R. N. Brogden, A. Carmine, R. Heel
Oct 1, 1982
Citations
2
Influential Citations
53
Citations
Quality indicators
Journal
Drugs
Abstract
SummarySynopsisRanitidine1 is a new histamine H2-receptor antagonist which, unlike cimetidine, does not contain an imidazole group. On a weight basis, ranitidine is 4 to 10 times more potent than cimetidine in inhibiting stimulated gastric acid secretion in humans.Therapeutic trials comparing ranitidine and cimetidine have demonstrated that ranitidine 150mg twice daily is an effective alternative to cimetidine 1000mg daily in 4 divided doses in increasing the rate of healing of duodenal and gastric ulcers over a period of 4 to 6 weeks. Ranitidine, given as a single 150mg dose at night, decreases the incidence of ulcer recurrence. Preliminary studies in the Zollinger-Ellison syndrome and in patients intolerant of, or unresponsive to cimetidine, indicate that ranitidine controls the gastric hyperacidity and heals most ulcers, including those which failed to respond to months of treatment with cimetidine 1 to 1.6g daily.Ranitidine, unlike cimetidine, has no antiandrogenic effects and does not alter hepatic metabolism of drugs.Ranitidine is well tolerated. Preliminary reports of the resolution of cimetidine-induced adverse effects following substitution of ranitidine, suggest that ranitidine may be of value in patients intolerant of cimetidine. However, wider clinical experience with ranitidine is needed to determine the clinical relevance of these reports.Pharmacodynamic StudiesStudies in animals have shown ranitidine to be a competitive inhibitor of histamine at histamine H2-receptor sites. In vitro and in vivo it is more active than cimetidine on a molar basis. In humans, ranitidine inhibits basal gastric acid secretion and that stimulated by pentagastrin, histamine and normal meals, being about 4 to 10 times more active than cimetidine in healthy subjects and in patients with duodenal ulcer. Single oral doses of ranitidine 50, 100, 150 and 200mg reduced pentagastrin-stimulated mean acid output by 42, 75, 85 and 95% respectively in healthy subjects. After a single 150mg oral dose of ranitidine, basal gastric acid secretion was inhibited by 70% and 38%, at 5 and 10 hours. In patients with duodenal ulcer, oral ranitidine 150mg twice daily produced a 70% reduction in 24-hour intragastric acidity. Nocturnal acid output decreased by 90%.Under conditions similar to those in clinical practice, 24-hour acidity was decreased by 69% and 71% with ranitidine 300mg and 400mg daily, respectively. Cimetidine 1000mg daily reduced 24-hour gastric acidity by 48%.In healthy subjects and duodenal ulcer patients, ranitidine administration did not significantly alter serum gastrin, pancreatic or mucus secretion. Pepsin output is decreased.Serum prolactin secretion is not usually increased by either acute or repeated administration of usual therapeutic doses of ranitidine but concentrations are elevated after intravenous injection of a 300mg dose. Unlike cimetidine, ranitidine does not have antiandrogen effects in animals or humans, and studies to date suggest that ranitidine does not affect hepatic metabolism of drugs.PharmacokineticsAfter oral administration, peak plasma concentrations are achieved within 1 to 2 hours and are not influenced by food. After a 150mg oral dose, mean peak plasma concentrations are about 400 ng/ml. Reported bioavailability after single doses has varied between about 40 and 88% but has most often been around 50%. Bioavailability and hepatic clearance values suggest significant ‘first-pass’ metabolism after oral administration. The apparent volume of distribution is 1.2 to 1.8 L/kg. In healthy subjects the cerebrospinal fluid concentration of ranitidine is one-twentieth to one-thirtieth of that in plasma sampled at the same time. Ranitidine is 15% protein bound. The majority of an oral or intravenous dose of ranitidine that is excreted in the urine is in the form of unchanged drug. Hepatic clearance is about 30% of total body clearance after intravenous injection and up to 73% after oral administration. After repeated oral doses the elimination half-life of ranitidine is 2.25 hours. Recent studies of the relationship between plasma concentration and inhibition of acid secretion indicate that a ranitidine concentration of around 160 ng/ml is required for 50% inhibition