Τόμος 8 (1990) – Τεύχος 2 – Άρθρο 4 – Επιθεώρηση Κλινικής Φαρμακολογίας και Φαρμακοκινητικής-Ελληνική Έκδοση – Volume 8 (1990) – Issue 2 – Article 4 – Epitheorese Klinikes Farmakologias και Farmakokinetikes-Greek Edition

8: 91-112 (1990)

PHARMAKON-Press: Epitheorese Klin. Farmakol. Farmakokinet.

8: 91-112 (1990)

The histamine Η₂-receptor antagonists (a) inhibit acid (basal and stimulated by food and various secretagogues) and pepsin gastric secretion (1-14), (b) stimulate gastric mucus synthesis (16), (c) leave unin­fluenced bicarbonate mucosal secretion (15) and gastric blood flow (17), (d) increase gastric mucosal proliferation (18), without any effect on cellular kinetics (19); (e) exert a mitogenic effect on fibroblasts (20), and (f) increase proliferating cells number in antral and fundic pits (21), circulating gastrin levels (22-24) and prostaglandins gastric and duodenal mucosal synthesis and content (25-28). Η₂-receptor antagonists are rapidly absorbed after oral administratiοn. Bioavailability varies from 40% with famotidine to 100% with nizatidine (table 1). Peak plasma concentrations are attained in about 1 to 2 hours after per os admini­stration of the drug and are increased in patients with renal and hepatic failure and in the elderly. The drugs are eliminated mainly by the kidneys and hepatic metabolism is respon­sible for the majority of nonrenal clearance (29-31). All drugs are effective in the healing of duodenal and gastric ulcers after 4-8 weeks of treatment, with healing rates from 59 to 86% for duodenal and from 69 το 90% for gastric ulcers (tables 2 and 3) (32-42). Ranitidine (150 mg/day at night) and cimetidine (400 mg/day at night) prevent duodenal ulcer relapses (37). Η₂-receptor antagonists have been shown to protect NSAID-induced gastric mucosal damage (43-50). Smoking appears to be a major factor in recurrence of duodenal ulcer; and in smo­kers giving up smoking may be more important in the prevention of ulcer recurrences than the administration of cimetidine (56-58). The most common unwanted reactions to Η₂-antagonists include diarrhoea and rashes (59-67). A few patients treated with high doses of cimetidine show antiandrogenic effects of gynecomastia, impotence and galactorrhea. Unwanted re­actions have necessitated withdrawal of Η₂-antagonists in less than 3% of patients. Other patients may encounter problems related to drug interactions as a result of the inhibition of mixed-function hepatic oxidative enzymes (cytochrome P₄₅₀ pathway) by cimetidine (mainly) and ranitidine (fewer significant effects) (60, 68). Naturally occurring prostaglandins (PGs) (fig. 1) are metabolites of arachidonic acid, synthesized in most cells and particularly abundant in the digestive tract. PGs almost certainly play an important role in maintaining the integrity of gastrointestinal mucosa (69-77). Synthetic PGs (Ε₁ and Ε₂ series) (fig. 2) inhibit acid and pepsin gastric secretion (78-86) (fig. 3), stimu­late secretion of mucus and bicarbonate (87­89) and enhance gastric mucosal blood flow (90-93). It has been proposed that PGEs preserve the mucosal proliferative zone cells . which are important in the recovery from mucosal injury (94-97), and some PGEs appear to inhibit gastrin release (93, 98) and improve antral gastritis (99, 100). Synthetic PGEs are used in acute gastroduodenal ulcer disease (tables 2 and 3); their efficacy is similar to cimetidine. Their usefulness in maintenance treatment is not demonstrated (101-103). PGEs prevent the occurrence of acute lesions caused by NSAIDs, alcohol, aspirin and stress (104-­110). Diarrhea is their main side effect, occurring in 10% of the patients, and is often transient (111-116): Misoprostol is contraindi­cated during pregnancy (115).

1. Galanopoulou, P., Giannakopoulos, P.: Histaminergic and other mechanisms involved in gastric acid secre­tion: Classical and newer H₂-receptor antagonists. Klin. Farmakol. Farmakokinet. El. Ekd. 7: 73 (1989)
2. Plessas, S.T., Plessas, Ch.T.: Editorial: Peptic ulcer and its drug treatment. Klin. Farmakol. Farmakokinet. El. Ekd. 7: 195 (1989)
3. Black, J.W., Leff, P., Shankley, N.P.: Further analysis of anomalous pkb values for histamine Η₂-receptor antagonists on the mouse isolated stomach assay. Br. J. Pharmacol. 86: 581 (1985)
4. Reeves, J.J., Stables, R.: The antisecretory profile of action of the Η₂-receptor antagonists famotidine, raniti­dine and L-643, 441 on the rat isolated gastric mucosa. Agents and Actions 20: 22 (1987)
5. Lin, Τ.M., Evans, D.C., Warrick, M.W., Pioch, R.P.: Actions of nizatidine, a selective histamine Η₂-receptor antagonist, on gastric secretion in dogs, rats and frogs. J.  Pharmacol. Exp. Ther. 239: 406 (1986)