NMJ and Cholinergic Pharmacology

Question 1

what is a cholinergic nerve?

Answer 1

one that uses ACh as a NT

Question 2

what nerves are cholinergic?

Answer 2

para (pre and post), sympathetic (pre), somatic, CNS and enteric

Question 3

where does choline come from and how is it up taken?

Answer 3

from diet, then stored in the liver / transported in the blood
taken up by nerve endings which have a high affinity Na+ dependant carrier

Question 4

How can choline uptake be inhibited?

Answer 4

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

Question 5

how is Ach formed, what enzymes, what substrates?

Answer 5

• 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

Question 6

how is the production of Ach inhibited?

Answer 6

Triethyl choline is also a substrate for ChAT and results in the formation of acetyltriethylcholine, inhibiting the production of Ach, - not used clinically

Question 7

how is Ach transported into the vesicle?

Answer 7

energy dependant, vesicular Ach Transporter

Question 8

what inhibts transport of Ach into vesicle?

Answer 8

vesamicol

Question 9

explain the poison of black widow spiders

Answer 9

α-latrotoxin causes a massive Ach vesicle release and hence depletion of stores

Question 10

what is the action of botulinum toxin

Answer 10

cleaves proteins needed for exocytosis

Question 11

what are the uses of botulinum toxin?

Answer 11

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

Question 12

what is the action and uses of sarin?

Answer 12

inhibits acetylcholinesterase, blocks skeletal neuromuscular junction transmission, initial contraction and then paralysis and augments parasympathetic effects
used in biological warfare (nerve agent)

Question 13

what are the 2 main receptors types for Ach and where are they located?

Answer 13

nicotinic receptors (mainly peripheral ganglia) and muscarinic receptors (mainly on outside of organs)

Question 14

how does nicotine effect nicotinic receptors?

Answer 14

agonist for these receptors, transiently stimulate ganglia / motor end plates, however after a few seconds receptors can be desensitised, blocking transmission, reducing neuron action

Question 15

what is the structure of a nicotinic receptor?

Answer 15

Nicotinic receptors are ligand gated sodium channels made of 5 subunits

Question 16

why is Hexamethonium a poor drug?

Answer 16

also blocked parasympathetic activity and other essential neurons leading to dry mouth, constipation
also poorly absorbed from the gut so had to be injected

Question 17

what is the action of Galantamine?

Answer 17

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

Question 18

what is the structure of muscarinic receptors?

Answer 18

G protein coupled receptors

Question 19

what are the used of antimuscarinic drugs?

Answer 19

inhibit parasympathetic drugs, promote sympathetic modes of action

Question 20

what are parasympathomimetic?

Answer 20

muscarinic agonists

Question 21

give 2 examples of an antimuscarinic drug

Answer 21

atropine to treat bradycardia
ipratropium, for asthma, promotes vasodilation, inhibits vasoconstriction

Question 22

what effect does binding of Ach to prejunctional nAchR have?

Answer 22

increase Ach release, positive feedback

Question 23

explain the structure of botulinum toxin

Answer 23

2 subunits, the first subunit binds to the presynaptic membrane, and the second cleaves proteins involved in exocytosis

Question 24

where does botulinum toxin come from?

Answer 24

clostridium botulinum which is an anaerobic bacteria that can grow in preserved food

Question 25

what are the 2 treatments for botulinum toxin poisoning?

Answer 25

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

Question 26

what are the 2 categories of post synaptic NMJ blockers?

Answer 26

non-depolarising blockers (antagonist) and depolarising blocker (agonist)

Question 27

give 2 examples of non depolarising NMJ blockers

Answer 27

pancuronium and vecuronium (competitive antagonists of nAchR)

Question 28

what was the original NMJ blocker used by Amazonian tribes in blow dart poison?

Answer 28

D-tubocurarine

Question 29

how are non depolarising blockers administered and how long do they last?

Answer 29

IV administration and can have effects varying from 15mins - 2 hours depending on the individual

Question 30

how are the effects of non depolarising blockers stopped?

Answer 30

metabolism or excretion

Question 31

what is the mechanism of suxamethonium?

Answer 31

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

Question 32

how is the action of suxamethonium stopped?

Answer 32

broken down by plasma cholinesterase

Question 33

when is suxamethonium used?

Answer 33

brief procedures such as intubation

Question 34

what are the unwanted side effects of suxamethonium?

Answer 34

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

Question 35

why should suxamethonium not be used to treat burn victims?

Answer 35

may express excess nAChR due to denervation super sensitivity resulting in lots of K+ leaking into the blood

Question 36

what are the uses / mechanisms of acetylcholine esterase inhibitors?

Answer 36

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

Question 37

what type of blocker can acetylcholinesterase not be used on?

Answer 37

make the effects of a depolarising blocker such as suxamethonium worse

Question 38

What is myasthenia gravis?

Answer 38

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

Question 39

how is myasthenia gravis treated?

Answer 39

* 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