Histamine Type-2 Receptor Antagonists (H2 Blockers) (2024)

OVERVIEW

The selective histamine type 2 receptor antagonists/blockers (H2 blockers) are widely used in the treatment of acid-peptic disease, including duodenal and gastric ulcers, gastroesophageal reflux disease and common heartburn. The four H2 blockers in current use are available by prescription as well as over-the-counter, and are some of the most widely used drugs in medicine. The H2 blockers are very well tolerated, but have been linked to rare instances of clinically apparent liver injury.

The H2 receptor blockers act by binding to histamine type 2 receptors on the basolateral (antiluminal) surface of gastric parietal cells, interfering with pathways of gastric acid production and secretion. The selectivity of H2 blockers is of key importance, as they have little or no effect on the histamine type 1 receptors, which are blocked by typical antihistamines that are used to treat allergic reactions and have little effect on gastric acid production. The selective H2 blockers are less potent in inhibiting acid production than the proton pump inhibitors (which block the common, final step in acid secretion) but, nevertheless, suppress 24 hour gastric acid secretion by about 70%. The effect of H2 blockers is largely on basal and nocturnal acid secretion, which is important in peptic ulcer healing. The selective H2 blockers were first developed in the early 1990s by Sir James Black, who subsequently received the Nobel Prize for his work developing selective receptor antagonists for clinical use (including the beta blockers as well as the H2 blockers). The initial H2 blocker approved for use in the United States was cimetidine (1977), which was followed by ranitidine (1983), famotidine (1986), and nizatidine (1988). All four of these agents are available by prescription and as over-the-counter oral formulations. Intravenous and intramuscular forms are available for cimetidine, ranitidine and famotidine.

The four H2 receptor blockers available in the United States have similar spectra of activity, side effects and clinical indications. These medications are extremely well tolerated and are used by a high proportion of the general population to treat peptic ulcer disease, heartburn, esophagitis, and miscellaneous minor upper gastrointestinal symptoms. Their listed indications are for treatment of gastric and duodenal ulcer and esophageal reflux disease, and to prevent stress ulcers. Side effects are uncommon, usually minor and include diarrhea, constipation, fatigue, drowsiness, headache and muscle aches. The H2 receptor blockers are metabolized in the liver by the cytochrome P450 system. Among the four agents, cimetidine is distinctive in its potent inhibition of the P450 system (CYP 1A2, 2C9 and 2D6), which can result in significant drug interactions. All four H2 receptor blockers have been implicated in rare cases of clinically apparent, acute liver injury. The most cases have been linked to ranitidine and cimetidine, but these two agents are also the most commonly used. The four H2 receptor blockers in clinical use are discussed separately, with references given after each.

Drug Class: Antiulcer Agents

  • Cimetidine

  • Famotidine

  • Nizatidine

  • Ranitidine

CHEMICAL FORMULAS AND STRUCTURES

DRUGCAS REGISTRY NUMBERMOLECULAR FORMULASTRUCTURE
Cimetidine51481-61-9C10-H16-N6-S
Famotidine76824-35-6C8-H15-N7-O2-S3
Nizatidine76963-41-2C12-H21-N5-O2-S2
Ranitidine66357-35-5C13-H22-N4-O3-S

ANNOTATED BIBLIOGRAPHY

References updated: 25 January 2018

  • Zimmerman HJ. H2 Receptors antagonists. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 719-20.

    (Expert review of hepatotoxicity published in 1999 states that cimetidine and ranitidine, despite enormous use, have been implicated in a small number of cases of hepatic injury, 39 for cimetidine, 35 for ranitidine, and 1 for famotidine, all cases recovering and signs of hypersensitivity being rare).

  • Wallace JL, Sharkey KA. Pharmacotherapy of gastric acidity, peptic ulcers, and gastroesophageal reflux disease. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 11093-22.

    (Textbook of pharmacology and therapeutics).

  • Freston JW. Cimetidine: II. Adverse reactions and patterns of use. Ann Intern Med. 1982;97:728–34. [PubMed: 6753681]

    (Review of side effects of cimetidine, which include diarrhea, nausea, rash and headache [<1% each]; hepatitis is rare but described, all cases being reversible).

