Nizatidine

Summary

Synopsis

Nizatidine is an H₂-receptor antagonist which in animal studies was more active on a weight-for-weight basis than cimetidine in inhibiting basal and stimulated gastric acid secretion. Similarly, studies in humans have confirmed that nizatidine is a potent inhibitor of basal, nocturnal and stimulated gastric acid secretion.

As might be expected at this stage of its development, published therapeutic experience with nizatidine is limited. Nevertheless, multicentre therapeutic trials have shown that nizatidine 300mg at bedtime or 150mg twice daily is significantly more effective than placebo for healing active duodenal ulcer, and is apparently as effective as standard doses of ranitidine in increasing the rate of healing of both duodenal and gastric ulcers, and as effective as a standard dose of cimetidine in active duodenal ulcer. When used prophylactically a single 150mg dose of nizatidine at night produces a decrease in the incidence of ulcer recurrence compared with placebo, and a similar rate of decrease to that achieved with ranitidine 150mg. Nizatidine is well tolerated. Unlike cimetidine it does not have any antiandrogenic effects or alter the hepatic metabolism of drugs. However, only wider clinical experience with nizatidine can accurately determine its relative efficacy and tolerability compared with other antiulcer therapy.

Thus, early clinical experience suggests that nizatidine is a useful alternative to the histamine H₂-receptor antagonists presently in clinical use.

Pharmacodynamic Properties

Studies in animals have shown nizatidine to be a competitive inhibitor of histamine at H₂-receptor sites. In vitro and in vivo it is more active on a weight-for-weight basis than cimetidine in inhibiting basal gastric acid secretion and that induced by metacholine and tetragastrin.

In healthy subjects, single oral evening doses of nizatidine 30, 100 and 300mg inhibited nocturnal gastric acid secretion by 57, 73 and 90%, respectively. Nizatidine 150 or 300mg has been shown to be significantly more potent (p < 0.05) than cimetidine 300mg in inhibiting pentagastrin- and caffeine-stimulated acid secretion in healthy subjects, but less potent than ranitidine 150mg against pentagastrin-stimulated acid secretion. From initial evidence pepsin output appears to be little affected by repeated administration of nizatidine. Serum gastrin concentrations in healthy volunteers and duodenal ulcer patients are not significantly altered by oral nizatidine administration. Nizatidine does not appear to influence hormone function or fertility and, unlike cimetidine, it does not have any antiandrogenic effects in animals or man.

Studies to date indicate that nizatidine does not affect the hepatic metabolism of other drugs.

Pharmacokinetic Properties

After oral administration of nizatidine peak plasma concentrations are achieved within 1 to 3 hours. Peak plasma concentrations, which increase linearly with dose, display wide intersubject variation and are between 700 and 1400 µg/L after a single 150mg oral dose and between 1400 and 3600 µg/L after a 300mg oral dose. A mean plasma concentration of 154 to 180 µg/L was required for 50% inhibition of pentagastrin-stimulated gastric acid secretion in healthy volunteers. Bioavailability is high, and has been reported to be 98%.

The apparent volume of distribution of nizatidine is 1.2 to 1.6 L/kg but the tissue distribution of the drug has not been reported. However, there is evidence that nizatidine undergoes placental transport in humans. Protein binding (predominantly to α1-acid glycoprotein) is relatively low (32 to 35%).

Nizatidine is largely excreted unchanged in the urine by both glomerular filtration and tubular secretion. Following administration of a 150mg oral dose of ¹⁴C-labelled nizatidine, over 90% of the dose is recovered in urine and about 6% in the faeces within 3 days. Almost all of the radioactivity in the urine is recovered within 16 hours. Unchanged nizatidine accounted for over 60% of the dose recovered. Three metabolites have been identified in urine: N-2-monodesmethylnizatidine, nizatidine N-2-oxide, and nizatidine sulphoxide, representing approximately 7, 6 and 6% of the dose, respectively. N-2-monodesmethylnizatidine has been shown to exhibit H₂-blocking activity. The elimination half-life of oral and intravenously administered nizatidine is between 1.1 and 1.6 hours in healthy subjects, but increases in patients with renal dysfunction, with values of between 5.8 and 8.5 hours being observed in patients undergoing haemodialysis.

