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Ranitidine

An Updated Review of its Pharmacodynamic and Pharmacokinetic Properties and Therapeutic Use in Peptic Ulcer Disease and Other Allied Diseases

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Summary

Synopsis

Ranitidine, a histamine H2-receptor antagonist, is now well established as a potent inhibitor of gastric acid secretion effective in the treatment and prophylaxis of gastrointestinal lesions aggravated by gastric acid secretion.

Therapeutic trials involving several thousands of patients with peptic ulcer disease confirm that ranitidine 300mg daily administered orally in single or divided doses is at least as effective as cimetidine 800 to 1000mg daily in increasing the rate of healing of duodenal and gastric ulcers. Similar dosages of ranitidine have been shown to relieve the symptoms of reflux oesophagitis and heal or prevent gastrointestinal damage caused by ulcerogenic drugs. Ranitidine 150mg orally at night maintains ulcer healing in the long term. Ranitidine has also demonstrated good results in the treatment of Zollinger-Ellison syndrome and in the prevention of aspiration pneumonitis when given prior to surgery and to pregnant women at full term. It may also have a place in the management of acute upper gastrointestinal bleeding and in the prevention of stress ulcers in the intensive care setting, although these areas require further investigation. Ranitidine has been used safely in obstetric patients during labour, in children, the elderly, and in patients with renal impairment when given in appropriate dosages. The drug is very well tolerated and is only infrequently associated with serious adverse reactions or clinically significant drug interactions. Even at high dosages, ranitidine appears devoid of antiandrogenic effects.

Ranitidine is clearly comparable or superior to most other antiulcer agents in the treatment and prevention of a variety of gastrointestinal disorders associated with gastric acid secretion. With its favourable efficacy and tolerability profiles, ranitidine must be considered a first-line agent when suppression of gastric acid secretion is indicated.

Pharmacodynamic Properties

In vitro studies have shown that ranitidine specifically antagonises histamine H2-receptors, receptors which appear to mediate a final common pathway in the release of gastric acid. In normal volunteers and patients with peptic ulcer disease, ranitidine 150mg daily or 300mg daily in 1 or 2 divided doses decreases the number of low intragastric pH-metry readings per 24 hours and decreases 24-hour integrated hydrogen ion activity predominantly through suppression of nocturnal acid secretion. Ranitidine suppresses basal acid output and experimentally stimulated acid secretion but usual therapeutic dosages do not consistently suppress normal meal-stimulated acid secretion. Ranitidine also suppresses pepsin output which, in conjunction with decreased gastric acidity, results in decreased pepsin activity. The pattern of acid and pepsin inhibition achieved during ranitidine treatment of peptic ulcer disease appears not to facilitate microbial colonisation of the stomach, although colonisation may occur during the sustained achlorhydria produced by high-dose intravenous regimens in the critically ill.

Cholinomimetic effects have been ascribed to ranitidine in vitro and in vivo in animals but evidence of clinically significant cholinomimetic effects in humans is lacking. Mixed results have been reported regarding ranitidine-induced changes in gastric motility; the underlying mechanisms and clinical significance of these motility-modifying effects are unclear.

Some studies suggest that ranitidine treatment is associated with an increase in serum gastrin concentration and/or an increase in meal-stimulated gastrin release. Elevated serum gastrin concentrations return to pretreatment levels once ranitidine is discontinued.

Ranitidine, in therapeutic dosages, does not induce clinically significant changes in serum prolactin, cortisol or thyroid-stimulating hormone, and has no apparent antiandrogen activity. Because ranitidine possesses a furan rather than an imidazole nucleus, it binds only weakly to cytochrome P450 and, in consequence, has minimal effects on drug metabolism by the liver.

