Lecture 11: Neuromuscular blocking agents (NMBAs) Flashcards
What are Neuromuscular blocking agents used for? (NMBAs)
Neuromuscular blocking agents are used mainly by anaesthetists to 1) paralyse patients who are undergoing surgery or 2) requiring assisted ventilation in critical care units.
Where do the NMBA work?
NMBA act at the neuromuscular junction.
What does NMBA stand for?
Neuromuscular Blocking Agents
Can NMBAs be used in isolation?
No. They must be used in combination with anaesthesia and with all the precautions. There must also be resuscitation equipment available.
NMBAs do not cause _____ and they have no ______ or _____
NMBAs do not cause amnesia and have no sedative function or analgesic properties.
hey must be used in combination with anaesthesia and with all the precautions.
What are the 3 main uses of NMBAs?
1) The main reason we use NMBAs is to Facilitate intubation of the trachea.
An awake patient maintains their own airway, but once someone is under anaesthesia this is not the case and airway maintenance is crucial for good oxygenation.
Having a relaxed airway when intubating a patient decreases damage to the vocal cords and postoperative hoarseness.
2) We also use it to prevent any movement during delicate procedures (especially during intrathoracic and intra-abdominal procedures)
3) Also used in intensive care units to improve conditions for ventilation of critically ill patients. by removing the work of breathing, oxygen consumption is decreased and barotrauma to the lung is prevented. Ventilating patients can be used to lower intracranial pressure in neurosurgical patients.
What is Tracheal intubation?
Intubation is the placement of a flexible plastic tube into the trachea (windpipe) to maintain an open airway or to serve as a conduit through which to administer certain drugs.
It is frequently performed in critically injured, ill, or anesthetized patients to facilitate ventilation of the lungs, including mechanical ventilation, and to prevent the possibility of asphyxiation or airway obstruction.
What are the 3 entities of the Nueromuscular Junction?
1) Presynaptic - area where ACh synthesis and storage into vesicles, release of Ach and reuptake of choline back into the vesicles and where control of ion flow across the nerve terminal occurs.
This terminal nerve fibre and muscle unit is a motor unit
2) Synaptic cleft- approx 50nm gap. Within the cleft there are adhesion molecules such as acetylcholinesterases. This esterase degrades ACh into acetate and choline, therefore terminating its activity. Choline is taken up again into the presynaptic terminal for resynthesis to ACh.
3) Postsynaptic Membrane- primary has shallow and secondary has deeper clefts to give it a large surface area. In the depths between the folds, there is a high density of voltage-gated Na+ channels for amplifying AChR-induced depolarisation.
Describe the Quantal theory of ACh release
The Synaptic vesicles are clustered along thickened patches of the nerve terminal called: Active Zones
The Voltage-gated Ca2+ channels are arranged between the vesicles.
The number of quanta released is high and is proportional to the concentration of extracellular Ca2+ concentration and its influx into the nerve
About 50% of the released Ach is immediately hydrolysed by synaptic acetylcholinesterase present in the cleft.
More Ach is released than needed to bind with the receptor, therefore ensuring successful transmission is successful.
About 500,000 AChReceptors are activated. The Na+ and Ca2+ ions that flow through the AChR channels cause maximal depolarization of the endplate resulting in an endplate potential that exceeds the threshold for stimulation of the muscle.
Describe the molecular features of Acetylcholine Receptors
Nicotinic AChR are pentameric ligand-gated ion channels with 5 subunits (a, a, B, y, E) surrounding a central ion-conducting pore.
The alha subunits each bind ACh. Both alpha units must be bound simultaneously.
Binding causes a conformational change, opening a channel through which ions flow along a concentration gradient causing muscle fibre contraction.
Describe the action of Acetylcholinesterases
A carboxylesterase enzyme primarily in the synaptic cleft.
It is secreted by the muscle and is attached by collagen to the basal lamina.
ACh molecules not bound to the AChReceptor are rapdily hydrolysed to acetate and choline.
