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

 

List:

·     Intro: types of interaction and clinical uses

·     Nicotinic effects

·     Muscarinic effects

 

Intro:

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

 

Nicotinic effects:

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)

 

Muscarinic effects:

PSNS post-ganglionic

·  Receptor effects:

o M1,3,5: Gq GPCR (↑IP3/↑Ca2+, ↑DAG)

o M2,4: 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