Nausea, Vomiting - Davis

Suffix for 5HT₃R antagonists

-setron

NK1 antagonist suffix

-pitant

Which functional group/structure do 5HT₃R antagonists mimic in serotonin?

Indole (Benzene connected to a nitrogen-containing ring), ondansetron has a carbazole (Similar to indole, nitrogen-containing ring packed between two hexagons

Which protein metabolizes all 5HT₃RAs

CYP3A4 (oxidizes aromatic rings)

Which 5HT₃RAs is/are pGP substrates?

Ondansetron only

Which 5HT₃RAs is/are CYP2D6 substrates? 2C9? 3A4

2D6: ondansetron, dolasetron, palonosetron

2C9: alosetron

3A4: ALL

Which functional group is in all H₁RAs? Which functional group is unique to meclizine? Which functional group is in the other antihistamines (not meclizine)?

All: diphenyl (two benzenes connected to one carbon)

Dox, Dime, Diph: ethanolamine (O-C-C-N), also in acetylcholine, makes these ones anticholinergic)

Meclizine: piperazine (two nitrogen hexagon), makes this one the least anticholingergic (i.e. drowsy)

Which enzyme are all H₁RAs substrates of? Which one(s) inhibit(s) the enzyme as well?

CYP2D6

Substrate: meclizine, doxylamine

Inhibitor + substrate: diphenhydramine, dimenhydrinate (contains diphenhydramine)

Which three functional groups are in the antimuscarinic anticholingerics?

1. Tertiary amine

2. Tropane core (tent-looking thing), not in acetylcholine —> sticks in receptor

3. Ester

Which of the antimuscarinics crosses the BBB? What does this lead to?

Scopolamine crosses BBB: antimuscarinics are anticholinergics —> drowsiness, dry mouth, constipation

What is the endogenous ligand of NK1 receptors?

Substance P

Which functional group is common to all NK1 antagonists?

Benzene with two trifluromethyl groups (-CF₃)

Which enzyme metabolizes all NK1 antagonists? Which two inhibit this enzyme?

All substrates of CYP3A4

Aprepitant and fosaprepitant (prodrug of aprepitant) inhibit 3A4, same metabolism

Which NK1 antagonist is a prodrug?

Fosaprepitant, metabolized to aprepitant

Which enzyme do some NK1 antagonists induce? Which drugs do so?

CYP2C9

Aprepitant and fosaprepitant (prodrug of aprepitant), same metabolism

Which of the NK1 antagonists lasts the longest in the body? What’s the half life?

Rolapitant

Half life = 7 days

Which of the NK1 antagonists is active as a parent drug and metabolite?

Rolapitant (active metabolite contributes to long half life, 7d)

Which protein is rolapitant a substrate of? Which proteins does rolapitant inhibit?

CYP3A4 substrate, as with all NK1s

Inhibits: CYP2D6, pGP/ABCB1

Which processes are involved in scopolamine’s metabolism?

phase I: CYP3A4 aryl hydroxylation (adding -OH to benzene)

phase II: glucuronidation, sulfation