Spectrum of Cholinomimetic Drugs

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Chapter: Medicinal Chemistry : Cholinergic Drugs

Early studies of parasympathetic nervous system showed that the alkaloid muscarine mimicked the effects of parasympathetic nerve discharge, that is, the effects were parasympathomimetic.


Early studies of parasympathetic nervous system showed that the alkaloid muscarine mimicked the effects of parasympathetic nerve discharge, that is, the effects were parasympathomimetic. Application of muscarine to ganglion and to autonomic effector tissue (smooth muscle, heart, exocrine glands) showed that para-sympathomimetic action of the alkaloid occurred through an action on receptors at effector cells, which are not in those of ganglia. Low concentrations of alkaloid nicotine stimulates autonomic ganglia and skeletal neuromuscular junction, but not autonomic effector cells. The ganglion and skeletal muscle receptors were, therefore, labelled nicotinic. Cholinoceptor are a protein linked (muscarinic) or ion channel (nicotinic) families, which functions on the basis of their trans-membrane signalling mechanism (Fig. 3.1).

Direct-acting Cholinoceptor Stimulants

The direct-acting cholinomimetic drugs can be divided on the basis of their chemical structure into esters of choline (including acetylcholine) and alkaloids (muscarine and nicotine). A few drugs are highly selective for specific muscarinic and nicotinic receptor. Many have effects on both receptors, for example, acetylcholine.


These drugs mediate the actions through muscarinic and nicotinic receptor subtypes. Stimulation of M1 or M3 receptors causes hydrolysis of polyphosphoinositides and mobilization of intracellular Ca2+, as a consequence of interaction with a G protein and phospholipase C is activated, which phosphorylates the target protein. In contrast, M2 and M4 inhibit adenylcyclase and regulate specific ion channels, that is, enhancement of K+ conductance in cardiac arterial tissue.

Cholinergic stimulation affects cardiac function directly by inhibiting the effects of adrenergic activation. As a part, it decreases the cAMP formation and reduction on L-Type Ca2+ channel activity. In arterial muscles, acetylcholine decreases the strength of contraction. This effect is due to M2 receptor mediated action of G protein regulated K+ channels. Increased K+ permeability leads to hyperpolarization and shortens the duration of action potentials.

Indirect Acting Cholinomimetic Drugs

The actions of acetylcholine released from autonomic and somatic motor nerves are terminated by enzymatic destruction of the molecule. Hydrolysis is accomplished by acetylcholinesterase. The indirect acting drugs have primary effect on the active site of this enzyme, although some also have direct actions at nicotinic receptors. The common differences between members of the group are chemical and pharmacokinetic, but their pharmacodynamic properties are identical.


Acetylcholinesterase (AchE) is a serine dependent isoenzyme capable of hydrolyzing Ach to choline and acetic acid. The active site of AchE comprises two distinct regions, an anionic site that possess a glutamate residue and an esteratic site in which histidine imidazole ring and serine –OH group are present. Catalytic hydrolysis occurs, thereby the acetyl group is transferred to the serine –OH group, leaving an acetylated enzyme molecule and a molecule of free choline. Spontaneous hydrolysis of the serine acetyl group occurs rapidly.

There are two main categories of AchE inhibitors:

  1. The amine or ammonium AchE inhibitors react reversibly with enzymes, these compounds reversibly acylate the esteratic serine hydroxyl, their duration of action are few minutes to few hours.

  2. The organophosphate type AchE inhibitors form an irreversible firm bond with the enzymes (esteratic site) and their duration of action are few weeks to months.

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