H2 Antagonists

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Chapter: Essential pharmacology : Drugs For Peptic Ulcer

These are the first class of highly effective drugs for acidpeptic disease. Four H2 antagonists cimetidine, ranitidine, famotidine and roxatidine are available in India; many others are marketed elsewhere.



These are the first class of highly effective drugs for acidpeptic disease. Four H2 antagonists cimetidine, ranitidine, famotidine and roxatidine are available in India; many others are marketed elsewhere. Their interaction with H2 receptors has been found to be competitive in case of cimetidine, ranitidine and roxatidine, but competitive-noncompetitive in case of famotidine. Cimetidine was the first H2 blocker to be introduced clinically and is described as the prototype, though other H2 blockers are more commonly used now.


Pharmacological Actions


1. H2 Blockade


Cimetidine and all other H2 antagonists block histamine-induced gastric secretion, cardiac stimulation (prominent in isolated preparations, especially in guinea pig), uterine relaxation (in rat) and bronchial relaxation (H2 blockers potentiate histamine induced bronchospasm). They attenuate fall in BP due to histamine, especially the late phase response seen with high doses. They are highly selective: have no effect on H1 mediated responses or on the action of other transmitters/autacoids.


2. Gastric Secretion


The only significant in vivo action of H2 blockers is marked inhibition of gastric secretion. All phases (basal, psychic, neurogenic, gastric) of secretion are suppressed dose-dependently, but the basal nocturnal secretion is suppressed more completely. Secretory responses to not only histamine but all other stimuli (ACh, gastrin, insulin, alcohol, food) are attenuated. This reflects the permissive role of histamine in amplifying responses to other secretagogues. The volume, pepsin content and intrinsic factor secretion are also reduced. However, normal vit B12 absorption is not interfered: no vit B12 deficiency occurs even after prolonged use.


The usual ulcer healing doses produce 60–70% inhibition of 24 hr acid output. The Hblockers have antiulcerogenic effect. Gastric ulceration due to stress and drugs (NSAIDs, cholinergic, histaminergic) is prevented. They do not have any direct effect on gastric or esophageal motility or on lower esophageal sphincter (LES) tone.




Cimetidine is adequately absorbed orally, though bioavailability is 60–80% due to first pass hepatic metabolism. Absorption is not interfered by presence of food in stomach. It crosses placenta and reaches milk, but penetration in brain is poor because of its hydrophilic nature. About 2/3 of a dose is excreted unchanged in urine and bile, the rest as oxidized metabolites. The elimination t½ is 2–3 hr. Dose reduction is needed in renal failure.


Adverse Effects


Cimetidine is well tolerated by most patients: adverse effects occur in < 5%. These are generally mild.


·     Headache, dizziness, bowel upset, dry mouth, rashes.

·  CNS effects like confusional state, restlessness, convulsions and coma have occurred infrequently in elderly patients, in those with renal impairment, especially with large doses infused i.v.

·  Bolus i.v. injection can release histamine—has caused bradycardia, arrhythmias and cardiac arrest: it should always be given by slow infusion.

· Cimetidine (but not other H2 blockers) has antiandrogenic action (displaces dihydrotestosterone from its cytoplasmic receptor), increases plasma prolactin and inhibits degradation of estradiol by liver. High doses given for long periods have produced gynaecomastia, loss of libido, impotence and temporary decrease in sperm count.

·    Transient elevation of plasma aminotransferases; but hepatotoxicity is rare.



Cimetidine inhibits several cytochrome P450 isoenzymes and reduces hepatic blood flow. It inhibits the metabolism of many drugs so that they can accumulate to toxic levels, e.g. theophylline, phenytoin, carbamazepine, phenobarbitone, sulfonylureas, metronidazole, warfarin, imipramine, lidocaine, nifedipine, quinidine. Metabolism of propranolol and diazepam is also retarded, but this may not be clinically significant.


Antacids reduce absorption of all H2 blockers. When used concurrently a gap of 2hr should be allowed. Ketoconazole absorption is decreased by cimetidine (probably by other H2 blockers also).


Dose: For ulcer healing—400 mg BD or 800 mg at bed time orally; maintenance—400 mg at bed time; for stress ulcer— 50 mg/hr i.v. infusion.


CIMETIDINE 200 mg, 400 mg, 800 mg tabs, 200 mg/2 ml inj., LOCK2 200 mg tab.




A nonimidazole (has a furan ring) H2 blocker, it has several desirable features compared to cimetidine:


a) About 5 times more potent than cimetidine. Though its pharmacokinetic profile and t½ of 2–3 hr is similar to cimetidine, a longer duration of action with greater 24 hr acid suppression is obtained clinically because of higher potency.


b) No antiandrogenic action, does not increase prolactin secretion or spare estradiol from hepatic metabolism—no effect on male sexual function or gynaecomastia.


c) Lesser permeability into the brain: lower propensity to cause CNS effects. In fact, little effect outside g.i.t. has been observed.


d) Does not significantly inhibit hepatic metabolism of other drugs; drug interactions mostly have no clinical relevance.


e)  Overall incidence of side effects is lower: headache, diarrhoea/constipation, dizziness have an incidence similar to placebo.


