Pirenzepine A Review of its Pharmacodynamic and Pharmacokinetic Properties and Therapeutic Efficacy in Peptic Ulcer Disease and Other Allied Diseases

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Abstract
Synopsis: Pirenzepine1 is a ‘selective’ tantimuscarinic agent which, unlike classic anticholinergic agents, inhibits gastric acid secretion at lower doses than are required to affect gastrointestinal motility, salivary, central nervous system, cardiovascular, ocular and urinary functions. On a weight basis, pirenzepine has one-tenth to one-eighth the potency of atropine in inhibiting stimulated gastric acid secretion in humans. Extensive controlled trials utilising endoscopy in outpatients with duodenal ulcers indicate that patient response to pirenzepine is dose related. Doses of 100 to 150 mg/day are superior to placebo in promoting duodenal ulcer healing and in diminishing day and night pain and supplementary antacid consumption. At such doses, the efficacy of pirenzepine appears to be superior to that of gefarnate 300 mg/day and generally not significantly different from that of Cimetidine 1 g/day in treating duodenal ulcers. A beneficial effect of pirenzepine in the prevention of duodenal ulcer recurrence was apparent in preliminary studies in small numbers of patients, but its efficacy in this regard needs further confirmation and the optimum dosage determined. Less extensive data on the treatment of benign gastric ulcers suggest that pirenzepine 100 to 150 mg/day is superior to placebo and gefarnate 300 mg/day and does not differ significantly from Cimetidine 1 g/day in promoting gastric ulcer healing. Pirenzepine is well tolerated by most patients, with a low incidence of typical antimuscarinic effects on the gastrointestinal tract, genitourinary system or heart being reported in clinical studies. However, dry mouth and blurred vision are the more common side effects with clinically effective doses. Thus, pirenzepine appears to have relatively selective antimuscarinic activity, although controlled studies comparing pirenzepine and conventional antimuscarinics in patients with peptic ulcer disease have not been reported. Pharmacodynamic Studies: Studies in animals have shown pirenzepine to be a competitive inhibitor of acetylcholine at muscarinic receptor sites, having one-hundredth to one-tenth the potency of atropine on a molar basis. Unlike classic anticholinergic agents, at low doses pirenzepine selectively blocks muscarinic receptors controlling gastric secretion, whereas higher doses are required to affect salivary, central nervous system, cardiovascular, ocular, urinary and gastrointestinal motility functions. In man, pirenzepine inhibits basal gastric acid secretion and that stimulated by pentagastrin, histamine and normal meals, having about one-tenth to one-eighth the potency of atropine (weight-for-weight) in healthy subjects and in patients with duodenal ulcer. In healthy subjects, single oral doses of pirenzepine 50 and 100mg reduced total acid output by 32% and 41%, respectively, whereas a 1-week regimen of 75 and 150mg daily reduced 24-hour acidity by 20% and 29%, respectively. In patients with duodenal ulcer, pirenzepine 25mg thrice daily administered orally reduced basal and pentagastrin-stimulated gastric acid output by 51% and 41%, respectively, over 4 weeks. Pirenzepine significantly decreased nocturnal acid output compared with placebo. Pirenzepine at one-twentieth to one-tenth the dose (weight-for-weight) of Cimetidine inhibited basal and pentagastrin-stimulated acid secretion to a similar or somewhat lesser degree, although pirenzepine appeared to have a longer duration of action. The addition of pirenzepine to Cimetidine or ranitidine inhibits gastric secretion to a much greater degree than the individual drugs alone in healthy subjects, and in patients with duodenal ulcers or Zollinger-Ellison syndrome. In healthy subjects and in patients with duodenal ulcer, usual doses of pirenzepine did not affect serum levels of gastrin, somatostatin, neurotensin, vasoactive intestinal peptide, secretin, gastric inhibitory polypeptide, trypsin, lipase, glucagon or insulin, or gastric mucus secretion, although enteroglucagon, pancreatic polypeptide, and basal motilin levels were significantly reduced. Parenteral doses reduced pepsin output and lower oesophageal sphincter pressure dose-dependently. Pirenzepine generally had no effect on the secretion of prolactin or of growth hormone. Pharmacokinetics: After oral administration, peak plasma concentrations were achieved within 2 to 3 hours. Single oral doses of pirenzepine 25 and 50mg produced peak plasma concentrations of 24 to 32 µg/L and 51 to 62 µg/L, respectively. The reported bioavailability after single doses was between 20 and 30%, although this may decrease to 10 to 20% when pirenzepine is taken with food. No significant ‘first-pass’ hepatic metabolism occurred. The apparent volume of distribution of pirenzepine in the central compartment (14L) is equivalent to the extracellular water space. In healthy subjects, the cerebrospinal fluid concentration of pirenzepine was one-tenth that in plasma sampled at the same time. Pirenzepine was 12% protein