2009B05 Describe the factors that may decrease the clinical response to
non-depolarising neuromuscular blocking agents.

 

List:

·      Intro

·      Phys

·      Path (kinetic and dynamic)

·      Drug factors

·      Drug interactions

 

Intro:

Non-depolariser

·  Competitive antagonist at α-subunit of nAChR at NMJ

·  Binds receptor, channel does not open

Nerve stimulation

·  Electrode over nerve (e.g. ulnar)

·  Electrode away from muscle (e.g. forearm)

·  Accelerometer (e.g. on thumb for adductor pollicis)

·  e.g. train-of-four (4 x 0.2 millisecond bursts at 60mA and 2Hz)

Measurable responses

·  Onset time (ON): time to 95% depression of single twitch height

·  Peak effect (PE): e.g. minimum post-tetanic count

·  Offset time (DUR): time to TOF ratio 0.9

Summary

·  Many factors affect response to paralytics

·  Hence monitoring is important

 

Physiology:

Age

·  Adult cf. neonate: ↑NMJ maturity -> ↓PE, ↓DUR

Sex

·  Male: ↑muscle mass -> ↓PE, ↓DUR

Muscle type

·  Larynx: ↑blood flow, ↑vesicles, ↑receptors -> ↓PE, ↓DUR

·  Adductor pollicis: ↓blood flow -> ↑ON

↑Temp

·  ↑Rate of ester hydrolysis and Hoffman elimination -> ↓DUR for atra, cisatra

↑pH

·  ↑Rate Hoffman elimination -> ↓DUR for cisatra > atra

↑K+

·  Pre-synaptic depolarisation -> ↑ACh release -> ↓PE, ↓DUR

 

Pathology:

Kinetic

·  ↓Cardiac output -> ↑transit time -> ↑ON if very short acting (e.g. rapacuronium)

·  Obesity/alcohol -> ↑pseudocholinesterase -> ↑ON, ↓PE, ↓DUR (mivacurium only)

·  CYP gain-of-function polymorphism -> ↑metabolism -> ↓DUR (e.g. vecuronium)

Dynamic

↑Extra-junctional receptors -> ↑ON, ↓PE, ↓DUR

·  Upregulated foetal type receptor: ααβγδ

·  Occurs if actual or function denervation, e.g. burns, immobility, spinal cord injury

·  Greatest 5-90 days post-insult

 

Drug factors:

↓Dose

e.g. 2 x ED95 cf. 4 x ED95 rocuronium

·  ↑ON, ↓PE, ↓DUR

↑Potency

e.g. vecuronium ED95 0.07mg/kg vs rocuronium ED95 0.3mg/kg (molar potency similar)

·  ↓Concentration gradient for a given ED95 multiple

·  ↑ON, ↓PE (i.e. Bowman principle)

 

Drug interactions:

Depolarising blockade

·  e.g. rocuronium antagonized by suxamethonium

·  ↓DUR

Anaesthetic type

·  e.g. propofol cf. volatile anaesthetic -> less potentiation

·  ↑ON, ↓PE, ↓DUR

Reversal drug

·  e.g. neostigmine -> ↑[ACh] at NMJ -> displacement from receptors

·  ↑ON, ↓PE, ↓DUR

Hepatic enzyme inducers

·  ↑Rate of metabolism

·  ↓DUR

 

 

 

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