Cholinoceptor Antagonists

Question 1

Where are nicotinic receptors found?

Answer 1

In ALL autonomic ganglia

At neuromuscular junctions (NMJs)

Question 2

Where are muscarinic receptors found?

Answer 2

At parasympathetic effector organs and on sweat glands

Question 3

What are the few clinically useful nicotinic receptor antagonists called and how do they block the receptor?

Answer 3

Ganglion Blockers These block the ion channel itself instead of the receptor, thus preventing the ions from moving through the pore

Question 4

Give two examples of ganglion blocking drugs.

Answer 4

Hexamethonium

Trimethaphan

Question 5

What is hexamethonium?

Answer 5

It is a ganglion blocker that was the first anti-hypertensive It has a generalised action and had loads of side-effects

Question 6

What is trimethaphan and when is it used?

Answer 6

The only ganglion-blocking drug that is still in clinical use.

Highly polar and cannot cross BBB. (Does not cause NMJ block either).

It is short acting but very potent and used when a controlled hypotension is needed in surgery.

Question 7

What does ‘use-dependent block’ mean?

Answer 7

The drugs work most effectively when the ion channels are open. This means that the more agonist is present at the receptor, the opportunity the antagonist has to block the channel, thus the more useful and effective the drugs can be (E.G. Noiceceptors are frequently opened)

Question 8

What determines the effect of ganglion blockade in a tissue?

Answer 8

It depends on which limb of the autonomic nervous system predominates in the particular tissue (at the time e.g. at rest)

Question 9

Which tissues are sympathetic dominated at rest?

Answer 9

Vasculature

Kidneys

Question 10

What is the overall effect of ganglion blockade in terms of loss of sympathetic dominance?

Answer 10

Hypotension. The sympathetic-mediated vasoconstriction is taken away and the ability of the kidneys to increase renin secretion and increase sodium and water reabsorption is also taken away

Question 11

Which tissues are parasympathetic dominated at rest?

Answer 11

Lungs – causes bronchoconstriction
Eyes – maintains partial pupillary constriction
Bladder, ureters and GI tract
Exocrine functions

Question 12

What would the effect of ganglion blockage be on these parasympathetic dominated tissues?

Answer 12

Bronchodilation Pupil dilation (blurred vision)
Bladder dysfunction
Loss of GI motility and secretions
Decrease in exocrine secretion

Question 13

How do receptor blockade antagonists have their effect?

Answer 13

These are irreversible – they bind covalently and prevent the ion channels from opening

Question 14

In what types of chemicals are nicotinic receptor blockade antagonists found?

Answer 14

Toxins and venoms

Question 15

Give an example of a nicotinic receptor blockade antagonist.

Answer 15

Alpha-bungarotoxin (common krait snake venom)

Question 16

What are the targets of muscarinic receptor antagonists?

Answer 16

Parasympathetic effector organs and sweat glands

Question 17

What effect do muscarinic receptor antagonists have on the CNS?

Answer 17

The parasympathetic nervous system is important in the CNS in terms of attention, memory and certain sleep pathways. At low doses atropine can cause mild restlessness At low doses hyoscine can be a good sedative At high doses, both drugs can cause CNS agitation

Question 18

Give four examples of muscarinic receptor antagonists.

Answer 18

Atropine
Hyoscine
Tropicamide
Ipratropium Bromide

Question 19

What is tropicamide used for?

Answer 19

It is used to dilate the pupil to observe the retina (it is used to examine the eye)

Question 20

What is an important use of muscarinic receptor antagonists with regards to surgery? Why is it useful in this circumstance?

Answer 20

Anaesthetic premedication It causes dilation of the airways so it is easier to intubate the patient

It reduces secretions thus reducing the risk of aspiration

It also knocks out the effect of the parasympathetic nervous system in decreasing heart rate and contractility (because general anaesthetics will decrease heart rate and contractility anyway)

Question 21

What can hyoscine be used to treat? Explain how.

Answer 21

Motion Sickness. Muscarinic receptors are important in relaying information from the labyrinth in the inner ear to the vomiting centres. Muscarinic receptor antagonists can reduce the flow of information from the labyrinth to the brain thus reducing the nausea.

Question 22

What degenerative disorder of the central nervous system can be treated by muscarinic receptor antagonists? Explain how.

Answer 22

Parkinson’s Disease. In Parkinson’s disease, many of the nigro-striatal dopamine neurones are lost (these are important in the fine control of movement) Musarinic receptors have a negative effect on this dopamine signalling so by blocking the muscarinic receptors (knocking out the M4 receptors) you can remove this inhibitory effect and allow the remaining dopaminergic neurones to fire at the maximum rate.

Question 23

Explain the use of muscarinic antagonists in treating asthma and COPD.

Answer 23

Ipratropium Bromide is used to treat asthma and COPD as it removes the parasympathetic mediated bronchoconstriction.

Note: It is highly polar and therefore cannot diffuse out, ensuring a localised effect

Question 24

Explain the role of muscarinic antagonists in treating irritable bowel syndrome.

Answer 24

Muscarinic antagonists will reduce smooth muscle contraction, gut motility and gut secretions thus relieving the symptoms of IBS.

Question 25

State some general unwanted side-effects of muscarinic antagonists.

Answer 25

Hot as hell (decreased sweating affects thermoregulation)
Dry as bone (due to reduced exocrine secretions)
Blind as a bat (due to effects on the accommodation ability of the ciliary muscle – cycloplegia)
Mad as a hatter (high doses will cause CNS agitation, restlessness, confusion etc.)

Question 26

How do you treat muscarinic receptor antagonist poisoning (e.g. atropine poisoning)?

Answer 26

Give an anticholinesterase e.g. physostigmine

Question 27

Describe how botulinum toxin causes paralysis.

Answer 27

It binds to the SNARE complex and prevents the fusion of the vesicles, containing acetylcholine, with the presynaptic membrane thus preventing the release of acetylcholine from the nerve terminal. This leads to muscle paralysis

Question 28

State the overall effects of ganglion blocking drugs on a subject at rest.

Answer 28

Hypotension 
Pupil dilation 
Bronchodilation 
Bladder dysfunction 
Decreased GI tone 
Decreased GI secretions

Question 29

What are the effects of Atropine and Hyoscine on the CNS?

Answer 29

Atropine - Little effect at normal dose, Overdose Restlessness/Agitation

Hyoscine - Normal dose Sedation, Toxic dose - CNS depression or paradoxical excitation (pain associated) Maybe higher selectivity for M1 receptor and more lipophilic

Question 30

What other disorders can centrally acting anti-muscarinics treat?

Answer 30

Dystonia and tremor