Histamine H2 Antagonists - Proteau

Question 1

H2 antagonist SAR

Answer 1

N-alpha-guanylhistamine. A partial agonist at H2 receptors. Starting point for development of H2 antagonists.
Imidazole - spacer- polar, non-basic group

Question 2

Burimamide

• structure
• problems

Answer 2

• thiourea

- first full H2 antagonist. not orally available

Question 3

Metiamide

• structure
• antagonism properties
• problems

Answer 3

• thiourea, but with theo in spacer and methyl on imidazole ring
• Full antagonist
• orally active, but causes agranulocytosis in animals

Question 4

Cimetidine

• structure
• interactions
• antagonist properties
• metabolism

Answer 4

• No thiourea; cyanoguanidine instead
• Moderately inhibits P450’s (1A2, 2D6, 3A4 and aldehyde oxidase)
• 1st successful H2 antagonist
• t1/2 = short 2 hours

Question 5

Ranitidine

• structure
• potency compared to cimetidine
• metabolism

Answer 5

2nd generation H2 antagonist

• furan ring (not just imidazole), tertiary amine, nitro group
• 6x more potent than cimetidine
• 2-3 hour t1/2 life. Weak P450 inhibitor (less than cimetidine because of furan instead of imidazole

Question 6

Nizatidine

• structure
• potency compared to cimetidine
• metabolism

Answer 6

• thiazole vs. furan ring, nitro group
• 10x more potent than cimetidine
• t1/2 is 1-2 hours, no P450 inhibition

Question 7

Famotidine

• structure
• potency compared to cimetidine
• metabolism

Answer 7

• thiazole, guanidine
• 40x more potent than cimetidine
• t1/2 = 2 1/2 - 4 1/2 hours, no p450 inhibition

Question 8

Omeprazole

• Structure
• mechanism of omeprazole
• Prodrug?

Answer 8

• Benzimidazole
• protonate, rearrange, take out water, thiole-enzymatic reaction, end with alkylated ATPase. Essentially irreversible inactivation
• Need to regenerate or resynthesizes the ATPase to regain full function (4-5 days after you stop taking the PPI)
• Prodrug (only activated under acidic conditions)

Question 9

Esomeprazole

• structure
• enantiomers
• Bioavailability compared to omeprazole
• metabolism

Answer 9

• S enantiomer of omeprazole. Lone electron pair on sulfur allows enantiomers to be separated.
• Both enantiomers are active PPIs, but S-enantiomer is more slowly metabolized
• Omeprazole is 30-40% bioavailable, and esomeprazole is 65% bioavailable
• 3A4 - sulfone, 2C19 - 5-hydroxyomeprazole (3A4 is more important for esomeprazole, which has less polymorphisms)

Question 10

Lansoprazole

• Structure
• metabolism
• Which enantiomer is used in the Dexlansoprazole formulation?

Answer 10

• asymmetric center is the sulfur atom
• 3A4 sulfonation and 2C19 para hydroxylation (in all PPIs)
• The R enantiomer is used in Dexlansoprazole. It is a special dual-release formulation that cannot compare to lansoprazole

Question 11

zwitterionic drugs:

Answer 11

ceterizine
olopatadine
fexofenadine
alcaftadine