Cholinoreceptor antagonists

Question 1

What qualities do agnoists/antagonists have?

Answer 1

Agonist: affinity and efficacy
antagonist: affinity but no efficacy

Question 2

Does the drug stay attached for a long time?

Answer 2

No, mostly there is constant binding and unbinding which allows for competition.

Question 3

Where are nicotinic receptors found?

Answer 3

• within the ganglions in the ANS

- on the adrenal gland

Question 4

What are nicotinic receptor antagonists also called sometimes?

Answer 4

Ganglion blocking drugs

=> ganglion blocking effect in both the sympathetic and parasympathetic nervous system.

Question 5

In what ways can nicotinic receptor antagonists work?

Answer 5

• by blocking the receptor

- by blocking the ion channel (so name is slightly wrong)

Question 6

Name 2 nicotinic receptor antagonists

Answer 6

• hexamethonium (historical drug) -> better at blocking the ion channel
• trimetaphan -> better at blocking the receptor

Question 7

Hexamethonium

Answer 7

• one of the first antihypertensives

- is better at blocking the ion channel

Question 8

Trimetaphan

Answer 8

• at the moment most commonly used nicotinic receptor antagonist.
• fairly short acting
• better at blocking the receptor
• Hypotension during surgery - Short acting!

Question 9

Use dependent block

Answer 9

• refers to the ability to block the ion channel, not the receptor.
• the more open the channels are the better the drug works
• more ACh (agonist) -> drug more effective because the
  channels are open and allow entry
• Here: incomplete block: the sodium can get through but not as effectively

Question 10

Do hexamethonium and trimetaphan have affinity?

Answer 10

Hexamethonium: no, it is a physical blockade of the ion channel
Trimetaphan: Yes, it binds to the receptor

Question 11

Which of the following effects would 
be observed at rest after treatment 
with a ganglion blocking drug?
a) Increased heart rate
b) Pupil constriction
c) Bronchodilation
d) Detrusor contraction
e) Increased gut motility

Answer 11

a)

c)

Question 12

Why do nicotinic receptor antagonists cause hypotension?

Answer 12

• act on kidney - Renin Angiotensin system
• act on the blood vessles and cause vasodilation - decrease in TPR leads to a decrease in BP
• act on the heart?

Question 13

What are the effects of nicotinic receptor antagonists on the CVS?

Answer 13

• Hypotension (due to effects on kidney and blood vessles)

- also: affect the heart

Question 14

What are the effects of nicotinic receptor antagonists on smooth muscle?

Answer 14

• Pupil dilation
• decreased G.I. tone
• bladder dysfunction
• bronchodilation

Question 15

What do the effects of nicotinic receptor antagonists depend on?

Answer 15

Which system (PS or S) is dominant at that time.
If PS is dominant then it blocks these effects.

Question 16

What are the effects of nicotinic receptor antagonists on secretions?

Answer 16

• decreased secretions (sweat, saliva, GI secretions)

Question 17

What is a clinical use of trimetaphan?

Answer 17

• Hypotension during surgery -> Short acting!

Question 18

Alpha - bungarotoxin

Answer 18

• most powerful nicotinic receptor antagonist on the planet
• binds covalently to nicotinic receptor (true receptor antagonist) -> tissue would have to replace the receptor to restore function
• there are ANS effects
• Real issue: skeletal muscle!

Question 19

Are there many venoms and toxins targeting the nicotinic receptor?

Answer 19

Yes.

Question 20

What is the most powerful nicotinic receptor antagonist toxin on the planet?

Answer 20

alpha bungarotoxin

-> from the common krait (Bungarus carelueus)

Question 21

What are venoms/toxins designed to do?

Answer 21

• affect your skeletal muscle so that you cannot move

Question 22

Are nicotinic receptor antagonists used widely clinically?

Answer 22

• no

- because they are quite messt and have too many side effects

Question 23

Where are muscarinic receptors found?

