Ranitidine, sold under the trade name Zantac among others, is a medication which decreases stomach acid production.[1] It is commonly used in treatment of peptic ulcer disease, gastroesophageal reflux disease, and Zollinger–Ellison syndrome.[1] There is also tentative evidence of benefit for hives.[3] It can be taken by mouth, by injection into a muscle, or into a vein.[1] Common side effects include headaches and pain or burning if given by injection.[1] Serious side effects may include liver problems, a slow heart rate, pneumonia, and the potential of masking stomach cancer.[1] It is also linked to an increased risk of Clostridium difficile colitis.[4] It is generally safe in pregnancy.[1] Ranitidine is an H2 histamine receptor antagonist that works by blocking histamine and thus decreasing the amount of acid released by cells of the stomach.[1] Ranitidine was discovered in 1976 and came into commercial use in 1981.[5] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[6] It is available as a generic medication.[1] The 2015 wholesale price in the developing world was about 0.01 to 0.05 USD per pill.[7] In the United States it is about 0.05 USD per dose.[1] Certain preparations of ranitidine are available over the counter (OTC) in various countries. In the United States, 75- and 150-mg tablets are available OTC. Zantac OTC is manufactured by Boehringer Ingelheim. In Australia and the UK, packs containing seven or 14 doses of the 150-mg tablet are available in supermarkets, small packs of 150-mg and 300-mg tablets are schedule 2 pharmacy medicines. Larger doses and pack sizes still require a prescription. For ulcer treatment, a night-time dose is especially important — as the increase in gastric/duodenal pH promotes healing overnight when the stomach and duodenum are empty. Conversely, for treating reflux, smaller and more frequent doses are more effective. Ranitidine used to be administered long-term for reflux treatment, sometimes indefinitely. However, PPIs have taken over this role. In addition, a fairly rapid tachyphylaxis can develop within six weeks of initiation of treatment, further limiting its potential for long-term use.[13] People with Zollinger–Ellison syndrome have been given very high doses without any harm.[14] Ranitidine is contraindicated for patients known to have hypersensitivity to the drug. The following adverse effects have been reported as events in clinical trials: Rare reports have been made of malaise, dizziness, somnolence, insomnia, and vertigo. In severely ill, elderly patients, cases of reversible mental confusion, agitation, depression, and hallucinations have been reported.[15] Ranitidine causes fewer CNS adverse reactions and drug interactions compared to cimetidine.[citation needed] Arrhythmias such as tachycardia, bradycardia, atrioventricular block, and premature ventricular beats have also been reported.[15] All drugs in its class have the potential to cause vitamin B12 deficiency secondary to a reduction in food-bound vitamin B12 absorption.[16] Elderly patients taking H2 receptor antagonists are more likely to require B12 supplementation than those not taking such drugs.[17] H2 blockers may also reduce the absorption of drugs (azole antifungals, calcium carbonate) that require an acidic stomach.[18] In addition, multiple studies suggest the use of H2 receptor antagonists such as raniditine may increase the risk of infectious diarrhoea, including traveller's diarrhoea and salmonellosis.[19][20][21][22][23] Finally, by suppressing acid-mediated breakdown of proteins, ranitidine may lead to an elevated risk of developing food or drug allergies, due to undigested proteins then passing into the gastrointestinal tract, where sensitisation occurs. Patients who take these agents develop higher levels of immunoglobulin E against food, whether they had prior antibodies or not.[24] Even months after discontinuation, an elevated level of IgE in six percent of patients was still found in this study. Cholestatic hepatitis, liver failure, hepatitis, and jaundice have been noted, and require immediate discontinuation of the drug.[15] Blood tests can reveal an increase in liver enzymes or eosinophilia, although in rare instances, severe cases of hepatotoxicity may require a liver biopsy.[25] Ranitidine and other histamine H2 receptor antagonists may increase the risk of pneumonia in hospitalized patients.[26] They may also increase the risk of community-acquired pneumonia in adults and children.