimetic agent:

  1. Epinephrine
  2. Phenylephrine
  3. Ephedrine
  4. Isoproterenol

Answer. 3. Ephedrine

Question 40. Epinephrine produces all of the following effects EXCEPT:

  1. Decrease in oxygen consumption
  2. Bronchodilation
  3. Hyperglycemia
  4. Mydriasis

Answer. 1. Decrease in oxygen consumption

Question 41. Epinephrine is used in the treatment of all of the following disorders EXCEPT:

  1. Bronchospasm
  2. Anaphylactic shock
  3. Cardiac arrhythmias
  4. Open-angle glaucoma

Answer. 4. Open-angle glaucoma

Question 42. Which of the following direct-acting drugs is a relatively pure a-agonist, an effective mydriatic and decongestant and can be used to raise blood pressure?

  1. Epinephrine
  2. Norepinephrine
  3. Phenylephrine
  4. Ephedrine

Answer. 3. Phenylephrine

Question 43. Isoproterenol is:

  1. Both an a- and B-receptor agonist
  2. B1-selective agonist
  3. B2-selective agonist
  4. Non-selective ẞ-receptor agonist

Answer. 4. Non-selective ẞ-receptor agonist

Question 44. Ephedrine causes:

  1. Miosis
  2. Bronchodilation
  3. Hypotension
  4. Bradycardia

Answer. 2. Bronchodilation

Question 45. Which of the following sympathomimetics is preferable for the emergency therapy of cardiogenic shock?

  1. Ephedrine
  2. Dobutamine
  3. Isoproterenol
  4. Methoxamine

Answer. 2. Dobutamine

Question 46. Which of the following sympathomimetics is related to short-acting topical decongestant agents?

  1. Albuterol
  2. Phenylephrine
  3. Terbutaline
  4. Norepinephrine

Answer. 3. Terbutaline

Question 47. Indicate the long-acting topical decongestant agent:

  1. Epinephrine
  2. Norepinephrine
  3. Isoproterenol
  4. Xylometazoline

Answer. 4. Xylometazoline

Question 48. Which of the following topical decongestant agents is an a1-selective agonist?

  1. Phenylephrine
  2. Clonidine
  3. Ephedrine
  4. Epinephrine

Answer. 1. Phenylephrine

Question 49. Indicate the agent of choice in the emergency therapy of anaphylactic shock:

  1. Methoxamine
  2. Terbutaline
  3. Phenylephrine
  4. Epinephrine

Answer. 4. Epinephrine

Question 50. Which of the following sympathomimetics is an effective mydriatic?

  1. Salmeterol
  2. Phenylephrine
  3. Dobutamine
  4. Norepinephrine

Answer. 2. Phenylephrine

Question 51. Sympathetic stimulation is mediated by.

  1. Release of norepinephrine from nerve terminals
  2. Activation of adrenoreceptors on postsynaptic sites
  3. Release of epinephrine from the adrenal medulla
  4. All of the above

Answer. 4. All of the above

Question 52. Which of the following sympathomimetics acts indirectly?

  1. Epinephrine
  2. Norepinephrine
  3. Ephedrine
  4. Methoxamine

Answer. 3. Ephedrine

Question 53. Catecholamine includes following EXCEPT:

  1. Ephedrine
  2. Epinephrine
  3. Isoprenaline
  4. Norepinephrine

Answer. 1. Ephedrine

Question 54. Which of the following agents is an a1-selective agonist?

  1. Norepinephrine
  2. Methoxamine
  3. Ritodrine
  4. Ephedrine

Answer. 2. Methoxamine

Question 55. All of the following agents are B-receptor agonists EXCEPT:

  1. Epinephrine
  2. Isoproterenol
  3. Methoxamine
  4. Dobutamine

Answer. 3. Methoxamine

Question 56. Indicate the direct-acting sympathomimetic, which is an a12 and B1 receptor agonist:

  1. Isoproterenol
  2. Ephedrine
  3. Dobutamine
  4. Norepinephrine

Answer. 4. Norepinephrine

Question 57. Indicate the indirect-acting sympathomimetic agent:

  1. Epinephrine
  2. Phenylephrine
  3. Ephedrine
  4. Isoproterenol

Answer. 3. Ephedrine

Question 58. Which of the following agents is an a1, a2, B1, and B2 receptor agonist?

  1. Methoxamine
  2. Albuterol
  3. Epinephrine
  4. Norepinephrine

Answer. 3. Epinephrine

Question 59. Which of the following sympathomimetics is a B2-selective agonist?

  1. Terbutaline
  2. Xylometazoline
  3. Isoproterenol
  4. Dobutamine

Answer. 1. Terbutaline

Question 60. Isoproterenol is:

  1. Both a- and ẞ-receptor agonist
  2. B1-selective agonist
  3. B2-selective agonist
  4. Nonselective ẞ-receptor agonist

Answer. 4. Nonselective ẞ-receptor agonist

Question 61. Ephedrine causes:

  1. Miosis
  2. Bronchodilation
  3. Hypotension
  4. Bradycardia

Answer. 2. Bronchodilation

Question 62. Indicate the long-acting topical decongestant agents:

  1. Epinephrine
  2. Norepinephrine
  3. Phenylephrine
  4. Xylometazoline

Answer. 4. Xylometazoline

Question 63. Indicate the agent of choice in the emergency therapy of anaphylactic shock:

  1. Methoxamine
  2. Terbutaline
  3. Norepinephrine
  4. Epinephrine

Answer. 4. Epinephrine

Question 64. Which of the following sympathomimetics is an effective mydriatic?

  1. Salmeterol
  2. Phenylephrine
  3. Dobutamine
  4. Norepinephrine

Answer. 2. Phenylephrine

Question 65. Which of the following drugs is a nonselective a-receptor antagonist?

  1. Prazosin
  2. Phentolamine
  3. Metoprolol
  4. Reserpine

Answer. 2. Phentolamine

Question 66. Indicate the α-selective antagonist:

  1. Phentolamine
  2. Dihydroergotamine
  3. Prazosin
  4. Labetalol

Answer. 3. Prazosin

Question 67. Which of the following drugs is a non-selective ẞ-receptor antagonist?

  1. Metoprolol
  2. Atenolol
  3. Propranolol
  4. Acebutolol

Answer. 3. Propranolol

Question 68. Indicate the ẞ1-selective antagonist:

  1. Propranolol
  2. Metoprolol
  3. Carvedilol
  4. Sotalol

Answer. 2. Metoprolol

Question 69. Which of the following drugs is a reversible non-selective a, ẞ-antagonist?

  1. Labetalol
  2. Phentolamine
  3. Metoprolol
  4. Propranolol

Answer. 1. Labetalol

Question 70. The principal mechanism of action of adrenoreceptor antagonists is:

  1. Reversible or irreversible interaction with adrenoreceptors
  2. Depletion of the storage of catecholamines
  3. Blockade of the amine reuptake pumps
  4. Non-selective MAO inhibition

Answer. 1. Reversible or irreversible interaction with adrenoreceptors

Question 71. Non-selective a-receptor antagonists are most useful in the treatment of:

  1. Asthma
  2. Cardiac arrhythmias
  3. Pheochromocytoma
  4. Chronic hypertension

Answer. 3. Pheochromocytoma

Question 72. Which of the following drugs is useful in the treatment of pheochromocytoma?

  1. Phenylephrine
  2. Propranolol
  3. Phentolamine
  4. Epinephrine

Answer. 3. Phentolamine

Question 73. Indicate adrenoreceptor antagonist agents, which are used for the management of pheochromocytoma:

  1. Selective ẞ2-receptor antagonists
  2. Non-selective ẞ-receptor antagonists
  3. Indirect-acting adrenoreceptor antagonist drugs
  4. a-receptor antagonists

Answer. 4. a-receptor antagonists

Question 74. Propranolol is used in the treatment all of the following diseases EXCEPT:

  1. Cardiovascular diseases
  2. Hyperthyroidism
  3. Migraine headache
  4. Bronchial asthma

Answer. 4. Bronchial asthma

Drugs Acting On Autonomic Nervous System Notes

Drugs Acting On Autonomic Nervous System Introduction

The central nervous system (CNS) is composed of the brain and spinal cord. These neurons cannot be regenerated if damaged. The peripheral nervous system (PNS) is made up of peripheral nerves that connect the CNS to the rest of the body. These neurons can be regenerated if damaged. Nerves that exit from the cranium are called cranial nerves while those exiting from the spinal cord are called spinal nerves. There are 31 pairs of spinal nerves and 12 pairs of cranial nerves.

Functional Importance:

  • Sensory: Gathers information about changes occurring within and around the body; sensory receptors, at the ends of peripheral nerves, send signals to CNS.
  • Integrative: Information is “brought together,” interpreted, to create sensations, create thoughts, add, to memory, make decisions, etc.
  • Motor: Sending of signals from CNS to muscles and/or glands to elicit a response.

Peripheral Nervous System

Nerves that transmit signals from the brain are called motor or efferent nerves, while those nerves that transmit information from the body to the CNS are called sensory or afferent. Spinal nerves serve both functions and are called mixed nerves.

The motor (efferent) portion of the nervous system is divided into three separate subsystems, the somatic, autonomic, and enteric nervous systems. Both autonomic and enteric nervous systems function involuntarily.

  • The somatic nervous system (mediate voluntary activities).
  • The autonomic nervous system (mediate involuntary activities).
  • The enteric nervous system (functions to control the gastrointestinal system).

The autonomic nervous system is largely independent (activities are not under direct conscious control). The cranial and spinal nerves connect CNS to heart, stomach, intestines and glands. It controls unconscious activities.

Read and Learn More Medicinal Chemistry III Notes

It is concerned primarily with visceral functions such as cardiac output, blood flow to various organs and digestion. The ANS is further subdivided into the sympathetic and the parasympathetic nervous systems. The sympathetic nervous system is activated in cases of emergencies to mobilize energy, while the parasympathetic nervous system is activated when organisms are in a relaxed state.

The somatic division is largely concerned with consciously controlled functions such as movement, respiration, and posture. The cranial and spinal nerves connect CNS to skin and skeletal muscles. It controls conscious activities.

Autonomic Nervous System (ANS):

The ANS has two major portions: The sympathetic (thoracolumbar) division and the parasympathetic (craniosacral) division. Both divisions originate in nuclei within the CNS and give rise to preganglionic efferent fibers that exit from the brain stem or spinal cord and terminate in motor ganglia.

  • The sympathetic preganglionic fibers leave the CNS through the thoracic and lumbar spinal nerves.
  • The parasympathetic preganglionic fibers leave the CNS through the cranial nerves (especially the 3rd, 7th, 9th and 10th) and the 3rd and 4th sacral spinal roots.

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Autonomic Nervous System

The sympathetic system leads to decrease in digestion, pupil size, urinary output and at the same time increases heart rate, bronchiole dilation, blood glucose, blood to skeletal muscle more of “fight or flight” response.

The parasympathetic system leads to decrease in heart rate, bronchiole dilation, blood glucose, blood to skeletal muscle and whilst, increase in digestion, pupil size, urinary output; more of “rest and digest” response.

Cholinergic Drugs

Nerve impulses elicit responses in smooth, cardiac, and skeletal muscles, exocrine glands, and postsynaptic neurons by liberating specific chemical neurotransmitters. By using drugs that mimic or block the actions of chemical transmitters, we can selectively modify many autonomic functions. These functions involve a variety of effector tissues, including cardiac muscle, smooth muscle, vascular endothelium, exocrine glands and presynaptic nerve terminals. Autonomic drugs are useful in many clinical conditions.

Cholinergic Neurotransmitters:

Cholinergic nerves (Parasympathetic nerves) are found in the peripheral nervous system and central nervous system (CNS) of humans. Parasympathetic nerves regulate processes connected with energy assimilation (food intake, digestion, absorption) and storage. These processes operate when the body is at rest, allowing increased bronchomotor tone and decreased cardiac activity.

Secretion of saliva and intestinal fluids promotes the digestion of foodstuffs, transport of intestinal contents is speeded up because of enhanced peristaltic activity and lowered tone of sphincter muscles.

To empty the urinary bladder (micturition), wall tension is increased by detrusor activation with a concurrent relaxation of sphincter tonus. Activation of ocular parasympathetic fibers results in narrowing of the pupil and increased curvature of the lens, enabling near objects to be brought into focus (accommodation).

Cholinergic neurons release acetylcholine (Ach) as the primary neurotransmitter, serves as mediator at terminals of all postganglionic parasympathetic fibers, in addition to fulfilling its transmitter role at ganglionic synapses within both the sympathetic and parasympathetic divisions and the motor endplates on striated muscle. However, different types of receptors are present at these synaptic junctions.

Synthesis, Storage and Release of Acetylcholine Biosynthesis:

Acetylcholine (Ach) is biosynthesized in cholinergic neuron, in which active transport mechanism is involved in picking up choline molecule from extra synaptic fluid into axoplasm. This transport depends on concentration of Na* and K+ ions. Choline is acetylated in cytoplasm by acetyl coenzyme-A (acetyl-CoA) which is biosynthesized in mitochondria present in nerve terminal. The acetylation is catalyzed by the enzyme choline acetyltransferase (biosynthesized itself in the cholinergic neurons).

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Acetylcholine

Some of the choline is biosynthesized from amino acid serine, but most of choline used to form Ach is recycled following the enzymatic hydrolysis of Ach in synaptic space.

Storage:

As soon as acetylcholine is synthesized, it is actively transported into cystolic storage vesicle (5000-10000 Ach) located in presynaptic nerve ending, where it is maintained until it is released. Some Ach remains in cystol and is eventually hydrolyzed to acetate and choline. Only the stored form of Ach serves as the functional neurotransmitter.

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Neurotransmitters from Cholinergic nerves

Release:

When impulse reaches to the nerve terminal, it results in release of Ach due to depolarization of the nerve terminal by the action potential. It alters membrane permeability to Ca++, which results into opening of voltage dependant Ca** channel affording an influx of Ca** causes exocytotic release of Ach into the synaptic cleft. (4 Ca** are taken up for each molecule of ACh release).

The ruptures cystolic (synaptic) vesicle is again re-shaped to store the fresh neurotransmitter. Each synaptic vesicle contains a quantum of Ach (one Quanta is equal to 12,000-60,000 molecules of ACh). A single action potential causes the release of several hundred quanta of ACh into the synapse.

Metabolism:

At the postsynaptic effector cell membrane, ACh interacts with its receptors. Because these receptors can also be activated by the alkaloid muscarine, they are referred to as muscarinic (M) cholinoceptors. In contrast, at ganglionic and motor endplate cholinoceptors, the action of ACh is mimicked by nicotine, therefore they are also said to be nicotinic (N) cholinoceptors.

Released ACh is rapidly hydrolyzed and inactivated by a specific acetylcholine esterase (AChE), present on pre- and post-junctional membranes, or by a less specific serum choline esterase (butyryl choline esterase), a soluble enzyme present in serum and interstitial fluid. Enzymatic hydrolysis, results into formation of choline which poorly binds to acetylcholine receptors.

There are enough AChE present in synapse to hydrolyse approximately 3 x 108 molecules of Ach in 1 millisecond. Thus there is adequate enzyme activity to hydrolyse all of ACh released by one action potential.

The empty synaptic vesicles, which are returned to the axonal terminal bulb by endocytosis, are filled with ACh.

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Acetate

The vascular release of ACh is reported to be inhibited by excess of Mg**. The release of ACh along with the extracelluler Ca** then mobilize the intracellular Ca** from sac present on sarcoplasmic reticulum. The increase in concentration of free intracellular Ca** activates calmodulin-dependent myosin light kinase and phosphorylation of myosin takes place which leads to muscle contraction.

Cholinergic Receptors

There are two different types of cholinergic receptors i.e. nicotinic receptor and muscarinic receptor. These receptors differ in composition, location and pharmacological functioning. They have specific agonists and antagonists activity. They have been characterised as nicotinic and muscarinic on the basis of their ability to be bound by the natural alkaloids nicotine and muscarine respectively. Both the receptors have subtypes that differ in location and specificity.

Nicotinic Receptors

Nicotinic receptors are coupled directly to ion channels and when activated by Ach, mediate very rapid responses. Ion channels are responsible for the electrical excitability of nerve and muscle cells and for the sensitivity of sensory cells. The channels are pores that open or close in an all or nothing fashion on time scales ranging from 0.1 to 10 milliseconds to provide aqueous pathways through the plasma membrane that ions can transverse.

The nicotinic ACh receptor is a glycoprotein embedded into the polysynaptic membrane and consists of 5 subunits of polypeptide chains. Subunits are arranged like a rosette surrounding the Na channel. The two alpha subunits carry two ACh binding sites with negatively charged groups which combine with the cationic group of ACh and open Na* channel.

When the neurotransmitter ACh binds to the nicotinic receptor, it causes a change in the permeability of the membrane to allow passage of small cations Ca** and Na* and K+. The. physiological action is to temporarily depolarize the nerve end plate to muscular contraction at a neuromuscular junction.

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Nicotinic receptor

Nicotinic Receptor Subtypes:

Nu-cholinoceptors (N):

  • Location: Neuromuscular junction.
  • Function: Depolarization of muscle end plate and contraction of skeletal muscle.
  • They are blocked by succinylcholine, d-tubocurarine and decamethonium, and are stimulated by phenyl trimethyl ammonium.

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 N-Cholinoceptors

NN-cholinoceptors (N2):

  • Location: Autonomic ganglia.
  • Function: Depolarization of post ganglonic membrane (in adrenal medulla- catecholamine release).
  • They are blocked by hexamethonium and trimethaphan, but are stimulated by tetramethyl ammonium and dimethyl-4-phenylpiperazinium (DMPP).

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Hexamethonium

Muscarinic Receptors

Muscarinic receptors play an important role in regulating the functions of organs innervated by the autonomic nervous system. The action of ACh on muscarinic receptors is to stimulate secretions from salivary and sweat glands, secretions and contraction of the gut and constriction of the respiratory tract. It inhibits contraction of the heart and relaxes smooth muscle of blood vessels.

Muscarinic receptors mediate their effects by activating guanosine triphosphate (GTP)- binding proteins (G-proteins). These receptors have seven protein helixes that passed through the plasma membrane, creating four extracellular domains and four intracellular domains. The extracellular domain of the receptor contains the binding site for Ach. The intracellular domain couples with G-proteins to initiate the biochemical changes that results in pharmacological action from receptor activation.

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Muscarinic receptor

Muscarinic Receptor Subtypes:

Subtypes of muscarinic receptors are located at the CNS and peripheral nervous system. Muscarinic receptor subtypes have been defined on the basis of their affinity for agonists, antagonists and the pharmacological effects cause.

They are classified into subtypes according to their molecular structure, signal transduction, and ligand affinity in the M1, M2, M3, M4 and Ms.

  • M1-receptors are present on nerve cells, exocrine glands and autonomic ganglia, where they mediate a facilitation of impulse transmission from preganglionic axon terminals to ganglion cells. In humans, these receptors seem to affect the rapid eye movement (REM), sleep, emotional responses, affective disorders including depression and modulation of stress. They are also located in intramural ganglia of stomach wall which on stimulation cause gastric secretion.
  • M2-receptors are also called cardiac muscarinic receptors because they are located in the atria and conducting tissue of the heart. Their stimulation causes a decrease in the strength and rate of cardiac muscle contraction. These effects may be produced by affecting intracellular K+ and Ca** levels in heart tissue. Opening of K+ channels leads to slowing of diastolic depolarization in sinoatrial pacemaker cells and a decrease in heart rate. These receptors may also act through an inhibitory G protein (G1) to reduce adenylate cyclase activity and lower cyclic 3′,5′-adenosine monophosphate (CAMP) levels in cardiac cells. M2-receptors can also serve as autoreceptors and inhibit release of ACh’ on presynaptic terminals of postganglionic cholinergic nerves.
  • M3-receptors are referred to as glandular muscarinic receptors. They are located in exocrine glands and smooth muscles and increase secretory activity such as secretions from lacrimal, salivary, bronchial, pancreatic and mucosal cells in the GIT. Stimulation of M3-receptors also results into contraction of visceral smooth muscles.
  • M4-receptors, like M2-receptors, they act through G1 protein to inhibit adenylate cyclase. They also function by a direct regulatory action on K* and Ca++ ion channels. Stimulation of M4-receptors in tracheal smooth, inhibit the release of Ach in same manner as M2-receptors.
  • Ms-receptors, messenger RNA (mRNA) is found in the substantia nigra. It may regulate dopamine release at terminals within the striatum.

Classification Of Para-Sympathomimetic Agents

Acetylcholine receptor stimulants and cholinesterase inhibitors:

Acetylcholine receptor stimulants comprise a large group of drugs that mimic ACh (cholinomimetic agents). Cholinoceptor stimulants are classified by their spectrum of action depending on the type of receptor-muscarinic (M) or nicotinic (N) that is activated. They are also classified by their mechanism of action, as some cholinomimetic drugs bind directly to (and activate) cholinoceptors, while others act indirectly by inhibiting the hydrolysis of endogenous ACh.

Direct-Acting Cholinergic Drugs:

  • Choline ester (stimulants of M- and N-receptors):
    e.g. Acetylcholine, Carbachol.
  • Cholinomimetic Alkaloids:
    • Stimulants of M-receptors
      e.g. Pilocarpine, Cevimeline, Bethanechol, Musacarine, Phalloidin
    • Stimulants of N-receptors
      e.g. Nicotine, Cytisine, Lobeline

Indirect-Acting Cholinergic Drugs (anticholinesterase (Anti-ChEs) drugs):

  • Reversible drugs (carbamates class)
    • With N3+ (cross BBB)
      e.g. Alkaloids: Galantamine, Physostigmine
      e.g. Synthetic drugs: Donepezil, Rivastigmine, Tacrin
    • With N4+ (do not cross BBB)
      e.g. Demecarium, Edrophonium, Neostigmine, Pyridostigmine
  • Irreversible anticholinesterase agents (organophosphates class)
    • Thiophosphate insecticides:
      e.g. Parathion, Malathion
    • Nerve paralytic gases (chemical warfare):
      e.g. Tabun, Sarin, Soman.

Structure-Activity Relationship: Choline ester (stimulants of M- and N- receptors):

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Choline ester

Quaternary Ammonium Group (N4*):

  • The quaternary ammonium group is essential for activity; at the cationic head is the major point of receptor interaction.
  • The replacement of nitrogen (N) by sulfur (S), arsenic (As) or selenium (Se) leads to decrease in activity.
  • The conversion of the quaternary ammonium group (N) to primary, secondary or tertiary leads to less active derivatives.
  • The replacement of the methyl (CH3) substitution with higher carbon skeleton (more ‘C’-atoms) functional groups like Propyl (C3H7) or higher alkyl groups leads to inactive derivatives.
  • The quaternary ammonium group should be followed by a chain of five atoms for maximal muscarinic activity; it is referred as “five-atom rule”.

Ethylene Bridge (-CH2-CH2-):

  • With the increase or decrease in the carbon chain length, the activity of the derivatives is rapidly reduced.
  • Substitution on the a or ẞ position with methyl (CH3) group results in decreased activity, but increased duration of action, this phenomenon is due to the reduced metabolism due to steric hindrance.
  • B-substituted choline derivative exhibits longer duration of action than that of its a-substituted choline analog.
  • The substitution of methyl (CH3) group on a or ẞ position leads to selectivity towards receptors.
  • a-Methylcholine (methyl group substituted at a-position derivative) is less potent than Ach, but has more nicotinic activity than muscarinic activity.
  • B-Methylcholine; Methacholine (methyl group substituted at B-position derivative) is less potent than ACh, but more selective to Muscarinic receptor.
  • Substitution on the aor B.position with alkyl function larger than methyl group like propyl or butyl leads to derivatives with no activity.

Acyl oxy group:

  • The conversion of acetyl (CH3CO) group to higher group like propionyl (C2H, CO) or butyryl (C3H,CO) functions results in decrease in activity, indicated by the five-atom rule.
  • The ester derivatives of higher molecular carboxylic acids or of aromatic acids results in antagonist property.
  • The acetyl (CH3CO) group/methyl ester in Ach is rapidly hydrolyzed by AchE, replacement of the same with carbomate (NH2CO) ester results in resistance to hydrolysis leading to potent derivative with increased duration of activity.
  • Carbachol (carbamate ester of choline) is more stable to hydrolysis and can be administered orally.
  • The replacement of the ester function with ether or ketonic function while sticking by the five-atom rule will also result in stable and potent derivatives.
  • Choline ethyl ether derivative is as potent as ACh.

Direct-Acting Cholinergic Drugs

Choline Ester

Acetylcholine:

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Choline Ester Acetylcholine

  • Acetylcholine is chemically, 2-acetyloxyethyl (trimethyl)azanium.
  • Acetylcholine chloride exerts a powerful stimulant effect on the parasympathetic nervous system.
  • It does not have any therapeutic importance as it is rapidly hydrolyzed by cholinesterase.
  • Stimulation of the vagus and the parasympathetic nervous system produces a tonic action on smooth muscle and induces a flow from the salivary and lacrimal glands. Its cardiac-depressant results in negative chronotropic effect (decrease in heart rate) and negative inotropic effect (decrease in the force of myocardial contractions).
  • It also has vasodilatory action on the peripheral vascular system.
  • When it gives systemically, it produces bronchial constriction as a characteristic side effect.
  • A non-selective muscarinic receptor antagonist (i.e. atropine) is the most effective antagonist to the action of Ach.

Uses:

  • Acetylchloline is a cardiac depressant and an effective vasodilator.
  • It is used during ophthalmic surgery (cataract)..
  • It is used as ex-vivo agent to study pharmacological effect of parasympathomimetic.

Carbachol:

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Choline Ester Carbachol

  • Carbachol is chemically, 2-carbamoyloxyethyl(trimethyl)azanium.
  • It is a choline carbamate, a parasympathomimetic that stimulates both muscarinic and nicotinic receptors.
  • The pharmacological activity of carbachol is similar to that of ACh.
  • It is not well absorbed in the gastro-intestinal tract and does not cross the blood- brain barrier.
  • It is usually administered topical ocular or through intraocular injection.
  • It is not easily metabolized by cholinesterase therefore, more stable in aqueous solutions.
  • It can also act indirectly by promoting release of ACh and by its weak anticho- linesterase activity.
  • It has a 2 to 5 minute onset of action and its duration of action is 4 to 8 hours with topical administration and 24 hours for intraocular administration.
  • Since carbachol is poorly absorbed through topical administration, benzalkonium chloride is mixed in it to promote absorption.

Uses:

  • Carbachol is primarily used for treating glaucoma, or during ophthalmic surgery (cataract).
  • It is administered as an ophthalmic solution, its principal effects are miosis and increased aqueous humour outflow.

Bethanechol:

  • Bethanechol is chemically, 2-carbamoyloxypropyl(trimethyl)azanium.
  • It is B-methylcholine carbamate and non-specific, that selectively stimulates muscarinic receptors without any effect on nicotinic receptors.
  • It is not readily hydrolyzed by cholinesterase and therefore has a long duration of action.
  • It has pharmacological properties similar to that of methacholine.

Uses:

  • Bethanechol is given orally or subcutaneously to treat urinary retention and abdominal distention resulting from general anaesthetic, diabetic neuropathy of the bladder, or a side effect of antidepressants; or to treat gastrointestinal lack of muscular tone.
  • It has potential benefit in the treatment of cerebral palsy.
  • It is contraindicated in patients with asthma, coronary insufficiency, peptic ulcers, intestinal obstruction and hyperthyroidism.

Methacholine:

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Choline Ester Methacholine

  • Methacholine is chemically, 2-acetyloxypropyl (trimethyl)azanium.
  • It is ẞ-methylcholine acetate and is a synthetic choline ester that acts as a non- selective muscarinic receptor agonist but has little effect on the nicotinic receptors.
  • It is not readily hydrolyzed by cholinesterase and therefore has a long duration of action.

Uses:

  • Methacholine is primarily used to diagnose bronchial hyper-reactivity (asthma and chronic obstructive pulmonary disease), known as the bronchial challenge test or methacholine challenge.
  • It also leads to adverse cardiovascular effects, bradycardia and hypotension.

Cholinomimetic Alkaloids

Pilocarpine:

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Cholinomimetic Alkaloids Pilocarpine

  • Pilocarpine is an alkaloid obtained from the dried leaflets of Pilocarpus jaborandi or Pilocarpus microphyllus.
  • It is chemically, (3S,4R)-3-ethyl-4-[(3-methylimidazol-4-yl)methyl]oxolan-2-one.
  • It is a non-selective agonist on the muscarinic receptors.
  • It works by activating cholinergic receptors of the muscarinic type which cause the trabecular meshwork to open and the aqueous humor to drain from the eye.

Uses:

  • Pilocarpine is used to treat increased pressure inside the eye (glaucoma).
  • As ophthalmic solution, it is used for angle closure glaucoma, ocular hypertension, and open angle glaucoma.
  • By oral medication, it stimulates the secretion of saliva and sweat and use to treat dry mouth.
  • Common side effects include irritation of the eye, increased tearing, headache, and blurry vision.
  • Systemic injection of pilocarpine can cross blood-brain barrier, which can lead to chronic epilepsy and can be used as epilepsy inducing agent in rodents in order to study human epilepsy.

Indirect-Acting Cholinergic Drugs/Cholinesterase Inhibitors

The acetylcholine action at the synaptic junction is terminated by metabolism catalyzed by the action of AchE. The AchE enzyme hydrolyses Ach to choline and acetate. Inhibition of the enzyme leads to increased concentration of Ach and prolongs the life of the available Ach at the synaptic junction, thus producing a cholinergic agonist effect. The enzyme inhibitors are classified based on the affinity towards the enzyme and the type of interaction.

Reversible Cholinesterase Inhibitors

Physostigmine:

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Cholinesterase Inhibitors Physostigmine

  • Physostigmine is an alkaloid obtained from the dried ripe seed of Physostigma venenosum.
  • It occurs naturally in the Calabar bean and the Manchineel tree.
  • It is chemically, [(3aR,8bS)-3,4,8b-trimethyl-2,3a-dihydro-1H-pyrrolo[2,3-b]indol-7-yl] N-methylcarbamate.
  • It is a highly toxic parasympathomimetic alkaloid, a reversible cholinesterase. inhibitor.
  • It acts by interfering with the metabolism of acetylcholine.
  • In solution it undergoes hydrolysis to form methyl carbamic acid and eseroline, neither of which inhibits Ach.

Uses:

  • Physostigmine is used to treat glaucoma and delayed gastric emptying.
  • As it enhances the transmission of acetylcholine signals in the brain and can cross the blood-brain barrier, physostigmine is used as an antidote to treat anticholinergic poisoning (Datura stramonium, Atropa belladonna, atropine, scopolamine, and other anticholinergic drug overdoses poisoning).

Neostigmine:

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Cholinesterase Inhibitors Neostigmine

  • Neostigmine is chemically, [3-(dimethylcarbamoyloxy)phenyl]-trimethylazanium.
  • It has quaternary nitrogen; hence, it is polar and does not cross the blood-brain barrier, but it does cross the placenta.
  • It works by blocking the action of acetylcholinesterase and therefore increases the levels of acetylcholine.

Uses:

  • Neostigmine is used to treat myasthenia gravis, ogilvie syndrome (acute dilation of the colon), and urinary retention. Common side effects include nausea, increased saliva and abdominal pain.
  • In myasthenia gravis there are too few acetylcholine receptors so with the acetyl cholinesterase blocked, acetylcholine can bind to the few receptors and trigger a muscular contraction.
  • It is also used as an antidote to non-depolarizing neuromuscular blocking drug.

Pyridostigmine:

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Cholinesterase Inhibitors Pyridostigmine

  • Pyridostigmine is chemically, (1-methylpyridin-1-ium-3-yl) N,N-dimethylcarbamate.
  • It is a quaternary carbamate inhibitor of cholinesterase that does not cross the blood-brain barrier.
  • Common side effects include nausea, diarrhea, frequent urination, and abdominal pain.

Uses:

  • Pyridostigmine is used to treat myasthenia gravis. (Long term neuromuscular disease that leads to varying degrees of skeletal muscle weekness).
  • It is used to treat muscle weakness in people with myasthenia gravis or forms of congenital myasthenic syndrome.
  • It is also used together with atropine to end the effects of neuromuscular blocking medication of the non-depolarizing type.

Edrophonium Chloride:

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Cholinesterase Inhibitors Edrophonium Chloride

  • Edrophonium is chemically, ethyl-(3-hydroxyphenyl)-dimethylazanium, chloride.
  • It is a readily reversible acetylcholinesterase inhibitor and acts by competitively inhibiting the enzyme.
  • It has a direct cholinomimetic effect on skeletal muscle, which is greater than that of most other anticholinesterase drugs.

Uses:

  • Edrophonium chloride is used as a diagnostic agent to differentiate myasthenia gravis from cholinergic crisis and Lambert-Eaton. (Lambert-Eaton myasthenic syndrome is an autoimmune disease where the neuron is unable to release enough ACh for normal muscle function).
  • In myasthenia gravis, the body produces autoantibodies which block, inhibit or destroy nicotinic acetylcholine receptors in the neuromuscular junction. Edrophonium reduces the muscle weakness in myasthenia gravis.
  • In a cholinergic crisis, resulting from too much neuromuscular stimulation, edrophonium will make the muscle weakness worse by inducing a depolarizing block.

