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Chapter 7: Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs

INTRODUCTION

Drugs with acetylcholine-like effects (cholinomimetics) consist of 2 major subgroups on the basis of their mode of action (ie, whether they act directly at the acetylcholine receptor or indirectly through inhibition of cholinesterase). Drugs in the direct-acting subgroup are further subdivided on the basis of their spectrum of action (ie, whether they act on muscarinic or nicotinic cholinoceptors).

Acetylcholine may be considered the prototype that acts directly at both muscarinic and nicotinic receptors. Neostigmine is a prototype for the indirect-acting cholinesterase inhibitors.

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DIRECT-ACTING CHOLINOMIMETIC AGONISTS

This class comprises a group of choline esters (acetylcholine, methacholine, carbachol, bethanechol) and a second group of naturally occurring alkaloids (muscarine, pilocarpine, nicotine, lobeline). Newer drugs are occasionally introduced for special applications, eg, the neonicotinoids clothianidin, imidacloprid, and others as insecticides. The members differ in their spectrum of action (amount of muscarinic versus nicotinic stimulation) and in their pharmacokinetics (Table 7–1). Both factors influence their clinical use.

TABLE 7–1Some cholinomimetics: spectrum of action and pharmacokinetics.
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TABLE 7–1 Some cholinomimetics: spectrum of action and pharmacokinetics.
Drug Spectrum of Actiona Pharmacokinetic Features
Direct-acting    
 Acetylcholine B Rapidly hydrolyzed by cholinesterase (ChE); duration of action 5–30 s; poor lipid solubility
 Bethanechol M Resistant to ChE; orally active, poor lipid solubility; duration of action 30 min to 2 h
 Carbachol B Like bethanechol
 Pilocarpine M Not an ester, good lipid solubility; duration of action 30 min to 2 h

 Nicotine

N

Not an ester; duration of action 1–6 h; high lipid solubility

 Neonicotinoids

N

Insecticides with largely nicotinic action; implicated in bee colony collapse
 Varenicline N Partial agonist at N receptors, high lipid solubility; duration 12–24 h
Indirect-acting    
 Edrophonium B Alcohol, quaternary amine, poor lipid solubility, not orally active; duration of action 5–15 min
 Neostigmine B Carbamate, quaternary amine, poor lipid solubility, orally active; duration of action 30 min to 2 h or more
 Physostigmine B Carbamate, tertiary amine, good lipid solubility, orally active; duration of action 30 min to 2 h
 Pyridostigmine B Carbamate, like neostigmine, but longer duration of action (4–8 h)
 Echothiophate B Organophosphate, moderate lipid solubility; duration of action 2–7 days
 Parathion B Organophosphate, high lipid solubility; duration of action 7–30 days; insecticide
 Sarin B Organophosphate, very high lipid solubility, nerve gas

aB, both M and N; M, muscarinic; N, nicotinic.

A. Classification

Muscarinic agonists are parasympathomimetic; that is, they mimic the actions of parasympathetic nerve stimulation in addition to other effects. Five subgroups of muscarinic receptors have been identified (Table 7–2), but the muscarinic agonists available for clinical use activate them nonselectively. Nicotinic agonists act on both ganglionic and neuromuscular cholinoceptors; agonist selectivity is limited. On the other hand, slightly selective muscarinic antagonists and relatively selective nicotinic receptor antagonists are available (Chapter 8).

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