Rocuronium

·   Non-depolarising relaxant

·   Competitive inhibitor at α-subunit of nAChR at NMJ

·   Must bind 70% of receptors before significant effect due to spare receptors

Measured responses

·   Onset time (time to 95% ↓single twitch height)

·   Depth (minimum post-tetanic count?)

·   Offset time (time to TOF ratio 0.9)

Muscle group differences

 Laryngeal muscle cf. adductor pollicis:

·   Physiological differences:

o ↑Blood flow

o ↑ACh vesicle release

o ↑ACh receptors

·   Clinical implication:

o Faster onset

o Less depth

o Shorter duration

Implications of inter-individual differences

·   ↑Potency and ↑duration: failure of reversal -> distress, T2RF, aspiration

·   ↓Duration: movement when dangerous e.g. neurosurgery

·   Twitch monitoring essential whenever relaxants used

Physiology

·   ↑K⁺: membrane depolarisation-> ↑ACh release -> ↓drug:ACh ratio

Pathology

·   Critical illness myopathy, burns -> proliferation of extrajunctional receptors -> ↓drug:ACh ratio

·   Malignant hyperthermia-> post-junctional activation

Competitive reversal

·   AChEi e.g. neostigmine: ↓drug:ACh ratio

(g-cyclodextrin chelates rocuronium in plasma, increases the gradient between effect site and plasma but does not alter the dose-response curve)

Toxins

·   Tetanus toxin: ↓inhibition of a-motor neurons -> ↑NMJ activity -> ↓drug:ACh ratio

Physiology

↓ACh release -> ↑drug:ACh ratio

·   Neonate: immature NMJ

·   Respiratory acidosis

·   ↑Mg²⁺: ↑competition with Ca²⁺

·   ↓K⁺: membrane potential more negative -↓ACh release

Pathology

·   Myasthaenia gravis: antibody against NMJ nAChR -> ↑drug:receptor ratio

·   Lambert-Eaton syndrome: antibody against pre-synaptic VDCC -> ↓competition with ACh

Pre-synaptic drugs

↓ACh release -> ↑drug: ACh ratio

·   ↓α-motor neuron activity: volatile anaesthetic

·   ↓ axonal action potential: peripheral nerve local anaesthetic (↓Na⁺ flux)

·   ↓Choline uptake: hemicholinium

·   ↓ACh transport into vesicles: vesamicol

·   ↓AMP/ATP synthesis (frusemide)

·   Block pre-synaptic nAChR (volatiles)

·   Block L-Ca²⁺ (CCB, Mg²⁺, aminoglycosides, volatiles)

Post-synaptic drugs

↓Ion flux through nAChR

·   Block post-synaptic nAChR: other non-depolarisers, volatiles, aminoglycoside, quinidine

·   Desensitisation blockade (volatiles, barbiturates)

·   Inhibit peri-junctional action potential: local anaesthetic ↓Na⁺ flux

Post-junctional drugs

·   Dantrolene: inhibit skeletal muscle ryanodine receptor

Toxins

·   Botox: cleave SNARE protein, ↓ACh release

·   Tetrodotoxin: VDNaC inhibition

Pathology

·   ↓Temp: ↓rate of Hoffman degradation and ester hydrolysis

·   ↑pH: ↓rate of ester hydrolysis

·   ↓pH: ↓rate of Hofmann degradation

·   Atracurium: 60% ester hydrolysis, 30%, Hoffman elimination, 10% in urine unchanged

·   Cisatracurium: 80% Hoffman elimination, 15% ester hydrolysis, 5% in urine unchanged

Pathology

·   Liver failure: accumulation of bile eliminated drug (e.g. vecuronium 70%)

·   Renal failure: accumulation of drug (e.g. gallamine 100% renal), metabolite (e.g. 3-OH-panc 50% potency)