7 - Cholinoceptor antagonists

Question 1

Define Affinity.

Answer 1

The strength with which an agonist binds to a receptor

Question 2

Define Efficacy.

Answer 2

Once the drug has bound to the receptor, the ability of the drug to transduce a response and activate intracellular signalling pathways is its efficacy

Question 3

What is the difference between agonists and antagonists in terms of affinity and efficacy?

Answer 3

Agonists – have affinity and efficacy

Antagonists – have affinity but NOT efficacy

Question 4

What are the 2 groups of cholinoreceptors and where are they found?

Answer 4

• nicotinic - found in ALL autonomic ganglia

- muscarinic - found at parasympathetic effector organs and on sweat glands in the SNS

Question 5

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

Answer 5

Ganglion Blockers
These block the ion channel itself, thus preventing the ions from moving through the pore (it doesn’t block the receptor but the channel itself)

Question 6

Give two examples of ganglion blocking drugs.

Answer 6

Trimethaphan

Hexamethonium

Question 7

Compare the affinity of nicotinic receptor antagonists and receptor blocking drugs

NOTE: all drugs can have both effects

Answer 7

NRAs - have affinity

GBDs - no affinity

Question 8

What does ‘use-dependent block’ mean?

Answer 8

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 they are more effective when there is more agonist present
NOTE: these drugs can only result in an incomplete block

Question 9

What determines the effect of ganglion blockade in a tissue?

Answer 9

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

Question 10

Which tissues are sympathetic dominated?

Answer 10

Vasculature

Kidneys

Question 11

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

Answer 11

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 12

Which tissues are parasympathetic dominated?

Answer 12

Lungs - causes bronchoconstriction 
Eyes - maintains partial pupillary constriction at rest 
Bladder, ureters and GI tract 
Exocrine functions (secretion)

Question 13

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

Answer 13

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

Question 14

What is hexamethonium?

NOTE: more of a channel blocker than a receptor antagonist

Answer 14

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

Question 15

What is trimethaphan and when is it used?

NOTE: more of a receptor antagonist than a channel blocker

Answer 15

The only ganglion-blocking drug that is still in clinical use
It is very potent and used when a controlled hypotension is needed in surgery.
It is very short acting.

Question 16

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

Answer 16

Toxins and venoms

Question 17

How do rector blockade antagonists bind to receptors and how does this make them different from most therapeutic drugs?

Answer 17

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

Question 18

Give an example of a nicotinic receptor blockade antagonist.

Answer 18

Alpha-bungarotoxin (common krait snake venom)

Question 19

What are the effects of alpha-bungarotoxin?

Answer 19

targets the skeletal muscle causing paralysis of them and the diaphragm ——> suffocation and death

Question 20

What are the targets of muscarinic receptor antagonists?

Answer 20

Parasympathetic effector organs and sweat glands

Question 21

Give four examples of muscarinic receptor antagonists.

Answer 21

Atropine
Hyoscine
Tropicamide
Ipratropium Bromide

Question 22

What effect do muscarinic receptor antagonists have on the CNS?
(be specific and name the drugs)

Answer 22

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

(atropine - excitatory
hyoscine - more sedating)

Question 23

What is tropicamide used for?

Answer 23

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

Question 24

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

Answer 24

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 25

What can hyoscine be used to treat? Explain how.

Answer 25

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 26

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

Answer 26

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 27

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

Answer 27

Ipratropium Bromide is used to treat asthma and COPD

It removes the parasympathetic mediated bronchoconstriction

Question 28

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

Answer 28

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

Question 29

State some general unwanted side-effects of muscarinic antagonists.

Answer 29

• 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 30

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

Answer 30

Give an anticholinesterase e.g. physostigmine

Question 31

Describe how botulinum toxin causes paralysis.

Answer 31

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 32

State the overall effects of ganglion blocking drugs on a subject at rest (a type of nicotinic receptor antagonists).

Answer 32

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