Histamine H-2 receptor blockers act by stopping the pathway that leads to the secretion of stomach acid. There are two kinds of pathways that react to stimulation by histamine. Histamine is produced in the body and released by mast cells in response to some types of injury or to the presence of an antigen. When histamine reaches the H-1 receptors, the reaction results in dilation of capillaries, leading to redness and swelling, along with itching. These reactions can be controlled with traditional antihistamines.
Histamine that reaches the H-2 receptors causes increased secretion of stomach acid.
H2 receptor blockers are used to treat conditions associated with excess amounts of stomach acid, although in some cases they have been replaced by the proton pump inhibitors, which have a greater effect on reducing acid secretions.
H2 receptor blockers are used to treat the following conditions:
- duodenal ulcer, as short term therapy and maintenance
- gastric ulcer, as short term therapy and maintenance
- gastroesophageal reflux disease (GERD), including endoscopically diagnosed erosive esophagitis
- pathological hypersecretory conditions such as Zollinger-Ellison syndrome, systemic mastocytosis, and multiple endocrine adenomas
- upper GI bleeding
- heartburn, acid indigestion, and sour stomach
None of the drugs in this class has been approved for use by children under the age of 12 years. However, standard pediatric texts have reported on use by infants and children.
There are four H2 receptor blockers on the market. Although they all work in the same manner and have similar effects, they are not all approved for the same uses.
Cimetidine (Tagamet) is available in both prescription and over-the-counter forms. The oldest of the group and the most studied, this drug is the least potent of the H2 receptor blockers, which means that higher dosages are required to provide comparable effects. There is no evidence that higher potency improves therapeutic results.
Cimetidine is the only drug in its class which is approved for prevention of upper gastro-intestinal bleeding. It has been reported on for a number of uses, with varying degrees of success. Cimetidine, like ranitidine, has shown some benefit in treatment of colorectal cancer. Although some claims have been made that cimetidine is useful in treatment of acetaminophen overdose, the evidence for this use is lacking, and cimetidine should not be used. Because cimetidine is a mild antiandrogen, it has been of some use in treatment of hirsutism (abnormal growth of hair on a woman's face and body).
The three other H2 receptor blockers, famotidine (Pepcid, Pepcid AC), nizatidine (Axid), and ranitidine (Zantac), are similar in their uses. All are approved for treatment of duodenal ulcer both acute treatment and maintenance therapy, gastro-esophageal reflux disease, including erosive esophagitis and gastric ulcer short term treatment, although in this group ranitidine alone is approved for maintenance treatment.
In their over-the-counter (non-prescription) forms, cimetidine and famotidine are approved for treatment of heartburn, acid indigestion, and sour stomach.
Drugs in this class are similar in other respects as well. Although study results vary, cimetidine will usually show its effects within one hour and last for about five hours after a single dose; famotidine and nizatidine also show effects within one hour but may act for up to 12 hours at maximum dosing. Ranitidine has a comparable onset of action and duration in adults but may be slower in the elderly. Onset and duration of action will vary with the individual, the dose of medication, and the presence or absence of food or antacids in the stomach.
When Facts and Comparisons, a widely used on-line drug information resource, compared the published reports on cure rates for duodenal ulcers, it found that after eight weeks of treatment, all drugs showed healing rates in the range of 82% to 95%. These results were based on comparing separate studies and did not represent comparative trials of the drugs against each other.
Cimetidine doses for patients over the age of 12 years, for oral administration.
- Short-term treatment of active duodenal ulcer: 800 mg at bedtime. Other dose regimens are sometimes used.
- Heartburn, acid indigestion, and sour stomach using the over-the-counter product: 100 to 200 mg with water when symptoms start. The dose may be repeated once in 24 hours.
- Prevention of heartburn, acid indigestion, and sour stomach using the over-the-counter product: 100 to 200 mg with water up to one hour before eating food or drinking beverages expected to cause symptoms. Dose should not exceed 400 mg in 24 hours.
- Treatment of hypersecretory conditions: 300 mg four times a day, with meals and at bedtime.
- Gastroesophageal reflux disease: 800 to 1600 mg a day, divided into smaller doses. Treatment usually lasts 12 weeks.
