Cimetidine

Abstract

Synopsis: Cimetidine¹ is a specific competitive histamine H₂-receptor antagonist which effectively inhibits gastric acid secretion and is advocated for the treatment of chronic peptic ulceration, haemorrhage from erosive gastritis, and the control of gastric hypersecretion and peptic ulceration in the Zollinger-Ellison syndrome. Placebo-controlled trials in outpatients have demonstrated its efficacy in promoting the healing of endoscopically diagnosed duodenal ulceration, during a period of 4 to 6 weeks, but its role in the treatment of gastric ulcer is less clear.* Preliminary evidence suggests that maintenance therapy with cimetidine reduces the rate of recurrence of duodenal ulcer, but further studies are required to clarify its role in this situation and in the treatment of oesophagitis and acute gastrointestinal haemorrhage. Cimetidine controls the peptic ulceration of Zollinger-Ellison syndrome in most patients when given continuously for up to 2 years. Side-effects have generally been trivial and have very seldom necessitated withdrawal of therapy except in the rare occurrence of gynaecomastia. The haematological abnormalities, particularly agranulocytosis, which lead to the withdrawal from clinical use of metiamide, have not been reported with cimetidine, except for 1 case of transient neutropenia. The safety of long-term cimetidine administration has yet to be determined. Animal Pharmacodynamics: In vitro, and in intact animals, oral or intravenous cimetidine acts as a competitive inhibitor of histamine at H₂-receptor sites. Administered orally or intravenously cimetidine inhibits basal (non-stimulated) acid secretion and that stimulated by histamine or pentagastrin, but is generally much less effective in inhibiting carbachol (carbamylcholine chloride)-stimulated acid secretion. Cimetidine has a lesser effect on the secretion of pepsin than on acid secretion. Controlled experimental studies have shown that pre-treatment with cimetidine protects rats against gastric ulceration caused by stress, pyloric ligation and treatment with aspirin, or indomethacin, and duodenal ulcers induced by carbachol-histamine. Cimetidine also protected guinea-pigs against histamine-induced ulceration. Cimetidine does not prevent gastric ulcers produced by serotonin or reserpine in rats. Oral cimetidine given for 10 or 12 consecutive days accelerated the spontaneous healing of gastric and duodenal ulcers produced by acetic acid in rats. Cimetidine possesses a weak anti-androgenic effect, and in toxicological studies reduced the rate of growth of the prostate and seminal vesicles. Human Pharmacodynamics: In healthy volunteers as well as in patients with duodenal ulcer, oral or intravenous cimetidine significantly reduces gastric acid secretion stimulated by solid, liquid or peptone meals as well as that stimulated by sham feeding or fundic distention, and by pentagastrin, histamine, caffeine or insulin infusion. The extent of inhibition is dose-related and a 50% reduction in gastric acid secretion is obtained by doses of cimetidine giving a blood concentration of 1 to 2μmol/L (0.25 to 0.5μg/ml). Cimetidine reduces both hydrogen ion concentration and volume of gastric secretion. Addition of an anticholinergic to cimetidine at dosages of greater than 400mg does not significantly enhance inhibition of acid output. Oral cimetidine 300mg is more effective in inhibiting meal-stimulated acid secretion than an optimal dose of propantheline bromide. A single 300 or 400mg dose maintains reduced acid secretion throughout the night. It appears that cimetidine does not significantly increase gastrin release in most patients studied. However, there was a marked increase in serum gastrin levels in patients whose basal antral pH was above 6 after 3 months of treatment with cimetidine 1.6g daily. Serum gastrin was lowered when acid secretion returned to normal. Further study of these patients after 1 year’s treatment with cimetidine showed significantly increased integrated gastrin response to an OXO test meal compared with pre-treatment and 3-month values, but fasting gastrin concentrations were not significantly altered. However, the three-fold increase in serum gastrin response in these patients did not result in a rebound of acid secretion on discontinuation of cimetidine. Studies which provide sequential results in individual patients during long-term cimetidine are needed to determine the likelihood of parietal cell hyperplasia consequent to increased serum gastrin concentration. Further studies are needed to define more clearly the effect of prolonged cimetidine treatment on the parietal cell, but present evidence suggests that acid output is not significantly altered after cimetidine withdrawal. Pepsin output is decreased by cimetidine, largely due to reduced volume, but to a lesser extent than acid output in the same patients. Pancreatic secretion of bicarbonate and enzymes is not influenced by cimetidine. Studies in healthy volunteers have demonstrated that cimetidine does not consistently alter gastric emptying or lower oesophageal sphincter pressure. Pharmacokinetics: Cimetidine is readily absorbed after oral administration and bioavailability is about 70%. In fasted subjects peak blood levels are attained 60 to 90 minutes after ingestion and