2004A02 Outline factors determining speed of onset of neuromuscular blocking agents.
List:
· Intro
· Kinetics: dose -> Cp
· Biophasics: Cp -> Ce (Fick’s law)
· Dynamics: Ce -> effect (factors affecting sensitivity)
Intro:
|
Onset definition |
· Time to 95% depression of single twitch height |
|
Determinants |
· Time for transport from site of injection to muscle · Time for transfer from plasma to effect site · Effect site concentration associated with onset |
Kinetics: factors ↑rate of Cp at muscle
|
Administration |
· Route: IV sux > IM sux · Site: CVC > PIVC in the foot · ↑Dose (see later) · Priming dose: e.g. atracurium o 2xED95 -> 3 mins o 0.05mg/kg / wait 3 min / 2xED95 -> 1.5 mins · Rate of injection: fast push |
|
Distribution |
· ↑Cardiac output -> ↓time to NMJ (e.g. pregnant) o Limiting factor for onset of suxamethonium o Note ↑Cardiac output also ↑dilution -> ↓max Cp · ↑Blood flow rate (i.e. larynx and diaphragm > adductor pollicis) · ↑Blood volume -> dilution -> ↓rate of rise Cp (e.g. heart failure, pregnancy) |
Biophasics: factors ↑ rate of transfer into NMJ (Ce) -> ↑speed
|
Fick’s law |
|
|
↑C1 |
· ↑Dose (e.g. rocuronium 2xED95 1-1.5mins, 4x ED95 0.45-1min) · Bowman principle: ↓molar potency -> ↑dose:duration ratio -> ↑C1 · ↓Toxicity -> ↑max safe dose (e.g. rocuronium no histamine release or mAChR effect) |
|
↑Diffusion coefficient |
· Less relevant due to fenestrated muscle capillaries |
Dynamics: Factors ↑ED95 (less important)
|
Physiology |
· ↑K+: membrane potential less negative -> ↑ACh release -> ↓drug:ACh ratio |
|
Pathology |
· Critical illness myopathy, burns -> proliferation of extrajunctional receptors -> ↓drug:ACh ratio · Malignant hyperthermia-> post-junctional activation |
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Drugs |
· AChEi e.g. neostigmine: ↓drug:ACh ratio |
|
Toxins |
· Tetanus toxin: ↓inhibition of a-motor neurons -> ↑NMJ activity -> ↓drug:ACh ratio |
Dynamics: factors ↓ED95 (less important)
|
Physiology |
· ↓ACh release -> ↑drug:ACh ratio · Neonate: immature NMJ · Elderly: ↓ACh spare receptors · Respiratory acidosis · ↑Mg2+: ↑competition with Ca2+ · ↓K+: membrane potential more negative -↓ACh release |
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Pathology |
· Myasthaenia gravis: antibody against NMJ nAChR -> ↑drug:receptor ratio · Lambert-Eaton syndrome: antibody against pre-synaptic VDCC -> ↓competition with ACh |
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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) |
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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 |
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Post-junctional drugs |
· Dantrolene: inhibit skeletal muscle ryanodine receptor |
|
Toxins |
· Botox: cleave SNARE protein, ↓ACh release · Tetrodotoxin: VDNaC inhibition |
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