2014A02 Draw and explain the characteristics of a log dose response curve
that describes the major clinical effect of rocuronium.
Describe how factors encountered in clinical practice may alter this curve.

List:

· Graph

· Intro

· Factors ↑ED₉₅ = R shift = ↓potency

· Factors ↓ED₉₅ = L shift = ↑potency

· Factors ↑duration (not relevant here)

Graph:

Population, quantal curve

Intro:

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

Factors ↑ED₉₅ = R shift = ↓potency:

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

Factors ↓ED₉₅ = L shift = ↑potency

Physiology	↓ACh release -> ↑drug:ACh ratio · Neonate: immature NMJ · Respiratory acidosis · ↑Mg^2+: ↑competition with Ca^2+ · ↓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-Ca^2+ (CCB, Mg^2+, 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

Addit: factors increasing duration

*All those causing ↑potency plus…*

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)