Medicinal Chemistry III

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 linkage between the CNS and the body.

PNS can be subdivided into sensory (afferent) nerves and motor (efferent) nerves. Sensory nerves send nerve impulse from the body to CNS to effector organs. Motor nerves are divided into the Somatic Nervous System (SNS) which regulates the voluntary contraction of the skeletal muscles and 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).

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.

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 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 as 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 neuro- transmitter. These neurons are found in the Central Nervous System and also in the Sympathetic Nervous System, where they serve as links between 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 are highly susceptible to oxidation in presence of oxygen to produce ortho- quinone like compound, which undergo further reaction to give mixture of coloured product. Hence solution of catechol amines is stabilized by addition of antioxidant (reducing agent) such as ascorbic acid or sodium bisulfite.

Synthesis, Storage and Release of Catecholamine

Catecholamines 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 possesses chiral carbon atoms, thus exist an enantiomeric pairs of isomers.

The enantionmer with R-configuration is biosynthesized by the body and possesses biological activity. Neurotransmission in adrenergic neurons is a process which 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 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: Post synaptic receptor is activated by the binding of neurotransmitter.
• Removal of norepinephrine: Released norepinephrine is rapidly taken into the neuron.
• Metabolism: Norepenephrine is methylated by COMT and oxidized by MAO.

All five enzymes which 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-dihydroxyphenyl)-α- alanine (DOPA) is a rate limiting step catalysed by the enzyme, tyrosine-hydroxylase. Decarboxylation of DOPA to dopamine takes place by the enzyme aromatic amino-acid decarboxylase. Dopamine formation takes place in cytoplasm.

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

The norepinephrine formed is stored in vesicles as its adenosine triphosphate complex until depolarizarion of neuron initiates the process of vesicle fusion with the plasma membrane and extrusion of norephenephrine 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 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 a 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.

Uptake and Metabolism of Catecholamines

The actions of norepinephrine at adrenergic receptors is 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 monoaminooxidase (MAO) and catechol-o-methyl transferase (COMT). Both of these enzymes are distributed widely throughout the body, with high concentration found in 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 primarily released into the circulation, where it undergoes the methylation by the COMT to give 3-methoxy-4-hydroxyphenylethylene glycol.

3,4-dihydroxyphenylglycolaldehyde undergoes dehydrogenation in 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 commonly referred as vanillylmandelic acid. It is the end product of several pathways of norepinephrine metabolism.

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 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.

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

Receptor Distribution:

• α-Adrenergic receptors: They are found in the smooth muscles of 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.

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 blood stream 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

Classification Of Sympathomimetic Agents

Sympathomimetic agents are sub-divided 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 which 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 which binds α1, α2, B1 and B2 receptors. It is non-selective sympathomimetic.

Dopamine: A neurotransmitter which 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 adenylylcyclase, 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

B-receptor stimulation:

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

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

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 the 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.

• 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.

• 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.

B-hydroxyl (B-OH) group:

• Due to chirality they exhibit high sterio 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 catechol group, the amino group and 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).

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 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 potent and ẞ2-receptor agonist, but has little affinity for a-receptors.

Example: 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-Butylnorepinephrine (Colterol)

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 introduction of chiral center i.e. a-methyl norepinephrine, is the erythro isomer that possess 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 design of selective ẞ2-receptor agonist.
• Replacement of the meta-OH of the catechol structure with a hydroxymethyl group shows B2 selectivity.
  Examples: Albuterol (Salbutamol)

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

Examples: Metaproterenol, Terbutaline

• 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

• 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.

• 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

• 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.

• 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.

Endogenous Catecholamines

Adrenaline (Epinephrine)

• 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.

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 bleedings 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):

• 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.

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:

• 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.

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:

• 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.

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:

• 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.

Uses:

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

Imidazolines:

Structure-Activity Relationship:

• These compounds interact differently with receptors to that of B-phenylethylamine. Heterocyclic imidazoline ring is linked to 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-imidazolin-2-ylmethyl)-2,4-dimethylphenol}

• 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.

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}

• 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.

Uses:

• Guanabenz and guanfacine are used as antihypertensive drugs.

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.

Uses:

• Clonidine is useful in the treatment of hypertension.

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.

Uses:

• Methyldopa is useful in the treatment of hypertension.

α and ẞ-adrenergic Receptor Agonists

Dobutamine:

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

Uses:

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

B-adrenergic Receptor Agonists

Isoproterenol:

• 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.
• It increases cardiac output by stimulating cardiac ẞ1 receptors and can bring about bronchodilation through stimulation of B2 receptors in the respiratory tract.
• It is available for use by inhalation and injection.
• It is metabolized by COMT.

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:

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

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):

• Salbutamol is chemically, 1-(4-hydroxy-3-hydroxymethylphenyl)-2-(tert-butylamino) ethanol.
• It is a selective ẞ2 receptor agonist whose selectivity results from 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.

Uses:

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

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.

Uses:

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

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 ending by the way of 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 lack of phenolic hydroxyl groups and presence of a-methyl groups. These compounds pass more readily through blood brain barrier because of increased lipophilicity.

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 methyl group at nitrogen renders the compound virtually inactive.
• Tertiary amino group substitution is ineffective as NE-releasing agent.

Amphetamine:

• 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.

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:

• 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.

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:

• 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.

Uses:

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

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.

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:

• 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.

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:

• 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.

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:

• 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.

Uses:

• Metaraminol is used for its vasopressor action for maintaining blood pressure during spinal anaesthesia 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 management of hypertension, being prostatic hypertrophy (prostate enlargement) and heart failure.

Non-selective a-receptor Antagonists:

Reversible a-receptor antagonists:

Example: Tolazoline and Phentolamine

• 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.

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

• 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.

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

• 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.

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

• 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.

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:

• 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.

Uses:

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

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.

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 agonist (e.g. Norepinephrine and epinephrine) at those B-receptor sites. B-antagonists are classified as non-selective and cardio selective. 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 thyro- toxicosis. It is also useful in management of chronic but not acute heart failure.

The common side effect 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 the patients with asthma, as it may lead to progressive heart block, broncho constriction 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 formation of dichloroisoproterenol, which is a ẞ-antagonist that blocks the effects of sympathomimetic amines on bronchodilation, uterine relaxation, and heart stimulation.

• 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 dichloroisoproterenol, but it was withdrawn from clinical testing because of tumor induction in animal tests.

• 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).

• 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 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 absent at meta position of aromatic ring is a common structural feature of cardio selective antagonist (B) i.e., 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-disubstitute compounds are inactive.
• B-blocking agent exhibits its effect based on stereo selectivity.
• The -OH bearing C-atom possess 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

• Propranolol is chemically, 1-naphthalen-1-yloxy-3-(propan-2-ylamino)propan-2-ol.
• It is a non-selective ẞ-adrenergic receptor antagonist, which blocks both B1 and B2 receptors.
• It acts 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 suppression of renin release from the kidney.
• It is contraindicated in the presence of conditions such as asthma and bronchitis.
• Its receptor blocking action can be reversed with sufficient quantity of B-agonist.
• It is well absorbed after oral administration, but undergoes extensive first-pass metabolism before it reaches to the systemic circulation.

Uses:

• Propranolol is used in treatment of hypertension, cardiac arrhythmias, angina pectoris, myocardial infarction, hypertrophic cardiomyopathy, pheochromocytoma and migraine prophylaxis.
• It has high lipophilicity and ability to penetrate the CNS, and found to be useful in treating disease of the CNS, such as anxiety.
• It is under investigation for the treatment of schizophrenia, alcohol withdrawal syndrome and aggressive behaviour.

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.

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.

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, leads to be 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 disease, such as hypertension. These drugs do not possess ẞ2-receptor antagonistic property, therefore can be used safely in patients who have bronchitis or bronchial asthma.

Because of 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 dose only. At normal therapeutic doses, most of the selective activity is lost.

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.

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 rapid onset of action and 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:

• 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 a-adrenergic receptor.
• 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.

Uses:

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

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.

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

Salbutamol

Tolazoline

Propranolol

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

Answer. 1. a-naphthol, epichlorhydrine 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 produces 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 statement 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 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.

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.

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).

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.

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.

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.

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.

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).

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.

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):

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:

• 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:

• 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:

• 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:

• 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:

• 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:

• 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:

• 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:

• 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:

• 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:

• 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:

• • 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):

• 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.

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:

• 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:

• 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:

• 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:

• 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:

• 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:

• 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:

• 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:

• 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:

• 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:

• 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:

• 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:

• 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:

• 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:

• 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:

• 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:

• 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:

• 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:

• 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:

• 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:

• 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:

• 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:

• 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:

• 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:

• 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

Neostigmine

Ipratropium Bromide

Dicyclomine Hydrochloride

Procyclidine Hydrochloride

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 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.

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.

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:

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.

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:

• 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:

• 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:

• 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.

Uses:

• It is a long acting benzodiazepine medication, and finds importance as anxiolytic, anticonvulsant, sedative, hypnotic, and skeletal muscle relaxant.

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:

• 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:

• 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.

• 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:

• 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.

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:

• 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:

• 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:

• 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:

• 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:

 

• 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:

 

• 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:

• 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:

• 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:

• 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:

• 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:

• 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:

• 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

Barbital

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

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,

• 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;

• 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:

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:

• 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:

• 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:

• 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:

• 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:

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:

• 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:

• 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:

• 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:

• 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:

• 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

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.

• 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:

• 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:

• 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.

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.

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.

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:

• 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:

• 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:

• 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:

• 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:

• 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:

• 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:

• 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:

• 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:

• 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:

• 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:

• 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

Carbamazepine

Ethosuximide

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

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:

• 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:

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:

• 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:

• 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:

Uses:

• Methoxyflurane provides rapid short-term analgesia using a portable inhaler device.
• Currently, methoxyflurane is rarely used for surgical, obstetric, or dental anesthesia.

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.

Uses:

• Enflurane may be used for induction and maintenance of general anesthesia.
• It can also be used to provide analgesia for vaginal delivery.

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:

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:

• 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:

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:

• 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:

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:

• 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:

• 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:

• 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:

• 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:

• 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.

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

Methohexital Sodium

Ketamine Hydrochloride

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

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).

• 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).

• 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.

 

• 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.

• 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.

• 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.

• 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.

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.

• 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.

• 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:

• 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.

• 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

• 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.

• 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.

Metabolism of Methadone:

 

Metabolism of Opioids (In liver):

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:

• 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:

• 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:

• 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:

• 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:

• 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:

• 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:

• 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:

• 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:

• 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:

• 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:

• 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:

• 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:

• 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

Methadone Hydrochloride

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.

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.

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:

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.

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:

• 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:

• 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.

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):

• 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):

• 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

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:

• 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:

• 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.

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:

• 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:

• 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

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:

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:

• 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:

• 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.

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:

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:

• 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:

• 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:

• 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:

• 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:

• 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:

• 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.

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:

• 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:

• 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

• 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

• 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:

• 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

Ibuprofen

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

Combinatorial Chemistry Definition

The synthesis of chemical compounds as ensembles (libraries)and the screening of those libraries for compounds with desirable properties “Potentially speedy route to new drugs, catalysts, and other compounds and materials.

Concept Of Combinatorial Chemistry

The use of combinatorial chemistry techniques has been explored as an alternative to conventional approaches for the synthesis of compounds in the drug discovery process.

• This technique is the starting point for the development of synthesis concepts that were intended to cover and explore the chemical space without having to prepare every individual compound.
• Combinatorial Chemistry technologies were developed in response to the increased screening capacities that are available.
• when drug discovery changed its screening paradigm from a pharmacology-based approach to target-oriented lead finding.

Solid Phase Synthesis

Most solid-state combinatorial chemistry is conducted by using polymer beads ranging from 10 to 750 pm in diameter.

The Solid support Must Have The Following Characteristics For An Efficient Solid-Phase Synthesis:

1. Physical stability and the right dimensions to allow for liquid handling and filtration;
2. Chemical inertness to all reagents involved in the synthesis;
3. An ability to swell while under reaction conditions to allow permeation of solvents and reagents to the reactive sites within the resin; 1
4. Derivatization with functional groups to allow for the covalent attachment of an appropriate linker or first monomeric unit.

Types of solids that are used:

• Polystyrene resins: In this Polystyrene is cross-linked with divinyl benzene (about 1% crosslinking) .polystyrene resins are suitable for nonpolar solvents.
• Tenta Gel resins: Polystyrene in which some of the phenyl groups have polyethylene glycol (PEG) groups attached in the tire para position. The free OH groups of the PEG allow the attachment of compounds to be synthesized. PEG-containing resins are suitable for use in polar solvents.
• Polyacrylamide resins: Like super blue, these resins swell better in polar solvents since they contain amide bonds, and more closely resemble biological materials.
• Glass and ceramic beads: These types of solid supports are used when high-temperature and high-pressure reactions are carried out.
• Linkers used in solid-phase synthesis: To support the attachment of a synthetic target, the polymer is usually modified by equipping it with a linker.

1. Linkers must be stable under the reaction conditions, but they must be susceptible to cleavage.
2. Some specialized linkers have been developed to meet particular reactions or product conditions this type of linker is known as a traceless linker, it can be cleaved from the resin with no residual functionality left.
3. This type of linker allows the attachment of aryl and alkyl products that do not have OH or NH functionality Examples of this linker include the silyl group (-Si(CH₃)₂) that is sensitive to acid and can be cleaved to give unsubstituted phenyl or alkyl product.

• Protecting groups these are important for blocking and regenerating certain functional groups in a reaction sequence. Example FMOC, TBOC
• Combinatorial synthesis on solid support is usually carried out using either parallel synthesis or mixed procedures
• Parallel synthesis’In this method, the compounds are prepared in separate vessels but at the same time that is in parallel.
• Mix and split technique: ‘May be used to make both large and small combinatorial libraries using relatively few reaction steps. The history of the bead is traced by using a suitable encoding method or deconvulsion.

Combinatorial Chemistry Application

1. Synthesis of Bis(2-picolyl)amine (BPA) molybdenum conjugate: In case when the attachment of a metal complex to the peptide on the solid support is not desirable

• For example with radioactive metal isotopes, an innocent anchoring group can be attached to the peptide during solid-phase synthesis.
• The ligand-peptide conjugate is then cleaved from the resin, purified and the metal label is only added to the solution immediately before use of the bioconjugate.

2. Bidentate Schiff base metal conjugates: A solid-phase synthesis approach for molybdenum carbonyl complexes was developed by Heinze.

