Neuromuscular blocking drugs Flashcards
Label the different areas of the NMJ
Structure of the NMJ
- At the NMJ the axon of the motor neurone divides into terminal buttons that indent the muscle fibre
- Synaptic cleft is 60nm wide and filled with extracellular fluid
- Post synaptic membrane is folded, with the nicotinic ACh receptors on the junctional folds and directly opposite the active sites of release of ACh from the nerve
Mechanism of breakdown of acetylcholine at NMJ
ACh is rapidly hydrolyzed by the enzyme acetylcholinesterase -> choline.
Choline is taken up by the neve terminal and re-used in making more ACh
Locations of ACh receptors at the NMJ (3)
Nicotinic ACh receptors are found
* Post-synaptic: On junctional folds of the post-synaptic membrane, directly opposite the active sites of release of ACh from the nerve
* Pre-synaptically on the nerve terminal: throught to be involved in a positive feedback mechanism by mobilizing further ACh to the active sites ready for the next nerve impulse
* Extra-junctional: normally present in small numbers. Can proliferate in disease states affecting the NMJ e.g. denervation injuries, burns
Mechanism of activation at NMJ
- Action potential passes down the motor nerve, depolarising the nerve terminal
- Calcium travels into nerve endings -> ACh is released from active sites into the synaptic cleft and further ACh is mobilised into the active zones
- ACh binds to nicotinic receptor -> end plate potential.
- If end plate potential > threshold -> all or nothing action potential -> calcium release from sacroplasmic reticulum -> muscle contraction
What are the two types of block produced by suxamethonium
Phase 1 (standard doses of suxamethonium i.e. 1-1.5mg/kg)
* Muscle fasciculation prior to onset of block
* Absence of fade. Absence of post tetanic facilitation
* Antagonism by prior administration of non-depolarizing relaxant
* Potentiation by other depolarizing agents
* No tachyphylaxis
Phase 2 (prolonged exposure, doses >2-5mg/kg)
* Block develops characteristics of non-depolarizing block. ‘Dual block’
* Fade with ToF and tetanic stimulation
* Post tetanic facilication
* Antagonised by anticholinesterase agents
* Tachyphylaxis
Non-depolarizing NMBs
Mechanism, elimination
Two groups:
* Benzylisoquinolinium group: atracurium, cisatracurium, mivacirium
* Aminosteroids: pancuronium, rocuronium, vecuconium
All have at least one quarternary ammonium group to bind ot the alpha subunit on post synaptic receptor
Mechanism:
* Competitive antagonists at the post synaptic Ach receptor by reversely binding to the alpha subunit of the receptor
* Do not change shape of post synaptic ACh receptor.
* Endplate potential produced is small, does not trigger an action potential, hence no muscle contraction
* 75% ACh receptors need to be blocked to prevent neuromuscular transmission
Elimination
* Not metabolised at the NMJ but diffuse into plasma down a concentration gradient
* Mechanisms differ by agent
Duration of action, mechanism of elimination of benzylisoquinolinium NDNMBs
Atracurium: 30-45 minutes, kidney: Hofmann elimination, ester hydrolysis
Cisatracurium: 40-75 minutes, liver; Hofmann elimination
Mivacurium: 15-20 mintues, hydrolysis by plasma cholinesterases
Duration of action, mechanism of elimination of benzylisoquinolinium NDNMBs
Rocuronium: 45-75 minutes, liver, kidney
Vecuronium: 45-90 minutes, liver, kidney
Pancuronium
Suxamethonium
Mechanism, dose, speed of offset and recovery
Quarternary ammonium compound
1-1.5mg/kg
Mechanism
* Causes initial depolarization and muscle contraction (fasciculation)
* Continues to occupy the post synaptic ACh receptor -> preventing repolarization and further action potentials
Speed of offset:
* Muscle relaxation persists until suxamethonium is hydrolysed by plasma cholinesterase
* Full effect 2-5 minutes
* Recovery from block complete in 12-15 minutes