[27] Thrombocytopenia is a rare but known side effect. Drug-induced thrombocytopenia usually takes weeks or months to appear, but may appear within 12 hours of drug intake in a sensitized individual. Typically, the platelet count falls to 80% of normal, and thrombocytopenia may be associated with neutropenia and anemia.[28] Rash, including rare cases of erythema multiforme and rare cases of hair loss and vasculitis have been seen.[15] With gastric malignancies, relief of symptoms due to the use of ranitidine does not exclude the presence of a gastric malignancy. In addition, with kidney or liver impairment, ranitidine must be used with caution. Finally, ranitidine should be avoided in patients with porphyria, as it may precipitate an attack.[29] This drug is rated pregnancy category B in the United States. Ranitidine enters breast milk, with peak concentrations seen at 5.5 hours after the dose in breast milk. Caution should be exercised when prescribed to nursing women.[30] In children, the use of gastric acid inhibitors has been associated with an increased risk for development of acute gastroenteritis and community-acquired pneumonia.[31] A cohort analysis including over 11,000 neonates reported an association of H2 blocker use and an increased incidence of necrotizing enterocolitis in very-low-birth-weight (VLBW) neonates.[32] In addition, about a sixfold increase in mortality, necrotizing enterocolitis, and infection (such as sepsis, pneumonia, urinary tract infection) was reported in patients receiving ranitidine in a cohort analysis of 274 VLBW neonates.[33] Ranitidine may return a false positive on some commercial drug testing kits.[34] Ranitidine is a competitive, reversible inhibitor of the action of histamine at the histamine H2 receptors found in gastric parietal cells. This results in decreased gastric acid secretion and gastric volume, and reduced hydrogen ion concentration. Absorption: Oral: 50% Protein binding: 15% Metabolism: N-oxide is the principal metabolite. Half-life elimination: With normal renal function, ranitidine taken orally has a half-life of 2.5–3.0 hours. If taken intravenously, the half-life is generally 2.0–2.5 hours in a patient with normal creatinine clearance. Excretion: The primary route of excretion is the urine. In addition, about 30% of the orally administered dose is collected in the urine as non-absorbed drug in 24 hours. In the elderly population, the plasma half-life of ranitidine is prolonged to 3–4 hours secondary to decreased kidney function causing decreased clearance.[35] In general, studies of pediatric patients (aged 1 month to 16 years) have shown no significant differences in pharmacokinetic parameter values in comparison to healthy adults, when correction is made for body weight.[35] Ranitidine was first prepared as AH19065 by John Bradshaw in the summer of 1977 in the Ware research laboratories of Allen & Hanburys, part of the Glaxo organization.[36][37] Its development was a response to the first in class histamine H2 receptor antagonist, cimetidine, developed by Sir James Black at Smith, Kline and French, and launched in the United Kingdom as Tagamet in November 1976. Both companies would eventually become merged as GlaxoSmithKline following a sequence of mergers and acquisitions starting with the integration of Allen & Hanbury's Ltd and Glaxo to form Glaxo Group Research in 1979, and ultimately with the merger of Glaxo Wellcome and SmithKline Beecham in 2000. Ranitidine was the result of a rational drug-design process using what was by then a fairly refined model of the histamine H2 receptor and quantitative structure-activity relationships. Glaxo refined the model further by replacing the imidazole ring of cimetidine with a furan ring with a nitrogen-containing substituent, and in doing so developed ranitidine. Ranitidine was found to have a far-improved tolerability profile (i.e. fewer adverse drug reactions), longer-lasting action, and 10 times the activity of cimetidine. Ranitidine has 10% of the affinity that cimetidine has to CYP450, so it causes fewer side effects, but other H2 blockers famotidine and nizatidine have no CYP450 significant interactions.[38] Ranitidine was introduced in 1981 and was the world's biggest-selling prescription drug by 1987. It has since largely been superseded by the even more effective proton-pump inhibitors, with omeprazole becoming the biggest-selling drug for many years. When omeprazole and ranitidine were compared in a study of 144 people with severe inflammation and erosions or ulcers of the esophagus, 85% of those treated with omeprazole healed within eight weeks, compared to 50% of those given ranitidine. In addition, the omeprazole group reported earlier relief of heartburn symptoms.[39]