Indirect Cholinergic Agonists

Question 1

Tacrine (Cognex)

Answer 1

Pharmacology: Binds anionic site of AChE preventing ACh binding. Non-covalent.
Indications: Alzheimer’s disease. Stops breakdown of endogenous ACh. Enhances cognitive ability. Does not slow progression of disease. (Extensively metabolized by CYP450 to at least three metabolites).
Adverse Effect: causes hepatoxicity

Question 2

Donepezil (Aricept)

Answer 2

Pharmacology: Binds to anionic site of AChE.
Indication: Alzheimer’s disease. Does not cause hepatoxicity.

Question 3

Galantamine (Razadyne/Reminyl)

Answer 3

Pharmacology: Reversible competitive AChE inhibitor. Extracted from daffodil. May be nicotinic receptor agonist. This drug is metabolized by CYP3A4 and CYP2D6)
Indication: Alzheimer’s disease.

Question 4

Physotigme (Antilirium)

Answer 4

Pharmacology: i.m or i.v. Naturally occuring in the Calabar bean. Carbamyl ester that interacts with anionic site. Carbamylated enzyme is much slower to hydrolyzed, thus reducing the recovery of the enzyme. Targets postganglionic parasympathetic junctions. Does not contain a quaternary ammonium so it can penetrate the BBB better than other AChE inhibitors.
Indications: Eye drops for treating glaucoma. To reverse the toxic CNS effects due to anticholinergic drugs (Atropine)

Question 5

Pyridostigmine (Mestinon)

Answer 5

Pharmacology: Carbamyl esters. More stable than both physostigmine and neostigmine.
Indication: Myasthenia gravis (they do not have the CNS effects associated with physostigmine). Largest scale administration occurred in 1990 in anticipation of nerve agent attack in the first persian gulf war.

Question 6

Neostigmine (Prostigmin)

Answer 6

Pharmacology: Carbamyl ester. More stable than physostigmine.
Indication: Myasthenia gravis (does not have the CNS effects that are associated with physostigmine). Also used as i.v. to competitively reverse neuromuscular block induced during surgery.

Question 7

Rivastigmine (Excelon)

Answer 7

Pharmacology: Pseudo-irreversible inhibitor. Inhibits AChE for 10 hours. Crosses BBB. Also available as transdermal patches.
Indications: Alzheimer’s Disease.
Adverse effects: Nausea, vomiting, anorexia, and weight loss.

Question 8

Isofluorphate

Answer 8

Indication: Glaucoma treatment. Toxicity associated with the generation of cataracts and retinal detachment. Topical administration as an oinment). Long-acting agents: decreases in IOP can be observed for up to 4 weeks.

Question 9

Echothiophate

Answer 9

Indications: Glaucoma treatment. Toxicity associated with the generation of cataracts and retinal detachments. Topical administration as a solution. Long-acting agent: decreases in IOP can be observed for up to 4 weeks.

Question 10

Malathion (Ovide)

Answer 10

Indication: Patients infected with head lice.
Contraindication: Lotion is contraindicated for neonates and infants because their scalps are more permeable and may have increased absorption of malathion.

Question 11

Nerve Gas, Sarin Tabun

Answer 11

These agents react with AChE to form phosphorylated AChE enzyme. The phosphorylated enzyme undergoes a process called “aging” that prevents reactivation of the enzyme by hydrolyss. (loss of alkyl groups) that prevents reactivation of the enzyme by hydrolysis.