BT_GS 1.36, 1.37, 1.47 - NMBAs

Question 1

Ideal properties of NMBAs
Physiochemical

Answer 1

Water-soluble formation
Stable in solution
Sterile without additives
Long shelf life
No refrigeration
Cheap
Compatible with other drugs

Question 2

Ideal properties of NMBAs
Pharmacokinetic

Answer 2

Rapid onset
Short duration
Rapid metabolism
Inactive metabolites
No transfer across the placenta and the BBB
Organ-independent elimination

Question 3

Ideal properties of NMBAs
Pharmacodynamic

Answer 3

Non-depolarizing MoA
Action confined to NMJ
Availability of specific reversal agent
No local or systemic effects
No histamine release
No trigger for MH

Question 4

Clinically Classify NMBAs

Answer 4

Question 5

Structure – activity relationships of NMBAs

Answer 5

Large, bulky molecules - undergo conformational to change to bind AChR
Structurally related to ACh
Monoquaternary vs bisquaternary structure
≥ 1 quaternary amine group (N+(CH3)3)
positive nitrogen atoms of NMDs are attracted to negatively charged ⍺-subunits of postsynaptic nAChR
Most NDMRs contain a second amine group, which may be tertiary or quaternary

Monoquaternary NDMRs
Rocuronium, vecuronium, D-tubocurarine
In acidaemia, the tertiary amine may become protonated → ↑potency of monoquaternary NDMRs → prolonged block in acidosis

Bisquaternary NDMRs
Pancuronium, atracurium
favours binding (and antagonist) to post ganglionic muscarinic ACh receptors causing a vagolytic effect
Pancuronium has a strong vagolytic effect, whilst rocuronium and vecuronium only have a weak vagolytic effect
More potent than the monoquaternary structure: pancuronium and atracurium are more potent than rocuronium and vecuronium

Potency
Increased length of carbon side chain — described as a “longer aliphatic tail” — at quaternary amine = ↓affinity for NAChR = ↓potency
rocuronium (3 carbon side chain) is less potent than vecuronium (1 carbon side chain)
Bisquaternary structure is more potent than the monoquaternary structure
Hence, pancuronium and atracurium are more potent than rocuronium and vecuronium

A ND-NMBD may show preference for one of the two ⍺-subunits. This may result in synergism if two ND-NMBDs with different selective preferences for each ⍺ subunit are administered simultaneously.

Question 6

The clinical duration of action is often referred to as?

Answer 6

The time required from administration of a dose to recovery of 25% T1 twitch height
Historically, this may have been considered the earliest time that reversal of residual neuromuscular blockade is recommended, but now they say 2 twitches minimum
25% T1 twitch height is usually when muscle relaxants need to be redosed for surgeries that require paralysis

Question 7

Potency definition

Answer 7

The dose needed to produce 95% suppression of single-twitch response (or 95% decrease in twitch height) in 50% of the population - based on AP. Is a QUANTAL measure. Is technically a misnomer and should be “ED50 for 95% T1 twitch height reduction.
Measured in presence of N2O-barbiturate-opioid anaesthesia unless stated otherwise (volatile agents have muscle relaxant effect)
NOT ‘effective dose in 95% of population’
and NOT a graded-response i.e. not the dose that produces a 95% reduction of T1 in an individual.

Question 8

Draw and label the dose-response graph for an individual, Cause of left and right shift?

Answer 8

Delay in take-off: ‘spare receptor theory’ – 75% of receptors blocked before clinical effect can be measured.
Straight steep slope: rapid movement from 75% to 100% receptor occupancy. Gradient of slope indicates effect of increase in drug dose (steep slope implies small ↑ dose → large ↑ in clinical effect).
Horizontal plateau at top: Further increase in drug dose produces no further increase in clinical effect.
Left-shift caused by factors which potentiate drug effect.
Right-shift cause by factors which inhibit drug effect.

Question 9

Draw and label the dose-response graph for a population, and cause of the left and right shift?

Answer 9

Cumulative percent of population achieving 95% decrease in twitch height (binary endpoint)
Delay in take-off: 75% receptors blocked before any ↓ in twitch height, and 90-95% receptors blocked before loss of twitch
Straight steep slope: minimal pharmacodynamic variability in population.
Short plateau at top: Curve stops because it is a cumulative percentage curve (100% population has responded at end of curve)
ED95 is median dose required to achieve 95% decrease in twitch height in 50% of the population.
Left-shift caused by factors which potentiate drug effect.
Right-shift cause by factors which inhibit drug effect.

