What are Neuromuscular Blocking Agents (NMBAs), and where do they act?
Drugs used by anaesthetists during surgery/ventilation in critical care units.
They act at the Neuromuscular junction, and allow us to access the patients airway!
However, NMBAs are NOT...
ANd NEVER used in isolation, just a part of 'the triad of balanced Anaesthesia'
What's the clinical use of NMBAs?
Facilitate intubation of the Trachea
Decr. vocal cord injury and post-op hoarseness.
Control of ventilation within operation.
- Facilitate surgical exposure, especially abdominal and thoracic surgery. we can do more surgeries!!
- Prevents movement during delicate surgery.
In Intensive Care....
- Ventilation of the critically ill
- Decr. O2 consumption
- Decr. risk of barotrauma to lungs
- stops increase in intracranial pressure
What is Intubation
Insertion of a plastic endotracheal tube for airway protection and ventilation (past teeth, tounge, vocal cords to the trachea).
Quickly cover the 3 entities of the NMJ (neuromuscular junction)
- Presynaptic Nerve Terminal: ACh synthesis and storage in vesicles occurs. Also where reuptake of choline into vesicles and control of ion flow across the nerve terminal occurs.
- Synaptic Cleft: ~50nm gap between nerve terminal and muscle ending (contains basal lamina)
- Post synaptic Motor End Plate: Contains the AcetylCholine receptor (AChR)
Give a quick bullet point summary on how ACh is stored and released into the synaptic cleft at NMJ
- ACh synthesized by the nerve is stored in small uniform vesicles
- When an AP travels down the motor nerve this stimulates voltage-gated Ca2+ channels to open → influx of Ca2+ into the nerve terminal. (down its electrochemical gradient)
- Increased Ca2+ causes ACh containing vesicles to fuse with the presynaptic membrane
- Ach released into the synaptic cleft
Describe the Nicotinic Acetyl Choline Receptor (AChR) on the post synaptic membrane.
- Pantameric ligand gated ion channel
- 4 sub-units *see picture
- Subunit is each made of 400-500 amino acids
- Synthesized in muscle cells
- Anchored to the endplate
How does the AChR work?
- ACh binds to postsynaptic Nicotinic AChR
- These heteropentameric ligand-gated ion channels allow Na+ influx
- This leads to endplate depolarization → muscle contraction
** 1 ACh molecule musce to to each of the 2 alpha sub-units in order for the channel to open.
What is Acetylcholinestrase (AChE)??
- AChE is a carboxylesterase enzyme found mainly in the synaptic cleft. (also found extrajunctionally)
- Secreted by the muscle
- Attached to the basal lamina
- ACh molecules not bound to receptor are hydrolysed in <1ms to acetate and choline.
- Choline → taken up by nerve terminal and reused to synthesize ACh
How do we classify NMBAs
Describe the Mechanism of action of depolarising NMBAs, and whats the only example we have?
Succinyl Choline (SCh) only example, mimics ACh effect.
- 1 molecule binds simultaneously to the 2-alpha subunits, blocking the receptor
- HOWEVER it is considered an agonist
- Intially opens the channel → continuous endokate depolarisation but doesn't allow repolarisation
Why is SCh said to have a biphasic action, and how is it broken down?
Biphasic Action: causes fasciculations (looks like shivering) followed by relaxation
As SCh is NOT susceptible to hydrolysis by AChE, therefore it remains in the cleft until plasma conc of SCh decreases due to breakdown by plasma/ pseudocholinesterase or elimination by the kidney
Whats the advantages of Succinylcholine
- Onset of action is FAST <60s
- Short duration of action; 3-5mins
- Broken down to succinylmonocholine and choline by pseudocholinesterase
- Elimination 1/2 life <1min
- Recovery delayed in conditions wherepseudocholinesterase is deficient or absent
WHat are the disadvantages of SCh?
- Can't be reversed! Has wear off by SChE or by kidney
- Anaphylaxis ~1:1000
- Fasiculations can be painful postop
- Masseter spasm, hard to intubate
- Cardiac Dysarithmias: bray/tachy
- Increased K+ due to depolarisation
- Inc. intracranial pressure
- Inc. intragastric pressure
- Inc.intraocular pressure
Potent trigger for MALIGNANT HYPERPYREXIA
Due to its advantages, what do we use SCh for?
Used in emergency condition, as its the quickest/safest way to have rapid complete relaxation for airway control.
Mechanism of non-depolarising NMBAs
- + charged quaternary ammonium compounds attracted to AChR
- These bind to 1-2 of alpha AChR subunits, preventing ACh binding and therefore stopping the ion channel opening. (as you only need 1 to block but 2 to open this is favourable for antagonist)
- Effect is NMBA and ACh concentration dependent
- NM block starts when >70% receptors are blocked, done once >90% are occupied.
Classification of non-depolarising NMBAs
Short Acting (10-15min): mivacurium
Intermediate Acting (25-45 min): Atracurium, vecuronium, Rocuronium
Long Acting (40-90min): Pancuronium
Atracurium (int acting). Onset and degredation, and effect.
- Onset 3-5 mins
2 Pathways of degredation
- Hofmann elimination
- Nonspecific ester Hydrolysis
Can be used in liver/kidney failure patients as they are independent of these organs
CV effects: histamine release (rash), hypotension, tachycardia
Mivacurium (short acting)
Advantages and degredation
- 3x potency of Atracurium
- slow onset 3-4 mins
- Advantage: short duration of action, 10-20min
- Degredation: like SCh by pseudocholinesterase.
Rocuronium (long acting)
- Low potency, so needs large doses
- Advatage: rapid onset of action
- Can be used instead of SCh for rapid intubation (duration longer), takes longer to wear off.
- minimal cardiac effects
- Degreedation: hepatic elimination
- Intermediate duration
- Slower onset but similar duration to Rocuronium
- Excreted in urine (so is prolonged in renal failure patients
- minimal cardiac effect-
- LEAST POTENTIAL for anaphylaxis
- High potency, slow onset
- Longest acting of all aminosteroids (1.5-2hours)
- Vagolytic effects; inc. BP, heart rate and cardiace output.
- Good for long cardiac procedures
- Excreted by liver and kidney
Whats the ideal characteristics of an NMBA?
This doesn't yet exist!
Why/when do we need to reverse NMBAs?
- Only for non-depolarising
- Patient needs to leave operation with un-impaired muscle strength
- Resp and upper airway muscles must function
How do we reverse NMBAs?
- Titrate perfectly for duration of action (hard)
- Accelerate reversal (better); increase ACh or decrease plamsa conc of NMBA
In order to reverse drugs by increasing ACh at the NMJ, how is this done>>
How do we do a reversal of the NM blockade?
How do we monitor NMBA
WHat is the mode of stimulation??