Pharmacokinetic Properties

Following oral administration, peak plasma ranitidine concentrations are reached within 1 to 3 hours and are not influenced by food. A single 150mg oral dose of ranitidine produces a peak plasma concentration of about 0.4 mg/L. Bioavailability, which varies markedly between individuals, averages about 50%. The apparent volume of distribution in normal adults is approximately 1.4 L/kg. Comparison of ranitidine pharmacokinetics following intravenous and oral administration suggests significant hepatic biotransformation following oral absorption. Thus, 30% of an administered oral dose of ranitidine is excreted unchanged in the urine versus 70% of an intravenous dose. The normal elimination half-life of ranitidine is 2 to 3 hours, but it is prolonged to 4 to 9 hours in patients with severe renal disease. Ranitidine is approximately 15% protein bound and, while it is removed by dialysis, the percentage of total dose recovered in dialysate is small and dosage supplementation is not recommended.

Although the degree of acid inhibition required for ulcer healing is unknown, dose-response studies have found that experimentally stimulated acid secretion is decreased 50% by ranitidine at plasma concentrations of about 0.1 mg/L, which are maintained for at least 10 hours following a single 150mg oral dose. Limited studies to date suggest that, in patients with duodenal ulcer, sensitivity of the gastric mucosa to secretagogues may change during ranitidine treatment; however, the role of ranitidine in this process and its clinical significance are unclear.

Therapeutic Trials

In non-comparative, placebo-comparative and other controlled clinical trials, oral ranitidine 200 to 320mg daily has achieved cumulative duodenal ulcer healing rates of 62 to 96% after 4 weeks and 78 to 98% after 8 weeks. The superiority of ranitidine over placebo has been confirmed in a number of recent trials in patients with duodenal ulcer. The rate of healing achieved with oral ranitidine 150mg twice daily was comparable to that obtained with a single 300mg nightly dose. Oral ranitidine 300mg daily was superior or comparable to cimetidine 800 to 1000mg daily in achieving duodenal ulcer healing after 4 and 8 weeks. In comparisons of orally administered ranitidine 300mg daily, famotidine 40 to 80mg daily and nizatidine 300mg nocte, there were no significant differences in healing rates. Trials comparing the efficacy of ranitidine, enprostil, misoprostol and rioprostil in the treatment of duodenal ulceration showed ranitidine to be superior with respect to rates of healing and relief of symptoms. Healing rates of duodenal ulcer achieved with ranitidine are comparable with those of deglycyrrhizinised liquorice (‘Caved-S’), colloidal bismuth subcitrate and sucralfate, while ranitidine was superior to antacids and was better tolerated. Evidence to date indicates that ranitidine heals duodenal ulcers more slowly than omeprazole, and although the rate of healing of duodenal ulcers is faster with ranitidine than with selective anticholinergics such as pirenzepine, the reverse is true with respect to duodenal erosions. In small studies, combining the anxiolytic, prazepam, with ranitidine appeared to accelerate healing. The combination of ranitidine with ofloxacin in patients with positive Campylobacter pylori cultures from the ulcer site appeared to speed healing over that obtained with ranitidine alone, although this combination was seemingly less effective in eradicating C. pylori or in healing ulcers than was a bismuth subsalicylate/ofloxacin combination.

Ranitidine 150mg orally twice daily healed 59 to 88% of gastric ulcers after 3 to 6 weeks, compared with 20 to 53% healing in placebo-treated patients. A single oral dose of 300mg nightly was as effective as 150mg twice daily. Ranitidine was similar to cimetidine in healing gastric ulcers after 4 and 8 weeks, and similar healing rates were seen in trials comparing ranitidine with deglycyrrhizinised liquorice, rioprostil, enprostil, famotidine, and colloidal bismuth subcitrate over the same period. However, in comparison with omeprazole, ranitidine heals gastric ulcers and relieves their symptoms more slowly. In comparison with the anticholinergic drug pirenzepine, ranitidine was superior in healing gastric ulcers, and inferior in healing gastric erosions. Patients with gastric or duodenal ulcers which fail to respond to cimetidine treatment may respond to a subsequent course of ranitidine.

Prophylactic oral administration of ranitidine 150mg daily in patients with recently healed duodenal or gastric ulcers resulted in relapse in 15 to 49% of patients after 12 months, while 59 to 87% of placebo-treated patients relapsed. Continuous daily ranitidine treatment was superior to intermittent seasonal dosage (in the spring and autumn) in preventing relapse. Ranitidine appeared to be superior to enprostil and cimetidine in preventing relapse, and similar to sucralfate after 12 months of continuous treatment, and has proven to be effective in preventing relapse in the majority of patients treated for as long as 5 years.

