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

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

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

 

 

 

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