CHOL Module 2 Infographic — Muscarinic Agonists and Acetylcholinesterase Inhibitors

Section 1 · Direct-Acting Muscarinic Agonists

Mechanism

Bind and activate muscarinic receptors directly — no dependence on acetylcholine release or acetylcholinesterase inhibition. Modified to resist enzymatic hydrolysis. Quaternary compounds carry a permanent positive charge: no blood-brain barrier crossing, no central nervous system effects. Tertiary amines cross membranes: central nervous system penetration possible.

Quaternary

Bethanechol

Use: non-obstructive urinary retention; neurogenic bladder
No nicotinic activity; no central nervous system effects
Avoid: obstruction, asthma, peptic ulcer disease

Tertiary

Pilocarpine

Uses: open-angle glaucoma; acute angle-closure glaucoma; xerostomia (Sjogren, radiation)
Crosses blood-brain barrier
Adverse effect: diaphoresis

Quaternary

Carbachol

Muscarinic and nicotinic activity
Use: intraocular miosis during cataract surgery; second-line glaucoma

Quaternary

Methacholine

Diagnostic only
Use: bronchoprovocation challenge for airway hyperresponsiveness in suspected asthma
No therapeutic role

Tertiary

Cevimeline

Muscarinic subtype 1 and subtype 3 selective
Use: Sjogren xerostomia
Longer duration than pilocarpine; less diaphoresis

Sections 2–4 · Acetylcholinesterase Inhibitors — Mechanism

Core Mechanism

Block acetylcholinesterase → acetylcholine accumulates at every cholinergic synapse → amplified and prolonged muscarinic and nicotinic effects. Quaternary agents (neostigmine, pyridostigmine, edrophonium): no blood-brain barrier crossing; peripheral effects only. Tertiary agents (physostigmine, donepezil, rivastigmine, galantamine): cross blood-brain barrier; central nervous system effects.

Inhibition Type 1

Carbamylation

Neostigmine, pyridostigmine, physostigmine, rivastigmine
Drug transfers a carbamyl group to acetylcholinesterase active site
Enzyme blocked for minutes to hours before regeneration
Called "reversible" — enzyme eventually recovers

Inhibition Type 2

Ionic Binding

Edrophonium only
Non-covalent electrostatic binding to active site
No covalent bond formed — effects resolve within minutes
Ultrashort duration → diagnostic use only

Section 2 · Peripheral Acetylcholinesterase Inhibitors

Drug	Duration	Primary Uses	Key Point
Neostigmine	Moderate (hours)	Myasthenia gravis; neuromuscular blockade reversal; Ogilvie syndrome	Co-administer glycopyrrolate for neuromuscular blockade reversal to block muscarinic adverse effects; poor oral absorption
Pyridostigmine	Longer than neostigmine	Myasthenia gravis (preferred oral long-term agent)	Sustained-release formulation for overnight dosing; dose-limiting adverse effects are muscarinic (cramping, diarrhea)
Edrophonium	Minutes only (ionic binding)	Diagnostic test for myasthenia gravis	Ultrashort duration is the feature that makes it diagnostically useful; atropine must be on hand during test

Section 3 · Myasthenic Crisis vs. Cholinergic Crisis

Too little drug / disease progression

Myasthenic Crisis

Worsening weakness, bulbar and respiratory
Secretions normal or minimal
Heart rate normal or elevated
Pupils normal
No gastrointestinal symptoms
Treatment: respiratory support; plasma exchange or intravenous immunoglobulin; resume drug when stable

Too much drug / excess acetylcholine

Cholinergic Crisis

Worsening weakness (depolarizing block)
Copious secretions — bronchorrhea, hypersalivation
Bradycardia
Miosis
Diaphoresis; gastrointestinal cramping and diarrhea
Treatment: hold all acetylcholinesterase inhibitors; atropine for muscarinic symptoms

Section 4 · Central Nervous System Acetylcholinesterase Inhibitors

Toxicology Use

Physostigmine

Tertiary amine — crosses blood-brain barrier
Reverses central nervous system anticholinergic toxidrome (delirium, agitation, hallucinations)
Short duration; may need repeated dosing
Contraindicated in tricyclic antidepressant overdose (risk of seizures and fatal arrhythmia due to cardiac sodium channel blockade)

Alzheimer Disease

Class Properties

Target: cholinergic deficit in basal forebrain projection to cortex and hippocampus
Modest symptomatic benefit only — no disease modification
Class adverse effects: nausea, diarrhea (muscarinic), bradycardia at high doses

Alzheimer Agent

Donepezil

Acetylcholinesterase-selective
Once-daily dosing (long duration of action)
Cytochrome P450 2D6 and 3A4 substrate — interaction risk with inhibitors
Bedtime dosing reduces gastrointestinal adverse effects

Alzheimer Agent

Rivastigmine

Acetylcholinesterase and butyrylcholinesterase inhibitor
No cytochrome P450 metabolism — preferred in high-polypharmacy patients
Transdermal patch reduces gastrointestinal adverse effects
Also approved for Parkinson disease dementia

Alzheimer Agent

Galantamine

Acetylcholinesterase inhibitor + nicotinic receptor allosteric modulator
Allosteric modulation enhances nicotinic receptor response to endogenous acetylcholine
Cytochrome P450 2D6 and 3A4 substrate — same interaction risk as donepezil

Section 5 · Drug Interactions — Three Categories

Category 1

Cytochrome P450 Pharmacokinetics

Donepezil and galantamine: cytochrome P450 2D6 and 3A4 substrates
Inhibitors (fluoxetine, azole antifungals, clarithromycin): raise levels → more cholinergic toxicity
Inducers (rifampin, carbamazepine): lower levels → reduced efficacy
Rivastigmine avoids this category — no cytochrome P450 metabolism

Category 2

Additive Bradycardia

Digoxin + acetylcholinesterase inhibitor: additive slowing of sinoatrial node through muscarinic subtype 2 receptors → monitor heart rate
Beta-blockers + acetylcholinesterase inhibitor: additive bradycardia
Risk greatest in elderly patients and those with reduced cardiac reserve

Category 3

Pharmacodynamic Antagonism

Anticholinergic drugs directly oppose acetylcholinesterase inhibitors for Alzheimer disease
Offenders: diphenhydramine, oxybutynin, tolterodine, tricyclic antidepressants, certain antipsychotics
Review and discontinue anticholinergic drugs when acetylcholinesterase inhibitor therapy begins