The choline is taken up again into the nerve terminal and is resynthesised to ACh ready for new action potentials and rerelease.
What are different ways of classifying NMBAs?
1) Depolarising muscle relaxants vs Non-depolarising
2) Chemical structure
3) Duration of action
Name a depolarising muscle relaxant
Succinylcholine
Describe how a specific depolarising muscle relaxant works
Succinylcholine (sux)
Ssuccinylcholine is structually similar to ACh (comprised of 2 ACh molecules bound at their acetate methyl groups).
SCh acts by binding to the AChR and mimics the effect of ACh by opening the ion channel, allowing ion flow and endplate depolarisation (AGONIST).
SCh has a biphastic effect on the muscle. Initially there is a depolarization followed by relaxation, which lasts 3-5 minutes.
SCh is not hydrolysed by acetlycholinesterase in the cleft (which is why it has a much longer effect than ACh)
The nueromuscular blocking activity is terminated by diffusion out of the NMJ into the plasma where it is hydrolysed by plasma cholinesterase into succinlymonochloline and choline.
The duration of the block (paralysis) depends on the time taken to hydrolyse or excrete the drug.
Describe the side effects and disadvantages of succinylcholine
1) SCh cannot be reverse by other drugs
2) Anaphylaxis to SCh is 1: 5000 to 1: 10000
3) Fasciculations (90% show this) and some show myalgia. It is benign but unleasant.
4) Cardiac dysrhythmias are not uncommon. (Bradycardias are more common but tachycardias can cause a significant risk)
5) Hyperkalaemia (increase in serum K+ due to depolarisation). If the patient has pre-existing hyperkalaemia (renal failure) or those with spinal cord injuries, muscular dystrophy, burns, severe stroke and crush injuries the potassium rise canr reach levels which predisposes the patient to cardiac arrhythmias and/or cardiac arrest.
6) Increased intracranial pressure- transient but can be danagerous in brain injuries.
7) Increased intragatsric pressure
8) Increased intraocular pressure
9) SCh is also a potent trigger for Malignant hyperpyrexia - potentially lethal condition.
What does fasciculations mean?
a brief spontaneous contraction affecting a small number of muscle fibres, often causing a flicker of movement under the skin.
What is Malignant hyperpyrexia?
Malignant hyperpyrexia is a dangerous complication of general anesthesia occurring in individuals with an underlying disease of muscle.
The essential clinical features of the syndrome are a drastic and sustained rise in body temperature, metabolic acidosis, and widespread muscular rigidity.
If there are such large number of side effects and disadvantages to Succinylcholine, why do we still use it?
SCh provides the quickest and most reliable relaxation for airway control
It gives excellent intubating conditions, with minimal time for aspiration in patients with full stomachs
It is mostly used in emergency situations.
Which NMBAs is often used in emergency situations? Why?
Succinylcholine.
SCh provides the quickest and most reliable relaxation for airway control
It gives excellent intubating conditions, with minimal time for aspiration in patients with full stomachs
It is mostly used in emergency situations.
Describe the Mechanism of action of Non-depolarising Neuromuscular Blocking Agents
Non-depolarising NMBAs are positive charged quaternary N compounds.
They block neuromuscular transmission by competitive antagonism of ACh at the ACh receptor.
They can bind to one or both of the alpha subunits of teh AChR which prevents binding of ACh, which prevents the opening of the ion channel.
Because only 1 molecule of NMBA is needed to prevent activation of the receptor and 2 ACh are required to open it, this bias favours the antagonist NMBA.
Neuromuscular blockade starts when >70% receptors are occupied and is complete when >90% are occupied by the NMBA
The effect of non-depolarsing NMBA depends on ________–
depends on the relative concentrations of ACh and drug (NMBA).
Neuromuscular blockade starts when >70% receptors are occupied and is complete when >90% are occupied by the NMBA
Name 5 Non-depolarising NMBAs
1) Atracurium
2) Mivacurium
3) Rocuronium
4) Vecuronium
5) Pancuronium
What are 2 ways of classifying Non-depolarising NMBAs?