Tacrine Hydrochloride:

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Cholinesterase Inhibitors Tacrine Hydrochloride

  • Tacrine hydrochloride is chemically, 1,2,3,4-tetrahydro-9-aminoacridine, hydro- chloride.
  • It is a centrally acting reversible anticholinesterase and indirect cholinergic agonist.

Uses:

  • It was the first centrally acting cholinesterase inhibitor approved for the treatment of Alzheimer’s disease (progressive loss of brain cells that leads to memory loss and decline of other thinking skills).

Ambenonium Chloride:

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Cholinesterase Inhibitors Ambenonium Chloride

  • Ambenonium dichloride is chemically, (2-chlorophenyl)methyl-[2-[[2-[2-[(2-chloro- phenyl) methyl-diethylazaniumyl)ethylamino]-2-oxoacetyl]amino]ethyl]-diethylazanium; dichloride.
  • It acts by suppressing the activity of AChE.
  • It possesses a relatively prolonged duration of action and causes fewer side effects in the GI tract than the other anticholinesterase agents.
  • Because of its quaternary ammonium structure, it is absorbed poorly from the GI tract.
  • In moderate doses, the drug does not cross the blood brain barrier.
  • Ambenonium chloride is not hydrolyzed by cholinesterases.

Uses:

  • Ambenonium is a reversible cholinesterase inhibitor used in the management of myasthenia gravis in patients who do not respond satisfactorily to neostigmine or pyridostigmine.
  • It is used to treat muscle weakness due to myasthenia gravis disease or defect of the neuromuscular junction.

Irreversible Cholinesterase Inhibitors

They covalently bond with the AchE enzyme to irreversibly deactivate them, they are referred as nervé poisons and are used as agricultural insecticides. Due to the irreversible inhibition of the enzyme, Ach accumulates at the synaptic junction leading to a high concentration of the Ach and thus to produce agonist effect. These compounds belong to the class of Organophosphorus esters. A general formula for such compounds is as follows:

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Inhibitors

    • R1 = Alkoxyl group
    • R2 = Alkyl / Alkoxyl / aryl/aryloxy/Tertiary Amine.
    • X = A good leaving group like F, CN, thiomalate, p-nitrophenyl
    • A Oxygen / Sulphur
  • ‘A’ is usually oxygen or sulphur, but may also be selenium.
  • When ‘A’ is other than oxygen, biological activation is required before the compound becomes effective as an inhibitor cholinesterase.
  • Phosphorothionates (when ‘A’ is ‘S’) have much poorer electrophilic character and 105 folds weaker anticholinesterase activity than their oxygen analogues.
  • ‘X’ is the leaving group when the molecule reacts with the enzyme.
  • The ‘R’ moiety imparts lipophilicity to the molecule and contributes to its absorption through the skin.
  • Inhibition of AChE by organo-phosphorous compound takes place in two steps, association of enzyme and inhibitor and the phosphorylation step.

Isofluorophate (Diisopropyl fluorophosphate):

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Isofluorophate

  • Diisopropyl fluorophosphates is chemically, 2-[fluoro(propan-2-yloxy) phosphoryl]- oxypropane.
  • It is an organophosphorus insecticide, a parasympathomimetic drug irreversible anti- cholinesterase.
  • Since it irreversibly inhibits cholinesterase, its activity lasts for days or even weeks.
  • It must be handled with extreme caution, as it can be absorbed readily through intact epidermis and more so through mucous tissues.

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Enzyme

Uses:

  • Isofluorophate has been used in ophthalmology as a miotic agent in treatment of chronic glaucoma.
  • It is also used as a miotic in veterinary medicine.
  • It is used as an experimental agent in neuroscience because of its acetyl- cholinesterase inhibitory properties and ability to induce delayed peripheral neuropathy.

Echothiophate Iodide:

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Echothiophate Iodide

  • Echothiophate iodide is chemically, 2-diethoxyphosphorylsulfanylethyl (trimethyl)- azanium; iodide.
  • It is also known as Phospholine. It is a parasympathomimetic drug, an irreversible acetylcholinesterase inhibitor.
  • It has long duration of action and its effects can last a week or more.

Uses:

  • Echothiophate iodide is used as an ocular antihypertensive in the treatment of chronic glaucoma and in accommodative esotropia.

Parathion:

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Parathion

  • Parathion is chemically, O,O-Diethyl O-(4-nitrophenyl) phosphorothioate.
  • It is a relatively weak cholinesterase inhibitor.
  • It is highly toxic to non-target organisms, including humans, so its use has been restricted.
  • Absorbed parathion is rapidly metabolized to paraoxon by enzymes present in liver microsomes and insect tissue.
  • Parathion is also metabolized by liver microsomes to yield p-nitrophenol and diethylphosphate; the later is inactive as an irreversible cholinesterase inhibitor.

Uses:

  • Parathion is an organophosphate insecticide and acaricide.
  • It is used as an agricultural insecticide.

Malathion:

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Malathion

  • Malathion is chemically, 2-[(dimethoxyphosphinothioyl)-thio]butanedionic acid diethyl ester, or diethyl-2-dimethoxyphosphinothioyl sulfanyl butane dioate.
  • It is a poor inhibitor of cholinesterases.
  • It is an organophosphate insecticide which acts as an acetylcholinesterase inhibitor.

Uses:

  • Malathion is used as an agricultural insecticide.

Acetylcholine Sterase Reactivators

Oxime class of compounds can provide a nucleophilic attack on the phosphorylated AchE (deactivated) and can regenerate the free enzyme. Choline-reactivating oximes are effective antidotes in organophosphorus insecticide or sulfonate poisoning, a state of acetylcholine excess because of cholinesterase inhibition.

Pralidoxime chloride:

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Pralidoxime Chloride

  • Pralidoxime chloride is chemically, 2-formyl-1-methylpyridinium chloride oxime.
  • It is also said to be 2-pyridine aldoxime methyl chloride or 2-PAM, usually as the chloride or iodide salts, belongs to a family of compounds called oximes that bind to organophosphate-inactivated acetylcholinesterase.
  • These drugs antagonize the effects of accumulated acetylcholine at the cholinergic synapses by reactivating the inhibited cholinesterase.
  • Reactivation of cholinesterases is importance for the survival due to organo- phosphorus insecticide poisoning.
  • It is a quaternary ammonium compound and most effective by intramuscular, subcutaneous, or intravenous administration.

Uses:

  • Pralidoxime chloride or 2-PAM is used to combat poisoning by organophosphates or acetyl cholinesterase inhibitors (nerve agents) in conjunction with atropine.
  • 2-PAM is the most popular oxime for this purpose.
  • It may be effective against some phosphates that have a quaternary nitrogen.
  • It is also an effective antagonist for some carbamates, such as neostigmine methylsulfate and pyridostigmine bromide.

Cholinergic Blocking Agents

Agents that block or antagonize the action of acetylcholine, at post ganglionic nerve ending are called as cholinergic blockers or parasympatholytic agents. They act by inhibiting muscarinic action of acetylcholine on smooth muscle contraction and including exocrine gland secretion.

Cholinergic blockers are classified into two classes, based on mechanism of action:

  • Agents that inhibit, synthesis or release of Ach: These agents are not been effective clinically and hence not used.
  • Agents that block Muscarinic receptor at nerve ending: These agents are also said to be parasympathetic post ganglionic muscarinic receptor blockers. These competitive reversible antagonists are large molecules, derived from muscarinic antagonist with one or more bulky groups, thus capable of binding to the receptor.

Structure-activity relationship of cholinergic blockers:

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Pivotal carbon

  • The Pivotal carbon is of crucial importance in relation to the development of cholinergic antagonists.
  • Generally, the amine function need to be a quaternary ammonium group (N4*) or it can be tertiary (N3*) that is protonated at physiological pH to form the cationic head. The quaternary ammonium group is essential for activity, as the cationic head is the major point of receptor interaction.
  • The amine function is separated from the pivotal carbon by a chain / bridge, the chain may be a ester, ether or a hydrocarbon function bridge.
  • The substitution ‘A’ and ‘B’ contains at least one aromatic moiety that can exhibit Van der Waals’ interaction with the receptor and the other one as cycloalkyl, aliphatic hydrocarbon or alkyl group for hydrophobic interaction with the receptor.
  • The ‘X’ function can be hydroxy function or a carboxamide group or just hydrogen to exhibit hydrogen bond interaction with the receptor.

The Amine Function:

  • The amine group should be cationic in nature, which is the primary point for interaction with the receptor core.
  • It may be a quaternary ammonium group (N4) or it can be tertiary (N3+) that is protonated at physiological pH to form the cationic head.

The ‘X’ Functions as Hydrogen (H) / Hydroxyl group (OH):

  • The hydroxyl group (OH) is not prerequisite for activity, but suitably placed alcoholic hydroxyl function enhances the activity.
  • The ‘OH’ group contributes in hydrogen bonding with the amino acid residues present in the receptor.

The Chain Function:

  • The chain function can be an ester/ether / amino alcohol / hydrocarbon moiety.
  • The ester moiety is found to be more effective, this can be indicated as the agonist, also poses a ester function, contributing for a better binding affinity at the receptor site.
  • The ether amino alcohol/ hydrocarbon moieties are also clinically effective derivatives.

The Cyclic Substituents – ‘A’ and ‘B’:

  • At least one cyclic moiety as a substituent at position ‘A’ / ‘B’ is prerequisite for activity.
  • The cyclic substituent may be phenyl, cyclohexyl etc., the phenyl moiety predominant as an important substitution.
  • Aromatic acid ester derivatives produce decrease in anticholinergic activity, but results in compounds with potential local anaesthetic activity.

Classification Of Muscarinic Receptor Blockers

  • Natural and semi-synthetic derivatives:
    • Solanaceous alkaloids and their synthetic analogs
  • Synthetic derivatives:
    • Amino alcohol ester derivatives
    • Amino alcohol ether derivatives
    • Amino alcohol derivatives
    • Amino amide derivatives
    • Miscellaneous derivatives

Natural and Semi-Synthetic Derivatives

Solanaceous Alkaloids and their Synthetic Analogs:

The solanaceous alkaloids, represented by hyoscyamine, atropine and scopolamine (hyoscine) are the major class of antimuscarinic drugs. These alkaloids are found principally in Henbane (Hyoscymus niger), deadly nightshade (Atropa belladonna) and Jimson weed (Datura stramonium).

Crude drugs containing these alkaloids have been used since early times for their marked medicinal properties which depend largely on inhibition of the parasympathetic nervous system and stimulation of the higher nervous centers.

  • Belladonna alkaloid (Atropine) possesses a weak local anaesthetic activity and has been used topically for its analgesic effect on hemorrhoids, certain skin infections and various itching dermatoses.
  • It is also used as mydriasis.
  • It increases the heart rate (by depression of the vagus nerve).
  • It depresses the motility of the GIT, and acts as an antispasmodic on various smooth muscles (ureter, bladder, and biliary tract).
  • It also directly stimulates the respiratory center.
  • The action of scopolamine containing drugs differs from those containing hyoscyamine and atropine in having no CNS stimulation; they have significant narcotic or sedative effect.
  • The use of this group of drugs is accompanied by a fairly high incidence of reactions because of individual idiosyncrasies.
  • Death from over dosage usually results from respiratory failure.

Atropine Sulphate:

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Atropine Sulphate

  • Atropine occurs naturally in a number of plants of the nightshade family including deadly nightshade, Jimson weed, and mandrake.
  • It is chemically, [(1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl] 3-hydroxy-2-phenyl- propanoate.
  • It is the tropine ester of racemic tropic acid and is optically inactive.
  • It is an enantiomeric / racemic mixture of d-hyoscyamine and l-hyoscyamine, with most of its physiological effects due to l-hyoscyamine.
  • Atropine sulfate is prepared by neutralizing atropine in acetone or ether with an alcoholic solution of sulfuric acid, with care used to prevent hydrolysis.
  • It is an antimuscarinic drug that works by inhibiting the parasympathetic nervous system.
  • Atropine is a competitive reversible antagonist of the muscarinic acetylcholine receptor types M1, M2, M3, M4 and Ms.
  • In the eye, atropine induces mydriasis by blocking contraction of the circular pupillary sphincter muscle, thereby allowing the radial iris dilator muscle to contract and dilate the pupil.

Uses:

  • Atropine is used to treat pesticide poisonings and to decrease saliva production during surgery.
  • As an ophthalmic preparation it is used to treat uveitis (swelling of the middle layer of the eye) and early amblyopia (vision development disorder).
  • Atropine induces cycloplegia by paralyzing the ciliary muscles and helps to relieve pain associated with iridocyclitis (an inflammation of the iris), and treats ciliary block (malignant) glaucoma.
  • Common side effects include a dry mouth, large pupils, urinary retention and constipation.

Hyoscyamine Sulphate:

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Hyoscyamine Sulphate

  • Hyoscyamine (daturine) is a tropane alkaloid.
  • It is a secondary metabolite found in certain plants of the family Solanaceae like Atropa belladonna.
  • It is chemically, [(1S,5R)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl] (2S)-3-hydroxy-2- phenylpropanoate.
  • It is the levorotatory isomer of atropine.

Uses:

  • Hyoscyamine is used to provide symptomatic relief of spasms caused by various lower abdominal and bladder disorders including peptic ulcers, irritable bowel syndrome, diverticulitis, pancreatitis, colic, and interstitial cystitis.
  • It has also been used to relieve some heart problems, control some of the symptoms of Parkinson’s disease, as well as for control of abnormal respiratory symptoms and “hyper-mucus secretions” in patients with lung disease.
  • It is also useful in pain control for neuropathic pain, chronic pain and palliative care; and for those with intractable pain from treatment resistant, untreatable, and incurable diseases.
  • It is used to treat disorders of the urinary tract.
  • It is used to treat spasms of the bladder and serves as a urinary stimulant.
  • When combined with opioids, it increases the level of analgesia obtained.

Scopolamine:

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Scopolamine

  • Hyoscine is produced from plants of the family Solanaceae like Atropa belladonna.
  • The name “scopolamine” is derived from one type of nightshade known as Scopolia, while the name “hyoscine” is derived from another type known as Hyoscyamusniger.
  • Hyoscine is in the antimuscarinic family of medications and works by blocking some of the effects of acetylcholine within the nervous system.

Uses:

  • Scopolamine (Hyoscine) is a medication used to treat motion sickness and postoperative nausea and vomiting.
  • It is also used before surgery to decrease saliva.
  • It is not recommended in people with glaucoma or bowel obstruction.

Homatropine:

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Homatropine

  • Homatropine is chemically, [(15,5R)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl]-2-hydroxy-2-phenylacetate.
  • It is available as the hydrobromide salt.
  • It is an anticholinergic medication that is an antagonist at muscarinic acetylcholine receptors.
  • It is less potent than atropine and has a shorter duration of action:-

Uses:

  • It is used as an ophthalmic preparation as a cycloplegic (to temporarily paralyze accommodation), and as a mydriatic (to dilate the pupil).
  • Homatropine is also given as an atropine substitute given to reverse the muscarinic and CNS effects associated with indirect cholinomimetic (Anti AChE) poisoning.

Ipratropium Bromide:

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Ipratropium Bromide

  • Ipratropium bromide is chemically, (8-methyl-8-propan-2-yl-8-azoniabicyclo[3.2.1]- octan-3-yl) 3-hydroxy-2-phenylpropanoate;bromide.
  • It is a muscarinic antagonist, a type of anticholinergic, which works by causing smooth muscles to relax.

Uses:

  • Ipratropium bromide is used to treat the symptoms of chronic obstructive pulmonary disease and asthma.
  • Ipratropium, sprayed into the nostrils as a nasal solution, can reduce rhinorrhea, but will not help nasal congestion.
  • Combination with beta-adrenergic agonists increases the dilating effect on the bronchi.
  • Common side effects include dry mouth, cough, and inflammation of the airways.

Synthetic Derivatives

The solanaceous alkaloids are found to be potent parasympatholytics, but they have the undesirable wide range of effects because of their non-specific action. For example, antispasmodic effects of the alkaloids most often result in side effects such as dryness of the mouth and fluctuations in pulse rate. To minimize such non-specific undesirable effects, the synthetic compounds are derived which possess specific cholinolytic actions.

The synthetic derivatives have tertiary amino function that is protonated in physiological pH or a quaternary ammonium group to form the cationic head, a crucial point of interaction. at the receptor cites. The tropic acid moiety is replaced by a large aromatic moiety like phenyl to provide hydrophobic interaction at the receptor cites.

Amino Alcohol Ester Derivatives:

Clidinium Bromide:

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Clidinium Bromide

  • Clidinium bromide is chemically, (1-methyl-1-azoniabicyclo[2.2.2]octan-3-yl)- 2-hydroxy-2,2-diphenylacetate;bromide.
  • It is a muscarinic antagonist and finds importance in management of the symptoms of cramping and abdominal/stomach pain by decreasing stomach acid, and slowing the intestines.

Uses:

  • Clidinium bromide is used in combination for the management of Peptic ulcer disease, GI motility disturbances (irritable bowel syndrome) and in acute enterocolitis.
  • It is contraindicated in glaucoma.

Cyclopentolate Hydrochloride:

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Cyclopentolate Hydrochloride

  • Cyclopentolate hydrochloride is chemically, 2-(dimethylamino)ethyl 2-(1-hydroxy-cyclopentyl)-2-phenylacetate;hydrochloride.
  • It blocks the acetylcholine receptor in the sphincter muscle of the iris and the ciliary muscle, thereby preventing contraction. This dilates the pupil, producing mydriasis, and prevents accommodation of the eye to different distances (cycloplegic).

Uses:

  • Cyclopentolate hydrochloride is used as a mydriatic medication where it acts as parasympatholytic.
  • It is commonly used during pediatric eye examinations.
  • It is also administered as an atropine substitute to reverse muscarinic and central nervous system effects of indirect cholinomimetic (anti AchE) administration.

Dicyclomine Hydrochloride:

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Dicyclomine Hydrochloride

  • Dicyclomine hydrochloride is chemically, 2-(diethylamino)ethyl. 1-cyclohexyl- cyclohexane-1-carboxylate;hydrochloride.
  • It has some muscarinic receptor subtype selectivity. It binds more firmly to M1 and M3 than M2 and M4 receptors.
  • It antagonizes muscarinic receptors on smooth muscle in the gastrointestinal (GI) tract, thereby preventing the actions of acetylcholine and reducing GI smooth muscle spasms.

Uses:

  • Dicyclomine hydrochloride is used as an antispasmodic and in urinary incontinence.
  • It has local anesthetic properties and is used in gastrointestinal, biliary, and urinary tract spasms.
  • It is used to treat the symptoms of irritable bowel syndrome, specifically hypermotility.
  • It is also useful in dysmenorrhea (pain during menstruation), pylorospasm (spasm of the pyloric sphincter) and biliary dysfunction.

Glycopyrrolate:

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Glycopyrrolate

  • Glycopyrrolate is chemically, (1,1-dimethylpyrrolidin-1-ium-3-yl) 2-cyclopentyl-2- hydroxy-2-phenylacetate;bromide.
  • It is a synthetic quaternary ammonium amine anticholinergic agent with antispasmodic activity.
  • It competitively binds to peripheral muscarinic receptors in the autonomic effector cells.
  • It does not cross the blood-brain barrier and consequently has no CNS effects.

Uses:

  • Glycopyrrolate is a preanesthetic medication to reduce salivary, tracheobronchial, and pharyngeal secretions as well as decreasing the acidity of gastric secretion.
  • It is also used to reduce excessive saliva.
  • It decreases acid secretion in the stomach and so may be used for treating stomach ulcers in combination with other medications.

Methantheline Bromide:

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Methantheline Bromide

  • Methantheline bromide is chemically, diethyl-methyl-[2-(9H-xanthene-9-carbonyloxy)ethyl]azanium;bromide.
  • It is a muscarinic antagonist and finds importance in management of the symptoms of cramping and abdominal/stomach pain by decreasing stomach acid and slowing the intestines.
  • It is an anticholinergic agent that also acts at the nicotinic cholinergic receptors of the sympathetic and parasympathetic systems as well as at the myoneural junction of the postganglionic cholinergic fibers.

Uses:

  • Methantheline bromide is used in combination for the managment of peptic ulcer and irritable bowel syndrome.
  • It is also used in treatment of gastritis, intestinal hypermotility, bladder irritability, cholinergic spasm and pancreatitis.
  • It is contraindicated in glaucoma.

Propantheline Bromide:

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Propantheline Bromide

  • Propantheline bromide is chemically, methyl-di(propan-2-yl)-[2-(9H-xanthene-9- carbonyloxy)ethyl]azanium;bromide.
  • It competitively antagonizes acetylcholine activity mediated by muscarinic receptors at neuroeffector sites on smooth muscle and exocrine gland cells.
  • It is five times more potent than methantheline and also finds importance to control the symptoms of irritable bowel syndrome.

Uses:

  • Propantheline bromide is an antimuscarinic agent used for the treatment of excessive sweating (hyperhidrosis), cramps or spasms of the stomach, intestines or bladder, and involuntary urination (enuresis).
  • Propantheline relaxes the gut muscle and can relieve pain in conditions caused by spasm of the muscle in the gut.
  • It relaxes the smooth muscle in the bladder and prevents the involuntary spasms that can allow leakage of urine from the bladder in the condition known as enuresis (involuntary urination in adults).
  • Propantheline can also be used to treat excessive sweating because acetylcholine block also reduces secretions such as sweat and tears.

Amino Alcohol Ether Derivatives:

These cholinergic blockers were introduced as antiparkinsonian drugs due to their beneficial effect in the management of parkinsonism. These derivatives also posess antihistaminic properties since they are structurally related to H1 class of a antihistaminic drugs.

Benztropine Mesylate:

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Benztropine Mesylate

  • Benztropine mesylate is chemically, 3-benzhydryloxy-8-methyl-8-azabicyclo[3.2.1] octane; methanesulfonic acid.
  • It is a centrally acting anticholinergic/antihistamine agent.
  • It is a selective M1 muscarinic acetylcholine receptor antagonist.
  • It partially blocks cholinergic activity in the basal ganglia and has also been shown to increase the availability of dopamine by blocking its reuptake and storage in central sites, and as a result, increasing dopaminergic activity.
  • It antagonizes the effect of acetylcholine, decreasing the imbalance between the neurotransmitters acetylcholine and dopamine, which may improve the symptoms of early parkinson’s disease.

Uses:

  • Benztropine mesylate is a centrally active muscarinic antagonist that has been used in the symptomatic treatment of Parkinson’s disease.
  • It is used to reduce extrapyramidal side effects of antipsychotic treatment.
  • It improves tremor and may alleviate rigidity and bradykinesia.
  • Benzatropine is also used for the treatment of dystonia, a rare disorder that causes abnormal muscle contraction, resulting in twisting postures of limbs, trunk, or face.

Orphenadrine Citrate:

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Orphenadrine Citrate

  • Orphenadrine citrate is chemically, phenylmethoxy]ethanamine; 2-hydroxypropane-1,2,3-tricarboxylic acid.
  • It is an anticholinergic drug of the ethanolamine antihistamine class (it is closely related to diphenhydramine).
  • It blocks cholinergic receptors, thereby interfering with the transmission of nerve impulses from the spinal cord to the muscles.

Uses:

  • Orphenadrine citrate is used to treat muscle pain and to help with motor control in parkinson’s disease.
  • It is used to relieve pain caused by muscle injuries like strains and sprains.
  • Orphenadrine and other muscle relaxants are sometimes used to treat pain arising from rheumatoid arthritis.
  • It also possess antihistamine property due to H1 receptor antagonist action.

Amino Alcohol Derivatives:

These cholinergic blockers were introduced in 1940s, and were established for their antispasmodic importance. They are also used as antiparkinsonian drugs due to their beneficial effect in the management of parkinsonism.

These derivatives have structural similarity with atropine derivatives possessing a bulky group and a cyclic amino function, amino propanol arrangement with three carbon chains between the hydroxy function and the amino group is the common structural features of these amino alcohol derivatives.

Biperidin Hydrochloride:

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Biperidin Hydrochloride

  • Biperiden hydrochloride is chemically, 1-(5-bicyclo[2.2.1]hept-2-enyl)-1-phenyl-3- piperidin-1-ylpropan-1-ol;hydrochloride.
  • It is a muscarinic antagonist that has effects in both the central and peripheral nervous systems.

Uses:

  • Biperiden hydrochloride is used to treat Parkinson disease.
  • Common side effects include blurred vision, dry mouth, sleepiness, constipation, and confusion.
  • It should not be used in people with a bowel obstruction or glaucoma.
  • It is used to improve acute extrapyramidal side effects, it relieves muscle rigidity, reduces abnormal sweating and salivation, improves abnormal gait (particular way of walking) and to lesser extent tremor.
  • It has a strong nicotine receptor blocking effect and helpful in nicotine induced convulsions hence, biperiden has been analyzed as an alternative anticonvulsant for usage.
  • It is contraindicated in all forms of epilepsy.

Procyclidine Hydrochloride:

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Procyclidine Hydrochloride

  • Procyclidine hydrochloride is chemically, (1R)-1-cyclohexyl-1-phenyl-3-pyrrolidin- 1-ylpropan-1-ol;hydrochloride.
  • It is a muscarinic antagonist that crosses the blood-brain barrier.
  • It acts by blocking central cholinergic receptors, and thus balancing cholinergic and dopaminergic activity in the basal ganglia.

Uses:

  • Procyclidine is principally used for the treatment of drug-induced extra pyramidal disorders and in parkinsonism, akathisia (feeling of inner restlessness) and acute dystonia (sustained muscle contractions) or secondary dystonia.
  • It is a second-line drug for the treatment of parkinson’s disease. It improves tremor, but not rigidity or bradykinesia.
  • It also has antispasmodic effect on smooth muscle and may produce mydriasis and reduction in salivation.

Tridihexethyl Chloride:

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Tridihexethyl Chloride

  • Tridihexethyl chloride is chemically, (3-cyclohexyl-3-hydroxy-3-phenylpropyl)- triethylazanium; chloride.
  • It is an anticholinergic, antimuscarinic and antispasmodic drug.
  • It may block all the three (M1, M2 and M3) types of muscarinic receptors.
  • It has a pronounced antispasmodic and antisecretory effect on the gastrointestinal tract.

Uses:

  • It may be used, usually in combination with other drugs, to treat acquired nystagmus (involuntary eye movement) or peptic ulcer disease.

Amino Amide Derivatives:

The amino amide derivatives are structurally similar to the amino alcohol derivatives, where the polar hydroxyl function is replaced by a polar amide function resulting in reduced metabolism, hence these derivatives have increased duration of action in comparison to the amino alcohol derivatives.

They also have structural features similarity with atropin derivatives. They possess a bulky aromatic group usually a phenyl moiety with respect to the both ‘A’ and ‘B’ substitutents on the pivotal carbon and amide function.

Isopropamide Iodide:

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Isopropamide Iodide

  • Isopropamide iodide is chemically, (4-amino-4-oxo-3,3-diphenylbutyl)-methyl- di(propan-2-yl)azanium;iodide.
  • It is most often provided as an iodide salt, but is also available as a bromide or chloride salt.
  • It is a long-acting quaternary anticholinergic drug.

Uses:

  • Isopropamide iodide is used in the treatment of peptic ulcers and other gastrointestinal disorders involving hyperacidity (gastrointestinal acidosis) and hypermotility.

Tropicamide:

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Tropicamide

  • Tropicamide is chemically, N-ethyl-3-hydroxy-2-phenyl-N-(pyridin-4-ylmethyl)- propanamide.
  • It is a synthetic muscarinic antagonist with having similar action to that of atropine and with an anticholinergic property.
  • It binds to and blocks the muscarinic receptors (M4) in the sphincter and ciliary muscle in the eye and thus works as a mydriatic and relaxes the sphincter muscle of the Iris and paralysis of the ciliary muscle.

Uses:

  • Tropicamide is an anticholinergic drug and is used to dilate the pupil and helps in examination of the eye.
  • It is a diagnostic agent and is used to produce short-duration mydriasis and cycloplegia.

Miscellaneous Derivatives:

Drugs discussed in the miscellaneous derivatives are synthetic molecules without any structural resemblance with the other synthetic anticholinergic agents.

Ethopropazine Hydrochloride:

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Ethopropazine Hydrochloride

  • Ethopropazine hydrochloride is chemically, N,N-diethyl-1-phenothiazin-10-ylpropan- 2-amine;hydrochloride.
  • It is a phenothiazine derivative with anticholinergic activity.
  • Drowsiness and dizziness are the most common side effects.
  • It is contraindicated in conditions such as glaucoma because of its mydriatic effect.

Uses:

  • Ethopropazine hydrochloride is used as an antiparkinsonian agent that also has antihistamine, and antiadrenergic actions.
  • It is also used in the alleviation of the extrapyramidal syndrome induced by drugs.
  • It is also effective on tremor, sialorrhea, (excessive salivation) and oculogyric crises (prolonged involuntary upward deviation of the eyes).

Synthesis

Carbachol

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Carbachol synthesis

Neostigmine

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Neostigmine Synthesis

Ipratropium Bromide

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Ipratropium Bromide Synthesis

Dicyclomine Hydrochloride

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Dicyclomine Hydrochloride synthesis

Procyclidine Hydrochloride

Medicinal Chemistry Drugs Acting On Autonomic Nervous System 2 Procyclidine Hydrochloride Synthesis

Multiple Choice Questions

Question 1. Acetylcholine is not a specific neurotransmitter at:

  1. Sympathetic ganglia
  2. Sympathetic postganglionic nerve endings
  3. Parasympathetic ganglia
  4. Parasympathetic postganglionic nerve endings

Answer. 2. Sympathetic postganglionic nerve endings

Question 2. Muscarinic receptors are located in:

  1. Autonomic ganglia
  2. Skeletal muscle neuromuscular junctions
  3. Autonomic effector cells
  4. Sensory carotid sinus baroreceptor zone

Answer. 3. Autonomic effector cells

Question 3. Substitution of acetylcholine at ẞ-position with respect to the nitrogen atom:

  1. Decreases the nicotinic activity
  2. Increases the nicotinic activity
  3. Increases the muscarinic activity
  4. Decreases both nicotinic and muscarinic activity

Answer. 3. Increases the muscarinic activity

Question 4. Indicate the location of M2 cholinoreceptor type:

  1. Heart
  2. Glands
  3. Smooth muscle
  4. Endothelium

Answer. 1. Heart

Question 5. Which of the following cholinomimetics activates both muscarinic and nicotinic receptors?

  1. Lobeline
  2. Pilocarpine
  3. Nicotine
  4. Bethanechol

Answer. 4. Bethanechol

Question 6. Atropine contains

  1. One asymmetric carbon
  2. Three asymmetric carbons
  3. Two asymmetric carbons
  4. Four asymmetric carbons

Answer. 2. Three asymmetric carbons

Question 7. Indicate a cholinomimetic agent, which is related to direct-acting drugs:

  1. Edrophonium
  2. Physostigmine
  3. Carbachol
  4. Isofluorophate

Answer. 3. Carbachol

Question 8. Acetylcholine is not used in clinical practice because:

  1. It is very toxic.
  2. The doses required are very high.
  3. It is very rapidly hydrolyzed.
  4. It is very costly.

Answer. 3. It is very rapidly hydrolyzed.

Question 9. Parasympathomimetic drugs cause:

  1. Bronchodilation
  2. Mydriasis
  3. Bradycardia
  4. Constipation

Answer. 3. Bradycardia

Question 10. Which of the following direct-acting cholinomimetics is mainly muscarinic in action?

  1. Bethanechol
  2. Carbachol
  3. Acetylcholine
  4. None of the above

Answer. 1. Bethanechol

Question 11. Which of the following direct-acting cholinomimetics has the shortest duration of action?

  1. Acetylcholine
  2. Methacholine
  3. Carbachol
  4. Bethanechol

Answer. 1. Acetylcholine

Question 12. Which of the following cholinomimetics is indirect-acting?

  1. Lobeline
  2. Edrophonium
  3. Pilocarpine
  4. Carbachol

Answer. 2. Edrophonium

Question 13. Indicate a reversible cholinesterase inhibitor:

  1. Isofluorophate
  2. Carbachol
  3. Physostigmine
  4. Parathion

Answer. 3. Physostigmine

Question 14. Which of the following cholinesterase inhibitors is irreversible?

  1. Physostigmine
  2. Edrophonium
  3. Neostigmine
  4. Isofluorophate

Answer. 4. Isofluorophate

Question 15. Indicate cholinesterase activator:

  1. Pralidoxime
  2. Edrophonium
  3. Pilocarpine
  4. Isofluorophate

Answer. 1. Pralidoxime

Question 16. Which of the following cholinomimetics is commonly used in the treatment of glaucoma?

