Pharmacology of Histamine and Antihistamines

Histamine, a pivotal mediator in various physiological and pathological processes, is synthesized from the amino acid L-histidine. This transformation is facilitated by the enzyme histidine decarboxylase. Histamine’s diverse roles in the body are mediated through its interaction with four types of G-protein-coupled receptors: H1, H2, H3, and H4, each distinct in their distribution and function [1-3].

Histamine synthesis
#Histamine synthesis

Detailed Functions of Histamine Receptors

Histamine receptors
Source: Nguyen PL, Cho J. Pathophysiological Roles of Histamine Receptors in Cancer Progression: Implications and Perspectives as Potential Molecular Targets. Biomolecules. 2021; 11(8):1232.

H1 Receptors:

These receptors are widely distributed in smooth muscles, endothelium, and the central nervous system. Activation of H1 receptors leads to classic symptoms of allergic reactions such as itching, bronchoconstriction, vasodilation, and increased vascular permeability. In the CNS, they are involved in regulating sleep-wake cycles, cognitive functions, and appetite [1, 2].

  • Induce vasodilation: H1 receptors activation leads to the dilation of blood vessels.
  • Increase vascular permeability: They cause the leakage of fluids from blood vessels into tissues.
  • Bronchoconstriction: Contraction of smooth muscles in the airways, contributing to respiratory symptoms in allergies.
  • Allergic symptoms: Responsible for itching, hives, and other allergy-related reactions.
  • CNS neurotransmission: Play a role in regulating sleep-wake cycles, cognitive functions, and appetite.

H2 Receptors:

Located primarily in the gastric parietal cells, H2 receptors are responsible for stimulating gastric acid secretion. They also play a role in modulating cardiac output and heart rate, as well as contributing to vasodilation in various vascular beds [1, 3].

  • Gastric acid secretion: Stimulate the production of gastric acid, aiding in digestion.
  • Modulate cardiac activity: Influence heart rate and cardiac output.
  • Vasodilation: Contribute to the relaxation of blood vessels in various vascular beds.

H3 Receptors:

These receptors are predominantly found in the central and peripheral nervous systems. They act mainly as autoreceptors or heteroreceptors, regulating the synthesis and release of histamine and other neurotransmitters, thereby influencing cognitive functions, arousal, and appetite control [2, 3].

  • Autoreceptors: Regulate histamine synthesis and release in histaminergic neurons.
  • Heteroreceptors: Modulate the release of other neurotransmitters, affecting cognitive functions, arousal, and appetite control.
  • Influence sleep-wake regulation and cognitive processes.

H4 Receptors:

Expressed mainly in cells of the immune system, H4 receptors are involved in the regulation of immune responses and inflammation. They modulate chemotaxis, cytokine production, and cell migration, playing a crucial role in allergic and inflammatory responses [3].

  • Immune regulation: Play a role in immune responses and inflammation.
  • Chemotaxis: Attract immune cells to sites of infection or inflammation.
  • Cytokine production: Modulate the release of cytokines involved in immune reactions.
  • Cell migration: Regulate the movement of immune cells during inflammatory responses.

Antihistamines: Types and Pharmacodynamics

Antihistamines are classified into first-generation and second-generation agents, based on their selectivity for histamine receptors and side effect profiles.

  1. First-Generation Antihistamines: These drugs, such as diphenhydramine and chlorpheniramine, are known for their non-selective antagonism of H1 receptors. They are effective in treating various allergic symptoms but are associated with central nervous system side effects like sedation and drowsiness due to their ability to cross the blood-brain barrier. They also exhibit anticholinergic effects, which can lead to dry mouth and urinary retention [4].
  2. Second-Generation Antihistamines: This class includes drugs like cetirizine, loratadine, and fexofenadine. They are more selective for peripheral H1 receptors, minimizing CNS penetration and thus reducing the risk of sedation. These antihistamines are preferred for chronic allergic conditions due to their improved safety profile and longer duration of action [4, 5].
Classification Generation Examples Characteristics     
H1 Receptor
First-Generation Diphenhydramine,
– Non-selective for H1 receptors
– Cross the blood-brain barrier
– Cause sedation
– Anticholinergic effects
Second-Generation Cetirizine,
– Selective for peripheral H1 receptors
– Minimal CNS penetration
– Less sedating
– Longer duration of action

Clinical Applications and Safety Considerations

Antihistamines are the cornerstone in the management of allergic diseases, including allergic rhinitis, urticaria, and conjunctivitis. While generally safe, they can cause side effects, particularly the first-generation antihistamines, which can impair cognitive function and motor skills due to their sedative effects. Second-generation antihistamines are recommended for patients who require long-term treatment due to their lower risk of sedation and better tolerability [4, 5].

Future Directions and Research

Recent research focuses on developing more selective histamine receptor modulators to target specific allergic and inflammatory conditions with fewer side effects. The exploration of H3 and H4 receptors as therapeutic targets in CNS disorders and immune-related diseases is an area of growing interest [1-5].


  1. Tiligada E, Ennis M. Histamine pharmacology: from Sir Henry Dale to the 21st century. Br J Pharmacol. 2020;177(3):469-489. doi:10.1111/bph.14524.
  2. Panula P, Chazot PL, Cowart M, et al. International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors. Pharmacol Rev. 2015;67(3):601-655. doi:10.1124/pr.114.010249.
  3. Thurmond RL, Gelfand EW, Dunford PJ. The role of histamine H1 and H4 receptors in allergic inflammation: the search for new antihistamines. Nat Rev Drug Discov. 2008;7(1):41-53. doi:10.1038/nrd2465.
  4. Church DS, Church MK. Pharmacology of antihistamines. Indian J Dermatol. 2011;56(3):251-257. doi:10.4103/0019-5154.82501.
  5. Simons FE, Simons KJ. Histamine and H1-antihistamines: celebrating a century of progress. J Allergy Clin Immunol. 2011;128(6):1139-1150.e4. doi:10.1016/j.jaci.2011.09.005.
Disclaimer: This article is for informational purposes only and does not constitute medical advice. Always seek the advice of a healthcare provider with any questions regarding a medical condition.

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