Chemical Structure
1) Aminosteroids (monoquaternary ammonium attached to a steriod group)
- rocuronium
- vecuronium
- pancuronium
2) Benzylisoquinolones (2 quaternary ammonium groups joined by a chain of methyl groups)
- atacurium
- cistracurium
- mivacurium
Duration of action
1) Short acting (10-15 min)
- mivacurium
2) Intermediate acting (25-40 min)
- atracurium
- vecuronium
- recouronium
3) Long acting (40-90min)
- pancuronium
Describe Atracurium
1) Classification
2) Pathways of elimination
3) Side effects
4) Advantages
Chemical structure: Benzylisoquinolones (biquaternary ammonium benzylisoquinolone)
Duration: Intermediate duration (40 mins) with an onset of 3-5 minutes.
Pathways of elimination:
1) Hofmann eliination- nonenzymatic, temperature and pH dependent breakdown to laudanosine and acrylates
2) Nonspecific ester hydrolysis
- The inactive breakdown products are excreted by the kidneys. Hofmann elimination is primarily responsible for inactivation with ester hydrolysis.
Side effects:
1) Dose-related histamine release (usually only manifest as skin rash but can cause hypotension and tachycardia)
Advantages
1) Because of Hofmann elimination, the duration is not prolonged in older patients and those with renal dysfunction.
Describe Mivacurium
1) Classification
2) Pathways of elimination
3) Side effects
4) Advantages
Chemical structure: Benzylisoquinolones (mixture of 3 isomers)- 3 times more potent than Atracurium
Duration: Short duration
Pathway of elimination: Hydrolysed by pseudocholinesterase (like SCh) but it is a non-depolarising NMBA
Side effects:
1) Histamine release (less than atacurium)
2) (Any condition causing abnormal pseudocholinesterase) will cause a delay in recovery
Used in:
1) Ambulatory surgery when shorter acting drugs are preferable.
Compare and contrast Atracurium and Mivacurium
Mivacurium is 3x more potent than Atracurium,
However mivacurium has a short duration but atracurium has an intermediate duration.
Also both cause histamine release, but mivacurium causes less histamine release than atracurium
Compared and contrast Mivacurium and Succylcholine
Both hydrolysed by Pseudocholinesterase
But SCh is a depolarising NMBA, whilst Mivcurium is a non-depolarising NMBA.
What NMBA is used in Ambulatory surgeries?
Mivacurium
Describe Recuronium
1) Classification
2) Pathways of elimination
3) Side effects
4) Advantages
Structure: Monoquaternary aminosteroid
Duration: rapid onset and intermediate duration of action
Elimination
1) 90% hepatic and 10% renal.
Side effects
1) Anaphylaxist (higher rate in NZ and Aussie)
2) Cardiac effeccts and histamine release are small
Advantages
-Used for rapid sequence induction instead of SCh (although its duration of action is longer)
Describe Vecuronium
1) Classification
2) Pathways of elimination
3) Side effects
4) Advantages
Structure: Aminosteroid
Duration: Intermediate duration and slow onset
Elimination: Active metabolites are excreted in the urine- so it accumulates in renal failure
Side effects: Cardiovascular
Advantages: Useful in patients with cardiac disease and has the least potential for anaphylaxis and histamine release.
What NMBA should NOT be used in renal failure patients?
Vecuronium
Eliminated via urine excretion, so it accumulates in renal failure patients.
Describe Pancuronium
1) Classification
2) Pathways of elimination
3) Side effects
4) Advantages
Structure: Bisquaternamry aminosteroid
Duration: Long duration
(high potency and slow onset of action)
Elimination:
Renal and hepatic
Side effects:
1) Raised blood pressure (vagolytic effects), increased heart rate and cardiac output, making it ideal for long cardiac surgical procedures
2) It is more difficult to reverse than the shorter acting non-depolarising NMBAs.