  1. Pilocarpine
  2. Lobeline
  3. Acetylcholine
  4. Neostigmine

Answer. 1. Pilocarpine

Question 17. Chronic long-term therapy of myasthenia is usually accomplished with:

  1. Edrophonium
  2. Neostigmine
  3. Echothiophate
  4. Carbachol

Answer. 2. Neostigmine

Question 18. Indicate the reversible cholinesterase inhibitor, which penetrates the blood-brain barrier:

  1. Physostigmine
  2. Edrophonium
  3. Neostigmine
  4. Piridostigmine

Answer. 1. Physostigmine

Question 19. Indicate a muscarinic receptor-blocking drug:

  1. Scopolamine
  2. Pipecuronium
  3. Trimethaphan
  4. Pilocarpine

Answer. 1. Scopolamine

Question 20. The mechanism of atropine action is:

  1. Competitive ganglion blockade
  2. Competitive muscarinic blockade
  3. Competitive neuromuscular blockade
  4. Non-competitive neuromuscular blockade

Answer. 2. Competitive muscarinic blockade

Question 21. Atropine is highly selective for:

  1. M1-receptor subtype
  2. M2-receptor subtype
  3. M3-receptor subtype
  4. All of the above

Answer. 4. All of the above

Question 22. Atropine causes:

  1. Miosis, a reduction in intraocular pressure and cyclospasm
  2. Mydriasis, a rise in intraocular pressure and cycloplegia
  3. Miosis, a rise in intraocular pressure and cycloplegia
  4. Mydriasis, a rise in intraocular pressure and cyclospasm

Answer. 2. Mydriasis, a rise in intraocular pressure and cycloplegia

Question 23. Atropine causes:

  1. Bradycardia, hypotension and bronchoconstriction
  2. Tachycardia, little effect on blood pressure and bronchodilation
  3. Decrease in contractile strength,conduction velocity through the AV node
  4. Tachycardia, hypertensive crisis and bronchodilation

Answer. 2. Tachycardia, little effect on blood pressure and bronchodilation

Question 24. Atropine is frequently used prior to administration of inhalant anesthetics to reduce:

  1. Muscle tone
  2. Secretions
  3. Nausea and vomiting
  4. All of the above

Answer. 2. Secretions

Question 25. Which of the following drugs is useful in the treatment of uterine spasms?

  1. Carbachol
  2. Vecuronium
  3. Atropine
  4. Edrophonium

Answer. 3. Atropine

Question 26. Indicate the antimuscarinic drug, which is used as a mydriatic:

  1. Pilocarpine
  2. Neostigmine
  3. Homatropine
  4. Ipratropium

Answer. 3. Homatropine

Question 27. Which of the following agents is used as an inhalation drug in asthma?

  1. Atropine
  2. Ipratropium
  3. Lobeline
  4. Homatropine

Answer. 2. Ipratropium

Question 28. Indicate an antimuscarinic drug, which is effective in the treatment of mushroom poisoning:

  1. Pralidoxime
  2. Homatropine
  3. Pilocarpine
  4. Atropine

Answer. 4. Atropine

Drugs Acting On Cns Sedative And Hypnotics Notes

Drugs Action On Central Nervous System Introduction

The drugs fall under this category having common effects as depression of neuronal activity in the Central Nervous System (CNS), i.e. the brain and spinal cord. In most of the cases the entire brain is intended as target organ, whereas in a few cases skeletal muscle or the spinal cord is targeted. Various classes of the drugs falling under CNS depressant are anxiolytics, sedatives and hypnotics, general anaesthetics, anticonvulsants and antipsychotics.

The Anxiolytic drugs are used is in the treatment of the anxiety disorders, which are conditions characterized by excessive or inappropriate anxiety. The major use of sedative is to calm the patient, whereas hypnotic drugs are used in the treatment of insomnias which are failures to get adequate sleep. The clinical significance of general anaesthetic agents is to produce unconsciousness and loss of perception to pain during surgical procedures.

Anticonvulsant drugs are mainly used to prevent or lessen the sudden excessive electrical activity in brain neurons that is a characteristic of the convulsions or epilepsies. Antipsychotics are used in the disorders like psychoses, most notably the schizophrenias.

Sedatives And Hypnotics Introduction

Hypnotics are used to induce sleep resembling the natural one. They are central nervous system depressants; and produce drowsiness and sound sleep. They find importance in the management of insomnia (sleeplessness) and also as a preanesthetic medication. They find similarity with sedatives.

A sedative drugs induce sedation by reducing irritability or excitement and are central nervous system depressants. Sedative drugs serve to calm or relieve anxiety, restlessness and emotional tension. Whilst, hypnotic drugs are to initiate and/or to sustain a quality sleep in the management of insomnia.

These drugs produce dose-dependent effects highlighting their anxiolytic effect and to that to produce sound sleep. Hence, they are collectively known as sedative-hypnotic drugs. Sedative-hypnotic drugs may produce dependence, and that optimal treatment is to use the lowest effective dose for the shortest therapeutic time period necessary, with gradual discontinuation. They are habit-forming and chronic use is known to disturb the human sleep pattern.

Insomnia is a sleep disorder highlighted with trouble sleeping or sleeplessness which may either no quality or quantity of sound sleep. Insomnia may be indicated with difficulty in falling asleep or staying asleep for the definite duration. Insomnia is followed by daytime sleepiness with low energy, irritability, and also a depressed mood.

Read and Learn More Medicinal Chemistry III Notes

Insomnia can be transient, short term or long term, lasting for days or weeks, or lasting for more than a month. Insomnia can occur independently or as a result of another problem like psychological stress, chronic pain, heart failure, hyperthyroidism, heartburn, restless leg syndrome, menopause and even dependence for caffeine, nicotine, and alcohol.

In addition to benzodiazepines, barbiturates, and a miscellaneous group, many drugs belonging to other pharmacological classes may possess one or more of the anxiolytic, sedative and hypnotic activities.

Mechanism Of Action Of Sedatives And Hypnotics

Gama Amino Butyric Acid (GABA) Activity Enhancers / GABA Receptor Modulators:

The GABAA receptor is one of the two ligand-gated ion channels responsible for mediating the effects of GABA, the major inhibitory neurotransmitter in the brain. The GABAergic stimulation in the brain via the activation of the GABAA also known as benzodiazepine receptors or referred as chloride channel complex, allows increased chloride conductance, thereby resulting in CNS depressant effect. The agonist drugs like barbiturates, benzodiazepines; bind to an allosteric site on the postsynaptic GABAA receptor complex that increase chloride conductance.

Medicinal Chemistry Drugs Action On Central Nervous System Mechanism of Sedative and Hyponotic drugs

Classification Of Hypnotics And Sedatives

An arbitrary classification of hypnotics and sedatives is as follows:

  • Benzodiazepine derivatives eg. Chlordiazepoxide, Diazepam, Oxazepam, Chlorazepate, Lorazepam, Alprazolam, Zolpidem.
  • Barbiturate derivatives e.g. Barbital, Phenobarbital, Mephobarbital, Amobarbital, Butabarbital, Pentobarbital, Secobarbital.
    • Long acting (Duration of action more than 6 hours) e.g. Barbital, Phenobarbital, Mephobarbital.
    • Intermediate acting (Duration of action of 3-6 hours) e.g. Amobarbital, Butabarbital.
    • Short acting (Duration of action of less than 3 hours) e.g. Pentobarbital, Secobarbital.
  • Miscellaneous:
    • Amide and Imide derivatives e.g. Glutethmide.
    • Alcohol and their carbamate derivatives e.g. Meprobomate, Ethchlorvynol.
    • Aldehyde and their derivatives e.g. Triclofos sodium, Paraldehyde.

Benzodiazepines

The benzodiazepines are lipophilic in nature and are in non-ionized form and thus well absorbed from the GI tract. The benzodiazepine derivatives with 3-hydroxyl function are polar compounds and are absorbed slowly in comparison to the other lipophilic derivatives.

Due to higher lipophilic nature, these drugs are bound to plasma proteins; but do not compete with other protein bound drugs. The benzodiazepine derivatives are effectively distributed because of its more lipophilic nature.

Structure-Activity Relationship Of Benzodiazepines:

Medicinal Chemistry Drugs Action On Central Nervous System Benzodiazepines

Benzodiazepine derivatives are chemically 5-aryl-1,4-benzodiazepine with a carboxamide function in the seven-member diazepine ring moiety. The SAR study has been classified into three fragments of the 5-aryl-1,4-benzodiazepine nucleus.

Ring A-Aryl or Heteroaryl Moiety

  • The primary fragment of the aryl or heteroaryl moiety as the ring A, the aromatic or heteroaromatic ring A is prerequisite for the activity. The moiety exhibits л-л stacking with the aromatic amino acid residues of the GABAA receptor.
  • Heteroaromatic moiety derivatives are more potent than aromatic moiety derivatives. An electronegative substituent like -Cl, -NO2 or -CF3 function with electron withdrawing ability at position 7 is required for activity, and better electro-negativity directly correlates with higher activity..
  • Any substitution at positions 6, 8, and 9 leads to loss of activity.

Ring B-1,4-benzodiazepine Moiety

  • The 1,4-benzodiazepine moiety represents the ring B; the second fragment of the SAR study.
  • The saturation of the double bond at positions 4 and 5 (N=C) or shifting of the same to the positions 3 and 4 results in decrease in the activity.
  • Any alkyl substitution irrespective of the higher or lower function at the position 3 leads to decrease in the activity.
  • Substitution with a hydroxyl (-OH) function at position 3 does not affect the activity of the molecule, but the polar function is readily converted to the glucuronide conjugate and is excreted in urine and thus is short-lived, resulting in decreased duration of action. It highlighted the importance of derivatives with short activity and helpful to induce sleep.
  • The absence of the hydroxyl group at position 3 (no substitution) indicates compounds with better duration of action. These derivatives are pharmacokinetically important, derivatives lacking a hydroxyl group at position 3 are non-polar in nature, and are metabolized to the pharmacologically active 3-hydroxylated metabolite in the hepatic CYP450 system slowly. The active 3-hydroxyl metabolites have longer half- lives resulting in increased duration of action.
  • The nitrogen at position 1 and the carbonyl (C=O) function at position 2 are important for activity.
  • The N-alkyl side chains are tolerated, usually a lower alkyl function.
  • A proton-accepting group, i.e. carbonyl (C=O) function at position 2 is required and interacts with histidine residue at the receptor core (a proton donor) in benzodiazepine binding site of GABAA receptor.
  • A triazole or imidazole rings are also equally effective, since they are also capable accepting a proton from the histidine residue at the receptor core and exhibiting the H-bonding. The triazole or imidazole moiety can be fused on positions 1 and 2, and eventually lead to the increase in the activity. Derivatives like triazolam and alprazolam highlight drugs with a fused triazolo ring.
  • While, Midazolam is a derivative indicated with a fused imidazole ring. Interestingly, an electron-attracting group at position 7 is not required for activity in few of these derivatives.
  • These triazole or imidazole rings derivatives are short acting as they are rapidly metabolized by a-hydroxylation of the methyl substituent on the triazolo or imidazolo moiety similar to benzylic oxidation via CYP450 mixed oxidase function. The resulting active a-hydroxylated metabolites are inactivated by glucuronidation. These derivatives are also metabolized by 3-hydroxylation of the benzodiazepine ring.

Ring C-Phenyl Substituent

  • A phenyl ring C at position 5 promotes activity.
  • Substitution on the phenyl group at ortho (2′) or diortho (2′,6′) positions with electron-withdrawing groups results in increased activity.
  • Whilst, substitution on the para (4′) results in profound decrease in activity.

Metabolism of Benzodiazepines:

The benzodiazepines are extensively metabolized via CYP450 mixed function oxidase system, majorly CYP4503A4 and CYP2C19; some of the metabolites of selective benzodiazepines are active and few also have longer half-lives indicating their increased duration of action.

The CYP3A4 inhibitors like ketoconazole or food like grapefruit juice inhibits their metabolism and can affect their duration of action and equally toxicity. The benzodiazepine derivatives have lower abuse potential and a much greater safety margin than that of the barbiturates.

Medicinal Chemistry Drugs Action On Central Nervous System Metabolism of Benzodiazepines

Chlordiazepoxide:

Medicinal Chemistry Drugs Action On Central Nervous System Chlordiazepoxide

  • Chlordiazepoxide is chemically, 7-chloro-2-methylamino-5-phenyl-3H-1,4-benzo- diazepine-4-oxide.
  • It is a sedative and hypnotic drug under the benzodiazepine class and the first benzodiazepine to be synthesized.
  • It is a long-acting drug and even its metabolite is active and has a long half-life.
  • It enhances GABAA receptor activity and results in an increased binding of the inhibitory neurotransmitter GABA to the GABAA receptor leading to inhibitory effects on the Central Nervous System.

Uses:

  • Chlordiazepoxide is used in the management of epilepsy, anxiety, insomnia and alcohol or drug abuse withdrawal symptoms.

Diazepam:

Medicinal Chemistry Drugs Action On Central Nervous System Diazepam

  • Diazepam is chemically, 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzo- diazepin-2-one.
  • It is a sedative and hypnotic drug under the benzodiazepine class and produces a calming effect.
  • It acts by increasing the effect of the neurotransmitter GABA. It enhances GABAA receptor activity leading to Central Nervous System depression.

Uses:

  • Diazepam is most frequently prescribed medications in the world under the class of benzodiazepines.
  • It is used in the management of epilepsy, anxiety, insomnia, muscle spasms, seizures, trouble sleeping, restless legs syndrome and alcohol or drug abuse withdrawal symptoms.

Oxazepam:

Medicinal Chemistry Drugs Action On Central Nervous System Oxazepam

  • Oxazepam is chemically, 7-Chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1, 4-benzo- diazepin-2-one.
  • Oxazepam acts on benzodiazepine receptors, resulting in increased effect of GABA to the GABAA receptor which results in inhibitory effects on the Central Nervous System. Oxazepam exists as a racemic mixture, and has no therapeutic benefit to the administration of a single enantiomer over the racemic mixture.
  • It is a short acting benzodiazepine with a slow onset of action. It is an example for an active metabolite formed during the metabolism of diazepam and other benzodiazepine drugs.
  • It is a 3-hydroxy benzodiazepine derivative highlighting its slow absorption and short action, and safer than other benzodiazepines in patients with impaired liver function as it does not require hepatic oxidation, and is simply metabolized by glucuronidation. So oxazepam is less likely to accumulate and cause adverse reactions.

Uses:

  • Oxazepam is used in the management of anxiety, insomnia and in the control of symptoms of alcohol withdrawal syndrome.

Clorazepate:

Medicinal Chemistry Drugs Action On Central Nervous System Clorazepate

  • Clorazepate is chemically, 7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzo- diazepine-3-carboxylic acid.
  • It acts on benzodiazepine receptors, resulting in increased effect of GABA to the GABAA receptor which results in inhibitory effects on the Central Nervous System.
  • Clorazepate is an example for prodrug, the parent drug undergoes decarboxylation in the acidic environment of the GIT to form nordiazepam; a non-polar and active metabolite with a half-life of more than forty hours.
  • The metabolite desmethyldiazepam is responsible for its therapeutic effects. The desmethyldiazepam is further metabolized to oxazepam which also possesses activity.

Medicinal Chemistry Drugs Action On Central Nervous System Active metabolite oxazepam

Uses:

  • It is a long acting benzodiazepine medication, and finds importance as anxiolytic, anticonvulsant, sedative, hypnotic, and skeletal muscle relaxant.

Lorazepam:

Medicinal Chemistry Drugs Action On Central Nervous System Lorazepam

  • Lorazepam is chemically, 7-Chloro-5-(2-chlorophenyl)-1,3-dihydro-3-hydroxy-2H- 1,4-benzodiazepin-2-one.
  • It acts on benzodiazepine receptors, resulting in increased effect of GABA to the GABAA receptor which results in inhibitory effects on the Central Nervous System.

Uses:

  • Lorazepam is a benzodiazepine medication, used to treat anxiety, insomnia, seizures, and chemotherapy-induced nausea and vomiting.
  • It is also finds importance as preoperative medication.

Alprazolam:

Medicinal Chemistry Drugs Action On Central Nervous System Alprazolam

  • Alprazolam is chemically, 8-chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4] benzodiazepine.
  • It acts on benzodiazepine receptors, resulting in increased effect of GABA to the GABAA receptor which results in inhibitory effects on the Central Nervous System.

Uses:

  • Alprazolam is a potent, short-acting benzodiazepine drug, and finds importance as an anxiolytic, sedative and hypnotic.
  • It is commonly used for the treatment of generalized anxiety disorder or social anxiety disorder.

Zolpidem:

Medicinal Chemistry Drugs Action On Central Nervous System Zolpidem

  • Zolpidem is chemically, N,N,6-Trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3- acetamide.
  • It acts on benzodiazepine receptors, resulting in increased effect of GABA to the GABAA receptor which results in inhibitory effects on the Central Nervous System.

Uses:

  • Zolpidem is a non-benzodiazepine and hypnotic of the imidazopyridine class, a medication primarily used for the short term treatment of sleeping problems.

Barbiturates

The barbiturates were previously used extensively as sedative-hypnotic drugs. Now, they have been replaced by the safer benzodiazepine. Barbiturates act by binding to an allosteric recognition site on GABAA receptors that positively modulate the effect of the GABAA. They bind at different binding sites unlike benzodiazepines, and have increased duration of the GABA-gated chloride channel openings.

Medicinal Chemistry Drugs Action On Central Nervous System Activity Relationship of Barbiturates

  • The barbiturates are chemically 5,5-disubstituted-2,4,6-trioxohexahydropyrimidine or 5,5-disubstituted barbituric acids.
  • The structure of barbituric acids indicates their acidic character.
  • The derivatives without methyl substituents on the nitrogen exhibit a pKa’s of about
  • 7.6; and with a methyl substituent they have pKa’s of about 8.4.
  • The free acids have poor water solubility and good lipid solubility.
  • The 2-thiobarbiturates also have greater lipophilicity, as the sulfur atom increases lipid solubility.
  • Sodium salts of the barbiturates are readily prepared and are water soluble.

Structure-Activity Relationship Of Barbiturates:

Medicinal Chemistry Drugs Action On Central Nervous System Activity Relationship of Barbiturates

  • The barbituric acid molety Le. 24,6-trioxohexahydropyrimidine lacks any kind of depressant activity.
  • The disubstitution at position 5 of barbituric acid, where both the hydrogens are needed to be replaced by an akyl/aryl group for CNS depression activity.
  • The activity is marked due to the replacement of both the hydrogens at position 5, as even if one of the hydrogen is available at position 5, the molecule 2,4,6-trioxohexahydropyrimidine or 5-substituted-24,6-trioxohexahydropyrimidine exhibits tautomerization resulting in a highly acidic trihydroxypyrimidine close to a pka value 4. Thus the compound is largely in the anionic form at physiological pH, with little nonionic lipid-soluble nature available to cross the blood-brain barrier.
  • The substitution with alkyls function of both the hydrogens at position 5 of the molecule confers activity with a rapid onset, but a decrease in duration of action.
  • This is attributed to the increasing lipophilicity, as an increase in lipophilicity leads to quick or rapid onset of action, and this may be attributed to an ability to penetrate the BBB. An increase in lipophilicity also enhances the hypnotic potency. Redistribution of the molecules confers to decreased concentration of the molecule in CNS and partitioning out of the brain to other sites results in decreased duration of action.
  • The short duration of action may also be attributed to its ability to penetrate liver microsomes and biotransformed inactive metabolite.
  • The substitution at position 5 with an alkyl group can be of increasing carbon skeleton up to about 5 to 6 carbon moiety for optimal activity. An increase beyond 7 to 9 carbon moiety leads to decrease in depression activity and precipitation of convulsion.
  • Substitution of branched cyclic or unsaturated carbon moiety leads to derivatives with short duration of action. These derivatives are oxidative metabolized to form hydroxyl function polar metabolite and eliminated rapidly via conjugation.
  • Substitution of lower alkyl group like ethyl and a phenyl moiety at position 5 results in compounds with lower lipophilicity and leads to derivatives with slower onset of action, but relatively longer duration of action.
  • There is an inverse correlation between the total number of carbon atoms substituted on the position 5 and the duration of action.
    • This can be better understood based on the character of the substituent taken into account.
    • The relatively polar character of a phenyl substituent results in long acting barbiturate.
    • An alkyl substituent (3-4 carbon aliphatic chain), branching of alkyls, presence of an isolated double or triple bond substituted derivatives result in compounds with intermediate to short active.
  • Substitution at position 1 on nitrogens with lower alkyl group results with increased lipophilicity of the molecule leading to increased activity.
  • Di-substitution on both the nitrogen at position 1 and 3 results in inactive compounds, this is attributed to the pharmacokinetic parameter, due to the inability to from sodium salt of the barbituric acid and completely water insoluble derivative.
  • Therefore following derivatives are only active:
    • 5,5-disubstituted barbituric acid.
    • 1,5,5-trisubstituted barbituric acid.
    • 5,5-disubstituted thio-barbituric acid.
  • While derivatives given below are inactive:
    • Non-substituted barbituric acid.
    • 5-monosubstituted barbituric acid.
    • 1,3-disubstituted barbituric acid.
    • 1,3,5,5-tetrasubstituted barbituric acid.

Synthesis of Barbiturates:

The barbiturates are 5,5-disubstituted barbituric acids. The following scheme shows how the 5.5-dialkyl compounds are synthesized.

Medicinal Chemistry Drugs Action On Central Nervous System Synthesis of Barbiturates

Metabolism of Barbiturates:

The substituent at position 5 can influence the ease of oxidative metabolism by effects on bond strengths as well as by influencing partitioning. The absorption from the GI tract of the barbiturates is optimal and exhibits substantial plasma proteins binding. The metabolism pattern of the compounds with low lipophilicity is usually excreted intact in the urine, while highly lipophilic compounds are excreted after metabolism to polar metabolites.

With the increase in the lipophilicity, generally the rate of metabolism increases, except for compounds having extremely high lipophilicity like thiopental, which tend to depotize and are thus relatively unavailable for metabolism.

Metabolism generally follows an oxidative biotransformation. N-methylation decreases duration of action, by increasing the concentration of the lipid-soluble free barbituric acid. 2-thiobarbiturates have a very short duration of action because its lipophilicity is extremely high, promoting depotization.

Side-effects of Barbiturates:

The common side effects of barbiturates include headache, drowsiness, dizziness, ataxia, respiratory depression, hypersensitivity reactions, paradoxical excitement and confusion.

Long Acting Barbiturates (Duration of action > 6 hours):

Barbital:

Medicinal Chemistry Drugs Action On Central Nervous System Barbital

  • Barbital is chemically, 5,5-diethyl-2,4,6(1H,3H,5H)-pyrimidinetrione.
  • It is also known as barbitone which is chemically 5,5-diethylbarbituric acid, the first commercially available barbiturate.
  • It increases the activity of the inhibitory neurotransmitter GABA to the GABAA receptor which results in inhibitory effects on the Central Nervous System.

Uses:

  • Barbital is used as a hypnotic and antiepileptic..

Phenobarbital:

Medicinal Chemistry Drugs Action On Central Nervous System Phenobarbital

  • Phenobarbital is chemically, 5-ethyl-5-phenylbarbituric acid.
  • It is a long acting barbiturate derivative and also known as Phenobarbitone, which is the oldest, but still used as anti-epileptic medication.
  • It increases the activity of the inhibitory neurotransmitter GABA to the GABAA receptor which results in increased influx of chloride ions leading to decreased excitability.
  • It also produces blockade of excitatory glutamate signaling.
  • Phenobarbital is a CYP450 inducer and hence dosing of other drugs is needed to be monitored.

Uses:

  • Phenobarbital is used as a sedative, hypnotic and also as an anticonvulsant for both generalized tonic-clonic and partial seizures.
  • It is occasionally used to treat drug withdrawal, as a pre anaesthetic medication, Crigler-Najjar syndrome and Gilbert syndrome patients to aid in the conjugation of bilirubin.

Mephobarbital:

Medicinal Chemistry Drugs Action On Central Nervous System Mephobarbital

  • Mephobarbital is chemically, 3-methyl-5-ethyl-5-phenylbarbituric acid.
  • It is a long acting barbiturate derivative, as the parent drug, it undergoes metabolically N-demethylated to phenobarbital and responsible for its activity.
  • It increases the activity of the inhibitory neurotransmitter GABA to the GABAA receptor which results in inhibitory effects on the Central Nervous System.

Uses:

  • Mephobarbital is used as a hypnotic and as an anticonvulsant.

Intermediate Acting Barbiturates (Duration of action = 3-6 hours)

Amobarbital:

Medicinal Chemistry Drugs Action On Central Nervous System Amobarbital

  • Amobarbital is chemically, 5-ethyl-5-(3-methylbutyl)-2,4,6-(1H,3H,5H)-pyrimidine- trione.
  • It is also known as amylobarbitone, which is an intermediate acting barbiturate with moderate duration of action of 4-5 hours.
  • It increases the activity of the inhibitory neurotransmitter GABA to the GABAA receptor which results in increased influx of chloride ions leading to decreased excitability.

Uses:

  • Amobarbital is used as sedative and hypnotic.

Butabarbital:

 

Medicinal Chemistry Drugs Action On Central Nervous System Butabarbital

  • Butabarbital is chemically, 5-ethyl-5-(1-methylpropyl)-2,4,6(1H,3H,SH)-pyrimidine- trione.
  • It is an intermediate acting barbiturate with moderate duration of action of 3-6 hours. It increases the activity of the inhibitory neurotransmitter GABA to the GABAA receptor which results in increased influx of chloride ions leading to decreased excitability.
  • It has a particularly fast onset of effects and short duration of action, has importance in management of severe insomnia and relieving anxiety before surgical procedures.

Uses:

  • Butabarbital is used as sedative and hypnotic.

Short Acting Barbiturates (Duration of action < 3 hours)

Pentobarbital:

 

Medicinal Chemistry Drugs Action On Central Nervous System Amobarbital

  • Pentobarbital is chemically, 5-ethyl-5-(1-methylbutyl)-2,4,6(1H,3H,5H)-pyrimidine-trione.
  • It is a short acting barbiturate with duration of action less than 3 hrs.
  • It increases the activity of the inhibitory neurotransmitter GABA to the GABAA receptor which results in increased influx of chloride ions leading to decreased excitability.

Uses:

  • Pentobarbital is used as sedative and hypnotic.
  • It also finds importance as a preanesthetic medication and in control of convulsions in emergencies.
  • It has an application in reducing intracranial pressure in Reye’s syndrome, traumatic brain injury and induction of coma in cerebral ischemia patients.
  • It is also used as a veterinary anaesthetic agent.

Secobarbital:

Medicinal Chemistry Drugs Action On Central Nervous System Secobarbital

  • Secobarbital is chemically, 5-(1-methylbutyl)-5-(2-propenyl)-2,4,6(1H,3H,5H)-pyrimidinetrione.
  • It is a short acting barbiturate derivative.
  • It increases the activity of the inhibitory neurotransmitter GABA to the GABAA receptor which results in increased influx of chloride ions leading to decreased’ excitability.

Uses:

  • Secobarbital is used as an anaesthetic, anticonvulsant, anxiolytic, sedative, and hypnotic drug.

Miscellaneous Sedatives and Hypnotic Derivatives

A wide range of chemical structures (e.g. imides, amides, alcohols) can produce sedation and hypnosis resembling those produced by the barbiturates. Despite this apparent structural diversity, the compounds have generally similar structural characteristics and chemical properties.

Amide and Imide Derivatives:

Glutethimide:

Medicinal Chemistry Drugs Action On Central Nervous System Glutethimide

  • Glutethimide is chemically, 2-ethyl-2-phenyl glutarimide.
  • It is one of the most active non-barbiturate hypnotics that is structurally similar to the barbiturates. Glutethimide is highly lipophilic and undergoes extensive oxidative metabolism with a half-life period of approximately 10 hours.

Uses:

  • It is used as a hypnotic and sedative drug.

Alcohols and their Carbamate Derivatives:

Meprobamate:

Medicinal Chemistry Drugs Action On Central Nervous System Meprobamate

  • Meprobamate is chemically, 2-methyl-2-propyl-1,3-propanediol dicarbamate.
  • Meprobamate does not act through GABA system.
  • It has inter-neuronal blocking properties at the level of the spinal cord, and responsible for its skeletal muscle relaxation.

Uses:

  • Meprobamate is indicated as an antianxiety agent and also as a sedative and hypnotic agent.
  • It is also effective against absence seizures and also a centrally acting skeletal muscle relaxant.

Ethchlorvynol:

Medicinal Chemistry Drugs Action On Central Nervous System Ethchlorvynol

  • Ethchlorvynol is chemically, 1-chloro-3-ethyl-1-penten-4-yn-3-ol.
  • It is a mild sedative and hypnotic with a quick onset and short duration of action. It is highly lipophilic and extensively metabolized to its secondary alcohol.
  • It is highly habit forming and extremely physically addictive.
  • A mechanism of action is similar to the benzodiazepines and barbiturates.
  • It increases the activity of the inhibitory neurotransmitter GABA to the GABAA receptor which results in increased influx of chloride ions leading to decreased excitability.

Uses:

  • Ethchlorvynol is used as a mild sedative and hypnotic drug.

Aldehydes and Their Derivatives

Triclofos sodium:

Medicinal Chemistry Drugs Action On Central Nervous System Triclofos sodium

  • Triclofos sodium is chemically, sodium-2,2,2-trichloroethyl hydrogen phosphate.
  • It is a prodrug which is metabolized in the liver into the active drug trichloro ethanol.
  • As trichloroethanol may cause liver damage, therefore triclofos should not be used for extended periods.
  • The half-life of triclofos is long and it may cause drowsiness the next day.

Uses:

  • Triclofos sodium is a sedative hypnotic drug used seldom for treating insomnia, as it caused dependence and only be used for the short term to relief of severe insomnia.

Paraldehyde:

Medicinal Chemistry Drugs Action On Central Nervous System Paraldehyde

  • Paraldehyde is chemically, 2,4,6-Trimethyl-1,3,5-trioxane.
  • It, also known as paracetaldehyde, is the cyclic trimer of acetaldehyde, a liquid with a strong characteristic odour and an unpleasant taste. These properties limit its use as medicine.

Uses:

  • Paraldehyde is a CNS depressant and an anticonvulsant, hypnotic and sedative.
  • It was also included in some cough medicines as an expectorant.
  • Paraldehyde is the oldest as it was introduced into clinical practice in 1882 and one of the safest hypnotics and was given to psychiatric and geriatric patients up to the 1960s.
  • As an anti-seizure, it was used in the treatment of convulsions to treat status epilepticus.
  • Industrially paraldehyde is used in resin manufacture and also as a preservative.

Synthesis

Diazepam

Medicinal Chemistry Drugs Action On Central Nervous System Diazepam synthesis

Barbital

Medicinal Chemistry Drugs Action On Central Nervous System Barbital synthesis

Multiple Choice Questions:

Question 1. Hypnotic drugs are used to treat:

  1. Psychosis
  2. Sleep disorders
  3. Narcolepsy
  4. Parkinsonian disorders

Answer. 2. Sleep disorders

Question 2. 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-one is IUPAC name of

  1. Oxazepam
  2. Nitrazepam
  3. Diazepam
  4. Chlordiazepoxide

Answer. 3. Diazepam

Question 3. The IUPAC name of glutethimide is:

  1. 3-Ethyl-3-phenyl-2,6-piperdine dione
  2. p-Sulphonamido chloroimido benzoic acid
  3. 3-(5-Nitrofurfurylideneamino)-oxazolidin-2-one
  4. 2-(2-Fluorobiphenyl-4-yl)propionic acid

Answer. 1. 3-Ethyl-3-phenyl-2,6-piperdine dione

Question 4. Which of the following chemical agents are used in the treatment of insomnia?

  1. Benzodiazepines
  2. Imidazopyridines
  3. Barbiturates
  4. All of the above

Answer. 4. All of the above

Question 5. Oxazepam is psychoneurotic has lower side effect due to:

  1. Geometric hydroxylation
  2. Ring oxidation
  3. Conjugation of 3-OH group
  4. M-demethylation

Answer. 3. Conjugation of 3-OH group

Question 6. Select a hypnotic drug, which is a benzodiazepine derivative:

  1. Zolpidem
  2. Chlorazepate
  3. Secobarbital
  4. Phenobarbitone

Answer. 2. Chlorazepate

Question 7. In benzodiazepine ring, some positions cannot be substituted to retain the depressant activity:

  1. Position 6, 8 and 9
  2. Position 4, 6 and 8
  3. Position 3, 6 and 8
  4. Position 2, 3 and 8

Answer. 1. Position 6, 8 and 9

Question 8. Introduction of -OH group at position 3 of benzodiazepine causes:

  1. Increase in activity
  2. Loss of activity
  3. Lowering of activity
  4. None of above

Answer. 3. Lowering of activity

Question 9. Tick a hypnotic agent – a barbituric acid derivative:

  1. Flurazepam
  2. Zaleplon
  3. Thiopental
  4. Triazolam

Answer. 3. Thiopental

Question 10. Substitution at 8 and 9 position in a benzodiazepine ring causes:

  1. Loss in the activity
  2. Increase in the activity
  3. Decrease in the activity
  4. None of above

Answer. 3. Decrease in the activity

Question 11. IUPAC name of Diazepam is:

  1. 7-chloro-1-methyl-5-phenyl-1,4-benzodiazepine-2-one
  2. 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-one
  3. 7-chloro-1-methyl-5-phenyl-1,4-benzodiazepine
  4. 6-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one

Answer. 2. 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-one

Question 12. Select a hypnotic drug, which is an imidazopyridine derivative:

  1. Pentobarbital
  2. Temazepam
  3. Zolpidem
  4. Chloral hydrate

Answer. 3. Zolpidem

Question 13. 2-amino-5-chlorobenzophenone is the convenient starting material for the synthesis of:

  1. Nitrazepam
  2. Diazepam
  3. Chloramphenicol
  4. Trimethoprim

Answer. 2. Diazepam

Question 14. Which of the following barbiturates is an ultra-short-acting drug?

