Molecular structure of cimetidine
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Tagamet

Cimetidine is a histamine H2-receptor antagonist that inhibits the production of acid in the stomach. It is largely used in the treatment of heartburn and peptic ulcers. It is marketed by GlaxoSmithKline under the trade name Tagamet®, and was approved by the Food & Drug Administration for prescriptions starting January 1, 1979. more...

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Clinical Use

History and development

Cimetidine was the prototypical histamine H2-receptor antagonist from which the later members of the class were developed. Cimetidine was the culmination of a project at Smith, Kline & French (SK&F; now GlaxoSmithKline) to develop a histamine receptor antagonist to suppress stomach acid secretion.

At the time (1964) it was known that histamine was able to stimulate the secretion of stomach acid, but also that traditional antihistamines had no effect on acid production. In the process, the SK&F scientists also proved the existence of histamine H2-receptors.

The SK&F team used a rational drug-design structure starting from the structure of histamine - the only design lead, since nothing was known of the then hypothetical H2-receptor. Hundreds of modified compounds were synthesised in an effort to develop a model of the receptor. The first breakthrough was Nα-guanylhistamine, a partial H2-receptor antagonist. From this lead the receptor model was further refined and eventually led to the development of burimamide - the first H2-receptor antagonist. Burimamide, a specific competitive antagonist at the H2-receptor 100-times more potent than Nα-guanylhistamine, proved the existence of the H2-receptor.

Burimamide was still insufficiently potent for oral administration and further modification of the structure, based on modifying the pKa of the compound, lead to the development of metiamide. Metiamide was an effective agent, however it was associated with unacceptable nephrotoxicity and agranulocytosis. It was proposed that the toxicity arose from the thiourea group, and similar guanidine-analogues were investigated until the ultimate discovery of cimetidine.

Shortcomings

Cimetidine is a known inhibitor of many isozymes of the cytochrome P450 enzyme system (specifically CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4). This inhibition forms the basis of the numerous drug interactions that occur between cimetidine and other drugs. For example, cimetidine may decrease metabolism of some drugs, such as oral contraceptives.

Adverse drug reactions were also found to be relatively common with cimetidine.

The development of longer-acting H2-receptor antagonists with reduced adverse effects such as ranitidine proved to be the downfall of cimetidine and, whilst it is still used, it is no longer amongst the more widely used H2-receptor antagonists.

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Solutions for an upset stomach
From Advocate, The, 11/8/05

For HIVers already experiencing gastrointestinal side effects from their antiretroviral drugs, the prospect of "traveler's tummy" may be enough to put those vacation plans on hold. But according to AIDS experts, you can minimize potential problems via:

PREVENTION: This could mean changing your antiretroviral regimen before you leave to include medications with fewer gastrointestinal side effects, and avoiding foods and drinks that may trigger digestive disturbances, like spicy dishes, greasy foods, dairy products, chocolate, coffee, soft drinks, alcohol, and wine. Raw and undercooked foods also can cause bacterial or parasitic infections, as can tap water in some foreign countries.

BE MINDFUL OF DRUG INTERACTIONS: If you do experience heartburn or upset stomach, your first instinct may be to stock up on antacids or antidiarrheal medications. But HIVers must be cautious: Many of these drugs interact badly with anti-HIV medications, boosting the risk for drug resistance and treatment failure, says Tom Barrett, MD, an HIV specialist at Chicago's Howard Brown Health Center. Alka-Seltzer, Maalox, Tums, and Rolaids can interfere with the stomach's absorption of Agenerase, Crixivan, Rescriptor, and Reyataz, while Axid, Pepcid, Tagamet, and Zantac should be entirely avoided by those taking Crixivan, Rescriptor, and Reyataz. Antidiarrheals like Imodium, Kaopectate, and fiber supplements are generally safe for HIVers, as are prescription anti-nausea medications, says Judith Feinberg, MD, former chair of the American Academy of HIV Medicine.

WHEN ALL ELSE FALLS: Try a "BRAT" diet--bananas, rice, applesauce, and toast, advise some health care providers.

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