neuromuscular blocking agents Flashcards
what are neuromuscular agents used for and not used for
Mainly used by anaesthetists to paralyse patients
Act at neuromuscular junction
Have no sedative action or cause amnesia (memory loss)
No analgesic property
Never used in isolation
clinical use of neuromuscular agents
- Facilitate intubation of the trachea
- Airway maintenance important for good oxygenation (less chance of vocal cord damage and postoperative hoarseness)
- NMBA enable control of ventilation intraoperatively
- Prevent deleterious movements
Neurosurgery = ventilating patients lowers intracranial pressure
Intensive care = improves conditions for ventilation
Lungs = decreases the work of breathing and O2 consumption, therefore barotrauma to the lungs prevented
intubation
insertion of an endotracheal tube for airway protection and ventilation
AChR
- Ligand-gated ion channels
- 5 subunits composed of 500 amino acids
- Alpha subunits bind ACh (both bound simultaneously)
- Binding causes conformational change, which opens the channel allowing ions to flow and muscle contraction to occur
- 1 ACh molecule must bind to each of the 2 alpha subunits to open the channel
AChE
In the synaptic cleft within basal lamina
Secreted by muscles
Hydrolyses ACh to acetate and choline
Choline taken up and resynthesized to ACh
mechanism of action of depolarising NMBAs
Succinylcholine (SCh) is the only example in use
Mimics the effect of ACh. 1 molecule binds simultaneously to the
2 α subunits
Binds to AChR, opens the channel, leads to continuous endplate depolarisation but not allowing repolarisation
Causes fasciculations followed by relaxation–biphasicaction BUT is not susceptible to hydrolysis by AChE
Remains in the cleft until plasma concentration of SCh decreases due to breakdown by plasma/pseudocholinesterase or elimination by the kidney
SCh clinically
- fast onset of action
- short duration of action: 3-5 minutes
- elimination half-life <1 minute
- broken down by pseudocholinesterase
SCh side effects
Cant be reversed Cardiac dysrhythmias Increased intracranial pressure Increased intraocular pressure Increased intragastrical pressure Increased serum K+ Muscle pain post-op Trigger for malignant hyperpyrexia
uses of SCh
- quickest, safest way to have rapid and complete relaxation for airway control
- intubating conditions excellent
- minimal time for aspiration in patients with full stomachs
- used in emergency conditions
mechanism of action of non-depolarising NMBAs
NMBA bind to 1 or both of the αsubunits of the AChR, preventing binding of ACh and therefore prevents opening of the ion channel
Competitive interaction between ACh and NMBA at the AChReceptor
Requirement for 1 molecule of NMBA to block the receptor but 2 ACh to open it. This bias favors the antagonist (NMBA)
The effect depends on relative concentrations of ACh and drug (NMBA)
NM block starts when >70% receptors are occupied and is complete when >90% are occupied
chemical structures of NMBAs and examples
Benzylisoquinolones
- atracurium - cisatracurium - mivacurium
Aminosteroids
- rocuronium - vecuronium - pancuronium
atracurium
-onset of action slow = 3-5min
Intermediate duration of action (40mins)
PH and temperature dependent elimination
Cardiovascular effects – hypotension and tachycardia
Skin rash
mivacurium
3X more potent than atracurium
Short acting (20mins)
slow onset of 3-5 minutes
hydrolyzed by pseudocholinesterase (non-depolarising though)
rocuronium
Intermediate duration of action, longer than SCh
Low potency, requires larger dose
Rapid onset of action
Cardiac effects minimal
Mainly hepatic elimination
Vecuronium
Intermediate duration
Slower onset but similar duration to recuronium
Active metabolites secreted in urine therefore not good for
a patient with renal failure
Minimal cardiac effects
Least potential for anaphylaxis
pancuronium
Longest acting
High potency, slow onset
Good for long cardiac surgery procedures
Minimal histamine released
Hepatic and renal clearance
reversal of NMBAs
- Only needed for non-depolarizing agents
- Respiratory and upper airway muscles must function normally
2 strategies:
Titrate perfectly for duration of action (DIFFICULT)
Accelerate reversal - (safer and more reliable)
-increase ACh conc at NMJ
-decrease plasma conc of NMBA
How do we increase the ACh concentration at the AChR?
Drugs which inhibit AChE
-inhibits hydrolysis of ACh therefore increase in ACh concentration at AChR
Anti-AChE drugs and side-effects
Neostigmine and pyridostigmine
Side effects:
Potent parasympathetic activtity
Vagal effects – bradycardia and bradyarrhythmia’s
Increased salivation and bowel motility
Atropine reverse these parasympathetic effects
antidote
Another way to get rid of a drug is to bind it = ANTIDOTE
Rocuronium = sugammadex
1:1 binding and then excreted in the urine
Return of muscle function in 2 minutes
danger of residual block
Ventilatory response to hypoxia is impaired and does not return to normal until TOFR > 0.9
Reduced pharyngeal muscle coordination with TOFR 0.6 – 0.8. Risk of airway collapse.
Increase mortality and morbidity if patient has residual block
Aspiration, hypoxia, death!
Reversal drug only given when a 4th twitch is visible, that is, once spontaneous recovery has begun.
monitoring neuromuscular blockage
Peripheral nerve is stimulated electrically and the response of the muscle is assessed Visual assessment of evoked response Mostly used in clinical setting Measure of TOF and TOF fade in 4 evoked twitches Measurement of evoked response -Mechanomyography -Electromyography -Accelerometry