• Neither peptide coupling nor metallated amino acids are used, because it illustrates that complex organometallic transformations are possible on solid support.
• A specific resin and linker system allows coordination under solid-phase reaction conditions and the cleavage of the metal complex from the solid support.
• Bidentate Schiff base 1 was used as the ligand.
• The phenolic hydroxyl group allows the attachment to the solid support. A silyl ether-based linker was chosen due to its stability under basic and acidic conditions and the possibility to cleave with fluoride ions, which are expected to be unreactive towards most metal complexes.
• In solution high temperature and rather harsh oxidative reaction conditions are necessary to synthesize the desired tricarbonyl compounds.
• Such harsh conditions have to be avoided in solid-phase chemistry with polystyrene resins as the molybdenum precursors can react with the aromatic residues of the support.
• Heinze and co-workers used [(CH₃CN)₃Mo(CO)₃] as a Mo(CO)₃ source and under mild reaction conditions the intensely blue-colored complexes 2 and 3 formed rapidly and had excellent yields.
• However, acetonitrile, a rather poor solvent for resin swelling, had to be used in a mixture with toluene.
• The cleavage was performed with tetra-n- butylammonium fluoride in dichloromethane and resulted in deeply colored solutions of the deprotonated complexes.

Solution Phase Synthesis

Most ordinary synthetic chemistry takes place in the solution phase. The use of solution-phase techniques has been explored as an alternative to solid-phase chemistry approaches for the preparation of arrays of compounds in the drug discovery process.

• Solution-phase work is free from some of the constraints of solid-phase approaches but has disadvantages concerning purification.
• In solution phase synthesis we use soluble polymer as support for the product.
• PEG is a common vehicle that is used in solution phase synthesis it can be liquid or solid at room temperature and shows varying degrees of solubility in aqueous and organic solvents.
• By converting one OH group of PEG to methyl ether (MeO-PEG-OH) it is possible to attach a carboxylic acid to the free OH and use in solution phase combinatorial synthesis.
• Another common support that is used in solution phase synthesis is liquid Teflon consisting mainly of a long chain of (-CF₂) groups attached to a silicon atom. When these phases are used as a soluble support for synthesis the resulting product can be easily separated from any organic solvent.

The reaction proceeds in Solution. Can be used to produce libraries that consist of single compounds or mixtures.

• Single compound libraries are prepared using parallel synthesis. ‘Easy characterization of intermediates as well as end product.
• No limitations in the attachment point.
• Faster validation times relative to solid phase synthesis. ‘Standard analytical protocols can be used to characterize products between each reaction step ‘Difficult to drive the reaction towards the product, extensive purification is needed.

Solution Phase Synthesis Application

Synthesis of Polymer By Solution Phase Combinatorial Chemistry

• Tartar and co-workers reported the synthesis of polymer-supported 1-hydroxybenzotriazole. Reaction of the reagent with a carboxylic acid in the presence of an activating agent afforded the polymer-bound activated ester which was reacted with amines to liberate the amide in solution.
• Supported electrophilic, nucleophilic, or ionic reagents used to remove impurities from solution have been termed scavenger reagents; polymer-supported quenching reagents (PSQ), or complementary molecular reactivity or molecular recognition polymer (CMR/R polymer).
• The use of such reagents provides a versatile counterpart to the approach.
• Booth and Hodges utilized a high-loading amine resin derived from chloromethyl polystyrene and tris (2 – aminoethyl)amine in the preparation of ureas, thioureas, sulphonamides, and amides.

Solution Phase Synthesis of Biologically Important Oligosaccharides

• We departed from the traditional goal of oligosaccharide total synthesis striving for maximum convergency, and followed a linear synthesis approach based on monosaccharide
  building blocks.
• Using this method similar to that practiced for peptides and oligonucleotides we assembled several complex structures.

Solution Phase Synthesis Importance

Combinatorial chemistry continues to provide an important technique, particularly to the medicinal chemist engaged in lead optimization work.

• Combinatorial chemistry and parallel synthesis can greatly benefit from the unique features offered by new synthetic technology.
• These include the possibilities of high-speed parallel processing of chemical transformations in the context of library production, and the rapid optimization of reaction conditions.
• Among the solid and solution phase synthesis, Solid-phase organic synthesis (SPOS) is the most important method for the production of combinatorial libraries because all the synthetic transformations are successfully applied to a solid phase, and with the development of high-throughput screening, libraries are widespread in pharmaceutical and agricultural chemistry.

Combinatorial Chemistry Short Question And Answers

Question 1. What is the combinatorial chemistry?
Answer:

Combinatorial chemistry: The synthesis of chemical compounds as ensembles (libraries)and the screening of those libraries for compounds with desirable properties ‘Potentially speedy route to new drugs, catalysts, and other compounds and materials.

Question .2 What is the concept of combinatorial chemistry?
Answer:

The concept of combinatorial chemistry: The use of combinatorial chemistry techniques has been explored as an alternative to conventional approaches for the synthesis of compounds in the drug discovery process.

• This technique is the starting point for the development of synthesis concepts that were intended to cover and explore the chemical space without having to prepare every individual compound.
• Combinatorial Chemistry technologies were developed in response to the increased screening capacities that are available when drug discovery changed its screening paradigm from a pharmacology-based approach to target-oriented lead finding.

Chapter 1 Introduction To Medicinal Chemistry

Medicinal chemistry is an interdisciplinary field of study which combines aspects of organic chemistry, physical chemistry, pharmacology, microbiology, biochemistry, as well as computational chemistry including bioinformatics and chemo informatics.

Medicinal chemistry is defined as an interdependent science that is a combination of applied (medicine) and basic (chemistry) sciences. It encompasses the discovery, development, identification, and interpretation of the mode of action of biologically active compounds at the molecular level.

It can be viewed as the melting pot of synthetic chemistry and molecular pharmacology that emphasizes the study of SAR of drug molecules; it therefore requires a clear understanding of both chemical and pharmacological principles. Drugs may be from natural origin or obtained through organic synthesis.

They are chemicals used for medicinal purposes. They interact with complex chemical systems (targets) of humans or animals. Medicinal chemistry is concerned with this interaction, focusing on the organic and biochemical reaction of drug substances with their targets.

The art of medicinal chemistry has enriched greatly from developments in the areas of organic chemistry, biology, biophysical/biochemical methods, and computational tools. While opportunities are enormous, advancing a drug candidate from bench top to clinic is associated with challenges as well, and a good understanding on both these aspects would significantly accelerate drug discovery process.

A drug molecule thus synthesized and clinically tested needs to be “developed” in suitable formulation before it comes to the shelves of the chemists for patient’s consumption purpose.

Medicinal chemistry continues to play a major role in drug research and development, taking advantage of newer techniques and increased knowledge of different branches of related sciences.

Important Techniques Used in Drug Development and Medicinal Chemistry:

• Quantitative structure activity relationship (QSAR)
• Molecular modeling
• Virtual screening and docking
• Drug target binding forces
• Combinatorial library design Bioinformatics
• Structure based drug design
• Peptidomimetics
• Analog design
• Rational drug design
• Chirality
• Study of structural basis for toxicity
• Use of natural products as drug leads

History And Development Of Medicinal Chemistry

Roots of Medicinal chemistry can be traced back to ancient folk medicine and early natural product chemistry. Since it serves as the link between chemical structure and observed biological activity, medicinal chemistry emerged about 100 years ago as a special discipline aiming to explore such relationships via chemical modification and structural mimicry of nature’s materials, particularly with the aim of enhancing the efficacy of substances thought to be of therapeutic value. Just as in all fields of science, the history of medicinal chemistry is comprised of the ideas, knowledge, and available tools that have advanced contemporary knowledge.

The Nineteenth Century Age of Innovation and Chemistry:

There is a long history of plants being used to treat various diseases. They figure in the records of early civilizations in Babylon, Egypt, India and China. The therapeutic properties of plants were described by the ancient Greeks and by the Romans and are recorded in the writings of Hippocrates, Dioscorides, Pliny and Galenus. Some metals and metal salts were also used at this time. In the middle ages various Materia Medica and pharmacopoeias brought together traditional uses of plants.

Exploration in the seventeenth and eighteenth centuries led to the addition of a number of useful tropical plants to those of European origin. Improved communications, between practitioners in eighteenth and nineteenth centuries resulted in progressive removal of preparations that were either ineffective or too toxic from herbals. It also led to a more rational development of new drugs.

The nineteenth century saw the beginnings of modern organic chemistry and consequently of medicinal chemistry. Their development is intertwined. Chemists throughout Europe refined and extended the techniques of chemical analysis. The synthesis of acetic acid by Kolbe in 1845 and of methane by Berthelot in 1856 set the stage for organic chemistry.

The emphasis was shifted from finding new medicaments from the vast world of plants to the finding of active ingredients that accounted for their pharmacologic properties. The isolation of a number of alkaloids including morphine, quinine and atropine from crude medicinal plant extracts was part of the analytical effort to standardize drug preparations and overcome fraud.

General anesthetics were introduced in surgery from 1842 onwards (diethyl ether, nitrous oxide and chloroform). Antiseptics such as iodine (1839) and phenol (1860) also made an important contribution to the success of surgery.

Many of the developments after the 1860s arose from the synthesis of compounds specifically for their medicinal action. Although the use of willow bark as a pain-killer was known to the herbalists, the analgesic activity of its constituent, salicin and of salicylic acid was developed in the 1860s and 1870s.

Once ideas of chemical structure were formulated in the mid-nineteenth century, the first theories of the relationships between chemical structure and biological activity began to emerge. Thus Crum-Brown and Fraser (1869) noted that a ‘relationship exists between the physiological action of a substance and its chemical composition! leading to the idea that cells can respond to the signals from specific molecules.

On the basis of observations that certain dyes selectively stained micro-organisms, Ehrlich in the 1890s put forward the idea that there were specific receptors for biologically active compounds – ‘lock and key’ relationships. The work of Meyer and Overton (1899-1901) to relate a physical property (the oil water distribution coefficient) to biological activity (anaesthesia) were the first rudimentary QSAR.

Another quantitative measurement that was made was the chemotherapeutic index, which was the ratio of the minimum curative dose to the maximum tolerated dose (CD50/LD50).

The Twentieth Century Age of Innovation and Chemistry:

Several different aspects of medicinal chemistry were developed in parallel through the second half of the twentieth century. Diseases of protozoal and spirochetal origin responded to synthetic chemotherapeutic agents. Interest in synthetic chemicals that could inhibit the rapid reproduction of pathogenic bacteria and enable the host organism to cope with invasive bacteria was dramatically increased.

The observation by Woods and Fildes in 1940 that the bacteriostatic action of sulfonamide-like drugs was antagonized by p-aminobenzoic acid, was one of the early examples in which a balance of stimulatory and inhibitory properties depended on the structural analogies of chemicals.

Together with the discovery of penicillin by Heming in 1929 and its subsequent examination by Florey and Chain in 1941 led to a water soluble powder of much higher antibacterial potency and lower toxicity than those of previously known synthetic chemotherapeutic agents. With the discovery of a variety of highly potent anti-infective agents, a significant change was introduced into medical practice.

Developments Leading to Various Medicinal Classes:

Psychiatrists have been using agents that are active in the central nervous system for hundreds of years. Stimulants and depressants were used to modify the mood and mental states of psychiatric patients. Amphetamine, sedatives, and hypnotics were used to stimulate or depress the mental states of patients. The synthesis of chlorpromazine by Charpentier ultimately caused a revolution in the treatment of schizophrenia.

The first pure hormone to be isolated from an endocrine gland was epinephrine, which led to further molecular modifications in the area of sympathomimetic amines. Subsequently, norepinephrine was identified from sympathetic nerves. The development of chroma- tographic techniques allowed the isolation and characterization of a multitude of hormones from a single gland. Various techniques emerged subsequently to take process of drug development to new heights.

The study of medicinal chemistry has certain defined objectives as mentioned below:

• Physico-chemical properties of drug molecules in relation to drug ADME.
• Chemical basis of pharmacology and therapeutics.
• Fundamental pharmacophores for drugs used to treat disease.
• Structure activity relationship (SAR) in relation to drug-target interactions.
• Chemical pathways of the drug metabolism.
• Application to making drug therapy decisions.

The Medicinal Chemist would strive hard to convert a chemical into suitable lead molecule and then into a drug using various tools and approaches of medicinal chemistry.

Physicochemical Properties In Relation To Biological Action

Classification of drugs:

Drugs are chemical substances which can generally be classified based on their therapeutic use as follows:

• Drugs which act upon various physiological functions of the body (Pharmacodynamic agents) e.g. sedatives, analgesics, antipyretic and antirheumatic agents, antipsychotic, antihistaminic and anti-allergic drugs, anti-inflammatory agents, diuretics, cardiovascular agents and drugs acting on the heart, adrenergic and cholinergic agents and drugs acting on the gastrointestinal tract (GIT), etc.
• Drugs acting on Central Nervous System (CNS agents) e.g. antidepressant drugs, anaesthetic, anticonvulsants, antipsychotics, hypnotics and sedatives etc.
• Drugs that are used to fight pathogenic organisms (chemotherapeutic agents): e.g. sulfonamides, antibiotics, anti-infective agents, antimicrobial, anti-amoebic, antifungal agents, antiviral agents, anticancer agents, anti-malarial agents, etc.
• Supplement agents: e.g. Vitamins, dietary supplements, etc.

It is an established fact that “structure” is the fundamental aspect of drug molecule which affects both its pharmacodynamic and pharmacokinetic properties. In the given Unit, we will discuss about how structural features of the drugs impact its pharmacological actions.

Whenever a drug molecule enters the body, it interacts with one or more biomolecules found in the extracellular fluid, in the cell membrane, and within cells. The type and the extent of this interaction will depend on the kind and number of chemically reactive functional groups and the polarity of the drug molecule. The drug-protein interaction does not involve covalent bonds that are relatively stable at body temperatures.

Instead, weak forces such as ionic bonds, hydrogen bonds, Van der Waals forces, dipole-ion, and dipole- dipole forces are involved. A biological response is produced by the interaction of a drug with a functional or an organized group of molecules, generally referred as receptor site (chemoreceptive substance).

The physical and chemical properties (physicochemical properties) which affect biological action of drug are as follows:

• Ionization
• Partition coefficient (Log P)
• Solubility
• Protein binding
• Chelation
• Bioisosterism
• Hydrogen bonding
• Optical and Geometrical Isomerism

Ionization

Ionization is the process of formation of ions, in which an atom or a molecule possesses a negative or positive charge by gaining or losing electrons, often in conjunction with other chemical changes.

