22. Histamine, antihistaminic drugs

Last updated on December 8, 2019 at 16:58


Histamine is a basic amine that is formed from histidine by histidine decarboxylase. Mast cells, basophils, histamininergic neurons and enterochromaffin cells produce it. Mast cells are especially abundant in the respiratory tract, GI tract and skin.

Mast cells have granules that contain histamine and other compounds. These granules are exocytosed (called degranulation) when the IgE molecules bound to the cell bind to an antigen. This is part of the hypersensitivity type I reaction.

Certain drugs force mast cells to granulate, like tubocurarine, suxamethonium, vancomycin and morphine. These drugs therefore cause itching as a side effect due to histamine release.

Enterochromaffin cells in the GI tract produce histamine in response to parasympathetic stimulation (acetylcholine) or gastrin. This causes the parietal cells to produce HCl.

Histamine is a neurotransmitter in the brain. It increases wakefulness, which is why blood brain barrier-crossing antihistamines may cause sedation.


Histamine binds to four receptors:

Receptor Response
Histamine 1 receptor (H1) Vasodilation

Smooth muscle contraction (except vascular)


Histamine 2 receptor (H2) Cardiac stimulation

HCl secretion

Histamine 3 receptor (H3) Not so important
Histamine 4 receptor (H4) Definitely not important

Triple response of Lewis:

If you give histamine intradermally will there be three responses, together called the “triple response of Lewis”: Erythema, wheal (elevated bump of intradermal oedema), flare (redness in surrounding area). The same response occurs if you get poisoned by stinging nettles.

You’re probably itching right now.

Histamine antagonists

H1 antagonists are divided into first generation and second generation.

First generation H1 antagonists


  • Promethazine
  • Cyclizine
  • Cinnarizine
  • Diphenhydramine


  • Antiemetic
  • Sedative
  • Motion sickness
  • Allergy
    • Anaphylactic shock

Mechanism of action:

These drugs block H1 receptors. The first generation H1 antagonists cross the blood brain barrier to a large degree. Blocking H1 receptors in the CNS causes sedation, but it also gives these drugs the ability to treat nausea and motion sickness, by acting on the vestibular system.


Most H1 antagonists, both first and second generation, are well absorbed orally and act for 3 – 6 hours. They are mainly metabolized in the liver and excreted with the urine.

Adverse effects:

  • Sedation

First generation H1 antagonists also block muscarinic receptors and therefore have anticholinergic side effects, like:

  • Dry mouth
  • Dry eyes
  • Dizziness
  • Urinary retention
Second generation H1 antagonists


  • Cetirizine
  • Loratadine
  • Fexofenadine


Allergy. Because these drugs don’t cause significant sedation they’re more commonly used against allergy than the first generation drugs.

Mechanism of action:

Second generation H1 antagonists don’t significantly cross the blood brain barrier and therefore mostly acts on H1 receptors in the periphery.


See the first generation H1 antagonists.

Adverse effects:

Second generation H1 antagonists can also cause anticholinergic side effects, but much less frequently than the first generation. They also cause less sedation than the first generation.

H2 antagonists


  • Ranitidine
  • Cimetidine
  • Famotidine


Used to decrease gastric HCl production in the case of heartburn, GERD or stomach ulcers, usually as a second-line treatment or in combination with proton pump inhibitors.

Mechanism of action:

These drugs block H2 receptors on parietal cells in the stomach, which inhibtis gastric HCl secretion.

Adverse effects:

Side effects of these drugs are rare. Long term treatment with cimetidine can cause gynecomastia and impotence, both of which subside after the treatment is stopped.

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21. Local anesthetics

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23. Pharmacology of eicosanoids. Drugs acting on smooth muscle

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