Question 10

Onset definition

Answer 10

The interval between injection of the muscle relaxant and development of maximal neuromuscular block.
time to 95% depression of single twitch height

Question 11

What is the relationship between speed of onset and affinity?

Answer 11

Muscle relaxants with a lower affinity for the AChR need to be administered in higher doses to achieve complete neuromuscular block
The high initial bolus dose required for this low-affinity drug is associated with a higher concentration gradient between the central compartment and the neuromuscular junction, and this results in rapid diffusion of the drug from the central compartment to the acetylcholine receptor, resulting in a faster onset of paralysis
In contrast, if the drug has a high affinity for the ACh receptor it will be administered in smaller doses (lower ED95) and the gradient for transfer of drug will be lower, resulting in slower onset

Question 12

Recovery index definition

Answer 12

the speed of the offset of effect of a muscle relaxant, and is defined as the time taken for recovery from 25% to 75% twitch height

Question 13

Side effects of muscle relaxants on carotid bodies

Answer 13

Neuronal-type nicotinic acetylcholine receptors are important in signaling of hypoxia from the peripheral chemoreceptors of the carotid body to the central nervous system.
Inhibition of neuronal AChRs at the carotid body by muscle relaxants reduces the AHVR which normally compensates for a ↓SO2 by ↑ the MV.
In clinically relevant concentrations, muscle relaxants such as atracurium and vecuronium are able to inhibit neuronal acetylcholine signaling in the carotid body, attenuating chemoreceptor responses to hypoxia

Question 14

Side effects of muscle relaxants on bronchial smooth muscle

Answer 14

Muscarinic GPCR are found on the smooth muscle of the bronchi
The M3 receptor facilitates contraction, postsynaptically. The M2 subtype plays a role in the auto-feedback mode to inhibit or enhance the release of acetylcholine. Antagonism (block) of the M2 receptor, which is presynaptic, enhances acetylcholine release. The released acetylcholine acts on the M3receptor, causing bronchoconstriction. Irritation of the airway by a foreign body, such as an endotracheal tube, can lead to parasympathetic activation and release of acetylcholine resulting in bronchoconstriction.
agents that are potent antagonists at the M3 muscarinic receptor should inhibit bronchoconstriction despite the M2 muscarinic receptor block and the increased release of acetylcholine from parasympathetic postganglionic nerves.
pancuronium, a potent M2 antagonist, is not associated with bronchoconstriction since it is also a potent M3 antagonist at doses in the clinical range
rapacuronium, which was taken off the US market owing to severe bronchospasm, blocks M2 receptors but activates M3receptors by allosteric binding, thereby increasing smooth-muscle tone and adding to its ability to provoke bronchospasm.
Vecuronium has similar muscarinic receptor activation pattern to rapacuronium, however doses of vec 15-20x smaller than rapa ∴ no effect on muscarinic receptors at clinical concentrations
Rocuronium also does not potentiate vagally induced bronchoconstriction; neither does cisatracurium or mivacurium

Question 15

Side effects of muscle relaxants - histamine release

Answer 15

Histamine release from mast cells can be induced by
an antigen–antibody reaction as a result of true anaphylaxis (mediated by IgE)
by activation of the complement system (IgG or IgM)
by direct action of molecules on the surface of mast cells.

Two types of mast cells are differentiated:
mucosal (in the bronchial system and gastrointestinal tract)
serosal (vascular endothelium, skin, connective tissue)

the quaternary ammonium structure of muscle relaxants presents a weak histaminergic effect on mast cells.
In clinical doses, SCh and benzylisoquinolines (D-tubocurarine, atracurium, mivacurium) can directly liberate histamine from serosal mast cells.
Sx are erythema, rash, tachycardia, and in rare cases hypotension.
Cisatracurium and commonly used steroidal muscle relaxants (pancuronium, vecuronium, rocuronium) has no direct histaminergic effects.

