BT_GS 1.37a - Rate of Onset & Offset of blockade Flashcards
(20 cards)
Factors that affect the speed of onset of muscle relaxation
Drug factors
- PK
- Biophasic
- PD
Patient factors
Equipment factors
Factors that affect the speed of onset of muscle relaxation
Elaborate on PK factors
Factors that ↓ the time for transport from site of injection to muscle
Administration
Route: IV sux > IM sux
Site: CVC > PIVC in the foot
↑Dose (see later)
Precurarisation / Priming dose: e.g. atracurium
initial dose should not exceed 10% the drug’s ED(95).
For drugs other than rocuronium, the optimal priming interval is not <5 min.
Contentious due to presence of unwanted respiratory side effects and signs of muscle weakness (e.g., diplopia) after the precurarizing dose
2xED95 -> 3 mins
0.05mg/kg / wait 3 min / 2xED95 -> 1.5 mins
Since some AChRs are blocked, the total SCh dose has to be ↑ to achieve the same neuromuscular blocking effect.
Rate of injection: fast push
Factors that affect the speed of onset of muscle relaxation
Elaborate on biophasic factors
Biophasics: factors ↑ rate of transfer into NMJ (Ce) -> ↑speed
Factors that ↑C1
↑Dose (e.g. rocuronium 2xED95 1-1.5mins, 4x ED95 0.45-1min)
Drug potency
More potent the non-depolarising NMBs –> clinically used at lower doses –> smaller concentration gradient between plasma and NMJ –> slower rate of onset (Bowman principle)
e.g. cisatracurium (ED95 = 0.03 mg/kg) is more potent than rocuronium (ED95 = 0.15 mg/kg) –> cisatracurium is used at lower dose (0.15 mg/kg) than rocuronium (0.6 mg/kg) for intubation –> cisatracurium (5 min to reach intubation condition) rate of onset is slower than rocuronium (2 min)
ED95 greater than 0.1 mg/kg is necessary for a rapid onset of effect
↓Toxicity -> ↑max safe dose (e.g. rocuronium no histamine release or mAChR effect)
↑Diffusion coefficient
Less relevant due to fenestrated muscle capillaries
Factors that affect the speed of onset of muscle relaxation
Elaborate on PD factors
Drug interactions
Neostigmine (AChE inhibitor) –> ↑[ACh] at synaptic cleft
–> would significantly ↑ time to onset of effect of these drugs if ~70% or nAChRs occupied by NDMRs
Sugammadex (chelates rocuronium and vecuronium) –> would significantly ↑ time to onset of effect of these drugs, potentially may cause them to have no effect at all
Factors that affect the speed of onset of muscle relaxation
Elaborate on patient factors
Factors affecting drug PK: Distribution
↑Cardiac output -> ↓time to NMJ (e.g. pregnant)
Limiting factor for onset of suxamethonium
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)
Age
Infants have a higher CO –> ↑ muscle blood flow –> faster onset
Elderly have a ↓ CO –> ↓ muscle blood flow –> slower onset
Pathological Factors affecting PD
Myasthenia Gravis
↓ number of post junctional ACh receptors
↑ sensitivity to NDMRs –> ↓ time to onset
should be given in incremental doses of 1/10th of the standard intubating dose, ideally guided by a quantitative neuromuscular monitoring device.
Ideally avoid alltogether, e.g. TIVA with remi
Otherwise, recommended roc and sugammadex
Resistance to SCh (↑ dose) –> ↑ time to onset
Doses as high as 2.5mg/kg reported
Conditions that cause upregulation of Foetal AChRs
e.g. Burns, denervation pathologies e.g. stroke, muscular dystrophy, trauma to UMN or LMN
↓ sensitivity to NDMRs –> ↑ time to onset
↑ sensitivity to SCh –> ↓ time to onset + hyperkalaemia
Hypercalcaemia (e.g. secondary to hyperparathyroidism) –> ↑ACh release
Hyperkalaemia –> Partial depolarisation
Factors that affect the speed of onset of muscle relaxation
Elaborate on equipment factors
The muscle group being monitored
E.g. diaphragm ↓ time to onset (central muscle with ↑ relative blood flow) vs adductor pollicis ↑ time to onset (peripheral muscle with ↓ relative blood flow)
Describe how NMB compares in these three muscle groups: diaphragm, larynx and AP
Draw a graph
Larynx > diaphragm > adductor pollicis (slowest)
Although the diaphragm and larynx are more ‘resistant’ to NDMRs, the major determinant is blood flow
Small muscles (larynx) blocked before larger muscles (diaphragm)
Faster onset but reduced peak effect as more ‘resistant’ to block
Why do central muscles have a faster onset of block compared to peripheral muscles
Centrally located muscles (laryngeal adductors, diaphragm) have faster onset of block compared to peripheral muscles (eg adductor pollicis) – despite being less sensitive to NDMRs – due to:
Higher blood flow per gram (primary cause) →
More rapid equilibration between plasma and effect site (shorter t1/2ke0)
t1/2ke0 2.7min vs 4.4min (laryngeal adductors vs adductor pollicis)
In physiologically-based pharmacokinetic models, the equilibration time constant for an organ = organ blood flow x organ effective volume
Central muscles recive a higher peak plasma concentration in the brief period before rapid redistribution occurs
means is that when you rapidly inject a bolus into a small volume of blood, the concentration in that small volume is very high
As the drug spreads throughout the circulating blood volume, due to the effects of mixing chambers and the characteristics of laminar flow, the concentration reduces
Thus an organ that is closer to the injection site will be exposed to a higher peak concentration than one that is further away
Shorter circulation time (likely marginal significance)
Sensitivity to block (not a huge factor here)
Onset at larynyx and diaphragm quicker than adductor pollicis, even though latter is more sensitive to block.