The first three stages of the pharmacokinetic process [absorption, distribution, metabolism and excretion (ADME)] are:

• Liberation: Release of the medicinal drug from a formulated medicine.
• Absorption: Movement of the liberated drug into the bloodstream.
• Distribution: Passage of the drug from the bloodstream to body tissues and organs.

Molecular compounds are less soluble in water than in non-polar solvents, while ionic compounds are more soluble in water than in non-polar solvents. In the body there are two distinct environments. One, such as blood plasma, is aqueous and so ionic compounds are more likely to be soluble in blood than are molecular compounds. The other is cell membrane which is mainly composed of non-polar lipids (phospholipids, glycolipids and cholesterol).

The central part of the membrane, therefore, consists mainly of long chain hydrocarbons and so molecular compounds are more likely to be soluble in cell membrane than are ionic compounds. An effective drug needs to be sufficiently soluble in water to dissolve in blood plasma and be carried around the body while also being sufficiently soluble in non-polar lipids to pass through cell membranes into cells.

Most drug molecules ionize in aqueous solution to give weakly acidic or basic solutions. Naproxen is a non-steroidal anti-inflammatory drug (NSAID). It is used to relieve pain and inflammation in diseases like rheumatic disease, sprains, strains, backache, gout, and menstrual pain.

A naproxen molecule has a carboxylic group and so it is a weak acid. It ionizes in water to give an equilibrium solution that contains a mixture of unionized molecules, carboxylate ions and hydroxonium ions.

Aspirin, fenoprofen and penicillin-G (benzylpenicillin) are the drug molecules that also contain carboxylic acid groups. All three compounds partially ionize in aqueous solution.

Diphenhydramine is a first generation antihistamine used to treat allergic symptoms though it does have as sedating effect. More recently developed antihistamines are not sedating. The sedating properties of diphenhydramine explain its use to treat insomnia and travel sickness. Diphenhydramine molecule has an amine group and hence it is a weak base. It ionizes in water to give an equilibrium solution that contains a mixture of unionized molecules, quaternary ammonium ions and hydroxide ions.

Other drugs which are bases include adrenaline, ephedrine, atropine and tetracycline. The rate of absorption depends on concentration of unionized form. Accumulation of an ionized drug in the body compartment is called as ion trapping. Drug ionization depends on pH and its pKa.

Most drugs can be classified as acids or bases as a large number of drugs can behave as either acids or bases, as they circulate in the patient in different dosage forms and end up in systemic circulation. Acid-base properties of a drug can considerably influence its bio-distribution and partitioning characteristics.

For the definition of acids and bases, the model used in pharmacy and biochemistry was developed independently by Lowry and Bronsted. An acid is a proton donor and a base is a proton acceptor.

Percent Ionization

Percent ionization is defined as the amount of a weak acid that exists as an ions at a particular concentration. Ionized drugs are water soluble and unionized drugs are lipid soluble.

HA Unionized acid, H2O= base, H,O= conjugate acid, A = ionized conjugate base.

B = Unionized base, H2O= acid, BH = conjugate acid, OH Conjugate base Change in pH changes the degree of ionization.

Examples:

• In Phenytoin, pKa = 8.3 i.e. at pH 8.3, it is 50% ionized. To ionize completely, its pH is raised to 12 by NaOH and complete ionization is ensured by maximum H2O solubility.
• In Aspirin, pKa= 3.5, pH = 1, it is 99% more unionized. It is lipid soluble and easily absorbed through stomach.

Acid-conjugate base:

Representative examples of pharmaceutically important acidic drugs are listed. Each acid, or proton donor, yields a conjugate base. Conjugate bases range from the chloride ion [reaction (a)], which does not accept a proton in aqueous media, to ephedrine [reaction (h)], which is an excellent proton acceptor.

Base-conjugate acid:

The Bronsted-Lowry theory defines a base as a molecule that accepts a proton. The product resulting from the addition of a proton to the base is the conjugate acid. Pharmaceutically important bases are listed. There are a variety of structures, including the easily recognizable base sodium hydroxide [reaction (a)]; the basic component of an important physiological buffer, sodium monohydrogen phosphate [reaction (b)], which is also the conjugate base of dihydrogen phosphate; ammonia [reaction (c)], which is also the conjugate base of the ammonium cation [reaction (c)]; sodium acetate [reaction (d)], which is also the conjugate base of acetic acid [reaction (d)] in the enolate form of phenobarbital [reaction (e)], which is also the conjugate base of phenobarbital [reaction (e)]; the carboxylate form of indomethacine [reaction (f)], which is also the conjugate base of indomethacine [reaction (f)]; the imidate form of saccharin [reaction (g)], which is also the conjugate base of saccharin [reaction (g)] in  and the amine ephedrine [reaction (h)], which is the conjugate base of ephedrine HCI.

Since, pKa = -log Ka and pH = -log [H3O]*.

The pH will be calculated according to the following equation:

It is now common to express the basicity of a chemical in terms of pka using the following equation:

Examples of calculations requiring the pKa (a):

To determine the ratio of ephedrine to ephedrine HCI, (pKa 9.6) in the intestinal tract at pH 8.07. Using Eq. (3) we get,

The number 1.6 whose log is 0.025, meaning that there are 25 parts ephedrine for every 1000 parts ephedrine HCI in the intestinal tract whose environment is pH 8.0.

To determine the pH of a buffer containing 0.1 mol/lit CH3COOH (pKa 4.8) and 0.08 mol/lit CH3COONa. Using Eq. (3) we get,

Importance of ionization of drugs:

• Unionized form of a drug can partition across biological membranes as the unionized form is lipophilic.
• Ionized form tends to be more water soluble as it is important for drug administration and distribution in plasma.
• Lower the pH with respect to pKa, greater will be the fraction of protonated drug which may be charged or uncharged.
• Weak acids are more lipid-soluble, because they are uncharged and hence, this form passes through biological membranes more rapidly. Acidic pH provides a proton to weak acids to form uncharged species.
  RCOO + H* → RCOOH
• Similarly alkaline pH will cause weak bases to lose a proton to form uncharged species.

Partition Coefficient

Partition coefficient (P) finds importance as it directly influences drug transport and drug distribution. It is defined as ratio of concentrations of compounds in two phases of a mixture of two immiscible liquids at equilibrium. E.g. Phenobarbitone has a high lipid / water partition coefficient of 5.9, whereas Thiopentone sodium has a chloroform / water partition coefficient of about 100 which states that the later is highly soluble in lipid. It is defined as equilibrium constant of drug concentration in two phases.

It is difficult to measure partition coefficient in a living system. It is usually estimated in vitro by using octanol as a lipid phase and phosphate buffer (pH 7.4) as the aqueous phase. Partition coefficient is dimensionless and its logarithm (log P) is widely used as the measure of lipophilicity. Factors affecting partition coefficient are:

• pH
• Co-solvents
• Surfactant
• Complexation

Log P can be determined by shake flask method in which drug molecule is partitioned between known quantity of octanol and that of buffer or water. The concentration of drug is determined by UV spectroscopy method. This method, however, is a cumbersome method. Another method includes HPLC method, in which compounds with known log P are injected onto a C18 reverse phase HPLC column followed by unknown compounds.

Applications of Partition Coefficient

• Solubility of drugs in water and other solvents and in mixture of solvents can be predicted.
• Drug absorption in vivo can be predicted.
• SAR for a series of drugs can be studied.
• Log P is an indicator of lipophilic and hydrophilic character of a drug molecule.

Solubility

Solubility is defined as the ability of a substance (solute) to enter into a bulk medium (solvent) and form a homogenous solution. Different compounds have different solubilities depending on various factors. Solubility refers to the concentration of dissolved solute, which is in equilibrium with solid solute at a given temperature. Sufficient solubility and good membrane permeability are prime factors affecting oral absorption.

It has been said that low solubility is at the top of the list of undesirable properties of a potential medicinal drug. So measurement of solubility and, if necessary, modification of a compound to alter its solubility without affecting its therapeutic properties is important.

Equilibrium solubility:

The equilibrium solubility of a compound is the concentration of a saturated solution in contact with an excess of undissolved solid.

Traditionally, excess compound is shaken with a solvent until a saturated solution is produced with an excess of the solid compound present. It is an accurate but very time-consuming method.

Kinetic solubility:

The kinetic solubility in water of a drug that is a weak acid is determined by:

• dissolving the acid in a known volume of base, e.g. potassium hydroxide solution;
• adding an acid, e.g. hydrochloric acid, until a precipitate is detected (the UV sensor ‘sees’ the first formation of cloudiness).

Rather than solubility, logs is usually calculated.

Aqueous solubility depends upon the following facts:

• Buffer and Ionic strength
• Polymorphism and purity of the sample
• PH
• Super saturation
• Thermodynamic vs. kinetic solubility

Aqueous solubility decreases with corresponding increase in various physicochemical properties like boiling point, viscosity, surface activity and partition coefficient across a homologous series. Solubility of a drug can be increased or decreased by derivatization e.g. water soluble methyl predinisolone acetate is transformed to methyl predinisolone sodium succinate which is water soluble.

Similarly, slightly soluble chloramphenicol can be converted into insoluble chloramphenicol palmitate. Solubility not only depends on the solute and solvent, but also to a larger extent on temperature, pressure and pH. Solubility of a molecule can also be expressed in terms of its affinity or philicity and repulsion or phobicity for either an aqueous (hydro) or lipid (lipo) solvent.

Various types of bonds like London forces, hydrogen bonds, dipole-dipole, etc. are responsible for keeping atoms and molecules together which are responsible for maintaining solubility. Following intermolecular attractive forces are responsible for solubility:

• Vander Waals’ forces: These are weakest (0.5 -1.2 kcal/mole) of all the forces resulting from induced dipole and occur between non-polar groups e.g. hydrocarbons.
• Dipole-dipole interaction: These are strong (1.2 to 10.8 kcal/mole) forces arising ionically between dipoles created due to an electronegative atom attached to carbon atom. E.g. Hydrogen bond that contributes for hydrophilicity.
• Ionic bonding: These arise mostly in inorganic compounds and their salts and are comparatively strong (5 kcal/mole) bonds. The degree of ionization for any molecule is an important factor affecting solubility.
• Ion-dipole bonding: These are relatively strong bonds (1.2 to 5.2 kcal/mole) similar to ionic interactions and arise electrostatically between a cation/anion and a dipole. These forces depend on distance and temperature.
• Covalent bond: Molecular bond that involves the sharing of electron pairs between atoms is a covalent bond and is greatly affected by electronegativity of atoms which determines the chemical polarity of the bond. These are the strongest of all the bonds and may vary from 50 kcal/mol to 110 kcal/mol depending on the elements involved.

Many methods have been tried and tested to improve solubility of drug molecules which include:

• Use of co-solvents (like glycols, sorbitol, ethanol etc.) for highly lipophillic molecules.
• Use of surfactants (like Tween 80) which being amphiphillic (polar head and non- polar tail), enhances solubility by forming micelles which partitions the non-polar drug into its hydrophobic core.
• Use of hydrotropes, which are organic molecules and when added in water, forms loose aggregates. The drug gets dissolved in the matrix of the hydrotrope.
• Structural alternations of drug molecule (e.g. Carrier linked prodrugs)
• Use of complexing agents which uses various forces like London dispersion forces, hydrogen bonding and hydrophobic interactions to form a complex with drug molecule leading to enhanced solubility. e.g. Cyclodextrin complexes.
• Changing the pH of aqueous solution of drug molecule so that ionization pattern is affected. Solubility increases with ionization as ions are more soluble in aqueous media than neutral molecules. Hence, pH of the solution can be increased or decreased depending on the nature of drug.

Factors Affecting Solubility:

• Temperature: Increase in temperature increases kinetic energy of the system, thereby increasing solubility. Heat energy gets converted to kinetic energy which causes the molecules of both solute and solvent to vibrate causing more interaction between the molecules.
• Pressure: Pressure doesn’t affect the solubility of solids and liquids to a great extent. However, the solubility of gases increases with increase in pressure.
• Particle size of solute: Smaller the particle size, more is the solubility. Small particle size results in large surface area and large surface area means more interaction with the solvent and hence, more dissolution. But extremely small particle sizes can lead to aggregation of the particles to form clumps which again decreases solubility.
• Polymorphism: Different forms of a compound have different solubilities. Generally, amorphous forms are more water soluble than crystalline materials as more surface area is available for solvent interactions due to finer particle size. Furthermore, in crystalline compounds, anhydrous forms are more soluble than hydrate forms as hydrate forms already contain bound water within their crystal lattice. Also, metastable forms of crystals have greater solubility than stable forms.
• Polarity: The polarity of solute as well as solvent can affect solubility of the solute. If a solute is polar in nature, it will dissolve only in a polar solvent. This is because of dipole-dipole interactions between the solute and the solvent molecules. The positive end of a solute molecule will have affinity for the negative ends of the solvent molecules and such interactions form a solution. Similarly, non-polar solutes will be soluble in non-polar solvents due to the presence of London dispersion forces. These are attractive forces that form temporary dipoles of atoms and molecules thus aiding solubility.

Some other factors include the nature of solute, nature of solvent, molecular size of solute, melting point of solid solutes, etc., which affect the extent of solubility of a compound in variable degrees.

Importance of Solubility:

• Solubility is of great concern as it is necessary that the drug must be in the solution form so that it can be absorbed by the body or have any biological activity.
• Drugs (mainly organic) with limited aqueous solubility won’t dissolve in the body fluids which decreases bioavailability.
• Not only lipophilicity plays an important role to cross the lipid bilayer of plasma membrane, but the drug must also dissolve in the aqueous portion of the cell for optimum absorption.
• Drugs must dissolve so that it can interact freely with biological targets.

Protein Binding

Binding of drug to protein may enhance distribution of drugs, or inactivate the drug by not enabling a sufficient concentration of free drug to target at receptor site or retard the excretion of such drug molecule. Interaction of drugs with protein may cause displacement of body hormones or change the configuration of protein or inactivates the drug biologically by forming a drug-protein complex.

Drug binding to a protein or multiple proteins mainly depends on nature (acidic or basic) of drug. Albumin is the most common protein that is involved in binding of drugs and comprises of more than half of blood proteins. Albumin can interact with both, acidic as well as basic drugs in the plasma by Van der Waals’ dispersion forces, hydrophobic bonding, hydrogen bonding and ionic interaction.

Protein binding values (% fraction bound) are normally given in terms of percentage of total plasma concentration of a drug that is bound to all plasma proteins. Drugs bind to protein either through hydrophobic interactions (e.g. binding of Ca2+ to target protein) or through self-association in which drug may self dissociate to form dimers, trimers or aggregates of larger size.