  • Brogden RN, Carmine AA, Heel RC, Speight TM, Avery GS. Ranitidine: a review of its pharmacology and therapeutic use in peptic ulcer disease and other allied diseases. Drugs. 1982;24:267–303. [PubMed: 6128216]

    (Extensive review of pharmacology, clinical efficacy and side effects of ranitidine; side effects occur in 3-5% of patients, are largely mild and include rash, headache and dizziness, 1 case of anicteric hepatitis reported; no mention of ALT elevations).

  • Jean-Pastor MJ, Jouglard J. [Evaluation of drug-induced hepatic complications collected by the French drug surveillance organization] Therapie 1984; 39: 493-500. French. PMID 6506005. [PubMed: 6506005]

    (Among 980 cases of drug induced liver injury analyzed by the French drug surveillance system, 6 were attributed to cimetidine and considered "plausible").

  • Black M. Hepatotoxic and hepatoprotective potential of histamine (H2)-receptor antagonists. Am J Med. 1987;83:68–75. [PubMed: 2892410]

    (Review of hepatotoxicity of cimetidine and ranitidine and their potential role in ameliorating acetaminophen hepatotoxicity, perhaps via their inhibition of P450 activity).

  • Cloud ML. Safety of nizatidine in clinical trials conducted in the USA and Europe. Scand J Gastroenterol Suppl. 1987;136:29–36. [PubMed: 2892253]

    (Analysis of clinical trials of nizatidine in 3800 patients; no drug related deaths, most common side effects were headache, rhinitis, abdominal discomfort, diarrhea, and nausea, but none were more frequent than with placebo; ALT elevations >3 times ULN occurred in 1% of nizatidine- and 0.9% of placebo recipients; among 7 patients with marked liver test abnormalities, none were symptomatic and none were clearly related to nizatidine therapy).

  • Lewis JH. Hepatic effects of drugs used in the treatment of peptic ulcer disease. Am J Gastroenterol. 1987;82:987–1003. [PubMed: 2889354]

    (Thorough review of hepatotoxicity of antiulcer medications; 10 published cases of hepatotoxicity due to cimetidine and 12 for ranitidine, none fatal and not all convincingly due to the medication; little information available on famotidine or nizatidine).

  • Price AH, Brogden RN. Nizatidine. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic use in peptic ulcer disease. Drugs. 1988;36:521–39. [PubMed: 2905640]

    (Review of pharmacology, clinical efficacy and side effects of nizatidine based upon 3800 patients in therapeutic trials; discontinuation for side effects was more common with placebo [6.5%] than nizatidine [2.5%], and common adverse events occurred equally with placebo, except for urticaria [0.5%], somnolence [2.4%] and sweating [1%]; low rates of ALT elevations occurred and rates were similar in placebo and ranitidine treated patients; no mention of hepatitis).

  • García Rodríguez LA, Wallander MA, Stricker BH. The risk of acute liver injury associated with cimetidine and other acid-suppressing anti-ulcer drugs. Br J Clin Pharmacol. 1997;43:183–8. [PMC free article: PMC2042728] [PubMed: 9131951]

    (Case control study in cohort of 100,000 users of antiulcer drugs in a UK general practice database; 33 cases of acute liver injury found, 12 on cimetidine for a relative risk [RR] of 5.5, 1 on omeprazole and 5 on ranitidine did not raise RR above baseline. Latency was <2 month in 80% of cases; most antiulcer drug cases had hepatocellular or mixed enzyme patterns [15 of 18]).

  • Russo MW, Galanko JA, Shrestha R, Fried MW, Watkins P. Liver transplantation for acute liver failure from drug-induced liver injury in the United States. Liver Transpl. 2004;10:1018–23. [PubMed: 15390328]

    (Among ~50,000 liver transplants reported to UNOS between 1990 and 2002, 270 [0.5%] were done for drug induced acute liver failure, but none were attributed to an H2 blocker or proton pump inhibitor).

  • de Abajo FJ, Montero D, Madurga M, García Rodríguez LA. Acute and clinically relevant drug-induced liver injury: a population based case-control study. Br J Clin Pharmacol. 2004;58:71–80. [PMC free article: PMC1884531] [PubMed: 15206996]

    (Analysis of General Practice Research Database from UK on 1.6 million persons from 1994-2000 found 128 cases of drug induced liver injury [2.4/100,000 person years]; 3 cases were attributed to cimetidine for an odds ratio of 2.0 compared to controls [n=5000], which was not statistically significant).

