Antihistamines

An antihistamine is a drug which serves to reduce or eliminate effects mediated by histamine, an endogenous chemical mediator released during allergic reactions, through action at the histamine receptor. Only agents where the main therapeutic effect is mediated by negative modulation of histamine receptors are termed antihistamines – other agents may have antihistaminergic action but are not true antihistamines.

In common use, the term antihistamine refers only to H₁-receptor antagonists, also known as H₁-antihistamines. It has been discovered that these H₁-antihistamines are actually inverse agonists at the histamine H₁-receptor, rather than antagonists per se. (Leurs, Church & Taglialatela, 2002)

Pharmacology

In allergic reactions an allergen (a type of antigen) interacts with and cross-links surface IgE antibodies on mast cells and basophils. Once the mast cell-antibody-antigen complex is formed, a complex series of events occurs that eventually leads to cell-degranulation and the release of histamine (and other chemical mediators) from the mast cell or basophil. Once released, histamine can react with local or widespread tissues through histamine receptors.

Histamine, acting on H₁-receptors, produces pruritus, vasodilatation, hypotension, flushing, headache, tachycardia, bronchoconstriction, increases vascular permeability, potentiates pain, and more. (Simons, 2004)

While H₁-antihistamines ameliorate these effects, they are only efficacious if administered prior to the allergen-challenge. In severe allergies, such as anaphylaxis or angioedema, these effects may be so severe as to be life-threatening. Epinephrine, often in the form of an autoinjector (Epi-pen), is required by people with such hypersensitivities.

Clinical use of antihistamines

Indications

H₁-antihistamines are clinically used in the treatment of histamine-mediated allergic conditions. Specifically, these indications may include: (Rossi, 2004)

allergic rhinitis
allergic conjunctivitis
allergic dermatological conditions (contact dermatitis)
urticaria
angioedema
pruritus (atopic dermatitis, insect bites)
anaphylactic or anaphylactoid reactions – adjunct only
nausea and vomiting (first-generation H1-antihistamines)
sedation (first-generation H1-antihistamines)

Antihistamines can be administered topically (through the skin, nose, or eyes) or systemically, based on the nature of the allergic condition.

Adverse drug reactions

Adverse drug reactions are most commonly associated with the first-generation H₁-antihistamines. This is due to their relative lack of selectivity for the H₁-receptor.

The most common adverse effect is sedation; this “side effect” is utilised in many OTC sleeping-aid preparations. Other common adverse effects in first-generation H1-antihistamines include: dizziness, tinnitus, blurred vision, euphoria, uncoordination, anxiety, insomnia, tremor, nausea and vomiting, constipation, diarrhoea, dry mouth, and dry cough. Infrequent adverse effects include: urinary retention, palpitations, hypotension, headache, hallucination, and psychosis. (Rossi, 2004)

The newer second-generation H₁-antihistamines are far more selective for peripheral histamine H₁-receptors and, correspondingly, have a far improved tolerability profile compared to the first-generation agents. The most common adverse effects noted for second-generation agents include: drowsiness, fatigue, headache, nausea and dry mouth. (Rossi, 2004)

Other agents

Inhibitors of histamine release

These agents appear to stabilise the mast cells to prevent degranulation and mediator release.

cromoglicate (cromolyn)
nedocromil

H₂-receptor antagonists

Clinically-relevant histamine H₂-receptors are found principally in the parietal cells of the gastric mucosa. H2-receptor “antagonists” are also inverse agonists, rather than true antagonists; and are used to reduce the secretion of gastric acid. Examples include cimetidine, ranitidine, and famotidine.

H₃– and H₄-receptor antagonists

These are experimental agents and do not yet have a defined clinical use.

H₃-receptors antagonists

Thioperamide
Clobenpropit
Impromidine
- Similar in structure to burimamide
  imidazole ring
  Polar moiety on the side chain – thiourea, isothiourea and guanidine
  other substituents are highly variable

H₄-receptors antagonists

Thioperamide

Other agents with antihistaminergic activity

Many drugs, used for other indications, possess unwanted antihistaminergic activity. These include tricyclic antidepressants, antipsychotics, etc.

References

Forneau E, Bovet D (1933). Recherches sur l’action sympathicolytique d’un nouveau derive du dioxane. Arch Int Pharmacodyn 46, 178-91.
Leurs R, Church MK, Taglialatela M (2002). “H₁-antihistamines: inverse agonism, anti-inflammatory actions and cardiac effects”. Clin Exp Allergy 32 (4): 489-98. PMID 11972592.
Nelson, WL (2002). In Williams DA, Lemke TL (Eds.). Foye’s Principles of Medicinal Chemistry (5 ed.). Philadelphia: Lippincott Williams & Wilkins. ISBN 0-683-30737-1
Rossi S (Ed.) (2004). Australian Medicines Handbook 2004. Adelaide: Australian Medicines Handbook. ISBN 0-9578521-4-2
Simons FE (2004, Nov 18). “Advances in H₁-antihistamines”. N Engl J Med 351 (21): 2203-17. PMID 15548781 Abstract.