Cimetidine antagonists

The sales of antagonists of receptors, eg, diphenhydramine, terfenadine, and astemizole, used in the treatment of allergic diseases, represent 1% of the overall pharmaceutical market, ie, 1.7 biUion (U.S.). antagonists, eg, cimetidine and ranitidine, are effective in peptic ulcer disease and esophageal reflux. Sales represent 3.5% of the world market, ie, 6 biUion (U.S.). agonists or antagonists have not yet found a clear indication. 

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). 

Etintidine (84), an imidazole-containing histamine H-2 receptor antagonist, is an antiiilcer agent conceptually related to cimetidine and ranitidine. It can be synthesized by various routes one of which terminates by an addition-elimination reaction of propargylamine with substituted N-cyano-S-methylisothiourea derivative 83 to give etintidine (84) [28]. 

Very recently, a very bold chemical model for histamine H2-receptors has been proposed using [18]aneN6-3H+ 84), which can chemically recognize histamine, histamine H2-agonists, and histamine H2-antagonists such as cimetidine XII or ranitidine XIII that are currently in world-wide use for treatment of peptic ulcers 85). 

FIGURE 1.7 Key compounds synthesized to eliminate the efficacy (burgundy red) and enhance the affinity (green) of histamine for histamine H2 receptors to make cimetidine, one of the first histamine H2 antagonists of use in the treatment of peptic ulcers. Quotation from James Black [10]. 

FIGURE 8.20 Drugs as subsets of clinical profiles. While burimamide, cimetidine, and metiamide are all active histamine H2 antagonists with ulcer healing activity burimamide lacks a suitable toxicity and pharmacokinetic profile and cimetidine is adequately absorbed but still toxic. Only metiamide fulfills the requirements of a clinically useful drug. 

Cheng-Prasoff relationship, 65-66, 214 Cholecystokinin receptor antagonists, 80 Cimetidine, 9-10 Clark, Alfred J., 3, 3f, 12, 41 Clark plot, 114 Clearance, 165—166 Clinical pharmacokinetics, 165 Cocaine, 149, 150f Competitive antagonism description of, 114 Gaddum equation for, 101-102, 113,... 

These drug inhibit die action of histamine at histamine H2 receptor cells of die stomach, which then reduces die secretion of gastric acid and reduces total pepsin output. The decrease in acid allows the ulcerated areas to heal. Examples of histamine H2 antagonists include cimetidine (Tagamet), famotidine (Pepcid), nizatidine (Axid Pulvules), ranitidine (Zantac). 

HISTAMINE H2 ANTAGONISTS. The nurse administers ranitidine and oral cimetidine before or with meals and at bedtime Nizatidine and famotidine are given at bedtime or, if twice-a-day dosing is prescribed, in the morning and at bedtime. These drugp are usually given concurrently with an antacid to relieve the pain. In certain situations or disorders, cimetidine and ranitidine may also be given by intermittent IV infusion or direct IV injection. 

Cimetidine, an H2 antagonist used therapeutically in patients with ulcers, inhibits activity of hepatic microsomal enzymes. When rats or mice were pretreated with cimetidine, dose-related lethality of methyl parathion was reduced, and cholinergic signs of toxicity were delayed. Simultaneous administration with methyl parathion did not reduce toxicity (Joshi and Thornburg 1986). 

Histamine Hj-antagonists such as cimetidine or ranitidine can be heipfu when combined with H,-antihistamines... 

Hj-antagonists alone, such as cimetidine or ranitidine, have a modest effect on cutaneous flush reaction and maybe also on the heart [14, 52]. However, when applied they should be given together with Hj-antagonists. There are some studies showing a beneficial effect of combined H - and Hj-antagonist treatment or pretreatment in anaphylaxis [46, 53]. 

Histamine receptors were first divided into two subclasses Hi and H2 by Ash and Schild (1966) on the basis that the then known antihistamines did not inhibit histamine-induced gastric acid secretion. The justification for this subdivision was established some years later when Black (see Black et al. 1972) developed drugs, like cimetidine, that affected only the histamine stimulation of gastric acid secretion and had such a dramatic impact on the treatment of peptic ulcers. A recently developed H2 antagonist zolantidine is the first, however, to show significant brain penetration. A further H3 receptor has now been established. It is predominantly an autoreceptor on histamine nerves but is also found on the terminals of aminergic, cholinergic and peptide neurons. All three receptors are G-protein-coupled but little is known of the intracellular pathway linked to the H3 receptor and unlike Hi and H2 receptors it still remains to be cloned. Activation of Hi receptors stimulates IP3 formation while the H2 receptor is linked to activation of adenylate cyclase. 

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. 

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

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

The histamine2-receptor antagonists or H2RAs (cimetidine, famotidine, nizatidine, and ranitidine) and proton pump inhibitors (omeprazole, esomeprazole, lansoprazole, pantopra-zole, and rabeprazole) reduce the amount of acid secreted into the stomach by gastric parietal cells. These agents are also helpful for nausea and vomiting related to gastric acid secretion. 

Intravenous histamine-2-receptor antagonists such as ranitidine, famotidine, and cimetidine are compatible with PN and can be added to the daily PN for prevention of stress-related mucosal damage and peptic ulcer disease. This provides a continuous acid suppression and reduces nursing time by avoiding intermittent scheduled infusions. 

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]... 

The bioslurry treatment successfully removed several of the PhC to non-detectable levels after 26 days three histamine H2-receptor antagonists (ranitidine, famotidine, cimetidine), two (1-blockers (atenolol, sotalol), one barbiturate (butalbital) and one antidiabetic compound (glibenclamide). The elimination of the sulfonamide antibiotics sulfapyridine (100%), sulfamethazine (91.0%) and... 

Collett, A., Higgs, N. B., Sims, E., Rowland, M., Warhurst, G., Modulation of the permeability of H2 receptor antagonists cimetidine and ranitidine by P-glycoprotein in rat intestine and the human colonic cell line Caco-2, J. Pharmacol. Exp. Ther. 1999, 288, 171-178. 

Nakamura, H., Sano, H., Yamazaki, M., Sugiyama Y., Carrier-mediated active transport of histamine H2 receptor antagonists, cimetidine and nizatidine, into isolated rat hepato-cytes contribution of type I system,... 

Intermittent, mild heartburn Lifestyle modifications plus patient-directed therapy Antacids Maalox or Mylanta 30 mL as needed or after meals and at bedtime Gaviscon 2 tabs after meals and at bedtime Calcium carbonate 500 mg, 2-4 tablets as needed and/or Nonprescription 11 receptor antagonists (taken up to twice daily) Cimetidine 200 mg Famotidine 10 mg Nizatidine 75 mg Ranitidine 75 mg or... 

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