YW - NMJ II Flashcards
What distinguishes non-depolarizing and depolarizing NMJ blocking agents?
Non-depolarizing blocking drug
Acts as a competitive inhibitor
- Can be reversed by increased [ACh]
e.g. tubocurarine. pancuronium and vecuronium
Depolarizing blocking drug
Acts as a non-competitive antagonist
- Cannot be reversed by increased [ACh]
e.g. decamethonium and succinylcholine
These toxins bind with high affinity to nicotinic acetylcholine receptor
- Causes a postsynapticblock at the NMJ
Features of competitive (non-depolarizing) agents
(curare) (4)
- Compete with ACh for binding to receptor
- flaccid, relaxed paralysis
- non-NMJ effects: ganglia, muscarinic blocking, histamine release
- NMJ block CAN be reversed by AChE inhibitors
Features of non-competitive (depolarizing) agents (2)
Phase 1 block
- Membrane depolarisation
- Transient fasciculations followed by paralysis
Phase 2 block
- Desensitisation
- Membrane depolarises, hypersensitive to ACh
NMJ block not reversed by AChE inhibitors
Name examples of competitive inhibitors (5) and their clinical uses (5)
Competitive inhibitors
- Tubocurarine
- Pancuronium
- Gallamine
- Mivacurium
- Atracurium
Clinical Uses of NMJ Blocking Agents
- Muscle relaxation in surgery
- Orthopedics
- Facilitate internal examinations
- Prevent traum
- Diagnostic
Name the natural (2), weapons (2) and drugs (5) related to acetylcholinesterase inhibitors
Natural:
- venoms
- poisons
Weapons:
- nerve agents
- insecticides
Drugs:
- To treat myasthenia gravis
- To treat Alzheimer’s disease
- To treat Lewy body dementia
- To treat glaucoma
- Antidote for anticholinergic poisoning
What do cholinestrase inhibitors do and what are 4 examples?
Increase the availability of acetylcholine (ACh), partially overcome the decreased receptor availability
- Reverse non-depolarising muscle blockade
- First line for ocular myasthenia
Edrophonium, Neostigmine, Pyridostigmine, Distigmine
(in order of increasing duration of action)
What are the symptoms after over-stimulation of the NMJ??
Cholinergic crisis
What casues an excess of ACh and what happens to the muscles responding to excess AChExcess of acetylcholine (ACh)
Excess of acetylcholine (ACh)
– Nerve gas
– Disease (e.g., Myasthenia gravis patients taking too much
medication)
– Surgery (too much ACh inhibitor to reverse surgical paralysis)
The muscles stop responding to the excess ACh
– Vasodilatation of blood vessels
– Sweating
– Salivation
– Bronchial secretions (mucus)
– Miosis (constriction of eye pupil)
– Flaccid paralysis
– Respiratory failure
What are the symptoms of nerve gas poisoning, and what is the antidote?
Nerve gas poisoning
Overstimulation of muscles, organs and glands
- Symptoms: Ataxia (lack of muscle control), slurred speech, areflexia (loss of reflexes), generalized convulsions, respiratory failure, death
ATROPINE IS AN ANTIDOTE!
- Atropine binds to the acetylcholine receptors and prevents acetylcholine from binding to the receptors
How do organophosphates affect acetylcholinesterase (AChE)?
Irreversible AChE inhibitors
- The phosphorous atom covalently binds to a serine hydroxyl group in the active site of acetylcholinesterase (AChE or ACE)
Enzyme no longer functional (inactive)
What is the mechanism of action of edrophonium, and when is it used?
Edrophonium is a readily reversible AChE inhibitor that prevents breakdown of ACh
myasthenic crisis: not enough neuromuscular stimulation:
- Edrophonium will reduce the muscle weakness by effectively supplying more ACh
Cholinergic crisis: too much neuromuscular stimulation:
- Edrophonium will make the muscle weakness worse by inducing a depolarizing block
What is Physostigmine and what are its clinical uses?
Reversible pseudo-competitive AChE inhibitor
Clinical uses:
- Physostigmine is used to treat myasthenia gravis, glaucoma, Alzheimer’s disease and delayed gastric emptying
It can cross the blood brain barrier and can be used to treat effects of atropine and other anticholinergic drug overdoses
What is the cholinergic hypothesis in dementia?
Cognitive decline is linked to the loss of cholinergic transmission in hippo and cortex
What do anstispasmodics do and what is an example?
Antispasmodics
- Inhibit the release of ACh
E.g Botulinum Toxin
What are the symptoms of botulism? (4)
Botulism Symptoms
- Blurred vision
- Muscle weakness
- Difficulty swallowing
- Slurred speech