Oral ranitidine is suitable for use in high dosages in the Zollinger-Ellison syndrome to reduce gastric acid secretion and resultant damage and symptoms, and as an adjunct to surgery, as it appears to lack the endocrine adverse effects and effects on hepatic metabolism sometimes seen with cimetidine. Dosage must be individualised, and results may be improved by addition of an anticholinergic agent such as pirenzepine. In this syndrome, the dosage of ranitidine required to reduce gastric acid to below 10 mEq/h has been found to be 3 to 4 times less than that of cimetidine but nearly 10 times greater than that of famotidine.

Ranitidine has been studied in attempts to control acute upper gastrointestinal bleeding and to reduce rebleeding. Compared with placebo, ranitidine 150mg administered intravenously in divided doses and oral ranitidine 300mg daily significantly (p < 0.05) lowered the incidence of severely bleeding gastric ulcers and reduced the need for blood transfusions in patients with gastric and duodenal ulcer. However, the drug was not thought to influence significantly the outcome for patients with acute bleeding. Ranitidine was significantly (p > 0.05) superior to antacid in controlling bleeding and preventing rebleeding in high risk patients. Ranitidine appeared to be comparable to cimetidine in acute bleeding, although preliminary studies suggest that somatostatin may be superior. Overall, the role of ranitidine in the treatment and prevention of upper gastrointestinal bleeding is still uncertain and further study is needed.

In critically ill patients, ranitidine was as effective as antacid in preventing stress ulcers when given orally or intravenously. Studies searching for optimal ranitidine dosages were equivocal, but found that continuous intravenous ranitidine infusion in the range of 0.125 to 0.25 mg/kg/h were effective. Ranitidine appeared to be comparable to cimetidine in preventing stress ulcers and ulcer bleeding, and although superior to pirenzepine in ulcer prevention, ranitidine-treated patients appeared to be at greater risk of pneumonia. Studies comparing ranitidine and sucralfate for stress ulcer prophylaxis show sucralfate recipients to be at a lower risk of both gastrointestinal bleeding and nosocomial pneumonia.

Ranitidine 150 to 300mg orally, 1 to 2.5 mg/kg or 50mg intravenously, or 50mg intramuscularly on the morning of surgery was superior to placebo or no treatment in reducing the risk of lung damage due to pulmonary aspiration of the acidic contents of the stomach while under general anaesthetic. Ranitidine appears to be comparable or superior to cimetidine and superior to metoclopramide alone, while the addition of metoclopramide to ranitidine provided no additional protection from pulmonary acid aspiration. In women in labour or undergoing emergency or elective caesarean section, intravenous or intramuscular (50mg) or oral (150mg) ranitidine provided adequate protection from acid aspiration, with no ill-effects on the newborn infant or complications in labour.

In gastro-oesophageal reflux disease oral ranitidine 300mg daily in single or divided doses healed lesions and significantly (p < 0.05) reduced symptoms of pain, pyrosis, regurgitation and dysphagia after 6 to 24 weeks compared with placebo group and baseline levels. After 4 to 8 weeks, ranitidine was comparable in efficacy to sucralfate, cisapride and domperidone, and superior to metoclopramide in treating reflux disease, but was less effective in relieving symptoms and slower at healing than omeprazole. Ranitidine appears to be useful in long term maintenance treatment of reflux disease, but further study is needed to clarify which patients will benefit from long term therapy of reflux disease.

Ranitidine is effective in preventing or treating gastrointestinal damage caused by non-steroidal anti-inflammatory drugs (NSAIDs), reducing bleeding, gastric mucosal and duodenal damage in patients with rheumatic disease and with peptic ulcer, often despite continuation of NSAID treatment. One study tested the ability of ranitidine to prevent gastrointestinal damage in patients receiving cytostatic drugs and prednisone for lymphoproliferative disease, with promising results in a small number of patients.