Many times binding to plasma proteins is reversible, and the concentration of the free and bound drug at equilibrium may be expressed as:

Free drug + Free protein = Drug-protein complex

Pharmacokinetic importance of protein binding:

• Drug-protein binding influences the distribution equilibrium of the drug.
• Plasma proteins exert a buffer and transport function in the distribution process.
• Only free and unbound drug acts can leave the circulatory system and diffuse into the tissue.
• Protein binding is affected by the presence of diseases. e.g. drugs like dapsone, morphine show decreased extent of protein binding in liver diseases, whereas drugs like barbiturates and sulphonamides show less binding in renal diseases.

Protein binding can be determined by many methods like dialysis, ultracentrifugation, ultra filtration, electrophoresis etc.

Chelation

Chelating agents are organic or inorganic compounds capable of binding metal ions to form complex ring-like structure called ‘chelates’. Chelating agents possess “ligand binding atoms that form either two covalent linkages or one covalent and one co-ordinate or two co-ordinate linkages in the case of bidentate chelates.

Mainly atoms like S, N and O function as ligand atoms in the form of chemical groups like -SH, -S-S, -NH2, NH, -OH, -OPO3H, or >C=O. Bidentate or multidentate ligands form ring structures that include the metal ion and the two-ligand atoms attached to the metal. Chelation is a result of a donor-acceptor mechanism (electrons or electron pair) or Lewis acid-base reaction (protons) leading to formation of complexes or coordination compounds.

Any non-metallic atom or ion (in free form or in neutral molecule or in ionic compound) that can donate an electron pair may serve as the donor. Any metallic ion or a neutral molecule may accept a pair of electrons and acts as acceptor. In addition, intramolecular forces can also be involved in the formation of complexes. Complexes may be divided broadly into two classes depending on whether the acceptor compound is a metal ion or an organic molecule.

Many a times, an ideal chelator in vitro might not prove so in vivo, either due to the toxicity considerations or due to the presence of endogenous substances (haemoglobin, cytochromes, etc.) that can also chelate metal ions and thus leads to competition. Also, pH appears to be an important factor influencing complex formation and stability.

Most chelating agents are unstable at low pH, whereas at high pH metals tend to form insoluble hydroxides which are less accessible to chelating agents. This feature becomes significant in pathological conditions leading to acidosis or alkalosis. Optimally effective chelation can be achieved by virtue of some combination of the basic properties of both the metal ions, chelating agents and the resulting metal complex.

Applications of chelation:

• It is significantly involved in biological system and to some extent in explaining drug action.
• Can lead to effective antidotes for organic arsenicals, treatment of poisoning due to antimony, gold and mercury, etc. e.g. Dimercaprol.
• Penicillamine is an effective antidote for treatment of copper poisoning because it forms water-soluble chelate with copper and other metal ions.
• 8-Hydroxyquinoline and its analogue acts as antibacterial and antifungal agent by complexing with iron and copper.

Bioisosterism

Longmuir coined the term isosterism. When two molecules or molecular fragments containing an identical number and arrangement of electron will have similar properties then they are termed as isosteres. Isosteres should be isoelectric i.e. they should possess same total charge. The phenomenon of isosterism is important because the biological characteristics of isosteres appear to be similar.

Bioisosterism is defined as the phenomenon by which compounds or groups that possess similar molecular shapes and volumes, approximately same electronic distribution and similar physical properties exhibits similar biological activities.

Classification:

Bioisosteres are classified into the following two types:

• Classical bioisosteres
• Non-classical bioisosteres

Classical bioisosteres:

• Classical bioisosteres have similarities in shape and electronic configuration of atoms, groups, and molecules, which they replace. They have similarities of shape and electronic configuration of atoms, groups and molecules which they replace.
• The classical bioisosteres may be,

Univalent atoms and groups:

Cl, Br, F, H, OH, NH, CH3 for H, SH and CF3

Bivalent atoms and groups:

Trivalent atoms and groups:

-CH=, N =, p =, – AS =

Tetravalent atoms and groups:

=N*, C=,=P*=,=As*=

Ring equivalents:

Non-classical Bioisosteres:

They do not follow the steric and electronic definition of classical isosteres. They do not have the same number of atoms as replacement. They have one of the following characteristic features, such as

• Electronic properties
• Physicochemical properties
• Spatial arrangements
• Functional moiety critical for biological activity

Exchangeable groups: Exchangeable group isosterism in which the properties of discrete functional elements are emulated. Eg. Carboxylic acid functionality can be exchanged with tetrazole or sulphonamido groups.

Cyclic versus non-cyclic structure:

Hydrogen Bonding

Among the secondary forces, hydrogen bonding is one of the most important forces that affects the physical property of the compound. Hydrogen bonds are created because of groups like -OH, -NH, etc. which can form intermolecular or intramolecular hydrogen bonds e.g. water, salicylic acid, o-nitro phenol etc. Hydrophobic bonds are seen between non-polar regions of the receptor and the drug e.g. isopropyl moiety, of a drug fits into a hydrophobic cleft on the receptor composed of hydrocarbon chains of amino acids valine, isoleucine and leucine.

Hydrogen bonds are generally, of two types, one, intermolecular hydrogen bonding and other one is intramolecular hydrogen bonding. The intermolecular hydrogen bonding occurs between different molecules of same compound so as to form polymeric aggregate. This cause increases in boiling point of the compound as well as its water solubility.

The reason for increase in solubility is the formation of intermolecular hydrogen bonding with water e.g. ethanol shows higher boiling point and higher solubility in water than dimethyl ether even though both have the same molecular weight. And the intramolecular hydrogen bonding occurs between different atoms of same molecule.

Such kind of bonding may result into ring like systems thus causing decrease in boiling point and water solubility. The reason for decrease in solubility is the restriction of possibility of intermolecular hydrogen bonding of the o-substituted groups with water that prevents association of the molecules to form an aggregate.

Effects of Hydrogen Bonding:

All physical properties such as boiling points, melting point, water solubility, etc. and several chemical properties like acid character, basic character, properties of carbonyl groups, etc. are affected by hydrogen bonding.

For example, Intermolecular hydrogen bonding cause association of several molecules of the same compound leading to increase in intermolecular forces and increased boiling point. The intramolecular hydrogen bonding cause chelation between the groups of same molecule thereby restricting the possibility of intermolecular hydrogen bonding and thus reduces melting point and boiling point.

Hydrogen bonding between the solvent and the solute increases aqueous solubility by many folds e.g. methanol and ethanol are highly soluble in water due to hydrogen bonding between molecules. Similarly, high solubility of polyhydric phenols and sugars may be due to availability of greater number of -OH groups for hydrogen bonding.

Compounds showing hydrogen bonding have higher surface tension and viscosity e.g. glycerol, glycol, sulphuric acid, sugar syrup, phosphoric acid, etc. Due to more number of -OH groups, the extent of hydrogen bonding is more in glycerol. So, it is more viscous than glycol. The tertiary structures of proteins and nucleic acids are due to hydrogen bonding.

In a-helices, hydrogen bonds are formed between hydrogen of polar N-H units with oxygen of polar C=O units. Also, the double strands of DNA are held together by hydrogen bonds. Replication of DNA depends on hydrogen bonds which selectively connect specific base pairs, as do the several steps by which the genetic message determines the specific order of amino acids in a protein.

Drug-Receptor interactions: Hydrogen bonding provides secondary binding force for drug-receptor interactions.

Isomerism

Isomers are the molecules of identical atomic compositions, but with different bonding arrangements of atoms or orientations of their atoms in space i.e., isomers are two or more different substances with the same molecular formula. Three types of isomerism are possible – Constitutional, Configurational, and Conformational. The terms configuration and conformation are often confused.

Configuration refers to the geometric relationship between a given set of atoms, for example, those that distinguish L- from D-amino acids. Interconversion of configurational alternatives requires breaking of covalent bonds. Conformation refers to the spatial relationship of every atom in a molecule. Interconversion between conformers occurs without covalent bond rupture, with retention of configuration, and typically via rotation about single bonds.

Geometrical Isomerism:

Stereochemistry, enantiomers, symmetry and chirality are impotent concepts in therapeutic and toxic effect of drug. The drug must possess a high degree of structural specificity or stereo selectivity. Many drugs show stereo selectivity because mostly the sites or targets are optically active biological macromolecules such as proteins, polynucleotides or glycolipids.

Geometrical isomers are stereoisomers having same molecular formula, same functional groups, same positions, but different orientation around a double bond or on a ring.

An important criteria to exhibit geometric isomerism is that the isomers cannot be interconverted through mere rotation around a single bond. The relative positions of atoms attached directly to multiple bonds are also fixed. For the double bond, cis- and trans- isomers result.

For example, diethylstilbestrol exists in two fixed stereoisomeric forms: trans- diethylstilbestrol is estrogenic, whereas the cis-isomer is only 7% active. In trans- diethylstilbestrol, resonance interactions and minimal steric interference tend to hold the two aromatic rings and connecting ethylene carbon atoms in the same plane.

Geometric isomerism is represented by cis/trans isomerism resulting from restricted rotation due to carbon-carbon double bond or in rigid ring system. They are two or more coordination compounds which contain the same number and types of atoms, and bonds (i.e., the connectivity between atoms is the same), but which have different spatial arrangements of the atoms. Specific isomer gives specific response and hence different pharmacological responses are obtained for different isomers.

Optical Isomerism:

Optical isomers are non-superimposable mirror images of each other (called a pair of enantiomers) and differ in their optical activity. Many drugs come from natural sources like plants. They are usually chiral and are generally found only as single enantiomers in nature rather than as racemic mixtures. Example, synthetic drugs like Ibuprofen are chiral, one of its enantiomers has analgesic and anti-inflammatory properties, the other does not (it is pharmacologically inactive).

Stereoisomers differ in pharmacokinetic and pharmacodynamic properties. Pharmaco- kinetic differences resulting out of stereo-isomerism can be in absorption, e.g. L-Methotrexate is better absorbed than D-Methotrexate, Esomeprazole is more bioavailable than racemic omeprazole; in distribution, e.g. S-Warfarin is more extensively bound to albumin than R-Warfarin, hence it has lower volume of distribution.

Levocetrizine has smaller volume of distribution than its dextroisomer, D-Propranolol is more extensively bound to proteins than L-Propranolol; in metabolism like S-Warfarin is more potent and metabolized by ring oxidation while R-Warfarin is less potent and metabolized by side chain reduction, half life of S-Warfarin is 32 hours, while it is 54 hours for R-Warfarin.

Pharmacodynamic differences resulting out of stereoisomerism can be in pharmaco- logical activity and potency like L-Propranolol has ẞ-adrenoceptors blocking action while D- Propranolol is inactive; Carvedilol is a racemic mixture, the S(-) isomer is a nonselective ẞ- adrenoceptor blocker, while both S(-) and R(+) isomers have approximately equally α- blocking potency; S-Timolol is more potent a-blocker than R-timolol but both are equipotent ocular hypotensive agents.

Conformational Isomerism:

Another form of isomerism is conformational isomerism which arises due to free rotation around carbon-carbon single bond. Conformational isomers (or conformers) are non- superimposable orientations. In order for a molecule to possess conformational isomers, it must possess at least one single bond that is not part of a ring system.

The reason for this restriction is that it is impossible to freely rotate a single bond within a ring system without breaking the ring in the process. The conformational flexibility of most open-chain neurohormones, such as acetylcholine, epinephrine, serotonin, histamine, and related physiologically active biomolecules, permits multiple biological effects to be produced by each molecule, due to their ability to interact in a different and unique conformation with different biological receptors.

For example, acetylcholine may interact with the muscarinic receptor of postganglionic parasympathetic nerves and with acetyl cholinesterase in the fully extended conformation and, in a different, more folded structure, with the nicotinic receptors at ganglia and at neuromuscular junctions.

In the structure of acetylcholine, the ethane bridge (i.e., atoms 4 and 5) between the ester oxygen and the quaternary nitrogen is a freely rotatable system and gives rise to a variety of different conformations. When the acetyl group and the quaternary nitrogen are situated 180° apart, the molecule is said to be in the trans or anti conformation.

Both a sawhorse representation and a Newman projection of the trans conformation are illustrated. Rotation of the trans Newman projection 60° in the counterclockwise direction gives rise to the gauche or skew conformation. Continued rotation by another 30° in the same direction provides the fully eclipsed conformation.

These rotations alter the spatial arrangement of the atoms without breaking a bond. Therefore, conformational isomers are not distinct molecules, but rather different orientations of the same molecule. Obviously, there are many more conformations possible.

Drug Metabolism

Metabolism (biotransformation) is a necessary phenomenon to eliminate drugs or other foreign compounds (xenobiotic) from body. During metabolism the lipophilic compounds are converted into hydrophilic one and are excreted out. Drug metabolism is also referred as detoxification process, (but prodrugs are exceptional to this) because of which toxic metabolites are wiped out of body.

Drug metabolism takes place in two phases:

• Phase 1 (Functionalization)
• Phase 2 (Conjugation)

Phase-1: Functionalization

Functionalization includes oxidation, reduction and hydrolysis. The purpose is to introduce a polar functional group like OH, COOH, NH2, SH, into xenobiotic molecules with the help of several enzymes.

This can be done in two ways:

• Direct introduction of functional group (aromatic /aliphatic hydroxylation)
• Modification or unmasking of existing functionalities.

e.g. Reduction of ketone and aldehyde to alcohol, oxidation of alcohols to acids, hydrolysis of esters and amide to acid, amines and OH groups, reduction of azo and nitro compound to give amino.

Phase-1 reaction may not be able to produce complete inactive metabolite or sufficient hydrophilic metabolite, but makes the molecules amenable to undergo phase-II reactions easily. Thus Phase-I reactions increase hydrophilicity of molecule, reduces its stability and facilitates conjugation process.

Phase-2: Conjugation

Basic purpose of these reactions is to attach small, polar and ionizable endogenous compounds to the metabolite obtained from phase-I. This group includes glucoronic acid, sulfate, glycine and other amino acid so as to form water soluble conjugates. Parent compounds having -OH, -COOH, -NH2 functional groups can directly be conjugated by phase-II enzymes.

These highly hydrophilic metabolites excreted in urine are non-toxic and have no pharmacological effect. Other phase-II pathways like methylation, acetylation, glutathione conjugation (GSH) either terminate biological activity or protect body against chemically reactive metabolites.

Sites of Drug Biotransformation:

Liver is the main site of drug metabolism. All orally administered drugs pass through liver and hence are susceptible to first pass hepatic metabolism before reaching to systemic circulation. This decreases oral bioavailability of drugs like lidocaine, meperidine, propranolol, etc.

