Histamine physiologic effects

Flavio Guzmán, MD — Thu, 20 Aug 2009 02:18:09 +0000

This post is part of a series on the pharmacology of histamine. The main histamine physiologic effects on H1 and H2 receptors will be discussed here as an introduction to antihistamines drug therapy and its clinical uses.

Histamine physiology: actions on tissues

Histamine is an autacoid (molecule secreted locally to increase or decrease the activity of nearby cells) synthesized from the amino acid histidine. Histamine actions are mediated by the activation of four receptor subtypes: H1, H2, H3 and H4, all of them G protein-coupled receptors. Currently only H1 and H2 receptors have clinical interest, but research on H3 and H4 receptors is being conducted.

The following figure summarizes histamine actions on different tissues such as bronchial smooth muscle, intestinal smooth muscle, bowel peristalsis and gastric mucosa.

Source: Lullman, H. Color Atlas of Pharmacology. Thieme, 2005.

Bronchial smooth muscle

Histamine causes contraction of bronchial smooth muscle, thus narrowing the airways. Asthmatic patients may be up to 1,000 times more sensitive to histamine mediated bronchoconstriction than individuals not affect by the disease.

Intestinal smooth muscle

Histamine activation of H1 receptors produces constrictiction of intestinal smooth muscle, which results in increased bowel peristalsis and diarrhea.

Peripheral nervous endings

Histamine stimulates sensory nerve endings, especially those mediating pain and itching. This effect, mediated by H1 receptors, is responsible for pain and itch after an injury such as insect bite.

Cardiovascular system

Histamine enhances Ca2+ influx into cardiac myocytes, this leads to minor increases in heart inotropism (force of contraction) and in chronotropism (rate of contraction).

Exocrine secretion

Histamine increases production of nasal and bronchial mucus, resulting in respiratory symptoms.

Edema and inflammation

Histamine acts especially on H1 receptors in the poscapillary vessels. The activation of H1 receptors produces contraction that leads to separation of endothelial cells, which allows the transudation of fluid and plasma proteins into the perivascular tissue. The clinical correlates of this phenomenon are urticaria and edema. This makes histamine a key mediator in the inflammatory response.

Gastric secretion

Through activation of H2 receptors, histamine potentiates gastrin-induced acid secretion. H2 receptor activation enhances the production of second messenger adenosine monophosphate (cAMP) by adenyl cyclase. As you can see in the figure, the other molecules involved in gastric hydrochloric acid secretion are gastrin and acethylcholine. H2 blockers, such as ranitidine, are drugs commonly used in the treatment of ulcers and heartburn.

References

Golan, David E (editor). “Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy”, 2nd edition. LWW: 2008.

Harvey, Richard; Champe, Pamela (series editors). “Lippincott illustrated reviews: Pharmacology”, 4th edition. LWW: 2009.

Lullmann, Heinz; Mohr Klaus. “Color Atlas of Pharmacology”, 2nd edition. Thieme: 1999.

Katzung, B. “Basic & Clinical Pharmacology”, 10th Edition. Mc Graw Hill Medical: 2007

EMEA public statement on the market withdrawal of Daclizumab (Zenapax)

Flavio Guzmán, MD — Sat, 24 Jan 2009 18:17:59 +0000

Daclizumab (Zenapax), a monoclonal antibody to the alpha subunit of the IL-2 receptor of T cells, has been withdrawn from the market in the European Union since Since 1 January 2009. According to an EMEA press release issued 16 January 2009:

On 26 February 1999, the European Commission granted a marketing authorisation valid throughout the European Union (EU) for the medicinal product Zenapax (daclizumab), indicated for the prophylaxis of acute organ rejection in de novo allogeneic renal transplantation and used concomitantly with an immunosuppressive regimen, including cyclosporine and corticosteroids in patients who are not highly immunised.

On 27 November 2006, the marketing authorisation holder (MAH) responsible for Zenapax, Roche Registration Limited, notified the European Commission of its decision to voluntarily withdraw the marketing authorisation for Zenapax for commercial reasons. The MAH confirmed that this decision is not related to any safety concerns with Zenapax.

On 10 June 2008, the European Commission issued a decision to withdraw the marketing authorisation for Zenapax, with effect from 1 January 2009. Pursuant to this decision, the European public assessment report (EPAR) for Zenapax will be updated to reflect that the marketing authorisation is no longer valid.

Source: Public statement on Zenapax (daclizumab) Withdrawal of the marketing authorisation in the European Union. PDF full text

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