Cholinergic transmission

Question 1

What are the major processes that can be affected by drugs during cholinergic transmission?

Answer 1

1. ACh synthesis
2. ACh release
3. ACh receptor binding
4. ACh breakdown
5. Breakdown product re-uptake

Question 2

Which drugs affect ACh systhesis?

Answer 2

Triethylcholine: Competitive antagonist for choline acetyltransferase (CAT)

Question 3

Which drugs affect ACh vesicular transport?

Answer 3

Vesamicol: Reversibly (but non-competitively) inhibits VAChT and prevents ACh loading into vesicles. Inhibits ACh release.

Question 4

Which drugs affect ACh release?

Answer 4

1. Botulinum toxin: Several isoforms all cut SNARE complex at different sites. Inhibits ACh release.
2. Tetanus toxin: Degrades synpatobrevin. Inhibits ACh release.
3. α-Latrotoxin: Causes massive uncontrolled discharge of ACh from nerve terminals and depletes ACh. Inhibits ACh release.
4. β-bungarotoxin: Causes activation of phospholipase A2, leading to destruction of pre-synaptic nerve terminal. Inhibits ACh release.

Question 5

Why does repeated use of botox result in decline in activity?

Answer 5

Botox is antigenic and neutralising antibodies eventually develop

Question 6

Which drugs affect ACh re-uptake?

Answer 6

Hemicholinium: Inhibits Na⁺-dependent choline transporters (ChT) and thus inhibits choline re-uptake. This decreases amount of choline available for ACh synthesis and thus decreases ACh availability. Inhibits ACh release.

Question 7

Which types of drugs affect ACh receptors?

Answer 7

1. Neuromuscular-blocking drugs (nicotinic receptor antagonists)
2. Ganglion stimulating/blocking drugs
3. Muscarinic receptor agonists/antagonists

Question 8

What are the types of neuromusclular-blocking drugs?

Answer 8

1. Depolarising blocking agents
2. Non-depolarising blocking agents

Question 9

What are the depolarising blocking drugs?

Answer 9

1. Suxamethonium
2. Decamethonium

Question 10

What is the mechanism of action of non-depolarising NMJ blockers?

Answer 10

All non-depolarising drugs are competitive antagonists of nAChRs (but more selective for N1).

Question 11

What are the non-depolarising blocking drugs?

Answer 11

• Clinically significant compounds include:
  1. Pancuronium
  2. Vecuronium
  3. Atracurium
  4. Mivacurium
• Clinically insignificant compounds include:
  1. Curare
  2. D-tubocurarine

Question 12

What is a non-reversible NMJ blocker?

Answer 12

α-bungarotoxin: Blocks nAChRs irreversibly in NMJ

Question 13

What is the mechanism of action of ganglion-stimulating drugs?

Answer 13

nAChR agonists that bind selectively to N2 receptors in parasympathetic ganglia.

Question 14

What are the ganglion stimulating drugs?

Answer 14

1. Nicotine
2. Lobeline
3. Epibatidine
4. Varenicline (clinically used to aid in nicotine withdrawal)

Question 15

What is the mechanism of action of ganglion-blocking drugs?

Answer 15

All ganglion bocking drugs are nAChR antagonists specific for N2 ACh receptors.

Question 16

What are the gangion blocking drugs?

Answer 16

1. Hexamethonium
2. Trimethapan

Question 17

What is the clinical significance of trimethapan?

Answer 17

Lowers BP to minimise bleeding during surgery

Question 18

What are the classes of muscarinic agonists?

Answer 18

1. Choline esters
2. Cholinomimetic alkaloids

Question 19

What are examples of choline esters?

Answer 19

• Acetylcholine
• Methacholine
• Carbachol
• Bethanechol

Question 20

What are examples of cholinomimetic alkaloids?

Answer 20

• Muscarine
• Arecoline
• Pilocarpine
• Cevimeline

Question 21

What are the clinically used muscarinic agonists?

Answer 21

1. Bethanechol
2. Pilocarpine
3. Cevimeline

Question 22

What is the clinical use of bethanichol?

Answer 22

Treatment of bladder/gastrointestinal hypotonia

Question 23

What is the clinical use of pilocarpine?

Answer 23

Treatment of glaucoma

Question 24

What is the clinical use of cevimeline?

Answer 24

Treatment of Sjögren’s syndrome

Question 25

What are the non-selective muscarinic antagonists?

Answer 25

- Atropine - Hyoscine butylbromide (scopolamine) - Benzilylcholine - Tropicamide - Ipratropium

Question 26

What are the clinical uses of atropine?

Answer 26

- Causes tachycardia (sinus bradycardia) - Inhibits GI mobility (diarrhoea) - [Low dose] Inhibits exocrine secretions (sweat, saliva, lacrimal...) - Used to reduce secretions in airways during surgery - Reduces GI and bladder spasms.

Question 27

What are the clinical uses of tropicamide/cyclopentolate?

Answer 27

Causes pupil dilation

Question 28

What are the clinical uses of scopolamine?

Answer 28

- Prevents motion sickness - Relaxes gut muscles during endoscopy

Question 29

What are the clinical uses of ipratropium/tiotropium?

Answer 29

Bronchodilation (asthma/COPD)

Question 30

What are the M₁ selective antagonists?

Answer 30

Pirenzepine

Question 31

What are the clinical uses of M₁ antagonists?

Answer 31

Reduces gastric secretion and is used to treat gastric ulcers

Question 32

What are the clinical uses of pirenzepine?

Answer 32

Reduces gastric acid secreton (GORD & peptic ulcers)

Question 33

What are the M₂ selective antagonists?

Answer 33

Tripitramine

Question 34

What are examples of M₃ selective antagonists?

Answer 34

Darifenacin

Question 35

What are the clinical uses of M₃-selective antagonists?

Answer 35

Relaxation of bladder (reduces urge for micturition)

Question 36

What are the classes of anticholinesterase drugs?

Answer 36

1. Short-acting (non-covalent) 2. Intermediate-acting (covalent) 3. Irreversible (covalent)

Question 37

What are the short-acting (non-covalent) anticholinesterases?

Answer 37

- Edrophonium: Diagnosis of myasthenia gravis - Tacrine: Treatment of Alzheimer's disease - Donepezil: Treatment of Alzheimer's disease

Question 38

What are the intermediate-acting (covalent) anticholinesterases?

Answer 38

- Neostigmine: 1. Intravenous → Reverses neuromuscular block 2. Oral → Treatment of myasthenia gravis - Pyriostigmine: Treatment of myasthenia gravis - Physostigmine: Glaucoma (topical)

Question 39

What are the irreversible (covalent) anticholinesterases?

Answer 39

- Echothiophate: Treatment of glaucoma - Dyflos: Treatment of glaucoma - Malathion: Treatment of headlice

Question 40

What are antidotes for organophosphate poisoning?

Answer 40

- Atropine: Counteracts systemic effects - Pralidoxime (2-PAM): Reactivates AChE by dephosphorylating Ser203