Covering exam 3 material from antiulcer, anticoagulants, antiplatelets, fibrinolytics, methylxanthines, misc. stimulants, b-phenylethylamines, amphetamines, ADHD, anti-depressants, migraine headaches, and n/v. For Medicinal Chemistry at EMSOP at Rutgers.
CONTAINS EVERYTHING YOU NEED TO KNOW VERY...
,Antiulcer Agents (H2 antihistamines and PPIs)
Causes of peptic ulcer Treatment options
1. Helicobacter pylori infection 1. Eradicating H.pylori
2. Long term use of NSAIDs 2. Controlling stomach acid secretion
3. Insufficient mucosal defense against gastric acid 3. Using cytoprotective agents like Pepto Bismol
Mechanism of acid 3 mediators that regulate the secretion of gastric acid from parietal cells
production in the gastric 1. Histamine by activation of H2 histamine receptor
parietal cells 2. Gastrin (17-AA peptide) - by activation of gastrin receptor
3. Acetylcholine (parasympathetic stimulation → gastric acid secretion) - by activation of M3 receptor
All these pathways converge at the activation of H+/K+-ATPase (proton pump) that releases H+ in exchange for K+
Pepsin aggravates Low pH stimulates the activity of pepsin (proteolytic enzyme that breaks down peptide bonds → damages ulcerated lesions)
peptic ulcers - Has maximal activity at low pH
Addition - Antisecretory agents are included in multidrug treatment protocols for eradication of H.pylori
- Antacid therapy is insufficient due to a large amount of acid secreted by stomach
Design Based off of endogenous Histamine structure except neutral thiourea (later thiourea bioisosteres) replaces the primary basic
amine
- Thiourea H2 antihistamines were never marketed due to toxicity and poor bioavailability (burimamide and metiamide)
5 membered heteroaryl + 4-atom side chain + polar non-basic urea isostere
,Structure Burimamide/thiourea = toxic
H2 Antihistamines cont.
Cimetidine First H2 antihistamine Treatment of Metabolism
discovered and used clinically - Duodenal ulcer 1. Hydroxylation
Oral F = 50% - Gastric ulcer 2. Oxidation of sulfur atom
- GERD 3. N-demethylation (minor)
Subject to first pass - Hypersecretory AEs
1. Imidazole metabolism conditions - Somnolence and confusion
2. N-cyanoguanidine - Gynecomastia (increased prolactin rxn)
CYP450 DDI - substrate inhibitor due to imidazole ring
- Many DDIs phenytoin, theophylline, procainamide
Ranitidine More potent than cimetidine Metabolism
Oral F = 50% 1. N-demethylation
2. S-oxide formation
Subject to first-pass
1. Furan metabolism No gynecomastia
2. 1,1-diamneonthrothene No major DDI
Eliminated through kidney
Famotidine Most potent H2 antihistamine ALL EXCEPT Major metabolite: S-oxide
Oral F = 50% hypersecretory
conditions No major DDI
Minimal first-pass metabolism
1. Thiazole
Nizatidine Similar to ranitidine in No major DDI
potency; approx. 4x more
potent than cimetidine DOES NOT affect CYP450
, Oral F = 90%
N-desmethyl compound = active metabolite
1. Thiazole - guanidine
2. Amindosylafamoylamin
e
Waves of recalls affect ranitidine and nizatidine due to the presence of NDMA (carcinogen) from dimethylamine + nitrosonium ion → NDMA
Proton Pump Inhibitors (PPIs) - “-prazoles” – Most potent suppressors of gastric acid secretion
MoA Proton Pump refers to H+/K+ ATPase
Inhibit the final convergent step in production of gastric acid secretion (irrespective of receptor stimulation of M3 or H2 receptor)
- PPIs inhibit basal and stimulated acid secretion because they are inverse agonists
- Diminish daily production of acid by 80-85%; treatment for 4-8 weeks
Mechanism of action via acid catalyzed generation of active intermediate (sulfenamide) = pharmacologically active species
- Parietal cells: PPIs undergo activation at the canalicular region
Mechanism of action of PPIs
- Prodrugs
- Require activation by an acid to an unstable reactive intermediate + active form → covalent bond formation
- Activated drug binds irreversibly to a cysteine residue through a covalent disulfide bond → inactivating the enzyme
Structure 1. Sulfoxide group = chiral; electrons have lowest priority
2. Benzimidazole
Racemic Omeprazole, Lansoprazole, pantoprazole, rabeprazole, tenatoprazole
(PLORT) - Esomeprazole (S enantiomer of omeprazole)
- Dexlansoprazole (R enantiomer of lansoprazole)
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