Muscarinic cholinergic receptor agonists can be divided into two groups: (1) ACh and several synthetic choline esters, and (2) the naturally occurring cholinomimetic alkaloids (particularly pilocarpine, muscarine, and arecoline) and their synthetic congeners. The structures and pharmacologic properties of a congeneric series are summarized by Table 7-1 and Figure 7-1.
Methacholine (acetyl-8-methylcholine) differs from ACh chiefly in its greater duration and selectivity of action. Its action is more prolonged because the added methyl group increases its resistance to hydrolysis by cholinesterases. Carbachol and bethanechol, unsubstituted carbamoyl esters, are completely resistant to hydrolysis by cholinesterases and thus survive long enough to be distributed to areas of low blood flow. Carbachol retains substantial nicotinic activity, particularly on autonomic ganglia; both its peripheral and its ganglionic actions are probably due, in part, to the release of endogenous ACh from the terminals of cholinergic fibers.
Of the three major natural plant alkaloids, muscarine acts almost exclusively at muscarinic receptor sites, arecoline also acts at nicotinic receptors, and pilocarpine has a dominant muscarinic action but causes anomalous cardiovascular responses (the sweat glands are particularly sensitive to this drug). Although these naturally occurring alkaloids are valuable as pharmacological tools, present clinical use is restricted largely to pilocarpine as a sialagogue and miotic agent (see Chapter 63).
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