Flashcards in 11 - NMBAs Deck (64):
- d-Tubocurarae 500 years ago by hunters
- first isolated in 1930s
- first used clinically in 1940s to induce neuromuscular blockade
What are NMBAs?
Used to paralyse patients during surgery and for patients requiring assisted ventilation. They act on the NMJ.
What are NMBAs not?
NMBAs do not cause sedation or analgesia or amnesia.
Can be NMBAs be used in isolation?
Balanced anaesthesia - sleep (anaesthetic), analgesia (opioid), muscle relaxation (NMBA)
What is the main clinical use of NMBAs?
To facilitate intubation of the trachea (relaxes)
When someone is under an anaesthetic they cannot maintain their own airways.
Why does the airway need to be relaxed during airway maintenance under anaesthetic?
Decreases damage to vocal cords and post-operative hoarseness caused by intubation.
Other clinical uses of NMBAs?
Facilitates intubation of the trachea.
Decreases vocal cord injury and post op hoarseness.
Control of ventilation intra-operatively.
Facilitates surgical exposure - esp abd and thoracic surgery.
Prevents deleterious movement during delicate surgery.
NMBA use in intensive care?
Improves conditions for ventilation of critically ill patients by removing the work of breathing. Therefore reduces oxygen consumption, reduces the risk of barotrauma to the lungs and prevents increases in intra-cranial pressure
What is intubation?
Insertion of an endotracheal tube for airway protection and ventilation
Parts of the NMJ - Pre-synaptic terminal
- ACh synthesis and storage in vesicles
- release of ACh and re-uptake of choline after ACh hydrolysis back into vesicles
- control of ion flow across the nerve terminal
- MN divides into 20-100 unmyelinated fibres each which innervate just one muscle fibre (motor unit)
Parts of the NMJ - Synaptic cleft
- 50nm gap between nerve terminal and muscle endplate.
- Contains the basal lamina which has adhesion molecules like AChEsterase > acetate and choline
Parts of the NMJ - Post-synaptic motor end plate
- Contains the AChRs
- at the peaks are AChRs while in the clefts are volt gated Na+ receptors for amplifying AChR-induced depolarisation.
Sequence of events at the NMJ?
- distal motor nerve is stimulated by an AP
- opens volt gated Ca++ channels
- Ca++ influx into nerve terminal
- fusion of ACh vesicles to the pre-synaptic membrane
- ACh binds to post synaptic nicotinic AChRs
> heteropentameric ligand gated ion channels
- Na+ influx
- endplate depol and muscle contraction
Where do the synaptic vesicles cluster?
Thickened patches of the nerve terminal called the active zone
The volt gated Ca++ channels are found between these vesicles
What is the quantal theory of ACh release?
The number of quanta released is high and proportional to the conc of extra-cellular Ca conc and its influx into the nerve terminal.
What % of the ACh is immediately hydrolysed?
More Ach is released than is needed to bind with the receptor - ensuring transmission is successful
[200 quanta each with 5000 molecules of ACh)
Maximal depol of end plate > end plate potential that exceeds the threshold for stimulation of the muscle
Features of the nicotinic AChR?
- pentameric ligand gated ion channel
- 5 subunits with each being made of 400-500 aa's (the 2 alpha subunits bind ACh and must be bound simultaneously)
- they are synthesised in muscle cells and are anchored to the endplate
- synaptic cleft and smaller amounts in the extra-junctional area
- is secreted by the muscle and anchored to the basal lamina by collagen
What happens to the choline?
How do you classify NMBAs?
Mechanism of action
- depolarising or non-depolarising
- Benzylisoquionolones and amino steroids
Duration of action
All NMBAs work by binding to the AChR and stopping ACh
What is the depolarising NMBA?
How does succinylcholine work?
- Structurally similar to ACh - is 2 ACh molecules bound
- mimics the effects of ACh by binding to the 2 alpha subunits of the AChR and opening the the ion channel allowing endplate depol
- leads to continuous endplate depolarisation but does not allow it to depolarise
Biphasic effect of succinylcholine?
Initial depolarisation (fasciculations) followed by a relaxation lasting 3-5 minutes.
How does Such differ from ACh
SCh is NOT hydrolysed by AChEsterase in the cleft
Instead it's neuromuscular blocking activity is terminated by diffusion out of the NMJ into the plasma where it is hydrolysed by plasma cholinesterase
(it remains in the cleft until plasma concentration of SCh decreases due to breakdown by pseudocholinesterase or elimination by the kidney)
Is SCh an antagonist or agonist?
It is really an agonist but it blocks the NM transmission after initial stimulation
What does the duration of the block/paralysis by SCh depend on?
The time taken to hydrolyse or excrete the drug
When may recovery from SCh be delayed for hours in patients?
Those who have deficient or absent pseudocholinesterase. 1/3200 are homozygous for the deficiency
Features of succinylcholine?
- fast onset less than 60 seconds
- short duration of action (3-5mins)
- half life is less than a minute
Suxamethonium (succinylcholine) apnoea occurs when a patient has been given the muscle relaxant suxamethonium, but does not have the enzymes to metabolise it. Thus they remain paralysed for an increased length of time and cannot breathe adequately at the end of an anaesthetic.
Completely awake but paralysed
What are some side effects and disadvantages of SCh?
- cannot be reversed by other drugs
- anaphylaxis can occur
- fasciculations in 90% of people due to its initial agonist effects; this can cause post op myalgia
- masseter spasm (jaw)
- cardiac dysrhythmias
> Brady and tachycardias due to catecholamine release
- hyperkalaemia; increase in K+ due to depolarisation
- increased intracranial/gastric/ocular pressure
- SCh is a potent trigger for MALIGNANT HYPERPYREXIA
Hyperkalaemia with SCh?