Nizatidine pharmacokinetics are unaffected by hepatic dysfunction. A slower elimination of nizatidine observed in some elderly patients is not due to advanced age per se but rather to an age-associated reduction in renal function.

Therapeutic Trials

In double-blind comparative trials nizatidine administered as a twice daily oral dose (25 or 150mg) or as a single bedtime dose (100 or 300mg) was significantly superior to placebo in increasing the rate of healing of duodenal ulcers. The endoscopically verified healing rates after therapy with nizatidine 100 or 300mg at bedtime or 150mg twice daily ranged from 77 to 82% after 8 weeks and from 54 to 76% at 4 weeks. A healing rate of 50% after 4 weeks’ treatment was achieved with nizatidine 25mg twice daily, compared with approximately 29% during the same period of treatment with placebo.

In well-controlled European multicentre trials involving almost 1,100 patients with acute duodenal ulcer, nizatidine 300mg was as effective as ranitidine 300mg, both given at night. Ulcers were healed in approximately 80 and 95% of patients at 4 and 8 weeks, respectively, with both drugs.

In a double-blind trial involving almost 400 patients with acute duodenal ulcer, nizatidine was as effective as cimetidine, both given at night. Ulcers were healed in 81% and 75% of patients, respectively, by 8 weeks.

Results from a long term (1 year) double-blind multicentre trial indicated that nizatidine 150mg given as a single dose at night is significantly superior (p < 0.001) to placebo in decreasing the endoscopically determined rate of recurrence of recently healed duodenal ulcer. Cumulative rates of ulcer recurrence at 3, 6 and 12 months, respectively, were 13, 24 and 34% for nizatidine compared with 40, 57 and 69% for placebo. Similarly, results from a 1-year multicentre study indicate that nizatidine 150mg is of similar efficacy to ranitidine 150mg at night in preventing ulcer recurrence in patients with recently healed duodenal ulcer (27.5% for nizatidine vs 22.3% for raniditine).

A double-blind multicentre comparative trial reported very similar healing rates for benign gastric ulcer following treatment with nizatidine administered either as 150mg twice daily or as a single 300mg dose and night, or ranitidine 150mg twice daily. After 8 weeks’ therapy ulcer healing rates of 90, 86.5 and 86.7% were recorded with nizatidine 150mg twice daily, nizatidine 300mg at night, and ranitidine 150mg twice daily, respectively.

Results from a 12-week double-blind trial indicated that nizatidine 150mg twice daily was more effective than nizatidine 300mg at bedtime or placebo in reducing the severity of oesophagitis in patients with gastro-oesophageal reflux disease.

Side Effects

The safety of nizatidine as treatment for active duodenal or gastric ulcer disease, or as maintenance therapy, has been assessed in almost 5,000 patients treated with the drug in placebo-controlled trials conducted in the USA and Europe, for periods ranging from 8 weeks to 1 year. Nizatidine was well tolerated and early discontinuations occurred more frequently in placebo-treated patients than in those administered nizatidine. Urticaria, somnolence and sweating occurred more frequently in nizatidine-treated patients. Other reported side effects included headache, asthenia, chest pain, pharyngitis, cough, pruritus and diarrhoea. No clinically relevant changes in laboratory test results were observed.

Dosage and Administration

The recommended oral dose of nizatidine for chronic active duodenal or gastric ulcer is 300mg at bedtime for 4 to 8 weeks. An alternative dosing regimen is 150mg twice daily. Duration of treatment may be shortened if endoscopy reveals the ulcer is healed. For the prevention of duodenal ulcer recurrence, maintenance therapy with 150mg at bedtime is recommended. Treatment may continue for up to 1 year.

Dosage adjustments according to the extent of renal impairment should be made in patients with renal disease.