Prevention
slower, graduated, or repetitive administration of the drug decreases the histaminergic side effect
Prophylactic administration of histamine (H1 and H2) receptor blockers

Question 16

Side effects of muscle relaxants - anaphylaxis reactions

Answer 16

Quaternary ammonium ion is the allergenic portion (epitope) that allows specific binding to IgE.
NMBDs cause 60% of anaphylaxis in OT
Antibiotics are most common cause overall in hospital.
In 50% of cases, reaction occurs with first exposure → suggests alternative source of sensitisation.
Cross-reactivity reported between NMBDs and cosmetics, food, disinfectants, industrial materials.
Histamine release by some NMBDs may mask or mimic anaphylaxis.
Causal relationship with cosmetics and cleaning chemicals, which often have quaternary ammonium structures, is speculated

The pholcodeine link
In 2001, Norway had 10x rate of anaphylaxis to NMBDs compared to Sweden.
Culturally and genetically similar but 40% Norwegians exposed to pholcodine (not available in Sweden).
Pholcodine consumption → production of specific IgE against quaternary ammonium ion.
Without ongoing consumption, antibody titres fall to low levels within 2 years but re-exposure has profound booster effect.
Pholcodine withdrawn from Norway in 2007 → ↓ rate of NMBD anaphylaxis seen at 3 yr, further improvement at 6 yr.
Patients who require surgery involving neuromuscular blocking agents may be more likely to experience anaphylaxis if they have taken pholcodeine in the last 12 months

Question 17

Describe the features, aetiology of a non-depolarising block

Answer 17

Competitive
No fasciculations
Monitoring
Fade with tetanic stimulation and TOF
↓ ACH mobilisation due to antagonism of prejunctional AChRs
Post-tetanic potentiation (facilitation)
↑ ACh synthesis and release
↑ Ca2+ in synaptic terminal
Responds to ↑ ACh
Muscle groups vary in sensitivity
resembles Phase II block when it is wearing off

Question 18

Describe the features, aetiology of a Depolarising / Phase I / accommodation block / flaccid paralysis

Answer 18

the result of acetylcholine receptors remaining open, with the resulting depolarisation of the motor end plate rendering the neuromuscular junction insensitive to further acetylcholine release.
Is competitively antagonised by NDMR
Non-competitive
Does respond to direct electrical stimulation of muscle fibre beyond inactivated Na channels
NAChR fixed open
The main features of Phase 1 block are:
A decrease of twitch amplitude
An absence of fade during train-of-four testing (i.e. the low-amplitude twitches all remain the same low amplitude during testing)
A potentiation with the use of acetylcholinesterase blockers (block deepens with neostigmine) as all the extra ACh merely depolarises more receptors and makes the membrane even less likely to return to restig potential.
Rapid onset and recovery
Monitoring
TOF - all (4 twitches) or nothing
TOFR - no fade - T4=T1- TOFR > 0.7
Tetanic stimulation - no fade (sustained response)
PTC - no facilitation
because the release of extra acetylcholine does nothing to reverse the paralysis.
May transition to phase II block

Question 19

Describe the features, aetiology of a phase II block

Answer 19

membrane gradually returns to resting membrane potential, but remains blocked

Cause
Sux
Large initial dose >3-5mg/kg, or repeated doses
or conventional dose if significant plasma cholinesterase polymorphism

Features
NAChR completely antagonised
Similar to non-depolarising blockade
TOF ratio <0.3,
fade during tetany, and TOF
post-tetanic potentiation: present
Reversal with the use of acetylcholinesterase blockers – however they may also worsen it

Monitoring
post-tetanic potentiation: present
fade during tetany, and TOF
Proposed mechanisms – unknown, speculation of:
Post-junctional receptor densitisation
Continuous agonist binding
Large Na+, K+, Ca2+ flux
Phosphorylation of tyrosine unit
Conformational change in receptor
Dysfunction of receptor and membrane
Flux between resting and desensitized state
Does not adopt activated state
Impervious to agonist binding
Pre-synaptic receptor blockade (lower affinity)
Activation of Na+K+ATPase by initial depolarisation

Risk factors
Neonates
Myasthenia Gravis
Atypical cholinesterase
Concurrent use of inhalational agents
Antagonism with anticholinesterases
Unpredictable response

Question 20

Describe the features, aetiology of a desensitisation block

Answer 20

physiological state of acetylcholine receptor closure during which the receptor is closed, and is not susceptible to opening in response to agonists (including acetylcholine).
This is distinct from a Phase I block (where it is fixed open) or a Phase II block (where it is competitively antagonised).
It is thought to be a physiologically normal state which these receptors can normally occupy during their routine function (a safety feature, supposed to prevent harmful repeated depolarisation)

