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

Where are nicotinic receptors found?

Answer 4

In ALL autonomic ganglia

At neuromuscular junctions

Question 5

Where are muscarinic receptors found?

Answer 5

At parasympathetic effector organs and on sweat glands

Question 6

What are nicotinic receptor antagonists also called and how do they act?

Answer 6

Ganglion Blockers
These work by blocking the nicotinic receptor + block the ion channel itself, thus preventing the ions from moving through the pore.

NB the blocking ion channel element doesnt contribute to a drug’s affinity because affinity is strictly talking about binding to a receptor. But it is an important part of how they work

Question 7

Give two examples of ganglion blocking drugs.

Answer 7

Hexamethonium
Trimetaphan

NB the wide range of side effects means that ganglion blocking drugs arent commonly used.
A lot of side effects because they block both para and sympa as they act on all autonomic ganglia.

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 more useful and effective the drugs can be

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 (sympa stimulates renin secretion)

these lack parasympathetic innervation

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 (aldosterone production reduced)

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

Question 13

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

Answer 13

As they block all ganglions, their side effect profile is quite broad.
Bronchodilation
Pupil dilation (blurred vision- loss of accommodation)
Bladder dysfunction
Loss of GI motility and secretions
Decrease in exocrine secretion

These are common side effects of these ganglion blocking drugs

Question 14

What is hexamethonium?

Answer 14

It is a ganglion blocker that was the first anti-hypertensive (remmeber that ganglion blocking drugs causes vessels to lose sympathetic tone and kidneys unable to secrete renin)
It has a generalised action and had loads of side-effects

Question 15

What is trimetaphan and when is it used?

Answer 15

The only ganglion-blocking drug that is still in clinical use (nicotinic receptor antagonist)
It is very potent and used when a controlled hypotension is needed in surgery ( to stop XS bleeding)
It is very short acting, so good for surgery

Question 16

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

Answer 16

Toxins and venoms

Question 17

How do receptor blockade antagonists found in toxins/venom have their effect?

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 found in snake venom

Answer 18

Alpha-bungarotoxin (common krait snake venom)

Question 19

What are the targets of muscarinic receptor antagonists?

Answer 19

Parasympathetic effector organs and sweat glands

Question 20

Give four examples of muscarinic receptor antagonists.

Answer 20

Atropine
Hyoscine (Hyoscine patch for nausea)
Tropicamide (retina examination)
Ipratropium Bromide (similar to atropine but with additional N+ group which makes it more polar so effect more localised, more commonly used than atropine)

Question 21

What effect do muscarinic receptor antagonists have on the CNS? (atropine and hyoscine)

Answer 21

The parasympathetic nervous system is important in the CNS in terms of attention, memory and certain sleep pathways.
Atropine:
normal dose- little effect
toxic dose- CNS stimulant, restlessness and even agitation

Hyoscine
Normal dose – Sedation, amnesia (memory loss)
Toxic dose – CNS depression (slow down brain activity) or paradoxical CNS excitation (associated with pain)

A paradoxical reaction or paradoxical effect is an effect of medical treatment, usually a drug, opposite to the effect which would normally be expected. An example of a paradoxical reaction is pain caused by a pain relief medication.

Question 22

What is tropicamide used for?

Answer 22

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

Question 23

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

Answer 23

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 (inhalation of foreign material, in this case it stops the patient from inhaling his own spit into the trachea)

-It also knocks out the effect of the parasympathetic nervous system in decreasing heart rate and contractility (Useful because general anaesthesia tends to lower BP so this counters that)

Question 24

What can hyoscine be used to treat? Explain how.

Answer 24

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

Question 25

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

Answer 25

Parkinson’s Disease

Substantia nigra sends dopamine via dopaminergic neurnons to the striatum to stimulate normal motor function via D1 receptors.
M4 receptor stimultion can suppress the effects from dopamine –D1 receptor binding. Parkinson’s patients suffer from diminishing substantia nigra and hence less dopamine to the striatum. Drugs can be used to inhibit M4 receptors so that less D1 receptors are inhibited by the M4.

Question 26

Explain the use of muscarinic antagonists in treating asthma andCOPD.

Answer 26

Ipratropium Bromide is used to treat asthma and COPD
It removes the parasympathetic mediated bronchoconstriction
It has very similar structure to atropine but atropine isn’t used clinically anymore because ipratropium has extra N+ group which localises its effect to the lungs

Question 27

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

Answer 27

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

Question 28

State some general unwanted side-effects of muscarinic antagonists.

Answer 28

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 29

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

Answer 29

Give an anticholinesterase inhibitore.g. physostigmine

Question 30

Describe how botulinum toxin causes paralysis.

Answer 30

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 31

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

Answer 31

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