2010B05 Describe the pharmacodynamic effects and clinical uses of anticholinesterase drugs.

Dynamic effects

1. Reversible hydrostatic attraction: edrophonium

2. Reversible carbamylate complex: -stigmine

3. Irreversible covalent bond: organophosphates

Clinical use

·   Reverse non-depolarising relaxant e.g. atracurium

·   Treat central anticholinergic syndrome (not quaternary amines)

·   Myasthaenia gravis

·   Bladder atonia

·   Pseudo-obstruction

·   Glaucoma

Muscle type

·   ↑[ACh] -> ↑Na⁺ influx > K⁺ efflux = Ca²⁺ influx -> end-plate potential ± action potential -> contraction

·   Displace and reverse non-depolarising relaxant

o Starting TOF count 3-4: adequate reversal

o Starting TOF count 1-2: inadequate

·   Augment and prolong depolarizing relaxant (↑ACh at NMJ, also inhibits PChE!)

·   Weakness if high dose (ceiling 0.07mg/kg)

Neuronal type

·   Autonomic ganglia (α₃β₄): stimulation then depression (see BJA-Ed)

·   Brain (α₄β₂): nil (quaternary amine, doesn’t cross BBB)

PSNS post-ganglionic

·   Receptor effects:

o M_1,3,5: G_q GPCR (↑IP₃/↑Ca²⁺, ↑DAG)

o M_2,4: Gi GPCR (↓cAMP)

·   Physiological effects:

o Bradycardia, AV block, ↓cardiac output (cardiac plexus M₂).

o Constriction of airway smooth muscle -> obstruction (airway smooth muscle M₃)

o ↑Tracheobronchial secretion -> cough, aspiration (M₃)

o ↑Salivation (M₃)

o ↑Lacrimation (M₃)

o ↑Ureteric peristalsis -> urination (treats bladder atony)

o ↑GIT peristalsis -> defecation, nausea/vomiting, abdo pain; treats pseudo-obstruction

·   CNS effects (non-quaternary amines)

o Treat anticholinergic toxicity

o Cause cholinergic toxicity (confusion, headache, seizure)

o Constriction of pupillary sphincter -> miosis (treats glaucoma) (M3)

SNS post-ganglionic

·   ↑Sweating

·   ↑Skin vasodilatation

·   ↑Skeletal muscle vasodilatation