Autonomic and Neuromuscular Pharmacology

Question 1

What are the ways the neuromuscular junction transmission can be inhibited?

Answer 1

Inhibit chloine transporter (eg hemicholinium)

Block voltage gates Ca2+ channels (eg black widow spider venom)

Block vesicle fusion (botulinium toxins)

Use non-depolarising nicotinic receptor blockers (eg d-tubocurarine)

Use depolarising nicotinic receptor blockers (e.g suxamethonemum = succinylcholine)

Question 2

How can the neuromuscular transmission be potentiated?

Answer 2

Block acetylcholinesterase (eg eserine)

Question 3

What neurotransmitter is released from the neuromuscular junction and what does it bind to?

Answer 3

Acetylcholine is being released

Binds to nicotinic cholinergic receptors on the muscle cell membrane

Question 4

How can acetylcholine be inactivated?

Answer 4

Degraded by an enzyme called acetylcholinesterase that breaks it down into choline.

Choline is taken into the cell, metabolised and is made into more neurotransmitter

Question 5

Explain the mechanism of inhibiting the choline transmitter as a means of inhibiting the transmission of the neuromuscular junction

Answer 5

Inhibiting the choline transporter means the choline is not going to get brought back into the motor neuron.

That means that the cell is going to run out of the raw materials to make more of that acetylcholine.

That means that ultimately it can’t release any more acetylcholine and transmission is stopped

Question 6

Explain the mechanism of blocking voltage gated Ca+ channels as a means of inhibiting the transmission of the neuromuscular junction

Answer 6

Block these calcium channels means there won’t be a calcium influx into the presynaptic terminal.

Therefore, we’re not going to get calcium-dependent exocytosis and no neurotransmitter is going to be released.

Question 7

Explain the mechanism of using non-depolarising nicotinic receptor blockers as a means of inhibiting the transmission of the neuromuscular junction

Answer 7

One example of a drug that does that is d-tubocurarine.

It is a competitive antagonist.

This means that it is going to bind with high affinity to these nicotinic receptors, but when it does so, it has ever no efficacy or low efficacy.

Therefore, those receptors are not going to be activated, those ion channels are not going to open and therefore there will be no response in the muscle cell.

Question 8

Explain the mechanism of blocking vesicle fusion as a means of inhibiting the transmission of the neuromuscular junction

Answer 8

A famous example of this is the botulinum toxin
and they interfere with the synaptic protein that’s involved in getting that vesicle to fuse with the cell membrane.

Question 9

Explain the mechanism of using a depolarising nicotinic receptor blocker as a means of inhibiting the transmission of the neuromuscular junction

Answer 9

An example of this is suxamethoneum.

This will have a high affinity for the nicotinic receptors but this time it’s an agonist.

That means that it’s going to open those channels
and sodium is going to flood into the muscle cell down its electrical and concentration gradients, leading to depolarisation.

An action potential will be evoked and ultimately you’re going to get muscle cell contraction.

However, this depolarising nicotinic receptor blocker is going to keep those channels open, meaning that the muscle cell will stay depolarised.

Therefore, the voltage-gated sodium channels are going to stay inactivated and in their refractory

Therefore, that means that you can’t stimulate more action potentials and you can’t make the muscle contract again.

Question 10

Explain the mechanism of blocking acetylcholinesterase as a means of potentiating the transmission of the neuromuscular junction

Answer 10

An example is eserine.

If we block this acetylcholinesterase, that means that acetylcholine isn’t going to be broken down into choline and then uptaken back into the motor neuron.

That means that the acetylcholine is going to hang around in the synaptic cleft for longer.

It’s therefore going to bind to more nicotinic receptors, activate them, and cause a bigger response.

Question 11

When are non-depolarising or depolarising blockers used for paralysis?

Answer 11

Surgical procedures
Electroconvulsive therapy
Controlling spasms in tetanus

Question 12

What can botulinum toxin be used for?

Answer 12

Treating muscle spasms
Cosmetic procedures

Question 13

When would anti-cholinesterases be used?

Answer 13

Treating myasthenia gravis
Reversing action of non-depolarising blockers
Countering botulinum poisoning

Question 14

What does acetylcholine act on?

Answer 14

Nicotinic and Muscarinic receptors

Question 15

What are the type of nicotinic receptors and where are they found?