  1. Secobarbital
  2. Amobarbital
  3. Thiopental
  4. Phenobarbital

Answer. 3. Thiopental

Question 15. Indicate the mechanism of barbiturate action (at hypnotic doses):

  1. Increasing the duration of the GABA-gated Cl- channel openings
  2. Directly activating the chloride channels
  3. Increasing the frequency of Cl-channel opening events
  4. All of the above

Answer. 1. Increasing the duration of the GABA-gated Cl- channel openings

Question 16. Alprazolam apart from 1,4-benzodiazepine ring also contains:

  1. Pyrole ring
  2. Pyrazole ring
  3. Triazole ring
  4. Furan ring

Answer. 3. Triazole ring

Question 17. Which of the following agents is preferred in the treatment of insomnia?

  1. Barbiturates
  2. Hypnotic benzodiazepines
  3. Ethanol
  4. Phenothiazide

Answer. 2. Hypnotic benzodiazepines

Question 18. Barbiturates are being replaced by hypnotic benzodiazepines because of:

  1. Low therapeutic index
  2. Suppression in REM sleep
  3. High potential of physical dependence and abuse
  4. All of the above

Answer. 4. All of the above

Question 19. The onset and duration of action of barbiturate are affected by:

  1. Number of carbon atoms situated on the 5-position
  2. Substitution of nitrogen atom at position-1
  3. Number of aromatic groups
  4. None of the above

Answer. 1. Number of carbon atoms situated on the 5-position

Question 20. Indicate the main claim for an ideal hypnotic agent:

  1. Rapid onset and sufficient duration of action
  2. Minor effects on sleep patterns
  3. Minimal “hangover” effects
  4. All of the above

Answer. 4. All of the above

Question 21. Sedative action of barbiturate is due to substitution at Cs, it is due to:

  1. High lipophilicity of group at Cs position
  2. Electronic withdrawing effect
  3. Steric effect
  4. Metal chelation

Answer. 1. High lipophilicity of group at Cs position

Question 22. Which of the following hypnotic drugs is used intravenously as anesthesia?

  1. Thiopental
  2. Phenobarbital
  3. Flurazepam
  4. Zolpidem

Answer. 1. Thiopental

Antipsychotics

Introduction

The term ‘psychosis’ used to describe a type of mental health issue that seriously affects the way that a person thinks or feels and where the person can lose contact with reality due to a disturbance in the functioning of the brain.

This type of mental health problem can happen to anyone and is much more common than most people realize. Sometimes people can have a one-off episode and after that they get better and never experience psychosis again. Other people may have episodes that come and go and they can be well for long periods in between.

There are two broad classes of functional psychotic disorders i.e. schizophrenia and bipolar disorder. Schizophrenia is a chronic condition with exacerbations, but always with some background symptoms. Bipolar disorder is generally an intermittent condition with the expectation of full recovery between episodes.

Symptoms of schizophrenia are grouped into two categories:

  • Positive symptoms: Hallucinations and delusions.
  • Negative symptoms: Social withdrawal and lack of energy and motivation that are similar to those found in depression.

Psychosis is characterized by

  • Loss of connectedness with reality.
  • Feeling of very anxious or agitated.
  • Have very low or high moods.
  • Persons may develop false ideas or beliefs about reality (delusions).
  • Persons may have false perceptions (hallucinations).
  • Persons also experience flaws in the ways they think (thought disorders).
  • Persons may think that people are against them and they may hear voices or sounds that aren’t real.
  • Poor physical health.
  • Significantly impairs work, family and social functioning.

The drugs that increase the dopaminergic activity like levodopa (a precursor), amphetamine (release of dopamine) and apomorphine (a direct dopamine receptor agonist) may aggrevate schizophrenia or produce psychosis in some patients.

Antipsychotic drugs are used mainly for the treatment of psychosis. Antipsychotic drugs diminish the underlying thought disorder associated with schizophrenia. As these agents often have a calming effect in agitated psychotic patients, they are also called as major tranquilizers and due to its lessen reactivity to emotional stimuli, with little effect on consciousness, these drugs are also known as neuroleptics.

Antipsychotic drugs are derived from several chemical groups. These drugs may be broadly classified as first-generation or typical or conventional agents (phenothiazines and older non-phenothiazines, such as haloperidol, with similar pharmacologic actions, clinical uses, and adverse effects), and second-generation or atypical agents, which are also called as newer non-phenothiazines.

Mechanism Of Action Of Antipsychotic Drugs

Medicinal Chemistry Drugs Action On Central Nervous System Antipsychotic drugs

Many antipsychotic drugs strongly block post-synaptic D2 receptors in CNS, especially in the mesolimbic-frontal limbic system and block the action of dopamine.

The most frequent uses of these agents are in manic disorders and the schizophrenias. In the manic disorders, the agents may block dopamine, (3,4-dihydroxyphenethylamine) at limbic D2 and D3 receptors, reducing euphoria, delusional thinking and hyperactivity.

In the chronic idiopathic psychoses (schizophrenias), both conventional (typical) and newer (atypical) antipsychotics appear to act to benefit positive symptoms by blocking dopamine at D2 and D3 limbic receptors. The activity of the atypical agents against negative symptoms may be due to blocking of serotonine2A receptor (5-HT2A).

Classification Of Antipsychotic Drugs

Antipsychotic drugs are classified into following categories:

  • Phenothiazines: Promazine hydrochloride, Chlorpromazine Triflupromazine, Thioridazine hydrochloride, Piperacetazine Prochlorperazine meleate, Trifluoperazine hydrochloride. hydrochloride, hydrochloride,
  • Ring Analogues of Phenothiazines: Chlorprothixene, Thiothixene, Loxapine succinate, Clozapine.
  • Fluoro buterophenones: Haloperidol, Droperidol, Risperidone.
  • Beta amino ketones: Molindone hydrochloride.
  • Benzamides: Sulpieride.

Phenothiazines

Many potentially useful phenothiazine derivatives have been synthesized and evaluated pharmacologically. Three sub-families of phenothiazine derivatives based on side chain. substitutions were found to be active against psychotic disorder.

Substitution with aliphatic derivatives (e.g., promazine, chlorpromazine and triflupromazine) and piperidine derivatives (e.g., thioridazine) are less potent, whereas substitutions with piperazine derivatives (e.g., prochlorperazine and trifluoperazine) are more potent and effective in small doses. The piperazine derivatives are more selective in their pharmacological activity.

Structure-Activity Relationship of Phenothiazines

Phenothiazines are fused tricyclic (heterocyclic) system, chemically constituted by both lipophilic and hydrophilic groups. Structural features are associated with activity. The general structure of phenothiazine antipsychotic drugs is as follows,

Medicinal Chemistry Drugs Action On Central Nervous System Phenothiazines

  • Position 2 in phenothiazine nucleus was found to be best position for substitution.
  • Substitution of electron withdrawing group (e.g. Chlorine) at position 2, increases the antipsychotic activity. (The importance of this substitution is formation of hydrogen bond between the hydrogen atoms of the protonated amino group of the side chain with an electron pair of an electron withdrawing group at position 2 substituent, to develop a dopamine like arrangement.)
  • Substitution at the position 3 can improve activity over non-substituted compounds, but not as significantly as substitution at the 2 position.
  • Substitution at positions 1 and 4 has a deleterious effect on antipsychotic activity.
  • The sulfur atom at position 5 is in a position analogous with that of p-hydroxyl of dopamine leads to assign a receptor-binding function.
  • A substituent at position 4 at phenothiazine nucleus might interfere with receptor binding by the sulfur atom.
  • Nitrogen-containing side-chain substituent at position 10 at phenothiazine nucleus is required for antipsychotic activity;

Medicinal Chemistry Drugs Action On Central Nervous System Phenothiazine nucleus

  • The ring nitrogen and side-chain nitrogen must be separated by a three carbon chain.
  • Shortening or lengthening the chain results into drastically decreased antipsychotic activity. (The three-atom chain length may be necessary to bring the protonated amino nitrogen into proximity with the 2-substituent.).
  • Decrease in size from a dimethylamino group to a monomethylamino group at side chain greatly decreases activity.
  • Substitution on the side chain with a large group (e.g. phenyl) decreases antipsychotic activity.
  • Branching with polar groups such as methyl branching on the B-position has a variable effect on antipsychotic activity.
  • The side chains are either aliphatic, piperazine, or piperidine derivatives. Substitution with piperazine side chains leads to greatest potency as well as pharmacological selectivity.

Phenothiazine Derivatives:

Medicinal Chemistry Drugs Action On Central Nervous System Phenothiazine Derivatives

Promazine Hydrochloride:

  • Promazine hydrochloride is chemically, N,N-dimethyl-3-phenothiazin-10-yl-propan- 1-amine; hydrochloride.
  • Promazine hydrochloride blocks postsynaptic dopamine receptors D1 and D2, mesolimbic receptors and decreases stimulation of psychotic effects, such as hallucinations and delusions.
  • It also blocks medullary chemoreceptor trigger zone (CTZ), of vomiting center and thus acts as antiemetic.
  • It also blocks alpha-adrenergic receptors and exhibits strong anticholinergic activity.

Uses:

  • It is primarily used as antipsychotic agent in short-term treatment of disturbed behaviour.
  • It is also used as antiemetic.

Chlorpromazine Hydrochloride:

  • Chlorpromazine hydrochloride is chemically, N, N-dimethyl-3(2-chloropheno- thiazine)-10-yl)-propan-1-amine; hydrochloride.
  • It exerts its antipsychotic effect by blocking postsynaptic dopamine receptors in cortical and limbic areas of the brain and thus preventing the excess of dopamine in the brain. Thereby it decreases stimulation of psychotic effects, such as hallucinations ,and delusions.
  • It also blocks dopamine receptors in the chemical trigger zone (CTZ) in the brain, thereby relieving nausea and vomiting.

Uses:

  • Chlorpromazine hydrochloride acts as an antipsychotic agent used to treat hallucinations and delusions.
  • It is also used as antiemetic and used in the treatment of uncontrollable hiccup.
  • It also has significant sedative and hypotensive properties, possibly reflecting central and peripheral noradrenergic blocking activity, respectively.

Triflupromazine Hydrochloride:

  • Triflupromazine hydrochloride is chemically, N,N-dimethyl-3-[2-trifluoromethyl) phenothiazine-10-yl]propan-1-amine; hydrochloride.
  • It is analogous with chlorpromazine hydrochloride, only changes of -CF3 in place of – Cl at position 2 leads to increase in antipsychotic activity.

Uses:

  • Triflupromazine hydrochloride is used as antipsychotic drug and is used to treat hallucinations and delusions.
  • It has lower sedative and hypotensive properties compared to chlorpromazine hydrochloride.

Thioridazine Hydrochloride:

  • Thioridazine hydrochloride is chemically, 10-[2-(1-methylpiperidin-2-yl)ethyl]-2- methylsulfanylphenothiazine; hydrochloride.
  • It is a piperidine sub-group of the phenothiazine block to mesolimbic postsynaptic dopamine receptor D2 and decreases dopamine activity, thereby it decreases stimulation of psychotic effects, such as hallucinations and delusions.
  • It also binds to serotonin 5-HT2 receptors, resulting in decreased serotonin activity.

Uses:

  • Thioridazine hydrochloride is a phenothiazine derivative used in the treatment of pshycotic disorder including schizophrenia.
  • It has sedative and hypotensive activity in common with chlorpromazine and less antiemetic activity.
  • Piperacetazine Hydrochloride:
  • Piperacetazine hydrochloride is chemically, 1-(10-(3-[4-(2-hydroxyethyl)-1- piperidinyl]propyl)-10H-phenothiazin-2-yl)ethanone; hydrochloride.
  • It is an antipsychotic prodrug, most notably used for schizophrenia.

Prochlorperazine Meleate:

  • Prochlorperazine meleate is chemically, 2-chloro-10-[3-(4-methylpiperazin-1-yl)- propyl]phenothiazine, meleate.
  • It is piperazine phenothiazine derivative and it blocks the postsynaptic dopamine D2-receptor in the chemoreceptor trigger zone (CTZ) of the brain and may prevent emesis.
  • It also blocks a-adrenergic receptors and results in sedation, muscle relaxation, and hypotension.

Uses:

  • Prochlorperazine maleate is a phenothiazine antipsychotic drug.
  • It is principally used in the treatment of nausea vomiting and vertigo.
  • It also has antihistaminic and anticholinergic activities.
  • It is used mainly for its antiemetic effect and not for its antipsychotic effect.

Trifluoperazine Hydrochloride:

  • Trifluoperazine hydrochloride is chemically,10-(3-(4-methylpiperazin-1-yl)propyl]-2- (trifluoromethyl) phenothiazine; hydrochloride.
  • It blocks central dopamine receptors and is used to treat delusions and hallucinations caused by an excess of dopamine.
  • It also blocks the postsynaptic dopamine D2-receptor in the chemoreceptor trigger zone (CTZ) of the brain and may prevent emesis.
  • It also blocks central adrenergic receptors and leads to anxiolytic effects.

Uses:

  • Trifluoperazine is piperazine phenothiazine derivative and antipsychotic agent that is no longer commonly used in clinical practice.
  • It also possesses anxiolytic, and antiemetic activities.

Ring Analogues of Phenothiazines

These agents have structural resemblance to that of the phenothiazine antipsychotics. Most of the drugs also have similar clinical properties and uses as that of phenothiazines.

Thioxanthene Derivative:

The thioxanthene system differs from the phenothiazine system by replacement of the N-H moiety with a carbon atom doubly bonded to the propylidene side chain with the substituent in the 2 position. These compounds (Chlorprothixene and Thiothixene) are very similar in pharmacological activities as that of phenothiazines.

Chlorprothixene:

Medicinal Chemistry Drugs Action On Central Nervous System Chlorprothixene

  • Chlorprothixene is chemically, 3-(2-chlorothioxanthen-9-ylidene)-N,N-dimethyl- propan-1-amine.
  • It is a tertiary amine typical antipsychotic drug of thioxanthenes class.
  • It produces its antipsychotic action by blocking the 5-HT2 D1, D2 and D3 receptors.
  • It also possesses histamine (H1), muscarinic and a-1 adrenergic receptors blocking action.

Uses:

  • Chlorprothixene is used as first generation antipsychotic.
  • It also has non-narcotic analgesic, antiemetic, sedative and cholinergic antagonist activity.

Thiothixene:

Medicinal Chemistry Drugs Action On Central Nervous System Thiothixene

  • Thiothixene is chemically, N,N-dimethyl-9-[3-(4-methylpiperazin-1-yl)propylidene] thioxanthene-2-sulfonamide.
  • It is a thioxanthene derivative. It produces antipsychotic activity by blocking postsynaptic dopamine receptors in the mesolimbic system.
  • It also blocks medullary chemoreceptor trigger zone leading to decreased stimulation of the vomiting center.

Uses:

  • Thiothixene is used as an antipsychotic agent.
  • It is also used as antiemetics.

Dibenzoxazepine Derivative:

Loxapine Succinate:

Medicinal Chemistry Drugs Action On Central Nervous System Loxapine Succinate

  • Loxapine succinate is chemically 8-chloro-6-(4-methylpiperazin-1-yl)benzo[b] [1,4]benzoxazepine, butanedioic acid.
  • It produces its action by blocking the dopamine receptors at postsynaptic receptor sites in the limbic system, cortical system and basal ganglia, thereby reducing the hallucinations and delusions.

Uses:

  • Loxapine succinate is an antipsychotic agent used in schizophrenia.
  • It also possesses antiemetic, sedative, anticholinergic and antiadrenergic actions.

Dibenzodiazepine Derivative:

Clozapine:

Medicinal Chemistry Drugs Action On Central Nervous System Clozapine

  • Clozapine is chemically 3-chloro-6-(4-methylpiperazin-1-yl)-5H-benzo[b][1,4] benzo- diazepine.
  • It is an important atypical antipsychotic.
  • It weakly blocks D2 receptors and relieves schizophrenic symptoms such as hallucinations, delusions and dementia.
  • It also has serotonin (bind with 5-HT2A/2c receptor) receptors antagonist activity.
  • It has notably low production of extra pyramidal symptoms (EPS) and reduction of negative symptoms.

Uses:

  • Clozapine is an important atypical antipsychotic.
  • Its use is restricted because of a relatively high frequency of agranulocytosis as a severe side effect.

Fluorobutyrophenones

Many of the fluorobutyrophenones possess antipsychotic activity. The general structural features for antipsychotic activity are as follows:

Medicinal Chemistry Drugs Action On Central Nervous System Fluorobutyrophenones

Structure Activity Relationship:

  • Aromatic ring with para fluoro substitution at R1 is required for optimum activity.
  • Carbonyl group (–) at ‘X’ is required for optimal activity, although the other groups like C(H)OH and C(H)aryl also have good antipsychotic activity.
  • Carbon chain length with 3 carbon atoms is required for optimal activity, whereas longer or shorter chain length decreases the activity.
  • The aliphatic amino nitrogen incorporated into a cyclic form is required for highest activity.
  • R2 must be an aromatic ring attached directly or occasionally separated by one intervening atom to the 4th position for optimal activity.
  • The ‘Y’ group can vary with different groups required to assist antipsychotic activity, Example: -OH group in haloperidol.

Haloperidol:

Medicinal Chemistry Drugs Action On Central Nervous System Haloperidol

  • Haloperidol is butyrophenone, chemically it is, 4-[4-(4-chlorophenyl)-4-hydroxy- piperidin-1-yl)-1-(4-fluorophenyl)butan-1-one.
  • It competitively blocks postsynaptic dopamine receptors in the mesolimbic system of the brain and so is used to treat delusion and hallucination.
  • It has strong affinity for D2 and D3 receptors.
  • It also blocks dopamine receptors in the chemoreceptive trigger zone (CTZ) and leads to its anti-emetic effect.

Uses:

  • Haloperidol is a typical antipsychotic drug.
  • It is a potent antipsychotic useful in schizophrenia and in psychoses associated with brain damage.
  • It also possesses neuroleptic and antiemetic activities.

Droperidol:

Medicinal Chemistry Drugs Action On Central Nervous System Droperidol

  • Droperidol is butyrophenone, chemically it is, 3-[1-[4-(4-fluorophenyl)-4-oxobutyl]- 3,6-dihydro-2H-pyridin-4-yl]-1H-benzimidazol-2-one.
  • It has general properties similar to those of haloperidol.
  • It acts by blocking dopamine D2 receptors.
  • It blocks dopamine receptors in the chemoreceptor trigger zone (CTZ) and leads to its anti-emetic effect.
  • It also acts on postsynaptic GABA receptors in the CNS and increases the inhibitory effect of GABA which leads to sedative and anti-anxiety activities.

Uses:

  • Droperidol is used as preanaesthetic neuroleptics.
  • It is used in combination with an opioid analgesic agent fentanyl preanaesthetically.
  • It also possesses anti-emetic, sedative and anti-anxiety properties.

Risperidone:

Medicinal Chemistry Drugs Action On Central Nervous System Risperidone

  • Risperidone is a benzisoxazole derivative, chemically it is, 3-[2-[4-(6-fluoro-1,2- benzoxazol-3-yl)piperidin-1-yl]ethyl]-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]- pyrimidin-4-one.
  • Risperidone selectively antagonizes serotonin 5-HT2 receptor.
  • It also binds with the limbic dopamine D2 receptor which leads to antipsychotic activity.

Uses:

  • Risperidone acts as an atypical antipsychotic agent.
  • It is reported to decrease the negative (e.g., withdrawal, apathy) as well as the positive (e.g., delusions, hallucination) symptoms of schizophrenia.

Beta Amino Ketones

Molindone Hydrochloride:

Medicinal Chemistry Drugs Action On Central Nervous System Molindone Hydrochloride

  • Molindone hydrochloride is chemically 3-ethyl-2-methyl-5-(morpholin-4-ylmethyl)- 1,5,6,7-tetrahydroindol-4-one;hydrochloride.
  • It exerts its effect by blocking dopamine receptors (D2 and D3) in the reticular activating and limbic systems, thereby decreasing dopamine excess in the brain. It also has moderate affinity for cholinergic and alpha-adrenergic receptors.

Uses:

  • Molindone is a conventional antipsychotic used in the therapy of schizophrenia and other psychoses.
  • It is useful in the treatment of the aggressive type of undersocialized conduct disorder.

Benzamides

Sulpieride:

Medicinal Chemistry Drugs Action On Central Nervous System Sulpieride

  • Sulpieride is benzamide derivative, chemically N-[(1-ethylpyrrolidin-2-yl)methyl]-2- methoxy-5-sulfamoylbenzamide.
  • It is more selective and acts primarily as a dopamine D2 antagonist.

Uses:

  • Sulpieride is used therapeutically as an antipsychotic.
  • It is also used as antidepressant and as a digestive aid.

Synthesis

Chlorpromazine Hydrochloride

Medicinal Chemistry Drugs Action On Central Nervous System Chlorpromezine hydrochloride synthesis

Multiple Choice Questions:

Question 1. Neuroleptics are used to treat:

  1. Neurosis
  2. Psychosis
  3. Narcolepsy
  4. Parkinsonian disorders

Answer. 2. Psychosis

Question 2. 5H-dibenz [b,f]azepine-5-carboxamide is chemical name for:

  1. Imipramine
  2. Carbamazepine
  3. Carbapenam
  4. Diazepam

Answer. 2. Carbamazepine

Question 3. Most antipsychotic drugs:

  1. Strongly block postsynaptic D2 receptor
  2. Stimulate postsynaptic D2 receptor
  3. Block NMDA receptor
  4. Stimulate 5-HT receptor

Answer. 1. Strongly block postsynaptic D2 receptor

Question 4. In phenothiazine tranquillizing agents, replacement of C-2 hydrogen by chlorine:

  1. Decreases activity
  2. Increases activity
  3. Do not affect activity
  4. Leads to penetration to CNS

Answer. 2. Increases activity

Question 5. Which of the following antipsychotic drugs is typical?

  1. Clozapine
  2. Quetiapine
  3. Haloperidol
  4. Olanzapine

Answer. 3. Haloperidol

Question 6. Chlorpromazine is derivative of 2-chlorphenothiazine which can be prepared from starting material:

  1. 2-Chlorophenothiazine
  2. 2- Nitrophenothiazine
  3. 2-Aminophenothiazine
  4. 2-Trifluoromethyl phenothiazine

Answer. 1. 2-Chlorophenothiazine

Question 7. Indicate the atypical antipsychotic drug:

  1. Haloperidol
  2. Clozapine
  3. Thioridazine
  4. Thiothixene

Answer. 2. Clozapine

Question 8. Which of the following antipsychotic drugs has high affinity for D4 and 5-HT2 receptors?

  1. Clozapine
  2. Fluphenazine
  3. Thioridazine
  4. Haloperidole

Answer. 1. Clozapine

Question 9. Choose the correct chemical name for chlorpromazine hydrochloride:

  1. [3-(2-chlorophenothiazine-10-yl)propyl]diethyl amine hydrochloride
  2. [2-(3-chlorophenothiazine-10-yl)propyl]dimethyl amine hydrochloride
  3. [3-(2-chlorophenothiazine-10-yl)propyl]dimethyl amine hydrochloride
  4. [3-(3-chlorophenothiazine-10-yl)propyl]dimethyl amine hydrochloride

Answer. 3. [3-(2-chlorophenothiazine-10-yl)propyl]dimethyl amine hydrochloride

Question 10. Indicate the antipsychotic drug, which is a phenothiazine aliphatic derivative:

  1. Thiothixene
  2. Risperidone
  3. Chlorpromazine
  4. Clozapine

Answer. 3. Chlorpromazine

Question 11. Indicate the antipsychotic drug, which is a butyrophenone derivative:

  1. Droperidol
  2. Thioridazine
  3. Sertindole
  4. Fluphenazine

Answer. 1. Droperidol

Question 12. Droperidol belongs to the class of:

  1. Carbamates
  2. Xanthanes
  3. Butyrophenone
  4. Phenothiazine

Answer. 3. Butyrophenone

Question 13. Indicate the antipsychotic drug, which is a thioxanthene derivative:

  1. Haloperidol
  2. Clozapine
  3. Chlorpromazine
  4. Thiothixene

Answer. 4. Thiothixene

Question 14. Indicate the antipsychotic agent – a dibenzodiazepine derivative:

  1. Fluphenazine
  2. Clozapine
  3. Risperidone
  4. Droperidol

Answer. 2. Clozapine

Question 15. Indicate the antipsychotic drug having significant peripheral a-adrenergic blocking activity:

  1. Haloperidol
  2. Chlorpromazine
  3. Clozapine
  4. Risperidone

Answer. 2. Chlorpromazine

Question 16. Indicate the antipsychotic drug having a muscarinic-cholinergic blocking activity:

  1. Chlorpromazine
  2. Clorprothixene
  3. Risperidone
  4. Haloperidol

Answer. 1. Chlorpromazine

Question 17. Which of the following antipsychotic agents is preferable in patients with coronary and cerebrovascular disease?

  1. Chlorpromazine
  2. Fluphenazine
  3. Haloperidol
  4. Perphenazine

Answer. 3. Haloperidol

Question 18. Haloperidol is a major tranquilizer, is belongs to the class of:

  1. Carbamates
  2. Propanediol
  3. Butyrophenone
  4. Phenothiazine

Answer. 3. Butyrophenone

Question 19. The mechanism of haloperidol antipsychotic action is:

  1. Blocking D, receptors
  2. Central alpha-adrenergic blocking
  3. Inhibition of norepinephrine uptake mechanisms
  4. All of the above

Answer. 4. All of the above

Question 20. Which of the following antipsychotic drugs has high affinity for D, and 5-HT2 receptors?

  1. Droperidol
  2. Clozapine
  3. Thlothixene
  4. Risperidone

Answer. 4. Risperidone

Anticonvulsants

Introduction

The word ‘epilepsy’ comes from the Greek word epilambanein (to seize). Epilepsy is not a contagious disease or psychological disorder; it can develop at any age. It is said to be common neuralgic disorder found in approximately 0.7% of the population of any age. Epilepsy is a group of chronic CNS disorders due to sudden and transitory seizures of abnormal motor and sensory neurons resulting into a repeated neuronal discharge.

It is a physical condition which causes burst of hyperactivity in brain characterized by chronic, recurrent, paroxysmal changes in neuralgic function. This hyperactivity produces ‘seizures’ which vary from one person to another in frequency and form. It is seen as a sudden abnormal function of the body, often with loss of consciousness, an excess of muscular activity, or sometimes loss of it, or an abnormal sensation. A seizure may last for few seconds to few minutes.

The terms epilepsy or convulsion or seizure are often used interchangeably and basically have the same meaning.

Epilepsy is said to be ‘symptomatic epilepsy’ which develops after a particular identifiable events such as asphyxia, head injury, meningitis, birth trauma or brain injury during pregnancy whereas, epilepsy is called as ‘idiopathic epilepsy’ which develops without any identifiable cause.

Classification Of Different Types Of Epilepsy (Seizure)

A brief classification of different types of epilepsy is important as it facilitates accurate diagnosis and drug selection for precise treatment against seizure disorder.

The major classification is as follows:

Generalized Seizures:

Generalized seizures essentially involve the entire brain and do not have an apparent local onset. Two major types of generalized seizures are as follows:

The generalized tonic-clonic seizure (grand mal)

It is the most common type of epilepsy in which the person often experiences an aura (feeling something around the body, fear and discomfort). It proceeds by a series of bilateral muscular jerks followed by loss of consciousness, which in turn is followed by a series of tonic and then clonic spasms. The seizures generally last from 2 to 5 minutes.

The non-convulsive seizures or absence seizures (petit mal)

This type of epilepsy is most frequently found in children. It consists of a sudden brief loss of consciousness, characterized by blank spells or loss of speech. This seizure is for very short period of time which usually last from 1 to 30 seconds even many persons are not aware that they have had a seizure. In petil mall epilepsy there is no motor activity or some minor clonic motor activity exists.

Partial (or focal) Seizures:

Partial seizures have a focus (i.e., begin locally). Major types of focal (partial) epilepsy are simple focal (Jacksonian motor epilepsy) and complex (psychomotor or temporal lobe) focal seizures.

Simple focal (Jacksonian motor epilepsy) seizures:

Jacksonian epilepsy is rare and usually associated with lesion of a certain part of the brain (cerebral cortex). It is characterized by focal or local clonic type convulsions of localized muscle groups (for example, thumb, big toe, and so forth). The patient does not loss consciousness and therefore be able to tell what happened. The seizures normally last from 1 to 2 minutes.

Complex (Psychomotor or temporal lobe) focal seizures:

Psychomotor epilepsy is uncommon and is characterized by certain abnormal types of behaviour (for example, extensive swallowing or chewing). It mostly occurs in children through adolescence. The individual may experience an aura followed by confusion and bizarre (very strange or unusual behaviour) with perceptual alterations, such as hallucinations or a strong sense of fear. The seizures normally last from 1 to 2 minutes. The seizure may be misdiagnosed as a psychotic episode and difficult to treat.

Status Epilepticus:

A status epilepticus occurs whenever a seizure persists for at least 30 minutes or it repeated so frequently that recovery between attacks does not occur. It is a dangerous condition which may result in brain damage (cerebral necrosis) with severe morbidity or death. A status may be the patient’s first epileptic event or may be precipitated by suddenly discontinuing anticonvulsant therapy.

Each of the epilepsy types is characterized by a typical abnormal pattern in the Electroencephalography (EEG) which gives sudden excessive electrical activity in the brain.

Anticonvulsant Drugs

The proper diagnosis of seizure type is essential to the selection of an appropriate anticonvulsant drug. If used for the wrong seizure type, some anticonvulsant drugs actually increase seizure activity.

The ‘anticonvulsants’ are also called as ‘antiepileptic drugs’ and ‘antiseizure drugs’ that are used regularly to control and manage the neurological disorder caused by excessive nerve cell discharge in the brain. Generally the term anticonvulsant is used for an agent that blocks experimentally produced seizures in laboratory animals whereas; antiepileptic drugs are used medically to control the epilepsies.

For many years, treatment options for epilepsy were limited. However, over the last decade, many new pharmacological therapies have been introduced, and several more are in development.

Classification of Anticonvulsant Drugs:

The anticonvulsants are classified as follows:

  • Barbiturates: Phenobarbital, Methabarbital.
  • Hydantoins: Phenytoin, Mephenytoin, Ethotoin.
  • Oxazolidinediones: Trimethadione, Paramethadione.
  • Succinimides: Phensuximide, Methsuximide, Ethosuximide.
  • Urea and monoacylureas: Phenacemide, Carbamazepine.
  • Benzodiazepine: Clonazepam, diazepam.
  • Miscellaneous: Primidone, Valproic acid, Gabapentin, Felbamate, Tiagabine, Lamotrigine, Zonisamide.

Mechanism of Action of Anticonvulsants:

The mode of action of anticonvulsants is not clear. However, it is believed that the anticonvulsants suppress seizures by depressing the cerebral (motor) cortex of the brain.

Gama amino butyric acid (GABA) is the major inhibitory neurotransmitter in the brain. Several of the anticonvulsant medicines work through the GABA system. A major mode of action of anticonvulsants (Benzodiazepine and barbiturate) can be positive allosteric modulation of GABAA receptors. The mechanism of action of barbiturates is based on their structure.

Phenobarbital acts by blocking voltage gated sodium channel, whereas calcium-T channel is blocked by 5,5-dialkyl substituted barbiturates members. Oxazolidine-2.4-diones and succinimides act via calcium T-type channel block. The major mode of action for phenytoin, carbamazepine, valproic acid, felbamate, lamoirigine and zonisarnide are reported to act by blocking voltage-gated sodium channel.

Structure – Activity Relationship of Anticonvulsants:

Several major groups of anticonvulsant drugs viz., Barbiturates, Hydantoins, Oxazolidine diones, Succinimides and Acetylureas have the common structural features as shown below. These groups have in common a similar heterocyclic ring structure with variety of substituents. Very small changes in structure can dramatically alter the mechanism of action and clinical properties of the compound.

Medicinal Chemistry Drugs Action On Central Nervous System Anticonvulsants

  • Both R and R’ should be hydrocarbon radicals.
  • If both R and R’ are lower alkyls, then it is more active against absence seizure (petit mal) and not active against generalized tonic-clonic (grand mal) or partial seizures.
  • If one of the hydrocarbon substituents is an aryl group, then the activity increases towards generalized tonic-clonic and partial seizures and no action against absence seizure.

