H2-receptor antagonist

FIGURE 6.25 Structures of some key compounds in the development of H2-receptor antagonists. 

CHAPTER 6 Strategies in the Search for New Lead Compounds or Original Working Hypotheses 

Clausewitz von, C. Vom Kriege, Drittes Buck, 1. Kapitel Strategic, 18-1973 ed. Ferdinand Diimmlers Verlag Bonn, 1832. 

Ramesha, C. S. How many leads from HTS - Comment. Drug Discov. Today 2000,5, 43-44. 

Wermuth, C. G. Selective optimization of side activities another way for drug discovery. J. Med. Chem. 2004, 47, 1303-1314. 

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Histamine H2 Receptor Antagonists. In 1972 a new class of histamine antagonists was described that was capable of antagonizing histamine-induced gastric acid secretion (6). The H2 antagonists are divided into five stmctural classes, some of which are shown in Table 3. A more complete review can be found in Reference 25. 

The principal OTC pharmaceutical products include cold remedies, vitamins and mineral preparations, antacids, analgesics, topical antibiotics, antiftingals and antiseptics, and laxatives. Others include suntan products, ophthalmic solutions, hemorrhoidal products, sleep aids, and dermatological products for treatment of acne, dandmff, insect parasites, bums, dry skin, warts, and foot care products (11). More recent prescription-to-OTC switches have included hydrocortisone, antihistamine and decongestant products, antiftingal agents, and, as of 1995, several histamine H2-receptor antagonists. 

From 1981 to 1995 other dmgs switched to OTC were the antifiingal preparations containing micona2ole nitrate [22832-87-7] (7) and clotrima2ole [23593-75-1] (8) the antiinflammatory agent ibuprofen [15687-27-1] (9) and the histamine H2-receptor antagonists famotidine [76824-35-6] (10) and cimetidine [51481-61-9] (11). 

Antacids are neutralizing agents. Examples are magnesium hydroxide, magnesium trisylicate and aluminium hydroxide. Prior to the introduction of histamine-H2 receptor antagonists and proton pump inhibitors, they were the standard drugs for the treatment of duodenal/ peptic ulcers. Today their clinical use is limited to the treatment of dyspepsia and the symptomatic relieve for patients with peptic ulcers. 

Ring J, Rothenberger KH, Clauss W Prevention of anaphylactoid reactions after radiographic contrast media infusion by combined histamine Hj- and H2-receptor antagonists results of a prospective controlled trial. Int Arch Allergy Appl Immunol 1985 78 9-14. 

Cimetidine and other imidazole-containing H2 receptor antagonists scavenge hydroxyl radicals at a frster rate than mannitol. This activity was attributed to the methyl imidazole moiety rather than the guanidine of cimetidine (Ching etal., 1993). 

Ching, T., Haenen, G. and Bast, A. (1993). Cimetidine and other H2 receptor antagonists as powerful hydroxyl radical scavengers. Chem. Biol. Interact. 86, 119-127. 

Opioids, benzodiazepines, barbiturates, corticosteroids, dopamine agonists (e.g., amantadine, bromocriptine, levodopa, pergolide, pramipexole, ropinirole), H2-receptor antagonists, anticholinergics (e.g., diphenhydramine, trihexylphenidyl), P-adrenergic blockers, clonidine, methyldopa, carbamazepine, phenytoin, baclofen, cyclobenzaprine, lithium, antidepressants (e.g., tricyclic antidepressants, selective serotonin reuptake inhibitors), and interleukin-2... 

Intravenous H2-receptor antagonist (preferred) or intravenous proton pump inhibitor (PPI)... 

Presence of a transpyloric feeding tube 0 H2-receptor antagonist or PPI... 

H2-receptor antagonists (adjust all doses for renal impairment) ° Famotidine 20 mg IV or enterally ql2h... 

May be preferred in patients whose risk of hospital-acquired pneumonia (HAP) is greater than upper gastrointestinal bleed. Data suggests a lower incidence of HAP when compared with H2-receptor antagonist... 

May be less effective than H2-receptor antagonist pharmacotherapy... 

Calcium carbonate requires an acidic medium for solubility ° H2-receptor antagonists and proton pump inhibitors... 

H2 receptor antagonists (Cimetidine, famotidine, nizatidine, ranitidine) Proton pump inhibitors Lansoprazole Omeprazole Pantoprazole Rabeprazole... 

BSS, bismuth subsalicylate H2RA, H2-receptor antagonist PPI, proton pump inhibitor RBC, ranitidine bismuth citrate (not available in the United States). 

H2-Receptor Antagonists Cimetidine 300 mg four times daily 400-800 mg daily... 

Ulcer prophylaxis H2-receptor antagonists Sucralfate Proton pump inhibitors Adjust dose in those with Rl decreased TAC absorption if Rl, caution aluminum content no Rl, caution hypophosphatemia... 

Calcium carbonate should be taken with food to maximize absorption. Elderly patients or patients receiving proton pump inhibitors or H2-receptor antagonists may have added difficulty absorbing calcium supplements because of reduced stomach acidity. Better absorption may occur in this setting with calcium citrate because an acid environment is not needed for absorption it may be taken with or without food. 

Epinastine Hr and H2-receptor antagonist, mast cell stabilizer, anti-inflammatory ... 

The incidence of community-associated C. difficile infection (defined as occurring in patients not hospitalized in the year prior to diagnosis) is increasing.36 In addition to antibiotic use, community-associated C. difficile cases are associated with the use of gastric acid suppressive agents (e.g., proton pump inhibitors and H2-receptor antagonists). 

The following amides prepared from 4-(3-nitro-l-pyrazolyl)butanoic acid, CDI, and primary amines represent partial structures of the histamine H2-receptor antagonists roxatidine, cimetidine, ranitidine, and famotidine [37]... 

Azolides used as inhibitors for monoamine oxidase1171 or human leucocyte elastase,1181 as inductors of recessive lethal genes in Drosophila,1191 as histamine H2-receptor antagonists,1201 as anti-ulcer agents,1211 or as pharmacophores for anthelmintic, analgesic, and antimicrobial activity 1221... 

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