Muscle relaxants and reversal agents Flashcards
How does signal transmission occur at the neuromuscular junction?
The neuromuscular junction is a synapse between a motor neurone and a muscle fibre. Each motor neurone synapses with several muscle fibres to form a motor unit. Each muscle fibre only has one neuromuscular junction. Acetylcholine is the neurotransmitter at the neuromuscular junction
- As a motor neurone approaches a muscle fibre it divides into several terminal branches. Acetylcholine is synthesized and stored in the terminal bulb of the motor neurone. There are active stores which are immediately available for release, and deep stores which act as reserves. Nerve signals are transmitted along the motor neurone to the terminal bulb. Depolarization causes opening of voltage-gated Ca2+ channels then triggers fusion of vesicles containing acetylcholine with the pre-synaptic membrane. Acetylcholine is then released into the synaptic cleft
- The synaptic cleft is the space between the terminal bulb of the motor neurone and the motor end plate. It is approximately 50nm wide and filled with interstitial fluid
- Nicotic acetylcholine receptors are present with the post-synaptic membrane of the motor end plate. The adult receptor has 2 α subunits and an acetylcholine molecule must be bound to a binding site on each α subunit to take effect. Binding of one molecule to one of the sites facilitates the binding of a second molecule at the other site. A conformational change occurs in the receptor which opens the central ion channel. The predominant effect is Na+ ion influx, however the channel is non-selective and influx of other cations such Ca2+ may occur, whilst K+ efflux may occur down its concentration gradient. Voltage-gated Na+ channels open in the motor end plate when the threshold potential is reached, resulting in rapid depolarization and generation of an action potential
- The pre-synaptic membrane also has acetylcholine receptors, which cause mobilization of deep acetylcholine stores and further release of acetylcholine into the synaptic cleft in a positive feedback mechanism
- Acetylcholine is metabolized to choline and acetate by acetylcholinesterase, which is present in the junctional folds of the muscle membrane
What is the structure and function of the nicotinic acetylcholine receptor?
Pentameric (5 subunits)
* 2x α subunits - where ACh binds
* β
* δ
* γ (foetal) or ε (adult)
Binding of ACh causes a conformational change to allow an influx of Na+ ions and subsequent membrane depolarization
How does depolarizing neuromuscular blockade occur?
Suxamethonium is the only depolarizing muscle relaxant used in clinical practice
It can be considered to be a partial agonist at the nicotinic acetylcholine receptor, as its binding stimulates the effect of depolarization in the motor end plate and muscle contraction (fasciculation). Neuromuscular blockade is essentially caused by the persistent binding of the drug to the receptor. The block is ‘non-competitive’ despite binding at the ligand receptor site, because increasing the concentration of the ligand (ACh) will not overcome the neuromuscular blockade
Each suxamethonium molecule binds to one of the acetylcholine binding sites at the nicotinic acetylcholine receptor, causing a conformational change and cation influx which leads to depolarization of the motor end plate. Suxamethonium is not broken down by acetylcholinesterase which is present within the synaptic cleft, and so continues to stay bound to the receptor. This causes persistent depolarization of the motor end plate which prevents further stimulation (which would require repolarization to have occurred) and inactivates nearby voltage-gated Na+ channels
The desired clinical effect of rapid, profound but brief neuromuscular blockade is described as ‘phase I’ neuromuscular blockade. Acetylcholinesterase inhibitors will potentiate phase 1 neuromuscular blockade and have no role in reversal. Volatile agents, magnesium and lithium may also potentiate the block
What is phase 2 depolarizing blockade?
Phase 2 neuromuscular blockade can occur following repeated doses or an infusion of a depolarizing muscle relaxant
The mechanism of phase 2 blockade is not fully understood, but may involve either desensitization of the post-synaptic membrane, or blockade at presynaptic receptors reducing the synthesis and mobilization of ACh
Phase 2 blockade is prolonged and may last for several hours. The results produced by a nerve stimulator are similar to those seen after a non-depolarizing muscle relaxant is used - i.e. the TOF ratio is reduced, tetanic fade is present, and post-tetanic potentiation occurs
The effects of phase 2 blockade can be antagonized by acetylcholinesterase inhibitors, however this is not recommended clinically due to variable effect / duration of effect
What results does a nerve stimulator produce if a depolarizing muscle relaxant has been administered? (in partial blockade)
Reduced amplitude of all twitches
No fade
TOF ratio maintained at or close to 1
No post-tetanic potentiation
Suxamethonium
Chemical - The dicholine ester of succinic acid. Two molecules of acetylcholine joined back to back at the acetyl group
Uses - Rapid onset, brief neuromuscular blockage - e.g. RSI
