2016A Question 04
Discuss the potential adverse effects of non-depolarising muscle relaxants.
Examiner Report
68% of candidates achieved a pass in this question.
This question was best answered by presenting the adverse effects by class of drug. The following details were expected: Benzylisoquinolones
- Histamine release – atracurium versus cisatracurium, relationship to methoxy groups; clinical effects and degree of release
- Ganglion blockade
- Laudanosine production Aminosteroids
- Vagolysis – pancuronium versus vecuronium, bronchoconstriction and muscarinic receptors
- Anaphylaxis – rocuronium highest, quaternary ammonium ions and IgE, mechanisms of sensitization, cross reactivity
Additional marks were awarded for active metabolite accumulation, reduced mivacurium metabolism, effects of concurrent neuromuscular diseases, and use of H1 and H2 blockers to prevent histamine effects.
Marks were not awarded for descriptions of the mechanism of action at nicotinic receptors, use of reversal agents, racemic mixture details, and details of the anaphylaxis pathway. Common mistakes include confusion around vagolytic and vagotonic effects, lack of detail with simply listing and not discussing, and repetition of information.
Model Answer
Structure:
- General adverse effects
- Benzylisoquinolinium specific
- Aminosteroid specific
General Adverse Effects
| Adverse Effect | Description |
|---|---|
| Unsafe paralysis | - Can’t intubate, can’t oxygenate → Desaturation → Death - Absent airway reflexes → Aspiration |
| Inadequate reversal | - Risk: Distress, type 2 respiratory failure, aspiration - Risk factors: - Physiology: Hypothermia → ↓ Rate of enzymatic degradation - Pathology: Liver failure (↓ metabolism), renal failure (accumulation), PChE deficiency for mivacurium - Long acting drug: e.g. Pancuronium 60 mins - Active metabolites: e.g. 3-OH pancuronium 50% potency and long-lasting - Other drugs: e.g. Volatile, calcium channel blocker |
| Critical illness myopathy | - Prolonged paralysis in ICU → Disuse atrophy - Vecuronium and atracurium implicated |
Benzylisoquinolinium Adverse Effects
| Benzylisoquinolinium Adverse Effects | Description |
|---|---|
| Histamine release | - Direct effect on mast cells. Not immune mediated. - Drugs: D-Tubocurarine > mivacurium, atracurium >> cisatracurium - Structure-activity: - Cisatracurium: The 1Rcis-1R’cis isomer of atracurium - R: Stereochemistry of the benzyltetrahydroisoquinoline rings - Cis: Geometry of the bulky methoxy at C1 and 2-alkylester at N1 - ↑ Methoxy groups = ↑ Potency, ↓ histamine release - e.g. Mivacurium 2, atracurium 4, doxacurium 6) - Effects: - Degranulation of mast cells - Effects via G protein coupled receptors - H1 (Gq): Vasodilatation, capillary leak, ↓ MAP; ↓ AV node conduction, coronary vasoconstriction, bronchoconstriction - H2 (Gs): ↑ Contractility, ↑ chronotropy, coronary vasodilatation, bronchodilation (N.B. H1-induced bronchoconstriction predominates) - Prevention: Antihistamine, slower injection - ↓ Severity with repeat doses; depletion of mast cells |
| Anaphylaxis | - Less common - 1 in 10,000 - See later |
| Autonomic ganglion blockade | - Mainly caused by d-tubocurarine - Structure-activity: ↑ risk if short interonium distance |
| Prolonged apnoea (mivacurium only) | - Cis-trans and trans-trans isomers metabolised by plasma cholinesterase - Two alleles. Variations: Normal, dibucaine-resistant, fluoride-resistant, silent - Rx prolonged apnoea: Sedate + ventilate in ICU +/- FFP +/- dialysis |
| Laudanosine toxicity | - Ester hydrolysis and Hofmann degradation product of atracurium and cisatracurium metabolism - Neurotoxic in animals → Seizure - Tiny concentration in man |
Aminosteroid Adverse Effects
| Aminosteroid Adverse Effect | Description |
|---|---|
| Anaphylaxis | - Common, often severe - Rocuronium highest 1 in 2,500 (cf. suxamethonium 1 in 2,000) - Structure-activity: - Usually due to quaternary NH4+ - ?Cross-reaction with pholcodine - Pathophysiology: - 1st exposure: Sensitization (antigen presented to T cell, stimulates B cell, IgE production, fixation on mast cells) - 2nd exposure: Systemic mast cell degranulation, angioedema, bronchospasm, vasodilatation/capillary leak |
| Cardiac mAChR effects | - Vecuronium: Agonist → ↓ HR (rare) - Pancuronium: Antagonist → ↑ HR (common) - Rocuronium: Minimal effect |