Pharmacology of Antihistamines

Introduction/Overview

Histamine, a biogenic amine synthesized from the amino acid L-histidine, functions as a critical mediator in physiological and pathological processes, including the regulation of gastric acid secretion, neurotransmission in the central nervous system, and the inflammatory response. The pharmacology of antihistamines centers on the antagonism of histamine receptors, predominantly the H₁ subtype, to mitigate the symptoms associated with allergic reactions and other histamine-mediated conditions. These agents constitute one of the most frequently prescribed and utilized classes of medications globally, available both by prescription and as over-the-counter preparations.

The clinical relevance of antihistamines is profound, extending beyond the symptomatic management of seasonal allergic rhinitis and urticaria. Their applications encompass sedation, antiemesis, motion sickness, and adjunctive therapy in anaphylaxis. The evolution from first-generation, sedating agents to second-generation, non-sedating compounds represents a significant advancement, markedly improving the therapeutic index by minimizing adverse effects on the central nervous system. Understanding the pharmacodynamics, pharmacokinetics, and appropriate clinical application of these drugs is therefore essential for safe and effective therapeutic decision-making.

Learning Objectives

• Classify antihistamines based on chemical structure, receptor selectivity, and clinical generation, and describe the clinical implications of these classifications.
• Explain the molecular mechanism of action of H₁ receptor antagonists, including the concepts of inverse agonism and receptor selectivity, and contrast this with the action of H₂ receptor antagonists.
• Analyze the pharmacokinetic profiles of representative first- and second-generation antihistamines, including absorption, distribution, metabolism, excretion, and resultant dosing considerations.
• Evaluate the approved therapeutic indications, common off-label uses, and the rationale for selecting specific antihistamines in different clinical scenarios.
• Identify the spectrum of adverse effects, significant drug interactions, and special population considerations associated with antihistamine therapy to optimize patient safety.

Classification

Antihistamines are systematically classified according to their primary receptor antagonism, chemical structure, and clinical pharmacological profile. The most therapeutically significant division is based on histamine receptor subtype selectivity.

Receptor Selectivity

The primary classification separates agents based on their affinity for specific histamine receptor subtypes (H₁, H₂, H₃, H₄). H₁ receptor antagonists are used for allergic and inflammatory conditions. H₂ receptor antagonists, such as cimetidine and ranitidine, inhibit gastric acid secretion and are used for peptic ulcer disease and gastroesophageal reflux. H₃ and H₄ receptor antagonists remain largely experimental, with potential roles in cognitive disorders and inflammatory diseases, respectively. Unless otherwise specified, the term “antihistamine” in clinical contexts typically refers to H₁ receptor antagonists.

Clinical-Generational Classification

H₁ antagonists are further categorized into first- and second-generation agents, a distinction based primarily on their propensity to cause sedation and anticholinergic effects.

• First-Generation Antihistamines: These lipophilic agents readily cross the blood-brain barrier, leading to pronounced central nervous system effects, including sedation, drowsiness, and impaired cognitive function. They also exhibit significant affinity for muscarinic cholinergic, α-adrenergic, and serotonin receptors, contributing to a broader side effect profile. Examples include diphenhydramine, chlorpheniramine, promethazine, and hydroxyzine.
• Second-Generation Antihistamines: Developed to minimize central nervous system penetration, these agents are generally more hydrophilic or are substrates for the P-glycoprotein efflux pump at the blood-brain barrier. They demonstrate greater selectivity for the peripheral H₁ receptor, resulting in a markedly reduced incidence of sedation and anticholinergic effects. Examples include loratadine, cetirizine, fexofenadine, and desloratadine.

Chemical Classification

First-generation H₁ antagonists can be grouped into several chemical classes, including alkylamines (e.g., chlorpheniramine), ethanolamines (e.g., diphenhydramine), ethylenediamines (e.g., pyrilamine), phenothiazines (e.g., promethazine), and piperazines (e.g., hydroxyzine). These structural classes loosely correlate with the prominence of certain side effects; for instance, ethanolamines tend to have strong sedative properties, while alkylamines produce less sedation. Second-generation agents are structurally diverse, often derived from the parent compounds of the first generation but with modifications that alter their pharmacokinetics and receptor selectivity.