Barbiturates

Phenobarbital:

Medicinal Chemistry Drugs Action On Central Nervous System Barbiturates Phenobarbital

  • Phenobarbital is chemically 5-ethyl-5-phenyl-1,3-diazinane-2,4,6-trione.
  • It is the drug of choice and is used virtually in all the three types of epileptic seizures viz, grand mal, petit mal and psychomotor.
  • It binds to an allosteric site on the GABAA receptor, and it enhances the GABA receptor mediated current by prolonging the opening of the chloride channels. It leads to membrane hyperpolarization and ultimately synaptic inhibition and decreased neuronal excitability.
  • It also blocks excitatory responses induced by glutamate,
  • It has a long half-life time and therefore it will take a few weeks before reaching a therapeutic and effective level,
  • The main side-effects of phenobarbitone are drowsiness, especially during the first week of treatment.

Uses:

  • Phenobarbital is a barbiturate that is widely used as a sedative and an antiseizure medication.
  • It is used in idiopathic generalized epilepsies.
  • It is also reasonably effective in other generalized seizures and in partial seizures.

Methabarbital:

Medicinal Chemistry Drugs Action On Central Nervous System Methabarbital

  • Methabarbital is chemically, 5,5-diethyl-1-methyl-1,3-diazinane-2,4,6-trione.
  • It is mostly demethylated to barbital in vivo. Also it possesses more sedating property than Phenobarbital.
  • It could be safely recommended for grand mal seizures.
  • It binds at a distinct binding site associated with a Clionopore at the GABA receptor, increasing the duration of time for which the Clionopore is open.

Uses:

  • Methabarbital has similar properties to phenobarbital and is used in the treatment of epilepsy.
  • It is also used for the treatment of short term insomnia.
  • It belongs to Central Nervous System depressants group that induce drowsiness and relieve tension or nervousness.

Hydantoins

  • The hydantoins are close structural relatives with barbiturate, only differing in lacking the 6-oxo group. They possess imidazoline-2, 4-dione heterocyclic system.
  • Absence of one carbonyl group leads to weaker organic acids than the barbiturates. Hydantoins show their effect by activating Na*- K* dependent and Ca** dependent ATPase and increase Na* transport.
  • Hydantoins are more active against partial and generalized tonic-clonic seizure rather than absence seizure.
  • All of the clinically useful hydantoins used in treatment of generalized tonic-clonic seizure, possess an aryl substituent on the 5 position.
  • Hydantoins with lower alkyl substituents are not active against absence seizure.

Medicinal Chemistry Drugs Action On Central Nervous System Hydantoins

Phenytoin:

  • Phenytoin is chemically, 5,5-diphenylimidazolidine-2,4-dione.
  • Phenytoin potentially acts by promoting sodium efflux from neurons located in the motor cortex. This inhibits neuronal firing and results in the stabilization of neuronal membranes, thereby preventing the spread of seizure activity at the motor cortex.
  • It acts as a anticonvulsant by blocking sodium channel and decreases presynaptic glutamic acid release. It also reduces glutamate-induced ischemic damage to neuron.

Uses:

  • Phenytoin is an anticonvulsant that is used to treat a wide variety of seizures.
  • It is useful against all types of seizures except absence seizure.
  • It is also used as an anti-arrhythmic and a muscle relaxant.

Mephenytoin

  • Mephenytoin is chemically, 5-ethyl-3-methyl-5-phenylimidazolidine-2,4-dione.
  • It has similar mechanism of action as that of phenytoin.
  • It is found to be relatively more toxic, therefore it is exclusively given to such patients who do not response to other treatments.

Uses:

  • Mephenytoin is more active against partial and generalized tonic-clonic seizure.
  • The adverse effect such as dermatitis, agranulocytosis or hepatitis associated with mephenytoin is higher than phenytoin.

Ethotoin

  • Ethotoin is chemically, 3-ethyl-5-phenylimidazolidine-2,4-dione.
  • It is recommended for the patients who are hypersensitive to phenytoin.
  • It has similar mechanism of action as that of phenytoin.
  • The adverse effect and toxicity are generally less severe than those associated with phenytoin, but it appears to be less effective.

Uses:

  • Ethotoin is used against generalized seizures.

Oxazolidinediones

  • Oxazolidine-2,4-diones are analogous to hydantoins, only replacement of the -NH group at position-1 with an oxygen atom.
  • These drugs are more active against absence seizures, provided that branched atom of these compounds is substituted with lower alkyls.
  • Aryl substituted oxazolidine-2,4-diones have shown activity against generalized tonic-clonic seizures.

Medicinal Chemistry Drugs Action On Central Nervous System Oxazolidinediones

Trimethadione

  • Trimethadione is chemically, 3,5,5-trimethyl-1,3-oxazolidine-2,4-dione.
  • It undergoes metabolism N-demethylation to active metabolite dimethadione. • Dimethadione blocks calcium-T channel and reduces T-type calcium currents in thalamic neurons, thereby stabilizing neuronal membranes.

Uses:

  • Trimethadione is an anticonvulsant effective in absence seizures.
  • It’s clinical use is limited because of dermatological and hematological toxicities.

Paramethadione:

  • Paramethadione is chemically 5-ethyl-3,5-dimethyl-1,3-oxazolidine-2,4-dione.
  • It blocks calcium-T channel and reduces T-type calcium currents in thalamic neurons. This inhibits corticothalamic transmission and raises the threshold for repetitive activity in the thalamus.

Uses:

  • Paramethadione is an anticonvulsant effective in absence seizures.

Succinimides

As oxazolidine diones are toxic, an extensive search was carried out to replace them with less toxic drugs. Substitution of ring oxygen in the oxazolidine diones with a -CH2 group gave the antiseizure succinimides. The precise mechanism of action of succinimides is unknown, but it is proposed to act by decreasing the activity of T- type calcium channel. These drugs are used in the treatment of absence (petit mal epilepsy) seizure.

Medicinal Chemistry Drugs Action On Central Nervous System Succinimides

Phensuximide:

  • Phensuximide is chemically 1-methyl-3-phenylpyrrolidine-2,5-dione.
  • It suppresses the paroxysmal three cycles per second spike and wave EEG pattern associated with lapses of consciousness in absence (petit mal) seizures.
  • N-demethylation occurs to yield the putative active metabolite.

Uses:

  • Phensuximide occasionally is used for the treatment of absence seizures.
  • The phenyl substituent leads to be active against generalized tonic-clonic and partial seizures.
  • It also had some activity against maximal electroshock seizure.

Methsuximide:

  • Methsuximide is chemically, 1,3-dimethyl-3-phenylpyrrolidine-2,5-dione.
  • It increases the seizure threshold and suppresses the paroxysmal three cycles per second spike and wave ECG pattern seen with absence (petit mal) seizures.
  • It is generally considered as more toxic than ethosuximide.

Uses:

  • Methsuximide is used primarily for the treatment of absence seizures and complex partial seizure.
  • It also had some activity against maximal electroshock seizure.

Ethosuximide:

  • Ethosuximide is chemically, 3-ethyl-3-methylpyrrolidine-2,5-dione.
  • It acts by blocking calcium T channel of the thalamic neurons. This results in decrease in burst firing of thalamocortical neurons, which stabilize the nerve activity in the brain and prevents seizures.
  • It is more active and less toxic than trimethadione.

Uses:

  • Ethosuximide is used in the treatment of absence (petit mal) seizures.
  • With other antiepileptic drugs it can be used to treat other types of epilepsy.

Urea and Monoacylureas

Phenacemide:

Medicinal Chemistry Drugs Action On Central Nervous System Phenacemide

  • Phenacemide is chemically, N-carbamoyl-2-phenylacetamide.
  • It acts on the Central Nervous System to reduce the number and severity of seizures.
  • It binds to and blocks neuronal Na* channels or voltage sensitive Ca** channels.
  • It blocks or suppresses neuronal depolarization and hyper synchronization.

Uses:

  • Phenacemide is used to control certain seizures in the treatment of epilepsy.

Carbamazepine:

Medicinal Chemistry Drugs Action On Central Nervous System Carbamazepine

  • Carbamazepine is chemically 5H-dibenz[b, f] azepine-5-carboxamide.
  • It is chemically related to tricyclic antidepressants (TCA) with anticonvulsant and analgesic properties.
  • It exerts its anticonvulsant activity by reducing polysynaptic responses and blocking post-tetanic potentiation.

Uses:

  • Carbamazepine is used as an anticonvulsant to control grand mal and psychomotor or focal seizures.

Benzodiazepines

Clonazepam:

Medicinal Chemistry Drugs Action On Central Nervous System Clonazepam

  • Clonazepam is chemically, 5-(2-chlorophenyl)-7-nitro-1,3-dihydro-1,4-benzo-diazepin-2-one.
  • It is a synthetic benzodiazepine derivative.
  • It produces its anticonvulsant activity by acting selectively at benzodiazepine allosteric binding sites on GABAA receptors and enhances GABA receptor responses.

Uses:

  • Clonazepam is an anticonvulsant used for several types of seizures such as myotonic or atonic seizures, photosensitive epilepsy and absence (petit mal) seizures.
  • It is reasonably effective in generalized tonic-clonic (grand mal) or partial seizures.

Diazepam:

Medicinal Chemistry Drugs Action On Central Nervous System Diazepam Benzodiazepines

  • Diazepam is a benzodiazepine derivative, chemically it is 7-chloro-1-methyl-5- phenyl-3H-1,4-benzodiazepin-2-one.
  • It binds with GABA receptor located in the limbic system and the hypothalamus and inhibits the activities of GABA. This leads to open chloride channel increases influx of chloride ions into the neuron, results into membrane hyper polarization and a decrease in neuronal excitability.

Uses:

  • Diazepam is the drug of first choice for the treatment of status epilepticus and administered by IV rout.
  • It is also useful in treating generalized tonic-clonic (grand mal) seizure.
  • It is also used as anti-anxiety and as hypno-sedative.

Miscellaneous

Primidone:

Medicinal Chemistry Drugs Action On Central Nervous System Miscellaneous Primidone

  • Primidone is chemically, 5-ethyl-5-phenyl-1,3-diazinane-4,6-dione.
  • It is an analog of phenobarbital with antiepileptic property.
  • It’s mode of action is similar to phenobarbital, i.e. activation of GABAA and increased frequency of opening of the chloride channel within the receptor complex. This leads to an alteration in the electrical activity of the nerve cell membrane results in to hyper polarization and prevention of partial and tonic-clonic seizures.
  • It produces its anti-seizure properties as such and through partially metabolism to phenobarbital and phenylethyl malonamide (PEMA), which may also contribute to its activity. Adverse effects are reported to be more frequent than with phenobarbital.

Uses:

  • The efficacy of primidone is against all types of seizures except absence seizure.

Valproic acid:

Medicinal Chemistry Drugs Action On Central Nervous System Miscellaneous Valproic acid

  • Valproic acid is chemically, 2-propylpentanoic acid.
  • It is synthetic derivative of propylpentanoic acid.
  • It may act by increasing GABA levels in the brain or by blocking voltage dependent sodium channels and disorganized electrical activity.
  • As this drug undergoes extensive dissociation at physiological pH produce poor partitioning across BBB, hence less potent compared to other drugs.

Uses:

  • Valproic acid has anticonvulsant properties and is used in the treatment of grand mal epilepsy, petit mal epilepsy and complex partial seizure.
  • It is also used as a mood stabilizer.
  • It possesses antineoplastic and antiangiogenesis activities.

Gabapentin:

Medicinal Chemistry Drugs Action On Central Nervous System Miscellaneous Gabapentin

  • Gabapentin is chemically, 1-(aminomethyl) cyclohexaneacetic acid.
  • It is synthetic GABA-mimetic analogue capable of penetrating the CNS.
  • It is a water-soluble amino acid, act by altering the metabolism or release of GABA and decreased CNS disorganized electrical activity.
  • It raises brain GABA levels in patients with epilepsy.
  • It also acts by binding with calcium channels.

Uses:

  • Gabapentin is used in refractory partial seizures and generalized tonic-clonic seizures.
  • It also approved for the treatment of postherpetic neuralgia.

Felbamate:

Medicinal Chemistry Drugs Action On Central Nervous System Miscellaneous Felbamate

  • Felbamate is chemically 2-phenylpropane-1,3-diyl dicarbamate.
  • It acts by interaction with strychnine-insensitive glycine recognition site of the N-methyl-D-aspartate (NMDA) receptor ionophore complex. Hence blocks the effect of excitatory amino acid and suppresses the neuronal disorganized electrical activity. It possesses GABA receptor blocking action and produces inhibitory effect on neuronal excitatory.
  • It also acts by blocking sodium channels.

Uses:

  • Felbamate is used in combination with other antiepileptic medications against generalized tonic-clonic and complex partial seizures.
  • As it is associated with a serious risk of aplastic anaemia and acute liver failure, its use is restricted.

Tiagabine:

Medicinal Chemistry Drugs Action On Central Nervous System Miscellaneous Tiagabine

  • Tiagabine is chemically, (3R)-1-[4,4-bis(3-methylthiophen-2-yl)but-3-enyl]piperidine- 3-carboxylic acid.
  • It is a nipecotic acid derivative with an improved ability to cross the blood-brain barrier.
  • It acts by blocking GABA receptor and inhibits GABA uptake by glial cells.

Uses:

  • Tiagabine is used largely as an adjunctive agent in therapy of partial seizures in adults or children.

Lamotrigine:

Medicinal Chemistry Drugs Action On Central Nervous System Miscellaneous Lamotrigine

  • Lamotrigine is a triazine compound and is chemically, 6-(2,3-dichlorophenyl)-1,2,4- triazine-3, 5-diamine.
  • It enhances the action of an inhibitory neurotransmitter, GABA, and reduces the pain- related transmission of signals along nerve fibers.
  • It acts by blocking sodium channels and preventing excitatory neurotransmitters (glutamate) release and inhibits serotonin reuptake.
  • It reduces neuronal cell death in ischemia by reducing glutamate release.

Uses:

  • Lamotrigine is an anti-epileptic agent and mood stabilizer.
  • It is effective against refractory partial seizures.
  • It also has analgesic property.

Zonisamide:

Medicinal Chemistry Drugs Action On Central Nervous System Miscellaneous Zonisamide

  • Zonisamide is chemically, 1,2-benzisoxazole-3-methanesulfonamide.
  • It is sulfonamide derivative and acts by blocking sodium channel and calcium-T channels, thereby stabilizing neuronal membranes and decreased CNS disorganized electrical activity..

Uses:

  • Zonisamide is new generation anticonvulsant used in combination with other antiepileptic drugs for use in the treatment of partial seizure.

Synthesis

Phenytoin

Medicinal Chemistry Drugs Action On Central Nervous System Phenytoin synthesis

Carbamazepine

Medicinal Chemistry Drugs Action On Central Nervous System Carbamazepine synthesis

Ethosuximide

Medicinal Chemistry Drugs Action On Central Nervous System Ethosuximide synthesis

Multiple Choice Questions:

Question 1. The mechanism of action of antiseizure drugs is:

  1. Enhancement of GABAergic (inhibitory) transmission
  2. Diminution of excitatory (usually glutamatergic) transmission
  3. Modification of ionic conductance
  4. All of the above mechanisms

Answer. 4. All of the above mechanisms

Question 2. Ethusuximide is an a-disubstituted derivative of succinimide. It contains:

  1. Two methyl groups
  2. Two ethyl groups
  3. One methyl and one ethyl group
  4. One methyl and one propyl group

Answer. 3. One methyl and one ethyl group

Question 3. Valproic acid is:

  1. 2-ethylpentoic acid
  2. 2-methylpentoic acid
  3. 2-propylpentoic acid
  4. 2-butylpentoic acid

Answer. 3. 2-propylpentoic acid

Question 4. Which of the following antiseizure drugs produces enhancement of GABA-mediated inhibition?

  1. Ethosuximide
  2. Carbamazepine
  3. Phenobarbital
  4. Lamotrigine

Answer. 3. Phenobarbital

Question 5. Which of the following antiseizure drugs produces a voltage-dependent inactivation of sodium channels?

  1. Lamotrigine
  2. Carbamazepin
  3. Phenytoin
  4. All of the above

Answer. 4. All of the above

Question 6. The drug for partial and generalized tonic-clonic seizures is:

  1. Carbamazepine
  2. Valproate
  3. Phenytoin
  4. All of the above

Answer. 4. All of the above

Question 7. Indicate an anti-absence drug:

  1. Valproate
  2. Phenobarbital
  3. Carbamazepine
  4. Phenytoin

Answer. 1. Valproate

Question 8. The drug against myoclonic seizures is:

  1. Primidone
  2. Carbamazepine
  3. Clonazepam
  4. Phenytoin

Answer. 3. Clonazepam

Question 9. The anticonvulsant drug belongs to category benzodiazepines:

  1. Primidone
  2. Carbamazepine
  3. Clonazepam
  4. Phenytoin

Answer. 3. Clonazepam

Question 10. The anticonvulsant drug belongs to category hydantoin:

  1. Primidone
  2. Carbamazepine
  3. Clonazepam
  4. Phenytoin

Answer. 4. Phenytoin

Question 11. The most effective drug for stopping generalized tonic-clonic status epilepticus in adults is:

  1. Lamotrigine
  2. Ethosuximide
  3. Diazepam
  4. Zonisamide

Answer. 3. Diazepam

Question 12. Select the appropriate consideration for phenytoin:

  1. It blocks sodium channels
  2. It binds to an allosteric regulatory site on the GABA-BZ receptor and prolongs the openings of the Cl-channels
  3. It effects on Ca2+ currents, reducing the low-threshold (T-type) current
  4. It inhibits GABA-transaminase, which catalyzes the breakdown of GABA Unit 4 | 4.52

Answer. 1. It blocks sodium channels

Question 13. Phenytoin is used in the treatment of:

  1. Petit mal epilepsy
  2. Grand mal epilepsy
  3. Myoclonic seizures
  4. All of the above

Answer. 1. Petit mal epilepsy

Question 14. The drug of choice for partial seizures is:

  1. Carbamazepine
  2. Ethosuximide
  3. Diazepam
  4. Lamotrigine

Answer. 1. Carbamazepine

Question 15. The mechanism of action of carbamazepine appears to be similar to that of:

  1. Benzodiazepines
  2. Valproate
  3. Phenytoin
  4. Ethosuximide

Answer. 3. Phenytoin

Question 16. Indicate the drug of choice for status epilepticus in infants and children:

  1. Phenobarbital sodium
  2. Clonazepam
  3. Ethosuximide
  4. Phenytoin

Answer. 1. Phenobarbital sodium

Question 17. Which of the following anticonvulsant drug belongs to category Oxazolidine diones?

  1. Paramethadione
  2. Carbamazepine
  3. Clonazepam
  4. Phenytoin

Answer. 1. Paramethadione

Question 18. Which of the following anticonvulsant drug belongs to category monoacylurea?

  1. Paramethadione
  2. Carbamazepine
  3. Clonazepam
  4. Phenytoin

Answer. 2. Carbamazepine

Question 19. The drug of choice in the treatment of petit mal (absence seizures) is:

  1. Phenytoin
  2. Ethosuximide
  3. Phenobarbital
  4. Carbamazepine

Answer. 2. Ethosuximide

Question 20. Valproate is very effective against:

  1. Absence seizures
  2. Myoclonic seizures
  3. Generalized tonic-clonic seizures
  4. All of the above

Answer. 4. All of the above

Question 21. Indicate the antiseizure drug – a benzodiazepine receptor agonist:

  1. Phenobarbital
  2. Phenytoin
  3. Carbamazepine
  4. Clonazepam

Answer. 4. Clonazepam

Question 22. The most dangerous effect of antiseizure drugs after large overdoses is:

  1. Respiratory depression
  2. Gastrointestinal irritation
  3. Alopecia
  4. Sedation

Answer. 1. Respiratory depression

Drugs Acting On Central Nervous System General Anesthetics Notes

Chapter 5 Drugs Action On Central Nervous System

General Anesthetics

Introduction

Earlier the pain-producing surgical procedures and dental surgeries were undertaken without the aid of acceptable anesthetic agents. Various chemical methods were adopted at that time included intoxication with ethanol, hashish, or opium, whereas physical methods included packing a limb in ice, creating ischemic conditions with tourniquets, inducing unconsciousness by a blow to the head, or the most common technique, employing strong armed assistants to hold down the helpless patient during the entire surgical procedure.

Nitrous oxide also known as “laughing gas” was first time used by Hartford dentist Horace Wells as a surgical anesthetic in 1844. This gas is still commonly used today, especially in combination with other anesthetic and analgesic agents. Another agent cyclopropane was popularly used as general anesthetics but because of its explosive nature like diethyl ether it is no longer used. For many years, the inhalational anesthesia was used for all major surgical procedures, however recently intravenous anesthesia has become more commonly used technique.

The inhalational anesthetic agents used today are hydrocarbons and ethers with halogen like, Cl, Br, or F and intravenous anesthetics (short acting barbiturates e.g. Thiopental sodium) possess most of the ideal characteristics.

Ideal Characteristics General Anesthetics

The ideal anesthetic state is characterized by a loss of all sensations and includes analgesia and muscle relaxation. It should possess following characteristics, but currently there is no such ideal agent that fulfils all these characteristics.

  • It should be non-reactive.
  • It should be inexpensive.
  • It should be non-toxic.
  • It should be non-flammable / non-explosive.
  • It should produce rapid and pleasant induction of surgical anesthesia.
  • It should produce rapid and pleasant withdrawal from anesthesia.
  • It should produce adequate relaxation of skeletal muscles.
  • It should be potent enough to permit adequate oxygen supply in mixture.
  • It should have wide margin of safety.
  • It should be free of adverse effects.
  • It should be chemically compatible with anesthetic devices.

General anesthesia is the induction of a state of unconsciousness with the absence of pain sensation over the entire body, through the administration of Anesthetic drugs. General anesthetic drugs produce controlled, reversible depression of the functional activities of the CNS producing loss of sensation and consciousness.

Purpose of General Anesthesia

  • To get relief of pain (analgesia).
  • To block memory of the procedure (amnesia).
  • To produce unconsciousness.
  • To inhibit normal body reflexes to make surgery safe and easier to perform.
  • To relax the muscles of the body.

Mechanism of Action of General Anesthetic Agents

General anesthetic agents are positive modulators of the action of GABA on GABAA receptors by binding to allosteric binding sites. They act by facilitation of GABA receptors to promote chloride ion conductance and at therapeutic concentrations, some of the agents (e.g. ethanol and phenobarbital) depress the function of ionotropic glutamate receptors (excitatory), which may contribute to the overall anesthetic effect.

Stages of Anesthesia

After administration of general anesthetic agent (lipophilic and unionised) to a patient, it passes most rapidly into the central nervous system. As the blood concentration of the agent increases, penetration into the CNS increases which leads to increased depth of anesthesia. Guedel in 1937, has defined four stages of anesthesia as follows:

  • Stage-1 (Stage of analgesia): This stage is the period from the beginning of administration of anesthesia to the maintain consciousness. Analgesia is produced and the patient progressively loses pain, therefore this stage is also called stage of analgesia. Since, in this stage higher cortical centers are depressed. This stage is also known as cortical stage
  • Stage-2 (Stage of delirium or stage of excitement): This stage extends from the loss of consciousness through a stage of irregular and specific breathing to the re-establishment of regular breathing. There is loss of consciousness. Due to further depression of cortical centers, patient leads to the excitement and may shout or struggle violently. Hence this stage is called as the stage of excitement. In this stage patient may salivate, vomit or develop cough excessively. In this stage the respiration is normal and regular.
  • Stage-3 (Stage of surgical anesthesia): In this stage excitement is lost and skeletal muscles are relaxed and hence most of the operative procedures are performed in this stage. This stage is divided into four different planes with progressive increase in depth of anesthesia and decrease in respiration and eye movement.
  • Stage-4 (Stage of medullary paralysis or respiratory paralysis): The respiration ceases as the depth of anesthesia reaches to stage-IV. This may happen due to the overdose or toxic effect of the anesthetic. In this stage respiratory and cardiovascular system gets collapsed and the tissue rapidly becomes anoxic. There is no any eye movement.

To avoid the toxic effect of anesthesia, anesthetics are either administered by intravenous or rectal rout (basal anesthetics or fixed anesthetics), which lead to loss of consciousness before volatile anesthetics given and hence transition from complete consciousness to the surgical anesthesia will be rapid and safe.

Pre-anesthetic Medication

For the safe and effective response of general anesthetics, pre-anesthetic medications are generally recommended. These are:

  • Hypnotics: Can be given one night before surgery, to assure good night sleep.
  • Atropine (or hyoscine): Can be given two hours before surgery to prevent excess secretion of saliva or mucous which might obstruct the process is anesthesia.
  • Morphine (or pethidine): It is given to minimize fear and anxiety.

Classification Of General Anestnetics

  • Inhalation anesthetics: Halothane, Methoxyflurane, Enflurane, Sevoflurane, Isoflurane, Desflurane.
  • Ultra short-acting barbitutrates: Methohexital sodium, Thiamylal sodium, Thiopental sodium.
  • Dissociative anesthetics: Ketamine hydrochloride.

Inhalation Anesthetics

Halothane:

Medicinal Chemistry Drugs Action On Central Nervous System Halothane

  • Halothane is chemically, 2-bromo-2-chloro-1,1,1-trifluoroethane.
  • It was introduced in 1956 as a non-flammable, non-explosive, halogenated volatile anesthetic that is usually mixed with air or oxygen.
  • The presence of the carbon-halogen bonds contributes to its non-flammability, volatility, and high lipid solubility (Blood/Gas partition coefficient = 2.3).
  • It activates GABAA and glycine receptors. It also acts as an NMDA receptor antagonist and inhibits nACh and voltage-gated sodium channels.

Structure Activity Relationship:

  • The SAR studies conducted independently by Meyer and Overton in the 1880s showed a distinct positive correlation between anesthetic potency and solubility.
  • The potency of alkanes, cycloalkanes, and aromatic hydrocarbons increases in direct. proportion to the number of carbon atoms in the structure upto a cutoff point 7. Within the n-alkane series, the cutoff number is 10, with n-decane showing minimal anesthetic potency.

Metabolism:

Medicinal Chemistry Drugs Action On Central Nervous System Halothane metabolism

Uses:

  • Halothane can be used to start or maintain anesthesia.
  • One of its benefits is that it does not increase the production of saliva which can be particularly useful in those who are difficult to intubate.

General Structure-Activity Relationship of Alkanol Series:

Medicinal Chemistry Drugs Action On Central Nervous System Alkonol series

  • Similar increase in potency with increase in carbon length was seen in the n-alkanol series.
  • In association, the n-alkanol with a given a number of carbons is more potent than the n-alkane with same chain length.

Effect of Halogenation on Ether:

  • Decrease the flammability of the ether, enhances their stability and increases their potency.
  • Higher atomic mass halogens increase potency more compared to lower atomic mass halogens. e.g. Replacing the fluorine (F) in desflurane with chorine (CI) to form isoflurane increases the potency more than four-fold.
  • Replacing the chlorine (CI) with bromine (Br) increases the potency three-fold i.e. isoflurane.
  • Unfortunately, halogenation also increases the toxicity.
  • Halogenated methyl ethyl ether was found to be more stable and potent than halogenated diethyl ether. i.e. enflurane and isoflurane.
  • For n-alkane series, fully saturating the alkane with fluorine (F) increases the potency. Number of carbon atoms was 2 to 4 which show highest potency. If it is more than 5, then the activity is diminished..
  • The stereoisomer of isoflurane (+) and (-) has been isolated and tested for anesthetic potency. The (+) isomer was found to be 53% more potent than (-) isomer.
  • The addition of double and triple bonds to anesthetics molecule decreases their potency.

Methoxyflurane:

Medicinal Chemistry Drugs Action On Central Nervous System Methoxyflurane

  • Methoxyflurane is chemically 2,2-dichloro-1,1-difluoro-1-methoxyethane.
  • It acts as a positive allosteric modulator of the GABAA receptor, it also acts as an NMDA receptor antagonist.
  • It should be administered with nitrous oxide to achieve a relatively light level of anesthesia, and a neuromuscular blocking agent given concurrently to obtain the desired degree of muscular relaxation.

Metabolism:

Medicinal Chemistry Drugs Action On Central Nervous System Methoxyflurane metabolism

Uses:

  • Methoxyflurane provides rapid short-term analgesia using a portable inhaler device.
  • Currently, methoxyflurane is rarely used for surgical, obstetric, or dental anesthesia.

Enflurane:

Medicinal Chemistry Drugs Action On Central Nervous System Enflurane

  • Enflurane is chemically 2-chloro-1-(difluoromethoxy)-1,1,2-trifluoroethane.
  • It acts as a positive allosteric modulator of the GABAA, glycine, and 5-HT3 receptors.
  • It is a fluorinated ether and very potent general anesthetic agent.
  • It is more stable inhalation anesthetic which provides rapid adjustments of anesthesia depth with little change in pulse or respiratory rate.

Metabolism:

  • Enflurane is metabolized via CYP2E1 to form a fluoride ion and difluoromethoxy difluoro- acetic acid metabolites.

Medicinal Chemistry Drugs Action On Central Nervous System Enflurane metabolism

Uses:

  • Enflurane may be used for induction and maintenance of general anesthesia.
  • It can also be used to provide analgesia for vaginal delivery.

Isoflurane:

Medicinal Chemistry Drugs Action On Central Nervous System Isoflurane

  • Isoflurane is an isomer of enflurane.
  • It is chemically 2-chloro-2-(difluoromethoxy)-1,1,1-trifluoroethane.
  • It is a fluorinated ether with general anesthetic and muscle relaxant activities.
  • It reduces pain sensitivity (analgesia) and relaxes muscles.
  • It likely binds to GABA, glutamate and glycine receptors, but has different effects on each receptor.
  • It acts as a positive allosteric modulator of the GABAA receptors.
  • It inhibits receptor activity in the NMDA glutamate receptor subtypes.
  • It inhibits conduction in activated potassium channels.
  • It also affects intracellular molecules and NADH dehydrogenase.

Metabolism:

Medicinal Chemistry Drugs Action On Central Nervous System Isoflurane metabolism

Uses:

  • Isoflurane is a general anesthetic.
  • It can be used to start or maintain anesthesia.
  • Often another medication is used to start anesthesia due to airway irritation with isoflurane.

Sevoflurane:

Medicinal Chemistry Drugs Action On Central Nervous System Sevoflurane

  • Sevoflurane is chemically, 1,1,1,3,3,3-hexafluoro-2-(fluoromethoxy)propane.
  • It is a fluorinated isopropyl ether with general anesthetic property.
  • It acts as a positive allosteric modulator of the GABAA receptor, it also acts as an NMDA receptor antagonist.

Metabolism:

Medicinal Chemistry Drugs Action On Central Nervous System Sevoflurane metabolism

Uses:

  • Sevoflurane is one of the most commonly used volatile anesthetic agents, particularly for outpatient anesthesia, across all ages, as well as in veterinary medicine.

Desflurane:

Medicinal Chemistry Drugs Action On Central Nervous System Desflurane

  • Desflurane is chemically, 2-(difluoromethoxy)-1,1,1,2-tetrafluoroethane.
  • It is a highly fluorinated methyl ethyl ether used for maintenance of general anesthesia.
  • It acts on the lipid matrix of the neuronal membrane, resulting in disruption of neuronal transmission in the brain.
  • It may also enhance the synaptic activity of the inhibitory neurotransmitter gamma- aminobutyric acid (GABA).
  • It may activate GABA channels and hyperpolarize cell membranes.
  • It also may inhibit certain calcium channels and therefore prevent release of neurotransmitters and inhibit glutamate channels.

Metabolism:

Medicinal Chemistry Drugs Action On Central Nervous System Desflurane metabolism

Uses:

  • Drugs Acting on Central Nervous System (II)
  • Desflurane is a non-flammable liquid general anesthetic administered via vaporizer. • It is indicated as an inhalation agent for induction of anesthesia for inpatient and outpatient surgery in adults.

Ultra Short-Acting Barbiturates

Thiopental sodium:

Medicinal Chemistry Drugs Action On Central Nervous System Thiopental sodium

  • Thiopental sodium is chemically, 5-ethyl-5(1-methylbutyl)-2-thiobarbiturate.
  • Thiopental binds to the chloride ionophore site of the gamma-aminobutyric acid GABA/chloride ionophore receptor complex, thereby enhancing the inhibitory actions of GABAA in the brain which leads to synaptic inhibition, decreased neuronal excitability and induction of anesthesia.
  • It also decreases glutamate responses.

Metabolism:

Medicinal Chemistry Drugs Action On Central Nervous System Thiopental sodium metabolism

  • Thiopental sodium is a barbiturate that is administered intravenously for the induction of general anesthesia of short duration.
  • It helps patients to relax before receiving general anesthesia with an inhaled medication.

Methohexital sodium:

Medicinal Chemistry Drugs Action On Central Nervous System Methohexital sodium

  • Methohexital sodium is chemically sodium, 5-(hex-3-yn-2-yl)-1-methyl-2,6-dioxo- 5-(prop-2-en-1-yl)-1,2,5,6-tetrahydropyrimidin-4-olate.
  • It binds to a distinct site which is associated with CI ionophores at GABAA receptors. This increases the length of time for which the CI ionopores are open, thus causing an inhibitory effect.

