33. Histamine, antihistaminic drugs

Histamine

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

Receptors

Histamine binds to four receptors:

Receptor	Response
Histamine 1 receptor (H1)	Vasodilation Smooth muscle contraction (except vascular) Itching
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

The triple response of Lewis, the reaction of the skin when exposed to histamine

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.

First generation H1 antagonists

H1 antagonists are divided into first generation and second generation.

You might associate antihistamines with allergy treatment, but first generation antihistamines cross the blood-brain barrier to such a degree that their antihistaminic effects on the brain is what they’re rather used for.

Compounds

• Promethazine (Phenergan®)
• Cyclizine
• Hydroxyzine (Atarax®)
• Cinnarizine
• Diphenhydramine (Benadryl®)

Indications

These drugs are mostly used as antiemetics and as sedatives. They may be used for allergy if the allergy is severe, such as in case of anaphylactic shock.

• Nausea, vomiting
• Motion sickness
• Sedation
• Pruritus
• Severe 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, as well as reducing nausea and motion sickness by acting on the vestibular system.

Adverse effects

• Sedation and somnolence

Sedation is the most important side effect of first generation antihistamines, and it’s this side effects which makes them inferior to second generation antihistamines for allergy. In fact, diphenhydramine is so famous for it’s significant somnolent side effects that there are memes about it.

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

Compounds

• Cetirizine (Zyrtec®)
• Levocetirizine (active enantiomer of cetirizine)
• Loratadine
• Desloratadine (active metabolite of loratadine)
• Fexofenadine (Telfast®)

Indications

• Allergy (rhinitis, conjunctivitis, urticaria)

Because these drugs don’t cause significant sedation they’re the first line drugs for allergy.

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, preventing histamine released during hypersensitivity type I reactions from binding to histamine H1 receptors and causing allergic symptoms.

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

These compounds are also called "H2 blockers".

Compounds

• Famotidine (Pepcid®)
• Ranitidine
• Cimetidine

Indications

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. Their use for GERD is limited because tachyphylaxis develops after 2 weeks, which limits their long-term effects.

Mechanism of action

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

Pharmacokinetics

H2 blockers are prone to development of tachyphylaxis if used more than 2 weeks.

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.