Answer 23

• at the end of PS nerves
• sweat glands

-> generally for blocking PS effects

Question 24

What are the main muscarinic receptor antagonists?

Answer 24

• Atropine

- Hyascine

Question 25

CNS effects of atropine?

Answer 25

- Normal dose – Little effect - Toxic dose - Mild restlessness -> Agitation (Less M1 selective)

Question 26

CNS effects of Hyascine?

Answer 26

- Normal dose – Sedation, amnesia - Toxic dose – CNS depression or paradoxical CNS excitation (associated with pain) (Greater permeation into CNS. Influence at therapeutic dose)

Question 27

Why does Hyascine have greater permeation into the CNS?

Answer 27

- slightly more lipid soluble -> can enter deeper in the brain

Question 28

Why do atropine and hyoscine have such different effects?

Answer 28

- not entirely sure - maybe because Hyoscine is far more M1 selective (perhaps that is where the sedation comes form) - Hyoscine is more lipid soluble and perhaps can penetrate deeper into the brain and have effects there.

Question 29

Ophthalmic effects of muscarinic receptor antagonists?

Answer 29

- e.g. tropicamide - allows for examination of the retina - causes pupil dilation - tropic amide paralyses a muscle

Question 30

Uses of muscarinic receptor antagonists as anaesthetic pre-medicaiton?

Answer 30

- trachea and bronchioles - blocks constriction - salivary glands - blocks copious, watery secretion - heart - blocks decreased rate and contractility (hyptensive effect, protects HR) + Sedation (if the right antimuscarinic is used)

Question 31

How can muscarinic receptor antagonists be used in motion sickness?

Answer 31

- motion sickness = sensory mismatch - cholinergic nerve goes to vomiting center - Hyoscine patch can help

Question 32

Muscarinic receptor antagonists in PD?

Answer 32

- PD = loss of dopaminergic neurones that project from the substantial migrant - M4R has a suppressive effect on D1R - blocking the M4R makes D1R more responsive to Dopamine, upregulates D1R function - reduces the effects of PD

Question 33

Muscarinic receptor antagonists in respiratory disease?

Answer 33

- e.g. Asthma it obstructive airway disease - blocks trachea and bronchiole constriction - e.g. Ipratropium Bromide (more likely to stay in the lungs -> better side effect profile) - e.g. Atropine -> local effect wanted, side effects occur if it enters the systemic

Question 34

Unwanted effects of muscarinic effector antagonsits

Answer 34

Hot as hell - decreased sweating, thermoregulation Dry as a bone - decreased secretions Blind as a bat - cyclopegia Mad as a hatter- CNS disturbance

Question 35

Cyclopegia

Answer 35

- paralysis of the ciliary muscle of the eye | - resulting in a loss of accommodation.

Question 36

Muscarinic receptor antagonists in GI disease

Answer 36

- e.g. IBS - decreases motility and tone - decreases secretions M3 receptor antagonists: Reduce side effects

Question 37

``` Which of the following drugs would you administer to treat an atropine overdose? a) Bethanechol b) Ecothiopate c) Hyoscine d) Physostigmine e) Pralidoxime ```

Answer 37

a) Bethanecol looks like ACh b) Ecothiopate (irreversible, not used in practice) d) Physostigmine: main drug used in atropine poisoning

Question 38

How does Botulinum toxin work?

Answer 38

- blocks SNARE complex | - prevents ACh exocytosis

Question 39

How can you treat atropine poisoning?

Answer 39

- with anticholinersterase (e.g. physostigmine) | - establishes competitive receptor agonism

Question 40

Botulinum toxin facts

Answer 40

- most toxic protein known - 1 gram of crystalline toxin, evenly dispersed and inhaled, would kill more than 1 million people - 2 molecules are enough to shut down a nerve - used commonly to remove wrinkles. - prevents ACh exocytosis

Question 41

How can you get atropine posioning?

Answer 41

- e.g. berries from atropine plant

Question 42

SNARE complex

Answer 42

- involved in exocytosis | - blocked by botulinum toxin