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This sqadia.com lecture addresses about muscarinic receptor agonists and antagonists. Muhammad Usman used ''Basic & Clinical Pharmacology'' by Bertram G. Katzung for explanation of this lecture.
General Introduction to Nervous System
Muscarinic acetylcholine receptors in the peripheral nervous system occur primarily on autonomic effector cells innervated by postganglionic parasympathetic nerve. Acetylcholine (ACh), the naturally occurring neurotransmitter for these receptors, has virtually no systemic therapeutic applications because its actions are diffuse, and its hydrolysis, catalyzed by both acetylcholinesterase (AChE) and plasma butyrylcholinesterase, is rapid. In the CNS, muscarinic receptors are widely distributed and have a role in mediating many important responses.
Two main groups according to type of neurons involved cholinergic: as the name indicate, these drugs act on receptors activated by Ach and adrenergic and act on receptors activated by adrenaline. Direct acting cholinergic agonists are agents mimic the effect of ACH by binding directly to cholinoceptors. They are synthetic esters of choline such as carbachol and bethanechol or naturally occurring alkaloids such as pilocarpine. Indirect acting cholinergic agonists are drugs that exert cholinergic actions by prolonging the life time of ACH via inhibition of acetyl-cholinesterase enzyme, this results in accumulation of ACH in synaptic space and provoke response at all cholinoceptors in the body including both muscarinic and nicotinic receptors as well as neuromuscular junction.
Direct Acting Cholinergic Drugs
Muscarinic cholinergic receptor agonists can be divided into two groups: 1) choline esters, including ACh and several synthetic esters; and 2) the naturally occurring cholinomimetic alkaloids (particularly pilocarpine, muscarine, and arecoline) and their synthetic congeners. Acetylcholine a quaternary ammonium compound that cannot penetrate membranes. Carbachol retains substantial nicotinic activity, particularly on autonomic ganglia. Bethanechol has mainly muscarinic actions, with prominent effects on motility of the GI tract and urinary bladder. The major natural alkaloid muscarinic agonists— muscarine, pilocarpine, and arecoline—have the same principal sites of action as the choline esters.
Indirect Acting Cholinergic Drugs
The drug increases intestinal and bladder motility, which serve as its therapeutic action in atony of either organ. It is placed topically in the eye, it produces miosis and spasm of accommodation, as well as a lowering of intraocular pressure. it is used to treat glaucoma, but pilocarpine is more effective. Physostigmine is also used in the treatment of overdose of drugs with anticholinergic actions, such as atropine, phenothiazines, and tricyclic antidepressants. Echothiophate is an organophosphate that covalently binds via its phosphate group to the serine-OH group at the active site of acetylcholinesterase. The loss of an alkyl group, which is called aging, makes it impossible for chemical reactivators, such as pralidoxime, to break the bond between the remaining drug and the enzyme. Echothiopate produces intense miosis and, thus has found therapeutic use.
Atropine, the prototype drug of this class, is a highly selective blocking agent for pre and post muscarinic receptors, but some of its synthetic derivatives have significant nicotinic blocking property as well. Antimuscarinic drugs block the muscarinic receptors, which can be reversed by increasing the concentration of muscarinic agonist. Most clinically available muscarinic antagonists are nonselective, and their actions differ little from those of atropin. No sub type selective antagonist, including pirenzepine, is completely selective. In fact, the clinical efficacy of some agents may arise from a balance of antagonistic actions on two or more receptor subtypes.