Advantages:
Minimal histamine release
Which NMBA has the longest duration?
Pancuronium (1-2 hours)
In long cardiac surgical procedures, what NMBA is idea?
Pancuronium
Describe the features of an ‘ideal’ muscle relaxant/NMBA
1) Rapid onset
2) Titratable effect (can control exact amount of drug)
3) Moderately rapid offset
4) Easily reversible
5) No histmine release or anaphylaxis
6) No haemodynamic side effects
7) Inactive metabolites
8) No propensity to accumulate
9) low cost.
What are 2 strategies for reversal of NMBAs
(note Succinylcholine is not reversible by any drug)
1) Titrate perfectly for duration of action which is very difficult to do as both patients and surgeons are unpredictable.
2) Accelerate reversal. This is safer and more reliable and can be achieved by either
a) increasing the concentration of the competitor, ACh at the acetelycholine receptor or
b) by decreasing the plasma concentration of NMBA
Why do we want to reverse the drug?
1) It is crucial that patients leave the operating room with unimpaired muscle strength. Residual paralysis in the recovery room has been shown to be associated with significant morbidity.
2) The respiratory and upper airway muscles must function normally so that breathing is unimpaired and aspiration is prevented.
Anticholinesterases are only given once spontaneous recovery of neuromuscular function has begun.
How do we increase the ACh concentration at the nicotinic acetylcholine receptor?
Anticholinesterase drug inhibit accetylcholinesterase.
e.g. neostigmine and pyridostigmine
Acetylcholinesterase is the enzyme in the synaptic cleft that hydrolyses ACh to choline and acetate.
Inhibiting this hydrolysis will increase the concentration of ACh at the motor end plate - which tilts the competition for the AChR in favour of ACh and reverses the neuromuscular blockade.
Name 2 anticholinesterase drugs
(reverse non-depolarizing NMBAs)
1) Neostigmine (routinely used)
2) Pyridostigmine
What are some side effects to Anticholinesterases
All act on the cholinergic synapses in the peripheral NS, which casues unwanted side effects.
They have potent parasympathetic activity and vagal effects, which causes bradycardia and bradyarrhythmias, bronchospasm, increased salivation and bowel motility.
Therefore Atropine and glycopyrrolate are antimuscarinic agents, which block these unwanted side effects so are given in combination with the anticholinesterase, neostigmine for reversal of NMBAs
When you want to reverse NMBA what drugS should you give the patient?
1) Neostigmine (or another anticholinesterase)
2) Atropine
3) Glycopyrrolate
The bottom two are to reverse unwanted side effects of the anticholinesterase.
When are the anticholinesterases often given?
Only given once spontaneous recovery of neuromuscular function has begun.
If the NMBA is not metabolized faster than the anticholinesterase, then neuromuscular lock can recur (recurarisation)
(should see the start of the 4th twitch in TOF before the reversal is started)
What is the perfect antidote for recuronium and vecuronium?
Why?
Sugammadex
It restores normal neuromuscular function by selectively binding to recouronium and rendering it incapable of binding to the ACChR
The tight 1:1 binding in plasma leads to a decrease in the free (unbound) recuronium
This favours movement of recuronium from the NMJ to the plasma and decreases neuromuscular blockade
Return of muscle function occurs within 2 minutes.
What is Sugammadex?
perfect antidote for recuronium (and to a lesser degree- vecuronium)
It restores normal neuromuscular function by selectively binding to recouronium and rendering it incapable of binding to the ACChR
The tight 1:1 binding in plasma leads to a decrease in the free (unbound) recuronium
This favours movement of recuronium from the NMJ to the plasma and decreases neuromuscular blockade
Return of muscle function occurs within 2 minutes.
Describing the monitoring of neuromuscular blockade
There is considerable patient variability in the effects of the NMBAs and the potential adverse consequences.
To test the function of the NMJ, a peripheral nerve is stimulated electrically and the response of the muscle is assessed.
