Pharmacology of the Neuromuscular Junction Flashcards
What are the 3 ways to block neuromuscular transmission?
Presynaptically, by inhibiting ACh synthesis
Presynaptically, by inhibiting ACh release
Postsynaptically by interfering with the actions of ACh on the receptor
When blocking neuromuscular transmission presynaptically by inhibiting ACh synthesis, what is the rate limiting step?
Choline uptake
What TYPES of substances may inhibit ACh release?
Local anaesthetics
General inhalational anaesthetics
Inhibitors/competitors of calcium
Neurotoxins
What inhibitors/competitors of calcium can inhibit ACh release?
– Magnesium ions
– Some antibiotics
—-• Aminoglycosides (e.g. gentamicin)
—-• Tetracycline
What neurotoxins may inhibit ACh release?
– Botulinum toxin (clostridium botulinum)
– β-Bungarotoxin (Taiwanese banded krait)
What is botulinum toxin (clostridium botulinum) more commonly known as?
Botox
What can botox be used to treat?
- Muscle spasticity (overactive muscles)
- Hyperhydrosis (lotsa sweat)
- Is used cosmetically
What are some clinical uses of neuromuscular- blocking drugs?
Endotracheal intubation
During surgical procedures
Infrequently in intensive care
During electroconvulsive therapy
During surgical procedures when may neuromuscular- blocking drugs be used?
– To allow surgical access to abdominal cavity
– To ensure immobility
—-• (e.g.prevent cough during head and neck surgery)
– Allow relaxation to reduce displaced fracture or dislocation
– ↓ concentration of general anaesthetic needed
When may neuromuscular- blocking drugs be used in intensive care?
– In mechanical ventilation at extremes of hypoxia
What is the structure of the nicotinic acetylcholine receptor?
It is made of five subunits: a beta, a delta, a gamma and two alpha. The delta is replaced with an epsilon in the adult form
Forming the gate of the pore are alpha-helices
Like any ligand gated ion channels opening of the nAChR channel pore requires the binding of a chemical messenger
What are the effects of an agonist on the nicotonic ACh Receptor and provide two examples?
- They cause the channel to open
- nicotine, suxamethonium
What are the effects of an antagonist on the nicotonic ACh Receptor and provide two examples?
- They keep the channel closed
- tubocurarine, atracurium
What are non-depolarising blockers of the nicotinic ACh receptors?
Competitive antagonists of Nicotinic ACh receptors at the NMJ.
e.g. tubocurarine, atracurium
What do non-depolarising blockers of the nicotinic ACh receptor do?
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
What are depolarising blockers of the nicotinic ACh receptors?
Agonists of Nicotinic ACh receptors at the NMJ
e.g. suxamethonium
What is the difference between a depolarising blocker and acetylcholine in regards to their binding to nicotinic ACh receptors?
Depolarising blockers are not metabolised by Acetylcholine esterase
What do depolarising blockers do?
Persistent depolarisation of the motor end plate
->
Prolonged EPP (end plate potential*)
->
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 generated
In how many phases may a depolarising block occur?
Two
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 kept inactivated
Phase 2
– Prolonged / increased exposure to drug
– “Desensitisation blockade”
• Depolarisation cannot occur, even in absence of drug
How does the body eliminate/metabolise atracurium?
(Non-depolarising blocker - muscle relaxant)
Ester hydrolysis and Hofmann elimination
How does the body eliminate/metabolise mivacurium?
(Non-depolarising blocker - muscle relaxant)
Plasma cholinesterases
How does the body eliminate/metabolise suxamethonium?
(depolarising blocker - muscular relaxant)
Plasma cholinesterases
How does the body eliminate/metabolise pancuronium?
(depolarising blocker - aminosteroid muscle relaxant)
Hepatic metabolism
How does the body eliminate/metabolise vercuronium?
(depolarising blocker - aminosteroid muscle relaxant)
Hepatic metabolism
How does the body eliminate/metabolise rocuronium?
(depolarising blocker - aminosteroid muscle relaxant)
It doesn’t really, - unchanged in bile/urine
What is the duration of action of ACh regulated by?
Hydrolysis
What enzymes hydrolyse ACh?
Acetylcholinesterase (ACh.E)
Plasma cholinesterase
How does acetylcholinesterase (ACh.E) act on ACh and where is it found?
– True cholinesterase, specific for hydrolysis of ACh
– Present in conducting tissue and red blood cells
– Bound to basement membrane in the synaptic cleft
How does plasma cholinesterase act on ACh and where is it found?
– Pseudocholinesterase, broad spectrum of substrates
– Widespread distribution
– Soluble in plasma
What are anticholinesterase drugs?
inhibitors of cholinesterase enzymes
What is the effect of anticholinesterase drugs?
As they inhibit cholinesterase enzymes, they therefore increase availability of ACh at NMJ by decreasing ACh degradation
So
– Increases duration of activity of ACh at NMJ
– More ACh to compete with non-depolarising blockers
Spit some anticholinesterase drugs dog 😎
(quartenary amines - med duration)
Neostigmine Pyridostigmine
(organophosphates - long duration)
Dyflos
Parathion
Describe the action of anticholinesterase drugs
Carbamylation slows rate of hydrolysis
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 central nervous system?
– Initial excitation with convulsions
– Unconsciousness and respiratory failure
What are the effects of anticholinesterases on the autonomic nervous system?
SLUDGE, Hi BP!
– Salivation – Lacrimation – Urination – Defecation – Gastrointestinal upset – Emesis (vomiting) – Bradycardia (Brachy=low) – Hypotension – Bronchoconstriction – Pupillary constriction (miosis)
What are the clinical uses of anticholinesterase?
In anaesthesia
For Myasthenia Gravis
For Glaucoma
For Alzheimer’s disease
How may anticholinesterases be used in anaesthesia?
– Reverse non-depolarising muscle blockade
– Given with atropine or glycopyrrolate to counteract
parasympathetic effects
How may anticholinesterases be used in myasthenia gravis?
– Increase neuromuscular transmission
How may anticholinesterases be used in glaucoma?
– Decrease intraocular pressure
How may anticholinesterases be used in Alzheimer’s disease?
– Enhance the cholinergic transmission in the CNS
What is myasthenia gravis?
Autoantibodies may be produced against the acetylcholine receptor blocking the interaction of the acetylcholine receptor with its ligand (acetylcholine) and leading to increased muscle weakness and death.
What is sugammadex
Selective relaxant binding agent (SRBA)
• Reverses effects of rocuronium and vecuronium
A potential origin for the sugandese?
How many binding sites for acetylcholine do nicotinic acetylcholine receptors have?
2
How wide is the pore of nicotinic acetylcholine receptors?
~0.7nm
What enzyme normally degrades Acetylcholine?
Acetylcholine esterase
What is Hofmann elimination?
Pretty much spontaneous elimination of a drug in the plasma
Sludge?
Salivation Lacrimation Urination Defecation Gastrointestinal upset Emesis All effects of anticholinesterases
