Drugs Acting on the Neuromuscular Junction Flashcards
List the 3 ways of blocking neuromuscular transmission.
-
Presynaptically, by inhibiting ACh synthesis.
- Rate limiting step is choline uptake - blocking of the choline transporter stops it from being taken up by the cell.
- Presynaptically, by inhibiting ACh release.
- Postsynaptically, by interfering with the actions of ACh on the receptor.
List substances which can inhibit ACh release.
- Local anaesthetics
- General inhalational anaesthetics
- Inhibitors / competitors of calcium
- Magnesium ions
- Some antibiotics
- Aminoglycosides (e.g. gentamicin)
- Tetracycline
- Neurotoxins
- Botulinum toxin
- β-bungarotoxin
How do local anaesthetics work to inhibit ACh release?
They block voltage-gated sodium channels.
What are the clinical uses of neuromuscular blocking agents?
- Endotracheal intubation
- During surgical procedures
- To allow surgical access to abdominal cavity.
- To ensure immobility
- E.g. to prevent cough during head and neck surgery.
- Allow relaxation to reduce displaced fracture dislocation.
- To decrease the concentration of general anaesthetic needed.
- Infrequently in intensive care
- Mechanical ventilation at extremes of hypoxia
- During ECT
Give examples of nicotinic ACh receptor agonists.
- Nicotine
- Suxamethonium - depolarising blocker of the NMJ.
Give examples of nicotinic ACh receptor antagonists.
- Tubocurarine
- Atracurium - non-depolarising blocker of the NMJ. It does not cause a conformational change.
Describe the action of non-depolarising blockers (competative antagonists of nicotinic ACh receptors at the NMJ).
For example: tubocurarine or atracurium.
- Prevents ACh binding to receptor by occupying site.
- Decreases the motor end plate potential (EPP).
- Decreases depolarisation of the motor end plate region.
- No activation of the muscle action potential.
Describe the action of depolarising blockers (agonists of nicotinic ACh receptors at the NMJ).
For example: suxamethonium.
- Persistent depolarisation of the motor end plate.
- Prolonged EPP.
- Prolonged depolarisation of the muscle membrane.
- Membrane potential above the threshold for the resetting of the voltage-gated sodium channels.
- Sodium channels remain refractory.
- No more muscle action potentials are generated.
What are the two phases of a depolarising block?
- Phase 1
- Muscle fasciculations observed, then blocked.
- Repolarisation inhibited
- K+ leaks from cells (hyperkalemia)
- Voltage-gated Na+ channels are kept inactivated
- Phase 2
- Prolonged / increased exposure to drug
- ‘Desensitisation blockade’
- Depolarisation cannot occur, even in the absence of the drug.
Give 3 examples of aminosteroidal non-depolarising neuromuscular blockers.
- Pancuronium
- Vecuronium
- Rocuronium
Give 2 examples of benzylisoquiolinium non-depolarising neuromuscular blockers.
- Atracurium
- Mivacurium
What is the primary depolarising neuromuscular blocker?
Suxamethonium
What are the properties of pancuronium?
- Onset - medium
- Duration - long
- Side effects - tachycardia
What are the properties of vecuronium?
- Onset - medium
- Duration - medium
- Few side effects
What are the properties of rocuronium?
- Onset - fast
- Duration - medium
- Side effects - tachycardia
What are the properties of atracurium?
- Onset - medium
- Duration - medium
- Side effects - hypotension / bronchospasm
- (Histamine release)
What are the properties of mivacurium?
- Onset - fast
- Duration - short
- Side effects - hypotension / bronchospasm
- (Histamine release)
What are the properties of suxamethonium?
- Onset - fast
- Duration - short
- Side effects:
- Bradycardia (muscarinic agonist effect)
- Cardiac dysrhythmias (increased plasma K+ concentration)
- Raised intraocular pressure (nicotinic agonist effect)
- Postoperative myalgia (muscle fasciculations)
- Malignant hyperthermia (ryanodine receptor related)
Which neuromuscular blockers are metabolised and eliminated by ester hydrolysis and Hofmann elimination?
Atracurium
Which neuromuscular blockers are metabolised and eliminated by plasma cholinesterases?
- Mivacurium
- Suxamethonium
NB - Plasma cholinesterase defficiency means that it is not so able to break down suxamethonium causing a very long prolonged block.
Which neuromuscular blockers are metabolised and eliminated by hepatic metabolism?
- Pancuronium
- Vecuronium
Which neuromuscular blocker is unchanged in bile / urine?
Rocuronium
What regulates the duration of the action of ACh?
Hydrolysis
Describe the properties of acetylcholinesterase (ACh.E).
- True cholinesterase, specific for hydrolysis of ACh.
- Present in conducting tissue and RBCs.
- Bound to basement membrane in the synaptic cleft.
NB - acetylcholinesterase can be used in myesthenia gravis (autoimmune disease) which (basically) blocks ACh. So anticholinesterases prevent the degradation of ACh so can restore transmission.
Describe the properties of plasma cholinesterase.
- Pseudocholinesterase, broad spectrum of substrates
- Widespread distribution
- Soluble in plasma
What are the properties of anticholinesterase drugs?
- Are all inhibitors of cholinesterase enzymes
- Therefore, there is an increased availability of ACh at the NMJ by decreased degradation.
- Increases duration of activity of ACh at NMJ.
- More ACh to compete with non-depolarising blockers.
Give 2 examples of anticholinesterase drugs which are quaternary amines.
- Neostigmine
- Pyridostigmine
Give 2 examples of anticholinesterase drugs which are organophosphates.
- Dyflos
- Parathion
What are the properties of neostigmine?
- Duration - medium
- Mechanism of action - formation of carbamylated enzyme complex.
What are the properties of pyridostigmine?
- Duration - medium
- Mechanism of action - formation of carbamylated enzyme complex
What are the properties of dyflos?
- Duration - long
- Mechanism of action - irreversible inhibition
What are the properties of parathion?
- Duration - long
- Mechanism of action - irreversible inhibition
What is the effect of carbamylation?
Slow the rate of hydrolysis
Describe phosphorylation by dyflos / parathion.
- Phosphorylation by dyflos / parathion is highly stable
- Recovery depends on synthesis of new enzyme
- Can be coaxed off by pralidoxime
What are the effects of anticholinesterases on the CNS?
- Initial excitation with convulsions
- Unconsciousness and respiratory failure
What are the effects of anticholinesterases on the autonomic nervous system?
- Salivation
- Lacrimation
- Urination
- Defacation
- Gastrointestinal upset
- Emesis
- Bradycardia
- Hypotension
- Bronchoconstriction
- Pupillary constriction
What are the clinical uses of anticholinesterases?
-
In anaesthesia
- Reverse non-depolarising muscle blockade
- Given with atropine or glycopyrrolate to counteract parasympathetic effects
-
Myasthenia gravis
- Increase neuromuscular transmission
-
Glaucoma
- Decrease intraoccular pressure
-
Alzheimer’s disease
- Enhance the cholinergic transmission in the CNS
What is sugammadex?
- Selective relaxant binding agent (SRBA)
- Reverses the effects of rocuronium and vecuronium
