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Histamine H2 Receptor Antagonists

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Histamine H2 Receptor Antagonists

References

 

        Secretion of acid by the stomach depends on the binding of gastric acetylcholine and histamine to their respective receptor on the parietal cell surface. Blocking either of these leads to a reduction in acid secretion. H1 receptors are located on blood vessels, smooth muscle and in the skin. H2 receptor are located in the stomach and stimulation results in gastric acid secretion. Drugs which block H2 receptors were developed in several stages. The first member of this group to be made commercially available was cimetidine which was released in the UK in November 1976. Since then, it and the other available H2 receptor antagonist ranitidine, which was marketed in 1981, have become widely used. (2)

 Cimetidine

        Cimetidine is used in the short-term treatment of active, benign, gastric ulcer. In studies in patients with gastric ulcers receiving supplemental antacid cimetidine promoted healing of ulcers in up to 70% of patients after 4 weeks and in 66-100% of patients after 6 weeks. In controlled studies, healing rate were consistently higher with cimetidine placebo, with ulcers healing is up to 55% of patients receiving placebo and supplemental antacids. The usefulness of cimetidine therapy for longer than 8 weeks in the treatment of active, benign gastric ulcer remains to be clearly determined. It should be kept in mind that symptomatic response does not preclude the presence of a gastric malignancy. There have been rare cases of transient healing of gastric ulcers despite subsequently documented malignancy.

        Current epidemiologic and clinical evidence supports a strong association between gastric infection with H. pylori and the pathogenesis of gastric ulcer and the ACG, NIH, and the most clinicians currently recommend that all patients with initial or recurrent gastric ulcer and documented H. pylori infection receive anti-infective therapy for treatment of the infection. The choice of a particular regimen should be based on the rapidly evolving data on optimal therapy including consideration of the patient's prior exposure to anti-infective agents the local prevalence of resistance, patient compliance and costs of therapy.

Dosage and Administration

        Cimetidine and cimetidine hydrochloride are administered orally. Cimetidine hydrochloride may also be given by IV or slow IV injection or by intermittent or continuous slow IV infusion, in hospitalized patients with pathologic hypersecretory conditions or intractable ulcer, or when oral therapy is not feasible. Antacids may be given as necessary for relief of pain in patients with ulcers but should not be administered simultaneously with oral cimetidine. Commercially available prefilled syringes of cimetidine hydrochloride are intended for IM injection or for preparation of IV admixtures. This is because the drug must be diluted prior to IV administration, the prefilled syringe must not be used for direct IV injection.

        Parental solutions of cimetidine hydrochloride injection may be given undiluted. Transient pain may occur at the site of IM injection.

        Dosage of cimetidine hydrochloride is expressed in terms of cimetidine. The usual adult IM or IV dosage of cimetidine is 300mg every 6-8 hours. If necessary, parenteral dosage may be increased by increasing the frequency of administration, but the manufacturer recommends that IM or intermittent IV dosage not exceed 2.4g daily. When feasible, IV dosage should be adjusted to maintain an intragastric pH of 5 or greater.

        When cimetidine is administered by continuous IV infusion in adults, the drug usually is infused at a rate of 37.5mg/hour, but the rate should be individualized according to patient requirements. For patients requite more rapid increases in GI pH, an initial 150mg IV loading dose may be required.

        For the treatment of active benign gastric ulcer, the usual adult oral dosage of cimetidine is 800mg at bedtime or 300mg 4 times daily with meals and at bedtime. Currently, the 800mg bedtime regimen is preferred for most patients with active benign gastric ulcer because of the decreased potential for drug interactions and maximal patient compliance. Therapy in controlled clinical trials was limited to 6 weeks, and efficacy for more than 8 weeks remains to be clearly determined. Patients with gastric ulcer should be monitored to ensure rapid progress to complete healing.

Ranitidine

        Ranitidine is used orally for short-term treatment of active, benign gastric ulcer. Antacids may be used concomitantly as needed for relief of pain. The efficacy of ranitidine in the treatment of gastric ulcer appears to be similar to that of cimetidine. Ranitidine promotes healing of ulcers in about 60-70% of patients after 4 weeks of treatment and about 70-80% of patients after 6 weeks in the treatment. The usefulness of ranitidine therapy for longer than 6 weeks in the treatment of active, benign gastric ulcer remains to be clearly determined. When ranitidine is used in the treatment of gastric ulcer, it should be kept in mind that symptomatic response does not preclude the presence of a gastric malignancy.

Dosage and Administration

        Ranitidine hydrochloride usually is administered orally. The drug also may be given by IM or slow IV injection or by intermittent or continuous slow IV infusion in hospitalized patients with pathologic hypersecretory condition or when oral therapy is not feasible. Because of the risk of including bradycardia, the recommended rates of IV administration should not be exceeded. Antacids may be administered concomitantly as necessary relief of pain.

        The 1g pharmacy bulk package of ranitidine hydrochloride is not intended for direct IV infusions, doses of the drug from the bulk package must be further diluted in a compatible IV solution prior to administration.

        Although USP currently  states that potency of ranitidine hydrochloride preparations should be expressed both in terms of the salt and the base, dosage currently is expressed in terms of the base.

        The usual adult IM or intermittent IV dosage of ranitidine is 50mg every 6-8 hours. If necessary, dosage may be increased by increasing the frequency of administration, but dosage should not exceed 400mg daily.

        When ranitidine is administered by continuous slow IV infusion, 150mg of ranitidine is infused at a rate of 6.25mg/hour over 24 hours. When the drug is administered by continuous slow IV infusion in adults with Zollinger-Ellison syndrome or other hypersecretory conditions, the infusion is usually started at a rate of 1mg/kg per hour. If after 4 hours the patient is still symptomatic or if the measured gastric acid secretion is greater than 10 mEq/hour, the dose should be titrated upward in increments of 0.5 mg/kg per hour, the gastric acid secretion should then be redetermined. Doses up to 2.5 mg/kg per hour and infusion rates as high as 220 mg/hour have been used.

        For treatment of active, benign gastric ulcer, the usual adult oral dosage of ranitidine is 150mg twice daily. For the treatment of active, benign gastric ulcer in children 1 month to 16 years of age, the usual oral dosage of ranitidine is 2-4 mg/kg twice daily up to a maximum daily dosage of 300mg. most patients demonstrate complete healing of gastric ulcers within 6 weeks, and the safety of ranitidine therapy for longer periods in the treatment of gastric ulcer have not been established.

        For maintenance therapy following healing of active, benign gastric ulcer to reduce ulcer recurrence, the usual adult oral dosage of ranitidine is 150mg daily at bedtime. For maintenance therapy following healing of active benign gastric ulcer in children 1 moth to 16 years of age, the usual oral dosage of ranitidine is 2-4 mg/kg once daily up to a maximum daily dosage of 150mg.(3)

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