STEPTRACKERPHARMACOLOGY | AUTONOMIC | HIGH-YIELD REVIEW

Cholinergic Agonists & Cholinesterase Inhibitors

Drugs that boost acetylcholine either sit on the receptor themselves (direct) or stop its breakdown (indirect) — the indication follows from where the extra ACh acts.

FOCUS ON

Direct muscarinic agonists: bethanechol (urinary retention, postoperative ileus; resists AChE), carbachol and pilocarpine (glaucoma, miosis; pilocarpine also for Sjögren dry mouth and a sweat test), methacholine (bronchoprovocation test for asthma). Cholinesterase inhibitors: neostigmine (quaternary, no CNS: myasthenia, reversal of nondepolarizing NM block, urinary retention), pyridostigmine (myasthenia maintenance), edrophonium (short; historical myasthenia test), physostigmine (tertiary, crosses BBB: anticholinergic toxicity), donepezil, rivastigmine, galantamine (Alzheimer). Toxicity = cholinergic excess: diarrhea, urination, miosis, bronchospasm, bradycardia, emesis, lacrimation, sweating, salivation. Give a muscarinic antagonist (glycopyrrolate) with neostigmine to block muscarinic side effects.

DRUG

MECHANISM · FEATURE

USE

NOTES · ADVERSE

Bethanechol

Direct M agonist; not broken down by AChE; no nicotinic action

Postoperative/neurogenic urinary retention, ileus

Activates bowel and bladder smooth muscle

Carbachol

Direct M + N agonist

Glaucoma, intraoperative miosis

Contracts ciliary muscle → opens trabecular meshwork

Pilocarpine

Direct M agonist, tertiary

Acute angle-closure glaucoma, xerostomia (Sjögren), sweat chloride test stimulus

Potent stimulator of sweat, tears, saliva

Methacholine

Direct M agonist (M3 airway)

Bronchial challenge test

Exaggerated bronchoconstriction = airway hyperreactivity (asthma)

Neostigmine

Reversible AChE inhibitor, quaternary (no CNS entry)

Reversal of nondepolarizing blockade, myasthenia, urinary retention, ileus

Give with glycopyrrolate or atropine

Pyridostigmine

Reversible AChE inhibitor, quaternary, longer acting

Myasthenia gravis maintenance

Doesn't treat the autoimmune process (add steroids, thymectomy)

Edrophonium

Very short-acting AChE inhibitor

Historic myasthenia test; myasthenic vs cholinergic crisis

Largely replaced by antibody testing

Physostigmine

Reversible AChE inhibitor, tertiary (crosses BBB)

Anticholinergic toxicity (atropine, jimsonweed, diphenhydramine)

Avoid in TCA overdose (seizures, asystole)

Donepezil · rivastigmine · galantamine

Centrally acting AChE inhibitors

Alzheimer disease (mild–moderate); rivastigmine also Parkinson dementia

Nausea, diarrhea, bradycardia, vivid dreams

Echothiophate

Irreversible (organophosphate) AChE inhibitor

Glaucoma (rare)

Cataracts with long use

Cholinergic toxicity

Muscarinic: secretions, bradycardia, miosis, bronchospasm · nicotinic: fasciculations, weakness

—

Atropine (muscarinic) ± pralidoxime (organophosphates)

Cautions

Excess ACh worsens

—

Asthma/COPD, peptic ulcer, bradycardia, bowel or bladder obstruction

Mechanism — two ways to more ACh

Direct agonistBinds M receptor itself

→

Works without nerve inputBethanechol, pilocarpine

AChE inhibitorACh lingers in synapse

→

Needs intact releaseActs at M and N (incl. NMJ)

Where each drug reaches

DRUG

CNS?

KEY USE

Neostigmine

No (quaternary)

Reverse NM block

Pyridostigmine

Myasthenia

Physostigmine

Yes (tertiary)

Anticholinergic delirium

Donepezil

Yes

Alzheimer

How it's tested

COMMON CONFUSIONWeakness in a treated myasthenic may be undertreatment (myasthenic crisis) or overdose (cholinergic crisis — with miosis, salivation, fasciculations); secure the airway first.

THE TRAPNeostigmine can't fix delirium (no CNS entry) — central anticholinergic toxicity needs physostigmine.

YOUR APPROACHOrgan to stimulate → direct agonist (smooth muscle, glands) or AChE inhibitor (needs nicotinic/NMJ or CNS action) → CNS penetration.

If you see… think…

Postoperative urinary retention, no obstruction → bethanechol

Positive bronchoprovocation test → methacholine (asthma)

Dry mouth in Sjögren syndrome → pilocarpine or cevimeline

Reversal of rocuronium (with glycopyrrolate) → neostigmine

Agitated, hot, dry, flushed patient after jimsonweed → physostigmine

Myasthenia gravis maintenance → pyridostigmine

Alzheimer drug causing bradycardia → AChE inhibitor (donepezil)

Acute angle-closure glaucoma constriction drug → pilocarpine

Diarrhea, sweating, miosis, bradycardia → cholinergic excess

Quaternary amine → doesn't cross the BBB