Pharmacology of Antihistamines

Introduction / Overview

Antihistamines constitute a pivotal class of therapeutics widely employed in the management of allergic disorders and various other clinical conditions. Their relevance extends from routine outpatient care to specialized inpatient settings, underscoring the necessity for a thorough understanding of their pharmacological profiles among medical and pharmacy trainees. The following learning objectives may guide the reader through the essential concepts:

• Identify the major chemical families of antihistamines and their structural features.
• Explain the pharmacodynamic interactions of antihistamines with histamine receptors and related signaling pathways.
• Describe the absorption, distribution, metabolism, and excretion characteristics that influence dosing regimens.
• Recognize approved therapeutic indications, commonly employed off‑label uses, and associated safety considerations.
• Appreciate the importance of drug–drug interactions and special patient populations in the clinical application of antihistamines.

Classification

By Generation and Chemical Structure

Historically, antihistamines have been grouped into first‑, second‑, and third‑generation categories, reflecting advances in receptor selectivity, central nervous system (CNS) penetration, and side‑effect profiles. The following table summarizes key distinctions:

Beyond generational classification, antihistamines may be divided into H1 antagonists and H2 antagonists based on receptor specificity, although the former predominates in allergy management. Additionally, certain agents such as bilastine and ebastine exhibit unique metabolic pathways that distinguish them within the H1 antagonist cohort.

By Mechanism of Receptor Interaction

Antihistamines generally function as competitive antagonists at the histamine H1 receptor (H1R). However, subtle differences in binding kinetics and allosteric modulation can be observed. Some compounds also possess ancillary activities, such as partial agonism at H2 receptors or modulation of muscarinic acetylcholine receptors, contributing to their side‑effect spectra.

Mechanism of Action

Pharmacodynamics

Histamine exerts its physiological effects via four G protein‑coupled receptors (H1–H4). Antihistamines primarily target H1R, which couples to Gq proteins, leading to phospholipase C activation, inositol triphosphate generation, and subsequent intracellular calcium mobilization. By occupying the orthosteric binding site, antihistamines block histamine binding, thereby attenuating downstream signaling responsible for vasodilation, increased vascular permeability, pruritus, and bronchoconstriction.

Binding affinity (K_i) values for first‑generation agents are typically in the low micromolar range, whereas second‑ and third‑generation compounds display submicromolar affinities, reflecting higher potency and reduced off‑target interactions. The dissociation rate (k_off) also influences clinical duration; agents with slower k_off values may sustain receptor blockade over extended periods, accounting for once‑daily dosing schedules.

Cellular and Molecular Mechanisms

Beyond straightforward antagonism, some antihistamines modulate intracellular signaling cascades. For instance, cetirizine and fexofenadine have been reported to inhibit mast cell degranulation via pathways independent of H1R blockade, potentially explaining their efficacy in refractory urticaria. Moreover, certain compounds exhibit anti‑inflammatory effects by down‑regulating cytokine production (e.g., interleukin‑4, interleukin‑13) in airway epithelial cells, thereby reducing eosinophilic infiltration.

Central nervous system penetration varies markedly across the generations. First‑generation agents readily cross the blood‑brain barrier (BBB), engaging central H1Rs and muscarinic receptors, which underlies sedation, anticholinergic symptoms, and potential cognitive impairment. In contrast, second‑ and third‑generation agents possess polar functional groups and are substrates for P-glycoprotein efflux transporters, limiting CNS exposure.

Pharmacokinetics

Absorption

Oral bioavailability of antihistamines ranges from moderate to high, depending on formulation and physicochemical properties. First‑generation drugs typically exhibit rapid absorption (T_max ≈ 0.5–2 h) and high C_max values, whereas third‑generation agents may display delayed peak concentrations due to altered solubility or prodrug status. Food intake can influence absorption; for example, the presence of high‑fat meals may decrease the bioavailability of cetirizine by approximately 20 %, whereas fexofenadine absorption is relatively unaffected.

