16A12: Exam Report
In relation to neuromuscular blocking drugs – Discuss the factors that influence the speed of ONSET of neuromuscular block.
38% of candidates passed this question.
The question specifically asked for factors that influenced the speed of onset of neuromuscular block. This information is different to the factors that influence neuromuscular blockade in general which was what many candidates focussed on. It was expected candidates would address the main factors known to influence the speed of onset of neuromuscular block: –
potency of the agent used (inverse relationship to speed of onset); rate of delivery of the agent to the NMJ (blood flow / muscle group); and mechanism of the neuromuscular block (non-depolarising vs depolarising).
14A09: Exam Report
Discuss the factors that may potentially influence the speed of onset of neuromuscular blockade.
16% of candidates passed this question.
Speed of onset is related to how quickly an effective dose reaches the neuromuscular junction, the type of interaction with the receptor and the margin of safety of the receptors. Examples of parameters that increase speed of onset include a high drug rate of delivery (high CO, high muscle group blood flow, and fast injection rate), high drug concentration (higher dose, low potency, higher ED 95, lower protein binding) or a depolarising block. A good answer would include a list of these factors, with a brief explanation. Mention of other factors such as electrolyte disturbances gained additional marks. It was expected that the direction of an effect would be clearly indicated (e.g. & “potency” would not score a mark unless the candidate wrote – “low potency increases speed of onset’, etc.). These drugs are charged molecules which do not cross cell membranes and have a low volume of distribution. Absorption from GIT, Lipid solubility, pKa, metabolism and clearance have minimal relevance to speed of onset.
L2i / 16A12 / 14A09: Discuss the factors that may potentially influence the speed of onset of neuromuscular blockade
Mechanism of Neuromuscular Blockade
- Blocks nAChR at NMJ
- Onset is measured by TOF = time taken for 95% decrease of T1 for an intubating dose
- Speed of onset depends on the speed with which 20% receptor occupancy (Depol MR) or 75% receptor occupancy (NDMR)
- Fast = Sux, Roc
- Intermediate = Vecuronium, Atracurium
- Slow = Cisatracurium, Pancuronium, Mivacurium
- Dose administered depends on the drug’s ED95 (2-3 x ED95 require to supress twitch height by 95%)
Drug Factors
Dose
NDMR require >75% receptor occupancy
High dose = greater concentration gradient = faster onset
eg
RSI ROC = 4xED95 = 1.2mg/kg = 60sec
Intub ROC = 2xED95 = 0.6mg/kg = 120sec
Drug Potency
Lower potency means a higher dose of the drug is needed to achieve affect.
Low affinity NMB requires high dose to achieve ED95
High affinity NMB requires low dose to achieve ED95
eg
Cisact intub = 0.15mg/kg
Roc intub = 0.6mg/kg
Depol v NDMR
Depol MR have much faster onset
eg
SUX 30-60sec
ROC RSI 60sec
Drug Interactions
Precurarization (priming)
Use of low dose NDMR 5 min prior will partially block the NMJ → follow this with an intubating dose of drug will decrease time to intubating conditions
Drugs that increase potency
LA, volatiles, aminoglycosides, frusemide → all enhance NDMR = faster onset
Drugs which improve CO
Inotropes and vasopressors which increase CO will enable the drug to reach effect site quicker, improving onset time
Drugs that affect ACh production
Corticosteroids common in ICU practice increase Ach synthesis and its spontaneous and stimulated release – delaying onset time.
Chronic steroids use decreases nAChR and increases resistance to NDMR
Patient Factors
nAChR Affinity
nAChR has 5 subunits
Strength of binding to 2x a subunits determines drug onset
In disease states
Burns/immobilisation – nAChR composed of 5 x a7 subunits, which is resistant to blockade because requires 5 subunits to be bound
Myesthenia gravis = fewer nAChR = faster onset with NDMR (slower onset sux)
Age
Onset Young adults > elderly
Sex
Onset Women > Men
Smoking
Onset Smokers > non smokers
Geography
Onset Lower plain region > High Altitude
Body Temp
Onset is delayed in hypothermina
Nutrition
Dose based on IBW
Poor nutrition, reduced muscular mass, increased TBW = delay onset
Electrolyte Disturbances
HypoK/Mg/Ca/Resp Acidosis = enhance onset time
Heart Failure/ Cardiogenic Shock
Reduced CO delays onset
Site of administration
CVC > Periph vein > intramuscular
Rate of injection → faster injection bolus = faster onset
Injection site above heart = faster
Muscle Group
Drug distribution to sk m
Muscle group type: larynx > diaph > adductor pollicis
Fast twitch have more AchR than slow twitch and thus faster onset