Ranitidine has been studied in children and was effective in healing and preventing the recurrence of peptic ulceration, particularly when dosages were titrated to reduce acid secretion by 90%. In critically ill children, ranitidine 0.75 to 1.5 mg/kg intravenously or 2 to 4 mg/kg orally prevented the development of stress ulcers. Ranitidine 2 mg/kg administered orally 1 to 3 hours prior to surgery protected children from the risk of pulmonary aspiration of the acidic contents of the stomach.

Adverse Effects

Ranitidine is very well tolerated, producing minor adverse effects such as headache, diarrhoea and constipation in less than 5% of patients. The frequency and profile of these effects are similar to those seen in patients receiving placebo. Serious and treatment-limiting adverse effects occur rarely, with elderly and seriously ill patients being more susceptible, or appear to be idiosyncratic. Hepatotoxicity, with raised hepatic enzyme levels and biopsy-proven hepatocellular changes, has been seen rarely. Haematological changes, such as thrombocytopenia, agranulocytosis and general myelosuppression, have been reported sporadically in a small number of patients. Central nervous system adverse effects of mental confusion, severe headache, hallucinations and mania have also occurred in small numbers of patients, but rarely in patients without predisposing risks. A variety of idiosyncratic reactions have been reported in individuals, including fever, rashes, bradycardia, heart block, gouty arthritis attacks, erosive duodenitis and gynaecomastia. Seriously ill patients and those with renal insufficiency may require close monitoring for unusual effects.

Dosage and Administration

The usual oral dosage of ranitidine for the treatment of duodenal or benign gastric ulcer or gastro-oesophageal reflux is 150mg twice daily or 300mg nightly, with treatment continuing for 4 to 8 weeks or until healing occurs. For maintenance prophylaxis oral ranitidine 150mg nightly may be given. In Zollinger-Ellison syndrome an initial dosage of 150mg twice daily may be increased up to 6g daily as needed. Ranitidine 50mg intravenously or intramuscularly every 6 to 8 hours may be used to treat and prevent acute upper gastrointestinal bleeding. A ranitidine dosage of 150mg orally 2 or more hours prior, or 50mg intravenously or intramuscularly 45 to 60 minutes prior to general anaesthesia may minimise the risk of pulmonary damage due to acid aspiration. Oral ranitidine 150mg 6-hourly in women in labour may be supplemented by a non-particulate antacid to prevent pulmonary acid aspiration in the event of emergency surgery. In patients with renal insufficiency (creatinine clearance < 50 ml/min) only half the normal ranitidine dose is recommended. Dosage adjustments may also be needed in elderly patients. Children aged 8 to 18 years have been treated with oral ranitidine up to 150mg twice daily.

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Various sections of the manuscript reviewed by: G. Bianchi Porro, Gastrointestinal Unit, Ospedale L. Sacco, Milano, Italy; J.F. Critchow, Department of Surgery, Beth Israel Hospital, Boston, Massachusetts, USA; H.G. Dammann, Krankenhau Bethanien, Hamburg, West Germany; D.B. Jones, Gastroenterology Unit, Repatriation General Hospital Concord, Sydney, Australia; M.J.S. Langman, Department of Internal Medicine, Queen Elizabeth Medical Centre, Birmingham, England; K. Lauritsen, Department of Medical Gastroenterology, Odense University Hospital, Odense, Denmark; I.N. Marks, Gastrointestinal Clinic, Department of Medicine, Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa; S. Okabe, Department of Applied Pharmacology, Kyoto Pharmaceutical University, Kyoto, Japan; D.W. Piper, Royal North Shore Hospital, St Leonards, Australia; C. Scarpignato, Universita’ Degli Studi Di Parma, Istituto di Farmacologia, Ospedale Maggiore, Parma, Italy; C. Tasman-Jones, Department of Medicine, University of Auckland, Auckland, New Zealand; K.G. Wormsley, Ninewells Hospital, Dundee, Scotland

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Grant, S.M., Langtry, H.D. & Brogden, R.N. Ranitidine. Drugs 37, 801–870 (1989). https://doi.org/10.2165/00003495-198937060-00003

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