2019A12 Outline the factors that determine the rate of recovery from non-depolarising neuromuscular block.

 

List:

·      Intro

·      Dose = starting [drug]

·      Biophasics = rate of transfer from effect site to central compartment

·      Kinetics = rate of ↓[drug]

·      Dynamics = [drug] for offset (could technically write about ↑sensitivity and ↓sensitivity)

 

Intro:

Determinants of time to recovery

·   Final effect site concentration after bolus or at end of infusion

·   Rate of removal from effect site

·   Rate of elimination from the plasma

·   Effect site concentration required for recovery of neuromuscular function

Compartment model

Standard

·   Train-of-four ratio 0.9 (or return to 25% baseline twitch height?)

Usual duration

·   30-45 mins for 2x ED95

·   45-60 mins for 4x ED95

 

Ce after bolus or at end of infusion (factors increasing it)

Administration

·   ↑Bolus size (e.g. 4x ED95 rocuronium cf. 2x ED95)

·   ↑Infusion rate

·   ↑Infusion duration

Drug

·   ↓Elimination rate (see below)

Patient

·   ↓Volume of distribution (see below)

 

Removal from effect site:

Fick’s law

Chelation reversal

·   γ-cyclodextrin chelates rocuronium > vecuronium >> pancuronium

o Interaction occurs in plasma, not receptor site

o ↓C2 -> ↑concentration gradient -> ↑rate of removal

o i.e. kinetic not dynamic interference

·   Dosing

o 16mg/kg immediately after intubating dose

o 4mg/kg moderate blockade

o 2mg/kg minimal residual blockade

 

Elimination from central compartment: (factors slowing it)

Short infusion

Offset during distribution phase

·   ↓Cardiac output (e.g. shock)

·   ↓Volume of distribution

o ↓Muscle mass (e.g. elderly, cachectic)

o ↑Water mass (e.g. hypovolaemia)

Long infusion

Offset during terminal elimination phase

·   ↑Cardiac output (e.g. pregnant, neonate)

·   ↑Volume of distribution

o ↑Muscle mass (e.g. athletic)

o ↑Water mass (e.g. heart failure, renal failure, liver failure)

·   ↓Metabolism

o ↓Phase 1,2 reactions (e.g. liver failure) -> ↑duration aminosteroids

o ↓Hoffman degradation (↓temp, ↓pH) -> ↑duration benzylisoquinoliniums

o ↓Ester hydrolysis (↓temp, ↑pH) -> ↑duration benzylisoquinoliniums

·   ↓Excretion of drug or active metabolite

o ↓Renal excretion (renal failure -> accumulate pancuronium, gallamine)

o ↓Biliary excretion (liver failure -> accumulate vecuronium, rocuronium)

*Note: muscle relaxants have a very small VDSS; my understanding was that distribution is unimportant,
but the examiner’s report suggests otherwise*

 

Ce at which offset occurs: (factors decreasing it)

Muscle group

·   Laryngeal adductors recover before adductor pollicis due to

o ↑Blood flow

o ↑ACh vesicles released

o ↑Number of receptors

Physiological factors

↓ACh release -> ↑drug:ACh ratio

·   Neonate: immature NMJ

·   Elderly: ↓ACh spare receptors

·   ↑Mg2+: antagonize Ca2+ at pre-synaptic L-Ca2+ channel

·   ↓K+: hyperpolarization

·   Hypothermia

·   Resp acidosis

Pathological factors

·   Myasthaenia gravis (↓↓spare receptors)

·   Lambert-Eaton syndrome (antibody against VDCC, ↓ACh released)

(note: denervation -> upregulation of extra-junctional receptors -> ↑Ce for offset)

Pre-synaptic drugs

·   ↓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

·   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

 

Ce at which offset occurs: factors increasing it

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

Competitive reversal

·   Acetylcholinesterase inhibitor (e.g. neostigmine -> ↑ACh:Drug ratio -> displacement

·   Obtain train-of-four ratio of >0.9 earlier

·   Should not be given until three TOF twitches

Toxins

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

 

 

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