2013C04 Describe how suxamethonium and non-depolarising neuromuscular blocking agents
produce their adverse cardiovascular effects.

 

List: “two Hs, three As”

·     Hyperkalaemia

·     Histamine release

·     Anaphylaxis

·     Arrhythmia

·     Autonomic ganglion blockade

 

Hyperkalaemia:

Pathophysiology

·  Suxamethonium NMJ nAChR agonism -> Na+ influx, K+ efflux -> plasma K+ ↑0.5mM

·  Denervation -> ↑↑extra-junctional receptors (γ-ε substitution)-> ↑ duration of opening -> ↑K+ release

·  e.g. burns, new spinal cord injury

·  Highest risk 1-10 weeks after insult

ECG findings

·  ECG Tall tented T waves, small/absent P waves, wide QRS, sine wave, asystole

Treatment

·  Stabilize the sarcolemma: calcium gluconate

·  Lower [K+]: insulin/glucose, salbutamol, frusemide etc

 

Histamine release:

Pathophysiology

·  Direct effect on mast cells. Non-IgE mediated

·  Degranulation of mast cells

·  H1 (Gq):

o  Vasodilatation, capillary leak, ↓mAP

o  ↓AV node conduction, coronary vasoconstriction

o  Bronchoconstriction

·  H2 (Gs):

o  ↑contractility, coronary vasodilatation

o  Bronchodilatation

o  Prevention: antihistamine, slower injection

·  ↓Severity with repeat doses due to depletion of mast cells

Culprits

·  d-Tubocurarine > mivacurium, atracurium

Structure-activity relationship

·  ↑Methoxy groups = ↑potency, ↓histamine release

·  e.g. mivacurium 2, atracurium 4, doxacurium 6

 

Anaphylaxis:

Pathophysiology

·  Histamine release, IgE-mediated

·  1st exposure: antigen presented to TH cell -> B cell produces IgE -> fixes on mast cells

·  2nd exposure: systemic degranulation, vasodilatation, capillary leak, angioedema, bronchospasm

·  Muscle relaxant-induced anaphylaxis is often severe and life-threatening

Culprits

·  ~1/2000 suxamethonium

·  ~1/2500 rocuronium

Structure-activity relationship

·  Due to quaternary NH4+ compound

·  ? Cross reaction pholcodine and rocuronium

 

Arrhythmia:

Suxamethonium

·  Agonist at m2AChR

·  Esp sinus bradycardia, AV block, asystole

·  Due to affinity for cardiac mAChR

·  Risk factors: big dose >2mg/kg, young children, AV node pathology

·  Rx: atropine

Aminosteroids

·  Vecuronium: agonist at m2AChR -> ↓HR (rare)

·  Pancuronium: antagonist at m2AChR -> ↑HR (common)

·  Rocuronium: minimal effect

 

Autonomic ganglion blockade:

Culprit

·  d-tubocurarine

Structure-activity relationship

·  ↑Risk if short interonium distance

Pathophysiology

·  ↓SNS and ↓PSNS ganglionic activity

·  Often ↓HR, ↓mAP