Anti Tubercular Agents Introduction

Tuberculosis

It is a disease of respiratory transmission. A person gets infected when he comes in contact with an environment contaminated with viable tubercle bacilli. It spreads through coughing, sneezing, and shouting of an infected person.

Causative Organism: Mycobacterium Tuberculosis

Isoniazid

It is a hydrazide of iso-nicotinic acid.

• The structure of INH is similar to Pyridoxine (Vit B₆).
• Bacteriostatic in action

Mechanisam Action: INH inhibits Mycolase Synthase, an enzyme necessary for the biosynthesis of mycolic acid (essential constitute of the mycobacterial cell wall).

Metabolism: N-acetylation, depends upon the transfer of the acetyl group from coenzyme A by N-acetyl transferase.

• The rate of acetylation is genetically controlled.
• Acetyl hydrazine: Toxic metabolite of INH which is responsible for hepatotoxicity.

Metabolism Adverse Effect:

• Peripheral Neuritis-Co administration of Pyridoxine (Vit B6) with INH prevents the symptoms of peripheral neuritis.
• GIT disturbance (Constipation, Loss of appetite)
• Hepatotoxicity

Read and Learn More Medicinal Chemistry III Notes

Metabolism Drug Interaction:

• Antacid (Aluminum Hydroxide) Inhibits the absorption of INH.
• PAS-Inhibits metabolism.
• INH also inhibits the metabolism of Phenytoin and carbamazepine.

streptomycin

Aminoglycoside antibiotic

• Bacteriostatic in action
• Used always in combination
• Nephrotoxicity and ototoxicity are major side effects.
• Streptomycin resistance strain treated with kanamycin and viomycin.

Ethambutol Or Myambutol

• The activity of EMB is stereospecific, dextro isomer having maximum activity than the levo form.
• It has two chiral centers.

Mechanism of action:

It inhibits the “Arabinosyl transferase enzyme” to prevent the polymerization of arabinoglycan in the mycobacterial cell wall.

• Ethambutol if used in a dose of 25 mg/kg per day for more than 9 months can cause Reterobulbar Neuritisimpairment of visual activity and red-green color discrimination.
• Ethambutol decreases renal excretion and it may produce gouty arthritis.
• Contraindicated in pregnancy and children below 2 years.
• A monthly eye examination of the patient is necessary when the patient is treated with EMB.

Rifampicin

It is an orally active bactericidal semi-synthetic derivative of rifamycin B.

• It is obtained from Streptomyces mediterranei.
• It is also known as Ansamycin antibiotics.

Rifampicin Mechanism of action: It strongly binds to the p subunit of bacterial ‘DNA dependent RNA polymerase’ enzyme. Thereby inhibits the RNA synthesis of bacteria. Mammalian RNA polymerase does not bind to rifampicin.

Rifampicin Adverse effect:

• Hepatitis risk may increase when used in combination with INH.
• The flu-like syndrome is characterized by fever, chills, myalgias, and thrombocytopenia.
• Rifampicin imparts a harmless red-orange color to urine.

Rifampicin Drug Interaction: Rifampicin has enzyme induction properties and hence accelerates the metabolism of several drugs like oral contraceptives, anti-coagulants, and protease enzymes.

Pyrazinamide

• It is a pyrazine analog of nicotinamide (containing a pyrazine ring).
• Principle metabolites are Pyrazinoic acid (Active metabolite) and 5-Hydroxy pyrazinoic acid.

Pyrazinamide : (PZA) Mechanism of Action: PZA enters the cell wall of M. tuberculosis via passive diffusion and it is converted to pyrazinoic acid (Active metabolite) by pyrazinamidase enzyme. Then later it inhibits mycobacterial fatty acid synthase-I enzyme and disrupts mycolic acid synthesis needed for mycobacterium cell wall synthesis.

