Cholinoceptor Antagonists

Question 1

Define Affinity.

Answer 1

The strength with which an agonist binds to a receptor

Question 2

Define Efficacy.

Answer 2

The ability of a drug to transduce a response + activate intracellular signalling pathways

Question 3

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

Answer 3

Agonists: have affinity + 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 + on sweat glands

Question 6

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

Answer 6

Ganglion Blockers
Either block receptor or block the ion channel itself, thus preventing the ions from moving through the pore (usually an incomplete block, just reduces amount getting through)

Question 7

Give 2 examples of nicotinic receptor antagonists

Answer 7

Hexamethonium (better at blocking ion channel)

Trimethaphan (better at blocking receptor)

Question 8

What does ‘use-dependent block’ mean?

Answer 8

Drugs work most effectively when the ion channels are open.
The more agonist present, the more opportunity the antagonist has to block the channel, thus the more useful + effective the drugs can be

Question 9

What determines the effect of a nicotinic receptor antagonist in a tissue?

Answer 9

Which limb of the ANS dominates in that particular tissue (at that time e.g. at rest). You observe a loss of function of that systems effects.

Question 10

In which tissues is the SNS dominant?

Answer 10

Vasculature

Kidneys

Question 11

What is the overall effect of nicotinic receptor antagonism in terms of loss of sympathetic dominance?

Answer 11

Hypotension
SNS vasoconstriction is lost: drug allows dilation, TPR decreases, BP decreases
SNS secretion of renin is lost, thus can’t increase Na+ + water reabsorption, so blood volume decreases

Question 12

Which tissues are parasympathetic dominated?

Answer 12

Lungs: causes bronchoconstriction
Eyes: maintains partial pupillary constriction at rest
Bladder, ureters + GI tract
Exocrine functions

Question 13

List 5 effects of nicotinic receptor antagonism on PNS dominated tissue?

Answer 13

Bronchodilation  
Pupil dilation (blurred vision)  
Bladder dysfunction  
Decreased GI motility + secretions  
Decrease in exocrine secretion

Question 14

What is hexamethonium?

Answer 14

Nicotinic receptor antagonist- the 1st anti-hypertensive

It has a generalised action + many side-effects

Question 15

What is trimethaphan and when is it used?

Answer 15

Nicotinic receptor antagonist in clinical use
It is very potent + used when a controlled hypotension is needed in surgery.
Very short acting.

Question 16

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

Answer 16

Toxins

Venoms

Question 17

How do many venom nicotinic receptor antagonists have their effect?

Answer 17

Bind covalently (irreversibly) + prevent ion channels from opening.
Main target= skeletal muscle, cause paralysis

Question 18

Give an example of a nicotinic receptor antagonist.

Answer 18

Alpha-bungarotoxin

Question 19

What are the targets of muscarinic receptor antagonists?

Answer 19

Parasympathetic effector organs

Sweat glands

Question 20

Give 4 examples of muscarinic receptor antagonists.

Answer 20

Atropine
Hyoscine
Tropicamide
Ipratropium Bromide

Question 21

What are the effects of a normal and toxic dose of Atropine on the CNS?

Answer 21

Normal: little effect
Toxic: CNS agitation

Question 22

What is tropicamide used for?

Answer 22

To dilate the pupil to observe the retina

Question 23

What is an important use of muscarinic receptor antagonists (e.g. Tropicamide) with regards to surgery? Why is it useful in this circumstance?

Answer 23

Anaesthetic premedication
Blocks bronchoconstriction= dilated airways (good for inhaling anaesthetic)
Reduces secretions: reduces risk of aspiration
Blocks PNS effect of decreasing HR + contractility (because GA will decrease HR + contractility anyway)
Sedative effect

Question 24

What can hyoscine be used to treat? Explain how.

Answer 24

Motion Sickness
Muscarinic receptors relay posture + balance info. from the labyrinth in the inner ear to the vomiting centres.
Hyoscine reduces the flow of info. from the labyrinth to the brain thus reducing 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
In PD: nigro-striatal dopamine neurones are lost (important in fine control of movement)
Musarinic receptors have a negative effect on dopamine signalling, so by blocking the M4 receptors you remove this inhibitory effect + allow remaining D1 receptors to be more responsive

Question 26

Name the muscarinic antagonist used in treatment of asthma and COPD and explain its MOA

Answer 26

Ipratropium Bromide is used to treat asthma + COPD
Removes the parasympathetic mediated bronchoconstriction.
We try to localise effects by making this drug polar to keep it in the lungs

Question 27

How do muscarinic antagonists treat symptoms of irritable bowel syndrome?

Answer 27

Reduce smooth muscle contraction, gut motility + gut secretions

Question 28

State 4 general unwanted side-effects of muscarinic antagonists.

Answer 28

Hot as hell (decreased sweating effects thermoregulation)
Dry as bone (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 cause CNS agitation, restlessness, confusion)

Question 29

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

Answer 29

Give an anticholinesterase e.g. physostigmine.

Allows ACh to accumulate + outcompete the atropine

Question 30

Describe how botulinum toxin causes paralysis.

Answer 30

Binds to + blocks SNARE complex
Prevents exocytosis of ACh from pre-synaptic nerve terminal
Leads to muscle paralysis

Question 31

State 7 effects of nicotinic receptor antagonists on a subject at rest.

Answer 31

Hypotension 
Pupil dilation (increases light sensitivity)
Bronchodilation 
Bladder dysfunction  
Decreased GI tone  
Decreased GI secretions
Decreased sweat production

Question 32

What are the effects of a normal and toxic dose of Hyoscine on the CNS?

Answer 32

Normal: Sedation
Toxic: CNS depression (greater penetration into CNS)

Question 33

When in botulinum toxin used clinically?

Answer 33

To remove wrinkles
To paralyse sweat glands
(must be VERY careful to localise to specific tissue)