Intestine is also important for metabolism of some of the drugs (extra hepatic metabolism of xenobiotic) e.g. levodopa, chlorpromazine and diethyl stilbesterol. Enzymes like esterase and lipase present in intestinal wall; bacterial flora in intestinal and colon wall are helpful in metabolism. Other tissues like kidney, lungs, adrenal glands, brain and skin do take part in metabolism; but in a smaller extent.

Factors Influencing Drug Metabolism

• Genetic factors: Species difference must be considered when the data from animals are used to extrapolate the results in human.
• Physiological factors: Age (elderly disorder), individual variations in hormones, sex, physiological difference, nutritional status (diet), etc also affect rate of metabolism. If protein deficiency exists, then hepatic enzymes are also reduced. If lipid deficiency exists, rate of oxidative metabolism also decreases. If vitamins deficiency exists, activity of microsomal enzymes decreases.
• Pharmacodynamic factors: Dose, frequency of dose administration, route of administration, tissue distribution of drugs, proteins binding, etc. affect rate of metabolism.
• Environmental factors: The body can be exposed to environmental factors like air, water and food contaminants or pollutants by design or by accident. Pollutants like polychlorinated biphenyls are resistant to hydroxylation and thus may be hazardous to life as it remains there for long time after absorption.

Phase 1: Pathways Of Metabolism

Oxidative biotransformation: This is most preferred and important pathway of metabolism and follows following reaction scheme:

Enzyme carrying out this metabolism is mixed function oxidase (FMO) or mono- oxygenases. FMO is made up of many components like Cytochrome P-450 enzyme which transfers oxygen atom to RH, NADPH dependent cytochrome P-450 reductase, NADH linked cytochrome bs.

Cytochrome P-450 is a hemeprotein abundantly found in liver. Heme is the iron containing porphyrin i.e. protoporphyrin-IX and protein is apoprotein. Reduced form of cytochrome P-450 (i.e. Fe2+) binds with -CO to form a complex having absorption maximum at 450 nm, hence the family of enzyme is referred as cytochrome P-450.

Cytochrome P-450 metabolizes number of diverse substrates by various oxidative mechanisms. This enzyme is membrane bound and exists in different forms. The apoprotein portions of various cytochrome P-450 differ in their structure. Because the apoprotein portion is important in substrate binding and catalytic transfer of activated oxygen, specific form may oxidize specific substrate only.

Oxidative Reactions:

Oxidation of Aromatic Compounds:

Hydroxylation: It causes oxidation of arene to arenol. Arene oxide (epoxide) is electrophilic, highly reactive because of strained 3-membered ring.

Many drugs follow this path e.g. (1) Propranolol, (2) Phenobarbital, (3) Phenytoin, (4) Warfarin, (5) Amphetamine.

Sometimes the Phase-I hydroxyl metabolites are pharmacologically active. For example, in case of phenylbutazone, its metabolite is more active and hence it is termed as prodrug.

Detoxification of arene oxides: Arene oxides can be further inactivated by various ways as follows:

• Spontaneous rearrangement to arenols via NIH (1, 2-hydride) shift
• Hydration to trans-dihydrodiols
• Glutathione adducts
• Macromolecule adducts

Sometimes, in molecules like benzene, detoxification forms covalent adduct with nucleophillic groups present on DNA or RNA leading to cellular damage. Hence such molecules are very toxic to mammalian systems.

NIH Shift (1, 2-hydride shift): The novel intramolecular hydride migration is termed as NIH shift. It was named after National Institute of Health (NIH), USA, who discovered this process. Not all aromatic hydroxylation occurs through this process. The phenolic products of the hydroxylation of aromatics containing ortho-/para-directing substituents (F, Cl, Br, I, OH, NH2, CH3, CH2CH3, and OCH3) were primarily para-phenols.

In contrast, with aromatics containing meta-directing substituents (NO2 and CN), the phenolic products were a more even mixture of meta- and para-phenols. Ortho-fluorophenol was the only ortho-phenolic product observed. The nature of the products suggested that the reaction involves an enzyme-specific, electrophilic addition to the aromatic ring so as favour hydroxylation at either the meta- or para-positions.

With the fluoro-, chloro- and bromobenzene substrates, the values for the migration and retention of hydrogen during hydroxylation (NIH shift) were nearly identical when the hydrogen was either at the site of hydroxylation or at an adjacent site, indicating a possible common intermediate.

Metabolism of Phenytoin:

Oxidation of Olefins:

Olefinic epoxidation of carbamazepine:

In drugs like alclofenac, secobarbital the epoxides are not stable and immediately converted to dihydroxy derivatives which are quite stable and isolable.

Sometimes epoxides formed are very reactive and produce toxic effects.

These reactive epoxides sometimes cause the destruction of cytochrome P450 enzymes e.g. epoxide of secobarbital, fluroxene (volatile anaesthetics) etc.

Oxidation of Benzylic C-Atoms:

Carbon attached to benzylic position in aromatic compound is susceptible to oxidation so as to form corresponding alcohol (carbinol) metabolite.

Oxidation of Aliphatic C-Atoms:

Metabolic oxidation at terminal methyl group is called as “o oxidation” and that of penultimate carbon atom (next to last carbon) is known as “o-1 oxidation”. This is generally observed in drug molecules with straight or branched alkyl chains.

Oxidation of C-Atoms Alpha to Carbonyls and Imines:

e.g. Metabolism in diazepam.

Oxidation of Alicyclic C-Atoms:

E.g. Oxidation of minoxidil

Oxidation of C-Hetero Atom Systems:

This involves two basic types of biotransformation processes. One hydroxylation of a-carbon attached directly to heteroatom leading to unstable intermediate and subsequent hydroxylation of heteroatom.

C-N Systems:

N-dealkylation: E.g. Codeine

N-oxide formation: E.g. Trimethoprim

N-hydroxylation: Eg. Dapsone

C-S Systems:

S-dealkylation: Eg. 6 methyl mercaptopurine

Desulfuration: Eg. Thiopental

S-oxidation: E.g. Cimetidine

C-O Systems: E.g. Phenacetin

Oxidation of Alcohol and Carbonyl Functions:

Carbinol/alcohol metabolite intermediates obtained after oxidation of different hydroxylation processes which may undergo further oxidation to aldehydes or ketones and finally to acids. Secondary alcohol group is more polar and functionalized and hence may not get oxidized further, but it can get conjugated easily.

Miscellaneous: E.g. Chloroform

Reductive Reactions:

Reduction of Carbonyl Functions: Reduction of aldehydes E.g. Chloral hydrate.

Reduction of Aromatic Ketone: E.g. Acetophenone

Reduction of N-Compounds: Eg. Nitrazepam.

Miscellaneous: E.g. Disulfiram

Hydrolytic Reactions:

Hydrolysis of esters and amides is done mainly by esterase, pseudo cholinesterase, amidases and deacylases. Esters are easy to hydrolyse as compared to amides. Functional groups like phosphate esters, sulphonyl urea, carbamate esters, epoxides and arene oxides are also susceptible to undergo hydrolysis.

Peptide hormones like insulin, prolactin etc. are also metabolized by hydrolysis. Sometimes ester hydrolysis may give pharmacologically active metabolite as in the case of chloramphenicol palmitate (prodrug). The palmitate ester is used to minimize the bitter test of the drug and increase palatability in the paeidatric patients.

Hydrolysis of Esters: E.g. Aspirin

Hydrolysis of Amides: E.g. Procainamide

Hydrolytic Dehalogenation: E.g. Dichloro diphenyls trichloroethane

Phase-2: Conjugation Reactions

Phase-1 metabolites need further conversion for easy excretion and hence small, polar and ionizable endogenous molecules like glucuronic acid, sulfate glycine and glutamine are attached to them leading to generation of Phase-II metabolites. These are biologically inactive, non-toxic. Some other phase-II reactions like methylation and acetylation do not increase water solubility, but terminate pharmacological activity. True detoxification occurs in phase-II pathway. Glutathione (GSH) combines with reactive phase-I metabolites and prevent them combining with biomolecules like DNA/RNA, thus cytotoxicity is prevented.

Mechanism of Action: Conjugating groups are activated in the forms of coenzymes and then are attached / transferred to accepting substrates; while in some other cases like glycine and glutamine conjugation, substrate is activated rather than conjugating groups. Transferase enzyme plays an important role in activation.

Glucuronic Acid Conjugation:

This is the most common pathway because:

• D-glucuronic acid is easily available (obtained from D-glucose).
• Many functional groups can combine enzymatically with glucuronic acid.
• Glucuronyl moiety can ionize carboxylate and polar hydroxyl group to increase water solubility.

Mechanism of Action: B-glucuronide moiety is attached to substrate with the help of microsomal uridine-5-diphospho-glucuronosyl transferase enzyme. All glucuronide conjugations have B-linkage or B-conjugation at C1.. Many functional groups undergo glucuronidation. According to hetero atom (O, S, N) attached to C1 of glucuronyl moiety, metabolic products of these conjugation are classified as –

• Oxygen glucuronidee.g.: Acetaminophen
• Nitrogen glucuronides – e.g.: Desipramine
• Sulfur glucuronides – e.g. Methimazole
• Carbon glucuronides – e.g. : Phenylbutazone

O-Glucuronides

N-glucuronides:

These are formed with aromatic amines, aliphatic amines, amides and sulfonamides. But generally aliphatic and aromatic amines are not glucurylated. They undergo N-acetyl preferably.

S-glucuronides: This is observed very rarely.

C-glucuronides:

Apart from xenobiotic, many endogenous substrates like bilirubin, steroidal hormones are also eliminated as glucuronide conjugates. In neonates and infants glucuronidation processes are not fully developed. So in such cases serious toxicity may be seen because of accumulation of drugs like bilirubin.

e.g. Neonatal hyperbilirubinemia- Inability to conjugate bilirubin with ẞ-glucuronide.

Gray baby syndrome – Inability to conjugate chloramphenicol with glucuronide.

Sulfate Conjugation:

This occurs primarily in phenols and also in alcohols, aromatic amines etc. Amount of sulfate available for conjugation is limited. Endogenous substance like heparin, steroids, catecholamine and thyroxin are also sulfate conjugated.

Mechanism: Sulfate group from PAPS (3-phosphoadenosine-5-phosphosulfate) is transferred to substrate with the help of sulfotransferase enzymes (in liver, kidney, intestine etc.) Phenols are more susceptible to this conjugation.

Examples:

a-Methyl dopa:

Acetaminophen:

Conjugation with Glycin, Glutamine and Other Amino Acids

This is specifically used for conjugation of aromatic acid and aryl alkyl acids. Limited quantities of amino acids are available for conjugation.

Mechanism: Substrate is activated with ATP and CoA to form Acyl-CoA complex. This acylates glycine/ glutamine under influence of specific enzymes like glycine/ glutamate N-acyltransferase Activation and acylation take place in mitochondria of liver/kidney cells.

Glycin conjugation:

Glutamine conjugation:

Glutathione (GSH) or Mercapturic Acid Conjugates:

This is also an important pathway for detoxification of chemically reactive electrophilic compound. GSH protects vital cellular constituents against chemically reactive species by its nucleophilic -SH group. This SH group reacts with electron deficient compound to form S-substituted GSH adduct. GSH conjugated with xenobiotic is further biotransformed into mercapturic acid, involving enzymatic cleavage of 2 amino acids (glutamic and glycine). GSH conjugation does not involve initial formation of activated coenzymes of substrate.

Mechanism of Action: Nucleophilic displacement at an electron deficient carbon/ heteroatom or nucleophilic addition to an electron deficient C=C. Many industrial chemicals are detoxified by this route.

Example: 2,4-dichloro nitrobenzene

GSH conjugation involving substitution at heteroatom like N, O, S:

Example: Azathioprine

Nucleophilic addition of GSH to electron deficient C=C:

The C=C is generally made electron deficient by resonance or conjugation with C=O group, esters, amides, nitriles etc. It generally occurs in a, B-unsaturated systems and undergoes Michael addition reaction with GSH to give GSH adduct.

Mechanism of nucleophilic addition of GSH to electron deficient C=C is as follows:

Example: Ethacrynic acid (Diuretic)

Sometimes chemically reactive a,ẞ-unsaturated systems are generated during various biotransformations. GSH reacts with these systems by Michael addition reaction.

Example: Acetaminophen

GSH conjugate may also cause toxicity due to metabolic intermediates which are electrophilic. Such electrophiles attack on DNA or RNA and produce cytotoxicity.

Example: 1,2-dichloroethane

Acetylation:

Drugs containing primary amines undergo metabolism by this route. It includes various functional groups like aromatic amines, sulphonamides, hydrazines, hydrazides and primary aliphatic amines. Soluble N-acetyl transferase are the enzymes which transfer the acetyl group from acetyl CoA to the accepting amino substrate. N-acetylation process doesn’t affect water solubility, but terminates the biological activity.

Examples:

Isoniazid

Nitrazepam

Biotransformation of sulfonamide:

Biotransformation of hydrazine and hydride derivative:

Acetylation Polymorphism:

The acetylation pattern of many drugs in human being can be classified as-slow and rapid acetylation. i.e. drug conjugates with acetyl CoA slowly or rapidly. This phenomenon is called as acetylation polymorphism and individual are called as slow acetylators or rapid acetylators. This variation in acetylation is genetic and depends on activity of N-acetyltransferases.

Asians and Eskimos are rapid acetylators and hence produce insufficient response at therapeutic dose. Egyptians and western population are slow acetylators and may produce adverse reaction at given dose. e.g. Half-life of isoniazid in rapid acetylators is 45-80 minutes, while in slow acetylators it is 140-200 minutes.

In the slow acetylators, accumulation of drug is seen which gives higher response and higher side effects. Slow acetylators are also susceptible to drug interaction. e.g. In isoniazid slow acetylators, isoniazid inhibit metabolism of phenytoin, thus its accumulation is more leading to toxicity.

While in case of rapid acetylators, the acetyl hydrazine metabolite formed by rapid biotransformation of isoniazid undergoes N-oxidation mediated by cytochrome P450 and gives reactive intermediate which may covalently bind to liver cells. So rapid acetylators have a greater risk of liver injury.

Methylation:

Catechols, phenols, amines, N-heterocyclic and thiol compounds undergo methylation. It plays an important role in inactivation of many physiologically active biogenic amines like dopamine, 5-HT, histamine and norepinephrine. It is minor pathway of conjugation. Most methylated products are inactive and non-toxic.

