NMJ and Cholinergic Pharmacology Flashcards
what is a cholinergic nerve?
one that uses ACh as a NT
what nerves are cholinergic?
para (pre and post), sympathetic (pre), somatic, CNS and enteric
where does choline come from and how is it up taken?
from diet, then stored in the liver / transported in the blood
taken up by nerve endings which have a high affinity Na+ dependant carrier
How can choline uptake be inhibited?
Hemicholinium - competitive inhibitor of the choline carrier, activity dependant as depleted choline appears after activation and no reuptake, has no clinical use as its effects are widespread
how is Ach formed, what enzymes, what substrates?
- Choline acetyltransferase (ChAT) catalysis’s the formation of acetylcholine by combining choline with acetyl CoA this results In the formation of Ach and CoA
- This reaction occurs in the nerve cytoplasm
how is the production of Ach inhibited?
Triethyl choline is also a substrate for ChAT and results in the formation of acetyltriethylcholine, inhibiting the production of Ach, - not used clinically
how is Ach transported into the vesicle?
energy dependant, vesicular Ach Transporter
what inhibts transport of Ach into vesicle?
vesamicol
explain the poison of black widow spiders
α-latrotoxin causes a massive Ach vesicle release and hence depletion of stores
what is the action of botulinum toxin
cleaves proteins needed for exocytosis
what are the uses of botulinum toxin?
used to treat achalasia, salivary drooling, axillary hyperhidrosis ( excessive armpit sweating) can be used for cosmetic appearance ( smooth skin), however can also be used in biological warfare - muscle failure, respiratory failure - death
what is the action and uses of sarin?
inhibits acetylcholinesterase, blocks skeletal neuromuscular junction transmission, initial contraction and then paralysis and augments parasympathetic effects
used in biological warfare (nerve agent)
what are the 2 main receptors types for Ach and where are they located?
nicotinic receptors (mainly peripheral ganglia) and muscarinic receptors (mainly on outside of organs)
how does nicotine effect nicotinic receptors?
agonist for these receptors, transiently stimulate ganglia / motor end plates, however after a few seconds receptors can be desensitised, blocking transmission, reducing neuron action
what is the structure of a nicotinic receptor?
Nicotinic receptors are ligand gated sodium channels made of 5 subunits
why is Hexamethonium a poor drug?
also blocked parasympathetic activity and other essential neurons leading to dry mouth, constipation
also poorly absorbed from the gut so had to be injected
what is the action of Galantamine?
acts on nicotinic receptors to increase their activity, positive allosteric modulation, can be used to treat Alzheimer’s disease e.g. increases alternes, it is also an acetylcholinesterase inhibitors
what is the structure of muscarinic receptors?
G protein coupled receptors
what are the used of antimuscarinic drugs?
inhibit parasympathetic drugs, promote sympathetic modes of action
what are parasympathomimetic?
muscarinic agonists
give 2 examples of an antimuscarinic drug
atropine to treat bradycardia
ipratropium, for asthma, promotes vasodilation, inhibits vasoconstriction
what effect does binding of Ach to prejunctional nAchR have?
increase Ach release, positive feedback
explain the structure of botulinum toxin
2 subunits, the first subunit binds to the presynaptic membrane, and the second cleaves proteins involved in exocytosis
where does botulinum toxin come from?
clostridium botulinum which is an anaerobic bacteria that can grow in preserved food
what are the 2 treatments for botulinum toxin poisoning?
4-aminopyridine, this is a blocker of voltage gated K+ channels meaning that the repolarisation phase is delayed, this means more Ca2+ influxes for a longer period resulting in more drive for Ach release to overcome the effects of botulinum
antitoxin that binds to botulinum which prevents its entry into the nerve terminal
what are the 2 categories of post synaptic NMJ blockers?
non-depolarising blockers (antagonist) and depolarising blocker (agonist)
give 2 examples of non depolarising NMJ blockers
pancuronium and vecuronium
(competitive antagonists of nAchR)
what was the original NMJ blocker used by Amazonian tribes in blow dart poison?
D-tubocurarine
how are non depolarising blockers administered and how long do they last?
IV administration and can have effects varying from 15mins - 2 hours depending on the individual
how are the effects of non depolarising blockers stopped?
metabolism or excretion
what is the mechanism of suxamethonium?
depolarising blocker, it consists of 2ACh linked by acetyl groups
binds to nAChR and cause depolarisation, however due to it not coming from a nerve terminal it binds randomly resulting in fasciculations (uncoordinated fine contractions)
remain and cause prolonged depolarisation, this inactivates the voltage gated Na channels leading to paralysis, this phase is known as the phase 1 block
how is the action of suxamethonium stopped?
broken down by plasma cholinesterase
when is suxamethonium used?
brief procedures such as intubation
what are the unwanted side effects of suxamethonium?
bradycardia (slow HR due to Ach receptors in the heart), it can lead to excess K+ release due to prolonged depolarisation, this can increase risk of cardiac arrest
increase in intraocular pressure due to contraction of extraocular muscles
why should suxamethonium not be used to treat burn victims?
may express excess nAChR due to denervation super sensitivity resulting in lots of K+ leaking into the blood
what are the uses / mechanisms of acetylcholine esterase inhibitors?
reverse the effects of non-depolarising blockers after surgery, increase Ach levels, which competes with the antagonist, leading to an increase in end plate potential
what type of blocker can acetylcholinesterase not be used on?
make the effects of a depolarising blocker such as suxamethonium worse
What is myasthenia gravis?
autoimmune condition that causes destruction of nAChR at the NMJ, it is a progressive disorder than can lead to paralysis and death if not treated
how is myasthenia gravis treated?
- Examples of Acetylcholinesterase inhibitors used to treat MG include Edrophonium – short duration; Diagnostic test of drug efficacy, Neostigmine – medium duration; muscarinic side effects, Pyridostigmine – Better oral absorption; long duration; less powerful