What muscle correlated well with block of laryngeal muscles and diaphragm, where is it found on the body and what is it commonly mistaken for, how far does AP lag behind this muscle on induction
Monitoring of facial nerve → corrugator supercilii (CS) correlates with block of laryngeal muscles and diaphragm
NB it is a common error for candidates to state that we are monitoring orbicularis oculi (OO), but this is incorrect and a bad mistake to make IMO as:
CS causes medial movement of the eyebrow (causing vertical frown lines), which is what we are monitoring for, while OO closes the eye
OO response correlates with the peripheral muscles, not the central muscles
Monitor for onset of block at CS → can predict quality of intubating conditions.
Onset of block of AP lags 1 – 2 mins behind CS
Upper airway muscles e.g. geniohyoid, time to onset - mimics what organ and why?
high blood flow so onset mimics diaphragm
Factors that ↑ time to onset
Physiological
Adductor pollicis: ↓blood flow -> ↑ON
Pathological
↓CO
Obesity –> ↑plasma cholinesterases (sux and mivacurium)
↑foetal type receptor: ααβγδ (for NDMR only)
Drug factors
↓ dose
↑ potency
Drug interactions
Anesthetic type e.g. propofol vs volatiles
Reversal drug e.g. neostigmine or sugammadex
How / why does offset occur
Occurs when the concentration of the NMB is reduced relative to Ach
Offset time definition
Different from different sources, some will say until 25% T1 twitch height, others say when TOFR0.9
What is the sequence of recovery of the 3 famous muscle groups, what are the implications for monitoring?
Diaphragm > larynx > adductor pollicis (slowest)
As diaphragm and abdominal muscles recover more quickly than AP, patient may still cough even if TOFC at AP is 0
Commonly seen as patient ‘breathing up’ over top of ventilator while still having profound peripheral block.
To prevent coughing, PTC should be kept <3
Adductor pollicis is suitable for monitoring offset, as it is slower to recover than central muscles, giving a safety of margin
If adductor pollicis fully recovers, larynx and diaphragm will have long recovered
What are the reasons why the central muscles recovery faster than peripheral muscles
1/ The central muscles are ‘less sensitive’ to NDMRs
Diaphragm and laryngeal muscles more resistant to block than AP (EC50 is 50–100% higher) due to higher proportion of fast twitch (Type II) fibres
Fast twitch fibres have
Higher receptor density
Greater ACh release
Lower AChE activity
Adductor pollicis
Low blood flow
More slow twitch fibres (low AChR density)
Hence a more receptors need to be blocked to prevent transmission across NMJ →
More resistant to being blocked nusually overshadowed by ↑BF)
Faster recovery than slow twitch fibres
The diaphragm generally recovers from a block 20–30 minutes earlier than AP
One reasons why an intubating dose is generally 2xED95 – if the EC50 of laryngeal adductors is double that of AP, then this is the minimum dose that would reliably provide good intubating conditions
2/ The central muscles receive a higher blood flow per gram
This means that the t1/2ke0 is shorter and the effect site concentration will not lag as far behind the fall in plasma concentration
What are the physiological factors that affect offset
elderly –> less muscle mass –> prolonged block
Degeneration NMJ
ΔPK: ↓ Cl and Vd
ΔPD: ↑ sensitivity
female –> less muscle mass –> prolonged block
In the neonate, the NMJ is immature until 2 months of age
nACh receptor is of an immature type
Only 1/10th the density in adults → more sensitive to blockade by NDMRs
Less ACh released with each stimulus
Vesicles containing ACh become deplete with tetanic stimulation → fade
More sensitive to NDMRs but more resistant to suxamethonium
In infants and older children, dose requirements are higher ? Than in neonates
↑ECF → ↑Vd → ↑dose requirements (higher ED95)
↑Cardiac output → faster onset
↑Clearance → shorter duration of action
What are the pathological factors that affect offset
Myasthenia gravis
Slower offset NDNMB
↑ risk of developing phase II block with sux
denervation -> upregulation of extra-junctional receptors
Faster offset NDNMB