Metabolism:

  • Metabolism of methohexital is primarily hepatic via demethylation and oxidation. Side-chain oxidation is the primary means of metabolism involved in the termination of the drug’s biological activity.

Uses:

  • Methohexital sodium is an intravenous anesthetic with a short duration of action that may be used for induction of anesthesia.
  • It has been commonly used to induce deep sedation or general anesthesia for surgery and dental procedures.

Thiamylal Sodium:

Medicinal Chemistry Drugs Action On Central Nervous System Thiamylal sodium

  • Thiamylal sodium is chemically sodium – 4,6-dioxo-5-pentan-2-yl-5-prop-2-enyl-1H- pyrimidine-2-thiolate.
  • It binds at a distinct binding site associated with a CI ionopore at the GABAA receptor, increasing the duration of time for which the CI ionopore is open. The post-synaptic inhibitory effect of GABA in the thalamus is, therefore, prolonged.

Uses:

  • Thiamylal sodium is a barbiturate that is administered intravenously for the production of complete anesthesia of short duration.
  • It has sedative, anticonvulsant, and hypnotic effects, and is used as a strong but short acting sedative.
  • It is still in current use, primarily for induction in surgical anesthesia or as an anticonvulsant.

Dissociative Anesthetics

Ketamine Hydrochloride:

Medicinal Chemistry Drugs Action On Central Nervous System Ketamine hydrochloride

  • Ketamine hydrochloride is chemically 2-(2-chlorophenyl)-2-(methylamino) cyclohexan-1-one;hydrochloride.
  • It interacts with N-methyl-D-aspartate (NMDA) receptors, opioid receptors (μ and σ), monoaminergic receptors, muscarinic receptors and voltage sensitive Ca+ ion channels and thereby reducing pain perception, inducing sedation, and producing dissociative anesthesia.
  • Unlike other general anesthetic agents, ketamine does not interact with GABA receptors.

Metabolism:

  • Ketamine presents a mainly hepatic metabolism and its major metabolite is nor-ketamine. The biotransformation of ketamine corresponds to N-dealkylation, hydroxylation of the cyclohexone ring, conjugation to glucuronic acid and dehydration of the hydroxylated metabolites for the formation of cyclohexene derivatives.

Medicinal Chemistry Drugs Action On Central Nervous System Ketamine hydrochloride metabolism

Uses:

  • Ketamine hydrochloride is a cyclohexanone derivative used for induction of anesthesia.
  • Anesthesia in children, as the sole anesthetic for minor procedures or as an induction agent followed by muscle relaxant and tracheal intubation.
  • It can be given to asthmatics or people with chronic obstructive airway disease.
  • It acts as a sedative for physically painful procedures in emergency departments.

Synthesis

Halothane

Medicinal Chemistry Drugs Action On Central Nervous System Halothane synthesis

Methohexital Sodium

Medicinal Chemistry Drugs Action On Central Nervous System Methohexital sodium synthesis

Ketamine Hydrochloride

Medicinal Chemistry Drugs Action On Central Nervous System Ketamine hydrochloride synthesis

Multiple Choice Questions:

Question 1. The state of “general anesthesia” usually includes:

  1. Analgesia
  2. Loss of consciousness, inhibition of sensory and autonomic reflexes
  3. Amnesia
  4. All of the above

Answer. 4. All of the above

Question 2. The IUPAC name of Halothane is

  1. 2-bromo-2-chloro-1,1,1-trifluoroethane
  2. 2-bromo-2-chloro-1,1, -difluoroethane
  3. 2-bromo-1,1,1-thrifluoroethane
  4. None of above

Answer. 1. 2-bromo-2-chloro-1,1,1-trifluoroethane

Question 3. Inhaled anesthetics and intravenous agents having general anesthetic properties:

  1. directly activate GABAA receptors
  2. facilitate GABA action but have no direct action on GABAA receptors
  3. reduce the excitatory glutamatergic neurotransmission
  4. increase the duration of opening of nicotine-activated potassium channels

Answer. 1. directly activate GABAA receptors

Question 4. Indicate the anesthetic, which is an inhibitor of NMDA glutamate receptors:

  1. Thiopental
  2. Halothane
  3. Ketamine
  4. Sevoflurane

Answer. 3. Ketamine

Question 5. Halothane contains the haloatoms

  1. Bromine, chlorine and fluorine
  2. Bromine, chlorine and iodine
  3. Bromine and iodine
  4. Chlorine and fluorine

Answer. 1. Bromine, chlorine and fluorine

Question 6. An ideal anesthetic drug would:

  1. induce anesthesia smoothly and rapidly and secure rapid recovery
  2. possess a wide margin of safety
  3. be devoid of adverse effects
  4. All of the above

Answer. 4. All of the above

Question 7. Which of the following general anesthetics belongs to inhalants?

  1. Thiopental
  2. Desfluran
  3. Ketamine
  4. Propofol

Answer. 2. Desfluran

Question 8. Which of the following inhalants is a gas anesthetic?

  1. Halothane
  2. Isoflurane
  3. Nitrous oxide
  4. Desflurane

Answer. 3. Nitrous oxide

Question 9. Indicate the intravenous anesthetic, which is an ultra-short-acting barbiturate:

  1. Fentanyl
  2. Thiopental
  3. Midazolam
  4. Ketamine

Answer. 2. Thiopental

Narcotic And Non-Narcotic Analgesics

Introduction

Pain is the most common complaint for which patients seek treatment. Pain has been classified into various types such as physiological (e.g. touching a hot object or getting a cut), inflammatory (e.g. infection and tissue injury), and neuropathic (e.g. injury to the PNS or CNS).

Agents that decrease pain are referred to as analgesics, or analgetics or pain-killing drugs. As these drugs act as pain relieving agents, they are also called antinociceptives (reduced sensitivity of pain).

There are number of classes of drugs which relieve pain. Mainly these drugs are categorized into two classes, (a) morphine and related compounds and (b) antipyretics and anti-inflammatory analgesics.

Non-Steroidal Anti-Inflammatory Agents (NSAID), have primarily a peripheral site of action and are useful to relive mild to moderate pain without loss of consciousness. These agents often have an anti-inflammatory effect associated with their pain killing action.

Historically, opioid analgesics have been called narcotic analgesics. Narcotic analgesics are selective CNS depressant that cause sleep or loss of consciousness (narcosis) in conjugation with their analgesic effect. These are extremely potent analgesics and are effective for the relief of severe pain. Not all opioid analgesics cause necrosis.

The side effects caused by opioid analgesics are respiratory depression, nausea and drowsiness. Long term administration may lead to tolerance, psychological and/or physical dependence called as addiction.

Because of addiction properties, opioid class has been the most problematic for use in the proper management of pain. The term opiophobia was coined to describe the reluctance of physicians to prescribe opioid drugs in adequate amounts or for long enough periods.

Opioid Receptors:

The neuronal located proteins to which opioid agent binds and initiate biological response are called as opioid receptors. There are three major types of receptors classified by the order in which they are cloned.

  • Delta (8) receptors are PO1 receptors.
  • Kappa (K) receptors are PO2 receptors.
  • Mu (u) receptors are PO3 receptors.

All of these receptors are located in human brain or spinal cord tissues and each has a role in the mediation of pain. These receptors have subtypes that provide varying degrees of analgesia, euphoria or dysphoria, central nervous system depression, and perhaps, the potential for tolerance.

Orphan opioid receptor (fourth receptor) has been identified and cloned (OP4) based on homology with cDNA sequence of the known (μ, 8 and K) opioid receptors. Despite the homology in cDNA sequence with known opioid receptors, this new receptor did not bind the classical peptide or non-peptide agonists or antagonists with high affinity.

Mechanism of Action of Narcotic Analgesics

The signal transition mechanism for (u, 8 and k) opioid receptors is through G-proteins. Activation of opioid receptors is linked through the G-protein to an inhibition of adenylate cyclase activity. This results into decrease in cAMP production, efflux of K* and closure of voltage gated Ca** channel leads to hyperpolarization of the nerve cell and strong inhibition of nerve firing.

Classification Of Narcotic Analgesics

  • Natural alkaloids: Morphine, Codeine.
  • Semi-synthetic analogues: Hydromorphone, oxymorphone, oxycodone.
  • Synthetic agents: Meperidine, Methadone, Phenazocine, Pentazocine, Fentanyl Dextropropoxyphene, Nalorphine, Naloxone, Naltrexone.

Morphine and Related Drugs:

The prototypic narcotic analgesic is (-)-morphine, the principal alkaloid obtained from juice or latex from the unripe seeds of the poppy plant, (Papaver somniferum). The first alkaloid to be isolated was morphine (10% in opium), which then underwent structural modifications to produce a number of derivatives of morphine. It also contains codeine. (0.5%), thebaine (0.2%), papaverine (1%) and noscapine (6%).

Morphine Analogues

Medicinal Chemistry Drugs Action On Central Nervous System Morphine Analogues

Structure-Activity Relationship

  • Morphine is a prototype opioid.
  • It is selective for μ opioid receptor.
  • Structure of morphine composed of five rings (fused) i.e. a benzene ring (A), two partially unsaturated cyclohexane rings (B and C), a piperidine ring (D) and a dihydrofuran ring (E).
  • Morphine molecule has 5 chiral centers with absolute stereochemistry, 5(R), 6(S), 9(R), 13(S) and 14(R).
  • Naturally occurring morphine is levo (-) rotatory.
  • Dextro (+) morphine has been synthesized and it is devoid of analgesic and other opioid activity.
  • Any major change will cause changes in the affinity and intrinsic activity of the new compound at each opioid receptor type.
  • Thus opioid receptor selectivity profile of new compound may be different than the structure from which it was made (e.g. from μ 8 or K).
  • It may also have different physiological properties such as solubility, partition coefficient, pKa etc. results in different pharmacokinetic characteristics and can affect its in-vitro activity profile.

Ring-A:

  • Ring ‘A’ and basic ‘N’ exist in protonated (ionized) form, required for opioid analgesic activity.
  • Aromatic ring ‘A’ and cationic ‘N’ may be connected by ethyl linkage (i.e. 9, 10 position of B-ring) or propyl linkage (either edge of the piperidine ring that forms the D-ring).
  • ‘A’ ring and basic ‘N’ are necessary components for every potent μ- agonist known. (iv) These two alone are not sufficient for μ-activity, however an additional pharmacophores are required such as,
    • Rigid structure (i.e. fused ring A, B, and D)
    • 3-OH and tertiary ‘N’ either greatly enhance or are essential for activity.

N-atom:

  • Tertiary ‘N’ group has good opioid activity.
  • Size of ‘N’ substitutions indicate agonist or antagonist properties.
  • N-CH3 substitution has good agonist activity.
  • Increase in ‘N’ substitution to 3-5 carbon (unsaturated or smaller carbocyclic ring), antagonist at some or all receptor types.
  • Longer substitution on ‘N’ returns agonist properties to the opioid.
  • N-phenyl ethyl substitution opioid is usually 10-fold more potent as a μ-agonist than the N-CH3 analogue.
  • N-CH2-CH=CH2 substitution leads to μ-antagonist activity (Naloxane).

3-phenolic hydroxyl group:

  • Substitution of 3-H instead of 3-OH decreases the activity 10 times.
  • Substitution of 3-CH3 in place of 3-OH decreases analgesic activity, the compound so formed possesses anti-tussive activity (i.e. Codeine).
    (Codeine is weak μ-agonist and it undergoes slow o-demethylation to morphine).

Medicinal Chemistry Drugs Action On Central Nervous System 3-phenolic hydroxyl group

  • Substitution of ester (CH3-CO-) at position 3 decreases the activity.
  • Diacetyl group at 3 and 6 position leads to formation of Heroin, which is synthesized in 1874 and marketed in 1898 by Friedrich Bayer Co. in Germanay.
    • Heroin is preferable to morphine as it does not disturb digestion or produce habit readily.
    • It has low affinity for u-receptors.
    • It has high lipophilicity compared to morphine and easily cross blood-brain barrier.
    • In body (including the brain), serum and tissue esterase hydrolyse 3-acetyl group to produce 6-acetyl morphine leads to increase μ-receptor activity in excess of morphine.
    • Administration of heroin by IV route rapidly converted to a potent μ-agonist provide a ‘euphoric rush’ – popular drug of abuse.
    • Repeated use of heroin develops tolerance, physical dependence and acquisition of the drug habit.
    • Self administration of heroin with unclean or shared hypodermic needle, results in transmission of HIV, hepatitis or other infectious disease.

C-ring:

  • 6-keto decreases the activity in pure morphine only.
  • 7,8-dihydro (no double bond between 7 and 8 carbon atom) with 6-keto derivative of morphine increases activity by 8-10 times than morphine (i.e Hydromorphone).

Medicinal Chemistry Drugs Action On Central Nervous System Keto derivatives

  • Substitution of 3-OCH; derivative of hydromorphone (hydrocodone) is more active than codeine.
  • Substitution of 6-H decreases the activity.

14a-hydroxy-6-keto derivatives:

  • Substitution of B-OH at 14 position increases the analgesic activity (oxymorphone).
  • Substitution of 3-OH and N-CH3 derivative is 10 times more potent than morphine.

 

Medicinal Chemistry Drugs Action On Central Nervous System C-ring

  • Substitution of 3-OCH3 derivative of oxymorphone (Oxycodone) is as potent as morphine when given parenterally, but oral dose is better than parenteral compared to morphine.
  • Substitution of N-cyclobutyl methyl and reduction of 6-keto to 6a-OH of oxymorphone (Nalbuphine) acts through K-receptor and possess approximately half analgesic potency of morphine. Nalbuphine acts as a μ-receptor antagonist.

Medicinal Chemistry Drugs Action On Central Nervous System Nalbuphine

  • Replacement of the potent narcotic agonist oxymorphone’s N-methyl group with an allyl group (-CH2-CH=CH2) (Naloxone) or methyl cyclopropyl group (Naltrexone) acts as pure opioid antagonist. Both the drugs act as antagonist of all types of opioid receptor.

Medicinal Chemistry Drugs Action On Central Nervous System Naltrexone

  • Substitution of -OH group at C14 and keto group at C6 is necessary for pure antagonist activity.

3,4-Epoxide Bridge (Morphinans):

Removal of 3,4-epoxide bridge (4-5 ether bridge) in the morphine structure results in compounds called as morphinans.

Medicinal Chemistry Drugs Action On Central Nervous System Morphine

  • Morphinan can be prepared by synthetic route only, as it is very difficult to remove it from morphine analogue.
  • The synthetic procedure yields compounds as racemic mixtures in which only the levo (-) isomers act as opioid analgesic, whereas dextro (+) isomers act as anti-tussive.
  • Morphinan derivative,
    • Levorphenol possesses 8 times more potent analgesic activity as compared with morphine due to increased μ-receptor affinity and increased lipophilicity.
    • Butorphenol have mixed agonist/antagonists activity. It is a u-receptor antagonist and K-receptor agonist.

Medicinal Chemistry Drugs Action On Central Nervous System Butorphenol

Benzomorphans:

  • Benzomorphans are synthetic compounds that lack both the epoxide E ring and C ring of morphine, having only A, B and D rings, retain opioid activity.

Medicinal Chemistry Drugs Action On Central Nervous System Benzomorphan

  • They are named chemically as benzomorphan or use a different nomenclature system as 2, 6-methano-3-benzazocine.
  • Analgesic activity increases in order of substitution of OH>H>NH2, NO2, F and Cl at 2′ position.
  • Trimethyl substitution at N=CH3, R5-CH3 and Rg-CH3 possesses 3 times more potent analgesic activity than dimethyl Rs-H and R9 CH3.
  • Substitution of R-CH3 increases the analgesic activity.
  • Substitution of R-OH having the same activity as substitution of -OH at 14th position of morphine leads to decease in analgesic activity.

Medicinal Chemistry Drugs Action On Central Nervous System Cyclazocin

  • Pentazocine is a weak μ-receptor antagonist, whereas it is a k-receptor agonist and thus produces analgesia.
  • Phenazocine (N-Phenylethyl substituted benzomorphan) is 10 times more potent than morphine as a μ- agonist.
  • Cyclazocine (N- Cyclopropyl methyl substituted benzomorphan) is a narcotic antagonist. It possesses considerable hallucinogenic properties.

4-Phenylpiperidines:

Medicinal Chemistry Drugs Action On Central Nervous System 4-Phenylpiperidines

  • 4-phenylpiperidines possess only A and D ring analogues of morphine.
  • The first agent among this class, meperidine, was synthesized in 1937 by Eislab, who was attempting to prepare antispasmodic agents, but serendipitously observed the opioid activity.
  • Meperidine is proved to be a typical μ-agonist, with approximately 1/4th potency of morphine. It have very short duration of action because of its esterases hydrolysis to a zwitter ionic metabolite.

Medicinal Chemistry Drugs Action On Central Nervous System Anileridine

  • Replacement of ethyl group of meperidine with isopropyl group (properidine), have 15 times more potent activity than meperidine.
  • Reversed esters of meperidine have greater potency. 1,2,5- trimeperidine (propionoxy compound) is 7.5 times more potent than meperidine.
  • Replacement of N-CH3 group of meperidine with N-p-amino phenyl ethyl group (Anileridine) is 4 times more potent than meperidine.

Anilinopiperidines:

  • Structural modification of the 4-phenylpiperidines results into discovery of new compounds, 4-anilidopiperidine or the fentanyl.
  • In fentanyl, phenyl and acyl groups are separated from the ring by nitrogen.
  • Fentanyl and its derivatives are μ-receptor agonists.
  • They are powerful analgesic (50 times stronger than morphine) with minimum side effects.
  • Its short duration of action makes it well suited for use in anesthesia. pa

Medicinal Chemistry Drugs Action On Central Nervous System Lofentanyl

  • Substitution of -CH3 at 3-postion of piperidine ring with addition of a small oxygen containing group at the 4-position of the piperidine ring, leads to the formation of analogues with extreme potent analgesic activity. (i.e. Lofentanyl – 8,400 times potent than morphine).
  • Alfentanyl, sufentanyl and remifentanyl are the other examples of fentanyl derivatives, which are having highly safety margin than other μ-agonists.

Diphenylheptanone:

  • German scientists synthesized another series of open-chain compounds as potential antispasmodics.
  • When the nitrogen ring of morphine is opened, the analgesic activity is virtually abolished.
  • Further modifications by scientists made the compound to possess both analgesic and spasmolytic activity.

Medicinal Chemistry Drugs Action On Central Nervous System Methadone

  • Methadone was the first analgesic agent..
  • Levo isomer of methadone and levo-isomethadone are twice active as their recimic mixture.
  • Reduction of keto group leads to decrease in activity.
  • Removal of any phenyl group leads to decrease in activity.
  • Replacement of dimethylamino group with pyrrolidyl group gives 3/4th activity as methadone.

Medicinal Chemistry Drugs Action On Central Nervous System Levo-isomethadone

Metabolism of Methadone:

 

Medicinal Chemistry Drugs Action On Central Nervous System Metabolism of Methadone

Metabolism of Opioids (In liver):

Medicinal Chemistry Drugs Action On Central Nervous System Metabolism of Opioids

Morphine sulphate:

Medicinal Chemistry Drugs Action On Central Nervous System Morphine sulphate

  • The prototypic narcotic analgesic is (-)-morphine, the principal alkaloid obtained from the Opium poppy (Papaver somniferum).
  • Morphine was isolated as a pure alkaloid by a German Pharmacist, Serturner in 1803. Morphine sulphate is chemically, (4R,4aR,75,7aR,12bS)-3-methyl-2,4,4,7,7,13- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-7,9-diol;sulphuric acid.
  • It exerts the major effects by interacting with opioids receptors (μ, 8 and K) in the CNS.
  • It activates 7 TM GPCRs located presynaptically and postsynaptically along pain transmission pathways.

Uses:

  • Morphine is used as narcotic analgesic.
  • It is used as pre-anesthetic medication.
  • It can also be used for the treatment of diarrhoea.
  • It produces sleep and sedation.

Codeine:

Medicinal Chemistry Drugs Action On Central Nervous System Codeine

  • Codeine is an alkaloid that occurs in opium, but the amount present is usually too small to be of commercial importance.
  • Conversion of the 3-OH to a 3-OCH3, yields codeine, reduces activity to 15% of morphine.
  • It is chemically, (4R,4aR,75,7aR,12bS)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-
  • 1H-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol.
  • It is available as a sulphate and phosphate salt and also as the free base and as tablets, elixir and solution for injection.
  • The 3-methoxy group protects the 3-position from glucuronide as occurs with morphine.

Uses:

  • Codeine is used as an analgesic, antitussive and cough suppressor.
  • It also possesses antidiarrheal and antihypertensive activity.
  • It has hypnotic and sedative property and can be used as antianxiety drug.

Meperidine Hydrochloride:

Medicinal Chemistry Drugs Action On Central Nervous System Meperidine hydrochloride

  • Meperidine hydrochloride is chemically ethyl-1-methyl-4-phenylpiperidine-4- carboxylate; hydro-chloride.
  • It has very short duration of action and largely metabolized in the liver with only a small quantum of it~ 5% gets excreted unchanged.
  • Importantly, the ‘esterases’ predominantly cause cessation of the ester linkage (as ethyl ester at para-position) to leave as residue the inactive-carboxylate analogue.
  • It also undergoes N-demethylation to yield the corresponding product known as ‘normeperidine’ – a metabolite which gets accumulated after a prolonged medication with meperidine.

Uses:

  • Meperidine is a narcotic analgesic that can be used for the relief of most types of moderate to severe pain, including postoperative pain and the pain of labour.
  • It can also use as a premedication before anesthesia.

Anileridine Hydrochloride:

Medicinal Chemistry Drugs Action On Central Nervous System Anileridine hydrochloride

  • Anileridine is chemically, ethyl 1-[2-(4-aminophenyl)ethyl]-4-phenylpiperidine-4- carboxylate; hydrochloride.
  • It is a synthetic analgesic drug and is a member of the piperidine class of analgesic agents.

Uses:

  • It differs from pethidine (meperidine) in that the n-methyl group of meperidine is. replaced by an N-aminophenethyl group, which increases its analgesic activity.

Diphenoxylate Hydrochloride:

Medicinal Chemistry Drugs Action On Central Nervous System Loperamide hydrochlorideMedicinal Chemistry Drugs Action On Central Nervous System Diphenoxylate hydrochloride

  • Diphenoxylate is chemically, ethyl-1-(3-cyano-3, 3-diphenylpropyl)-4-phenyl- isonipecotate.
  • Diphenoxylate is a narcotic antidiarrheal drug related chemically to loperamide.
  • It reduces bowel contractions and consequently the frequency and fluidity of bowel movements.
  • Although diphenoxylate is chemically related to narcotics, it does not have pain relieving (analgesic) actions like most other narcotics.
  • In higher doses, like other narcotics, diphenoxylate can cause euphoria (elevation of mood) and physical dependence.

Uses:

  • It is a synthetic analogue of pethidine (meperidine) with some analgesic activity, but is mostly used in the treatment of diarrhoea associated with gastroenteritis, irritable bowel, acute infections, hyper motility, ulcerative colitis and sometimes even food poisoning.
  • It prevents hyper gastrointestinal propulsion by reducing intestinal motility.

Loperamide Hydrochloride:

Medicinal Chemistry Drugs Action On Central Nervous System Loperamide hydrochlorideMedicinal Chemistry Drugs Action On Central Nervous System Loperamide hydrochloride

  • Loperamide hydrochloride is loperamide, a synthetic, piperidine derivative.
  • It is chemically, 4-(4-chlorophenyl)-4-hydroxy-N,N-dimethyl-a,a-diphenyl-1-piperidine butyramide hydrochloride.
  • It acts on the μ-receptors in the intestinal mucosa.
  • It slows intestinal motility by acting on the nerve endings and/or intramural Ganglia embedded in the intestinal wall.
  • The prolonged retention of the feces in the intestine results in reducing the volume of the stools, increasing viscosity, and decreasing fluid and electrolyte loss.

Uses:

  • Loperamide hydrochloride is used as opioid agonist.
  • It is used in symptomatic relief of acute non-specific diarrhoea and of chronic diarrhoea associated with inflammatory bowel disease.

Fentanyl citrate:

Medicinal Chemistry Drugs Action On Central Nervous System Fentanyl citrate

  • Fentanyl citrate is chemically N-phenyl-N-[1-(2-phenylethyl)piperidin-4-yl] propanamide-N-(1-phenylethyl-4-piperidinyl) propionanilide, citrate.
  • It is a very potent synthetic opiate, which can be used, as an analgesic.
  • It is structurally related to phenylpiperidines (e.g. meperidine) and produces strong analgesia, similar to morphine.
  • It possesses an inherent rapid onset and short duration of action.

Uses:

  • Fentanyl is 80 times more potent than morphine as analgesic primarily employed as an analgesic for the arrest of pain after all types of surgical procedures.
  • It is used as an aid for induction and maintenance of inhalation anesthesia.
  • It may be employed also as an adjuvant to all such drugs mostly used for regional and general anesthesia.

Methadone Hydrochloride:

Medicinal Chemistry Drugs Action On Central Nervous System Methadone hydrochloride

  • Methadone hydrochloride is a synthetic narcotic drug.
  • It is chemically, 6-(dimethylamino)-4,4-diphenylheptan-3-one.
  • Methadone shows optical activity. Among the optical isomers, l-methadone is a more potent analgesic, while d-isomer is antitussive.
  • It is more active and more toxic than morphine.

Uses:

  • Methadone hydrochloride is used for the relief of many types of pain.
  • It is also used in the treatment of some heroin addicts.
  • It is used as a narcotic substitute in addiction treatment because it prevents morphine abstinence syndrome.

Propoxyphene Hydrochloride:

Medicinal Chemistry Drugs Action On Central Nervous System Propoxyphene hydrochloride

  • Propoxyphene hydrochloride is chemically, [(25,3R)-4-(dimethylamino)-3-methyl-1,2- diphenylbutan-2-yl] propanoate; hydrochloride.
  • This agent mimics the effects of the endogenous opiate dextropropoxyphene, by binding to μ-receptors located throughout the central nervous system.

Uses:

  • Propoxyphene hydrochloride is used as narcotic analgesic.

Pentazocine:

Medicinal Chemistry Drugs Action On Central Nervous System Pentazocine

  • Pentazocine is a novel drug possessing of both opioid agonistic and antagonistic properties.
  • It is an agonist at the 8 and K opioid receptors and has a weak antagonist action at the μ-receptor.
  • It presumably acts on K-receptors to produce analgesia and sedation.
  • Like other narcotics, it produces analgesia, sedation and respiratory depression.
  • The bioavailability of pentazocine after oral administration is only 20-50% due to the first pass metabolism.
  • It gets metabolized extensively in the liver; and subsequently, excreted by the urinary tract.

Uses:

  • Pentazocine is used in oral and parenteral forms as an analgesic for moderate-to- severe pain.

Levorphanol Tartarate:

Medicinal Chemistry Drugs Action On Central Nervous System Levorphanol tartarate

  • Levorphanol tartarate is a synthetic phenanthrene with potent opioid analgesic activity.
  • It mimics the actions of endogenous peptides at CNS opioid receptors, thereby producing the characteristic morphine-like effects on the μ-opioid receptor.

Uses:

  • Levorphanol tartarate has morphine like effects such as analgesia, euphoria, sedation, respiratory depression, miosis, bradycardia and physical dependence.

Narcotic Antagonists

  • Narcotic antagonists are drugs which block the “high” and other effects of narcotics. They also precipitate withdrawal symptoms in the narcotic addict.
  • This feature of narcotic antagonists makes them extremely useful in treating overdoses.
  • They are structurally related to morphine with the exception of the group attached to nitrogen, hence they act by competing for the same analgesic receptor sites. Research is currently going on to determine the usefulness of antagonists as maintenance drugs.
  • Present narcotic antagonists (such as naloxone and cyclazocine) have too brief effect and too many side effects to be completely satisfactory.
  • A new drug, naltrexone, appears to be more promising since its effects last longer, and it appears to be more acceptable to the treatment clients.
  • Narcotic antagonists prevent or abolish excessive respiratory depression caused by the administration of morphine or related compounds.
  • They are also used to treat asphyxia neonatorum and for the diagnosis of possible narcotic addiction.

Nalorphine Hydrochloride:

Medicinal Chemistry Drugs Action On Central Nervous System Nalorphine Hydrochloride

  • Nalorphine hydrocholoride is N-allylmorphine. In morphine tertiary nitrogen is attached to an allyl (-CH2CH=CH2) group.
  • It is a narcotic antagonist with some agonist properties. It is an antagonist at μ-opioid receptors and an agonist at K-opioid receptors.
  • Nalorphine hydrochloride is white colored, odorless, crystalline powder.
  • It darkens on exposure to light.
  • It is soluble in water and dilute alkali hydroxide solution, but insoluble in chloroform and ether.
  • It must be kept in tightly closed light resistant containers.

Uses:

  • Nalorphine is a narcotic antagonist used to treat narcotic-induced respiratory depression.
  • It is administered by intravenous injection for treating the overdosage of morphine, pethidine, methadone and levorphanol.
  • Nalorphine precipitates withdrawal symptoms and produces behavioral disturbances in addition to the antagonism action.

Levallorphan Tartarate:

Medicinal Chemistry Drugs Action On Central Nervous System Levallorphan tartarate

  • Levallorphan is available as tartarate salt.
  • Levallorphan tartarate occurs as white colored, odorless, crystalline powder.
  • It melts at 175°C and is slightly soluble in water, but insoluble in ether and chloroform.

Uses:

  • Levallorphan is a potent narcotic antagonist used in the treatment of narcotic induced respiratory depression.

Naloxone Hydrochloride:

Medicinal Chemistry Drugs Action On Central Nervous System Naloxone hydrochloride

  • Naloxone is (5R, 9R, 135, 14S)-N-allyl-4, 5-epoxy-3, 14-dihydroxymorphinan-6-one.
  • It is a derivative of 7, 8-dihydro-14-hydroxymorphinone having an allyl group at the nitrogen.
  • It is administered by IV or IM (low oral bioavailability and slow action) and has a relatively short half-life (1 hour).
  • It is a specific narcotic antagonist which, unlike nalorphine, possesses no morphine- like properties. It is considered to be an effective antagonist for mixed agonist- antagonist like pentazocine.
  • It may also reverse some of the adverse effects of narcotic antagonists having agonist actions owing to its lack of respiratory depressant property.
  • It has been found to reverse narcotic analgesic and possesses little analgesic properties of its own.

Uses:

  • Naloxone is a pure antagonist with no morphine like effects.
  • It blocks the euphoric effect of heroin when given before heroin.

Synthesis

Fentanyl Citrate

Medicinal Chemistry Drugs Action On Central Nervous System Fentanyl citrate synthesis

Methadone Hydrochloride

Medicinal Chemistry Drugs Action On Central Nervous System Methadone hydrochloride synthesis

Multiple Choice Questions:

Question 1. The drug naloxone

  1. produces morphine like activity
  2. produces respiratory depression
  3. induces constipation
  4. precipitates withdrawal symptoms in morphine addicts

Answer. 1. produces morphine like activity

Question 2. Kappa and delta agonists:

  1. inhibit postsynaptic neurons by opening K+ channels
  2. close a voltage-gated Ca** channels on presynaptic nerve terminals
  3. both (a) and (b)
  4. Inhibit of arachidonate cyclooxygenase in CNS

Answer. 2. close a voltage-gated Ca** channels on presynaptic nerve terminals

Question 3. Pentazocine is a benzomorphan derivative. It has alkyl group at C-3 position, identify it

  1. – CH = (CH3)2
  2. -CH2-CH=C(CH3)2
  3. = CH2-CH2-CH(CH3)2
  4. – CH(CH3)2

Answer. 2. -CH2-CH=C(CH3)2

Question 4. 3-etherification of morphine molecule causes

  1. Morphine antagonism
  2. No change in activity
  3. Decrease of analgesic and addiction
  4. Increase of analgesic and addiction.

Answer. 3. Decrease of analgesic and addiction

Question 5. Naltrexone is morphine

  1. Agonist
  2. Antagonist
  3. Partial antagonist
  4. All of above

Answer. 2.Antagonist

Question 6. The activity of the one of the following drug is dependant on phenyl-N-alkyl piperidine moiety:

  1. Meperidine
  2. Imipramine
  3. Diazepam
  4. Chlorpromazine

Answer. 1. Meperidine

Question 7. Which of the following analgesics is a phenanthrene derivative?

  1. Fentanyl
  2. Morphine
  3. Methadone
  4. Pentazocine

Answer. 2. Morphine

Question 8. Pentazocine belongs to the class

  1. Benzomorphans
  2. Morphinans
  3. Phenyl piperidine
  4. Azepine

Answer. 1. Benzomorphans

Question 9. Which one is the pure opioid antagonist among the following?

