Autonomic and Neuromuscular Pharmacology Flashcards Preview

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Flashcards in Autonomic and Neuromuscular Pharmacology Deck (13):
1

Describe synaptic transmission at the NMJ

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

2

How can drugs minimise synaptic transmission in the NMJ?

- 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

3

How does hemicholinium affect synaptic transmission in the NMJ?

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

4

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

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

5

How does botulinum toxin affect synaptic transmission in the NMJ?

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

6

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

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.

7

How does succinylcholine affect synaptic transmission in the NMJ?

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.

8

How can drugs increase synaptic transmission in the NMJ?

- 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.

9

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

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.

10

How does eserine affect synaptic transmission in the NMJ?

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

11

How could you decrease ganglionic transmission?

• 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)

12

Why are postsynaptic muscarinic receptors such a huge pharmacological target?

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.

13

What is atropine?

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