7 - Cholinoceptor Antagonists

Question 1

What is the difference between an agonist and antagonist?

Answer 1

Both have affinity but only agonists have efficacy

Question 2

What determines the strength of interaction?

Answer 2

The strength of the bond

Question 3

What are nicotinic receptor antagonists also known as?

Answer 3

Ganglion blocking drugs

Question 4

Giving examples in what two ways can nicotinic antagonists act?

Answer 4

1. ‘Classically’ block receptors coupled to ion channels - trimetaphan
2. Block the ion channel directly (ion channel blockers) - hexamethonium (historical drug)

Question 5

What is ‘use-dependent block’ and its link to ion channel blockers?

Answer 5

‘Use dependent block’ describes the phenomenon in which the ability of a drug to block the ion channels are linked to how open they are.

N.B. Therefore, the more agonist is present, the more effective the blockade.

Question 6

Do nicotinic receptor antagonists display efficacy?

Answer 6

Ones which bind to the receptor do as they often cause a conformational change.

However, ion channel blockers do not as they are simply occupying physical space.

Question 7

Given that nicotinic receptors can be found in both branches of the autonomic nervous system, how can the we predict which system will be ‘knocked out’?

Answer 7

This depends on which system is predominant at that moment in time e.g. parasympathetic at rest

Question 8

How do nicotinic receptor antagonists cause hypotension given that they increase cardiac output?

Answer 8

They increase CO via HR and contractility

But they also decrease renin secretion* and dilate blood vessels to reduce total peripheral resistance.

*thus decreases aldosterone production (aldosterone promotes water retention) and angiotensin 2 secretion

Question 9

What can possible problems be with systemic nicotinic antagonists e.g. hexamethonium when used as antihypertensives

Answer 9

There can be quite serious side effects due to the non-specific effect

In the case of hexamethonium

Dilates pupils (light sensitivity)
Decreases GI motility (constipated)
Bladder dysfunction
Decreases secretions (saline, can't sweat)

Question 10

Outline the properties of trimethaphan as a nicotinic blocking drug?

Answer 10

Is a true receptor antagonist (binds to receptor) - covalent, irreversible
It is short acting and used as a hypotensive during surgery. Superseded by newer drugs but sometimes used to control bleeding in neurosurgery.

Fun facts: alpha-bungarotoxin (common krait), most powerful nicotinic receptor antagonist on the planet.
Most venoms and toxins target nicotinic receptors in skeletal muscle of somatic nervous system causing suffocation.

Question 11

Why are nicotinic receptor antagonists therapeutically limited when compared to muscarinic ones?

Answer 11

Overall they are too messy; their side effect profile is too broad for them to be clinically useful.

Question 12

What do muscarinic antagonists focus on doing?

Answer 12

Blocking parasympathetic effects or sweat glands

Question 13

What are the two most common muscarinic antagonists?

Answer 13

Atropine and hyoscine

Question 14

Name 5 common uses of muscarinic blockers by system

Answer 14

1. CNS - sedation (hyoscine)
2. Opthalmic - examine back of retina (tropicamide)
3. Neurological - motion sickness (hyoscine patch), Parkinson’s disease
4. Respiratory - Asthma, obstructive airway disease (ipratropium bromide)
5. GI - Irritable bowel syndrome

+ Anesthetic premedication (tropicamide)

Question 15

Why does atropine have little effect on the CNS when compared to hyoscine?

Answer 15

It is less M1 selective

Question 16

How to the toxic doses of atropine and hyoscine compare in the CNS?

Answer 16

Atropine - agitation

Hyoscine - CNS depression, sometimes paradoxical excitation (w/ pain) ; more lipid soluble

Question 17

How do muscarinic antagonists work as anaesthetic premedication?

Answer 17

They bronchodilate, produce thick copious salivary secretions, raise BP via HR and contractility (as anaesthesia has hypotensive effect), sedates (e.g. hyoscine)

Question 18

How do hyoscine patches prevent motion sickness?

Answer 18

In motion sickness there is a sensory mismatch between balance and vision in the ear labyrinth

Hyoscine is lipid soluble so it diffuses to the vomiting centre and blocks the muscarinic receptors

Question 19

How do muscarinic antagonists work for Parkinson’s?

Answer 19

Parkinson’s is a loss of dopaminergic neurons that project from the substantia nigra resulting in less dopamine release in the striatum.

The dopamine receptor is called D1R. D1R controls fine muscle movement.

M4 muscarinic receptors usually inhibit the D1R receptors.

Question 20

Why is ipratropium bromide (a modified version of atropine) preferable for treating airway diseases?

Answer 20

It is charged so is less likely to cross lipid membranes.

Will stay in lungs, therefore better side effect profile.

Question 21

Which receptor subtype do muscarinic antagonists target for irritable bowel syndrome?

Answer 21

M3 receptor antagonists, they act to reduce the side effects of IBS

Question 22

What are the common side effects of muscarinic antagonists?

Answer 22

Hot as hell - decreased sweating, thermoregulation
Dry as a bone - decreased secretions
Blind as a bat - cyclopegia (paralysis of ciliary muscles and inability to change focus)
Mad as a hatter - CNS disturbance

Question 23

Which of the following drugs would you use to treat atropine overdose?

Bethanechol
Ecothiopate
Hyoscine
Physostigmine
Pralidoxime

Answer 23

The first 4 are all cholinomimetics.

Pralidoxime is the gold standard for organophosphate poisoning, ‘saves the enzymes’.

Bethanechol is a ‘stable ACh’
Ecothiopate and physostigmine are both indirect, irreversible and reversible respectively.

Therefore would most likely be physostigmine, a reversible anticholinesterase that would indirectly increase ACh conc. so that it could surmount the atropine blockade.

Question 24

What is a parasympatholytic?

Answer 24

It is a drug that reduces the activity of the parasympathetic system

Question 25

What is another example of a parasympatholytic?

Answer 25

Botulinum toxin - blocks SNARE complex involved in exocytosis of ACh - skeletal muscle paralysis in somatic nervous system

Botox - can also paralyse sweat glands in armpits, must be localised in tissue, bad if systemic