Coenzyme like 5-adenosylmethione and enzymes like methyl-transferase play crucial role here. Methyl-transferase is a group of enzymes which contain catechol-o-methyltransferase (COMT), phenol-o-methyl-transferase, non-specific N-methyl-transferase and S-methyl-transferase etc.

COMT causes O-methylation of neurotransmitter like norepinephrine, dopamine. Other drugs methylated by COMT include methyl dopa. Bismethylation do not occur in above case. 1,2-dihydroxy group. is necessary for the action of COMT. Hence in case of 1,3 and 1,4-dihydroxy benzene scaffold selective O-methylation is not possible. Hence isoproterenol undergoes O-methylation, whereas terbutaline does not.

Other examples:

Factors Affecting Drug Metabolism

• Age Difference
• Species and Strain
• Genetic/Hereditary factors.
• Sex differences
• Enzyme Induction
• Enzyme Inhibition

Age Difference:

In case of fetus and newborn babies, oxidative and conjugative enzymes are either deficient or underdeveloped. Hence their response to metabolism of certain drug is very different. e.g. Oxidative metabolism of tolbutamide is less in newborn, while half-life in adult is 8 hours and in infants it is greater than 40 hrs. Activity of glucuronyltransferase is less in infants. Neonatal hyperbilirubinemia and gray baby syndrome are examples of such underdeveloped metabolism systems, in which infants are unable to glucuronidate bilirubin and chloramphenicol respectively.

Species and Strain:

Metabolism of many drugs and foreign compounds is species dependent. Cats lack glucuronyltransferase enzymes, hence phenolic xenobiotic are metabolized by sulfation, rather than glucuronidation only. But in pigs, due to lack of sulfotransferase enzymes, these phenolic drugs are metabolized by glucuronidation only. Example of strain difference includes cottontail rabbit liver microsomes metabolizes hexobarbital more rapidly than New Zealand rabbit liver microsomes.

Genetic/Hereditary factors:

As seen above, acetylation of isoniazid is different in different races and accordingly they are categorized as – rapid and slow acetylators. Genetic factor influences rate of oxidation of some drugs like phenytoin, phenylbutazone etc.

Sex differences:

Nicotine and aspirin are metabolized differently in women and men. Adult male rats metabolize many foreign compounds at faster rate than female.

e.g. N-demethylation of aminopyrine.

Enzyme induction:

Activity of cytochrome P-450 dependent Mixed Function Oxidases (MFO) can be enhanced upon exposure to many drugs, pesticides, polycyclic aromatic hydrocarbons etc. This is called as enzyme induction. Enzyme induction causes increase in drug metabolism and decreases duration of drug action. e.g. Induction of microsomal enzyme by phenobarbital increases metabolism of warfarin and thus decreases anticoagulant effect.

Other example is enhanced metabolism of endogenous substances like cortisol, testosterone, vitamin D and bilirubin by phenobarbital. Phenobarbital also induces glucuronyltransferase enzyme and thus increases conjugation of bilirubin with glucuronic acid and hence it can be used to treat hyper bilirubinemia in neonates.

Enzyme inhibition:

Some drugs can inhibit metabolism of other drugs. Decreased metabolism leads to accumulation, prolonged drug action and serious adverse effect. Enzyme inhibition takes place by many mechanisms like substrate competition, interference with protein synthesis, fractionation of drug metabolizing enzymes and hepatotoxicity leading to impairment of enzyme activity etc. e.g. Phenylbutazone inhibits metabolism of S (-) warfarin stereo- selectivity due to which, increased anticoagulant effect (hypoprotothombinemia) is seen. Other examples include metabolism of phenytoin is inhibited by drugs like disulfiram, isoniazid and chloramphenicol.

Miscellaneous factors:

• Dietary factor – Protein or carbohydrate ratio affects metabolism of many drugs. Vitamins, minerals, starvation and malnutrition also influence drug metabolism.
• Physiological factor Pathogenic state of liver, pregnancy, hormonal disturbances, etc. also affect metabolism.

e.g. Indoles present in vegetables like cabbage, cauliflower and polycyclic aromatic hydrocarbons present in boiled beef causes enzymes induction and increases metabolism of many drugs.

Stereochemical Aspects Of Drug Metabolism

Stereoselectivity is also observed in drug disposition particularly for those processes which depend on an interaction with a chiral biological macromolecule, e.g. active transport processes, binding to plasma proteins, and drug metabolism. In drug metabolism, stereoselectivity in metabolism is probably responsible for the majority of the differences observed in enantioselective drug disposition.

Stereoselectivity in metabolism may arise from differences in the binding of enantiomeric substrates to the enzyme active site and/or be associated with catalysis owing to differential reactivity and orientation of the target groups to the catalytic site. As a result, pair of enantiomers is frequently metabolized at different rates and/or via different routes to yield alternative products.

Example: Drug receptor interaction of (R)-(-)-epinephrine, (S)-(+)-epinephrine and N-methyl dopamine.

The stereoselectivity of the reactions of drug metabolism may be classified into three groups in terms of their selectivity with respect to the substrate, the product, or both. Thus, there may be substrate selectivity when one enantiomer is metabolized more rapidly than the other; product stereoselectivity, in which one particular stereoisomer of a metabolite is produced preferentially; or a combination of the above, i.e. substrate- product stereo- selectivity, where one enantiomer is preferentially metabolized to yield a particular diastereoisomeric product.

An alternative classification involves the stereochemical consequences of the transformation reaction. Using this approach, metabolic pathways may be divided into five groups:

Prochiral to chiral transformations: Metabolism taking place either at a prochiral center or on an enantiotopic group within the molecule e.g. phenytoin undergoes stereoselective para-hydroxylation to yield (S)-4′-hydroxyphenytoin in greater than 90% enantiomeric excess.

Chiral to chiral transformations: The individual enantiomers of a drug undergo metabolism at a site remote from the center of chirality with no configurational consequences e.g. (S)-warfarin undergoes aromatic oxidation mediated by CYP 2C9 in the 7- and 6-positions to yield (S)-7-hydroxy- and (S)-6-hydroxywarfarin in the ratio 3.5:1.

Chiral to diastereoisomer transformations: A second chiral center is introduced into the drug either by reaction at a prochiral center or via conjugation with a chiral conjugating agent e.g. stereoselective glucuronidation of oxazepam.

 

Chiral to achiral transformations: The substrate undergoes metabolism at the center of chirality, resulting in a loss of asymmetry e.g. oxidation of the benzimidazole proton pump inhibitors, e.g., Omeprazole, which undergoes CYP 3A4-mediated oxidation at the chiral sulfoxide to yield the corresponding sulfone. The reaction shows tenfold selectivity for the S-enantiomer in terms of intrinsic clearance.

 

Chiral inversion: One stereoisomer is metabolically converted into its enantiomer with no other alteration in structure, e.g. 2-arylpropionic acids like ibuprofen, fenoprofen, flurbiprofen, ketoprofen, and the related 2-aryloxypropionic acid herbicides, e.g., haloxyfop. The reaction is essentially stereospecific, the less active, or inactive, R-enantiomers undergoing inversion to the active S-enantiomers.

Multiple Choice Questions

Question 1. The term “biotransformation” includes the following:

1. Accumulation of substances in a fat tissue
2. Binding of substances with plasma proteins
3. Accumulation of substances in a tissue
4. Process of physicochemical and biochemical alteration of a drug in the body

Answer. 4. Process of physicochemical and biochemical alteration of a drug in the body

Question 2. Biotransformation of the drugs is to render them:

1. Less ionized
2. More pharmacologically active
3. More lipid soluble
4. Less lipid soluble

Answer. 4. Less lipid soluble

Question 3. Metabolic transformation (phase 1) is:

1. Acetylation and methylation of substances
2. Transformation of substances due to oxidation, reduction or hydrolysis
3. Glucuronide formation
4. Binding to plasma proteins

Answer. 2. Transformation of substances due to oxidation, reduction or hydrolysis

Question 4. Confirmational isomerism is

1. Cis-trans isomerism
2. Optical isomerism
3. Dextro and levo rotatory
4. Non-identical spatial arrangement of the atoms in molecule resulting from rotation about one or more simple bonds

Answer. 4. Non-identical spatial arrangement of the atoms in molecule resulting from rotation about one or more simple bonds

Question 5. Conjugation is:

1. Process of drug reduction by special enzymes
2. Process of drug oxidation by special oxidases
3. Coupling of a drug with an endogenous substrate
4. Solubilization in lipids

Answer. 3. Coupling of a drug with an endogenous substrate

Question 6. Which of the following processes proceeds in the second phase of biotransformation?

1. Acetylation
2. Reduction
3. Oxidation
4. Hydrolysis

Answer. 1. Acetylation

Question 7. According to pH partition theory, a weakly acidic drug will most likely be absorbed from the stomach because the drugs which exist primarily in the:

1. Un-ionized, more lipid soluble
2. Ionized, more water soluble
3. Form a weak acid and more soluble in water media
4. Ionic form of the drug which facilitates diffusion

Answer. 1. Un-ionized, more lipid soluble

Question 8. Conjugation of a drug includes the following EXCEPT:

1. Glucuronidation
2. Sulphate formation
3. Hydrolysis
4. Methylation

Answer. 3. Hydrolysis

Question 9. Metabolic transformation and conjugation usually results in an increase of a substance’s biological activity:

1. True
2. False

Answer. 2. False

Question 10. An antagonist is a substance that:

1. binds to the receptors and initiates changes in cell function, producing maximal effect.
2. binds to the receptors and initiates changes in cell function, producing submaximal effect.
3. interacts with plasma proteins and doesn’t produce any effect.
4. binds to the receptors without directly altering their functions.

Answer. 4. binds to the receptors without directly altering their functions.

Question 11. Irreversible interaction of an antagonist with a receptor is due to:

1. Ionic bonds
2. Hydrogen bonds
3. Covalent bonds
4. All of the above

Answer. 3.Covalent bonds

Prodrugs Introduction

An inactive precursor of a drug is converted into its active form in the body by normal metabolic processes. Prodrugs are used when drugs have unattractive physicochemical properties.

• Prodrugs are reversible derivatives of drug molecules that undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug, which can then exert the desired pharmacological effect.
• In both drug discovery and development, prodrugs have become an established tool for
  improving the physicochemical, biopharmaceutical, or pharmacokinetic properties of pharmacologically active agents. ,
• About 5-7% of drugs approved worldwide can be classified as prodrugs, and the implementation of a prodrug approach in the early stages of drug discovery is a growing trend.
• The applicability of the prodrug strategy, this article describes the most common functional groups that are amenable to prodrug design and highlights examples of prodrugs that are either launched or are undergoing human trials.

Prodrugs Undesirable Properties

Physical Properties Poor

• aqueous solubility Low
• lipophilicity Chemical
• instability Pharmacokinetic
• Properties
• Poor distribution across biological membranes
• Good substrate for first-pass metabolism
• Rapid absorption or excretion when long-term effect desired
• Not site-specific

Prodrugs Can Be Classified Into Two Major Types, Based On How The Body Converts The Prodrug Into The Final Active Drug Form.

Type I prodrugs are bioactivated intracellularly: Examples of these are antiviral nucleoside analogs and lipid-lowering statins.

Type II prodrugs are bioactivated extracellular: Especially in digestive fluids or in the body’s circulation system, Examples of these are antibody, gene, or virus-directed enzyme prodrugs [ADEP/GDEP/ VDEP] used in chemotherapy or immunotherapy.

Some examples of Prodrug :

Carisoprodol is metabolized into meprobamate. Carisoprodol was not a controlled substance in the United States.

• However, meprobamate was classified as a potentially addictive controlled substance that can produce dangerous and painful withdrawal symptoms upon discontinuation of the drug.
• Enalapril is bioactivated by esterase to the active enalaprilat.
• Valaciclovir is bioactivated by esterase to the active aciclovir.
• Fosamprenavir is hydrolysed to the active amprenavir.
• Levodopa is bioactivated by DOPA decarboxylase to activate dopamine.
• Chloramphenicol succinate ester is used as an intravenous prodrug of chloramphenicol because pure chloramphenicol does not dissolve in water.
• Psilocybin is dephosphorylated to the active psilocin.
• Heroin is deacetylated by esterase to the active morphine.
• Molsidomine is metabolized into SIN-1 which decomposes into the active compound nitric oxide.
• Paliperidone is an atypical antipsychotic for schizophrenia. It is the active metabolite of risperidone.
• Prednisone, a synthetic corticosteroid drug, is bioactivated by the liver into the active drug prednisolone, which is also a steroid.
• Primidone is metabolized by cytochrome 450 enzymes into phenobarbital, which is major, and phenylethylmalonamide, which is minor.
• Dipivefrine, given topically as an anti-glaucoma drug, is bioactivated to epinephrine.
• Lisdexamfetamine is metabolized in the small intestine to produce dextroamphetamine at a controlled (slow) rate for the treatment of attention-deficit hyperactivity disorder
• Diethylpropion is a diet pill that does not become active as a monoamine releaser or reuptake inhibitor until it has been Ndealkylated to ethylpropion.
• Fesoterodine is an antimuscarinic that is bioactivated to 5 hydroxymethyl tolterodine, the principal active metabolite of tolterodine.
• Tenofovir disoproxil fumarate is an anti-HIV drug (NtRTI class) that is bioactivated to tenofovir (PMPA).

Steps In Prodrug Design

Identification of drug delivery problem

• Identification of desired physic-chemical properties
• Selection of transport moiety which will give prodrug desired transport properties to be readily cleaved in the desired biological compartment

Depending upon the Nature of the Carrier used, the Carrier Linked prodrug Further Be Classified Into

Double prodrugs: pro-prodrugs, or cascade-latentiated prodrugs, where a prodrug is further derivatized in a fashion such that only enzymatic conversion to prodrug is possible before the latter can cleave to release the active drug.

1. Macromolecular prodrugs: where macromolecules like polysaccharides, dextrans, cyclodextrins, proteins, peptides, and polymers are used as carriers.

2. Site-specific prodrugs: where a carrier acts as a transporter of the active drug to a specific targeted site.

3. Mutual prodrug:

• • Where the carrier used is another biologically active drug instead of some inert molecule A mutual prodrug consists of two pharmacologically active agents coupled together so that each acts as a moiety for the other agent and vice versa.
  • The carrier selected may have the same biological action as that of the parent drug and thus might give synergistic action, or the carrier may have some additional biological action that is lacking in the parent drug, thus ensuring some additional benefit.
  • The carrier may also be a drug that might help to target the parent drug to a specific site or organ or cells or may improve the site specificity of a drug. The carrier drug may be used to overcome some side effects of the parent drugs as well.

