Autonomic and Neuromuscular Pharmacology

Question 1

Describe synaptic transmission at the NMJ

Answer 1

1. Synthesis and packaging of neurotransmitter (usually) in presynaptic terminals
2. Na+ action potential invades terminal
3. Activates voltage gated Ca2+-channels
4. Triggers Ca2+-dependent exocytosis of pre-packaged vesicles of transmitter
5. Transmitter diffuses across cleft and binds to ionotropic and/or metabotropic receptors to evoke postsynaptic response
6. Presynaptic autoreceptors inhibit further transmitter release
7. Transmitter is (usually) inactivated by uptake into glia or neurones
8. Transmitter is metabolised within cells

Question 2

How can drugs minimise synaptic transmission in the NMJ?

Answer 2

• Stop the Ach being packaged into the vesicles e.g. hemicholinium
• Stop release by blocking the voltage gated Ca2+ channels – black widow spider toxin
• Stop release by preventing vesicle fusion – botulinum toxin
• Stop ACh activating the postsynaptic nicotinic receptors by using a competitive antagonist – d-tubocurarine, atracurium.
• Use depolarising nicotinic receptor blockers - suxamethoneum/succinylcholine

Question 3

How does hemicholinium affect synaptic transmission in the NMJ?

Answer 3

Stop the Ach being packaged into the vesicles e.g. by blocking choline transport – hemicholinium does this but it is going to affect all cholinergic synapses

Question 4

How does black widow spider toxin affect synaptic transmission in the NMJ?

Answer 4

Stop vesicle release by blocking the voltage gated Ca2+ channels – for example, black widow spider toxin would do that, but probably block all transmitter release anywhere. All are still too unspecific

Question 5

How does botulinum toxin affect synaptic transmission in the NMJ?

Answer 5

Stop release by preventing vesicle fusion – botulinum toxin would do that, but probably block all transmitter release at all synapses, unless locally injected (botox)

Botulinum toxin used for:
– Treating muscle spasm
– Cosmetic procedures

Question 6

How does d-tubocurarine affect synaptic transmission in the NMJ?

Answer 6

Stop ACh activating the postsynaptic nicotinic receptors by using a competitive antagonist – d-tubocurarine (1942) does this and now there are several others, usually ending in –ium, which have varied selectivity for the NMJ over the ganglionic receptors, eg atracurium.

Question 7

How does succinylcholine affect synaptic transmission in the NMJ?

Answer 7

Use depolarising nicotinic receptor blockers - Curiously, you can “block” these receptors with an agonist that activates the ion channel and keeps it activated which causes a brief muscle twitching and then paralysis as the voltage gated channels stay in their inactivated (refractory) state – suxamethoneum/succinylcholine does that. It has the advantage of having a very short lasting action (3-7 minutes), but the disadvantage that the twitching stage can cause damage and subsequent pain.

Question 8

How can drugs increase synaptic transmission in the NMJ?

Answer 8

• Prolong the action potential - you can let more Ca2+ and therefore trigger more Ach release by making the Ca2+ action potential longer. It is normally curtailed by K+ entering through voltage gated K+ channels (just like the Na+ action potential), so if you block them you get more release. 3,4-aminopyridine does this, but will probably do the same at all synapses everywhere.
• Block acetylcholinesterase - you can stop the breakdown of Ach by blocking the acetylcholinesterase so it hangs around in the synaptic cleft for longer. Eserine does this.

Question 9

How does 3,4-aminopyridine affect synaptic transmission in the NMJ?

Answer 9

Prolongs the action potential - you can let more Ca2+ and therefore trigger more Ach release by making the Ca2+ action potential longer. It is normally curtailed by K+ entering through voltage gated K+ channels (just like the Na+ action potential), so if you block them you get more release. 3,4-aminopyridine does this, but will probably do the same at all synapses everywhere.

Question 10

How does eserine affect synaptic transmission in the NMJ?

Answer 10

Blocks acetylcholinesterase - you can stop the breakdown of Ach by blocking the acetylcholinesterase so it hangs around in the synaptic cleft for longer. Eserine does this.

Anti-cholinesterases used for:
– Treating myasthenia gravis (Abs against AchRs)
– Reversing action of non-depolarising blockers
– Countering botulinum poisoning

Question 11

How could you decrease ganglionic transmission?

Answer 11

• Inhibit choline transporter (e.g. hemicholinium)
• Block voltage gated Ca2+ channels (e.g. black widow spider venom)
• Block vesicle fusion (e.g. botulinium toxins)
• Block ACh activated channel (e.g. hexamethoneum)
• Non-depolarising nicotinic receptor blockers (e.g. mecylamine)
• Depolarising nicotinic receptor blockers (e.g. suxamethoneum)

Question 12

Why are postsynaptic muscarinic receptors such a huge pharmacological target?

Answer 12

Postganglionic parasympathetic transmission involves the release of acetylcholine, which then binds to G-protein coupled muscarinic receptors on the target tissues. Most therapeutic drugs target GPCRs, making the postsynaptic muscarinic receptors a huge target.

Question 13

What is atropine?

Answer 13

Muscarinic receptor antagonists: a medication used to treat certain types of nerve agent and pesticide poisonings, to slow HR, and to decrease saliva production during surgery