Pharm Chem Exam 1 Part 4

histamine is synthesized from the essential AA histidine through histidine decarboxylase

H1: mast cells store histamine in granules as heparin salts (sulfate)

H2: enterochromafffin-like cells of gastric mucosa; activate protein pump which secretes HCl

see pharmacophore on page 33

• 1G antihistamine: H1 receptor antagonist
• X=O
• enthanolamine antihistamine
• salt version: Benadryl (diphenhydramine chlorotheophyllinate) decreases drowsiness due to the stimulant effect of theophylline
• chloro group of benadryl increases acidity salt and favors the salt conformation

• 1G H1-receptor antagonists
• X=N
• ethylenediamine antihistamine
• less anticholinergic SEs which can induce cough

• 1G H1-receptor antagonists
• X=C
• alkylamine antihistamine
• reduced drowsiness
• FYI: other examples: dimetapp, acetifed

• 1G H1-receptor antagonists
• piperazine antihistamine

• 1G H1-receptor antagonists
• phenothiazine antihistamine
• 10% as antidopaminergic as chlorpromazine
• Tx: allegic rhinitis, N&V, muscarinic antagonist

• non-sedating
• highly polar preventing penetration of BBB

• 2G H1-receptor antagonists
• victim drug
• oxidized by 3A4 (DDIs!!!!!)
• perpertrator drug

• 2G H1-receptor antagonists
• %F unknown
• fecal elimination
• good Pgp substrate
• no known DDIs

• 2G H1-receptor antagonist
• shorter half life than parent drug desloratadine
• metabolized by 2D6 and 3A4 DDIs: carbamate --- amine
• went from Rx to OTC

• 2G H1-receptor antagonist
• long half life
• no 3A4 DDI or 2D6 polymorphism
• premetabolized
• BBB Pgp effluxes BBB --- non-sedative

• 2G H1 receptor antagonist
• metabolite of 1G hydroxyzine
• COOH derivative so it does not cross BBB so much is excreted unchanged (typical of AA drugs) --- also decreases DDI

• racemic switch of cetirizine
• claims of decreased sedation

Tx: gastric ulcers, GERD

• H2 receptor antagonist
• largely excreted unchanged
• guanidine-like functional group
• imidazole problem
• binds to and inhibits a wide range of CYPs --- many DDIs
• inhibits gastric alcohol dehydrogenase

• H2 receptor antagonist
• largely excreted unchanged
• no imidazole ring --- only 10% as much CYP inhibition as cimitidine
• "me better" drug of cimitidine

• H2 receptor antagonist
• no CYP inhibition
• "me too" drug of cimitidine

• H2 receptor antagonist
• 90% bioavailable
• no CYP inhibition
• "me too" drug of cimitidine

• covalent binding to sulfhydryl group on parietal cells
• targets proton and/or potassium pumps

• PPI
• broad range of PD half life because it is a prototypic 2C19 inhibitor
• 3A4 substrate
• marketed as a racemic sulfoxide
• enteric coated to prevent premature activation

PPI + amoxicillin + clarithromycin (H. Pylori)

• PPI
• S-enantiomer eliminating 2C19 issues leading to predicatable plasma levels of parent drug and clarithromycin
• dose: 2x of omeprazole
• chiral center is at the S-sulfoxide group

PPI

• PPI
• more acid stable so not affected by food stimulated acid production

• PPI
• sulfone group is acted on by 3A4 and the O-demethyl group is acted on by 2C19

• irreversible long acting inhibitors of H+, K+ ATPase
• forms cystine (disulfide) linkages with enzyme after prodrug is acid-activated to electrophilic sulfenamide
• ion trapping effect at canaliculi

• Prostaglandin
• Tx: anticulcer, NSAID-induced ulcers
• opposes influence of HA on PP

• marijuana
• makes your hair grow --- Hippies!