Causes
AChE inhibitors in overdose - increase Ach binding
Neostigmine
Pyridostigmine
Agonists
Ach at high levels
SCh
Decamethonium
Antibiotics
Aminoglycosides
Anticonvulsants
Carbamazepine
Phenytoin
Ca channel blockers
Local anaesthetics/cocaine
Ketamine
Volatiles

Proposed mechanism – not fully understood
might be due to a certain acetylcholine receptor subtype that contains α8β2 subunits instead of α1β1.
subtype is especially stimulated at high concentrations of agonists, at which the ion channel opens with a high selectivity for calcium ions
Calcium activates protein kinase C on the inside of the postjunctional membrane, which in turn phosphorylates the “normal” (2α1β1δε) acetylcholine receptor, thereby desensitizing it

Implications
presence of desensitized receptors –> ↓ functional receptor channels available to induce a transmembrane current –> ↓ margin of safety of neuromuscular transmission –> ↑ the susceptibility to antagonists, i.e., NDMRs.
If many receptors are desensitized, insufficient nondesensitized normal receptors are left to depolarize the motor endplate, and effective neuromuscular transmission will not occur

characterised by:
Increased sensitivity to non-depolarising agents
Lack of reversal with the use of acetylcholinesterase blockers

Clinical relevance
? why we only give a certain amount of neostigmine post operatively, because too much can ? Cause post operative recurarisation through this method

Question 21

Describe the features, aetiology of a Channel Block

Answer 21

direct channel block
Non-competitive antagonism - because site of action is not at ACh binding site
Occur when molecules that bind to the AChR change its conformation in such a way that any further binding of ACh to the α subunit is prevented
cannot be reversed by acetylcholinesterase inhibitors
believed to play a role in some drug-induced alterations of neuromuscular function. E.g. antibiotics, cocaine, quinidine, piperocaine, tricyclic antidepressants, naltraxone, naloxone, and histrionicotoxin.
NDMRs can also cause channel block
If a profound paralysis by a NDMR is antagonized by AChE inhibtior.
↑[ACh] molecules displaces the NDMR.
ACh competitively prevents the muscle relaxant from binding to the α subunit.
channel is, however, kept open by acetylcholine.
NDMR which are still present at a high concentration, can then enter the open channel and block the receptor for a longer duration than the original block produced by binding at the α subunit.
acetylcholinesterase inhibitors by themselves can cause a channel block

Question 22

General PK features of all NMBAs - Absorption

Answer 22

Poor absorption; minimal oral bioavailability

Question 23

General PK features of all NMBAs - Vd

Answer 23

All have at least one positively charged quaternary amine group, which remains ionised independent of pH value.
The positive charge makes it almost impossible for muscle relaxants to bind to lipids. Therefore the volume of distribution (Vd) of muscle relaxants is almost exclusively in the extracellular space and consists of 0.2–0.5 L kg–1.
If muscle relaxants are administered over a prolonged period of time (> 24 hours), distribution into less perfused tissue occurs. resulting in a volume of distribution that can then increase up to 10x.

Question 24

General PK features of all NMBAs - PPB

Answer 24

muscle relaxants bind to plasma proteins, particularly to albumin and γ-globulins.
Values for % of protein binding are inconsistent and highly dependent on the method of determination
In the presence of inflammation, a protein called α1-acid glycoprotein ↑ in plasma. This protein binds to all muscle relaxants, resulting in a decreased free fraction in plasma.

Question 25

General PK features of all NMBAs - dosing in obesity

Answer 25

At normal doses, the positive charge of the muscle relaxant prevents its absorption into fat tissue. Therefore, the bodyweight-related volume of distribution (Vd kg–1), and clearance in obese patients is markedly reduced compared to normal patients. The elimination half-life, however, remains almost unaltered. AKA Vd proportional to LBM However, sux still dosed based on total body weight due to ↑ plasma cholinesterase relative to body weight

Question 26

General PK features of all NMBAs metabolism and elimination

Answer 26

Effect of a single dose of muscle relaxant primarily terminated by redistribution of drug from the NMJ and central compartment to the peripheral compartment. After repeated injection or continuous infusion, however, the redistribution capacity may become saturated, and the muscle relaxants and their active metabolites may be distributed back into the central compartment. In this case, neuromuscular recovery is determined primarily by the elimination of the drug.

