Histamine H2-receptor antagonists.

In summary, histamine initiates acid secretion by stimulating the H2 subtype histamine receptor on parietal cells. Cimetidine, rantidine, famotidine, and nizantidine are histamine H2-receptor antagonists that block this action of histamine, reducing gastric acid output and concentration under both basal and stimulated conditions. These agents are used for treatment and prevention of peptic and stress ulcers as well as for hypersecretory states. Because of their effectiveness and low incidence of side effects, H2-antagonists have largely replaced more traditional antiulcer regimens.     

H2-receptor antagonists in perspective.

Cimetidine, like its predecessors burinamide and metiamide, has been shown in vitro to be a specific competitive histamine H2-receptor antagonist. In vivo, it is a potent inhibitor of histamine-stimulated gastric acid secretion in animals and man after both intravenous and oral administration. Doses sufficient to inhibit gastric secretions are without measureable effects on other physiologic systems. The main indication for cimetidine is in the treatment of duodenal ulcer and of the Zollinger-Ellison syndrome. Useful indications are treatment of gastric ulcer and pnacreatic insufficiency. Possible indications are prevention of gastrointestinal bleeding and treatment of peptic esophagitis. The neutrophil toxicity seen with metiamide has so far not been demonstrated with cimetidine; side effects with cimetidine have generally been trivial. In the future, H2-receptor antagonists are likely to become key therapeutic agents in diseases in which gastric acid-pepsin secretion plays a pathogenetic role.     

H2-receptor antagonists are scavengers of oxygen radicals

Abstract. Potential oxygen radical scavenging properties of the H₂-receptor antagonists cimetidine, ranitidine and famotidine were investigated. These drugs, although ineffective against superoxide anion and hydrogen peroxide, can scavenge hydroxyl radical (OH·) with a very high rate constant, which is about tenfold higher than that of the specific scavenger mannitol for famotidine (1·7 × 10¹⁰ mol^?1 s^?1) and cimetidine (1·6 × 10¹⁰ mol^?1 s^?1), ranitidine displaying a rate constant of 7·5 × 10⁹ mol^?1 s^?1. These OH· scavenging effects are significant beginning from 10, 28 and 100 μmol 1^?1 concentration for famotidine, cimetidine and ranitidine, respectively, thus suggesting that the drugs may effectively act as OH· scavengers in vivo especially in the gastric lumen. Only cimetidine can apparently bind and inactivate iron, which further emphasizes its antioxidant capacity. Moreover, all drugs, even at 10 μmol 1^?1 concentration, show powerful scavenging effects on hypochlorous acid and monochloramine, which are cytotoxic oxidants arising from inflammatory cells, such as neutrophils. These data suggest that some therapeutical effects of H₂-receptor antagonists in peptic ulcer may also be related to their antiradical-antioxidant capacity, and that these drugs could potentially be used in other disease entities characterized by free radical-mediated oxidative stress in vivo.     

Radiographic findings of intractable gastric ulcers with H2-receptor antagonists

Background: To clarify the radiographic characteristics of intractable gastric ulcers with H₂-receptor antagonists. Methods: The radiographic findings at the time of starting treatment were compared between 42 patients with gastric ulcers that did not heal within eight weeks of starting treatment with H₂-receptor antagonists (the intractable group) and 58 patients whose ulcers healed within the eight-week period (the tractable group). Results: The following radiographic findings in the intractable group were observed at a significantly higher incidence than those in the tractable group and included: an ulcer located on the angle, linear ulcers, a greater depth, an uneven mound surrounding an ulcer, prominent folds' convergence, an overhanging gastric mucosa, an irregular ulcer base, a shortening of the lesser curvature and a U-shaped deformity of the angle. A multiple logistic regression analysis showed that the following three factors had a significant and independent delaying effect on healing: a U-shaped deformity of the angle, an uneven mound surrounding an ulcer and prominent folds' convergence. The relative risk of these factors were 12.7, 14.4 and 12.5, respectively. Conclusions: Intractable gastric ulcer with H₂-receptor antagonists can be predicted based on the characteristic radiographic findings at the start of treatment. Received: 23 December 1994/Accepted: 25 January 1995     

Toxicity of H2-receptor antagonists to isolated rat hepatocytes: structure-activity relationships

Oxmetidine is a potent and specific antagonist of the histamine H2-receptor. Oxmetidine is also cytotoxic to isolated rat hepatocytes through inhibition of mitochondrial oxidative phosphorylation. The purpose of this investigation was to test a variety of H2-receptor antagonists that are structural analogs of oxmetidine in an attempt to identify a critical structural component or a physicochemical property of the molecule which may be responsible for cytotoxicity. Six histamine receptor H2-antagonists were tested. The minimum drug concentrations that caused 100% cell death (leakage of intracellular lactate dehydrogenase and loss of intracellular potassium) ranged from 0.87 to 22.50 mM for the analogs tested. At toxic concentrations, two of the least potent analogs, SK&F 92909 and SK&F 9205A both caused a rapid decrease in hepatocyte O2 consumption and ATP content which occurred before any evidence of cell injury. The potency of these molecules as cytotoxicants to isolated hepatocytes did not correlate with their potency as histamine H2-receptor antagonists whereas there was a significant correlation between increasing potency and increasing octanol/water partition coefficients. These data suggest that lipid solubility may be a key factor in the cytotoxicity of this class of drugs to isolated rat hepatocytes.     