Criteria For Prodrug

A well-designed carrier-linked prodrug should satisfy certain criteria. The linkage between the drug and the carrier should usually be a covalent bond.

• As a rule, the prodrug itself should be inactive or less active than the parent drug.
• The linkage should be reversible. The prodrug and the earner released after an in vivo enzymatic or non-enzymatic attack should be nontoxic.
• The generation of active form must take place ‘with rapid kinetics to ensure effective drug levels at the site of action.
• The bioavailability of cancer-linked prodrug is modulated by using a transient moiety.
• The lipophilicity is generally the subject of profound alteration of the parent molecule.
• The bioactivation process is exclusively hydrolytic and sometimes a redox system. An ideal carrier should be without intrinsic toxicity.
• It should be nonimmunogenic and non-antigenic and should not accumulate in the body.
• It should possess a suitable number of functional groups for drag attachment and adequate loading capacity.
• It should be stable to chemical manipulation and autoclaving.
• It should be easy to characterize and should mask tire liganded drag’s activity until the release of active agent at the tire’s desired site of action.
• In the mutual prodrug approach, the carrier should have some biological activity of its own.

Applications Of Prodrug

Prodrug to Improve Patient Acceptability:

• One of the reasons for poor patient compliance, particularly in the case of children is the bitterness, acidity, or causticity of the drag. Two approaches can be utilized to overcome the bad taste of drag. The first is the reduction of drag solubility in saliva and the other is to lower the affinity of drag towards taste receptors.
• Chloramphenicol has a bitter taste, so it is not well accepted by children. The pa Imitate ester of it is less soluble in saliva, so it masks the bitter taste.
• Several drags (NSAIDS, Nicotinic acid, Kanamycin, Diethylstilboestrol) cause irritation and damage to the gastric mucosa.
• Examples of prodrugs designed to overcome such problems of gastric distress are below (Aspirin & INH).

Prodrug to Improve Stability:

• Many drugs are unstable and may either break down on prolonged storage or are degraded rapidly on administration.
• Several drugs may decompose in GIT when used orally. Although enteric coatings may be used, it is also possible to utilize prodrug design to overcome this problem.
• An anti-neoplastic drug Azacytidine hydrolyses readily in acidic pH, but the bisulfite prodrug is more stable.

Prodrug to improve absorption: Ampicillin a wide-spectrum antibiotic is readily absorbed orally as the inactive prodrug, Pivampicillin, Bacampicillin, and Talampicillin which are then converted by enzymatic hydrolysis to Ampicillin.

A prodrug for slow release (sustained drug action):

• A common strategy in the design of slow-release prodrugs is to make long-chain aliphatic esters because these esters hydrolyze slowly and inject intramuscularly.
• Fluphenazine has a shorter duration of action (68h), but the prodrug Fluphenazine deconate has a duration of activity of about a month.

1. Prodrug to Improve Membrane Transport: Dopamine used for the treatment of Parkinson’s disease can be improved by administering its prodrug 3,4-dihydroxy phenylalanine (Levodopa).
2. Prodrug for Prolonged Duration of Action: Nordazepam, a sedative drug loses activity quickly due to metabolism and excretion. A prodrug Diazepam improves the retention characteristics, due to the presence of N- methyl group.

Prodrugs Short Question And Answers

Question .1 What are the mutual prodrugs?
Answer:

The mutual prodrugs: Where the carrier used is another biologically active drug instead of some inert molecule a mutual prodrug consists of two pharmacologically active agents coupled together so that each acts as a moiety for the other agent and vice versa.

Question . 2 Write the steps of designing of prodrug.
Answer:

The steps of designing of prodrug

• Identification of drug delivery problem
• Identification of desired physic-chemical properties
• Selection of transport moiety which will give prodrug desired transport properties to be readily cleaved in the desired biological compartment.

Tetracycline Introduction

Tetracyclines are a group of broad-spectrum antibiotic compounds that have a common basic structure and are either isolated directly from several species of Streptomyces bacteria or produced semi-synthetically from those isolated compounds.

Tetracycline molecules comprise a linear fused tetracyclic nucleus (rings designated A, B, C, and D) to which a variety of functional groups are attached

Tetracycline Mode Of Action

The antimicrobial activity of tetracyclines reflects reversible binding to the bacterial 30S ribosomal subunit, specifically at the aminoacyl-tRNA acceptor (“A”) site on the mRNA ribosomal complex, thus preventing ribosomal translation Adverse Effect discoloration of teeth, kidney damage (Fanconi syndrome)

Chemistry Of Tetracycline

Carbon atom 4,4a, 5, 5a, 6 and 12a are potentially chiral.

• Oxytetracycline and doxycycline each with 5-OH substituents have six asymmetric centers while others have only five.
• The basic ring present in Tetracycline is polycyclic naphthalene carboxamide.
• All Tetracycline is amphoteric.
• At pH-7, it is converted into Zwitter-ion.

Ability to undergo epimerization at C₄ in a solution of neutral pH range

Tetracycline Classification

 

 

Tetracycline Contraindication

Tetracycline forms a chelate complex with many metals like calcium, magnesium, and iron.

• Chelates are usually insoluble in water which impairs the absorption of tetracycline in the presence of milk, Ca, Mg, and A α-containing antacids.
• The affinity of tetracycline for calcium causes them to be incorporated into newly forming bones and teeth as a tetracycline-calcium orthophosphate complex.
• Deposition of these antibiotics in teeth causes yellow discoloration.
• In pregnancy, Tetracycline is distributed into the milk of the lactating mother and it crosses the placental barrier into the fetus hurting the bones and teeth of a child.

Sar Of Tetracycline

Tetracyclines are composed of a rigid skeleton of 4 fused rings. The ring structure of tetracyclines is divided into an upper modifiable region and a lower non-modifiable region.

• An active tetracycline requires a C₁₀ phenol as well as a C₁₁-C₁₂ keto-enol substructure in conjugation with an OH group and a C₁-C₃ diketo substructure. Removal of the dimethylamine group at C4 reduces antibacterial activity.
• Replacement of the carboxylamine group at C₂ results in reduced antibacterial activity but it is possible to add substituents to the amide nitrogen to get more soluble analogs like the prodrug lymecycline.
• The simplest tetracycline with measurable antibacterial activity is 6-deoxy 6- demethyltetracycline and its structure is often considered to be the minimum pharmacophore for the tetracycle class of antibiotics can be modified to make derivatives with varying antibacterial activity

Tetracycline Multiple Choice Question And Answers

Question 1. The adverse effect of tetracycline is…

1. Gray baby syndrome
2. Fanconi syndrome
3. Ototoxicity

Red Man syndrome

Answer: 2. Fanconi syndrome

Question 2. Tetracycline act on…

1. 50s position
2. 30s position
3. Both
4. None

Answer: 2. 30s position

Question 3. Epimerization in tetracycline takes place at…

1. 3 position
2. 4 position
3. 5 position
4. 6 position

Answer: 2. 4 position

Question 4. Yellow discoloration of teeth is caused by …

1. Chloramphenicol
2. Amino glycoside
3. Tetracycline
4. Macrolide

Answer: 3. Tetracycline

Question 5. Photo Toxicity is the adverse effect of…

1. Chlortetracycline
2. Rolitetracycline
3. Demeclocycline
4. Doxycycline

Answer: 3. Demeclocycline

Tetracycline Short Question And Answers

Question 1. Classify natural tetracycline.
Answer:

Natural tetracycline: Chlortetracycline, Tetracycline, Oxytetracycline, Demeclocylin

Question 2. Write the name of the semi-synthetic tetracycline.
Answer:

The name of the semi-synthetic tetracycline: Minocycline, Lymecycline, Rolicycline, Clomocycline, Methacycline

Question 3. What is the mode of action of tetracycline?
Answer:

The mode of action of tetracycline: The antimicrobial activity of tetracyclines reflects reversible binding to the bacterial 30s ribosomal subunit, specifically at the aminoacyl-tRNA acceptor (“A”) site on the mRNA ribosomal complex, thus preventing ribosomal translation.

Question 4. What position is responsible for epimerization in tetracycline?
Answer:

C4 position.

Question 5. What is zwitter ion?
Answer:

Zwitter ion: The compounds contain both charges in their structure.

Macrolide Antibiotics Introduction

Macrolides belong to one of the most commonly used families of clinically important antibiotics used to treat infections caused by Gram-positive bacteria such as Staphylococcus aureus, Streptococcus pneumonia, and Streptococcus pyogenes.

Chemically, macrolides are represented by a 14-, 15- or 16-membered lactone ring carrying one or more sugar moieties and additional substitutions linked to various atoms of the lactone ring

Macrolide Antibiotics Mechanisam Of Action

Bind to 50s subunit of ribosome causing them to dissociate from the mRNA resulting in premature termination of the amino acid chain and cessation of protein synthesis.

Macrolide Antibiotics Classification

Pharmacokinetics

Tacrolidc antibiotics are fairly absorbed from the gastrointestinal tract They penetrate moot tissues and host cells excellently. The concentrations in phagocytic cells exceed peach maximum serum levels by several folds.

• On me other hand, macrolides penetrate poorly into the brain, synovial fluid, and fetal tissues, macrolide antibiotics are excreted into mucosal fluid, breast milk, bile, and urine. The ratio of urinary or fecal excretion is variable.
• The portion of macrolide antibiotics excreted into bile is partially reabsorbed in the gut enterohepatic circulation,) Some drug is metabolized in the liver as well.

Read and Learn More Medicinal Chemistry III Notes

Spectrum of Activity

• Active against give bacilli and give cocci
• Also active against H-Influenza, mycoplasma pneumonia, N.Gonorrhoea, and legionella

Chemistry Of Macrolides

The commercial product is Erythromycin A which is different from Erythromycin B in having -OH group at 12 position of aglycon.

• Erythronolide-Aglycon part of Erythromycin
• Glycon part-1. Basic ring-Desosamine 2. Neutral ring-cladinose While in the case of Erythromycin C, it has Mycarose as a neutral glycogen part instead of Cladinose
• It acts as an Enzyme inhibitor (Cyto-P-450 oxidase) for other drugs.
• Like Theophylline, Hydroxy coumarine, Benzodiazepine (Alprazolam, Midazolam), carbamazepine. Cyclosporine is an antihistaminic drug While the activity of terfenadine and astemizole is potentiated by Erythromycin.
• The stability of Erythromycin is at or neutral pH (7)
• Clarithromycin-6-methyl ether derivative of Erythromycin. (6-OH group is methylated to 6-OCH₃).
• It acts as an Enzyme inhibitor (Cyto-P-4aO oxidase) for other drugs.
• Specifically used to treat Lyme disease caused by Borrelia Burdorferi.
• Azithromycin, prepared by Beckmann rearrangement of 9-Oxime followed by N-methylation and reduction of resulting ring-expanded lactam. Nitrogen-containing 15-membered rings Macrolide is known as Azalides.
• It does not act as an enzyme inhibitor (Cyto-P-450 oxidase) for other drugs.
• Removal of 9-keto group-increasing stability of azithromycin to acid-catalyzed degradation. These changes also increase lipid solubility.
• Dirithromycin-Having 9N, 11 O-Oxazine ring

Sar

Chloramphenicol

Chloramphenicol is a broad-spectrum antibiotic with bacteriostatic activity and a wide spectrum of activity but is currently a backup drug for infections due to Salmonella typhi, B. fragilis, Rickettsia, and possibly bacterial meningitis.

• It was initially obtained from Streptomyces Venezuela
• Chloramphenicol has a broad spectrum of activity resembling that of the tetracyclines except that it exhibits a bit less activity against some gram-positive bacteria.
• It contains chlorine and is obtained from an actinomycete, and thus, named Chloromycetin.
• It is specifically recommended for the treatment of serious infections caused by H. influenza, S. typhi (typhoid), S. pneumoniae, and N. meningitides.
• Its ability to penetrate the CNS presents an alternative therapy for meningitis and exhibits anti-rickettsial activity.

Chloramphenicol The adverse effects: Chloramphenicol causes bone marrow depression and fatal blood dyscrasias.

Chloramphenicol Properties:

• Chloramphenicol is a white or greyish-white or yellowish-white crystalline powder or fine crystals, slightly soluble in water, soluble in alcohol, and propylene glycol.
• It was the first and still is the only therapeutically important antibiotic to be produced in competition with microbiological processes.
• It contains a nitrobenzene moiety and is a derivative of dichloroacetic acid. Since it has two chiral centers, four isomers are possible.
• The D is the biologically active form.

Chloramphenicol Mechanisam Of Action

• Chloramphenicol is a bacteriostatic by inhibiting protein synthesis.
• It prevents protein chain elongation by inhibiting the peptidyl transferase activity of the bacterial ribosome.
• It specifically binds to A2451 and A2452 residues in the 23S rRNA of the 50S ribosomal subunit, preventing peptide bond formation.
• Chloramphenicol palmitate Prodrug is designed to mask the bitter taste
• Chloramphenicol succinate Prodrug designed to increase water solubility

Chloramphenicol Adverse Effects

• Dose-dependent bone marrow suppression is common
• Aplastic anemia is rare (1 in 35, 000).
• Gray baby syndrome in neonates (decreases glucuronysyl transferase)
• Optic neuritis in children.
• Broad spectrum antibiotic
• Nowadays, it is prepared by synthetic route from p-Nitro acetophenone.

Chemistry of chloramphenicol:

• It has two chiral carbons, so a total of four (4) isomers are possible D-erythro,  L-L-erythro, D-threo, and L-threo.
• Among these four isomers, the D-three isomer is the most active. The prodrug of Chloramphenicol viz., Chloramphenicol palmitate (USP) which is a tasteless product is intended for pediatric usage.

Sar Of Chloramphenicol

Modification of the p-nitrophenyl group:

The para-nitrophenyl group may be modified through the following ways:

1. Replacement of the nitro group by other substituents leads to a reduction in activity.
2. Shifting of the nitro group from the para position also reduces the antibacterial activity.
3. Replacement of the phenyl group by the alicyclic moieties results in less potent compounds.

Modification of dichloro acetamido side chain: Other halo derivatives of the side chain are less potent although major activities are retained.

Modification of 1,3-propanediol: If the primary alcoholic group on the C-l atom is modified, it results in a decrease in activity; hence, the alcoholic group seems to be essential for activity.

