Cholinomimetic drugs

Question 1

Bethanechol

Answer 1

Direct-acting choline ester (also recall carbachol)

MOA
- muscarinic agonist

Effects
- activates M₁, M₂, M₃ in all peripheral tissues→increased secretion, smooth muscle contraction (except vascular SM relaxes), changes in HR

Clinical
- postoperative & neurogenic ileus, urinary retention

Kinetics, tox, int.

• PO, duration 30min, doesn’t enter CNS
• excessive parasympathomimetic fx, esp. bronchospasm in asthmatics
• additive with other parasympathomimetics

Question 2

Pilocarpine

Answer 2

Direct-acting muscarinic alkaloid (also recall cevimeline as M₃-selective synthetic)

MOA&effects

• like bethanechol, partial agonist
• fx like bethanechol

Clinical
- glaucoma, Sjögren’s

Kinetics, tox, int.

• oral lozenge & topical
• like bethanechol

Question 3

Nicotine

Answer 3

Direct-acting nicotinic agonist (also varenicline, selective partial agonist at α4ß2 nicotinic receptors used for smoking cessation)

MOA
- N_N, N_M agonist

Effects

• activates autonomic postggl neurons (symp+parasymp) and skeletal muscle neuromuscular end plates
• enters CNS and activates N_N receptors

Clinical

• smoking cessation
• smoking, insecticides

Kinetics, tox, int.

• oral gum, patch for smoking cessation
• acutely increased GI activity, nausea, vomiting, diarrhea
• increased bp
• high doses → seizures
• long-term GI and CV risk factor
• additive with CNS stimulants

Question 4

Edrophonium

Answer 4

Short-acting cholinesterase inhibitor (alcohol)

• MOA
• briefly binds to active site of AChE and prevents access of ACh
• Effects
• amplifies all actions of ACh
• increases parasymp activity and neuromuscular transmission
• Clinical
• dg and acute treatment of MG
• Kinetics, tox, int.
• parenteral
• quartenary amine
• doesn’t enter CNS
• toxicity through parasymp. excess
• additive with parasympathomimetics

Question 5

Neostigmine

Answer 5

Intermediate-acting cholinesterase inhibitors (carbamates)
- also pyridostigmine (longer acting), physostigmine (natural alkaloid tertiary amine, enters CNS)

• MOA
• forms covalent bond with AChE, but hydrolyzed and released
• Effects
• like edrophonium but longer-acting
• Clinical
• MG
• postoperative and neurogenic ileus and urinary retention
• Kinetics, tox, int.
• oral, parenteral
• quaternary amine, doesn’t enter CNS
• duration 2-4h
• tox+int. like edrophonium

Question 6

Echothiophate

Answer 6

Long-acting cholinesterase inhibitors (organophosphates)
Also: Malathion, parathion (insecticides), sarin

• MOA
• like neostigmine but slower release
• Effects
• like neostigmine but longer-acting
• Clinical
• obsolete
• Kinetics, tox, int.
• topical only
• tox: brow ache, uveitis, blurred vision