Introduction to Medical Pharmacology  ·  Chapter 6  ·  Module 1
Cholinergic Receptors and Acetylcholine Neurotransmission
Synthesis, storage, release, receptor pharmacology, and autonomic balance — visual summary
Section 1
The Cholinergic Cycle — Synthesis to Termination
Choline uptake
rate-limiting step
→
Choline acetyltransferase
synthesis
→
Vesicular storage
→
Ca²+-triggered exocytosis
→
Receptor activation
→
Acetylcholinesterase hydrolysis
choline recycled
Presynaptic block
Botulinum Toxin
  • Cleaves proteins required for vesicle fusion
  • Blocks acetylcholine release
  • Flaccid paralysis at neuromuscular junction
  • Therapeutic: spasticity, dystonia, hyperhidrosis, overactive bladder
Synaptic cleft
Acetylcholinesterase Inhibitors
  • Block hydrolysis of acetylcholine
  • Amplify and prolong all cholinergic signals
  • Therapeutic: Alzheimer disease, myasthenia gravis, reversal of neuromuscular blockade
  • Toxic: organophosphate poisoning
Butyrylcholinesterase
Plasma enzyme synthesized by the liver. Metabolizes succinylcholine. Genetic variant → prolonged neuromuscular blockade. No role in synaptic neurotransmission.
Section 2
Muscarinic Receptor Subtypes — Gq (odd) and Gi (even)
M1 — Gq
Cortex & Ganglia
  • Cognition; memory
  • Ganglionic modulation
  • Blockade → delirium
  • Target: benztropine
M2 — Gi
Heart
  • Sinoatrial node, atrioventricular node
  • Vagal slowing of heart rate
  • Atropine → tachycardia
  • Atropine for bradycardia
M3 — Gq
Smooth Muscle & Glands
  • Bladder detrusor contraction
  • Bronchoconstriction
  • Miosis; accommodation
  • Salivation; sweating
M4 — Gi
Striatum
  • Dopaminergic modulation
  • Movement control
  • Target: Parkinson disease tremor drugs
Selective Muscarinic Antagonists
M3 bladder: darifenacin, solifenacin (overactive bladder)  ·  M3 airway: ipratropium, tiotropium (chronic obstructive pulmonary disease, asthma)  ·  M1/M4 central nervous system: benztropine, trihexyphenidyl (Parkinson disease tremor)  ·  Non-selective: atropine, scopolamine (all five subtypes → full anticholinergic syndrome)
Section 3
Nicotinic Receptor Subtypes — Ligand-Gated Ion Channels
N-M — Neuromuscular junction
Muscle-Type Receptor
  • Non-depolarizing block (rocuronium, vecuronium): competitive antagonism; reversed by acetylcholinesterase inhibitors
  • Depolarizing block (succinylcholine): activates then desensitizes; not reversed by acetylcholinesterase inhibitors
  • Myasthenia gravis: autoimmune destruction of N-M receptors → fatigable weakness
N-N — Autonomic ganglia
Neuronal-Type Receptor
  • Both sympathetic and parasympathetic ganglia
  • Hexamethonium, trimethaphan block all ganglia simultaneously
  • Result: orthostatic hypotension, tachycardia, mydriasis, dry mouth, urinary retention
  • Abandoned as antihypertensives
Alpha4-beta2 — Central nervous system
Brain Nicotinic Receptor
  • Primary site of nicotine action in brain
  • Dopamine release in reward pathways
  • Varenicline: partial agonist → reduces craving and blocks nicotine reward
Section 4
Two Mirror-Image Clinical Syndromes
Cholinergic excess
SLUDGE Toxidrome

Salivation · Lacrimation · Urination
Defecation · Gastrointestinal distress · Emesis

  • Bradycardia, bronchospasm, bronchorrhea
  • Neuromuscular junction: fasciculations → flaccid paralysis
  • Central nervous system: seizures, loss of consciousness
  • Cause: acetylcholinesterase inhibitor toxicity, organophosphate poisoning
  • Treatment: atropine; pralidoxime (if given early)
Cholinergic deficit
Anticholinergic Syndrome

Hot as a hare · Dry as a bone
Red as a beet · Blind as a bat · Mad as a hatter

  • Hyperthermia from anhidrosis
  • Dry mouth, dry skin
  • Mydriasis, cycloplegia
  • Tachycardia, urinary retention, constipation
  • Confusion and delirium (central nervous system penetrating agents)
  • Risk: highest in elderly patients
Section 5
Cholinergic Imbalance in Three Disease States
Disease
Alzheimer Disease
  • Loss of basal forebrain cholinergic neurons
  • Deficit in cortex and hippocampus
  • Correlates with cognitive decline
  • Treatment: acetylcholinesterase inhibitors (donepezil, rivastigmine, galantamine)
Disease
Parkinson Disease
  • Loss of dopaminergic neurons in substantia nigra
  • Relative cholinergic excess in striatum
  • Contributes to tremor and rigidity
  • Treatment: muscarinic antagonists (benztropine, trihexyphenidyl) restore dopaminergic-cholinergic balance
Disease
Myasthenia Gravis
  • Autoimmune destruction of N-M nicotinic receptors
  • Reduced safety margin at neuromuscular junction
  • Fatigable weakness that worsens with use
  • Treatment: acetylcholinesterase inhibitors (neostigmine, pyridostigmine)

Introduction to Medical Pharmacology  ·  Chapter 6  ·  Module 1 Visual Summary