  • Björnsson E, Jerlstad P, Bergqvist A, Olsson R. Fulminant drug-induced hepatic failure leading to death or liver transplantation in Sweden. Scand J Gastroenterol. 2005;40:1095–101. [PubMed: 16165719]

    (Survey of all cases of DILI with fatal outcome from Swedish Adverse Drug Reporting System from 1966-2002; 103 cases identified as highly probable, probable or possible, one case attributed to ranitidine and one to omeprazole).

  • Sabaté M, Ibáñez L, Pérez E, Vidal X, Buti M, Xiol X, Mas A, et al. Risk of acute liver injury associated with the use of drugs: a multicentre population survey. Aliment Pharmacol Ther. 2007;25:1401–9. [PubMed: 17539979]

    (Population based survey of 126 cases of acute liver injury due to drugs between 1993-1999 in Spain; 8 were attributed to ranitidine alone [incidence 5.1/100,000 person-years] and 5 to omeprazole alone [2.1/100,000]).

  • Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J., Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology. 2008;135:1924–34. [PMC free article: PMC3654244] [PubMed: 18955056]

    (Among 300 cases of drug induced liver disease in the US collected between 2004 and 2008, 2 were attributed to ranitidine, none to cimetidine or omeprazole).

  • Ferrajolo C, Capuano A, Verhamme KM, Schuemie M, Rossi F, Stricker BH, Sturkenboom MC. Drug-induced hepatic injury in children: a case/non-case study of suspected adverse drug reactions in VigiBase. Br J Clin Pharmacol. 2010;70:721–8. [PMC free article: PMC2997312] [PubMed: 21039766]

    (World wide pharmacovigilance database contained 9036 hepatic adverse drug reactions in children, no antiulcer medication was among the top 41 causes).

  • Reuben A, Koch DG, Lee WM., Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology. 2010;52:2065–76. [PMC free article: PMC3992250] [PubMed: 20949552]

    (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury, but none were linked to an antiulcer medication).

  • Lee TH, Vega KJ, El Khoury JG. Ranitidine induced hepatitis. J Gastrointestin Liver Dis. 2010;19:337–8. [PubMed: 20922203]

    (27 year old man developed jaundice while taking over-the-counter ranitidine for an undefined period [bilirubin 10.7 mg/dL, ALT 2544 U/L, Alk P 199 U/L], resolving within 2 months of stopping).

  • Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology. 2013;144:1419–25. [PubMed: 23419359]

    (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, but none were attributed to H2 blockers or other antiulcer medications).

  • Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A, Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America. An analysis of published reports. Ann Hepatol. 2014;13:231–9. [PubMed: 24552865]

    (Systematic review of literature of drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases, the most commonly implicated agents being nimesulide [n=53], cyproterone [n=18], nitrofurantoin [n=17] and antituberculosis drugs [n=13]; no case was linked to an antiulcer agent or H2 blocker).

  • Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al. United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology. 2015;148:1340–52. [PMC free article: PMC4446235] [PubMed: 25754159]

    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 6 cases were attributed to antiulcer medications, 3 to H2 blockers [all 3 to ranitidine] and 3 to proton pump inhibitors [PPIs], but none to cimetidine).

Histamine Type-2 Receptor Antagonists (H2 Blockers) (2024)

FAQs

What are histamine type 2 receptor antagonists H2 blockers? ›

Histamine H2-receptor antagonists, also known as H2-blockers, are used to treat duodenal ulcers and prevent their return. They are also used to treat gastric ulcers and for some conditions, such as Zollinger-Ellison disease, in which the stomach produces too much acid.

What do histamine 2 H2 antagonists block the release of in response to? ›

Histamine 2–Receptor Antagonists

Histamine 2 (H2)–receptor antagonists inhibit gastric acid secretion by means of competitive inhibition of H2 receptors of the gastric parietal cells. H2-receptor antagonists are generally well tolerated. Common adverse effects include nausea and headache.

Do H2 blocker drugs block the action of histamine on receptors? ›

The H2 receptor blockers act by binding to histamine type 2 receptors on the basolateral (antiluminal) surface of gastric parietal cells, interfering with pathways of gastric acid production and secretion.

