Pharmacology of the Neuromuscular Junction Flashcards
Briefly describe what happens at the NMJ (refer to ACh)
ACh is created and packaged into vesicles, so that when we have excitation of that motor neuron, that stimulates the release of the vesicle.
ACh is released and acts on the post-synaptic nicotinic receptor.
This action is degraded rapidly by the presence of acetylcholine esterase enzymes.
State 3 ways to block the neuromuscular junction
Presynaptically by INHIBITING ACh synthesis
Presynaptically by INHIBITING ACh release
Postsynaptically by interfering with the actions of ACh on the receptor
State ways of achieving presynaptic blockade
By inhibiting ACh release :
- Local anaesthetics
- General inhalational anaesthetics
- Inhibitors/competitors of calcium
- Neurotoxins
How do local anaesthetics work ?
They bind and block the voltage gated sodium channels.
State some inhibitors of calcium release
Antibiotics :
- Aminoglycosides (e.g. gentamicin)
- Tetracycline
State a competitor of calcium
Magnesium ions
Name some neurotoxins
Boutilin toxin
Beta-Bungarotoxin
Boutilin toxin cause
clostridium botulinum
Uses of botox
Prevents muscle spasticity
Cosmetic reasons
Prevents hyperhydrosis (sweating)
How does botox work ?
Prevents the release of ACh, but also influences other neurons, not specific to inhibit the control of muscle.
State ways of achieving postsynaptic blockade
Endotracheal intubation
During surgical procedures
Infrequently in intensive care
During electroconvulsive therapy
Why are neuromuscular blocking drugs used during surgical procedures ?
To allow access to abdominal cavity
To ensure immobility
To allow relaxation to reduce displaced fracture or dislocation
Advantage of using neuromuscular blocking drugs during surgical procedures
Lowers the concentration of general anaesthetic needed
Describe the structure of the nicotinic acetylcholine receptor
Alpha2Beta1Gamma1Delta1
Has 2 ACh gates
The ACh gates require the binding of 2 molecules of ACh to the receptor to cause a conformational change that allows it to open.
What are agonists ?
Things that open the channel and act as the endogenous ligand would on that system.
What are antagonists ?
They block the action of ACh on the receptor, so they prevent ACh from opening the channel and having its effect.
Name some nicotinic ACh receptor agonists
ACh
Nicotine
Suxamethonium
Name some nicotinic ACh receptor antagonists
Tubocurarine
Atracurium
What are non-depolarising blockers ?
They act as competitive antagonists of nicotinic ACh receptors at the NMJ.
Name some non-depolarising blockers
Tubocurarine
Atracurium
Describe the action of non-depolarising blockers
Prevents ACh binding to the 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 happens at the end-plate ?
The end plate is where you get the synapse between your motor neuron and the muscle fibre that’s controlling.
What are depolarising blockers ?
They are agonists of nicotinic ACh receptors at the NMJ.
Name a depolarising blocker
Suxamethonium
-> opens nicotinic ACh receptors
Describe the action of suxamethonium
Suxamethonium will activate nicotinic acetylcholine receptors and open them.
This allows sodium to come into the cell, which would cause an action potential.
This results in contraction of the muscle.
Initial contraction, relaxation and no further ability to cause contraction. (overstimulation of cell)
Suxamethonium is not degraded as rapidly as ACh. It is only degraded by the acetylcholine esterase found in the patients plasma.
Describe the action of depolarising blockers
Persistent depolarisation of the motor end plate
Prolonged EPP
Prolonged depolarisation of the muscle membrane
Membrane potential above the threshold for resetting of voltage gated sodium channels.
Sodium channels remain refractory
No more muscle action potentials generated
Describe phase 1 of the depolarising block
Muscle fasciculations observed, then blocked
Repolarisation inhibited
- K+ leaks from cells (hyperkalaemia)
Voltage gated Na+ channels kept inactivated
Describe phase 2 of the depolarising block
Occurs when prolonged/ increased exposure to drug
“Desensitisation blockade”
- Depolarisation cannot occur, even in absence of drug
List the drugs that affect NMJ neurotransmission
Pancuronium
Vecuronium
Rocuronium
Atacurium
Mivacurium
Suxamethonium
Describe the drug : Pancuronium
Onset : Medium
Duration : Long
Main side effect(s) : Tachycardia
Describe the drug : Vecuronium
Onset : Medium
Duration : Medium
Main side effect(s) : Few side effects
Describe the drug : Rocuronium
Onset : Fast
Duration : Medium
Main side effect(s) :Tachycardia
Describe the drug : Atacurium
Onset : Medium
Duration : Medium
Main side effect(s) : Hypotension / Bronchospasm
Describe the drug : Mivacurium
Onset : Fast
Duration : Short
Main side effect(s) : Hypotension / Bronchospasm
Describe the drug : Suxamethonium
Onset : Fast
Duration : Short
Main side effect(s) :
- Bradycardia
- Cardiac dysrhythmias
- Malignant hypothermia
etc.
Describe the action of atracurium
Atracurium undergoes ester hydrolysis and Hofmann elimination
Describe the action of mivacurium and suxamethonium
These drugs are metabolised by plasma cholinesterases
This breaks down ACh which is present in plasma.
Describe the action of pancuronium and vecuronium
These drugs undergo hepatic metabolism and are dependent on liver function.
Describe the action of rocuronium
Unchanged in bile/urine
State ways to reverse neuromuscular blockade
Cholinesterases : the duration of action of ACh is regulated by hydrolysis
Describe acetylcholinesterase
True cholinesterase, specific for hydrolysis of ACh
Present in conducting tissue and red blood cells
Bound to the basement membrane in the synaptic cleft
Describe plasma cholinesterase
Pseudocholinesterase, broad spectrum of substrates
Widespread distribution
Soluble in plasma
Describe how cholinesterases act
If you inhibit the activity of acetylcholinesterase, in the synaptic region, the concentration of ACh present in the synaptic region increases.
As the concentration of ACh released increases, this increases the amount able to bind to the nicotinic receptors.
Restoration of transmission
What are anti-cholinesterase drugs ?
They are all inhibitors of cholinesterase enzymes.
How do anti cholinesterase drugs act ?
They increase the availability of ACh @ the NMJ by decreasing degradation.
This increases the duration of activity of ACh @ NMJ
More ACh to compete with non-depolarising blockers
Name some anti cholinesterase drugs
Neostigimine
Pyridostigmine
Function of carbamylation
Slows the rate of hydrolysis
Describe some effects of anticholinesterases on the CNS
Initial excitation with convulsions
Unconsciousness and respiratory failure
Describe some effects of anticholinesterases on the ANS
Salivation
Lacrimation
Urination
Defecation
Gastrointestinal upset
Emesis
Bradycardia
Hypotension
Bronchoconstriction
Pupillary constriction
State some clinical uses of anticholinesterases
In anaesthesia
Myasthenia Gravis
Glaucoma
Alzheimer’s disease
How do anticholinesterases work in anaesthesia ?
Reverse non-depolarising muscle blockade
Given with atropine or glycopyrrolate to counteract parasympathetic effects
How do anticholinesterases work in myasthenia gravis ?
Increase neuromuscular transmission
How do anticholinesterases work in glaucoma ?
Decrease intraocular pressure
How do anticholinesterases work in Alzheimer’s disease ?
Enhances the cholinergic transmission in the CNS
Myasthenia Gravis
Autoantibodies may be produced against the acetylcholine receptor, blocking the interaction of the acetylcholine receptor with its ligand.
This leads to increased muscle stiffness and weakness.
