2016A04 Discuss the potential adverse effects of non-depolarising muscle relaxants.

 

List:

·      General adverse effects

·      Benzylisoquinolinium specific

·      Aminosteroid specific

 

General adverse effects:

Unsafe paralysis

·   Can’t intubate, can’t oxygenate -> desaturation -> death

·   Absent airway reflexes -> aspiration

Inadequate reversal

·   Risk: distress, type 2 resp failure, aspiration

·   Risk factors:

o Physiology: hypothermia -> ↓rate of enzymatic degradation

o Pathology: liver failure (↓metabolism), renal failure (accumulation), PChE deficiency for mivacurium

o Long acting drug e.g. pancuronium 60 mins

o Active metabolites: e.g. 3-OH pancuronium 50% potency and long-lasting

o Other drugs: e.g. volatile, calcium channel blocker

Critical illness myopathy

·   Prolonged paralysis in ICU -> disuse atrophy

·   Vecuronium and atracurium implicated

·   ? specific drug effect ? immobility

 

Benzylisoquinolinium adverse effects:

Histamine release

·   Direct effect on mast cells. Not immune mediated.

·   Drugs: d-Tubocurarine > mivacurium, atracurium >> cisatracurium

·   Structure-activity:

o 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

o ↑Methoxy groups = ↑potency, ↓histamine release

§  e.g. mivacurium 2, atracurium 4, doxacurium 6)

·   Effects:

o Degranulation of mast cells

o Effects via G protein coupled receptors

o H1 (Gq): Vasodilatation, capillary leak, ↓mAP; ↓AV node conduction, coronary vasoconstriction

o H2 (Gs): ↑contractility, coronary vasodilatation

o H2 (Gs): Bronchospasm, ↑airway resistance, ↑airway pressure

·   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

·   Effects: ↓HR, ↓mAP (i.e. no baroreceptor response)

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:

Anaphylaxis

·   Common, often severe

·   Rocuronium highest 1 in 2,500 (cf. sux 1 in 2,000)

·   Structure-activity:

o Usually due to quaternary NH4+

o ? cross-reaction with pholcodine

·   Pathophysiology:

o 1st exposure: sensitization (antigen presented to T cell, stimulates B cell, IgE production, fixation on mast cells)

o 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

 

 

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