bound. Very little pirenzepine is metabolised, and the small amount of the desmethyl metabolite formed is pharmacologically inactive. Over a period of 96 hours after oral administration, 10% of pirenzepine was excreted unchanged in the urine, and 90% in the faeces. Because of its hydrophilicity, no tubular reabsorption occurs. Total plasma clearance was about 15 L/h, renal clearance is equivalent to the glomerular filtration rate, and hepatic clearance is about 7.5 L/h. The mean elimination half-life of pirenzepine is 11 hours in healthy subjects. A plasma concentration of 70 to 165 µg/L was required for optimum inhibition of meal-stimulated gastric acid. However, since dosages needed to produce such plasma concentrations also cause anticholinergic side effects, lower dosage regimens are used in clinical practice. Therapeutic Trials: Results from numerous double-blind, randomised, placebo-controlled studies in outpatients with endoscopically verified duodenal ulcers indicate that ulcer healing with pirenzepine is dose related. In general, pirenzepine 100 to 150 mg/day significantly improves healing rates compared with placebo, but smaller doses do not. Overall, duodenal ulcers usually healed in 32 to 57% of patients treated with placebo, in 45 to 75% of those taking less than 100 mg/day of pirenzepine and in 70 to 90% of patients taking pirenzepine 100 to 150 mg/day over a 4-week period. Day and night pain, and antacid consumption, were usually decreased in pirenzepine-treated patients compared with placebo controls. Duodenal ulcer healing with pirenzepine 100 to 150 mg/day did not usually differ significantly from that achieved with Cimetidine 1 g/day in numerous double- or single-blind outpatient studies, some of which were relatively large. However, in one double-blind study in 96 patients, ulcer healing following 6 weeks’ treatment with Cimetidine 1 g/day was superior to that with pirenzepine 100 mg/day. Most studies found that symptoms such as day and night pain, and antacid requirements, were reduced to a similar degree by the end of treatment with pirenzepine or Cimetidine, although some results indicated that remission of symptoms occurred faster with Cimetidine. Duodenal ulcer healing with pirenzepine 100 or 125 mg/day was superior to that achieved with gefarnate 300 mg/day (p < 0.01) in 2 relatively large double-blind studies. Small studies comparing long term prophylactic therapy with low doses of pirenzepine (30 to 50 mg/day) with placebo or Cimetidine 400 mg/day have not consistently demonstrated any statistically significant differences in duodenal ulcer recurrence rates. The superiority of pirenzepine 100 mg/day over placebo in one double-blind 12-month study requires confirmation in well-designed studies, as the patient groups differed in age. The efficacy of pirenzepine in treating benign gastric ulcers has been less extensively studied than that in duodenal ulcers. Pirenzepine 150 mg/day was superior to placebo in promoting ulcer healing and minimising ulcer symptoms in a small double-blind study. When compared with other drugs, ulcer healing with pirenzepine 100 to 150 mg/day did not differ significantly from that with Cimetidine 1 g/day in a large non-blinded study. Similarly, pirenzepine 50 to 75mg daily was not significantly different from carbenoxolone 200 to 300mg daily in several small double-blind studies in outpatients. However, pirenzepine 75 to 150 mg/day was superior to gefarnate 300 mg/day in large double-blind studies in hospitalised patients and outpatients. Controlled comparisons of pirenzepine and placebo or Cimetidine have also been conducted in patients with non-ulcerous dyspepsia, duodenitis and/or gastritis. Pirenzepine 100 mg/day was superior to placebo in improving the endoscopic appearance of the gastric or duodenal mucosa and in providing relief from dyspepsia in patients with non-ulcerous dyspepsia. The addition of pirenzepine to short or long term therapy with Cimetidine or ranitidine in a few patients with Zollinger-Ellison syndrome has yielded some favourable results. Side Effects: In short term controlled studies, pirenzepine was tolerated well by most patients and seldom discontinued (2%) because of adverse effects. Dry mouth (14%), blurred vision (2%), constipation (3%), diarrhoea (3%), headache (2%) and mental confusion (1.5%) were the most frequently reported side effects, upon questioning, following daily dosages of 100 to 150mg. The incidence of blurred vision appeared to be dose dependent (1% with 100 mg/day, 5.6% with 150 mg/day). The side effect profile of pirenzepine and Cimetidine differed in that central nervous system, allergic and endocrine reactions occurred less frequently with pirenzepine, but dry mouth and blurred vision seemed to be less frequent with cimetidine. Dosage: The usual adult dosage in the treatment of duodenal or benign gastric ulceration is 100mg daily in 2 divided doses at bedtime and in the morning before meals. Treatment should be continued until the ulcer has healed, or if endoscopic reassessment is not possible, for 4 to 8 weeks. Unlike classic anticholinergic drugs, pirenzepine is not contraindicated in glaucoma or prostatic hypertrophy.