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

 

List:

·     Intro

·     Muscle type: pre, post, extra

·     Neuronal type: autonomic ganglia, brain

 

Intro:

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

 

Muscle type:

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+]

 

Neuronal type:

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