are dose-related in doses of up to 400mg. Peak blood levels are delayed and lower when cimetidine is given with food, but the percentage inhibition of gastric acid secretion is similar whether the drug is given before, with or after food. Most of a dose of cimetidine is recovered in the urine within 24 hours, about half as unchanged drug, although there is a tendency for a higher proportion of a dose of less than 200mg to be recovered unchanged. Excretion is reduced and the half-life prolonged in patients with renal failure, but blood levels are readily lowered by haemodialysis. Therapeutic Trials: Placebo-controlled therapeutic trials in outpatients have demonstrated the efficacy of cimetidine 0.8 to 2g daily in increasing the proportion of duodenal ulcers healed during a period of 4 to 6 weeks. Endoscopic evidence of duodenal ulcer healing has been reported in 67 to 93% of patients treated with cimetidine and in about 25 to 40% given placebo. The relative efficacy of cimetidine and other agents used to accelerate healing of duodenal ulcer has yet to be demonstrated in comparative studies. Preliminary evidence suggests that maintenance treatment* with cimetidine 400 to 800mg daily lowers the recurrence rate of duodenal ulcer, but its role in this regard has yet to be clarified. Studies of cimetidine in gastric ulcer* have given varying results. Whereas some studies have shown cimetidine to completely heal gastric ulcer more frequently than placebo, others could find no difference. Further suitably designed studies in adequate numbers of patients are in progress and may clarify the role of cimetidine in gastric ulcer relative to that of other agents in use. Cimetidine has yet to be shown to be of value in oesophagitis, but appears to be useful in many patients for the control of gastric hypersecretion and peptic ulceration in the Zollinger-Ellison syndrome. The optimum dosage, long-term safety and best method of use of cimetidine in this latter disease has still to be determined, but the drug certainly has a role in the elderly, in those in whom the risk of surgery is high, and in preparation for surgery. Some workers advocate long-term maintenance with cimetidine as the treatment of choice in the Zollinger-Ellison syndrome, because of the appreciable mortality of total gastrectomy, especially in patients who have had previous surgery, and because of the frequent inoperability for technical reasons, or because of the presence of secondary deposits of the primary tumour. Cimetidine has been successfully used to prevent acute gastrointestinal haemorrhage in patients with fulminant hepatic, failure, and to treat acute gastrointestinal haemorrhage associated with gastritis and gastric and/or oesophageal erosions.* However, its role in gastrointestinal haemorrhage from chronic gastric or duodenal ulcer or from oesophageal varices has not yet been clarified* and H₂-receptor blockade should not at present be allowed to modify the established principles of clinical management of upper gastrointestinal haemorrhage. Side-Effects: Although minor side-effects occur in about a quarter of patients treated with cimetidine, they have also been reported in a similar proportion of patients given placebo. The most frequently reported side-effects are headache, tiredness, diarrhoea, muscular pain, skin rash and dizziness. Withdrawal of treatment because of side-effects has been necessary in only 1.4% of patients and in only some of these instances was there a likely association between cimetidine and the side-effects. Withdrawal of treatment was necessary in 1.2% of patients receiving placebo. Long-term surveillance of a larger number of patients than have been studied to date will be necessary to determine its long-term effects and the symptoms. Haematological abnormalities, such as were reported with metiamide, have not occurred with cimetidine with the exception of a case of transient neutropenia. Breast changes, including gynaecomastia, have been reported in a few male patients, mostly with Zollinger-Ellison syndrome receiving long-term therapy. A few instances of galactorrhoea in women, associated with elevated prolactin levels, have also been reported. Dosage: The dose size and daily dosage of cimetidine vary in some countries. In benign gastric* and duodenal ulceration the usual dosage in most countries is 200mg 3 times daily with meals and 400mg at bedtime. In the USA and Canada however, tablets of cimetidine contain 300mg and the corresponding dosage is 300mg 4 times daily, with meals and at bedtime. Treatment should be continued until ulcer healing occurs or if reassessment is not possible then for 4 to 6 weeks. In Zollinger-Ellison syndrome the dosage may be increased if necessary to 1.6 to 2g daily in most countries, or to 2.4g daily in the USA and Canada. By intravenous injection the usual dose is 200mg at intervals of 4 to 6 hours in most countries. In the USA and Canada, ampoules of cimetidine contain 300mg and the recommended intravenous dose is 300mg every 6 hours. Patients with moderate or severe renal impairment should receive an initial dose of 200mg (or 300mg in the USA and Canada) every 12 hours orally or by intravenous injection. Any increase in dosage in these patients is best achieved by increasing the frequency of 200mg (or 300mg) doses.