Distribution

Volume of distribution (V_d) is generally high for lipophilic first‑generation antihistamines, facilitating extensive tissue penetration, including the CNS. Second‑generation drugs exhibit lower V_d values, reflecting reduced penetration of lipophilic barriers such as the BBB. Plasma protein binding varies considerably: diphenhydramine is highly bound (>90 %) to albumin, whereas fexofenadine demonstrates modest binding (~25 %).

Metabolism

Cytochrome P450 (CYP) isoenzymes mediate the biotransformation of many antihistamines. Diphenhydramine is primarily metabolized by CYP2D6, yielding desmethyl‑diphenhydramine, which retains antihistaminic activity. Cetirizine undergoes minimal hepatic metabolism, largely excreted unchanged. Fexofenadine is not metabolized by CYP enzymes, resulting in a low drug‑interaction potential. Genetic polymorphisms in CYP2D6 may alter the clearance of first‑generation agents, necessitating dose adjustments in poor metabolizers.

Excretion

Renal elimination predominates for most antihistamines, particularly those with polar structures. Diphenhydramine metabolites and first‑generation agents are excreted via glomerular filtration and tubular secretion. Fexofenadine clearance is largely renal (≈ 90 %), with a terminal elimination half‑life (t_1/2) of approximately 8 h. In patients with impaired renal function, dose reduction or extended dosing intervals may be required to prevent accumulation.

Half‑Life and Dosing Considerations

Therapeutic dosing schedules are guided by half‑life, receptor occupancy, and side‑effect profiles. First‑generation antihistamines typically have shorter half‑lives (≈ 4–6 h) and are dosed multiple times daily, whereas second‑ and third‑generation agents possess half‑lives of 8–24 h, permitting once‑daily regimens. The sustained receptor blockade afforded by prolonged half‑life supports consistent symptom control, particularly in chronic urticaria and seasonal allergic rhinitis.

Therapeutic Uses / Clinical Applications

Approved Indications

Antihistamines are indicated for a spectrum of allergic and non‑allergic conditions:

• Acute allergic reactions (urticaria, angioedema, anaphylaxis) – first‑generation agents are preferred for rapid symptom relief.
• Chronic spontaneous urticaria – second‑generation antihistamines form the first‑line therapy, with up‑dosing strategies (up to 4× the standard dose) employed in refractory cases.
• Allergic rhinitis (seasonal and perennial) – second‑generation antihistamines provide effective control of nasal congestion, rhinorrhea, and itching.
• Eczema and dermatitis – topical antihistamines (e.g., diphenhydramine cream) may relieve pruritus, though evidence for systemic benefits is limited.
• Motion sickness – first‑generation agents (e.g., dimenhydrinate) are commonly used prophylactically.

Off‑Label Uses

Several antihistamines are frequently employed beyond their primary indications, often supported by emerging clinical evidence:

1. Sleep aid – diphenhydramine and doxylamine are widely used for short‑term insomnia, leveraging sedative properties.
2. Migraines – antihistamines such as cyproheptadine are prescribed for vestibular migraine due to their antihistaminic and antiserotonergic actions.
3. Psychiatric conditions – hydroxyzine is occasionally used for anxiety and agitation, capitalizing on its anxiolytic effect.
4. Asthma – limited evidence suggests antihistamines may alleviate nocturnal wheeze in selected patients, though they are not first‑line bronchodilators.

Adverse Effects

Common Side Effects

Side‑effect profiles differ markedly between generations. First‑generation antihistamines are associated with sedation, dry mouth, blurred vision, urinary retention, and orthostatic hypotension. Second‑ and third‑generation agents exhibit markedly lower rates of sedation (< 2 %), although mild dizziness or headache may occur. Anticholinergic effects are generally uncommon in second‑generation drugs but may emerge at high doses or in susceptible individuals.

Serious / Rare Adverse Reactions

Exacerbation of asthma, paradoxical bronchospasm, and severe hypotension can arise, particularly with first‑generation agents in asthmatic patients. Rare but noteworthy reactions include Stevens–Johnson syndrome, toxic epidermal necrolysis, and severe cutaneous adverse reactions, typically associated with structural moieties such as piperazine rings. Antihistamine use during pregnancy has been linked to increased risk of congenital malformations in some observational studies, warranting caution.

