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Cholinergic and Anticholinergic Pharmacology

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Cholinergic and Anticholinergic Pharmacology — Key Facts for FMGE Core concept: Acetylcholine acts at muscarinic and nicotinic receptors; muscarinic antagonists (anticholinergics) block parasympathetic effects High-yield point: Atropine is the prototype anticholinergic; know its uses and side effects ⚡ Exam tip: Anticholinergic toxicity (dry as a bone, red as a beet, hot as a hare, mad as a hatter, blind as a bat) is a classic FMGE scenario

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Cholinergic and Anticholinergic Pharmacology — FMGE Study Guide

Cholinergic Neurotransmission

Acetylcholine Synthesis and Release

Synthesis:

  • Choline + Acetyl-CoA → Acetylcholine (ACh)
  • Enzyme: Choline acetyltransferase (ChAT)
  • Occurs in presynaptic nerve terminal (cytoplasm)

Storage:

  • Packaged into synaptic vesicles (100-300 molecules per vesicle)
  • Vesamicol blocks vesicular ACh transporter

Release:

  • Depolarization → Ca²⁺ influx → vesicle fusion with presynaptic membrane
  • SNARE proteins (synaptobrevin, SNAP-25, syntaxin) mediate vesicle fusion
  • Botulinum toxin blocks presynaptic ACh release (used for muscle spasm, wrinkles)

Receptors:

  • Muscarinic (GPCR): M1, M2, M3, M4, M5
  • Nicotinic (Ligand-gated ion channel): Nm (skeletal muscle), Nn (autonomic ganglia, CNS)

Acetylcholinesterase (AChE)

  • Terminates ACh action by hydrolysis
  • AChE located on postsynaptic membrane
  • Hydrolyzes ACh to choline + acetate (takes ~1 millisecond)
  • Irreversible inhibitors: Organophosphates, nerve agents (sarin, VX) - phosphorylate serine OH group → aging → irreversible
  • Reversible inhibitors: Physostigmine, neostigmine (carbamylate serine residue)

Cholinergic Receptors

Muscarinic receptors:

  • M1 (Gq): CNS, gastric parietal cells, autonomic ganglia
  • M2 (Gi): Heart (↓heart rate, ↓conductivity); autoreceptors on presynaptic terminals
  • M3 (Gq): Smooth muscle (bronchoconstriction, GI motility, bladder contraction), glands (salivation, lacrimation), vascular endothelium (NO-mediated vasodilation)
  • M4, M5: CNS

Nicotinic receptors:

  • Nm (M1): Skeletal muscle end-plate; blocked by non-depolarizing agents
  • Nn (M2): Autonomic ganglia (sympathetic and parasympathetic); blocked by ganglion blockers
  • CNS nicotinic: Involved in cognition, addiction

Cholinergic Agonists

Direct-Acting Cholinergic Drugs

Acetylcholine:

  • Non-selective; rapidly hydrolyzed by AChE
  • Used only in ophthalmology (miosis in cataract surgery)

Choline esters:

  • Bethanechol: Selective for bladder and GI tract (M3); used for urinary retention, gastroparesis
  • Methacholine: M1 and M3 agonist; used in bronchial challenge testing for asthma diagnosis

Alkaloids:

  • Pilocarpine: Non-selective muscarinic agonist; used for glaucoma (opens trabecular meshwork → ↓IOP) and xerostomia
  • Muscarine: Found in poisonous mushrooms; activates M1, M2, M3
  • Arecoline: Active principle in betel nut; partial agonist at muscarinic and nicotinic receptors

Indirect-Acting Cholinesterase Inhibitors

Reversible:

  • Short acting: Edrophonium (ultra-short; used for myasthenia gravis diagnosis)
  • Intermediate: Neostigmine, physostigmine, pyridostigmine, donepezil, rivastigmine, galantamine
  • Long acting: Tacrine (hepatoxic, rarely used), donepezil (Alzheimer disease), galantamine (Alzheimer)

Uses of cholinesterase inhibitors:

  • Myasthenia gravis: Neostigmine, pyridostigmine (improves muscle strength by increasing ACh at Nm receptors)
  • Anticholinergic toxicity: Physostigmine (crosses BBB, unlike neostigmine)
  • Glaucoma: Echothiophate (irreversible)
  • Alzheimer disease: Donepezil, rivastigmine, galantamine (↑ACh in brain)
  • Reversal of neuromuscular blockade: Neostigmine (with glycopyrrolate to prevent bradycardia)
  • Atropine poisoning: Physostigmine (antidote)

Irreversible Cholinesterase Inhibitors (Organophosphates)

Agents: Sarin, VX, tabun, soman (nerve agents); malathion, parathion (insecticides) Mechanism: Phosphorylate serine OH on AChE → irreversible (hours to days unless treated immediately) Aging: Dealkylation over minutes to hours → truly irreversible

