The ability of a competitive antagonist to influence the receptor occupancy by an agonist is determined by its affinity for the receptor and by the concentrations of both the agonist and antagonist. The important characteristic of competitive antagonism is that the antagonism can always be reversed by increased concentrations of the agonist. However, for slowly reversible or irreversible antagonism, increasing the agonist concentration will not result in a reversal of the effects of the antagonist.

Histamine H1 Receptors
Histamine, released from storage or producing cells into the extracellular space, acts via G-protein-coupled receptors.¹ There are four major subtypes of histamine receptors – H1 to H4 – which differ in their location, their coupling to second messengers and their affinity for histamine. All subtypes can be stimulated by histamine, whose actions can be antagonised by subtype-specific antagonists.²

The human H1 receptor is a 487-amino acid protein with seven transmembrane domains. It is believed that histamine interacts with amino acids in the third and fifth transmembrane domains. In addition, different histamine H1 receptor agonists and antagonists may also bind to different portions of the receptor complex. Stimulation of H1 receptors leads to the hydrolysis of phosphatidyl 4,5-biphosphate and to the formation of inositol-1,4,5 triphosphate and 1,2-diacylglycerol. Inositol-1,4,5-triphosphate mobilises intracellular calcium, while diacylglycerol activates protein kinase C. In accordance, histamine has been shown to induce the production of inositol phosphates and consequently to increase intracellular calcium. The increase in intracellular calcium explains the wide variety of pharmacological effects of H1-receptor stimulation.³

Histamine H1 receptors are involved in the pathological processes of allergy. Clinical trials of H1 receptor antagonists have demonstrated the efficacy of these agents in reducing the sneezing, pruritus and rhinorrhoea associated with allergic rhinitis.

There are very few reports on human H1-receptor polymorphism. A recent paper by Swan et al.⁴ revealed a polymorphism, but in the promotor region of the gene. This may affect the regulation and the expression level of the receptor, but not its affinity towards ligands. Another article by Hong et al.⁵ reports a polymorphism in the coding region of the receptor located in the third intracellular loop at position 349, where a glutamate is replaced by an aspartate. Since it is a conserved mutation (these are two acidic amino acids) and because of its localisation (outside the transmembrane regions), it is not expected to have an influence on antihistamine affinity.

Histamine Metabolism
The histamine released from storage or producing cells into the extracellular space must be inactivated to terminate its effect via histamine receptors on target cells. To be inactivated, histamine must be removed from the extracellular space and metabolised into inactive metabolites. Histamine is metabolised by two main catabolic pathways: oxidative deamination by diamine oxidase (DAO) to imidazole acetic acid and methylation by histamine N-methyltransferase (HNMT) to telemethylhistamine, which is then oxidatively deaminated to methylimidazole acetic acid by monoamine oxidase.⁶ As histamine is unable to easily enter the intracellular space where the enzymes responsible for its metabolism are located, high-affinity transporters for histamine have been considered to be required, and indeed organic cation transporters (OCT)-2 and -3 appear to be important for histamine transport and/or inactivation.^7,8

Tissue Localisation of H1 Receptors, Concentrations of H1 Antihistamines at the Receptor Site and Volume of Distribution of H1 Antihistamines
The H1 receptor is abundant in human respiratory tissues and in various cells of the immune system that play a role in allergic syndromes. H1 receptors are present on T cells, B cells, monocytes, lymphocytes, endothelial cells (e.g. endothelial cells of nasal mucosal blood vessels), gland cells, smooth-muscle cells (e.g. airway and gastrointestinal smooth muscle), neuronal cells, conjunctival epithelial cells and keratinocytes. This list is not intended to be exhaustive, but shows that H1 receptors are widely distributed.^2,3,9

As for every drug administered orally, the prerequisite in order for an H1 antagonist to interact with the receptors is to have a high absolute bioavailability. This means that most of the intact drug should reach the general circulation and should therefore not only be absorbed, but also not be extensively metabolised by enzymes present in the gastrointestinal tract and in the liver.