  1. Nalorphine
  2. Nalbuphine
  3. Naloxone
  4. Levallorphan

Answer. 3. Naloxone

Question 10. Tick narcotic analgesic, which is a phenylpiperidine derivative:

  1. Codeine
  2. Dezocine
  3. Fentanyl
  4. Buprenorphine

Answer. 3. Fentanyl

Question 11. Petazocine belongs to

  1. N-methylmorphinan
  2. Benzomorphan
  3. Meperidine
  4. Methadone

Answer. 2. Benzomorphan

Question 12. Morphine and heroin differs from each other in respect of

  1. Methyl group on nitrogen
  2. Acetyl group at C3 and C6
  3. Absence of double bond between C4 and C5
  4. Absence of D-ring

Answer. 2. Acetyl group at C3 and C6

Question 13. N,N-Dimethyl-(1-methyl-1-oxo-3,3-diphenyl hexyl) ammonium chloride is the chemical name for

  1. Methadone hydrochloride
  2. Meperidine hydrochloride
  3. Alpha proline hydrochloride
  4. Darvon

Answer. 1. Methadone hydrochloride

Question 14. Which of the following opioid analgesics is a strong μ-receptor agonist?

  1. Naloxone
  2. Morphine
  3. Pentazocine
  4. Buprenorphine

Answer. 2. Morphine

Question 15. Indicate the narcotic analgesic, which is a natural agonist:

  1. Meperidine
  2. Fentanyl
  3. Morphine
  4. Naloxone

Answer. 3. Morphine

Question 16. Select the narcotic analgesic, which is an antagonist or partial μ-receptor agonist:

  1. Fentanyl
  2. Pentazocine
  3. Codeine
  4. Methadone

Answer. 2. Pentazocine

Question 17. Which of the following agents is a full antagonist of opioid receptors?

  1. Meperidine
  2. Buprenorphine
  3. Naloxone
  4. Butorphanol

Answer. 3. Naloxone

Question 18. Which of the following opioid analgesics is used in obstetric labor?

  1. Fentanyl
  2. Pentazocine
  3. Meperidine
  4. Buprenorphine

Answer. 3. Meperidine

Question 19. Which of the following opioid agents is used in the treatment of acute opioid overdose?

  1. Pentazocine
  2. Methadone
  3. Naloxone.
  4. Remifentanyl

Answer. 3. Naloxone.

Anti-Inflammatory Agents

Introduction

Non-steroidal anti-inflammatory drugs (NSAIDs) are successfully used to treat a wide range of painful conditions and for the management of edema and tissue damage resulting from inflammation. Most of the drugs under this category are used in the treatment of fever as they possess antipyretic activity in addition to having analgesic and anti-inflammatory actions. Non-steroidal anti-inflammatory drugs (NSAIDs) reduce inflammation which helps to ease joint pain and stiffness. They are used in rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and dysmenorrhea therapy.

Inflammation

The inflammatory response involves the migration of immune system cells into a damaged tissue. In some cases, this is beneficial especially for fighting infection, but in many cases, the inflammatory response increases the damage to the tissue such as in case of asthma, several forms of arthritis. In addition to this, inflammation may also be a step on the pathway towards certain cancers, especially colon cancer.

There are four signs of inflammation:

  • Redness: Due to local vessel dilatation.
  • Heat: Due to local vessel dilatation.
  • Swelling: Due to influx of plasma proteins and phagocytic cells into the tissue spaces.
  • Pain: Due to local release of enzymes and increased tissue pressure.

Role of Cyclooxygenase (COX):

Humans and most other mammals have two genes (isoenzyme) for cyclooxygenase, COX-1 and COX-2. Both are quite similar in structure, with only subtle differences. They catalyze the same reactions, although COX-2 works with a wider range of substrates.

COX-1 is constitutively expressed in most of the tissues such as gastrointestinal (GI) tract, the kidneys, and the circulatory system. In contrast, COX-2 is inducible, especially by inflammatory stimuli and found in few cell types such as macrophages, leukocytes, fibroblasts and endothelial cells.

COX-1 is responsible for generating the prostaglandins required for protection of the gastrointestinal tract, platelet aggregation, renal electrolyte haemostasis and renal blood flow maintanace while COX-2 is responsible for the increased prostaglandin synthesis associated with inflammation, fever, and pain responses.

Medicinal Chemistry Drugs Action On Central Nervous System COX inhibitors

General Structure of Prostaglandins (PG):

Prostaglandins and related molecules are called eicosanoids. The term eicosanoid is derived from “eicosa” meaning “twenty”, referring to the 20 carbons in most of the molecules. Prostaglandin is a naturally occurring 20-carbon cyclopentano fatty acid derivative. Most prostaglandins are synthesized from arachidonic acid.

Medicinal Chemistry Drugs Action On Central Nervous System Prostaglandind

Mechanism of Action of NSAIDs:

Inflammation can be treated with two major classes of anti-inflammatory drugs: steroids (corticosteroids), and non-steroids. The steroids are compounds with glucocorticoid activity, and include the physiological glucocorticoid, cortisol, and synthetic glucocorticoid analogs such dexamethasone.

Glucocorticoids inhibit inflammatory responses by several mechanisms, and are more powerful drugs than NSAIDs. One mechanism is phospholipase A2 inhibition; this inhibits both prostaglandin and leukotriene synthesis, and therefore has a stronger effect than COX inhibition alone. In addition, glucocorticoids have other effects, unrelated to eicosanoid pathways.

The non-steroidal compounds are called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). Most NSAIDs inhibit both COX-1 and COX-2 with varying degree of selectivity. Selective COX-2 inhibitor may eliminate the side effects associated with NSAIDs due to COX-1 inhibition, such as gastric and renal effect. Some of the most widely used drugs, including aspirin, ibuprofen, and naproxen fall into this class.

Possible side-effects of NSAIDs include

  • Stomach upsets
  • Heartburn
  • Indigestion
  • Rashes
  • Headaches
  • Wheeziness
  • Fluid retention, which can cause swelling of the ankles.

General Structure And Properties Of Nsaids

In general, NSAIDs structurally consist of an acidic moiety (carboxylic acid, enols) attached to a planar, aromatic functionality. Some analgesics also contain a polar linking group, which attaches the planar moiety to an additional lipophilic group. This can be represented as follows:

Medicinal Chemistry Drugs Action On Central Nervous System NSAIDS

The NSAIDs are characterized by the following chemical/pharmacological properties:

  • All are relatively strong organic acids with pKa in the 3.0-5.0 range. Most, but not all, are carboxylic acids. Thus, salt forms can be generated upon treatment with base and all of these compounds are extensively ionized at physiologic pH. The acidic group is essential for COX inhibitory activity.
  • The NSAIDs differ in their lipophilicities based on the lipophilic character of their aryl groups and additional lipophilic moieties and substituents.
  • The acidic group in these compounds serves a major binding group (ionic binding) with plasma proteins. Thus all NSAIDS are highly bound by plasma proteins (drug interactions).
  • The acidic group also serves as a major site of metabolism by conjugation. Thus a major pathway of clearance for many NSAIDS is glucuronidation (and inactivation) followed by renal elimination.

Classification Of Anti-Inflammatory Agents

  • Salicylic acid derivatives: Sodium salicylate, Aspirin, Diflunisal, Salsalate, Sulphasalazine.
  • p-Amino phenol derivatives: Paracetamol, Phenacetin.
  • Pyrazolidine dione derivatives: Phenyl butazone, Oxyphenbutazone, Sulphin- pyrazone.
  • Anthranilic acid derivatives: Mefenemic acid, Flufenemic acid, Meclofenamate.
  • Arylalkanoic acid derivatives:
    • Indole acetic acid derivatives: Indomethacin.
    • Indene acetic acid derivatives: Sulindac.
    • Pyrrole acetic acid derivatives: Tolmetin, Zomepirac.
    • Aryl and heteroaryl acetic/propionic acid derivatives: Ibuprofen, Diclofenac, Naproxen, Caprofen, Fenoprofen, Keto-profen, Flurbiprofen, Ketorolac, Etodaolac.
  • Oxicams: Piroxicam, Meloxicam, Tenoxicam.
  • Selective COX-2 inhibitors: Celecoxib, Rofecoxib, Valdecoxib.
  • Miscellaneous: Nimesulide.

Salicylic Acid Derivatives (Salicylates)

  • Salicylates have potent anti-inflammatory activity with mild analgesic and antipyretic activities.
  • These compounds mainly act on COX-1 and bind higher affinity to COX-1.
  • The therapeutic and some of the toxic actions of salicylates (aspirin) are related to its ability to inhibit COX-1 in various tissues and participate in trans-acetylation reactions in vitro.

Metabolism of salicylic acid derivatives: The initial route of metabolism of these derivatives is their conversion to salicylic acid, which is excreted in urine as free acid (10%) or undergoes conjugation with either glycine to produce the major metabolites of salicylic acid (75%) or with glucuronic acid to form glucuronide (15%).

In addition, small amount of metabolites resulting from microsomal aromatic hydroxylation leads to gentisic acid.

Medicinal Chemistry Drugs Action On Central Nervous System Salicylic acid

Structural – Activity Relationship (SAR) of Salicylates:

  • The active moiety of salicylates is salicylate anion, side effects of aspirin, particularly GIT effects appear to be associated with the carboxylic acid functional group.
  • Reducing the acidity of the carboxy group results in a change in the potency. of activity. Example: The corresponding amides (salicylamide) retains the analgesic action of salicylic acid, but is devoid of anti-inflammatory properties.
  • Substitution on either the carboxyl or phenolic hydroxyl group may affect the potency and toxicity. Benzoic acid itself has only week activity.
  • Placement of the phenolic hydroxyl group at meta or para position to the carboxyl group abolish the activity.

Sodium Salicylate:

Medicinal Chemistry Drugs Action On Central Nervous System Sodium Salicylate

  • Sodium salicylate is the sodium salt of salicylic acid.
  • Sodium salicylate is chemically sodium; 2-hydroxybenzoate.
  • It is an organic molecular entity.
  • It irreversibly acetylates COX-1 and COX-2, thereby inhibiting prostaglandin synthesis and associated inflammation and pain.
  • This salicylate produces the same adverse reactions as Aspirin, but there is less occult gastrointestinal bleeding.

Uses:

  • Sodium salicylate is a non-steroidal anti-inflammatory agent, used to treat inflammation and pain.

Aspirin:

Medicinal Chemistry Drugs Action On Central Nervous System Aspirin

  • Acetylsalicylic acid (aspirin) is an acetyl derivative of salicylic acid.
  • It is chemically 2-acetyloxybenzoic acid.
  • It acts as an inhibitor of cyclooxygenase which results in the inhibition of the biosynthesis of prostaglandins.
  • It binds to and acetylates serine residues in cyclooxygenase.
  • It can be prepared by the reaction between salicylic acid and acetic anhydride. In this reaction, the hydroxyl group on the benzene ring in salicylic acid reacts with acetic anhydride to form an ester functional group. Thus, the formation of acetyl salicylic acid is referred to as an esterification reaction.

Medicinal Chemistry Drugs Action On Central Nervous System Esterification reaction

Uses:

  • Aspirin is the prototypical analgesic used in the treatment of mild to moderate pain.
  • It has anti-inflammatory and antipyretic properties.
  • It also acts as antirheumatic.
  • It also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis.

p-Amino Phenol Derivatives (Anilides)

  • These drugs are having somewhat different mechanism of action than other NSAIDs.
  • They are believed to act as scavengers of hydroperoxide radicals (Hydroperoxide radicals have a stimulating effect on COX).
  • Therefore the anilides have no anti-inflammatory action.
  • The lack of an acidic functionality and COX inhibitory activity imparts several advantages including limited gastric irritation, ulceration, respiratory effects and little effect on platelets.

Metabolism of p-aminophenol Derivatives:

These drugs undergo hydrolysis to yield aniline derivatives that produce directly or through their conversion to hydroxylamine derivatives, such as acetaminophen that undergoes rapid first pass metabolism in the GIT to o-sulphate conjugate.

The N-hydroxylamine is then converted into a reactive toxic metabolite, acetimino- quinone, which produces toxicity to the kidney and liver in conjugation with hepatic glutathione to form mercapturic acid or cysteine conjugates.

Structure – Activity Relationship of p-amino Phenol Derivatives:

  • Etherification of the phenolic function with methyl or propyl groups produces derivatives with greater side effects than ethyl derivatives.
  • Substituents of the nitrogen atom, which reduce the basicity, also reduce activity unless the substituent is metabolically labile. e.g. acetyl groups.
  • Amides derived from aromatic acid. e.g. N-phenyl benzamides that are less active or inactive.

Phenacetin (Acetophenetidin):

Medicinal Chemistry Drugs Action On Central Nervous System Phenacetin

  • Phenacetin is chemically N-(4-ethoxyphenyl) acetamide.
  • It is a phenylacetamide that was formerly used in analgesics, but nephropathy and methemoglobinemia led to its withdrawal from the market.

Uses:

  • Phenacetin is an analgesic and an antipyretic with similar effectiveness as an aspirin.
  • It has a greater potential for toxicity (hemolytic anaemia and methemoglobinaemia) than paracetamol.

Paracetamol (p-acetaminophen):

Medicinal Chemistry Drugs Action On Central Nervous System Paracetamol

  • Paracetamol is chemically N-(4-hydroxyphenyl)acetamide.
  • Paracetamols produce antipyresis by inhibition of prostaglandin synthesis and release in the central nervous system (CNS) and by acting on the hypothalamic heat- regulating centre.
  • It produces analgesia by elevating the pain threshold.
  • It may inhibit the nitric oxide (NO) pathway mediated by a variety of neurotransmitter receptors including N-methyl-D-aspartate (NMDA), resulting in elevation of the pain threshold.
  • Hepatic necrosis and death have been observed following over dosage.
  • It may cause liver, blood cell, and kidney damage.

Uses:

  • Acetaminophen is a p-aminophenol derivative with analgesic and antipyretic activities.
  • Acetaminophen has weak anti-inflammatory properties and is used as a common analgesic.

3,5-Pyrazolidinedione Derivatives

Medicinal Chemistry Drugs Action On Central Nervous System Pyrazolidinedione derivatives

Structure – Activity Relationship of 3,5-Pyrazolidinediones:

  • Replacement of one of the nitrogen atom in the pyrazolidinediones with an oxygen atom yields isoxazole analogues, which are as active as pyrazolidinedione derivatives.
  • In 3,5-pyrazolidinedione derivatives, pharmacological activities are closely related to their acidity, the dicarbonyl function at the 3rd and 5th positions enhance the acidity of hydrogen atom at the 4th position.
  • Presence of a keto group in the y-position of the butyl side chain produces the active compound.
  • Decreasing or eliminating acidity by removing the acidic proton at 4th position (e.g. 4, 4-dialkyl derivatives) abolishes anti-inflammatory activity. Thus, if the hydrogen atom at the 4th position of phenyl butazone is replaced by substituents, such as a methyl group, anti-inflammation activity is abolished.
  • If acidity is enhanced too much, anti-inflammatory and sodium-retaining activities decrease; while other properties, such as the uricosuric effect increase.
  • Introduction of polar function in these alkyl groups give mixed results. The -hydroxy-n-butyl derivative possesses pronounced uricosuric activity, but give fewer anti-inflammatory effects.
  • Substitution of 2-phenyl thio ethyl group at the 4th position produces antigout activity (sulphinpyrazone).
  • Presence of both the phenyl groups is essential for neither anti-inflammatory nor analgesic activity.
  • m-substitution of aryl rings of the phenyl butazone gives uniformly inactive compounds.
  • p-substitution, such as methyl, chloro, nitro, or OH of one or both rings retains activity.

Phenylbutazone:

Medicinal Chemistry Drugs Action On Central Nervous System Phenylbutazone

  • Phenylbutazone is chemically, 4-butyl-1,2-diphenylpyrazolidine-3,5-dione.

Uses:

  • Phenylbutazone is a pyrazole derivative that has antipyretic, analgesic, and anti- inflammatory actions.
  • It is especially effective in the treatment of ankylosing spondylitis.
  • It is also useful in arthritis, acute superficial thrombophlebitis, painful shoulder, and Reiter’s disease.

Antipyrine:

Medicinal Chemistry Drugs Action On Central Nervous System Antipyrine

  • Antipyrine is chemically, 2, 3-dimethyl-1-phenyl-3-pyrazolin-5-one.

Uses

  • Antipyrine has analgesic, anti-inflammatory and antipyretic activities.
  • It exerts a paralytic action on the sensory and the motor nerves, resulting in some anesthesia and vasoconstriction, and it also exerts a feeble antiseptic effect.

Anthranilic Acid Derivatives (Fenamates)

  • The anthranilates are primarily anti-inflammatory with some analgesic and antipyretic activity and are non-COX selective.
  • The anthranilates are used as mild analgesics and occasionally to treat inflammatory disorders.
  • Diclofenac is used for rheumatoid arthritis, osteoarthritis and post-operative pain and mefenamic acid as an analgesic for dysmennorhea.
  • The utility of this class of agents is limited by a number of adverse reactions including nausea, vomiting, diarrhoea, ulceration, headache, drowsiness and hematopoietic toxicity.

Medicinal Chemistry Drugs Action On Central Nervous System Fenamates

Structure – Activity Relationship of Anthranilic Acid Derivatives (Fenamates):

  • The position of the carboxyl function is important for the activity of anthranilic acid derivatives that are active, whereas the 3 and 4 amino benzoic acid analogues are not active.
  • Replacement of carboxylic acid function with the isosteric tetrazole results in the retention of anti-inflammatory activity.
  • Placement of substitution on the anthranilic acid ring generally reduces the activity.
  • Substitution on the N-aryl ring can lead to conflicting results. In the ultraviolet erythema assay for anti-inflammatory activity, the order of activity was generally 3′> 2′>4′ for mono-substitution with CF3 group (flufenamic acid) being particularly potent. The opposite order of activity was observed in rat paw oedema assay, the 2′-Cl derivatives being more potent than 3′-Cl analogues.
  • In disubstituted derivatives, where the nature of the two substitutes is the same, 2′,3′-disubstitution appears to be the most effective (mefenemic acid).
  • The NH moiety of anthranilic acid is essential for the activity as the replacement of NH function with O, CH2, S, SO2, N-CH3, or NCOCH3 functionalities significantly reduced the activity.

Mefenamic acid:

Medicinal Chemistry Drugs Action On Central Nervous System Mefenamic acid

  • Mefenamic acid is anthralinic acid NSAID.
  • It is chemically 2-(2,3-dimethylphenylamino) benzoic acid.
  • It is an inhibitor of cyclooxygenase.
  • It inhibits the activity of the enzyme COX-1 and COX-2, resulting in a decreased formation of precursors of prostaglandins and thromboxanes, thereby inhibiting platelets aggregation.

Uses:

  • Mefenamic acid is used as an analgesic and anti-inflammatory agent.
  • It also possesses antipyretic property.

Metabolism:

  • Its metabolism occurs through regioselective oxidation of 3-methyl group and glucuronidation of mephanamic acid. Majority of the 3-hydroxy methyl metabolites and dicarboxylic acid products are excreted.

Meclofenamate Sodium:

Medicinal Chemistry Drugs Action On Central Nervous System Meclofenamate sodiumMedicinal Chemistry Drugs Action On Central Nervous System Meclofenamate sodium

  • Meclofenamate sodium is anthralinic acid NSAID.
  • It is chemically, sodium 2-(2,6-dichloro-3-methylphenylamino)benzoate.
  • It inhibits the activity of the enzyme COX-1 and COX-2, resulting in a decreased formation of precursors of prostaglandins and thromboxanes thereby inhibiting platelets aggregation.

Uses:

  • Meclofenamate sodium is used as an analgesic and anti-inflammatory agent.
  • It also possesses antipyretic property.

Arylalkanoic Acids

Medicinal Chemistry Drugs Action On Central Nervous System Arylalkanoic acids

Structure – Activity Relationship of Arylalkanoic Acids:

  • The largest group of NSAIDS is represented by the class of arylalkanoic acids.
  • Drugs of this class share a number of common structural features.
  • The centre of acidity is usually located one carbon atom adjacent to a flat surface represented by an aromatic or hetero aromatic ring.
  • The distance between these centres is crucial, because increasing this distance to two or three carbons generally decreases activity.
  • All agents possess a centre of acidity, which can be represented by a carboxylic acid (R=COOH) and hydroxamic acid (R=CONHOH), a sulphonamide (R=SO2NH2), phenol or a terazole.
  • Substitution of a methyl group on the carbon atom separating the aromatic ring leads to enhancement of anti-inflammatory activity.
  • Groups larger than methyl decrease activity, but incorporation of this methyl group as part of an alicyclic ring system does not drastically affect activity.

Indole Acetic Acid Derivatives:

Medicinal Chemistry Drugs Action On Central Nervous System Acetic acid

Structure – Activity Relationship of Indene and Indole Acetic Acid Derivatives:

  • The carboxyl group is essential for anti-inflammatory activity.
  • Placement of other acidic functionalities instead of the carboxyl group decreases activity and the amide derivatives are inactive.
  • Alkyl group especially -CH3 at 2nd position is much active than aryl substituted analogues.
  • The 5th position of the indole ring is most flexible with regard to the nature of substituents that enhance activity. Substituents such as methoxy, fluoro, dimethylamino, methyl, allyloxy, and acetyl are more active than the unsubstituted indole ring.
  • The presence of indole ring nitrogen is not essential for activity because the corresponding 1-benzylidenylindene analogue (sulindac) is also active.
  • Acylation of the indole nitrogen with aryl/alkyl carboxylic acids results in the decrease of activity.
  • Presence of substituents on the N-benzoyl derivatives in the p-position with F, CI, CF3, or S-CH3 groups provide greatest activity.

Indomethacin:

Medicinal Chemistry Drugs Action On Central Nervous System Indomethacin

  • Indomethacin is chemically, 1-(p-chloro benzoyl)-5-methoxy-2-methylindole-3-acetic acid.
  • It inhibits the enzyme COX necessary for the formation of prostaglandins and other autocoids.

Uses:

  • It is a more potent antipyretic than either aspirin or acetaminophen.
  • It possesses approximately 10 times the analgesic potency of aspirin.
  • It is used as anti-inflammatory and analgesic in rheumatic arthritis, spondylitis, and to lesser extent in gout.
  • The most frequent side effects are gastric distress and headache.
  • It has also been associated with peptic ulceration, blood disorders, and possible deaths.
  • It is recommended only for patients who cannot tolerate aspirin and in place of phenylbutazone in long-term therapy.

Indene Acetic Acid Derivatives:

Sulindac:

Medicinal Chemistry Drugs Action On Central Nervous System SulindacMedicinal Chemistry Drugs Action On Central Nervous System Sulindac

  • Sulindac is a prodrug.
  • It is chemically 5-fluoro-2-methyl-1[(4 methyl sulphinyl) phenyl methylene] indene-3- acetic acid.

Metabolism:

  • Sulindac reaches peak blood levels within 2 to 4 hours and undergoes a complicated, reversible metabolism. The parent sulfinyl has a plasma half-life of 8 hours. It forms active metabolites of sulphide having plasma half-life of 16.4 hours. In addition to it, sulindac is oxidized to corresponding sulfoxide. The more polar and inactive sulphoxide is virtually the only form excreted.

Medicinal Chemistry Drugs Action On Central Nervous System Sulindac metabolism

Uses:

  • Sulindac has analgesic, antipyretic, and anti-inflammatory properties.
  • It is recommended for rheumatoid, osteoarthritis and ankylosing spondylitis.
  • It is used in the treatment of muscular skeletal disorders and acute gouty arthritis.
  • It may produce gastric bleeding, nausea, diarrhoea, dizziness as adverse effects, but with a lower frequency than with aspirin.

Pyrrole Acetic Acid Derivatives:

Medicinal Chemistry Drugs Action On Central Nervous System Pyrrole acetic acid

Structure – Activity Relationship of Pyrrole Acetic Acid Derivative:

  • Replacement of the p-tolyl group (tolmetin) with a p-chloro benzoyl moiety produced little effect on activity.
  • Introduction of a methyl group in the 4th position and 5-p-chloro benzoyl analogues (zomepirac) proved to be four times potent as tolmetin.

Tolmetin Sodium:

Medicinal Chemistry Drugs Action On Central Nervous System Tolmetin sodium

  • Tolmetin sodium is chemically, sodium-2-(1-methyl-5-(4-methylbenzoyl)-1H-pyrrol- 2-yl) acetate.
  • It inhibits the enzyme prostaglandin synthase, thus prevent synthesis of the inflammatory prostaglandin E2 (PGE2) from the precursor prostaglandin H2 (PGH2).

Uses:

  • Tolmetin sodium has antipyretic, analgesic, and anti-inflammatory actions.
  • It is employed in the treatment of rheumatic and musculoskeletal disorders.
  • The drug is, however, comparable to indomethacin and aspirin in the control and management of disease activity.

Zomepirac:

Medicinal Chemistry Drugs Action On Central Nervous System Zomepirac

  • Zomepirac is chemically, 1,4-dimethyl-5-(p-chloro benzoyl)pyrrole-2-acetic acid.
  • It has associated with fatal and near-fatal anaphylactoid reactions.

Uses:

  • Zomepirac is recommended in greater degree of analgesia for severe pain.
  • It is used as an analgesic and an anti-inflammatory drug.
  • It is four times as potent as tolmetin.

Aryl and Heteroaryl Acetic/Propionic Acid Derivatives:

Ibuprofen:

Medicinal Chemistry Drugs Action On Central Nervous System Ibuprofen

  • Ibuprofen is chemically 2(p-isobutyl-phenyl)-propionic acid.
  • The activity resides in the (s)-(+) isomer, not only in Ibuprofen, but also throughout the arylacetic acid series.
  • These isomers are the more potent inhibitors of prostaglandin synthase.
  • The precursor Ibufenac (acetic acid in place of propionic acid), has abandoned hepatotoxicity and is less potent.

Uses:

  • Ibuprofen is an anti-inflammatory drug that possesses antipyretic and analgesic action and is used for the treatment of rheumatoid arthritis and osteoarthritis.

Diclofenac:

Medicinal Chemistry Drugs Action On Central Nervous System Diclofenac

  • Diclofenac is chemically o-(2,6-dichloro anilino)-phenyl acetic acid.
  • It is available in sodium and potassium salt form.
  • It acts by inhibiting COX and decreased prostaglandin production.
  • It binds and chelates both COX-1 and COX-2, thereby blocking the conversion of arachidonic acid to pro-inflammatory-prostaglandins.

Uses:

  • Diclofenac sodium is used in the treatment of rheumatic arthritis, osteoarthritis and ankylosing spondylitis.
  • The potassium salt is faster acting and is used for the management of acute pain.

Naproxen:

Medicinal Chemistry Drugs Action On Central Nervous System Naproxen

  • Naproxen is chemically, (±) 2-(6-methoxy-2-naphthyl)-propionic acid.
  • The effectiveness of naproxen is partly due to its ability to inhibit COX-1 and COX-2, resulting in a decreased formation of precursors of prostaglandins and thromboxanes.
  • It decreases in the formation of thromboxane A2 synthesis, by thromboxane synthase, thereby inhibiting platelet aggregation.
  • It irreversibly blocks the enzyme cyclooxygenase (prostaglandin synthase), which catalyzes the conversion of arachidonic acid to endoperoxide compounds.

Uses:

  • Naproxen is fairly comparable to aspirin both in the management and control of disease symptoms.
  • It has lesser frequency and severity of nervous system together with milder GI-effects. It possesses analgesic, anti-inflammatory, and antipyretic actions.
  • It is used in the treatment of rheumatic arthritis, dysmenorrhea, and acute gout.

Ketorolac:

Medicinal Chemistry Drugs Action On Central Nervous System Ketorolac

  • Ketorolac is chemically 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid.
  • It is non-selective and it inhibits the enzymes COX-1 and COX-2.
  • The inhibition of COX-2, prevents conversion of arachidonic acid to pro-inflammatory prostaglandins, whereas the inhibition of COX-1 prevents the normal steady-state production of prostaglandins that play housekeeping roles in the protection of the gastrointestinal tract.

Uses:

  • Ketorolac is a potent analgesic indicated for the treatment of moderately severe and acute pain.
  • It also possesses analgesic and antipyretic activities.
  • Because of a number of potential side effects, its administration should not exceed 5 days.

Oxicams

  • Oxicams are COX-2 selectivity than many other NSAIDs, particularly meloxicam.
  • These agents have utility in treatment of rheumatoid arthritis and osteoarthritis.

Medicinal Chemistry Drugs Action On Central Nervous System Oxicams

Structure Activity Relationship of Oxicams:

  • The most active analogues have substituent CH3 on the nitrogen and electron withdrawing substituents on the anilide phenyl groups, such as – Cl and -CF3.
  • The introduction of heterocyclic ring in the amide chain significantly increases the anti-inflammatory activity. Example: 2-thiazolyl derivative sudoxicam is more potent than indomethacin.
  • The most active benzothiazine have acidities in the pKa range of 6-8.

Piroxicam:

Medicinal Chemistry Drugs Action On Central Nervous System Piroxicam

  • Piroxicam is chemically, 4-hydroxy-2-methyl-N-2-pyridinyl-1,2-benzothiazine-3- carboxamide-1,1-dioxide.
  • It binds and chelates both isoforms of COX-1 and COX-2 and prevent conversion of arachidonic acid into prostaglandin.

Uses:

  • Piroxicam has anti-inflammatory, antipyretic and analgesic properties.
  • It employed for acute and long-term therapy for the relief of symptoms of osteoarthritis and rheumatoid arthritis.
  • It also possesses uricosuric action and has been used in the treatment of acute gout.

Selective COX-2 Inhibitors

  • Cyclooxygenase-2 (COX-2) is an inducible enzyme release in response to injury or inflammation.
  • COX-2 inhibitors are the new-generation NSAIDs that may selectively block the COX-2 isoenzyme without affecting COX-1 function.
  • This may result in control of pain and inflammation with a lower rate of adverse effects compared with older non-selective NSAIDs.
  • Rapidly evolving evidence suggests that COX-2 enzyme has a diverse physiologic and pathologic role.

Celecoxib:

Medicinal Chemistry Drugs Action On Central Nervous System Celecoxib

  • Celecoxib is chemically, 4-[5-(4-methylphenyl)-3-(trifluoromethyl)pyrazole-1-yl]- benzenesulfonamide.
  • It has a central pyrazole ring with two adjacent phenyl substituents.
  • One phenyl ring contains a methyl group at p-position, whereas other contains a polar sulfonamide moiety at p-position.
  • The sulfonamide have ability to bind with a distinct hydrophilic region that is present on COX-2, but not COX-1.

Rofecoxib

Medicinal Chemistry Drugs Action On Central Nervous System Rofecoxib

  • Rofecoxib is chemically, 3-(4-methylsulfonylphenyl)-4-phenyl-2H-furan-5-one.
  • It has a central furanose ring and two adjacent phenyl substituents.
  • One phenyl ring contains a methyl sulfone group, whereas other phenyl ring is unsubstituted.
  • It binds to and inhibits the enzyme COX-2 resulting in an inhibition of the conversion of arachidonic acid to prostaglandins.
  • It has greater potency and a longer half-life than celecoxib.

Valdecoxib

Medicinal Chemistry Drugs Action On Central Nervous System Valdecoxib

  • Valdecoxib is chemically, 4-(5-methyl-3-phenyl-1,2-oxazol-4-yl)-benzenesulfonamide.
  • It is an aryl sulfonamide derivative like celecoxib.
  • It acts by inhibiting prostaglandin synthesis by blocking COX-2 thereby preventing the conversion of arachidonic acid to prostaglandins, which are involed in the regulation of pain, fever and inflammation.
  • At therapeutic plasma concentrations valedecoxib does not inhibit COX-1.

Uses:

  • Valdecoxib is non-steroidal anti-inflammatory drugs that exhibit anti-inflammatory, analgesic and antipyretic properties.
  • These drugs are also recommended for rheumatoid arthritis, osteoarthritis and juvenile arthritis.
  • It is also recommended to treat painful menstruation and menstrual symptoms.

Miscellaneous

Nimesulide:

Medicinal Chemistry Drugs Action On Central Nervous System Nimesulide

  • Nimesulide is chemically N-(4-nitro-2-phenoxyphenyl)-methanesulfonamide.
  • It inhibits the COX (COX-2) mediated conversion of arachidonic acid to pro- inflammatory prostaglandins.

Uses:

  • Nimesulide has anti-inflammatory activity.
  • It is recommended in the treatment of acute pain.

Synthesis

Mafenamic Acid

Medicinal Chemistry Drugs Action On Central Nervous System Mafenamic Acid synthesis

Ibuprofen

Medicinal Chemistry Drugs Action On Central Nervous System Ibuprofen synthesisMedicinal Chemistry Drugs Action On Central Nervous System Ibuprofen synthesis

Multiple Choice Questions:

Question 1. Non-narcotic analgesics are mainly effective against pain associated with:

  1. Inflammation or tissue damage
  2. Trauma
  3. Myocardial infarction
  4. Surgery

Answer. 1. Inflammation or tissue damage

Question 2. IUPAC name of the sulindac analogue is

  1. (Z)-5-fluoro-2-methyl-1-[(p-methyl sulfinyl)phenyl] methylene-1H-indene-3- acetic acid
  2. (E)-5-fluoro-2-methyl-1-phenyl methylene-1H-indene-3-acetic acid
  3. (Z)-5-fluoro-2-methyl-2-[(p-methyl sulfinyl)phenyl] methylene-1H-indene-4- acetic acid
  4. (R)-5-fluoro-2-methyl-1-1-phenyl methylene-1H-indene-3-acetic acid

Answer. 1. (Z)-5-fluoro-2-methyl-1-[(p-methyl sulfinyl)phenyl] methylene-1H-indene-3- acetic acid

Question 3. Non-narcotic analgesics are all of the following drugs EXCEPT:

  1. Paracetamol
  2. Acetylsalicylic acid
  3. Butorphanol
  4. Ketorolac

Answer. 3. Butorphanol

Question 4. Which isomer of ibuprofen is more active?

