Antihistamines

Mechanism of Action

Histamine is synthesised from the precursor histidine, an essential amino acid. Histamine is predominantly stored in mast cells and is released in response to immunoglobin IgE binding to Fc receptors on the cell surface. Histamine is also present in histaminergic neurons in the brain. 

When histamine binds and activates H1 receptors, this leads to elevation of cAMP and can lead to the following downstream effects:

• Smooth muscle contraction in ileum, bronchi and uterus 
• Dilation of blood vessels 
• Increased vascular permeability 

Widespread histamine release can contribute to anaphylaxis, which may involve generalised vasodilation, increased vascular permeability, bronchoconstriction and tissue oedema. 

Histamine release in the upper respiratory tract contributes to the symptoms of seasonal allergic rhinitis, commonly known as hayfever, while histamine release in the skin contributes to urticaria and pruritus. 

Antihistamines reduce the effects of histamine at H1 receptor via competitive reversible blockade of histamine-H1-receptor sites on tissues. Many H1 antihistamines are classified as inverse agonists rather than simple competitive antagonists, because they stabilise the inactive conformation of the receptor. 

Antihistamines are used not only for treatment of allergies, but also in sedation and travel sickness. In anaphylaxis, antihistamines are not first-line treatment and must not delay intramuscular adrenaline. They may be used as an adjunct for persistent cutaneous symptoms after appropriate emergency treatment. 

Central Effects

First-generation antihistamines readily cross the blood-brain barrier and block central H1 receptors. This can cause central nervous system depression and drowsiness, which is a common adverse effect of many first-generation antihistamines.

It is important to note that some antihistamines such as promethazine (Sominex) are used for their sedating effect, such as in the treatment of insomnia.

Histamine is involved in the control of nausea and vomiting via activation of H1 receptors in the chemoreceptor trigger zone (CTZ) and in the vomiting centre, both of which are located in the medulla. First-generation antihistamines used for their antiemetic effect include 

• Promethazine
• Cyclizine
• Cinnarizine

These drugs can cross the blood-brain barrier and reduce histaminergic signalling involved in nausea, vomiting and motion sickness.

Created in BioRender. Boucher, M (2026) https://BioRender.com/cch4abh

Fig 1
Mechanism of Action of Antihistamines – central effects

Peripheral Effects

Second-generation antihistamines cross the blood brain barrier to a much lesser extent than first-generation agents. For allergic conditions such as hayfever, second-generation antihistamines are often preferred because they are less likely to cause drowsiness, although sedation can still occur with some agents, particularly cetirizine.

H1 antihistamines reduce the effects of histamine released from mast cells, by binding to H1 receptors and stabilising them in their inactive conformation.

Created in BioRender. Boucher, M. (2026) https://BioRender.com/2v8mz7u

Fig 2
Mechanism of action of antihistamines – peripheral effects

The table below lists commonly used H1 antihistamines, classified into first- and second-generation.

Pharmacokinetics

The antihistamines discussed in this article are all available as oral formulations. Chlorphenamine is also available to be administered parenterally, including intravenous administration in appropriate clinical circumstances. The following table describes pharmacokinetic properties of commonly used antihistamines: 

For more information on antihistamines used in nausea and vomiting, visit our article about antiemetics. 

Contraindications

There are few contraindications for antihistamines, many of which are widely available to purchase in the UK without a prescription. 

• Cetrizine is contraindicated in end stage renal disease, where eGFR <15ml/min
• Hydroxyzine should be avoided in patients with known acquired or congenital QT-interval prolongation or other significant risk factors for QT prolongation.
• Chlorphenamine is contraindicated in patients who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days because MAOIs can intensify its anticholinergic effects.

Cautions and Adverse Effects

Due to central blockade of H1 receptors, first-generation antihistamines can cause drowsiness and dizziness. Second-generation antihistamines generally cause less sedation, although drowsiness and fatigue can still occur. 

Other general side effects of antihistamines include: 

• Headache
• Nausea
• Fatigue
• Skin reactions

Chlorphenamine should be avoided in severe liver disease as it can precipitate hepatic encephalopathy. Furthermore, caution should be undertaken in patients with severe liver impairment and loratadine as hepatic metabolism may be affected.

Cinnarizine, cyclizine, promethazine and chlorphenamine also block muscarinic receptors leading to anticholinergic side effects such as dry mouth, urinary retention, movement disorders, blurred vision, drowsiness, constipation and arrhythmias.

Hydroxyzine and promethazine can cause QT prolongation and caution should be undertaken with cetirizine in epilepsy.

For patients requiring allergy skin tests, there should be a washout period of 2-3 days for antihistamines otherwise the response to the test may be diminished.

Interactions

Chlorphenamine is contraindicated in patients who have been treated with MAOIs in the last 14 days due to anticholinergic burden. Furthermore, antihistamines should be used cautiously with other medicines that have anticholinergic properties because of the risk of additive anticholinergic adverse effects.

Chlorphenamine inhibits phenytoin metabolism which can lead to elevated phenytoin levels.

Fexofenadine is a P-glycoprotein transporter and organic-anion-transporting polypeptide (OATP) substrate, therefore P-gp inducers or inhibitors may affect fexofenadine levels – however no clinically significant adverse effects have been reported with concomitant administration. 

Fexofenadine administration should be separated from administration of aluminium or magnesium containing antacids by 2 hours due to predicted reduced absorption. 

Loratadine is a CYP3A4 and CYP3A6 substrate therefore there is potential for interactions to occur with CYP inhibitors – however no adverse effects have been observed during concomitant administration. 

Cetirizine and loratadine reduce the effects of betahistine, fexofenadine is predicted to cause the same effect.

References

1. Hydroxyzine hydrochloride | Drugs | BNF | NICE  Accessed 16/7/26
2. YK, MacEwan DJ. Rang & Dale’s Pharmacology. 9th ed. London: Elsevier; 2019.
3. Hitchings BSc, M., Lonsdale, D., Burrage, D., Baker, E. (2022). The Top 100 Drugs – E-Book. Netherlands: Elsevier.
4. Chlorphenamine 4mg tablets – Summary of Product Characteristics (SmPC) – (emc) | 14298 Accessed 18/7/26
5. Cetirizine hydrochloride 10 mg film-coated tablets – Summary of Product Characteristics (SmPC) – (emc) | 12956 Accessed 19/7/26
6. Fexofenadine 120mg film coated tablets – Summary of Product Characteristics (SmPC) – (emc) | 14743  Accessed 19/7/26
7. Loratadine 10 mg Tablets – Summary of Product Characteristics (SmPC) – (emc) | 8911  Accessed 19/7/26
8. Oral antihistamines | Prescribing information | Allergic rhinitis | CKS | NICE  Accessed 19/7/26