What is the mechanism of action of antihistamines (Anti-Histamine)?

From the Guidelines

Antihistamines work by blocking histamine receptors in the body, primarily the H1 receptors, which prevents histamine from binding and causing allergy symptoms. When allergens enter the body, mast cells and basophils release histamine, which normally binds to H1 receptors on blood vessels and smooth muscle, causing inflammation, itching, and other allergic responses.

Key Points

• First-generation antihistamines like diphenhydramine (Benadryl) and chlorpheniramine cross the blood-brain barrier, causing sedation as a side effect 1.
• Second-generation antihistamines such as loratadine (Claritin), cetirizine (Zyrtec), and fexofenadine (Allegra) are less lipophilic and generally don't cross the blood-brain barrier, resulting in minimal sedation 1.
• Antihistamines are most effective when taken before exposure to allergens, as they prevent histamine from binding rather than reversing effects that have already occurred.
• For optimal symptom control, antihistamines should be taken regularly during allergy season rather than only when symptoms appear.
• The onset of action varies from 30 minutes to 2 hours depending on the specific medication, with effects typically lasting 12-24 hours for second-generation antihistamines.

Mechanism of Action

Antihistamines act as inverse agonists at histamine receptors; they are effective therapy for patients with urticaria and can treat many of the cutaneous signs and symptoms associated with anaphylaxis including pruritus, flushing, and urticaria 1.

Clinical Considerations

• Second-generation antihistamines are generally preferred over first-generation antihistamines for the treatment of allergic rhinitis due to their lower likelihood of adverse effects such as sedation, performance impairment, and anticholinergic effects 1.
• Before prescribing or recommending a first-generation antihistamine, the physician should ensure that the patient understands both the potential for adverse effects and the availability of alternative antihistamines with a lower likelihood of adverse effects.
• There are important differences among the second-generation antihistamines in regard to their sedative properties, with fexofenadine, loratadine, and desloratadine being nonsedating at recommended doses 1.

From the FDA Drug Label

Purpose Antihistamine PURPOSE Antihistamine The mechanism of antihistamines is not explicitly stated in the provided drug labels.

• The labels only mention that the drugs are antihistamines, but do not describe their mechanism of action. The FDA drug label does not answer the question.

From the Research

Antihistamines Mechanism

The mechanism of antihistamines involves the competitive antagonism of histamine binding to cellular receptors, specifically the H1-receptors 2. This is the primary mechanism of action in the treatment of allergic diseases.

• Antihistamines function as inverse agonists that bind to the H1 receptor to inhibit histamine-induced inflammation 3.
• The binding of antihistamines to the H1 receptor blocks the movement of the toggle switch residue W4286.48, thereby exerting inverse regulation 4.
• Antihistamines may also have additional pharmacological properties, such as anticholinergic, sedative, local anaesthetic, and anti-5-HT effects, which can affect the symptoms of the allergic response and contribute to side-effects 2.
• Second-generation antihistamines have been designed to minimize blood-brain barrier penetration by reducing lipophilicity and increasing the affinity for P-aminnoglycoprotein, resulting in less drowsiness and functional impairment 5.

Types of Antihistamines

There are different types of antihistamines, including:

• First-generation antihistamines, which have a well-documented negative adverse effect profile and are no longer recommended for patient use 3.
• Second-generation antihistamines, which are safer and more effective, and have been shown to be effective in treating allergic conditions such as allergic rhinitis and urticaria 3, 6.
• Newer generation antihistamines, which are being developed to have additional properties that can help reduce the allergic response, such as mizolastine 2.

Regulation of Histamine H1 Receptor

The regulation of the histamine H1 receptor by antihistamines involves:

• The binding of antihistamines to the H1 receptor, which blocks the movement of the toggle switch residue W4286.48 4.
• The identification of a secondary ligand-binding site in H1R, which potentially may support the introduction of new derivative groups to generate newer antihistamines 4.
• The use of cryo-EM structure of H1R in the apo form and bound to different antihistamines to uncover the details of the regulation of H1R by antihistamines 4.