Mechanism of Action

The therapeutic and adverse effects of H₁ receptor antagonists are directly attributable to their interaction with the histamine H₁ receptor, a G-protein coupled receptor (GPCR).

Histamine Receptor Physiology

Histamine exerts its effects by binding to and activating four known GPCR subtypes: H₁, H₂, H₃, and H₄. The H₁ receptor is coupled to the G_q/11 protein. Upon activation by histamine, phospholipase C is stimulated, leading to the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP₂) into inositol trisphosphate (IP₃) and diacylglycerol (DAG). IP₃ mobilizes intracellular calcium, while DAG activates protein kinase C. This cascade results in smooth muscle contraction (especially in bronchi and the gastrointestinal tract), increased vascular permeability, pruritus, prostaglandin synthesis, and the promotion of nitric oxide release, which contributes to vasodilation.

Molecular Mechanism of Antagonism

Classically, H₁ antagonists were described as competitive reversible inhibitors that occupy the receptor binding site, preventing histamine from binding and initiating signal transduction. Contemporary understanding suggests that many of these agents function as inverse agonists. In the two-state model of receptor activation, GPCRs exist in an equilibrium between an inactive (R) and an active (R*) conformation. Histamine, an agonist, stabilizes the active conformation. Inverse agonists possess a higher affinity for the inactive receptor conformation, shifting the equilibrium away from the active state, thereby reducing basal constitutive receptor activity. This inverse agonist activity may contribute to the efficacy of antihistamines in conditions where histamine is not the sole mediator.

Receptor Selectivity and Off-Target Effects

The clinical profile of an antihistamine is heavily influenced by its selectivity for the H₁ receptor versus other receptors. First-generation agents, due to their less selective chemical structures, often exhibit antagonistic activity at muscarinic acetylcholine receptors (causing dry mouth, urinary retention, blurred vision), α₁-adrenergic receptors (causing hypotension), and serotonin receptors. Second-generation agents are designed for higher H₁ receptor selectivity, minimizing these off-target interactions and their associated adverse effects.

Central versus Peripheral Action

Histamine acts as a neurotransmitter in the central nervous system, promoting wakefulness and alertness via projections from the tuberomammillary nucleus. The sedative effect of first-generation antihistamines is primarily due to the blockade of central H₁ receptors. Their lipophilicity allows for efficient blood-brain barrier penetration. Second-generation agents are largely excluded from the CNS due to their physicochemical properties (e.g., greater hydrophilicity, zwitterionic nature of cetirizine) or active efflux by P-glycoprotein, resulting in minimal sedation at therapeutic doses.

Pharmacokinetics

The pharmacokinetic properties of antihistamines vary significantly between agents, influencing their dosing regimens, onset and duration of action, and potential for drug interactions.

Absorption

Most H₁ antagonists are well absorbed following oral administration. The time to reach peak plasma concentration (t_max) typically ranges from 1 to 3 hours. Absorption can be influenced by food; for instance, the bioavailability of fexofenadine is reduced by approximately 30% when taken with fruit juices (e.g., apple, orange, grapefruit) due to inhibition of the intestinal uptake transporter OATP1A2. Conversely, the absorption of some first-generation agents may be enhanced by food. Topical, ophthalmic, and intravenous formulations are also available for specific indications.

Distribution

Distribution characteristics are a key differentiator between generations. First-generation agents are generally lipophilic and exhibit a large volume of distribution (V_d), readily distributing into tissues including the central nervous system. Second-generation agents tend to have lower V_d values and are more restricted to the plasma and extracellular fluid due to higher hydrophilicity or plasma protein binding. Protein binding varies widely, from approximately 70% for cetirizine to over 95% for loratadine and its active metabolite desloratadine.

Metabolism

Metabolism is a critical determinant of antihistamine activity, duration, and interaction potential. Most are extensively metabolized by hepatic cytochrome P450 (CYP) enzymes.

