Cholinergic Synapses And Drugs

Question 1

How is acetylcholine synthesised?

Answer 1

• In the pre-synaptic terminal

- Acetyl CoA (glycolysis byproduct) + choline (diet) converted to ACh + coenzyme A by choline acetyltransferase.

Question 2

Why does ACh have a very limited synaptic cleft 1/2 life?

Answer 2

• Converted to acetate + choline by (acetyl)cholinesterase (AChE).
• Most choline recaptured by choline transporter in pre-synaptic terminal and recycled.

Question 3

Describe the effect of cholinesterase inhibitors and the therapeutic applications of these.

Answer 3

• Limit rate of ACh breakdown - enhance activity of endogenously-released ACh.
• Used to:
  Acutely reverse effects of non-depolarising neuromuscular blocking agents often used in anaesthesia.
  Treatment of myasthenia gravis (pyridostigmine)
  Treatment of early stages of Alzheimer’s disease (donepezil)

Question 4

Describe the clinical applications of nAChR antagonists.

Answer 4

• May have a preferential ganglion or neuromuscular blocking action.
• Former rarely used clinically though can be used in hypertensive emergencies and to produce controlled hypotension during surgery (trimethaphan).
• Latter used to cause muscle paralysis during anaesthesia .

Question 5

Describe the clinical applications of mAChR agonists.

Answer 5

Some clinical uses, esp if administered locally. E.g. Used in:

• treatment of glaucoma (increased intraocular pressure) - pilocarpine (applied as eye drops)
• stimulation of bladder emptying (bethanechol)

Question 6

Describe the clinical applications of mAChR antagonists.

Answer 6

Some clinical uses, esp if administered locally. E.g. Used in treatment of:

• some forms of asthma (where bronchoconstriction caused by increased parasympathetic discharge) and COPD (ipratropium & tiotropium).
• overactive bladder (tolterodine)

Question 7

What is the major issue when using ACh receptor (ant-)agonists?

Answer 7

• Relative lack of selectivity (5 mAChR subtypes, M1-5) - unwanted side effects often limit usage.
• E.g. Non-selective mAChR agonists can mimic parasympathetic activity, can cause:
  Heart - decreased heart rate and C/O
  Smooth muscle - increased bronchoconstriction (issue for asthmatics) and GI peristalsis
  Exocrine glands - increased sweating and salivation

Question 8

What are the pathological effects of massive discharge of parasympathetic NS?

Answer 8

• SLUDGE:
  Salivation (stimulation of salivary glands)
  Lacrimation (stimulation of lacrimal glands)
  Urination (relaxation of urethral internal, sphincter muscle and detrusor muscle contraction)
  Defecation
  Gastrointestinal upset (SM tone changes, GI probs inc diarrhoea)
  Emesis (vomiting)
• SLUDGE usually occurs in cases of:
  Drug overdose
  Ingestion of magic mushrooms
  Exposure to organophosphorus insecticides or nerve gases - covalently modify AChE, irreversibly deactivate it so increase [ACh].
• Symptoms mainly due to chronic overs-stimulation of mAChRs in organs and muscles innervated by parasympathetic NS.