Usually a small increase but can be significant in patients with already increased K+ i.e. renal failure, spinal cord injuries, muscular dystrophy, BURNS, stroke, crush injuries
Why do we use SCh when it has so many side effects?
Succinylcholine provides the quickest, safest and most reliable relaxation for airway control. Provides excellent intubating conditions with minimal time for aspiration in patients with full stomachs.
Is mostly used in emergency conditions.
What is the mechanism of the NON-depolarising NMBAs?
Non-depol NMBAs are positively charged quaternary N compounds (ammonium) that are attracted to the AChR.
They block neuromuscular transmission by competitive antagonism of ACh at the AChR
What do NMBAs bind?
One OR both of the alpha subunits of the AChR - preventing binding of ACh and opening of the ion channel.
Only 1 molecule of NMBA is needed while 2 ACh are needed and so this bias favours the antagonist
When does neuromuscular blockade start with non-depot NMBAs
When more than 70% of the receptors are occupied and is then completed when more than 90% of the receptors are occupied by the NMBA (totally paralysed)
How are non-depot NMBAs classified?
3 examples of amino steroids?
3 examples of benzylisoquinolones?
- slow onset (3-5min)
- stable at pH of 4 but in the ph of 7 of a patient it breaks down
What is the only long acting muscle relaxant?
What is atracurium elimination dependent on?
Temp and pH (Hofmann elimination > laudanosine and acrylates
Non enzymatic degradation and so is independent of liver/kidneys (is non-specific ester hydrolysis)
Means that the duration is NOT prolonged in older patients and those with renal dysfunction
CV effects of atracurium?
- causes histamine release in a dose related manner which can cause a transient skin rash
- can also cause hypotension and tachycardia
- is 3x more potent than atracurium but same slow onset
- short duration (advantage - 20-25 mins)
- hydrolysed by pseudocholinesterase (like SCh)
- less histamine release
- rapid onset and intermediate duration
- can be used for rapid induction sequence instead of SCh but has a longer duration of action
- lower potency so needs a larger dose
- small cardiac and histamine effects
- 90% hepatic and 10% renal elimination
- higher anaphylaxis incidence
- intermediate duration and slow onset
- has NO CV SIDE EFFECTS
- its active metabolites are excreted into the urine so accumulates in renal failure
- useful in patients with cardiac disease
- least potential for anaphylaxis and histamine release
- longest duration of action (1-2 hours)
- high potency and slow onset of action
- has vagolytic effects
> increase BP/HR/CO so it is ideal for long cardiac surgical procedures
- minimal histamine release
What does the perfect NMBA look like?
(currently no existing NMBA that is perfect for all occasions)
- rapid onset
- has a titratable effect (can give the exact amount you want)
- moderately rapid offset
- easily reversible
- no histamine release or anaphylaxis
- no haemodynamic side effects
- inactive metabolites
- indeed elimination of hepatic and renal function
- no propensity to accumulate
- low cost
Why is reversal of NMBAs needed?
Can only reverse non-depot NMBAs.
The patient must have unimpaired muscle strength/no residual paralysis/resp muscles must function normally so breathing is not impaired.
How do reverse the effects of NMBAs after you have finished a procedure?
1. Titrate perfectly for the duration of action (difficult)
2. Accelerate the reversal by
> increasing the concentration of the competitor (ACh)
> decrease the plasma conc of NMBA
How to increase the ACh conc at the NMJ to reverse an NMBA?
reverses the neuromuscular blockade
2 examples of anti-cholinesterase drugs?
These drugs act at ALL cholinergic synapses in the PNS so have unwanted side effects.
anti-cholinesterase side effects?
- increased saliva and bowel mobility (need to give a drug to prevent these - atropine a anti-muscarinic agent)
Drug combination for reversal of an NMBA
Atropine and neostigmine
What is sugammadex and how does it work?
- perfect antidote for rocuronium and vecuronium
- restores normal NM function by selectively binding to rocuronium so it can't bind to the AChR
- leads to a decrease in free/unbound rocuronium in the plasma so there is movement of rocuronium from the NMJ to the plasma and decreases NM blockade
How quickly does muscle function return when using sugammadex?
How do you monitor a NM block?
- a peripheral nerve is stimulated electrically and the response of the muscle is assessed
- there is then a visual assessment of the evoked response and given a measure of TOF and TOF fade in 4 evoked twitches
(can also measure via mechanomyography, electromyography, accelerometry)
Monitoring of a NM blockade includes:
A nerve stimulator is connected to the patient at the ulnar nerve. 4 stimuli are given 0.5 seconds apart at a frequency of 2 Hz. The movement of the adductor pollicis muscle is assessed.
What is TOF
The number of twitches seen after 4 stimuli are given
What is the TOF ratio
The ratio of the 4th to the 1st twitch
Intact NM transmission TOF vs complete NM blockade?
Intact - TOF count of 4 and ration of 1 (all same height twitches)
Blocked - TOF of 0 and ratio of 0
On recovery from the blockade; first twitch returns and gives.a count of 1 ...
What does a TOF fade represent?
Represents a deficiency of NM transmission that requires intervention. Fade is only seen in NON-depol NMBAs
Example of a muscle that is less susceptible to NMBAs?
Diaphragm is less susceptible than peripheral muscles. Recovers function faster.
The adductor policies muscle is in the periphery so recovers function quite late and is used as a surrogate measure of muscle recovery
Double burst stimulation?
Compares the fade of the 2nd twitch to the first.
More accurate and easier to visualise.
Full recovery is two equal twitches.