A nerve stimulator is connected to the patient at the ulnar nerve. 4 stimuli are given, 0.5 s apart at a frequency of 2Hz.
The movement of the adductor pollicis muscle of the thumb is observed and the relative magnitude of each twitch is assessed.
This is called the Train of Four.
The 2 measurements made are TOF count and the TOF ratio.
TOF count is the number of twitches seen after 4 stimuli are given
TOF ratio is the ratio of the 4th to the 1st twitch as a percentage, T4/T1
Intact nueromuscular transmission reveals 4 twiches of identical height, a TOF count of 4 and a TOF ratio of 1.
Complete NMBlockade reveals a TOF of 0 and therefore a TOF ratio of 0.
When recovering from the neuromuscular block, the twitches return. Return of 1st twitch is a TOF count of 1, followed by consecutive recovery of 2nd, 3rd and 4th twitches (TOF counts of 2, 3, and 4 respectively).
If the 4th twitch is 50% height of the 1st the TOF count is 4 and the TOF ratio is 0.5
TOF fade may be present. TOF fade represents a deficiency of neuromuscular transmission that requires intervention.
Fade is only seen with non-depolarising NMBAs.
The diaphragm is less susceptible than peripheral muscles and upper airway muscles, the laryngeal adductors
The daiphragm recovers function faster than muscles int he extremity e.g. addutor pollicis.
Adductor pollicis TOF count is a surrogate measure of muscle recovery
Describe how the Train-of-four studies are undertaken
A nerve stimulator is connected to the patient at the ulnar nerve. 4 stimuli are given, 0.5 s apart at a frequency of 2Hz.
The movement of the adductor pollicis muscle of the thumb is observed and the relative magnitude of each twitch is assessed.
The 2 measurements made are TOF count and the TOF ratio.
TOF count is the number of twitches seen after 4 stimuli are given
TOF ratio is the ratio of the 4th to the 1st twitch as a percentage, T4/T1
Intact nueromuscular transmission reveals 4 twiches of identical height, a TOF count of 4 and a TOF ratio of 1.
Complete NMBlockade reveals a TOF of 0 and therefore a TOF ratio of 0.
When recovering from the neuromuscular block, the twitches return. Return of 1st twitch is a TOF count of 1, followed by consecutive recovery of 2nd, 3rd and 4th twitches (TOF counts of 2, 3, and 4 respectively).
If the 4th twitch is 50% height of the 1st the TOF count is 4 and the TOF ratio is 0.5
TOF fade may be present. TOF fade represents a deficiency of neuromuscular transmission that requires intervention.
Fade is only seen with non-depolarising NMBAs.
The diaphragm is less susceptible than peripheral muscles and upper airway muscles, the laryngeal adductors
The daiphragm recovers function faster than muscles int he extremity e.g. addutor pollicis.
Adductor pollicis TOF count is a surrogate measure of muscle recovery
______________ is a surrogate measure of muscle recovery
Adductor pollicis TOF count is a surrogate measure of muscle recovery
What is another way of measuring the muscle recovery after NMBAs (aside from TOF)
Double Burst (DB) stimulation
It compares fade of 2nd twitch to the 1st.
It is possibly more accurate and easier to visualise
2-3 short bursts of high freq ettanic stimulation is administered, followed by 2nd series of short bursts, each resulting in a single twitch.
The 2 twitches are compared.
Full recovery is 2 equal twithces
Both TOF and DB as used in clinical stiuations require visual (qualitative) not measured (quantitative) assessment.
It is difficult to “eyeball” the response accurately between TOF ratio 0.5 and 1.
What are some dangers of residual blocks?
1) Ventillatory response to hypoxia is impaired and odes not return to normal until TOFR > 0.9
2) reduced pharyngeal muscle coordination with TOFR 0.6-0.8 Risk of airway collapse.
Increase mortality and morbidity if patient has residual block
Asipriation, hypoxia and death!
reversal drug is only given when a 4th twitch is visible, that is once spontaneous recovery has begun.