• First-Generation: Agents like diphenhydramine and chlorpheniramine are metabolized primarily by CYP2D6 and other isoforms. Their metabolism can be subject to genetic polymorphism and significant drug interactions.
• Second-Generation: Loratadine is a prodrug activated by CYP3A4 and CYP2D6 to desloratadine. Consequently, its efficacy can be reduced by strong CYP3A4 inhibitors (e.g., ketoconazole). Cetirizine is minimally metabolized, with most of the dose excreted unchanged in urine. Fexofenadine is not significantly metabolized by CYPs but is a substrate for P-glycoprotein. Its metabolism involves phase II conjugation, and it is not affected by CYP inhibitors, though P-gp inhibitors can increase its plasma concentration.

The presence of active metabolites is common. For example, hydroxyzine is metabolized to cetirizine, and loratadine to desloratadine. These metabolites often have prolonged half-lives, contributing to the extended duration of action of the parent drug.

Excretion

Elimination occurs via renal and biliary pathways. The elimination half-life (t_1/2) dictates dosing frequency. First-generation agents typically have shorter half-lives (4-12 hours), necessitating multiple daily doses. Second-generation agents generally have longer half-lives (12-27 hours), allowing for once-daily dosing. Cetirizine and levocetirizine are predominantly renally excreted, requiring dose adjustment in renal impairment. Fexofenadine is excreted in feces (≈80%) and urine (≈11%).

Pharmacokinetic Parameters of Selected Agents

Representative pharmacokinetic values include: Diphenhydramine (t_max ~2h, t_1/2 ~9h, V_d ~3-4 L/kg); Loratadine (t_max ~1.5h, t_1/2 ~8h for parent, ~28h for desloratadine); Cetirizine (t_max ~1h, t_1/2 ~8h, renal clearance dominant); Fexofenadine (t_max ~2.5h, t_1/2 ~14h).

Therapeutic Uses/Clinical Applications

H₁ antihistamines are employed in a wide array of clinical conditions, primarily for their ability to antagonize the effects of histamine on capillaries, smooth muscle, and sensory nerves.

Approved Indications

• Allergic Rhinitis: This is the most common indication. Antihistamines effectively reduce sneezing, rhinorrhea, nasal pruritus, and ocular symptoms. Second-generation agents are preferred first-line therapy due to their superior side effect profile.
• Chronic Spontaneous Urticaria: Antihistamines are first-line therapy for reducing pruritus and wheal formation. Up-dosing (up to four times the standard dose) of second-generation agents is often employed in treatment guidelines for non-responders.
• Allergic Conjunctivitis: Ophthalmic formulations (e.g., olopatadine, ketotifen) provide direct relief from ocular itching and redness.
• Anaphylaxis Adjunct Therapy: While epinephrine is the first-line and life-saving treatment, H₁ antagonists (and H₂ antagonists) are administered intravenously or intramuscularly to help control cutaneous symptoms and potentially mitigate further histamine-mediated effects, though they do not reverse upper airway obstruction or hypotension.
• Motion Sickness and Vertigo: First-generation agents with antimuscarinic properties, such as dimenhydrinate and meclizine, are effective prophylactics for motion sickness and in the management of vestibular disorders like Ménière’s disease.
• Sedation and Sleep Aid: The sedating properties of first-generation agents like diphenhydramine and doxylamine are utilized in over-the-counter sleep aids. Their use for this purpose is generally recommended for short-term management only due to risks of tolerance, anticholinergic effects, and next-day drowsiness.
• Antiemesis: Promethazine and other phenothiazine derivatives are used for the prevention and treatment of nausea and vomiting, particularly postoperative nausea and vomiting, though their use has declined with the advent of more selective antiemetics.

Off-Label Uses

• Atopic Dermatitis: Used primarily for their sedative and antipruritic effects, especially first-generation agents at bedtime to break the itch-scratch cycle.
• Insomnia: As mentioned, first-generation agents are commonly used off-label for insomnia, despite guidelines favoring other drug classes.
• Anxiety: Hydroxyzine has anxiolytic properties and is sometimes used for generalized anxiety, though it is not a first-line agent.
• Common Cold: The anticholinergic properties of first-generation antihistamines may reduce rhinorrhea, though their efficacy is modest and side effects are a significant drawback.

Adverse Effects

The adverse effect profile of antihistamines is closely linked to their receptor selectivity and ability to penetrate the central nervous system.

