Pharmacology of the Neuromuscular Junction Flashcards
What are the 3 ways to block neuromuscular transmission?
+ Presynaptically, by inhibiting ACh synthesis (rate-limiting step in choline uptake)
+ Presynaptically, by inhibiting Ach release
+ Postsynaptically (by interfering with the actions of ACh on the receptor)
What can inhibit ACh release?
+ Local anaesthetics
+ General inhalation anaesthetics
+ Inhibitors/competitors of calcium
+ Neurotoxins
What are examples of inhibitors/competitors of calcium?
+ Magnesium ions
+ Some antibiotics
- aminoglycosides (gentamicin)
- tetracycline
What are some examples of neurotoxins that inhibit ACh release presynaptically?
+ Botulinum toxin (clostridium botulinum)
+ β-Bungarotoxin (Taiwanese banded krait)
What are some clinical uses of neuromuscular-blocking drugs?
+ Endotracheal intubation
+ During surgical procedures: ↓ concentration of general anaesthetic needed
+ In intensive care: during mechanical ventilation at extremes of hypoxia
+ During electroconvulsive therapy
what are examples of nicotinic Ach receptor agonists?
+ nicotine
+ suxamethonium
what are examples of nicotinic Ach receptor antagonists?
+ tubocurarine
+ atracurium
what are non-depolarising blockers?
competitive ANTAGONISTS of nicotinic Ach receptors at the NMJ
how do non-depolarising blockeres/competitive antagonists work?
- prevent Ach binding to receptor by occupying site
- decreases motor end plate potential (EPP)
- decreases depolarisation of motor end plate region
- no activation of the muscle action potential
what are depolarising blockers?
AGONISTS of nicotinic Ach receptors at NMJ
- not metabolised by Ach esterase
how do depolarising blockers/agonists work?
- persistent depolarisation of motor end plate
- prolonged EPP
- prolonged depolarisation of muscle membrane
- membrane potenial above the threshold for resetting of voltage-gated sodium channels
- sodium channels remain refractory
- no more muscle action potentials generated
how many phases does a depolarising block occur in?
2 phases
what is phase 1 of a depolarising block?
+ muscle fasciculations observed, then blocked
+ repolarisation inhibited
- K+ leaks from cells (hyperkalemia)
+ voltage-gated Na+ channels kept inactivated
what is phase 2 of a depolarising block?
+ prolonged/increased exposure to drug
+ “desensitisation blockade”
- depolarisation cannot occur, even in absence of drug
which neuromuscular blocking drug is unchanged in bile/urine?
rocuronium
which neuromuscular blocking drug is affected by hepatic metabolism?
- pancuronium
- vecuronium
which neuromuscular blocking drug is affected by plasma cholinesterases?
- mivacurium
- suxamethonium
which neuromuscular blocking drug is affected by ester hydrolysis and hofmann elimination?
atracurium
what type of onset does suxamethonium have?
fast
what type of duration does suxamethonium have?
short
which neuromuscular blocking drugs have a medium onset?
- pancuronium
- vecuronium
- atracurium
which neuromuscular blocking drugs have a fast onset?
- rocuronium
- mivacurium
- suxamethonium
which neuromuscular blocking drugs have a long duration?
pancuronium
which neuromuscular blocking drugs have a medium duration?
- vecuronium
- rocuronium
- atracurium
which neuromuscular blocking drugs have a short duration?
- mivacurium
suxamethonium
what are the main side effects of suxamethonium?
- bradycardia
(muscarinic agonist effect) - cardiac dysrhymias
(increased plasma K+ concentration) - raised intraocular pressure
(nicotinic agonist effect) - postoperative myalgia
(muscle fasciculations) - malignant hyperthermia
(ryanodine receptor related)
what are features of acetylcholinesterase (Ach.E)?
- true cholinesterase, specific for hydrolysis of ACh
- present in cinducting tissue and red blood cells
- bound to basement membrane in synaptic cleft
what are features of plasma cholinesterase?
- pseudocholinesterase, broad spectrum of substrates
- widespread distribution
- soluble in plasma
what is the main role of anticholinesterase drugs?
inhibit cholinesterase
what is the effect of inhibiting cholinesterase enzymes?
- ↑ availability of ACh at NMJ by ↓ degradation
- increases duration of activity of ACh at NMJ
- more ACh to compete with non-depolarising blockers
what are some anticholinesterase drugs?
- neostigmine
- pyridostigmine
- dyflos
- parathion
what is the mechanism of action employed by anticholinesterase drugs, neostigmine and pyridostigmine?
formation of carbamylated enzyme complex
what is the mechanism of action employed by anticholinesterase drugs, dyflos and parathion?
irreversible inhibition (by phosphorylation)
what is the effect of carbamylation?
slows rate of hydrolysis
what are the effects of anticholinesterases on the central nervous system?
- initial excitation with convulsions
- unconscious and respiratory failure
what are the effects of anticholinesterases on the autonomic nervous system?
- Salivation
- Lacrimation
- Urination
- Defecation
- Gastrointestinal upset
- Emesis
- Bradycardia
- Bronchoconstriction
- Hypotension
- Pupillary constriction (miosis)
what are some clinical uses of anticholinesterases?
- in anaesthesia
- myasthenia gravis
- glaucoma
- alzheimer’s disease
what is the effect of anticholinesterases in anaesthesia?
- reverse non-depolarising muscle blockade
- given with atropine or glycopyrrolate to counteract parasympathetic effects
what is the effect of anticholinesterases in myasthenia gravis?
increase neuromuscular transmission
what is the effect of anticholinesterases in glaucoma?
decrease intraocular pressure
what is the effect of anticholinesterases in alzheimer’s disease?
enhance cholinergic transmission in CNS
what is sugammadex?
selective relaxant binding agent (SRBA)
- reverses effects of rocuronium and vecuronium (very specific)