What are over-the-counter histamine 2 H2 blockers? ›

H2 blockers are medications that suppress stomach acid production. They're a short-term treatment for stomach ulcers, duodenal ulcers and acid reflux. You can get them over the counter or by prescription. Brands include Tagamet®, Pepcid® and Axid®.

What is the safest H2 blocker to take? ›

Famotidine is typically less likely to cause drug-to-drug interactions than cimetidine. Famotidine is available by prescription and over-the-counter under different generic and brand names, such as Pepcid AC or Pepcid Oral, as well as intravenous and intramuscular forms.

Who should not take H2 blockers? ›

If you are breastfeeding or pregnant, talk to your provider before taking these medicines. If you have kidney problems, do not use famotidine without talking to your provider. Tell your provider about other medicines you are taking. H2 blockers may change the way certain drugs work.

How long can you take H2 blockers? ›

Do not take the maximum daily dosage continuously for more than 2 weeks, unless directed to do so by your doctor. If you have trouble in swallowing, or persistent abdominal pain, see your doctor promptly. These may be signs of a serious condition that may need different treatment.

What is the most potent H2 blocker? ›

Cimetidine is an imidazole derivative; ranitidine belongs to the basically substituted furans, famotidine is a member of the guanidinothiazole group; and roxatidine belongs to the aminoalkylphenoxy series. Famotidine is the most potent, selective H2-receptor antagonist yet available for ulcer therapy.

Is Tums an H2 blocker? ›

Antacids like TUMS relieve occasional heartburn by neutralizing the acid content in the stomach and esophagus — they are fast acting and can be taken as needed. H2 blockers relieve recurring heartburn by reducing the amount of acid in the stomach and can last up to 12 hours.

Are histamine H2 receptor antagonists better than PPI? ›

Both medications work by blocking and decreasing the production of stomach acid, but PPIs are considered stronger and faster in reducing stomach acids. However, H2 receptor blockers specifically decrease the acid released in the evening, which is a common contributor to peptic ulcers.

Which H2 blocker has the most drug interactions? ›

tidine is the H2-receptor antagonist that has been most often associated with clinically significant drug- drug interactions; however, studies show that ranitidine to a lesser ex- tent also presents problems.

How to clear histamine from body? ›

Exercise regularly: Regular physical activity can help reduce inflammation and lower histamine levels. Aim for at least 30 minutes of moderate-intensity exercise a day. Stay hydrated: Drinking enough water can help flush out histamine and other toxins from the body. Aim for at least 8 cups of water a day.

Which H2 blocker was taken off the market? ›

On April 1, 2020, the FDA requested that all forms of ranitidine (Zantac, generic versions), including prescription and over-the-counter products, be removed from the market.

Is Pepcid AC a histamine 2 blocker? ›

Original Strength PEPCID AC® and Maximum Strength PEPCID AC® contain an H2 blocker that begins to work in 15-30 minutes and helps control acid all day or all night. * PEPCID COMPLETE® combines an H2 blocker with an antacid that starts neutralizing acid in your stomach in seconds, so it works even faster.

Why take famotidine at night? ›

Why do people tend to take Pepcid at bedtime? Pepcid may reduce acid production for 12 or 24 hours, depending on which type you take. Many people tend to take Pepcid at bedtime to reduce waking up in the night from acid reflux and heartburn. Avoiding late or heavy meals can also help prevent symptoms.

What is an example of an H2 blocker? ›

There are four H2 blockers available by prescription: cimetidine (Tagamet) ranitidine (Zantac)** nizatidine (Axid)

Is Pepcid a histamine-2 receptor antagonist? ›

PEPCID® is the original brand with the active ingredient famotidine which is a histamine-2 blocker (H2 blocker) that provides relief for occasional heartburn.

What drugs are histamine H2 receptor agonists? ›

H2 inverse agonists such as cimetidine, famotidine, ranitidine, and tiotidine, which reduced basal levels of cAMP production, show a bias toward ERK pathway, i.e., though they reduce cAMP levels, treatment with these ligands leads to robust activation of ERK.

What do H2 blockers do in allergic reactions? ›

These agents block effects of released histamine at H2 receptors, thereby treating vasodilation, possibly some cardiac effects, and glandular hypersecretion. H2 blockers with H1 blockers have additive benefit over H1 blockers alone in treating anaphylaxis.

References

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