of pentagastrin-stimulated secretion over a 2-hour period.Therapeutic TrialsIn open trials, placebo-controlled trials and comparative trials with cimetidine, the rate of healing of duodenal ulcers after 4 weeks’ treatment has ranged between 60 and 100%. Ranitidine 150mg twice daily, the dose administered in most studies, has been demonstrated to be more effective than placebo and usually not significantly different from cimetidine 1000mg daily in 4 divided doses. In placebo-controlled studies the rate of ulcer healing with placebo has ranged from 27 to 46%. As has been found with other treatments effective in accelerating the healing of peptic ulcer, pain generally decreased as healing progressed, but there was no good correlation between the presence or absence of symptoms and endoscopic ulcer healing.Comparisons with cimetidine have usually been single blind, with the endoscopist being unaware of the individual patient’s treatment. No significant difference between ranitidine 300mg daily and cimetidine 1000mg daily was found in all except one large multicentre study. This study found ranitidine to be the more effective drug in accelerating the healing of duodenal ulcer after 4 weeks’ treatment, although the healing rates were not greatly different (74 and 68%). Other studies have reported a healing rate at 4 weeks, of 63 to 77% in patients treated with ranitidine 300mg daily and of 60 to 84% in patients receiving 1000mg daily of cimetidine. After 8 weeks of treatment, healing rates have ranged from 85 to 92% with ranitidine and from 88 to 95% with cimetidine.Ranitidine 300mg daily has been used successfully in the treatment of peptic ulceration which had persisted despite treatment with cimetidine 1 to 1.6g daily for 2 to 36 months.Placebo-controlled studies have demonstrated the efficacy of ranitidine 150mg twice daily in increasing the rate of healing of gastric ulcers. The healing rate with ranitidine has ranged from 59 to 76% after 3 or 4 weeks’ treatment, whilst with placebo, the healing rate was 23 to 44%. Comparisons with cimetidine have found no significant differences between ranitidine and cimetidine with respect to healing rates or tolerability.Recently conducted placebo-controlled trials and comparisons with cimetidine, indicate that ranitidine 150mg as a single dose at night decreases the rate of duodenal ulcer recurrence. After 12 months of maintenance treatment with either ranitidine 150mg or cimetidine 400mg, the rate of ulcer recurrence was 25% with ranitidine and 24% with cimetidine.Studies in patients with reflux oesophagitis, which was confirmed by endoscopy and biopsy, have consistently shown ranitidine 150mg twice daily to be superior to placebo in improving the endoscopic appearance of oesophagitis.Preliminary studies in the Zollinger-Ellison syndrome in patients intolerant of cimetidine, have shown ranitidine at doses of up to 900mg daily, to control symptoms over prolonged periods and to heal the ulcers, without causing troublesome side effects.Initial studies of ranitidine in the treatment and prevention of acute upper gastrointestinal bleeding in acutely ill patients, have been too small to permit any clear conclusions regarding the possible beneficial effects of the drug, although results from some studies have been encouraging in patients with duodenal ulcer.Side EffectsIn short term controlled and open studies in the treatment of peptic ulceration, and in patients treated for longer periods, ranitidine 100 to 150mg twice daily has been well tolerated with side effects such as skin rash, headache and dizziness having been reported in a total of 3% of patients. In individual case reports, ranitidine has been substituted for cimetidine in patients intolerant of this drug, without causing a recurrence of gynaecomastia and sexual impotence.DosageThe usual oral adult dose of ranitidine is 150mg twice daily in the treatment of duodenal or benign gastric ulcer. Treatment should be continued until the ulcer has healed, or if endoscopic reassessment is not possible, for 4 to 8 weeks. In limited experience in treatment of the Zollinger-Ellison syndrome, the dosage of ranitidine has been 600 to 900mg daily in divided doses. Ranitidine 150mg at night is used as maintenance treatment to prevent ulcer recurrence.Dosage should be decreased in patients with impaired renal function.