PharmacologyTier 1Medical Sciences concept

Botulinum toxin mechanism (presynaptic SNARE cleavage, NMJ)

Core concept

Presynaptic toxin at the neuromuscular junction (and autonomic cholinergic synapses)
Cleaves SNARE proteins (SNAP-25, syntaxin, or VAMP/synaptobrevin depending on serotype) required for ACh vesicle docking/fusion
-> blocks ACh release -> flaccid paralysis (contrast tetanus toxin, which blocks inhibitory neurotransmitter release centrally -> spastic paralysis)

Serotype A (most clinically used, e.g. Botox) cleaves SNAP-25; serotype B cleaves VAMP -- different SNARE targets, same functional outcome
Onset over days (axonal sprouting eventually restores function over ~3 months) -- not immediate like a depolarising blocker
Food-borne botulism: descending flaccid paralysis, starts with cranial nerves (diplopia, dysarthria, dysphagia) then descends -- pupils may be fixed/dilated (autonomic cholinergic block too)

Therapeutic uses exploit the reversible, localised chemodenervation: dystonia, spasticity, chronic migraine, hyperhidrosis, achalasia (LOS injection), overactive bladder
Treatment of botulism: antitoxin (binds unbound circulating toxin only -- does not reverse toxin already bound intracellularly) + supportive/ventilatory care while recovery occurs via new synapse formation
Trap: antitoxin does not speed clinical recovery once toxin has entered the nerve terminal -- recovery is by axonal sprouting over months, not reversal

Contrast with tetanus toxin: retrograde axonal transport to CNS -> blocks glycine/GABA release from inhibitory interneurons -> spastic paralysis, trismus, opisthotonus
Contrast with organophosphates: block acetylcholinesterase (excess ACh, cholinergic crisis) -- opposite direction (too much ACh vs none)
Contrast with myasthenia gravis (postsynaptic ACh receptor antibodies) and Lambert-Eaton (presynaptic VGCC antibodies, dec ACh release) -- botulinum toxin mimics Lambert-Eaton's presynaptic release defect but via direct enzymatic cleavage, not antibody

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