Presentation - Clear aqueous solution containing 50mg/ml of suxamethonium chloride, stored at 4 degrees C
Action - Depolarizing neuromuscular blockade
Dose / duration / route
* IV: 1-2mg/kg, effects last 3-5mins
* IM: up to 2.5mg/kg
Effects
* CVS - Repeat doses may produce bradycardia due to muscarinic receptor stimulation
* Resp - Respiratory arrest
* CNS - Initially causes fasciculations followed by phase 1 depolarizing block. Intracranial pressure is increased
* Other - Intraocular pressure raised. Increases intragastric pressure, however lower oesophageal sphincter tone also increases
Toxcity / side effects
* Myalgia
* Hyperkalaemia - A small rise in serum K+ is expected, however the effect may be exaggerated in burns patients or those with neuromuscular or denervation disorders - due to the development of extrajunctional acetylcholine receptors (which are of the foetal subtype). These immature receptors have ion channels which open for much longer when the receptor is activated, resulting in greater efflux of K+ ions. Burns patients are at risk from around 24 hours post-injury for up to 18 months. The period of particular risk in paraplegic patients is the first 6 months, however the risk continues in progressive disease
* Malignant hyperthermia trigger
* Anaphylaxis - most common trigger of all neuromuscular blocking agents
* Prolonged block - Repeated doses / infusions may cause a prolonged type 2 depolarizing block
* - Suxamethonium apnoea - Plasma cholinesterase abnormalities may result in prolonged apnoea. These may be inherited - the most common abnormal alleles being atypical, silent and fluoride-resistant - all on chromosome 3. Dibucaine is an amide local anaesthetic that inhibits the variants of plasma cholinesterase by various amounts. The dibucaine number indicates the % inhibition of a specific type of plasma cholinesterase, and may be used to give an indication of the subtype present. Acquired causes of plasma cholinesterase deficiency include: Pregnancy, liver disease, renal failure, heart failure, thyrotoxicosis, cancer, drugs including metoclopramide, ketamine, OCP, lithiuim, lidocarine, pancuronium, cytoxic agents. The general management involves ongoing mechanical ventilation until the block resolves, however FFP could be used as a source of plasma cholinesterases
Absorption - IV administration the usual route - ?high bioavailability of IM
Distribution - Initial rapid redistribution phase contributes to the brief duration of action. Appears to be protein-bound to an unknown extent. All muscle relaxants are highly ionized at physiological pH and therefore poorly lipid soluble with a small volume of distribution - they cannot cross the BBB and have no effect on the CNS
Metabolism - 80% of an administered dose is hydrolysed before it reaches the neuromuscular junction. Suxamethonium undergoes rapid hydrolysis by plasma cholinesterase to succinylmonocholine (weakly active) and choline. Succinylmonocholine undergoes further hydrolysis by plasma cholinesterase to produce succinic acid and choline. Plasma cholinesterase is found in the liver and plasma, and is not present at the NMJ
Excretion - Less than 10% excreted unchanged in the urine
Suxamethonium apneoa
Suxamethonium apnoea occurs due to a deficiency or abnormality of plasma cholinesterase, which results in prolonged neuromuscular blockade due to impaired metabolism of suxamethonium
Inherited
* The ‘normal’ genotype for plasma cholinesterase activity is Eu:Eu (homozygous
* The inheritance of abnormal cholinesterase is linked to several autosomal recessive genes, which can be classified according to their %inhibition when exposed to dibucaine or fluoride. The common abnormalities may be grouped into atypical, silent or fluoride-resistant
Acquired
* Most cases result in prolongation of action for no more than 30 minutes
* Reduced plasma cholinesterase concentration - Liver disease, pregnancy, chronic renal failure, hypothyroidism
* Reduced plasma cholinesterase activity - Ester local anaesthetics, ketamine, acetylcholinesterase inhibitors, OCP, lithium, metoclopramide
The general management involves ongoing mechanical ventilation and sedation until the block resolves. FFP could be used as a source of plasma cholinesterases, but is generally not recommended due to the risks of infusing a blood product outweighing the benefits of a relatively small reduction in block resolution time
Note - The action of mivacurium would also be prolonged, as it is also metabolized by plasma cholinesterase
How does non-depolarizing neuromuscular blockade occur?
Non-depolarizing muscle relaxants work by competitive antagonism at the nicotinic acetylcholine receptor. More than 70% of receptors must be blocked before muscle contraction fails. The competitive antagonism can be overcome by increased amounts of acetylcholine at the NMJ, as occurs when an acetylcholinesterase inhibitor is given
There are two main types of non-depolarizing muscle relaxants:
* Aminosteroids - Rocuronium, vecuronium, pancuronium
* Benzylisoquinolinium compounds - Atracurium, mivacurium, tubocurarine
What results does a nerve stimulator produce if a non-depolarizing muscle relaxant has been administered? (in partial blockade)
Fade
Reduced TOF ratio
Post-tetanic potentiation
What factors prolong the duration of action of non-depolarizing muscle relaxants?