Metabolism

Major route: Formation of 3-O-Glucrodination

Minor route: Reduction of the p-Nitro group to amino

Metabolism Use

• Meningitis
• Active against gm+ve and gm-ve bacteria that are resistant to PenicillinG and ampicillin.
• Active against H.Influenza, S.Typhi, S.Pneumonia, B.fragilis and N.meningitis
• In UTI
• Rickettsial infections as “Rocky Mountain Spotted Fever”

Synthesis Of Chloramphenicol

Vancomycin

Vancomycin is an antibiotic that has been around for the last forty years. Recently, however, vancomycin has been increasing in popularity because of its effectiveness in treating resistant organisms. One of two glycopeptide antibiotics in clinical use, vancomycin has a unique chemical structure.

• Vancomycin is comprised of a glycosylated hexapeptide chain containing unusual amino acids. In addition, vancomycin is fairly rigid because of aromatic rings that are halogenated and crosslinked by aryl ether bonds.

Vancomycin can penetrate the gram-positive cell wall and therefore is effective against gram-positive organisms. Vancomycin shows no activity against gram-negative organisms, however, because it is unable to penetrate the gram-negative cell wall.

Vancomycin Mechanism Of Action

• Vancomycin acts by inhibiting bacterial cell wall biosynthesis. Specifically, vancomycin binds to the D-Alanyl-D-Alanine portion of the dipeptide, a key component for the transpeptidase reaction, and forms three hydrogen bonds.
• By covering the substrate for cell wall transaminase, vancomycin prevents the molecule from being transported to the cell wall. Cross-linking does not occur and the integrity of the bacterial cell wall is compromised. The bacterial cell cannot withstand changes in osmotic pressure and it will rupture and die. Vancomycin is bactericidal.

Use Of Vancomycin: Vancomycin is FDA-approved for the treatment of several bacterial infections, including infections caused by susceptible staphylococcus, streptococcus, enterococcus, and diphtheroid organisms. Vancomycin is commonly used in clinical practice to treat endocarditis and meningitis.

Vancomycin Adverse Effects: The most common side effects associated with vancomycin include nausea and vomiting. Rarely, nephrotoxicity, ototoxicity, and neutropenia.

Vancomycin Drug Interactions: Many drugs may increase the adverse effects of vancomycin. Medicines that affect the kidneys, such as aminoglycosides, may increase the risk of kidney damage and should be avoided.

• In addition, co-administration of vancomycin and succinylcholine may result in a prolonged neuromuscular blockade.
• Patients should be monitored and a dose adjustment may be necessary.
• Vancomycin also has been reported to moderately interact with warfarin, potentially increasing the risk of bleeding.
• Patients who take warfarin should be closely monitored as they initiate and stop vancomycin therapy.

Clindamycin

Clindamycin belongs to a class called Lincomycins which were isolated from Streptomyces. This class resembles another antibiotic class called Macrolides and is active against both gram-negative, and gram-positive bacteria, and anaerobes.

Lincomycin

Lmcomycin shows cross-resistance with other Macrolides and Stre’ptoGramins because they bmd to the ribosome m the same way. Lincomycins are water soluble and when given as a HC1 salt they can distribute to other body tissues.

Lincomycin Mechanisam Of Action: The Lincomycins, like the Macrolides, are bacteriostatic. They act by binding to the 50S ribosomal subunit and causing the release of a fragmentary peptide by preventing the translocation of peptidyl-tRNA from the A-site to the P-site. By inducing the formation of these incomplete peptides, the growth of the bacterial cell is inhibited.

Use Of Clindamycin

Clindamycin is FDA-approved for the treatment of bacterial infections due to Staphylococcus aureus, Staphylococcus epidermidis, and Streptococcus pyogenes, as well as for the treatment of acne vulgaris, bacterial vaginosis, and pelvic inflammatory disease.

Clindamycin Adverse Effects

• The most common adverse effects reported with clindamycin use are diarrhea, nausea, and rash. In rare cases, clindamycin may cause pseudomembranous enterocolitis.
• Clindamycin may also affect the liver, resulting in jaundice and increased liver function tests. Clindamycin is contraindicated in patients with an allergy to clindamycin or lincomycin.

Macrolide Antibiotics Multiple Choice Question And Answers

Question 1. The commercial product of macrolides is…

1. Erythromycin A
2. Erythromycin B
3. Erythromycin C Macrolides act on…
4. Erythromycin D

Answer: 1. Erythromycin A

Question 2. Macrolide acts on.

1. Erythromycin A
2. 30s ribosome
3. Both
4. None

Answer: 1. Erythromycin A

Question 3. Which macrolides contain a 15-membered ring in their structure …

1. Erythromycin
2. Azithromycin
3. Clarithromycin
4. Roxithromycin

Answer: 2. azithromycin

Question 4. Dopamine is a.

1. Acidic ring
2. Basic ring
3. Neutral
4. None

Answer: 2. Basic ring

Question 5. Phototoxicity is the adverse effect of

1. Chlortetracycline
2. rolitetracycline
3. Demeclocycline macrolide acts on
4. doxycycline

Answer: 3. Demeclocycline macrolide acts on

Question 6.Macrolide act on

1. 50s subunit
2. 30s subunit
3. 80s subunit
4. 70s Subunit

Answer: 1. 50s subunit

Question 7. Chloramphenicol act on

1. 50s subunit
2. 30s subunit
3. 80s subunit
4. 70s subunit

Answer: 2.30s subunit

Question 8. Adverse effect of chloramphenicol is

1. Gray baby syndrome
2. Fanconi syndrome
3. Ototoxicity
4. Red man syndrome

Answer: 1. Gray baby syndrome

Question 9. The drug of choice for Rocky Mountain spotted

1. Chloramphenicol
2. Aminoglycosides
3. tetracycline
4. Macrolide

Answer: 1. Chloramphenicol

Question 10. Vancomycin acts on

1. D-Alanyl-D-Alanine
2. L- Alanyi D- Alanyl-D-Alanineboth
3. Both
4. None

Answer: 1. D-Alanyl-D-Alanine

Macrolide Antibiotics Short Question And Answers

Question 1. Classify 14 membered macrolides
Answer:

14 membered macrolides

• Clarithromycin
• Dirithromycin
• Flurithromycin
• Troleandomyci
• Erythromycin
• Roxithromycin

Question .2 Write In mime ketolides.
Answer:

In mime ketolides

• Modithromycin
• Telithromycin
• Cethromycin
• Modithromycin
• Telithromycin
• Solithromycin

Question 3. What In the mode of action of macrolides?
Answer:

The mode of action of macrolides: Bind 509 Hiibunil of ribosome causing them to dissociate from the mRNA resulting in premature termination of the amino acid chain and cessation of protein synthesis.

Question 4 . How does azithromycin degrade?
Answer:

Removal of 9-keto group-increasing stability of azithromycin to acid-catalyzed degradation. These changes also increase lipid solubility.

Question 5. What is the activity spectrum of macrolides?

Answer:

The activity spectrum of macrolides: Active against gm+ve cocci, bacilli, and gm-ve cocci Also active against H.Influenza, mycoplasma pneumonia, N.Gonorrhoea, and legionella

Question 6. Write the mode of action of macrolide.
Answer:

Mode of action of macrolide: Bind to 50s subunit of ribosomes causing them to dissociate from the mRNA resulting in premature termination of the amino acid chain & cessation of protein synthesis.

Question 7. Write the mode of action of chloramphenicol.
Answer:

Mode of action of chloramphenicol: Chloramphenicol is a bacteriostatic by inhibiting protein synthesis. It prevents protein chain elongation by inhibiting the peptidyl transferase activity of the bacterial ribosome. It specifically binds to A2451 and A2452 residues in the 23S rRNA of the 50S ribosomal subunit, ‘preventing peptide bond formation.

Question 8. Write the adverse effect of chloramphenicol.
Answer:

The adverse effect of chloramphenicol: Aplastic anemia is rare Gray baby syndrome in neonates (decreases glucuronysyl transferase) optic neuritis in children.

Question 9. Write the adverse effects of clindamycin.
Answer:

The adverse effects of clindamycin: The most common adverse effects reported with clindamycin use are diarrhea, nausea, and rash. In rare cases, clindamycin may cause pseudomembranous enterocolitis.

Question 10 Write the mode of action of clindamycin.
Answer:

The mode of action of clindamycin: They act by binding to the 50S ribosomal subunit and causing the release of a fragmentary peptide by preventing the translocation of peptidyl-tRNA from the A-site to the P-site. By inducing the formation of these incomplete peptides, the growth of the bacterial cell is inhibited.

Question 11. Write the mode of action of vancomycin.
Answer:

The mode of action of vancomycin: Vancomycin acts by inhibiting bacterial cell wall biosynthesis. Specifically, vancomycin binds to the D-Alanyl-D-Alanine portion of the dipeptide, a key component for the transpeptidase reaction, and forms three hydrogen bonds. By covering the substrate for cell wall transaminase, vancomycin prevents the molecule from being; transported to the cell wall.

Amino Glycosides Introduction

Aminoglycoside is a medicinal and bacteriologic category of traditional Gram-negative antibacterial therapeutic agents that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside (sugar).

• The term can also refer more generally to any organic molecule that contains amino-sugar substructures.
• The aminoglycoside antibiotics contain one or more amino sugars linked to an aminocytitol ring by glycosidic bonds.
• Aminoglycoside antibiotics display bactericidal activity against Gram-negative aerobes and some anaerobic bacilli were resistant to Gram-positive and anaerobic Gram-negative bacteria. Streptomycin is the first antibiotic of this group.

Aminoglycosides

• Systemic aminoglycosides
• Streptomycin Amikacin
• Gentamicin
• Sisomicin
• Kanamycin
• Netilmicin
• Tobramycin
• Paromomycin

Topical aminoglycosides

• Neomycin
• Framycetin

Amino Glycosides Mode Of Action

The aminoglycosides exhibit bactericidal effects as a result of several phenomena. Klbosomal binding on the 30s and SOs subunits as well as (the interface produces misreading; this is normal protein synthesis, Cell membrane damage also plays an integral part in ensuring bacterial cell death.

Read and Learn More Medicinal Chemistry III Notes

Amino Glycosides Adverse Effect

The aminoglycoside can produce severe adverse effects, which include nephrotoxicity, ototoxicity, and neuro effects.

These properties have limited the use of aminoglycoside chemotherapy to serious systemic indications.

Amino Glycosides Classification

Streptomycin: It is used in the treatment of infections caused by gram-negative bacteria of particular interest and has a high degree of activity against P. aeruginosa, where the important causative factor is burned skin. It is used topically in the treatment of infected bed sores, pyodermata, burns, and eye infections.

Neomycin: It is photosensitive and its main use is in the treatment of ear eye and skin infections This includes burns wounds nuclear and infected dermatoses.

Tobramycin: Its activity is similar to gentamycin. The superior activity of tobramycin against P. aeruginosa may make it useful in the treatment of bacterial osteomyelitis and pneumonia caused by Pseudomonas species.

Sar Of Amino Glycoside

The aminoglycosides consist of two or more amino sugars joined in glycoside linkage to a highly substituted 3 diaminocyclo hexane (amino cyclitol), which is a centrally placed ring.

• The ring is a 2-deoxy streptamine in all aminoglycosides except streptomycin and dihydrostreptomycin, where it is streptidine. Thus,
• In the kanamycin and gentamycin families, two amino sugars are attached to 2-deoxy streptamine.
• In streptomycin, two amino sugars are attached to strepidine.
• In the neomycin family, there are amino sugars attached to 2-deoxy streptamine.

The aminoglycoside antibiotics contain two important structural features. They are amino sugar portions and centrally placed hexose rings, which are either 2-deoxystreptamine or streptidine.

Amino sugar portion

The bacterial inactivating enzymes target C-6 and C-2 position and the substitution with methyl group at C-6 increases the enzyme resistance. Cleavage of 3-hydroxyl or the 4-hydroxyl or both groups does not affect the activity.

Centrally placed hexose ring (aminocyclitol ring): Various modifications at the C-l amino group have been tested.

• The acylation (for example amikacin) and ethylation (for example  1-N-ethylsisomycin) though do not increase the activity help to retain the antibacterial potency.
• In the sisomicin series, 2-hydroxylation and 5-deoxygenation result in the increased inhibition of bacterial inactivating enzyme systems.
• Thus, very few modifications of the central ring are possible, which do not violate the activity spectrum of aminoglycosides.

Amino Glycosides Multiple Choice Questions

Question 1. Which effect is related to aminoglycoside

1. Gray baby syndrome
2. Ototoxicity
3. Fanconi syndrome
4. None

Answer: 2. Ototoxicity

Question 2. Amino glycoside gives.

1. Bactericidal effect
2. Bacteriostatic effect
3. Fungicidal effect
4. None

Answer: 1. Bactericidal effect

Question 3. How aminoglycosides act as …

1. Act on 30s ribosome
2. Framacitin
3. Both 30s and 50s
4. None

Answer: 3. Both 30s and 50s

Question 4. Which aminoglycoside is used as topical?

1. Neomycin
2. Framacitin
3. Both
4. None

Answer: 3. Both

Question 5. Which linkage is found in the aminoglycoside ring and sugar

1. Glycosidic linkage
2. Hydrogen Bonding
3. Covalent Bond
4. All

Answer: 1. Glycosidic linkage

Amino Glycosides Short  Question And Answers

Question 1.  What is the mode of action of aminoglycoside?
Answer:

Mode of action of aminoglycoside: The aminoglycosides exhibit bactericidal effects as a result of several phenomena. Ribosomal binding on 30s and 50s subunits as well as the interface produces misreading; this disturbs the normal protein synthesis.

Question 2. What is the structure of neomycin?
Answer:

Structure of neomycin

 

Question 3. What is the role of the amino cyclitol ring in the SAR of aminoglycoside?
Answer:

Role of the amino cyclitol ring in the SAR of aminoglycoside: Various modifications at the C-l amino group have been tested. The acylation (for example, amikacin) and ethylation (for example 1-N ethylsisomycin) though do not increase the activity help to retain the antibacterial potency.

Question 4. What is the common adverse effect of aminoglycoside?
Answer:

Common adverse effects of aminoglycoside: The aminoglycoside can produce severe adverse effects, which include nephrotoxicity, ototoxicity, and neuro effects. These properties have limited the use of aminoglycoside chemotherapy to serious systemic indications

Question 5. What are aminoglycosides?
Answer:

Aminoglycosides: Aminoglycoside is a medicinal and bacteriologic category of traditional Gram-negative antibacterial therapeutic agents that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside (sugar).

• The term can also refer more generally to any organic molecule that contains amino-sugar substructures.
• The aminoglycoside antibiotics contain one or more amino sugars linked to an aminocytitol ring by glycosidic bonds.