Second Line Agent

Ethionamide:

R = -C₂H₅ = Ethionamide 2 – ethyl thiosonicotinamide

R = -C₃H₇ = Prothionamide-2-propyl thiosonicotinamide

• Prothionamide Or Ethionamide are congeners of this nicotinamide.
• It is also known as the Thioamide analog of Isoniazide.

Ethionamide Mechanism of Action: It may interfere with peptide synthesis by acting as an antimetabolite and inhibiting the incorporation of sulfur (-SH) containing amino acids. (Cysteine, methionine)

P-Amiito Salicylic acid:

• Because of its sour taste and irritant nature, this drug is mainly used in the form of its Na+, K+, and Ca+ salts.

Mechanism of action: Same as sulphonamide

sulphonamide Adverse effect

• Crystalluria
• Lupas like syndrome
• GIT irritation

Thiacetazone:

Chemically, it is a thiosemicarbazone derivative.

Cycloserine:

• Analog of D alanine
• Chemically, D-4-amino 3-isoxazolidone.
• Broad spectrum antibiotics.
• Steriochemically similar to D-Serine.

Cycloserine Adverse Effect

• Peripheral Neuritis
• Tremors
• Psveotlc
• Behavioral changes

Synthesis Of Isoniazid

Synthesis Of Para Amino Salicylic Acid

Anti Tubercular Agents Multiple Choice Question And Answers

Question 1. Isoniazid is

1. Pyridine derivative
2. Trioxane derivative
3. Guanidine derivative
4. None

Answer: 1. Pyridine derivative

Question 2. Isoniazid act on

1. Mycolic acid
2. Arabinose galactose
3. Cox
4. All

Answer: 1. Mycolic acid

Question 3. Ethambutol act on

1. Mycolic acid
2. Arabino galactose
3. Cox
4. All

Answer: 2. Arabino galactose

Question 4. Neurotoxicity is the adverse effect of

1. Isoniazid
2. Ethambutol
3. Both
4. None

Answer: 1. Isoniazid

Question 5. Visualdisruotion Adverse Effect of

1. Isoniazid
2. Pyrazinamide
3. Ethambutol
4. None

Answer: 3. Ethambutol

Anti Tubercular Agents Short  Question And Answers

Question. 1 Write the mode of action of isoniazid.
Answer:

Mode of action of isoniazid: INH inhibits Mycolase Synthase, an enzyme necessary for the biosynthesis of mycolic acid (essential constitute of mycobacterial cell wall).

Question .2 Write the mode of action of pyrazinamide.
Answer:

Mode of action of pyrazinamide

PZA enters me cell wall of M. tuberculosis via passive diffusion and it is converted to pyrazine acid (Active metabolite) by the pyrazinamide enzyme. Then later it inhibits mycobacterial fatty acid synthase-I enzyme and disrupts mycolic acid synthesis needed for mycobacterium cell wall synthesis.

Question. 3 Write the adverse effect of Cycloserine.
Answer:

The adverse effect of Cycloserine

• Peripheral Neuritis
• Tremors
• Psychotic
• Behavioral changes

Question .4 Write the adverse effect of isoniazid.
Answer:

The adverse effect of isoniazid: Peripheral Neuritis-Co administration of Pyridoxine (Vit B6) with INH prevents the symptoms of peripheral neuritis. GIT disturbance (Constipation, Loss of appetite) Hepatotoxicity

Question .5 Write the mode of action of Rifampicin.
Answer:

The mode of action of Rifampicin: It strongly binds to the [3 subunit of bacterial ‘DNA dependent RNA polymerase’ enzyme. Thereby inhibits the RNA synthesis of bacteria. Mammalian RNA polymerase does not bind to rifampicin.

Question 6. Write the adverse of Rlfamplcin.
Answer:

The adverse of Rlfamplcin: Hepatitis risk may increase when used in combination with INH. A flu-like syndrome is characterized by fever, chills, myalgias, and thrombocytopenia. Rifampicin imparts a harmless red-orange color to urine.