Black Box Warnings

First‑generation antihistamines carry boxed warnings regarding sedation and impairment of psychomotor performance, especially when combined with alcohol or other CNS depressants. Some third‑generation agents have warnings related to visual disturbances due to ocular effects. The presence of such warnings emphasizes the importance of judicious patient selection and counseling.

Drug Interactions

Major Drug–Drug Interactions

• Cytochrome P450 Inhibitors/Inducers: Diphenhydramine clearance may be reduced by strong CYP2D6 inhibitors (e.g., fluoxetine), leading to accumulation and heightened sedation. Conversely, CYP2D6 inducers (e.g., carbamazepine) may increase metabolism, diminishing efficacy.
• Anticholinergic Overlap: Concomitant use of antihistamines with other anticholinergic agents (e.g., tricyclic antidepressants, antipsychotics) may augment dry mouth, urinary retention, and cognitive impairment.
• Central Nervous System Depressants: Combined administration with benzodiazepines, opioids, or alcohol may potentiate sedation and respiratory depression.
• P‑glycoprotein Substrates: Some second‑generation antihistamines are P‑gp substrates; inhibitors such as ritonavir may increase plasma concentrations, heightening side‑effect risk.

Contraindications

Absolute contraindications include severe hepatic insufficiency (for first‑generation agents with extensive hepatic metabolism) and known hypersensitivity to the drug or any excipient. Relative contraindications encompass uncontrolled asthma, narrow‑angle glaucoma, and significant cardiovascular disease, where anticholinergic or sedative effects may be deleterious.

Special Considerations

Pregnancy / Lactation

Pregnancy category B agents, such as cetirizine and fexofenadine, have limited teratogenic data and are generally considered safe. First‑generation antihistamines carry category C or D labels, reflecting potential risks such as fetal bradycardia or teratogenicity. Lactation advisories recommend selective use of second‑generation agents due to lower transfer into breast milk. However, the minimal systemic absorption of fexofenadine (< 1 %) suggests negligible infant exposure.

Pediatric / Geriatric Considerations

In children, dosing must account for developmental pharmacokinetics. First‑generation antihistamines are often avoided in infants due to sedation and anticholinergic risk. Second‑generation agents, particularly fexofenadine, can be administered at weight‑based doses (e.g., 1 mg/kg) with minimal CNS side‑effects. Geriatric patients exhibit altered hepatic and renal clearance, necessitating dose adjustments for agents such as diphenhydramine and cetirizine to prevent accumulation and cognitive impairment.

Renal / Hepatic Impairment

Renal dysfunction markedly affects clearance of hydrophilic antihistamines. Dose reduction or interval extension is advised for fexofenadine (e.g., 12.5 mg q12h) in patients with creatinine clearance < 30 mL/min. Hepatic impairment may necessitate avoidance of first‑generation agents with significant CYP2D6 metabolism; alternative agents such as loratadine, which undergo minimal hepatic biotransformation, may be preferable.

Summary / Key Points

• Antihistamines are categorized by generation, chemical structure, and receptor affinity, influencing CNS penetration and side‑effect profiles.
• Primary pharmacodynamic action involves competitive antagonism at H1 receptors, attenuating histamine‑mediated allergic responses.
• Pharmacokinetic characteristics—absorption, distribution, metabolism, and excretion—must guide dosing, particularly in special populations.
• Second‑ and third‑generation antihistamines are the preferred agents for chronic allergic conditions due to lower sedation and anticholinergic burden.
• Drug interactions, especially involving CYP2D6 and P‑gp pathways, require careful review to avoid toxicity or therapeutic failure.
• Pregnancy, lactation, pediatrics, geriatrics, and organ impairment necessitate individualized dosing strategies and vigilant monitoring.

Incorporation of these pharmacological principles into clinical decision‑making ensures maximized therapeutic benefit while minimizing adverse outcomes associated with antihistamine therapy.

References

1. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
2. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
3. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
4. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
5. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
6. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.
7. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
8. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.