Dose: for ulcer healing 300 mg at bed time or 150 mg BD; for maintenance 150 mg at bed time. Parenteral dose— 50 mg i.m. or slow i.v. inj. every 6–8 hr (rapid i.v. injection can cause hypotension), 0.1–0.25 mg/kg/hr by i.v. infusion has been used for prophylaxis of stress ulcers.


For gastrinoma 300 mg 3–4 times a day.


ULTAC, ZINETAC 150 mg, 300 mg tabs; HISTAC, RANITIN, ACILOC, RANTAC 150 mg, 300 mg tabs, 50


mg/2 ml inj.




A thiazole ring containing H2 blocker which binds tightly to H2 receptors and exhibits longer duration of action despite an elimination t½ of 2.5–3.5 hr. Some inverse agonistic action on H2 receptors (in the absence of histamine) has been demonstrated. It is 5–8 times more potent than ranitidine and antiandrogenic action is absent. Because of low affinity for cytochrome P450 and the low dose, drug metabolism modifying propensity is minimal.


The oral bioavailability of famotidine is 40–50% and it is excreted by the kidney, 70% in the unchanged form. Incidence of adverse effects is low: only headache, dizziness, bowel upset, rarely disorientation and rash have been reported. Because of the higher potency and longer duration, it has been considered more suitable for ZE syndrome and for prevention of aspiration pneumonia.


Dose: 40 mg at bed time or 20 mg BD (for healing); 20 mg at bed time for maintenance; upto 480 mg/day in ZE syndrome; parenteral dose 20 mg i.v. 12 hourly.


FAMTAC, FAMONITE, TOPCID 20 mg, 40 mg tabs; FAMOCID, FACID 20, 40 mg tabs, 20 mg/2 ml inj.




The pharmacodynamic, pharmacokinetic and side effect profile of roxatidine is similar to that of ranitidine, but it is twice as potent and longer acting. It has no antiandrogenic or cytochrome P450 inhibitory action.


Dose: 150 mg at bed time or 75 mg BD; maintenance 75 mg at bed time.


ROTANE, ZORPEX 75 mg, 150 mg SR tabs.




The H2 blockers are used in conditions in which it is profitable to suppress gastric acid secretion. Used in appropriate doses, all available agents have similar efficacy. However, proton pump inhibitors (PPIs), because of higher efficacy and equally good tolerability, have outstripped H2 blockers.


Duodenal Ulcer


H2 blockers produce rapid and marked pain relief (within 2–3 days); 60–85% ulcers heal at 4 weeks and 70–95% ulcers at 8 weeks.


Suppression of nocturnal secretion by single high bed time dose is equally efficacious and physiologically more sound (continuous achlorhydria is considered undesirable). About ½ of the patients relapse within 1 year of healing with H2 blockers. Maintenance therapy with bedtime dose reduces the relapse rate to 15–20% per year. However, when such treatment is withdrawn relapses occur with the same frequency.


Gastric Ulcer


Healing rates obtained in gastric ulcer are somewhat lower (50–75% at 8 weeks). However, doses remain the same. Maintenance therapy reduces recurrences as long as continued. H2 blockers can heal NSAID associated ulcers, but are less effective than PPIs or misoprostol. H2 blockers (i.v. or oral) are commonly administered in bleeding peptic ulcer, but benefits are uncertain.


Stress Ulcers And Gastritis


Acutely stressful situations like hepatic coma, severe burns and trauma, prolonged surgery, prolonged intensive care, renal failure, asphyxia neonatorum, etc. are associated with gastric erosions and bleeding. Intravenous infusion of H2 blockers successfully prevents the gastric lesions and haemorrhage.


Zollinger-Ellison Syndrome


It is a gastric hypersecretory state due to a rare tumour secreting gastrin. H2 blockers in high doses control hyperacidity and symptoms in many patients, but relief is often incomplete and side effects frequent. PPIs are the drugs of choice. Definitive treatment is surgical.


Gastroesophageal Reflux Disease (GERD)


H2 blockers afford symptomatic relief and facilitate healing of esophageal erosions by reducing acidity of gastric contents that are refluxed; long-term treatment, preferably with 2–3 divided daily doses, is needed. However, they are less effective in this condition than PPIs; are indicated only in mild or stage1 cases of GERD.


Prophylaxis Of Aspiration Pneumonia


H2 blockers given preoperatively (preferably evening before also) reduce the risk of aspiration of acidic gastric contents during anaesthesia and surgery.


Other Uses


H2 blockers have adjuvant beneficial action in certain cases of urticaria who do not adequately respond to an H1 antagonist alone.


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