Question 27

General PK features of all NMBAs - Renal insufficiency

Answer 27

If the renal function is impaired or completely absent, there is ↓ clearance (prolonged renal elimination) of relaxants. neuromuscular effect of a single injection of muscle relaxant is mainly terminated by redistribution --> ↓ renal elimination rate usually does not cause prolonged recovery times after a single dose After repetitive injections or continuous infusion, however, the decreased renal clearance of relaxants prolongs the neuromuscular effect of muscle relaxants eliminated primarily by the renal route. The activity of plasma cholinesterase is reduced in renal failure --> prolonged effect of succinylcholine and mivacurium altered fluid balances during dialysis change the Vd of the muscle relaxants, making it difficult to predict the neuromuscular blocking effect Changes in acid–base balance as well as electrolyte status

Question 28

General PK features of all NMBAs - Hepatic diseases

Answer 28

Liver failure often associated with secondary hyperaldosteronism, which results in fluid retention and an ↑ in the Vd of muscle relaxants. larger than normal doses must be administered to achieve a given paralysis. higher dose, once administered, may stay in the central compartment for a longer time because of poor elimination by the liver. Pts with hepatobiliary diseases often have a prolonged duration of action of muscle relaxants. After a single dose, however, the elimination (clearance) times are relatively unimportant because redistribution within the compartments is the major factor determining duration of action after repetitive or continuous administration of vecuronium, rocuronium, or pancuronium accumulation occurs (note metabolites may be pharmacologically active) ↓ plasmacholinesterase production atracurium and cisatracurium are independent of hepatic function The plasma protein deficiency associated with liver failure barely increases the free fraction of muscle relaxant, since the overall plasma protein binding of relaxants to albumin is relatively low.

Question 29

Sux - Structure

Answer 29

Two Ach molecules bound at acetate methyl groups (dicholine ester of succinate)

Question 30

Sux Metabolism

Answer 30

Question 31

Sux MoA

Answer 31

Partial Agonist at AChRs - binds α-δ and α-ε subunits at postsynaptic NAChR Mechanism Motor end plate RMP ~ -90mV Suxamethonium is an orthosteric agonist of the nicotinic receptor (binds to the receptor in the same place where the endogenous ligand would bind). Quaternary ammonium cations attach to one or both ⍺-subunits --> mimics actions of ACh --> Suxamethonium activates the nAChR - influx of Na/Ca and efflux of K leads to depolarisation of the end plate membrane (Na/Ca > K), The depolarised membrane produces a transient action potential. When the endplate potential reaches the threshold of around -70 mV, voltage-gated sodium channels open, and a wave of depolarisation spreads from the motor endplate. The suxamethonium continues to have an abnormally long effect on the receptor. The normal lifespan of acetylcholine in the synapse is < 1ms, owing to the enthusiastic activity of high-affinity acetylcholinesterase. suxamethonium, which is resistant to degradation, and which remains in position to stabilise the channel in an open but desensitised state Cation traffic therefore continues, and the membrane remains depolarized at ~ -30 to -60 mV. The partially depolarised junction achieves an inexcitable state. this insensitivity is due to the inactivation of perijunctional sodium channels which close, but never enter a "ready" active state, because the membrane around them is not back to its resting potential. Time dependent inactivation (h) gate then closes Inactivation gate cannot reopen until the voltage (m) gate closes Hence with continuous depolarisation the inactivation gate remains closed and propagation of AP to the sarcolemma is inhibited Phase I block or "accommodation block" is the term given to this state. The surrounding voltage-gated sodium channels therefore remain inactive. Because of this, pot-tetanic potentiation does not work - the release of extra acetylcholine does nothing to reverse the paralysis. During this time, it is still possible to stimulate the muscle directly using electrical current, and the twitches will all be of the same amplitude. Only require 20% of receptors to be activated (cf > 75% for NDMR) - hence faster onset Not degraded by AChE and hence able to repeatedly bind SCh remains at NMJ until it diffuses out into plasma down concentration gradient and is metabolised by pseudocholinesterase or renally eliminated The result is sustained AChR activation and depolarisation of the NMJ

