1. H2-receptor antagonists
Domina Petric, MD
H2-receptor antagonists

2. Pharmacokinetics Cimetidine, ranitidine, famotidine and nizatidine.
All four agents are rapidly absorbed from the intestine.
Cimetidine, ranitidine and famotidine undergo first-pass hepatic metabolism resulting in a bioavailability of approximately 50%.
Nazitidine has little first-pass metabolism.

3. Pharmacokinetics The serum half-lives range from 1,1 to 4 hours.
Duration of action depends on the dose given to the patient.
H2 antagonists are cleared by a combination of hepatic metabolism, glomerular filtration and renal tubular secretion.
Dose reduction is required in patients with moderate to severe renal and hepatic insufficiency.
In the elderly, there is a decline of up to 50% in drug clearance as well as a significant reduction in volume of distribution.

4. Drug
Relative potency
Dose to achieve >50% acid inhibition for 10 hours
Usual dose for acute duodenal or gastric ulcer
Usual dose for GERD
Usual dose for prevention of stress related bleeding
Cimetidine 1 mg
800 mg HS or 400 mg bid
800 mg bid
50 mg/h continuous infusion
Ranitidine
4-10
150 mg
300 mg HS or 150 mg bid
150 mg bid
6,25 mg/h continuous infusion or
50 mg iv. every 6-8 h
Nizatidine
Not available
Famotidine
20-50
20 mg
40 mg HS or 20 mg bid
20 mg bid
20 mg iv. every 12 h

5. Pharmacodynamics
These drugs exhibit competitive inhibition at the parietal cell H2 receptor and suppress basal and meal-stimulated acid secretion in a linear, dose-dependent manner.

6. Pharmacodynamics
They are highly selective and do not affect H1 or H3 receptors.
The volume of gastric secretion and the concentration of pepsin are also reduced.

7. Mechanisms of action
Histamine released from ECL cells by gastrin or vagal stimulation is blocked from binding to the parietal cell H2 receptor.
Direct stimulation of the parietal cell by gastrin or acetylcholine has a diminished effect on acid secretion in the presence of H2-receptor blockade.

8. Pharmacodynamics
When given in usual prescription doses all inhibit 60-70% of total 24-hour acid secretion.
H2 antagonists are very effective at inhibiting nocturnal acid secretion which depends largely on histamine.

9. Pharmacodynamics
H2 antagonists have a modest impact on meal-stimulated acid secretion which is stimulated by gastrin and acetylcholine, as well as histamine.

10. Pharmacodynamics
Nocturnal and fasting intragastric pH is raised to 4-5, but the impact on the daytime, meal-stimulated pH profile is less.
Recommended prescription doses maintain greater than 50% acid inhibition for 10 hours.

11. These drugs are given twice daily.
Pharmacodynamics
These drugs are given twice daily.

12. Clinical use

13. GERD (gastroesophageal reflux disease)
Patients with infrequent heartburn or dyspepsia (<3 times per week) may take either antacids or intermittent H2 antagonists.
Antacids provide faster symptom relief, but with short-lived effect (1-2 hours) in comparisson to H2 antagonists (6-10 hours).

14. GERD H2 antagonists may be taken prophylactically before meals.
Frequent heartburn is better treated with twice-daily H2 antagonists or proton pump inhibitors.
Proton pump inhibitors are preferred in patients with erosive esophagitis.

15. Peptic ulcer disease
Proton pump inhibitors are preffered in this indication.
Nocturnal acid suppression by H2 antagonists affords effective ulcer healing in most patients with uncomplicated gastric and duodenal ulcers.

16. Peptic ulcer disease
H2 antagonist, administered once daily at bedtime, results in ulcer healing rates of more than 80-90% after 6-8 weeks of therapy.

17. Peptic ulcer disease
In cases of patients that have to take NSAID, proton pump inhibitors are preferred, as well as in the case of Helicobacter pylori infection.
H2 antagonists may be given daily at bedtime in half of the usual ulcer therapeutic dose to prevent ulcer recurrence.

18. Nonulcer dyspepsia
H2 antagonists are commonly used as over-the-counter agents and prescription agents for treatment of intermittent dyspepsia not caused by peptic ulcer.

19. Prevention of bleeding from stress-related gastritis
Clinically important bleeding from upper gastrointestinal erosions or ulcers occurs in 1-5% of critically ill patients as a result of impaired mucosal defense mechanisms caused by poor perfusion.

20. Prevention of bleeding from stress-related gastritis
Agents that increase intragastric pH reduce the incidence of clinically significant bleeding.
For patients without a nasoenteric tube or with significant ileus, H2 antagonists in continuous infusion are preferred.

21. Adverse effects
Diarrhea, headache, fatigue, myalgias and constipation in <3% of the patients.
Iv. H2 antagonists may increase the risk of nosocomial pneumonia in critically ill patients, as well as mental status changes: confusion, hallucinations, agitation.

22. Adverse effects
Cimetidine inhibits binding of dihydrotestosterone to androgen receptors, inhibits metabolism of estradiol and increases serum prolactin levels.
In the case of long-term use or in high doses, it may cause gynecomastia or impotence in men and galactorrhea in women.

23. Adverse effects
H2 antagonists cross the placenta so they should not be administered to pregnant women, unless absolutely necessary.
These agents are also secreted into breast milk and may affect nursing infants.

24. Adverse effects H2 antagonists may rarely cause blood dyscrasias.
Blockade of cardiac H2 receptors may cause bradycardia and hypotension, especially if given in rapid iv. infusion.
Iv. injections should be given over 30 minutes.

25. Drug interactions
Cimetidine interferes with P450 drug metabolism pathways: CYP1A2, CYP2C9, CYP2D6 and CYP3A4.
The half-lives of drugs metabolized by these pathways may be prolonged.

26. Drug interactions
Ranitidine binds 4-10 times less avidly than cimetidine to cytochrome P450.
H2 antagonists compete with creatinine and certain drugs (procainamide) for renal tubular secretion.

27. Drug interactions
All of these agents, except famotidine, inhibit gastric first-pass metabolism of ethanol, especially in women.

28. Literature
Katzung, Masters, Trevor. Basic and clinical pharmacology.