Toxicity (Cholinergic crisis):

  • Muscarinic effects (SLUDGE or DUMBBELSS):
    • Salivation, Lacrimation, Urination, Defecation, GI distress, Emesis
    • Diarrhea, Urination, Miosis, Bradycardia, Bronchospasm, Bronchorrhea, Emesis, Lacrimation, Salivation
  • Nicotinic effects: Muscle fasciculations, weakness, paralysis (depolarizing block)
  • CNS effects: Confusion, seizures, respiratory depression

Antidotes:

  • Atropine (muscarinic antagonist): Blocks excessive parasympathetic stimulation
  • Pralidoxime (2-PAM) (cholinesterase reactivator): Must be given before aging occurs; removes phosphate group from AChE

Anticholinergic (Muscarinic Antagonist) Drugs

Mechanism

Competitive antagonist at muscarinic receptors; blocks ACh from binding

Prototype: Atropine

Pharmacokinetics:

  • Alkaloid from Atropa belladonna (deadly nightshade)
  • Crosses BBB → causes CNS effects
  • Topical ophthalmic use causes mydriasis and cycloplegia

Effects (by dose):

  • Low dose: ↓salivation, ↓lacrimation (sweating NOT affected - eccrine sweat glands use sympathetic muscarinic)
  • Moderate: Mydriasis, cycloplegia, ↑heart rate (blocks M2 on SA node)
  • High: Hyperthermia (↓sweating), urinary retention, constipation, confusion, delirium

Atropine in eye:

  • Blocks M3 in iris sphincter → mydriasis (pupil dilation)
  • Blocks M3 in ciliary muscle → cycloplegia (loss of accommodation)
  • Contraindicated in narrow-angle glaucoma

Other Antimuscarinics

Short-acting (bronchodilators for asthma/COPD):

  • Ipratropium: Inhaled; COPD, asthma; less systemic effects
  • Tiotropium: Long-acting inhaled; COPD

For motion sickness:

  • Scopolamine: Also has anti-nausea and amnestic effects; patch behind ear

For Parkinsonism:

  • Trihexyphenidyl (Artane), Benztropine: Crosses BBB; reduces extrapyramidal symptoms

For GI痉挛: Hyoscine (scopolamine), dicyclomine

For ophthalmology:

  • Tropicamide, Cyclopentolate: Shorter duration than atropine for fundus examination

Anticholinergic Toxicity

Classic mnemonic:

  • “Dry as a bone”: Anhidrosis (no sweating)
  • “Red as a beet”: Flushed skin (cutaneous vasodilation)
  • “Hot as a hare”: Hyperthermia
  • “Mad as a hatter”: Confusion, delirium, hallucinations
  • “Blind as a bat”: Mydriasis, cycloplegia (can’t see near)
  • “Full as a flask”: Urinary retention

Toxicity causes: Antihistamines, TCAs, antiparkinson agents, antispasmodics, atropine and related compounds, Jimson weed (Datura)

Treatment:

  • Stop offending agent
  • Physostigmine (acetylcholinesterase inhibitor) - specific antidote
  • Supportive care: Cooling blankets for hyperthermia, catheterization for urinary retention

Neuromuscular Blocking Agents

Non-Depolarizing Blockers (Competitive Antagonists at Nm)

Examples: Vecuronium, rocuronium, atracurium, cisatracurium, pancuronium Mechanism: Compete with ACh for Nm receptors; reversed by acetylcholinesterase inhibitors (neostigmine) Properties: Twitch response (single then tetanic fade); no fasciculations Uses: Surgical paralysis, intubation

Depolarizing Blockers

Succinylcholine (suxamethonium):

  • Mech: Binds Nm receptors → continuous depolarization → phase I block (initial fasciculations)
  • Phase II block: Prolonged depolarization → channel stays open → desensitization
  • Eliminated by: Pseudocholinesterase (not AChE); genetic deficiency → prolonged apnea
  • Side effects: Myalgia, hyperkalemia (potentially fatal in burns/trauma patients), malignant hyperthermia
  • Contraindicated: Burns, trauma, denervation (upregulated receptors → massive hyperkalemia)

Ganglionic Blockers

Examples: Mecamylamine, trimethaphan Mechanism: Block Nn receptors at autonomic ganglia → sympathetic and parasympathetic blockade Use: Rarely used clinically (excessive side effects); previously for hypertension Effects: ↓sympathetic tone (hypotension), ↓parasympathetic tone (dry mouth, constipation, urinary retention)

Clinical Applications Summary

DrugUse
PilocarpineGlaucoma, xerostomia
NeostigmineMyasthenia gravis, reversal of NMJ blockade
PhysostigmineAnticholinergic toxicity (crosses BBB)
AtropineBradycardia, ophthalmology, antispasmodic
ScopolamineMotion sickness
IpratropiumCOPD, asthma
SuccinylcholineIntubation, surgical paralysis

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