24-01-22 - Pharmacology of the Neuromuscular Junction Flashcards
Learning outcomes
- To list the drugs that affect neuromuscular junction neurotransmission
- To explain the mechanism of action of such drugs
- To relate the mechanism of action of these drugs to the therapeutic outcome
- To identify the side effects of such drugs
- To explain how recovery from neuromuscular block occurs and this can be induced
What are the 3 ways to block neuromuscular transmission?
• Ways to block neuromuscular transmission:
1) Presynaptically, by inhibiting Ach Synthesis (rate-limiting step is choline uptake)
2) Presynaptically by inhibiting Ach release
3) Postsynaptically by interfering with the actions of Ach on the receptor
What are the 4 methods of inhibiting Ach release? How do they each work?
• Methods of inhibiting Ach release:
1) Local anaesthetics
• Block voltage gated Na+ channels responsible for propagation of action potential down a neuron in excitable tissue
2) General inhalational anaesthetics
• Works by changing the fluidity of membranes, altering their excitability
• This can cause patients to lose consciousness/awareness, and the ability to control muscles
3) Inhibitors/competitors of calcium
• Magnesium ions can compete with calcium for intake into the cell, but don’t cause the release of vesicles
• Some antibiotics
• Aminoglycosides e.g gentamicin
• Tetracycline can bind to calcium to reduce the amount available to get into the cell
4) Neurotoxins
• Botulinum toxin (clostridium botulinum) can inhibit snare and synaptobrevin proteins needed for the fusion of vesicles with the presynaptic membrane
• Β-bungarotoxin (Taiwanese banded krait snake) – interferes with synaptobrevin
What does botulinum toxin (Botox) block?
What does this cause?
What 3 things can Botox be used to treat?
- Botox pre-synaptically blocks the release of Ach
- This causes localised relaxation of the muscle, as the toxins stays where it is injected and doesn’t spread around the body
• Botox can be used to treat:
1) Muscle spasticity e.g unwanted muscle contraction from cerebral palsy
2) Cosmetic treatment
3) Hyperhydrosis
What are the 4 clinical uses of neuromuscular blocking drugs?
• Clinical uses of Neuromuscular blocking drugs:
1) Endotracheal intubation
2) During surgical processes
• To allow surgical access to abdominal cavity
• To ensure immobility e.g prevent coughing during head and neck surgery
• Allow relaxation to reduce displaced fracture or dislocation
• Decrease concentration of general anaesthetic needed
3) Infrequently in intensive care
4) During electroconvulsive therapy
What is the structure of the nicotinic Ach receptor on the post-synaptic membrane of muscle cells?
What does it function as?
What moves in and out of it?
What occurs when there is a sufficient influx of calcium through the receptor pore?
- The nicotinic Ach receptor consists of 5 subunits and 2 ACh binding sites
- It is a pore that allows the movement of sodium and potassium ions across the membrane of a cell when ACh binds to both binding sites and causes a conformation shape change
- This allows sodium to come into the cell and potassium to move out of the cell
- When there is a sufficient influx of sodium, it will result in depolarisation of the target muscle cell, allowing an action potential to be generate din the NMJ of the target muscle cell
- This can then spread across the muscle fibre and induce contraction
What are agonists and antagonists of the Nicotinic ACh receptors?
Where do antagonists bind?
What are the 2 types of ACh blockers?
- Agonists are molecules that when bound to the Nicotinic ACh receptor, causing it to open e.g nicotine and suxamethonium
- When antagonists bind, the receptor stays closed e.g tubocurarine and atracurium
- Antagonists bind to the same site as ACh, preventing it from binding
- There are non-depolarising and depolarising blockers
What are non-depolarising blockers?
What are 2 examples?
What are the 4 steps of hoe these blocker work?
- Non-depolarising blockers are competitive agonists of nicotinic ACh receptors
- Tubocurarine and atracurium are non-depolarising blockers
• Function of these receptors:
1) Prevents Ach binding to receptor by occupying the binding site
2) Decreases the motor end plate potential
3) Decreases depolarization of the motor end plate region
4) No activation of the muscle action potential
What are depolarising blockers of nicotinic ACh receptors?
What is an example?
What is their structure like?
Describe the 6 steps of their function
- Depolarising blockers of ACh receptors are agonists
- Suxamethonium is a depolarising blocker that acts as an agonist
- Suxamethonium is like 2 molecules of ACh together, and is broken down slowly compared to ACh, which is degraded rapidly
- This keeps the receptor open for a long period of time
• Function of depolarising blockers:
1) Persistent depolarisation of the motor end plate
2) Prolonged end plate potential
3) Prolonged depolarisation of the muscle membrane
4) Membrane potential above the threshold for the resetting of voltage-gated sodium channels (EPP has to be reset to generate new contraction)
5) Sodium channels remain refractory
6) No more muscle action potentials generated
What are the two phases of depolarisation blocks?
