Histamine antagonist

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A histamine antagonist or antihistamine binds to histamine receptors without activating a cell surface receptor, thus preventing histamine or histamine agonists from acting on the cell. There are multiple types of histamine receptors, so different histamine antagonists have different effects.

H1 receptors arewidely associated with allergic reactions, including on the skin and in the airways. Both H1 and H2 have been found in the airway of rhesus momkeys[1]

Histamine1 antagonists

In common usage, "antihistamine" refers to a H1 antagonist, which primarily is responsible for inflammation in the respiratory system, on the skin, and other conditions associated with "allergy". Diphenhydramine is a common example of the class; while available as a generic, it is known by the trade name Benadryl in the U.S., and Gravol in Canada.

The first drugs of the group, such as dimenhydrinate, were introduced as antiemetics for motion sickness. They were administered, on a large-scale basis, to the invasion force for the Battle of Normandy; it has been said that they saved the battle by preventing seasickness. [2] Dimenhydrinate has not been studied in allergy, but diphenhydramine is a common antiemetic in Canadian practice as well as used worldwide for allergy.

First-generation antihistamines

Introduced for motion sickness, and then found useful for allergy, the prototype for this class of drug is diphenhydramine.[3] In general, these drugs are considered sedating, although a given member of the class may or may not sedate a specific person.

Second-generation antihistamines

The distinguishing characteristic of this group is that they rarely are sedating. While the group considered quite safe, and the first member, terfenadine, was actively being considered being changed, in the U.S., from prescription to over-the-counter status, a cluster of a serious and fatal arrythmias, torsade de pointes was found. The effect sometimes only appeared after years of use, or when other drugs or foods such as large amounts of grapefruit, were ingested. Terfenadine was a prodrug for the actual H1 blocker, fexofenadine.

Fexofenadine itself, which is now available in pure form, is quite safe. Accumulations of terfenadine, however, could be toxic to the heart.

Histamine2 antagonists

For more information, see: Histamine H2 antagonist.

Drugs in this class, such as ranitidine or famotidine, are most often used in the treatment of gastric hyperacidity and ulcers. They complement the role of proton pump antagonists such as omeprazole. [4]

They do have a relaxing effect on smooth muscle, which makes them useful in bronchospasm and other respiratory emergencies.

All members of the group have shown central nervous system toxicity, although it is rare. [5] is the inhibition of acid secretion in the treatment of gastrointestinal ulcers. Smooth muscle may also be affected. Some drugs in this class have strong effects in the central nervous system, but these actions are not well understood.

Histamine3 antagonists

H3 are inhibitory autoreceptors on histamine-containing nerve terminals and have since been shown to regulate the release of several neurotransmitters in the central and peripheral nervous systems. While they are still in the preclinical stage, possible applications include treatment of obesity, attention deficit disorder with hyperactivity, dementias, schizophrenia, and sleep disorders.[6]


  1. Greenberger P, Harris K, Patterson R., "The effect of histamine-1 and histamine-2 antagonists on airway responses to histamine in the rhesus monkey.", J Allergy Clin Immunol. 1979 Sep;64(3):189-96
  2. "Dramamine Oral", Medscape Drug Reference
  3. "Diphenhydramine HCl Oral", Medscape Drug Reference
  4. "Famotidine Oral", Medscape Drug Reference
  5. Cantú TG, Korek JS (1991 Jun 15), "Central nervous system reactions to histamine-2 receptor blockers", Ann Intern Med. 114(12): 1027-34
  6. Esbenshade TA, Fox GB, Cowart MD. (2006 Apr), "Histamine H3 receptor antagonists: preclinical promise for treating obesity and cognitive disorders.", Mol Interv. (2): 77-88, 59.