  1. (S) (-) isomer
  2. (S) (+) isomer
  3. (R) (+) isomer
  4. (R) (-) isomer

Answer. 2. (S) (+) isomer

Question 5. Select the non-narcotic drug, which is a para-aminophenol derivative:

  1. Analgin
  2. Aspirin
  3. Baclophen
  4. Paracetamol

Answer. 4. Paracetamol

Question 6. Phenylbutazone is the acidic drug. It is due to

  1. Easily replaceable hydrogen
  2. CO-CH2-CO moiety
  3. Two keto groups
  4. Two nitrogen atoms

Answer. 2. CO-CH2-CO moiety

Question 7. Which of the following is an active form of sulindac?

  1. Z-form
  2. E-form
  3. Z & E-form
  4. None of above

Answer. 1. Z-form

Question 8. Which of the following non-narcotic agents is salicylic acid derivative?

  1. Phenylbutazone
  2. Ketamine
  3. Aspirin
  4. Tramadol

Answer. 3. Aspirin

Question 9. Starting material for ibuprofen is

  1. Isopropyl benzene
  2. Isobutyl benzene
  3. Isobutyl acetophenone
  4. Isopropyl acetophenone

Answer. 2. Isobutyl benzene

Question 10. Pyrazolone derivative is:

  1. Methyl salicylate
  2. Analgin
  3. Paracetamol
  4. Ketorolac

Answer. 2. Analgin

Question 11. Which of the following is N-aryl anthranilic acid derivative?

  1. Mefenamic acid
  2. Toletine
  3. Indomethacine
  4. Paracetamol

Answer. 1. Mefenamic acid

Question 12. Chemically ibuprofen is

  1. 2-(4-isobutyl phenyl) propionic acid
  2. 3,20-di-oxo-4-pregnen-17a-yl benzoate
  3. 2-(4-isopropyl phenyl) propionic acid
  4. 2-(4-isopropyl methyl) propionic acid

Answer. 1. 2-(4-isobutyl phenyl) propionic acid

Question 13. Which one of the following non-narcotic agents inhibits mainly cyclooxygenase (COX) in CNS?

  1. Paracetamol
  2. Ketorolac
  3. Acetylsalicylic acid
  4. Ibuprofen

Answer. 1. Paracetamol

Question 14. Which of the following ring is present in sulindac?

  1. Indol
  2. Indene
  3. Isoxazole
  4. Furan

Answer. 2. Indene

Question 15. Most of non-narcotic analgetics have:

  1. Anti-inflammatory effect
  2. Analgesic effect
  3. Antipyretic effect
  4. All of the above

Answer. 4. All of the above

Question 16. Indicate the non-narcotic analgesic, which lacks an anti-inflammatory effect:

  1. Naloxone
  2. Paracetamol
  3. Metamizole
  4. Aspirin

Answer. 2. Paracetamol

Question 17. Ibuprofen is a

  1. 2-(4-propylphenyl)propionic acid
  2. 2-(4-isobytylphenyl)propionic acid
  3. 2-(4-ethylphenyl)propionic acid
  4. 2-(4-hexylphenyl)propionic acid

Answer. 2. 2-(4-isobytylphenyl)propionic acid

Question 18. Paracetamol is a 4-acetaminophenol. It is an intermediate in the preparation of

  1. Chlorphenesin
  2. Phenacetine
  3. Hexachlorophan
  4. Hexylresorcinol

Answer. 2. Phenacetine

Question 19. Methemoglobinemia is possible adverse effect of:

  1. Aspirin
  2. Paracetamol
  3. Analgin
  4. Ketorolac

Answer. 2. Paracetamol

CS Company Law – Inter Corporate Loans Investments Guarantees Question and Answers

An Overview Of Inter Corporate Loans, Investments, Guarantees And Security, Related Party Transactions

Investments

Investments have been used in a limited sense in the lesson to mean the investing of money in shares, stock, debentures, or other securities.

Loans and Investments by Companies (Section 186)

A company shall unless otherwise prescribed, invest in not more than two layers of investment companies. [Sub-section (1) of section 186]

However, the aforesaid provisions shall not affect-

  • A company from acquiring any other company incorporated in a country outside India if such other company has investment subsidiaries beyond two layers as per the laws of such country;
  • a subsidiary company from having any investment subsidiary for meeting the requirements under any law or under any rule or regulation framed under any law for the time being in force. [Proviso to sub-section (1) of Section 186]

Limits for Loans, Guarantees, Security and Investment – Section 186(2)

No Company shall, directly or indirectly:

  • Give any loan to any person or other body corporate;
  • Give any guarantee, or provide security, in connection with a loan to any other body corporate or person; and
  • Acquire, by way of subscription, purchase, or otherwise the securities of any other body corporate;

exceeding 60% of its paid-up share capital, free reserves, and securities premium account or 100% of its free reserves and securities premium account, whichever is more unless the same is previously authorized by a special resolution passed in a general meeting.

Non-Applicability of Section 186

Sub-section (11) of Section 186 provides that nothing contained in this section, except sub-section (1), shall apply-

  • To any loan made, any guarantee given any security provided, or any investment made by a banking company, an insurance company, a housing finance company in the ordinary course of its business, or a company established with the object of and engaged in the business of financing industrial enterprises, or of providing infrastructural facilities;
  • To any investment-
    • made by an investment company;
    • made in shares allotted in pursuance of clause (a) of sub-section (1) of Section 62 or in shares allotted in pursuance of rights issues made by a body corporate;
    • made, in respect of investment or lending activities, by a non-banking financial company registered under Chapter 3-B of the Reserve Bank of India Act, 1934 and whose principal business is the acquisition of securities.

Inter Corporate Loans And Investments Cs

Penalty for Contravention of Section 186

If a company contravenes the provisions of this section, the company shall be punishable with a fine which shall not be less than twenty-five thousand rupees but which may extend to five lakh rupees and every officer of the company who is in default shall be punishable with imprisonment for a term which may extend to two years and with fine which shall not be less than twenty-five thousand rupees but which may extend to one lakh rupees.

Investments to be held in the company’s own home

As per the Act, all investments made or held by a company in any property, security, or other asset shall be made and held by it in its name. This requirement is confined to only those investments which are made by it on its behalf and not on behalf of someone else. However, in certain circumstances, the Act exempts the companies from complying with the above provisions.

Investment not held in the company’s own home

When any shares or securities in which a company has made investments are not held by it in its name as a beneficial owner when such investments are held in the name of a depository according to permissible conditions given in the Act, the company shall forthwith enter in a register maintained by it for the purpose, particulars as specified in the Act.

Related Party Transactions

According to Section 2(76) of the Companies Act, 2013, “related party”, concerning a company, means-

  • A director or his relative;
  • A key managerial personnel or his relative;
  • A firm, in which a director, manager or his relative is a partner;
  • A private company in which a director or manager or his relative is a member or director;
  • A public company in which a director or manager is a director and holds along with his relatives, more than two percent (2%) of its paid-up share capital;
  • Anybody corporate whose Board of Directors, managing director, or manager is accustomed to act by the advice, directions, or instructions of a director or manager;
  • Any person on whose advice, directions, or instructions a director or manager is accustomed to act:
  • Provided that nothing in sub-clauses (6) and (7) shall apply to the advice, directions, or instructions given in a professional capacity;
  • Anybody corporate which is-
    • a holding, subsidiary, or an associate company of such company;
    • a subsidiary of a holding company to which it is also a subsidiary; or
    • an investing company or the venturer of the company.

Nature of Related Party Transactions

The scope of dealing with Related Party Transactions has been widened in the Companies Act, 2013. Section 188 (1) of the Act provides that except with the consent of the Board of Directors given by a resolution at a meeting of the Board and subject to such conditions as prescribed under Rule 15 of the Companies (Meetings of Board and its Powers) Rules, 2014, no company shall enter into any contract or arrangement with a related party with respect to-

  • Sale, purchase, or supply of any goods or materials;
  • Selling or otherwise disposing of, or buying, property of any kind;
  • Leasing of property of any kind;
  • Availing or rendering of any services;
  • Appointment of any agent for the purchase or sale of goods, materials, services, or property;
  • Such related party’s appointment to any office or place of profit in the company, its subsidiary company, or associate company; and
  • Underwriting the subscription of any securities or derivatives thereof, of the company:

List of Important Forms

Company Law An Overview Of Inter Corporate Loans Investments List of Important forms

Inter Corporate Loans Under Companies Act 2013

Distinguish Between

Question 1. Distinguish between the following:

  1. ‘Free Reserves’ and ‘Net Worth’ under the provisions of the Companies Act,
  2. ‘Related Party’ and ‘Relative’ as defined and applied under the Companies Act, 2013.

Answer:

Free Reserves

As per Section 2(43) “free reserves” means such reserves which, as per the latest audited balance Sheet of a company, are available for distribution as dividends:

Provided that:

  • any amount representing unrealized gains, notional gains or revaluation of assets, whether shown as a reserve or otherwise, or
  • any change in the carrying amount of an asset or of a liability recognized in equity, including surplus in profit and loss account on measurement of the asset or the liability at fair value, shall not be treated as free reserves.

Whereas “Net Worth” means the aggregate value of the paid-up share capital and all reserves created out of the profits and securities premium account, after deducting the aggregate value of the accumulated losses, deferred expenditure and miscellaneous expenditure not written off, as per the audited balance sheet, but does not include reserves created out of revaluation of assets, write-back of depreciation and amalgamation.

Amendment made by Companies (Amendment) Act, 2017 account and debit or credit balance of profit and loss account, after deducting the aggregate value of the accumulated losses, deferred expenditure and miscellaneous expenditure not written off, as per the audited balance sheet, but does not include reserves created out of revaluation of assets, write-back of depreciation and amalgamation.

According to Section 2(76) of the Companies Act, 2013, “related party”, about a company, means:

  • A director or his relative;
  • A key managerial personnel or his relative;
  • A firm, in which a director, manager or his relative is a partner;
  • A private company in which a director or manager or his relative is a member or director;
  • A public company in which a director or manager is a director and holds along with his relatives, more than two percent (2%) of its paid-up share capital;
  • Anybody corporate whose Board of Directors, managing director, or manager is accustomed to act per the advice, directions, or instructions of a director or manager;
  • Any person on whose advice, directions, or instructions a director or manager is accustomed to act:
  • Provided that nothing in sub-clauses (vi) and (vii) shall apply to the advice, directions, or instructions given in a professional capacity;
  • Any company which is-
    • A holding, subsidiary, or an associate company of such company; or
    • A subsidiary of a holding company to which it is also a subsidiary;
    • According to Notification No. GSR 464(E), dated 05/06/2015 in the case of Private Companies this subclause shall not apply concerning Section 188.
  • Such other person as may be prescribed;

Rule 3 of the Companies (Specification of Definitions Details) Rules, 2014 prescribes, that a director other than an independent director or key managerial personnel of the holding company or his relative about a company, shall be deemed to be a related party.

According to Section 2(77), ‘relative’ concerning any person means anyone who is related to another, if: (i) they are members of a HUF; (ii) they are husband and wife; or (iii) one person is related to the other in such manner as may be prescribed.

According to Rule 4 of the Companies (Specification of Definitions Details) Rules, 2014, a person shall be deemed to be the relative of another, if he or she is related to another in the following manner, namely:

  • Father: Provided that the term “Father” includes step-father.
  • Mother: Provided that the term “Mother” includes the stepmother.
  • Son: Provided that the term “Son” includes the stepson.
  • Son’s wife.
  • Daughter.
  • Daughter’s husband.
  • Brother: Provided that the term “Brother” includes the step-brother;
  • Sister: Provided that the term “Sister” includes the step-sister. -Space to write important points for revision

Descriptive Questions

Question 1. Your company, which is a public limited company wishes to make investments in shares of a company. The total investment exceeds the statutory limit stipulated by the Companies Act, 2013. What are the formalities to be complied with in this regard?

Answer:

Company Law An Overview Of Inter Corporate Loans Investments Provisions of Sec. 186

Inter Corporate Guarantees Rules

Question 2. What transactions are considered as ‘related party transactions’ under the provisions of the Companies Act, 2013? Explain.

Answer:

Provisions of the Companies Act Regarding Related Party Transaction

Meaning of related party. Sec. 2(76) of Companies Act, 2013

Concerning company, the term ‘related party’ means and includes the following:

  • a director or his relative,
  • KMP or their relative,
  • a firm in which a director, manager, or his relative is a partner,
  • a private company in which a director or manager is a director or member,
  • a public company in which a director or Manager is a director or holds along with his relatives more than 2% of its paid-up share capital.
  • a person on whose advice, directions, or instruction (except given in a professional capacity) a director or manager is accustomed to act,
  • a holding/ subsidiary or associate company, subsidiary’s subsidiary, and such person as would be prescribed.

Related Party Transaction Sec. 188

The escape of dealing with related party transactions has been given in the Companies Act, 2013, stating that the contracts or arrangements with above mentioned related party which comes to the following shall be covered under the scope of the provision:

  • Sale, purchase, or supply of any goods or materials;
  • Selling or otherwise disposing of, or buying, property of any kind;
  • Leasing of property of any kind;
  • Availing or rending of any services;
  • Appointment of any agent for the purchase or sale of goods, materials, services, or property;
  • Such, related party’s appointment to any office or place of profit in the company, its subsidiary company or associate company; and Underwriting the subscription of any securities or derivatives thereof, of the company.

Ordinary Resolution

  • Provided that no contract or arrangement, in the case of a company having a paid-up share capital of not less than such amount, or transactions not exceeding such sums, as may be prescribed, shall be entered into except with the prior approval of the company by an ordinary resolution.
  • Provided further that no member of the company shall vote on such ordinary resolution, to approve any contract or arrangement that may be entered into by the company, if such member is a related party. (This proviso is not applicable on private companies)

When Prior Approval of

Company by Ordinary Resolution Required for Related Party Transactions [Rule 15 of Companies (Meeting of Board and its Powers) Rules, 2014]

  • Transaction
    • Sale, purchase, or supply of any goods or materials, directly or through the appointment of an agent.
    • Selling or otherwise disposing of or buying property of any kind, directly or through the appointment of an agent.
    • Leasing of property of any kind
    • Availing or rendering of any services, directly or through the appointment of an agent
    • Is for appointment to any office or place of profit in the company, its subsidiary company, or associate company
    • Is for remuneration for underwriting the subscription of any 6. securities or derivatives thereof, of the company
  • When Ordinary Resolution is Required
    • Exceeding ten percent of the turnover of the company or rupees one hundred crore, whichever is lower.
    • Exceeding ten percent of the net worth of the company or rupees one hundred crore, whichever is lower.
    • Exceeding ten percent of the net worth of the company or ten percent. of turnover of the company or rupees one hundred crore, whichever is lower
    • Exceeding ten percent. of the turnover of the company or rupees fifty crore, whichever is lower
    • At a monthly remuneration exceeding two and a half lakh rupees
    • Exceeding one percent of the net worth.

Question 3. Who is a “related party” as defined in Section 2(76)?
Answer: According to Section 2(76) of the Companies Act 2013, “related party”, about a company, means-

  • A director or his relative:
  • A key managerial personnel or his relative;
  • A firm, in which a director, manager or his relative is a partner;
  • A private company in which a director or manager or his relative is a member or director;
  • A public company in which a director or manager is a director and holds along with his relatives, more than two percent (2%) of its paid-up share capital;
  • Any body corporate whose Board of Directors, managing director, or manager is accustomed to act by the advice, directions, or instructions of a director or manager;
  • Any person on whose advice, directions, or instructions a director or manager is accustomed to act: Provided that nothing in sub-clauses (6) and (7) shall apply to the advice, directions, or instructions given in a professional capacity:
  • Any body corporate which is
    • A holding, subsidiary, or an associate company of such company;
    • A subsidiary of a holding company to which it is also a subsidiary; or
    • An investing company or the venturer of the company.

Explanation: For this clause, “the investing company or the venturer of a company” means a body corporate whose investment in the company would result in the company becoming an associate company of the body corporate Such other person as may be prescribed.

Question 4. A company passed a special resolution in its general meeting for the grant of a loan to another body corporate more than the limits specified in section 186(2). However, one of the directors contended that prior approval of their financial institution is also required for such lending. Explain whether the contention of the director is acceptable.

Answer:

Section 186(5) of the Companies Act, 2013 provides that no investment shall be made loan guarantee, or security given by the company unless the resolution sanctioning it is passed at a meeting of the Board with the consent of all the directors present at the meeting and the prior approval of the public financial institution (PFI) concerned where any term loan is subsisting, is procured.

Although the prior consent of a Public Financial Institution shall not be needed where the aggregate of loans and investments so far made, the amounts for which guarantee or security so far provided to or in all other bodies corporate, along with the investments, loans, guarantee or security proposed to be made or given does not exceed the limit of 60% of its paid-up share capital, free reserves, and securities premium account or 100% of its free reserves and securities premium account, whichever is higher and there is no default in repayment of loan installments or payment of interest thereon as per the terms and conditions of such loan to the public financial institution.

In the above case, the Company is passing the special resolution under Section 186(2) of the Companies Act, 2013, indicating thereby that the proposed loan together with the loans already given is already more than the limits given under Section 186 (2) of Companies Act, 2013. Therefore the contention of the director is correct as the company aggregate of loans and investments so far made, exceed the limit under Section 186(2) of the Companies Act, 2013.

However, if the aggregate loans/ investments are well within the limits of consent and the company is passing the Special Resolution either in terms of its Article of Association (AOA) or voluntarily only due to some other commercial requirement other than Section 186(2) of Companies Act, 2013, then the prior consent from Financial Institution will not be required.

CS Company Law – Inter Corporate Loans Investments Guarantees Question and Answers

Practical Questions

Question 1. The board of directors of Joy Ltd., by a resolution passed at its meeting, decided to provide a loan of 50 crores to Happy Ltd. The paid-up share capital of Joy Ltd. on the date of resolution was 100 crore and the aggregate balance in the free reserves and securities premium account stood at 40 crore. Examining the provisions of the Companies Act, 2013, decide whether the Board’s resolution to provide a loan of 50 crores to Happy Ltd. is valid.

Answer:

Company Law An Overview Of Inter Corporate Loans Investments Provisions of Sec.186(2)

Cs Company Law Investment And Loans Questions

Question 2. Virat, a person of 21 years of age is pursuing MBA (Finance) course at a reputed recognised business school. He is not a shareholder of Grow (Pvt.) Ltd. He wishes to inspect the register of investments in securities not held in company’s name and annual return of Grow (Pvt.) Ltd. He also wants to take copies thereof. Examining the relevant provisions of the Companies Act, 2013, advise Virat whether he would be successful in this regard.

Answer:

Company Law An Overview Of Inter Corporate Loans Investments Section 187

Question 3. Barkha Ltd. has four directors on its Board. A Board meeting was convened which was attended by only two directors, where Rekha was appointed as an additional director. Rekha is related to both the directors. Referring to the provisions of the Companies Act, 2013, examine the validity of the appointment. 

Answer:

Company Law An Overview Of Inter Corporate Loans Investments Section 188 of Companies

Question 4. RR Limited has decided to make investments in other companies for ₹ 50 lakhs, which is over 60% of the company’s paid-up share capital, free reserves, and securities premium account. The company has 5 directors. Four directors were present in the Board meeting, three directors have given their consent but one director abstained from voting. The decision of the Board was noted in the minutes of Board meeting and decided to make such an investment by passing of Board resolution with the majority. Referring to the provisions of Companies Act, 2013, examine the validity of the Board’s decision.

Answer:

By the provisions of the Companies Act, 2013, as contained in Section 186 (5), no investment shall be made or loan or guarantee or security given by the company unless the resolution sanctioning it is passed at a meeting of the Board with the consent of all the directors present at the meeting and the prior approval of the public financial institution concerned where any term loan is subsisting, is obtained.

Further, under the provisions of Section 186(2) and 186(3), the loan amount must not exceed 60% of its paid-up capital, free reserves, and securities premium account or 100% of free reserves and securities premium account, whichever is more. In case, the company wishes to exceed the said limit, prior approval, of the company through special resolution would be acquired.

In the given case, in the absence of adequate information, even if we assume that 50 lakh does not exceed 100% of free reserves and securities premium account, RR Limited has not complied with the provisions of Section 186 (5) of the Companies Act, 2013 where consent of all-the directors present is required. The resolution of the Board of Directors, therefore, is not valid and has no legal effect.

Question 5. XYZ Ltd., a company, has a paid-up share capital of * 60 crores and free reserves of 25 crores. It desires to make a loan of 20 crores to M Ltd. The company XYZ Ltd. has already made investments in many other companies including loans to the extent of 35 crores. Can the company go ahead with a loan to M Ltd.? Please advise the company about the procedure to be followed by it.

Answer:

As per Section 186 of the Companies Act, 2013 a company shall make investments up to 60 percent of paid-up share capital and free reserves or 100 percent of free reserves and securities premium account whichever is more.

In this case, the company can make a maximum investment of 60% (60+25) = 51 crores.

Since the company has already invested 35 crores it can further invest 16 crores only.

To invest upto 20 crores they need to take approval of shareholders through a special resolution.

Inter Corporate Loans Limits And Regulations

Question 6. HIJ Engineers Ltd. has a paid-up capital of * 20 lahks, Free Reserves of 3 lakh, and a Securities Premium of 2 lakh. It has granted a loan of 14 lakh to KLM Traders Ltd. The Board of Directors is proposing the following transactions without securing approval of the members:

  1. Sanctioning a loan of 2 lakh to KLM Cement Ltd. and
  2. Sanctioning a loan of ₹ 3 lakh to an employee of the company.

Can the Board of Directors sanction the aforesaid loans?

Answer:

According to Section 186 (2) of the Companies Act, 2013 provides that, no company shall directly or indirectly give any loan to any person or other body corporate exceeding 60% of its paid-up share capital, free reserves and securities premium account or 100% of its free reserves and securities premium account, whichever is higher.

As per Section 186(3) of the Companies Act, 2013 states that where the aggregate of the loans and investment so far made, along with the investment or loan, proposed to be made or given by the Board, exceed the limits specified under section 186(2), no investment or loan shall be made unless previously authorised by a special resolution passed in a general meeting.

Therefore, as per section 186(2) of the Companies Act, 2013, the limits for the loan and investment will be the amount whichever is higher of the following:

  1. 60% of paid up share capital, free reserves and securities premium account 15 lakh or
  2. 100% of free reserves and securities premium account = 5 lakh In the above case, since the company has already given loans of 14 lakh to KLM Traders Ltd and further proposed to grant loan, of 2 Lakh to KLM Cement Ltd, it will exceed the limit of 15 lakh, therefore prior approval by special resolution in the general meeting will be required to be passed by HIJ. Engineers Ltd. in terms of Section 186(3) of the Companies Act, 2013.

As per Explanation w.r.t. to Section 186(2) of the Companies Act, 2013, the word person, used under this sub-section does not include any individual who is in the employment of the company.

Accordingly, there are no limit imposed on the right of a company to sanction a loan to an employee of the company under Section 186(2) of the Companies Act, 2013, the Board of directors can grant a loan of 3 lakhs to the employee. No need to require any approval from the members.. Space to write important points for revision

Question 7. Jupiter Ltd. Intends to acquire shares in another company. How much amount can be invested by Jupiter Ltd. without passing special resolution considering the facts mentioned below?

 

Company Law An Overview Of Inter Corporate Loans Investments Jupiter Limited

Answer:

As per section 186(2) of the Companies Act, 2013, no company shall, directly or indirectly:

  • give any loan to any person or other body corporate;
  • give any guarantee or provide security in connection with a loan to any other body corporate or person; and
  • acquire by way of subscription, purchase or otherwise, the securities of any other body corporate, exceeding 60% of its paid-up share capital, free reserves and securities premium account or 100% of its free reserves and securities premium account, whichever is higher.

Further, where the aggregate of the loans and investment so far made, the amount for which guarantee or security so far provided to or in all other bodies corporate along with the investment, loan, guarantee or security proposed to be made or given by the Board, exceed the limits specified under Section 186(2) of the Companies Act, 2013, no investment or loan shall be made or guarantee shall be given or security shall be provided unless previously authorised by a special resolution passed in a general meeting.

Company Law An Overview Of Inter Corporate Loans Investments Particulars

Hence, a further investment that can be made by Jupiter Ltd. without passing a special resolution will be higher of (iv) or (v) or E reduced by investment already made i.e. (864-78084 Crore)

Inter Corporate Loans And Investments Cs

Question 8. XYZ Ltd. is an investment company whose principal business is the acquisition of shares and debentures of other companies. The following figures were derived from the books of XYZ Ltd.:

Assets:

Investment in shares and debenture      ₹ 95 Lakh

Other Assets                                           ₹ 105 Lakh

Total                                                        ₹ 200 Lakh

Income:

Income from investment business        ₹ 12 Lakh

Other Income                                        ₹ 18 Lakh

Total                                                      ₹ 30 Lakh

Whether the company is an investment company as per section 186 and eligible to claim exemption given thereunder?

Answer:

As per explanation to Section 186 (13) of the Companies Act, 2013; the expression “investment company” means a company whose principal business is the acquisition of shares, debentures or other securities and a company will be deemed to be principally engaged in the business of acquisition of shares, debentures or other securities, if its assets in the form of investment in shares, debentures or other securities constitute not less than fifty percent. of its total assets, or if its income derived from investment business constitutes not less than fifty per cent. as a proportion of its gross income.

Conclusion: Since no condition is satisfied, XYZ Limited cannot be categorized as an Investment Company and hence cannot claim exemption given thereunder.

Question 9. The Board of Directors of XYZ Ltd is considering the proposal for making the investment in ABC Ltd. The company has 5 directors on board and in the board meeting 4 directors were present, three of them given consent to the proposal and one director abstained from voting. Comment on the same. 

Answer:

Under section 186(5) of the Companies Act, 2013, no investment shall be made or loan or guarantee or security given by the company, unless the resolution sanctioning it is passed at a meeting of the Board of Director with the consent of all the directors present at the meeting and the prior approval of the public financial institution (PFI) concerned where any term loan is subsisting is obtained.

Conclusion:

In the above problem, the Board of Directors of XYZ Ltd. while considering the proposal for making the investment in ABC Ltd. has not complied with the provision of section 186(5) of the Companies Act, 2013, where the consent of all the directors present at the meeting is required.

The resolution of the board of directors therefore is not valid and has no legal effect.

Short Notes

Question 1. Write short note on the following:

  1. Related Party not to vote on resolution
  2. Arm’s length transaction

Answer:

Second Proviso to Section 188 (1) of the Act provides that no member of the company shall vote on such resolution, to approve any contract or arrangement which may be entered into by the company, if such member is a related party.

This shall not apply to a company in which ninety per cent. or more members, in number, are relatives of promoters or are related parties.

  • Exemption to Private Companies: In case of private companies second proviso shall not apply (Notification No. GSR 464(E) dated5-6-2015).
  • Exemption to Government Companies: In case of Government companies above mentioned Second Proviso to the section 188 (1) of the Act shall not apply to –
    • a Government company in respect of contracts or arrangements entered into by it with any other Government company or with Central Government or any State Government or any Combination thereof;
    • a Government company other than a listed company, in respect of contracts or arrangements other than those referred to in clause (a), in case such company obtains approval of the Ministry or Department of the Central Government which is administratively in charge of the company, or, as the case may be the State Government before entering into such contract or arrangement. (Notification No. GSR 463(E) dated5-6-2015).
  • As per the explanation (2) to Section 188(1) of the Act, the expression “arm’s length transaction” means a transaction between two related parties that is conducted as if they were unrelated, so that there is no conflict of interest.
  • The phrase ‘on an arm’s length basis’ is in fact ‘at arm’s length’ or ‘an arm’s length relationship’ which means avoiding intimacy or close contact. The phrase ‘at arm’s length’ in relation to dealings between two parties is used to refer to dealings when neither party is controlled by the other.
  • Arm’s length is the condition or fact that the parties to a transaction are independent and on an equal footing. Arm’s length transaction is a transaction between unrelated persons or organizations, in which there is no improper influence exercisable by one party over another, and no conflict of interests of or relating to dealings between two parties who are not related or not on close terms and who are presumed to have roughly equal bargaining power; not involving a confidential relationship.
  • Parties are said to deal at “arm’s length” when they conduct the business without being subject to the other’s control or overmastering influence. An arm’s length transaction is a transaction between companies or people that do not have close contact or any financial connections and be or deal at arm’s length means without a close relationship with a person or a company.
  • The burden to establish that a transaction was at arm’s length would be on the company and there must be sufficient and pertinent material to prove that the terms of the transaction with a related party were purely commercial and the same as in the case of a transaction between the company and a non- related party and there were no extra-commercial considerations.

Inter Corporate Loans Under Companies Act 2013

Descriptive Questions

Question 2. Discuss the role of Audit Committee in Related Party transactions.

Answer:

Section 177(4)(iv) of the Companies Act, 2013 provides that the terms of reference of Audit Committee shall include approval or any subsequent modification of transactions of the company with related parties;

Provided that the Audit Committee may make omnibus approval for related party transactions proposed to be entered into by the company subject to such conditions as may be prescribed;

Thus, it is the responsibility of the audit committee to approve the transactions of the company with related parties.

As per Rule 6A of Companies (Meeting of Board and its Powers) Second Amendment Rules, 2015, the audit committee may make omnibus approval for all related party transactions proposed to be entered into by the company subject to the following conditions, namely –

  • The Audit Committee shall, after obtaining approval of the Board of Directors, specify the criteria for making the omnibus approval which shall include the following, namely:
    • maximum value of the transactions, in the aggregate, which can be allowed under the omnibus route in a year;
    • the maximum value per transaction that can be allowed;
    • extent and manner of disclosures to be made to the Audit. Committee at the time of seeking omnibus approval;
    • review, at such intervals as the Audit Committee may deem fit, related party transactions entered into by the company pursuant to each of the omnibus approvals made;
    • transactions that cannot be subject to the omnibus approval by the Audit Committee.
  • The Audit Committee shall consider the following factors while specifying the criteria for making omnibus approval, namely:
    • The repetitiveness of the transactions (in the past or future);
    • Justification for the need for omnibus approval.
  • The Audit Committee shall satisfy itself on the need for omnibus approval for transactions of a repetitive nature and that such approval is in the interest of the company.
  • The omnibus approval shall contain or indicate the following:-
    • Name of the related parties;
    • Nature and duration of the transaction;
    • The maximum amount of transactions that can be entered into;
    • The indicative base price or current contracted price and the formula for variation in the price, if any; and
    • Any other information relevant or important for the Audit Committee to decide on the proposed transaction:
      Provided that where the need for related party transaction cannot be foreseen and aforesaid details are not available, the audit committee may make ‘omnibus approval for such transactions subject to their value not exceeding rupees one crore per transaction.
  • Omnibus approval shall be valid for a period not exceeding one financial year and shall require fresh approval after the expiry of such financial year.
  • Omnibus approval shall not be made for transactions in respect of selling or disposing of the undertaking of the company. Space to write important points for revision

Question 3. Which companies are exempt from the provisions about loans and investments by companies?

Answer:

Non Applicability of Section 186

Exemptions

Sub-section (11) of Section 186 provides that nothing contained in this section, except sub-Section (1), shall apply-

  • to any loan made, any guarantee given any security provided or any investment made by a banking company, an insurance company, a housing finance company in the ordinary course of its business, or a company established with the object of and engaged in the business of financing industrial enterprises, or of providing infrastructural facilities;
  • to any investment-
    • made by an investment company;
    • made in shares allotted in pursuance of clause (a) of sub-section (1) of Section 62 or in shares allotted in pursuance of rights issues made by a body corporate;
    • made, in respect of investment or lending activities, by a non-banking financial company registered under Chapter III-B of the Reserve Bank of India Act, 1934 and whose principal business is the acquisition of securities.

Exemption from Applicability of Section 186 to Government Company Given the Central Government’s notification dated 5th June 2015 under Section 462 of the Companies Act, 2013, Section 186 shall not apply to:

  • a Government company engaged in defense production;
  • a Government company, other than a listed company, in case such company obtains approval of the Ministry or Department of the Central Government which is administratively in charge of the company, or, as the case may be, the State Government before making any loan or giving any guarantee or providing any security or making any investment under the section.

Penalty for Contravention of Section 186

If a company contravenes the provisions of this section, the company shall be punishable with a fine which shall not be less than twenty-five thousand rupees but which may extend to five lakh rupees and every officer of the company who is in default shall be punishable with imprisonment for a term which may extend to two years and with fine which shall not be less than twenty-five thousand rupees but which may extend to one lakh rupees.