Effect of histamine H2-receptor antagonists on vitamin B12 absorption.

OBJECTIVE: To discuss the potential of histamine H2-receptor antagonists (H2RAs) to cause malabsorption of vitamin B12 (cyanocobalamin). DATA SOURCES: Pertinent literature was identified via a MEDLINE search. Journals and references cited in published articles also were used as data sources. STUDY SELECTION: Studies evaluating the effect of H2RAs on vitamin B12 absorption were reviewed. DATA SYNTHESIS: H2RAs decrease acid secretion by the gastric parietal cells. Gastric acid and pepsin produced by these cells are required for the cleavage of vitamin B12 from dietary sources. Intrinsic factor (IF), also produced by gastric parietal cells, is required for vitamin B12 absorption from the gastrointestinal tract. Although H2RAs have not conclusively been shown to decrease IF secretion, studies have demonstrated a significant reduction in food-bound vitamin B12 absorption secondary to decreased acid secretion in patients taking these drugs. CONCLUSIONS: H2RAs have the potential to cause vitamin B12 deficiency. This may be important in patients with inadequate stores of vitamin B12 (e.g., poor diet), particularly those receiving H2RA therapy continuously for more than two years. Healthcare providers should be aware of this potential adverse effect.     

Effects of H2-receptor antagonists upon physiological acid secretory states in animals

The results reported in this paper indicate that representative H2-receptor antagonists are capable of maximally inhibiting gastric acid secretion in animals under the two general circumstances in which it occurs physiologically. Interdigestive or basal secretion was examined in chronic gastric fistula rats and food-stimulated secretion in vagally innervated, lesser curvature pouch dogs. The H2 antagonists studied and omeprazole, an inhibitor of the proton pump H+, K+-adenosine triphosphatase, also decreased pepsin secretion in rats, although not to the same maximal degree as acid secretion. Gastric emptying was increased by each H2 antagonist but only at high acid inhibitory doses. Omeprazole, in contrast, did not alter gastric emptying at a similar antisecretory dosage level. In dogs, a representative H2-receptor antagonist markedly inhibited food-stimulated acid secretion. These data suggest that the predominant effect of omeprazole and H2-receptor antagonists upon gastric function is to inhibit acid secretion and that H2-receptor antagonists may be capable of maximally inhibiting endogenous acid secretion in humans, as does omeprazole, if given under proper conditions.     

Proton-pump inhibitors versus H2-receptor antagonists in triple therapy for Helicobacter pylori eradication

Triple therapy with two antibiotics and acid-suppressing drugs is widely accepted for H. pylori eradication. Both H2-receptor antagonist and proton-pump inhibitor are reported to enhance the eradication rate when antibiotics are administered together. Comparative studies using H2-receptor antagonist or proton-pump inhibitor in triple therapy were reviewed. The efficacy of H. pylori eradication regimens with H2-receptor antagonist or proton-pump inhibitor with two antibiotics is not significantly different.     

Inhibition of sympathetic nervous system by histamine:studies with H1- and H2-receptor antagonists.

A study was designed to investigate the effect of histamine on sympathetic transmission to the myocardium in pentobarbital-anesthetized dogs. Intravenous infusion of histamine (1.0 and 2.0 microgram/kg/min) produced dose-related decreases in blood pressure and caused significant impairment of cardioacceleration observed during stimulation of the right postganglionic cardiac sympathetic nerve fibers. Positive chronotropic effects of intravenously administered norepinephrine as well as tyramine were not altered during histamine infusion. Blockade of neuronal reuptake with desipramine did not modify the inhibitory action of histamine on sympathetic nerve function. Prior administration of mepyramine (pyrilamine), a histamine type H1-receptor antagonist caused partial attenuation of the depressor action of histamine, but did not prevent histamine-induced inhibition of neurogenic function. Further treatment with metiamide, a histamine type H2-receptor antagonist caused nearly complete attenuation of the depressor response to histamine and also significantly antagonized the inhibitory action of histamine on sympathetic transmission to the myocardium. It is concluded that while the depressor action of histamine is due to the activation of both H1- as well as H2-receptors, histamine causes impairment of sympathetic nerve function to the myocardium by acting on H2-receptors which may be located on sympathetic nerve terminals.     

Proton pump inhibitors in the treatment of peptic ulcers resistant to H2-receptor antagonists]

The aim of this study is to evaluate the therapeutic effect of proton pump inhibitors on peptic ulcers resistant to H2-receptor antagonists. Patients with ulcers resistant to at least 3 months treatment with standard or greater doses of H2-receptor antagonists were treated with 20 mg of omeprazole or 30 mg of lansoprazole, once daily, for 2 to 8 weeks. Endoscopy was performed every 2 weeks to confirm ulcer healing. Eleven of 28 (39%) gastric ulcers healed within 4 weeks and 20 (71%) within 8 weeks with omeprazole. Eight of 19 (42%) gastric ulcers healed within 4 weeks and 14 (74%) within 8 weeks with lansoprazole. All of the duodenal ulcer healed within 6 weeks with omeprazole or lansoprazole. No adverse effects were observed in this study. These results suggest that proton pump inhibitors are highly effective in the treatment of peptic ulcer resistant to H2-receptor antagonists.