Drugs Affecting the Neuromuscular Junction Flashcards
How do drugs modulate at the Cholinergic synapse (presynaptic modulation)?
- First there is synthesis of Ach. The Cholinacetyltransferase (CAT) catalysis the transfer of the acetyl group from the coenzyme, acetyl-CoA, to choline yielding acetylcholine (Ach). No drugs affect this.
- The carrier transports Ach into the vesicle (blocked by vesamicol).
- Choline transprter (blocked by Hemicholinium)
- Exocytosis of vesicle containing Ach (blocked by toxins) clinically used drug - eg. botulinum.
How is botulinum toxin produced, what are its two subunits and what is its function.
Botulinum toxin is produced by anaerobic bacterium - Clostridium Botulinum. (10 to the power -12 grams is lethal to a mouse.
Two subunits:
1. Binds to the presynaptic neurone membrane
2. (peptidase) cleaves the proteins involved in exocytosis.
It blocks exocytosis of Ach vesicles.
How does botulinum toxin eliminate wrinkles?
It blocks nerve signals that tell your muscles to contract, by preventing the release of Ach onto the postsynaptic membrane this temporarily weakens or paralyzes the facial muscle and eliminates wrinkles (BOTOX) - lasts a few months.
How do non-depolarising blockers affect postsynaptic action?
Competitive Antagonists acting at the nAChRs. This decreases the endplate potential therefore preventing muscle contraction.
Eg) Curare (D-Tubocurarine), Pancuronium.
It is used as an anaesthetic (muscle relaxation).
-IV administration; 15min-2hr effectiveness
-Allows use of lower amounts of anaesthetic = safer
How do depolarising blockers affect postsynaptic action?
Agonist at nAChRs. Eg. Suxamethonium
1. Phase 1 block:
Causing endplate depolarisation; action potentials and uncoordinated, fine contractions affecting a small number of muscle fibres (fasciculations). The drug is not broken down my acetylcholinesterase (AchE) in the synaptic clef. Therefore contractions are long causing paralysis due to inactivation of voltage-gated Na+ channels.
2. Phase 2 block:
Broken down by plasma cholinesterase.
Paralysis is caused by inactivation of nAChRs
What are the advantages and unwanted effects of depolarising blockers affecting postsynaptic action
Advantages: Used for quick procedures - 10 mins
Unwanted effects:
Bradycardia: Activation of muscarinic Ach receptors in the heart.
K+ release - via nAChRs increases K+ plasma levels, this can cause cardiac arrest, an increase in intraocular pressure (contraction of extraocular muscles)
An individual who is deficient in the cholinesterase enzyme will experience prolonged paralysis.
How do postsynaptic modulators, Cholinesterase inhibitors work?
Cholinesterase inhibitors interact with AChE and plasma cholinesterase (where acetyl group binds). This prevents the breakdown of ACh, the effects of this enhance the synaptic function.
This inhibitor affects any synapse where ACh is the neurotransmitter. - Autoganglionic and postganglionic parasympathetic nerves.
What chemical interaction does edrophonium drug have with enzymes and how long are the affects of its action?
Edrophonium is a readily reversible acetylcholinesterase inhibitor. It forms ionic interactions with enzymes and the duration of its action is minutes long.
What chemical interaction does neostigmine drug have with enzymes and how long are the affects of its action?
Neostigmine is a medicine used to treat myasthenia gravis. It forms covalent bonds with enzymes and the duration of its action is hours long.
What chemical interaction does organophosphate drug have with emzymes and how long are the affects of its action?
Organophosphates are used a war gases; pestides. It phosphorylates enzymes, the effect of this is irreversible.
How do you reverse the effects of non-depolarising NMJ blockers?
At the end of an operation. By increasing the concentration of Ach this competes with the antagonist this increase the end plate potential, allowing an action potential to form. Ach requires Suxamethonium (neuromuscular relaxant) like action.
What is myasthenia gravis?
Myasthenia gravis is an autoimmune disease in which antibodies against the nicotinic AchR are present. This means action potentials cannot be propagated- failure of NMJ transmission, the muscle cannot contract, this weakens the muscle and eventually causes death.
Drugs (eg. Neostigmine) can be used to increase Ach levels to try and overcome a decrease in nAchRs.
What effect does edrophonium drug have on the NMJ?
Reversible acetylcholinesterase inhibitor. Prevents breakdown of neurotransmitter ACh and acts by competitively inhibiting the enzymes acetylcholinesterase.
What effect does neostigmine and pyridostigmine have on the NMJ?
Causes neuromuscular blocking medication of the depolarising type.