- Hypokalaemia
- Hypocalcaemia
- Hypermagnesaemia
- Hypoproteinaemia
- Dehydration
- Acidosis
- Hypercapnia
- Drugs - volatile agents esp. isoflurane, induction agents, fentanyl, suxamethonium, diuretics, CCBs, alpha and beta blockers, lidocaine, metronidazole and aminoglycoside antibiotics
Rocuronium
Chemical - Monoquaternary aminosteroid
Uses - To facilitate tracheal intubation, RSI, and maintain muscle relaxation e.g. to allow mechanical ventilation
Presentation - Clear, colourless solution containing 10mg/ml of rocuronium bromide. Stored in fridge at 2-8 degrees C, but stable and can be used for up to 12 weeks if the temperature is below 30 degrees C. Should be protected from light
Action - Competitive antagonism at the nicotonic acetylcholine receptor of the NMJ to cause non-depolarizing neuromuscular blockade
Dose / duration / route
* IV normal intubating dose: 0.6mg/kg - intubating conditions in ~2mins
* IV RSI dose: 1-1.2mg/kg - intubating conditions in <1min
* (Ideal body weight should be used in morbid obesity)
* Duration of effects depends on dose given
* Rocuronium has a relatively rapid onset in clinical use due to its low potency - a high dose must be given which produces a large concentration gradient from the plasma to the NMJ
Effects
* CVS - Large dose may cause slight rise in heart rate and BP due to vagal blockade
* Resp - Apneoa
* CNS - No effect
Toxcity / side effects
* Anaphylaxis is relatively rare
* Pain on injection
Absorption - IV administration
Distribution - 30% protein binding. All muscle relaxants are highly ionized at physiological pH and therefore poorly lipid soluble with a small volume of distribution - they cannot cross the BBB and have no effect on the CNS
Metabolism - No metabolites
Excretion - Primarily by hepatic uptake and excretion unchanged in the bile, with a smaller amount excreted unchanged in the urine
Can be reversed using neostigmine or sugammadex
Vecuronium
- Monoquaternary aminosteroid
- Presented as a yellow freeze-dried powder for reconsitution, as it is unstable in solution. Vecuronium is diluted in water before use to produce a 2mg/ml clear, colourless solution
- IV intubating dose: 0.1mg/kg achieves intubating conditions within 2 minutes, and has a medium duration of action ~25 - 40 minutes
- No effects on CVS, and not associated with histamine release
- May be associated with critical illness myopathy
- Metabolized by decacetylation in the liver - produces active metabolites but little clinical significance due to low concentrations and short half lives. Biliary and renal excretion of metabolites and unchanged drug
- Can be reversed by neostigmine or sugammadex
Pancuronium
- Bisquaternary aminosteroid
- Clear, colourless solution of 2mg/ml stored at 2-8 degrees C, but stable at room temperature for up to 6 months
- IV intubation dose: 0.1mg/kg achieves intubating conditions within 2 - 2.5 minutes, and has a relatively long duration of action ~45 - 60 minutes
- Causes tachycardia due to inhibition of cardiac muscarinic receptors
- Metabolized by deacetylation in the liver, which are then excreted in the bile - has active metabolites. ~50% excreted in urine as unchanged drug
Atracurium
Chemical - Bisquaternary benzylisoquinolinium ester which is a mixture of ten stereoisomers due to the presence of four chiral centres
Uses - Facilitate intubation and controlled ventilation
Presentation - Clear, colourless solution containing 10mg/ml of atracurium besilate. Stored in fridge at 2-8 degrees C. Should be protected from light
Action - Competitive antagonism at the nicotinic acetylcholine receptor of the NMJ to cause non-depolarizing neuromuscular blockade
Dose / duration / route
* IV intubation dose: 0.3 - 0.6mg/kg. A dose of 0.5mg/kg should result in intubating conditions within 2 minutes. Initial dose lasts around 30mins
* IV maintenance dose: 0.1 - 0.2mg/kg
Effects
* CVS - Histamine release may cause hypotension
* Resp - Apnoea. Histamine release may cause bronchospasm
* CNS - No effect
Toxcity / side effects
* Histamine release with larger doses may lead to localized erythema / cutaneous flushing, hypotension, bronchospasm
* Anaphylaxis is relatively rare
* Associated with critical illness myopathy when administered as an infusion in critical care
Absorption - IV administration only
Distribution - ~80% protein binding. All muscle relaxants are highly ionized at physiological pH and therefore poorly lipid soluble with a small volume of distribution - they cannot cross the BBB and have no effect on the CNS
Metabolism
* Hofmann degradation (primary pathway) - Spontaneous breakdown of atracurium occurs at physiological pH and temperature to produce laudanosine and a quaternary monoacrylate (inactive)
* Hydrolysis by non-specific esterases (minor pathway) - Produces a quaternary alcohol and a quaternary acid
* The metabolism of atracurium is independent of hepatic or renal function, and therefore may be preferred in patients with organ failure
Excretion - Biliary and renal excretion of metabolites
Note - Cisatracurium is one of the stereoisomers which is present in the formulation of atracurium. It is more potent than atracurium, and therefore has a slower onset because a lower dose is used. It is associated with less histamine release
Mivacurium
- Benzylisoquinolinium ester. Chiral mixture of three stereospecific isomers
- IV dose: 0.07 - 0.25mg/kg. The recommended dose for intubation is 0.2 - 0.25mg/kg which will achieve intubating conditions in ~2 minutes, and a clinically effective block for ~20 - 25 minutes
- Short duration of action due to rapid metabolism (hydrolysis) by plasma cholinesterases - therefore blockade may be prolonged in patients with reduced / abnormal plasma cholinesterases (as with suxamethonium)
- Associated with histamine release