acidosis –> slower metabolism, increased affinity of tertiary amine for ACh receptor
hypothermia –> slower metabolism
prolongs duration of NDMR by 15 mins for each degree drop in temp below 36.5 C
Hypothyroidism
↓ BMR
hypocalcaemia –> ↓pre-synaptic ACh release at NMJ
hypokalaemia –> hyperpolarise post-synaptic membrane
hypermagnesaemia –> competes with Ca2+ –> ↓pre-synaptic ACh release
CKD
uraemia impairs enzyme activity, impairs excretion of both active metabolites and unchanged parent NMB
Hepatic failure
synthesises BChE, biliary excretion impaired, metabolism impaired
In contrast, alkalosis, hyperthermia, ↑K, ↑Ca, ↓Mg all speed up rate of recovery
Describe drug factors that slow the rate of recovery / ↑ the durationof action
Volatiles
↓ tone of skeletal muscles
The magnitude of potentiation depends on
Duration of inhalational anaesthesia
Specific agent used
Des > sevo > iso > halo > N2O
Concentration of agent used
Mechanisms
Central effect on CNS α motor neurones and interneuron synapses → ↓muscle tone
Pre-synaptic: ↓α-motor neuron activity
Inhibition of pre-synaptic NAChR → ↓positive feedback loop
Block pre-junctional Ca2+ channels → ↓ACh release
Post-synaptic
Direct NAChR antagonism
Desensitisation block
Augmentation of NDMRs affinity for binding site via allosteric binding
Increased muscle blood flow and delivery of NMB to effect site
? Post synaptic desensitisation blockade
An intubating dose of SCh prolongs the effect of ND NMB.
It is describing an open channel block. When sux binds it opens the channel (for non-depolariser it does not). If the sux binds and opens the channel, then you give vec, it will cause an open channel block.
Aminoglycosides
↓ ACh release from prejunctional membrane
Competition with Ca2+ ? Block L-Ca2+
Block post-synaptic nAChR
Local anaesthetics
Na+ channel blockade
Stabilisation of post junctional membrane
↓ pre-junctional release of ACh
Direct muscle depression in large doses
Ester LAs compete with mivacurium for plasma cholinesterase
Post synaptic ↓Na+ flux
Ca2+ channel antagonists
Block L-Ca2+ –> ↓Ca2+ influx –> ↓ ACh release
Class I antiarrhythmics (e.g. quinidine) –> ↓ACh release + ? Block post-synaptic nAChR
frusemide –> interferes with calcium flux and secondary intracellular messaging decrease acetylcholine release.
hypermagnesaemia –> competes with Ca2+ –> ↓pre-synaptic ACh release
Lithium
Na+ channel blockade
Chronic anticonvulsant therapy (eg barbiturates, carbamazepine, phenytoin)
↑ Clearance of NDMRs by inducing CYP
↑ Binding of NDMRs to α1-acid glycoprotein
Upregulation of NMJ ACh receptors
Hemicholinium: ↓Choline uptake
Vesamicol: ↓ACh transport into vesicles
Botox: cleave SNARE protein, ↓ACh release
Tetrodotoxin: VDNaC inhibition
Dantrolene: inhibit skeletal muscle ryanodine receptor
Metoclopramide has been shown to block both AChE and plasma cholinesterase
Short term use phenytoin attenuated NMBD blockade
Factors that ↓ duration of action / hasten recovery
Physiological
Sex –> M –> ↑ muscle mass
Muscle: Larynx + diaphragm compared to AP: ↑blood flow, ↑vesicles, ↑receptors
↑ temp –> ↑Rate of ester hydrolysis and Hoffman elimination
↑pH –> ↑Rate Hoffman elimination
↑K+ –> Pre-synaptic depolarisation -> ↑ACh release
Pathology
Obesity -> ↑pseudocholinesterase
CYP gain-of-function polymorphism -> ↑metabolism (vecuronium)
Upregulated foetal type receptor: ααβγδ (NDNMB only)
Drug factors
↓ Dose
↑ potency
Drug interactions
Reversal drugs: neostigmine / sugammadex
Hepatic enzyme inducers
Anesthetic type e.g propofol vs volatiles
Insulin/dextrose infusion causes hypokalaemia – This prolongs ND NMB effect due to hyperpolarisation of the postjunctional membrane
Aminopyridines (potassium channel blockers)
used in treatment of MS - potassium channel blockers - increase presynaptic ACh release/prolongs nerve AP -> counteracts NMBD
Chronic use phenytoin reduces duration NMBD blocked
How does the offset of upper airway muscles, eg geniohyoid, compare to other groups
are most sensitive to blockade, offset mimics peripheral muscles
At emergence, if TOFR at AP < 0.9, patient may breath well but there is still significant weakness of pharyngeal muscles
Extubation at this point → ↑risk of airway obstruction and aspiration
