2010A07 Briefly describe the pharmacological role of the nicotinic cholinergic receptor.

Definition

·   Acetylcholine receptor with affinity for nicotine

Structure

·   Pentameric ligand-gated ion channel

·   Non-specific central ion channel (Na⁺ = K⁺ > Ca²⁺)

·   Muscle type: ααβδε adult, ααβγδ foetal or extrajunctional, α₃β₂ pre-junctional

·   Ganglionic type: α₃β₄   i.e. (α₄)₃(β₂)₂

·   Brain type: α₄β₂

·   Hence differences in drug action

Activation

·   1 x ACh bound to each a-subunit

·   Depolarisation -> mini-endplate potential

·   Spatial and temporal summation -> action potential

Post-junctional

·   Depolarising: suxamethonium -> fasciculation then paralysis (note plasma K ↑0.5mM)

·   Non-depolarising: e.g. rocuronium (competitive antagonist) also volatiles, aminoglycosides, quinidine

·   Desensitisation (big dose suxamethonium, volatile, barbiturate, local anaesthetic)

Pre-junctional

·   Antagonised by non-depolarisers (e.g. rocuronium)

·   Hence train-of-four ratio <0.3, fade, post-tetanic potentiation

Extra-junctional

·   Foetal type. Longer channel opening, ↑ion flux.

·   Proliferates after denervation

·   Suxamethonium -> dangerous ↑[K⁺]

Autonomic ganglia

·   SNS, PSNS, adrenal medulla (modified SNS)

·   Agonist: nicotine

·   Antagonist: trimetaphan (BP lowering), d-tubocurarine (NM blocker)

Brain

·   Important in ascending reticular activating system (ARAS)

·   Drugs must cross blood-brain barrier i.e. lipid soluble

·   Agonist: nicotine -> stimulation (note addictive)

·   Antagonist: volatile anaesthetic -> sedation, hypnosis, ketamine