Cholinoceptor antagonists

Question 1

what is the definition of affinity?

Answer 1

ability of drug to bind to receptor and produce drug-receptor complex

Question 2

Do both agonists and antagonists have affinity?

Answer 2

Yes

Also remember that the stronger the affinity, the more longer-lasting the complex

Question 3

What does efficiacy mean?

Answer 3

the ability of drug to induce a biological response

Question 4

Do agonists and antagonists have efficiacy?

Answer 4

NO agonists have efficiacy and antagonists do not.

Question 5

What is a common muscarinic antagonist?

Answer 5

atropine

Question 6

What do nicotinic receptor antagonists do?

Answer 6

Mostly block the receptor (classic antagonist) but some act as physical channel blockers (they are technically ion channel blockers- not classic antagonist).

Another word for nicotinic receptor antagonist is ‘ganglion blocking drug’

Question 7

Give 2 examples of nicotinic receptor antagonists

Answer 7

1. Hexamethonium (primarily blocking ion channel- there is not a lot of affinity)
2. Trimetaphan (better at blocking the receptor- has affinity).

Question 8

What does use-dependent block mean?

Answer 8

The more open the channels are the more effective the drugs are.

I.e. the more competitive agonists around, the more the channel will be used and therefore the better the drug works (because the channel will be open). There will never be complete blockade- the drug just makes it more difficult for molecules to pass through.

Question 9

What is the difference between antagonism and a physical blockade?

Answer 9

Sitting in the channel pore is a physical blockade.

Note that not all nicotinic receptor antagonists will have affinity as some will just act by blocking ion channel itself.

Question 10

What is the main effect of nicotinic antagonists?

Answer 10

Nicotinic receptor antagonists can cause hypotension.

Vasoconstriction is inhibited- TPR goes down and so does BP. Reduces renin secretion too. Therefore, there is less aldosterone and less water reabsorption.

Question 11

What are the other effects of nicotinic receptors?

Answer 11

They will also dilate your pupils (light-sensitive), will interfere with GI and bladder function (causing constipation), and reduced secretions (make it difficult to produce saliva, gut secretions and sweat).

Question 12

are hexamethonium and trimetaphan reversible?

Answer 12

yes

Question 13

Why is hexamethonium not used as an anti-hypertensive?

Answer 13

As there are too many side effects and the drug is too general. Still used carefully today. Trimetaphan used to control blood flow during surgery.

Question 14

What is an irreversible nicotinic antagonist? and what happens to the body?

Answer 14

Alpha- bungarotoxin binds very strongly to the receptor, blocking it irreversibly. Found in snake venom.

This toxin mainly binds to somatic nicotinic receptor (NRs) whereas the nicotinic receptors above are for the autonomic nervous system.

Toxins are designed to target skeletal muscle (diaphragm doesn’t work and causes paralysis and death).

Question 15

A general note about muscarinic receptor antagonists

Answer 15

Generally, they are PNS antagonists because the only muscarinic receptors found in the SNS are found in sweat glands.

Question 16

What are the 2 most common muscarinic antagonists (hint in the cards before)?

Answer 16

1. Atropine
2. Hyoscine

Question 17

What are the CNS effects of atropine?

Answer 17

Normal dose – Little effect

Toxic dose - Mild restlessness –> Agitation

(Less M1 selective)

Question 18

What are the CNS effects of hyoscine?

Answer 18

Normal dose – Sedation, amnesia- useful therapeutic effects

Toxic dose – CNS depression or paradoxical CNS excitation (associated with pain- not common)

(Greater permeation into CNS. Influence at

therapeutic dose)

Question 19

Why is there a difference between the CNS effects of hyoscine and atropine?

Answer 19

Hyoscine is more M1 selective and will get there faster. It is also theorised that hyoscine is more lipid-soluble and can penetrate deeper into the brain.

Question 20

What are the ophthalmic effects of tropicamide (muscarinic antagonist)?

Answer 20

Use of tropicamide to examine the back of the retina. It paralyses the muscle which causes muscle constriction so the pupil dilates

Question 21

What is the role of muscarinic antagonists as anaesthetic premedication?

Answer 21

It blocks bronchoconstriction and you have dilated airways (useful if you are inhaling anaesthetic.

Also blocks the production of watery secretions- saliva- possibility for saliva to go down the airways causing choking so don’t want that in surgery.

It also reduces the rate and contractility of the heart. Protects the heart from slowing effects of other drugs and acts like a sedation.

Question 22

What is the role of muscarinic antagonists in motion sickness aid?

Answer 22

Motion sickness is an information mismatch- between the visual and the labyrinth in the ear. The mismatch is relayed to the vomiting sensor (activates cholinergic nerve).

people with motion sickness often use a hyoscine patch. The patch inhibits muscarinic receptors in the vomiting centre reducing motion sickness.

Question 23

How do muscarinic antagonists help with Parkinson’s disease?

Answer 23

Caused by loss of dopaminergic neurones. Therefore, less dopamine release- not detected by D1 Receptors.

Increases the D1 receptors so the little dopamine Is more effective.

Question 24

What is the muscarinic antagonist action with regards to D1 receptors?

Answer 24

The muscarinic antagonist is given to reduce M4 receptors leaving the D1 receptors alone, allowing it to sense the dopamine.

Question 25

What are the respiratory effects fo muscarinic antagonists?

Answer 25

Causes bronchodilation.

Question 26

What is ipratropium bromide?

Answer 26

Ipratropium bromide has a similar molecular shape to atropine, but it has a charged nitrogen group, making it polar. It is more likely to stay confined to the lungs for a longer period of time (unable to cross the mucosa).

Question 27

What are the Gi effects of muscarinic antagonists?

Answer 27

decreased secretion, motility and tone

Used in the treatment of IBS- slow gut down (M3 antagonist)

Question 28

What are some of the unwanted effects of muscarinic receptor antagonists?

Answer 28

• Hot as hell- decreased sweating/ thermoregulation
• Dry as a bone- decreased secretions
• Blind as a bat- cycloplegia (ciliary muscles cant contract)
• Mad as a hatter- CNS disturbance

Question 29

What should you administer to someone with atropine poisoning?

Answer 29

Essentially, you want to top up with ACh imitating things- you use muscarinic agonists:

• Bethanechol- similar to Ach to compete with the muscarinic antagonist
• Ecothiopate- irreversible anticholinesterase
• Physostigmine- reversible anticholinesterase

You want to give a drug that either enhances Ach activity (anticholinesterase) or inhibits atropine.

DON’T use hyoscine or pralidoxime (anti-cholinesterase rescuer).

Question 30

What is botulinum toxin?

Answer 30

Blocks the SNARE complex involved in exocytosis of Ach release into synapse. The vesicles can’t dock on the inner membrane. Ach won’t be released to muscle and will be paralysed. Very potent only need one or two molecules to shut down the SNARE complex

Question 31

What does botulinum toxin do? and what is it used for commercially?

Answer 31

Used to paralyse skeletal muscle in the face (and sweat glands)- Botox. Need to make sure it’s localised to tissues- if it enters the systemic system it is an issue.