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Histamine
histamine is synthesized from the essential AA histidine through histidine decarboxylase
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Histamine (HA) receptor subtypes
H1: mast cells store histamine in granules as heparin salts (sulfate)
H2: enterochromafffin-like cells of gastric mucosa; activate protein pump which secretes HCl
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First generation antihistamines: H1-receptor antagonists
see pharmacophore on page 33
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Diphenhydramine (NyQuil, Robitussin)
- 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
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Pyrilamine (Midol)
- 1G H1-receptor antagonists
- X=N
- ethylenediamine antihistamine
- less anticholinergic SEs which can induce cough
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Chlorpheniramine
- 1G H1-receptor antagonists
- X=C
- alkylamine antihistamine
- reduced drowsiness
- FYI: other examples: dimetapp, acetifed
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Hydroxyzine (Vistaril)
- 1G H1-receptor antagonists
- piperazine antihistamine
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Promethazine (Phenergan)
- 1G H1-receptor antagonists
- phenothiazine antihistamine
- 10% as antidopaminergic as chlorpromazine
- Tx: allegic rhinitis, N&V, muscarinic antagonist
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2G H1-receptor antagonists
- non-sedating
- highly polar preventing penetration of BBB
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Terfenadine (Seldane)
- 2G H1-receptor antagonists
- victim drug
- oxidized by 3A4 (DDIs!!!!!)
- perpertrator drug
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Fexofenadine (Allegra)
- 2G H1-receptor antagonists
- %F unknown
- fecal elimination
- good Pgp substrate
- no known DDIs
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Loratadine (Claritin)
- 2G H1-receptor antagonist
- shorter half life than parent drug desloratadine
- metabolized by 2D6 and 3A4 DDIs: carbamate --- amine
- went from Rx to OTC
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Desloratadine (Clarinex)
- 2G H1-receptor antagonist
- long half life
- no 3A4 DDI or 2D6 polymorphism
- premetabolized
- BBB Pgp effluxes BBB --- non-sedative
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Cetirizine (Zyrtec)
- 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
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Levocetirizine
- racemic switch of cetirizine
- claims of decreased sedation
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H2 receptor antagonists (blockers)
Tx: gastric ulcers, GERD
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Cimitidine (Tagament)
- 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
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Ranitadine
- H2 receptor antagonist
- largely excreted unchanged
- no imidazole ring --- only 10% as much CYP inhibition as cimitidine
- "me better" drug of cimitidine
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Famotidine (Pepcid)
- H2 receptor antagonist
- no CYP inhibition
- "me too" drug of cimitidine
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Nizatidine (Axid)
- H2 receptor antagonist
- 90% bioavailable
- no CYP inhibition
- "me too" drug of cimitidine
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Proton Pump Inhibitors (PPIs)
- covalent binding to sulfhydryl group on parietal cells
- targets proton and/or potassium pumps
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Omeprazole (Prilosec)
- 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
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Tx: GERD
PPI + amoxicillin + clarithromycin (H. Pylori)
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Esomeprazole (Nexium)
- 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
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Lansoprazole (Prevacid)
PPI
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Pantoprazole (Protonix)
- PPI
- more acid stable so not affected by food stimulated acid production
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Rabeprazole (Aciphex)
- PPI
- sulfone group is acted on by 3A4 and the O-demethyl group is acted on by 2C19
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PPI PD:
- 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
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Misoprostol (Cytotec)
- Prostaglandin
- Tx: anticulcer, NSAID-induced ulcers
- opposes influence of HA on PP
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THC
- marijuana
- makes your hair grow --- Hippies!
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