Question 32

Why can sux not be reversed with AChEis

Answer 32

During a phase I block anything that increases the amount of acetylcholine at the junction (eg. acetylcholinesterase inhibitors) tends to deepen the block and increase its duration, as all the extra acetylcholine merely depolarises more receptors and makes the membrane even less likely to return to RMP

Question 33

How does sux block wear off

Answer 33

SCh remains at NMJ until it diffuses out into plasma down concentration gradient and is metabolised by pseudocholinesterase or renally eliminated NAChRs will close once sux unbinds and diffuses away from NMJ down concentration gradient --> ends the influx of Na/Ca and efflux of K --> busy little chloride and potassium channels start trying to repolarise it again, aiming to return to the resting potential of around -90 mV --> voltage (m) gate closes on sodium channels --> Time dependent inactivation (h) gate then closes --> end plate reset

Question 34

Describe the clinical response seen when sux is given. Why do we get fasciculations?

Answer 34

Biphasic response Initial muscle activity (fasciculations) Secondary period of muscle inactivity/relaxation Duration of block is dictated by the time to metabolise/eliminate SCh Termed accommodation During accommodation, neuromuscular transmission via ACh release is blocked When the endplate potential reaches the threshold of around -70 mV, voltage-gated sodium channels open, and a wave of depolarisation spreads from the motor endplate, creating the fasciculations we see Sux exerts pre-junctional action --> retrograde conduction up motor neuron --> triggers axon to depolarise entire motor unit --> fasciculation observed prior to onset of depolarising block

Question 35

Overview/list of adverse effects of sux

Answer 35

"Sassy, intelligent anaesthetic underdogs hustle and make senior males fucking horny – Machiavelli" Sux Apnoea Increased ICP, IOP, IGP Anaphylaxis Unsafe Paralysis Histamine Release Arrhythmias Malignant Hyperthermia Secretions (Increased Salivation and Gastric Secretions) Masseter Spasm Fasciculations Hyperkalemia Myalgia

Question 36

Expand on Sux Apnoea as an adverse effect

Answer 36

Two stage metabolism by plasma cholinesterase (PChE) to inactive products Two alleles for PChE. Variations: normal, dibucaine-resistant (DR), fluoride-resistant, silent Treatment: sedate and ventilate in ICU; consider FFP or dialysis Follow up: testing of patient and family

Question 37

Expand on Increased ICP, IOP, IGP caused by sux as an adverse effect

Answer 37

Transient and often not clinically significant Due to muscle contraction - can be attenuated by small dose of NDMR IOP Transient ↑IOP by 4–10mmHg, 1 min after administration, peaks at 2 – 4 min, resolved by 6 min Contraction of extraocular muscles, dilatation of choroidal blood vessels ↑Resistance to aqueous humour outflow Relatively contraindicated in open eye injury due to concerns re extrusion of ocular contents Offset by co-administration thopental IGP More variable than ↑IOP and likely related to fasciculation of abdominal muscles and ↑vagal tone (7-12 cm H2O increase) ↑Risk of regurgitation from ↑IGP is offset by concomitant ↑lower oesophageal tone Reduced oesophageal tone with paralysis may increase aspiration risk ICP Mechanism is unclear - relatively contraindicated in closed head injury due to concerns re causing coning

Question 38

Expand on sux anaphylaxis as an adverse effect

Answer 38

1 in 2000-2500 (population dependent) 1st exposure: activation of specific T cell, IgE produced by specific B cell, fixes on mast cells and basophils 2nd exposure: systemic degranulation of mast cells, IgE mediated

Question 39

Expand on sux unsafe paralysis as an adverse effect

Answer 39

Can’t intubate, can’t oxygenate -> desaturation -> death Can’t protect the airway -> aspiration

Question 40

Expand on sux histamine release as an adverse effect

Answer 40

Direct effect on mast cells. Not immune-mediated. Degranulation of mast cells H1 (Gq): Vasodilatation, capillary leak, ↓mAP ↓AV node conduction, coronary vasoconstriction Bronchoconstriction H2 (Gs): ↑contractility, coronary vasodilatation Bronchodilatation