Famotidine doses for patients over the age of 12 years, for oral administration.
- Treatment of duodenal ulcers: 40 mg once a day at bedtime. If necessary, 20 milligrams two times a day may be used.
- Prevention of duodenal ulcers: 20 mg once a day at bedtime.
- Gastric ulcers: 40 mg once a day at bedtime.
- To treat heartburn, acid indigestion, and sour stomach using the over-the-counter product: 10 mg with water when symptoms start. The dose may be repeated once in 24 hours.
- Hypersecretory conditions: 20 mg every six hours.
- Gastroesophageal reflux disease: 20 mg two times a day, usually for up to six weeks.
Nizatidine doses for patients over the age of 12 years, for oral administration.
- Treatment of duodenal or gastric ulcers: 300 mg once a day at bedtime. Alternately, 150 mg two times a day.
- Prevention of duodenal ulcers: 150 mg once a day at bedtime.
- Prevention of heartburn, acid indigestion, and sour stomach: 75 mg taken thirty to sixty minutes before meals which may cause symptoms. The dose may be repeated once in 24 hours.
- Gastroesophageal reflux disease: 150 mg two times a day.
Ranitidine doses for patients over the age of 12 years, for oral administration.
- Duodenal ulcers, treatment: 150 mg two times a day. Alternately, 300 mg once a day at bedtime.
- Duodenal ulcers, prevention: 150 mg at bedtime.
- Gastric ulcers, treatment: 150 mg two times a day.
- Heartburn, acid indigestion, and sour stomach, treatment: 75 mg with water when symptoms start. The dose may be repeated once in 24 hours.
- Heartburn, acid indigestion, and sour stomach, prevention: 75 mg with water taken thirty to sixty minutes before meals or beverages which may cause symptoms. The dose may be repeated once in 24 hours.
- Hypersecretory conditions: 150 mg two times a day.
- Gastroesophageal reflux disease: 150 mg two times a day. The dose may be increased as needed.
Overall, the histamine H2 receptor blockers are a safe class of drugs. However, some patients may be particularly susceptible to adverse effects of these drugs. H2 receptor blockers are metabolized in the liver and excreted through the kidneys. Therefore, patients with kidney or liver problems may require reduced doses in order to maintain safe blood levels of the drugs.
Although the safety and effectiveness of H2 receptor blockers in patients over the age of 65 appears to be similar to that seen in younger patients, age-associated reductions in kidney function may lead to elevated blood levels.
Allergic reactions to these drugs are rare but have been reported.
The histamine H2 receptor blockers are Pregnancy category B. There are no adequate and well-controlled studies with these agents in pregnant women. Women should use them only when clearly needed and when the potential benefits outweigh the potential hazards to the fetus. Cimetidine is known to cross the placenta.
All drugs in this class are excreted into breast milk and should not be taken by nursing women. Decide whether to discontinue nursing, or discontinue the drug, taking into account the importance of the drug to the mother.
These drugs may mask the symptoms of stomach cancer.
Although side effects due to the H2 receptor blockers are relatively rare and usually mild, a large number of adverse effects have been reported, in part because of the high use of these drugs. For example, the most common single adverse effect of cimetidine has been a 4% incidence of breast enlargement among males taking the drug in high doses for hypersecretory conditions. Similarly, the incidence of headache among high-dose cimetidine patients was 3.5%. Among patients taking lower doses, the frequency of headache was 2.1% compared to 2.3% in a placebo control group. Decreased white blood cell count was reported in 1 in 1,000,000 patients.