Answer 15

N1 - ganglia
N2 - NMJ

Question 16

What are the type of muscarinic receptors and where are they found?

Answer 16

M1 - neuronal
M2 - cardian & presynaptic
M3 - smooth muscle and glands

Question 17

What do noradrenaline and adrenaline act on?

Answer 17

Adrenergic receptors - α1&2 and β1&2

Question 18

How can you target transmission at the autonomic ganglia?

Answer 18

With any of the drugs that affect the NMJ however it will affect both sympathetic and parasympathetic ganglia leading to complex effects with many side effects

Question 19

How can you target transmission at the autonomic ganglia?

Answer 19

With any of the drugs that affect the NMJ however, it will affect both sympathetic and parasympathetic ganglia leading to complex effects with many side effects

Question 20

What is the clinical application of ganglionic transmission?

Answer 20

There are no clinical application

Question 21

What is the key feature of ganglionic transmission?

Answer 21

Hexamethonium blocks nicotinic receptors at the autonomic ganglia but not at the NMJ

Question 22

What are the ways to modulate parasympathetic and post-ganglionic transmission?

Answer 22

1. Use a muscarinic receptor - parasymp

The rest are for post ganglionic transmission

2. Block the enzymes that produce noradrenaline
3. Introduce a “false” transmitter (eg methyldopa)
4. Activate inhibitory presynaptic (alpha2) autoreceptors (eg methyldopa)
5. Block alpha or beta postsynaptic receptors (eg doxazosin or propranolol)

Question 23

How do muscarinic receptor agonists modulate parasympathetic transmission?

Answer 23

These muscarinic receptor agonists are going to bind to the muscarinic receptors and activate them, mimicking the effects of parasympathetic innervation

Question 24

How do muscarinic receptor agonists modulate parasympathetic transmission?

Answer 24

Muscarinic receptor antagonists, in a stirring turn of events, are going to block the actions of parasympathetic innervation and they’re going to have the opposite effects

Question 25

What can help reduce gut mobility in IBS?

Answer 25

Beta 2 agonists

Question 25

How can you inhibit sympathetic postganglionic transmission?

Answer 25

Block the enzymes that produce noradrenaline (eg carbidopa)

Introduce a false neurotransmitter (eh methyldopa)

Activate inhibitory

Block alpha or beta postsynaptic receptors (eg doxazosin or propanolol)

Question 26

What are the clinical applications of sympathetic postganglionic transmission?

Answer 26

α1 agonists as decongestants and to dilate pupil

α2 agonists for the treatment of hypertension

β1 agonists for treatment of asthma

β2 antagonist for the treatment of hypertension, angina and cardiax arrhythmias

Question 27

What type of agonist is a mydriatic?

Answer 27

Alpha 1 (dilates the pupil)

Question 28

What is noteworthy about parasympathetic muscarinic antagonists?

Answer 28

Not selective and will block all three types of muscarinic receptor – M1, M2 and M3

Question 29

What is the effect of hemicholinium?

Answer 29

Blocks choline transport and so stops acetylcholine being packaged into the vesicles - affects all choline synapses

Question 30

How do you improve ganglionic transmission?

Answer 30

Activate nicotinic receptors - more potent at ganglia than the NMJ

Question 30

How do you improve ganglionic transmission?

Answer 30

Activate nicotinic receptors - more potent at ganglia than the NMJ

Question 30

What can reduce the production of aqueous humour?

Answer 30

Alpha agonists and beta blockers

Question 31

What is the effect of carbidopa?

Answer 31

Blocks the enzymes that produce NA (affects sympathetic post ganglionic transmission)

Question 32

What is the effect of resperine?

Answer 32

Blocks the transporters that fill the vesicles with NA (affects sympathetic post ganglionic transmission)

Question 33

What is the effect of methyldopa?

Answer 33

False transmitter, also activates inhibatory presynaptic autoreceptors (affects sympathetic transmission)

Question 34

What is the effect of doxazosin or propanolol?

Answer 34

Block post synaptic receptors (affects sympathetic post ganglionic transmission)

Question 35

What is the effect of cocaine, on the sympathetic post ganglionic transmission?

Answer 35

Causes an increase in the noradrenaline in the synaptic cleft