Question 41

Expand on sux arrhythmias as an adverse effect

Answer 41

Sux binds all of the cholinergic receptors of the ANS Arrhythmias including tachycardia, bradycardia, junctional rhythms, and ventricular dysrhythmia may occur Ectopic beats common Bradyarrhythmia Stimulation of muscarinic ACh receptors in SA node and nAChR in parasympathetic ganglia May cause sinus brady, junctional escape rhythm or sinus arrest More likely in children due to high vagal tone More likely in adults after a repeat dose Tachyarrhythmias and hypertension Stimulation of NAChR in sympathetic ganglia and in adrenal glands ↑circulating catecholamines May cause sinus tachycardia or ventricular tachyarrhythmias Seen with large doses whether or not the sympathetic or parasympathetic action in the autonomic nervous system dominates is dependent on the pre-existing dynamic equilibrium. These dysrhythmic effects often are observed when high vagal tone is present, which is common in paediatric patients or after vagal stimulation induced by the laryngoscopy blade. Stimulation of other parasympathetically innervated structures (dilation of cervix, stimulation of carotid body or eyeballs) can potentiate the bradycardia By premedicating with atropine, bradyarrhythmias can be prevented; however, ventricular arrhythmias are not attenuated by atropine pretreatment.

Question 42

Expand on sux masseter spasm as an adverse effect

Answer 42

Exaggerated fasciculation Often in patients susceptible to MH or undiagnosed myotonia - initial sign in 25% of MH Can lead to difficulty in ventilating/oxygenating - use BMV and nasopharyngeal

Question 43

Expand on sux fasiculations as an adverse effect

Answer 43

Especially in muscular adults Several theories as to why fasciulations occur – exact mechanism unknown When the endplate potential reaches the threshold of around -70 mV, voltage-gated sodium channels open, and a wave of depolarisation spreads from the motor endplate, creating the fasciculations we see Sux exerts pre-junctional action --> retrograde conduction up motor neuron --> triggers axon to depolarise entire motor unit --> fasciculation observed prior to onset of depolarising block Moderate and severe fasciculations → ↑venous return → ↑ cardiac output, ↑ BP, ↑ ICP. Associated with ↑ electromyographic activity.

Question 44

Expand on sux Hyperkalaemia as an adverse effect

Answer 44

Increases K efflux via NAChR - in healthy patients increase of [K+] by 0.5 mmol/L May be significant if renal failure with existing ↑K+ Conditions muscular dystrophy esp Duchenne or Becker muscular dystrophy, Myotonic dystrophy Common in young male paediatric patients May be clinically unrecognised Burns Denervation conditions CVA, spinal cord injuries, para- and hemiplegia, GBS, MS, polyneuropathy, tetanus, severe Parkinson’s disease, diabetic neuropathy Severe skeletal muscle trauma Severe abdominal infections Metabolic acidosis and hypovolaemia botox Hyperkalaemia post-SCh is NOT seen in cerebral palsy or meningomyelocoele Pathophysiology Proliferation of immature extrajunctional Ach receptors and possible life threatening hyperkalaemia leading to cardiac arrest K increase of 3-5 mmol/L Lower density of receptors per area than mature NAChR, but greater total number Immature NAChR can remain open 10x longer = greater K efflux Upregulation of Ach receptors lasts up to 2 years The serum potassium level does not reflect the potential for increased potassium release from the muscle after succinylcholine injection. ECG changes (in order) Repolarisation abnormalities (tall T waves) >Atrial paralysis (small or absent P wave) Conduction delay (AV block, wide QRS) Cardiac arrest ~8-9mM (sine wave, asystole) Pre-existing hyperkaelaemia and renal failure per se are not contraindications to SCh use, BUT there is risk of producing rises in serum K+ to levels where there is a high risk of cardiac arrhythmias

Question 45

Expand on sux myalgia as an adverse effect

Answer 45

Incidence ~ 50% In facial, neck, intercostal and upper abdominal muscles More common in females, middle aged patients after early ambulation Proposed mechanism Muscle fiber damage during fasiculations Prevention: 5% ED95 non-depolarising relaxant prior (not very effective) Treatment: analgesia, NSAID (not very effective)

Question 46

NDNMRs - MoA

Answer 46

Competitive antagonists of Ach at the the post synaptic nicotinic AChR of the NMJ Final outcome (i.e. block or transmission) depends on relative concentrations and comparative affinities for the receptor. Higher concentrations of ACh can displace the antagonist from the receptor Antagonists bind AChR for roughly 1 ms, slightly longer than the lifespan of ACh Rapid cleavage of Ach by AChE shifts balance heavily into favour of antagonist The binding is dynamic with repeated association and dissociation Antagonist only needs to bind one of the ⍺ subunits of the AChR to prevent channel opening and ∴ depolarisation Ach needs to bind both alpha subunits to activate the NAChR - one low affinity and one high affinity site Further shifts balance in favour of antagonist ACh binding site on α/ε-subunit interface has a 5-10x greater affinity for non-depolarizing agents than comparable site on α/δ-subunit. Prevents end-plate potential from reaching threshold for AP propagation. >75% of postsynaptic nAChRs need to be blocked to affect contraction (large safety factor).

