Drugs acting on the Neuromuscular Junction Flashcards
Name the three ways to block neuromuscular transmissions
- Presynaptically by inhibiting ACh synthesis
- Presynaptically by inhibiting ACh release
- Postsynaptically (interfering with the actions of ACh on the receptor)
Name some of the ways you can inhibit ACh release
Local Anaesthetics - Blocks propagation of an action potential
General inhalation anaesthetics
Magnesium - It competes for calcium but when inside the cell it won’t trigger the release of NTs
Some antibiotics - Aminoglycosides and tetracyclins (as these bind to calcium)
Neurotoxins - e.g. Botulinum toxin
Name some of the clinical uses of neuromuscular blocking drugs
- Endotracheal intubation
- During surgical procedures ( to allow for surgical access to abdominal cavity, to ensure immobility, allow for relaxation to reduce displaced fracture/dislocation and to decrease the concentration of general anaesthetics needed)
- Infrequently in intensive care (for mechanical ventilation)
- During electroconvulsive therapy
What does an antagonist and agonist do to the nicotinic acetylcholine receptor?
Antagonist - occupies the channel but does not induce the conformational change
Agonist - Binds to the receptor and causes the conformational change
Describe how non-depolarising blockers work (competitive antagonists)
Prevents ACh from binding by occupying the site. Decreases the motor end plate potential (EPP). Decreases depolarisation of the motor end plate region. So no activation of the muscle action potential.
Describe how depolarising drugs work
Persistent depolarisation of the motor end plate (because ACh receptor kept open) leading to prolonged EPP. Prolonged depolarisation of the muscle membrane. The membrane potential remains above the threshold for the resetting of the voltage-gated sodium channels. Sodium channels remain refractory and so no more muscle action potentials are generated
Depolarisation block can occur in two phases; Describe these two phases
Phase 1 - Muscular fasciculations observes then blocked. Repolarisation is blocked. Potassium leaks from cells leading to hyperkalemia and voltage-gated sodium channels kept inactive.
Phase 2 - Prolonged or increased exposure to the drug leads to ‘desensitisation blockade’ which is where depolarisation cannot occur even when the drug is absent
Name some of the non-depolarising blocking drugs
Pancuronium
Vecuronium
Rocuronium
Atracurium
Mivacurium
Describe the onset, duration and side effects of pancuronium
Onset - Medium
Duration - Long
Side effects Tachycardia
Describe the onset, duration and side effects of Vecuronium
Onset - medium
Duration - medium
Side effects - very few
Describe the onset, duration and side effects of Rocuronium
Onset - Fast
Duration - Medium
Side effects tachycardia
Describe the onset, duration and side effects of Atracurium
Onset - Medium
Duration - Medium
Side effects - Hypotension and bronchospasm
Describe the onset, duration and side effects of Mivacurium
Onset - fast
Duration - Short
Side effects - Hypotension and bronchospasm
Describe the onset, duration and side effects of Suxamethonium
Onset - Fast
Duration - Short
Side Effects- Bradycardia, Cardiac disrhythmias, Raised intraocular pressure, postoperative myalgia (flu like feelings of muscle aches) and Malignant Hypothermia
How is Atracurium metabolised?
Ester hydrolysis and hofmann elimination
How are mivacurium and suxamethonium metabolised? and what can be an issue with this metabolism?
Via plasma cholinesterases. However genetic variation in the population means that there can be a prolonged block meaning it takes some people longer to metabolise the drug
How are pancuronium and Vecuronium metabolised?
Via hepatic metabloism
How is Rocuronium metabolised?
Its unchanged in bile and urine
Name the two cholinesterases
Acetylcholinesterase and Plasma cholinesterase
Describe some of the features of acetylcholinesterase
Specific for the hydrolysis of ACh.
Present in conducting tissue and red blood cells.
Bound to the basement membrane in the synaptic cleft
Describe some of the features of plasma cholinesterase
Pseudocholinesterase.
Broad spectrum of substrates.
Widespread distribution.
Soluble in plasma.
Describe the features of anticholinesterase drugs
They increase the availability and duration of ACh at the NMJ by decreasing degradation. It means there is more ACh to compete with non-depolarising blockers
Name some of the anticholinesterase drugs
Most commonly used in clinical practice -Neostigmine and Pyridostigmine
Not used clinically - Dyflos and Parathion
What is the duration and mechanism of neosigmine and pyridostigmine
Duration - medium
Action - Formation of carbamylated enzyme complex
What is the duration and mechanism of action of Dyflos and Parathion
Duration - long
Action - irreversable inhibition
What will prevent dyflos and parathion from dystroying the enzyme?
A drug called pralidoxime. It can ‘coax’ the drugs off the enzyme
Name some of the effects of anticholinesterases on the CNS
- Initiate excitation with convulsions
- Unconsciousness and respiratory failure
Name some of the effects of anticholinesterases on the autonomic NS
SLUDGE + PHBB (Puppy Had a Big Ball) Salivation Lacrimation (flow of tears) Urination Defecation (discharge of faeces from body) GI upset Emesis (vomiting)
Pupillary constriction
Hypotension
Bradycardia
Bronchoconstriction
Name some of the clinical uses of anticholinesterases
In anaesthesia - To reverse non-depolarising muscle blockade however it is given atropine or glycopyrrolate to counteract the parasympathetic effects
Myasthenia Gravis - increase neuromuscular transmission
Glaucome - Decrease intraocular pressure
Alzheimer’s disease - enhance the cholinergic transmission in the CNS
What class of drug is Sugammadex and what does it do?
Class - Selective Relaxant Binding Agent (SRBA)
Does - reverses the effects of rocuronium and vecuronium by engulfing them