• Phases of depolarising blocks:
1) Phase 1
• Muscle fasciculations observed, then blocked
• Repolarisation inhibited
• K+ leaks from cells through nicotinic ACh receptors – can lead to hyperkalaemia (increased potassium in the blood)
2) Phase 2
• Prolonged/increased blood exposure to drug
• Desensitisation blockade
• Muscle is refractory and can’t be stimulated, even though the suxamethonium
• Depolarisation cannot occur for a period of time, even in the absence of drug
What are the 5 non-depolarising neuromuscular blocking drugs?
What is the depolarising neuromuscular blocking drugs?
What is their onset?
What is their duration?
What are their main side effects?
Why is knowing the metabolism and rate of removal of drugs important?
What are 4 ways drugs can be metabolised/ removed?
What are examples of drugs metabolised by each type?
- Knowing the metabolism and rate of removal of drugs will indicate how long the drug will have an effect on the blockage
- It is also important, as the metabolism/removal of certain drugs relies on the liver and kidney function
- If a patient has compromised liver and kidney function, this will increase the length of the blockade.
- 4 methods of metabolism/removal:
1) Ester hydrolysis and Hofman elimination
• Drug atracurium
• Rapidly degraded and removed
• Removed independent of liver/kidney function
2) Plasma cholinesterases
• Drugs mivacurium and suxamethonium
• 4% of the population have a prolonged block (apnoea) – block lasts 10 minutes instead of a minute
• 0.04% of the population may have no plasma cholinesterases, resulting in the block lasting hours
3) Hepatic metabolism
• Drugs pancuronium
• Vecuronium
4) Unhanged in bile/urine
• Drug rocuronium
What is the action of ACh regulated by?
What are the 2 types of cholinesterases?
What are their substrates?
Where are they found?
• The action of ACh is regulated by hydrolysis from cholinesterases
1) Acetylcholineterases
• True cholinesterase specific for hydrolysis
• Present in conducting tissue and red blood cells
• Bound to basement membrane in synaptic cleft
2) Plasma cholinesterase • Psuedocholinesterase • Broad spectrum of substrates • Widespread distribution (found in plasma) • Soluble in plasma
What are all anticholinesterase drugs?
What 3 effects does their use lead to?
What are the 2 different types of anticholinesterase drugs?
What are examples of each?
What are each used for?
How do they each work?
- All anticholinesterase drugs are inhibitors of cholinesterase enzymes
- Their use leads to:
1) Increases availability of ACh at NMJ by reducing degradation
2) Increases duration of activity at NMJ
3) More ACh to compete with non-depolarising blockers
• 2 different types of anticholinesterase drugs:
1) Quarterenary amines
• Drugs Neostigmine and pyridostigmine
• Clinically used
• Low down the function of ACh enzymes
• Binds to esteratic site and gets cleaved, but at a slower rate than ACh, which slows down the action of the enzyme
• This is known as carbamylation, which slows the rate of hydrolysis
• Only works for non-depolarising blockers, as more ACh from polarising blockers will release ACh to an already overstimulated muscle cell
2) Organophosphates
• Drugs Dyflos and Parathion
• Very toxic and not clinically used
• Irreversible inhibit cholinesterases
• These drugs phosphorylate the esteratic site, leading to it being ihbited permanently
• Recovery depends on synthesis of new enzyme, which can be coaxed by pralidoxime
What are 2 effects of excess doses of anticholinesterases on the CNS?
What are the 10 effects on the ANS?
• Effects of excess doses of anticholinesterases on the CNS:
1) Initial excitation with convulsions
2) Unconscious and respiratory failure
• Effects on the ANS (sludge):
1) Salivation
2) Lacrimation (flow of tears)
3) Urination
4) Defecation
5) GI upset
6) Emesis (vomiting)
7) Bradycardia (slow HR)
8) Hypotension
9) Bronchoconstriction
10) Pupillary constriction (miosis)
What are the 4 clinical uses of anticholinesterases?
• Clinical uses of anticholinesterases:
1) In anaesthesia
• Reverse non-depolarising muscle blockade
• Given with atropine or glycopyrrolate to counteract to parasympathetic effects
2) Myasthenia gravis
• Increase neuromuscular transmission
• Autoantibodies may be produced against the acetylcholine receptor, blocking the interaction of the ACh receptor with ACh
• This leads to muscle weakness, and potentially death
• Anticholinesterases prevent ACh degradation at NMJ, which increases the ACh present
• This will increase the probability of ACh binding on to receptors that aren’t blocked by antibodies, which will restore some normal transmission and control of skeletal muscle
3) Glaucoma
• Decrease intraocular pressure
4) Alzheimer’s disease
• Enhance the cholinergic transmission in the CNS
What is sugammadex?
What drugs does it work on?
How does it work?
- Sugammadex is a selective relaxant binding agent (SRBA)
- It can bind with non-depolarising blockers rocuronium and vecuronium, preventing them from interacting with nicotinic ACh receptors
- It engulfs and binds to the molecules of these drugs
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