Question 47

NDMRs - Neuromuscular fade mechanism

Answer 47

Due to presynaptic binding of AChR which reduces positive feedback Presynaptic α3β2 AChR stimulate mobilisation of Ach vesicles for release Mobilises Ach vesicles toward the release sites but does not stimulate the actual process of Ach release Morphologically different to post-synaptic receptors Vecuronium most potent at these receptors, mivacurium least potent Inhibition of these receptors results in reduced mobilisation of Ach vesicles and thus reduced release of Ach with each subsequent stimulus resulting in diminishing contraction and fade Similar fade seen in myasthenia gravis

Question 48

NDMRs - Post-tetanic potentiation mechanism

Answer 48

in which a 5-second tetanic stimulation produces an amplified subsequent response to stimulation Tetanic stimulus mobilises prejunctional calcium and allows for the positive feedback on presynaptic AChR Previously unavailable Ach is released into the synaptic cleft, producing a transiently exaggerated response

Question 49

Salient features of aminosteroid compounds

Answer 49

Contain of a steroidal backbone to which ACh-like moieties are attached Do not cause histamine release Are dependent on organ function for elimination Vagolytic - pancuronium > Rocuronium > vecuronium Partially block cardiac muscarinic receptors

Question 50

Salient features of Benzylisoquinolinium compounds

Answer 50

Two quaternary ammonium groups joined by a methyl carbon chain Methyl carbon chain contains one or more chiral centres → stereoisomeric forms Lack any vagolytic effect but are more likely to release histamine Do not block cardiac muscarinic receptors More liable to break down in plasma than aminosteroids Autonomic ganglion blockade Mainly caused by d-tubocurarine Structure-activity: ↑risk if short interonium distance Effects: ↓HR, ↓mAP (i.e. no baroreceptor response)

Question 51

What is the difference between an ester and an ether linkage 

Answer 51

Sux, remifentanil, and esmolol all have the ester linkages and therefore can be broken down by plasma esterases The ether bond you see in volatile anaesthetics, which is hard to break down, volatiles barely get metabolised.

Question 52

Indications for Muscle Relaxation

Answer 52

Facilitation of airway instrumentation Whilst deep anaesthesia can allow for good intubating conditions – particularly in combination with high dose opioids – the best conditions are most reliable provided by muscle relaxation Facilitation of surgical access Peripheral surgery generally doesn’t require muscle relaxation However, intra-cavity surgery benefits from muscle relaxation Deep muscle relaxation (PTC 1–2) provides better surgical conditions than moderate relaxation (TOFC 1–2) during laparoscopic surgery Prevention of catastrophic movement When patient coughing or movement could prove to be catastrophic, eg during delicate neurosurgery or middle ear surgery, deep paralysis can prevent this possibility During ECT, inadequate muscle relaxation may result in bone fractures Tight control in critically ill patients ARDS Status asthmaticus ↑ICP Patient-ventilator dysynchrony

Question 53

What determines whether a NMBA will act via a non-depolarising vs a depolarising mechanism

Answer 53

Small molecules 'leptocurare' act as depolarising agents: ACh, sux and decamethonium Large molecules 'pachycurare' act as non-depolarising agents

Question 54

What is this molecule?

Answer 54

Acetylcholine

Question 55

What is this molecule?

Answer 55

Suxamethonium

Question 56

What is this molecule?

Answer 56

Mivacurium

Question 57

What is this molecule?

Answer 57

Atracurium

Question 58

What is this molecule? What structure confers a vagolytic effect

Answer 58

Pancuronium The quaternary group attached to the A-ring of the steroid backbone

Question 59

What is this molecule?

Answer 59

Rocuonium

Question 60

What is this molecule?

Answer 60

Vecuronium