The reported side effects from the H2 receptor blocks are:
- abdominal pain
- back, leg, or stomach pain
- bleeding or crusting sores on lips
- blistering, burning, redness, scaling, or tenderness of skin
- blisters on palms of hands and soles of feet
- changes in vision or blurred vision
- coughing or difficulty in swallowing
- dark-colored urine
- fast, pounding, or irregular heartbeat
- fever and/or chills
- flu-like symptoms
- general feeling of discomfort or illness
- inflammation of blood vessels
- joint pain
- light-colored stools
- mood or mental changes, including anxiety, agitation, confusion, hallucinations (seeing, hearing, or feeling things that are not there), mental depression, nervousness, or severe mental illness
- muscle cramps or aches
- nausea, vomiting, or loss of appetite
- peeling or sloughing of skin
- red or irritated eyes
- shortness of breath
- skin rash or itching
- slow heartbeat
- sore throat
- sores, ulcers, or white spots on lips, in mouth, or on genitals
- sudden difficult breathing
- swelling of face, lips, mouth, tongue, or eyelids
- swelling of hands or feet
- swollen or painful glands
- tightness in chest
- troubled breathing, unusually slow or irregular breathing
- unusual bleeding or bruising
- unusual tiredness or weakness
- yellow eyes or skin
Less frequently reported are
- decreased sexual ability (especially in patients with Zollinger-Ellison disease who have received high doses of cimetidine for at least 1 year)
- decrease in sexual desire
- difficult urination
- dryness of mouth or skin
- increased or decreased urination
- increased sweating
- loss of hair
- ringing or buzzing in ears
- runny nose
- swelling of breasts or breast soreness in females and males
- trouble in sleeping
Not all of these adverse effects have been reported with all of the H2 receptor blockers, and some of the adverse effects may not have been drug related. However, because of the high similarity between drugs in this class, any of the reported adverse effects may be considered a possible result of therapy.
Cimetidine and ranitidine are both metabolized in the liver using the cytochrome P450 oxidase enzyme system. Since the same enzymes metabolize many drugs, taking two or more drugs that affect the same group of enzymes may cause one of the drugs to be retained in the body longer than would have been expected. The following is a partial list of drugs which may interact with cimetidine, or to a lesser extent with ranitidine.
- benzodiazepines, including Valium, Librium and Xanax
- calcium channel blockers, including Adalat, Calan, Procadia, and others
- sulfonylureas (includes many of the drugs used to treat diabetes)
- theophyllines (used to treat asthma; Dyphylline, a member of this group, does not interact with cimetidine)
- triamterene (a diuretic drug rarely used alone but may be found in fixed combinations, including Dyazide and Maxzide)
- tricyclic antidepressants (a group that includes amitriptyline, imipramine, and others)
- valproic acid
Duodenal — Pertaining to the first part of the small intestine.
Gastric — Pertaining to the stomach.
Hirsutism — Abnormal growth of hair on a woman's face and body.
Histamine — A physiologically active compound found in plant and animal tissue and released from mast cells as part of an allergic reaction in humans. It stimulates gastric secretion and causes dilation of capillaries, constriction of bronchial smooth muscle, and decreased blood pressure.
Hypersecretory — Excessive secretions, over production of stomach acid.
Mast cell — A cell found in connective tissue that releases substances such as heparin and histamine in response to injury or inflammation of bodily tissues.
Peptic — Induced by or associated with the action of digestive secretions.
Ulcer — A slow-healing sore on the surface of a mucous membrane, especially the membrane lining the stomach or other part of the digestive tract.
Zollinger-Ellizon syndrome — Severe peptic ulceration from excessive stomach acid production stimulated by one or more tumors that produce a powerful acid secretion.
Additional drugs may also interact with the H2 receptor blockers, particularly those which might have a similar mechanism or action or adverse effects.
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Physicians' Desk Reference 2005. Montvale, NJ: Thomson Healthcare, 2004.
Robertson, Jason, et al. The Harriet Lane Handbook: A Manual for Pediatric House Officers. Orlando, FL: Mosby Inc., 2005.
Black, R. A., and D. A. Hill. "Over-the-counter medications in pregnancy." American Family Physician 67, no. 12 (June 15, 2003): 2517-24.
Chandramouli, J. "What is the most effective therapy for preventing NSAID-induced gastropathy?" Journal of Pain and Palliative Care Pharmacotherapy 16, no. 2 (2002): 23-36.
American College of Gastroenterology. PO Box 342260, Bethesda, MD 20827-2260. (301)263-9000. www.acg.gi.org.
American Gastroenterological Association. 4930 Del Ray Avenue, Bethesda, MD 20814. (301)654-2055. www.gastro.org.