Common Side Effects

• Central Nervous System Effects: Sedation, drowsiness, fatigue, and impaired cognitive and psychomotor performance are hallmark effects of first-generation agents. Paradoxical excitation, including restlessness, insomnia, and tremors, can occur, particularly in children and the elderly.
• Anticholinergic Effects: Dry mouth, blurred vision, urinary retention, constipation, and tachycardia are common with first-generation agents due to muscarinic receptor blockade.
• Gastrointestinal Effects: Nausea, vomiting, epigastric distress, and changes in appetite may occur.
• Miscellaneous: Headache and pharyngitis are occasionally reported with second-generation agents.

Serious/Rare Adverse Reactions

• Cardiac Effects: Certain second-generation antihistamines that were withdrawn from the market (e.g., terfenadine, astemizole) were associated with life-threatening ventricular arrhythmias, specifically torsades de pointes. This was due to blockade of the cardiac potassium channel (hERG) leading to QT interval prolongation, particularly when metabolism was inhibited (e.g., by CYP3A4 inhibitors). Available second-generation agents like fexofenadine and loratadine (at recommended doses) carry minimal risk.
• Severe Hypersensitivity Reactions: Rare cases of anaphylaxis, angioedema, and bronchospasm have been reported.
• Blood Dyscrasias: Agranulocytosis, thrombocytopenia, and hemolytic anemia are extremely rare idiosyncratic reactions.
• Seizures: Overdose of first-generation agents can lower the seizure threshold.

Black Box Warnings

Currently, no H₁ antihistamines available in most major markets carry a black box warning from regulatory agencies like the U.S. Food and Drug Administration. The serious cardiac warnings associated with terfenadine and astemizole led to their removal, underscoring the importance of post-marketing surveillance.

Drug Interactions

Antihistamines can participate in pharmacokinetic and pharmacodynamic interactions that may alter their efficacy or increase toxicity.

Major Pharmacokinetic Interactions

• CYP450 Inhibitors: Strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir) can significantly increase plasma concentrations of metabolically dependent antihistamines like loratadine. While the risk with current agents is low, caution is advised. The interaction was fatal with terfenadine.
• P-glycoprotein Inhibitors: Drugs like verapamil, cyclosporine, and grapefruit juice can inhibit intestinal P-gp, increasing the bioavailability of substrates like fexofenadine.
• Enzyme Inducers: Agents like rifampin and carbamazepine may reduce the efficacy of metabolized antihistamines by increasing their clearance.

Major Pharmacodynamic Interactions

• CNS Depressants: First-generation antihistamines have additive sedative effects with alcohol, benzodiazepines, opioids, sedative-hypnotics, and tricyclic antidepressants, significantly impairing alertness and motor coordination.
• Anticholinergic Agents: Concomitant use with other drugs possessing antimuscarinic activity (e.g., tricyclic antidepressants, antipsychotics, antispasmodics) can precipitate severe anticholinergic syndrome (hyperthermia, delirium, ileus, urinary retention).
• Monoamine Oxidase Inhibitors (MAOIs): MAOIs may potentiate the anticholinergic and sedative effects of first-generation antihistamines.
• QT-Prolonging Agents: Although the risk is minimal with standard doses of available agents, concomitant use with other drugs known to prolong the QT interval (e.g., certain antiarrhythmics, antipsychotics, antibiotics) warrants caution, especially in patients with underlying cardiac disease or electrolyte disturbances.

Contraindications

Absolute contraindications are relatively few but important. First-generation antihistamines are contraindicated in patients with narrow-angle glaucoma, symptomatic prostatic hypertrophy, or pyloroduodenal obstruction due to their anticholinergic effects. They are also contraindicated in premature infants and neonates. Specific agents may be contraindicated in severe hepatic or renal impairment if no dose adjustment is possible. Known hypersensitivity to a particular antihistamine or its chemical class is an absolute contraindication.

Special Considerations

The safe use of antihistamines requires careful consideration in specific patient populations where pharmacokinetics, pharmacodynamics, or risk-benefit ratios are altered.

Pregnancy and Lactation

Treatment decisions must balance maternal benefit against fetal risk. As a class, first-generation agents like chlorpheniramine and diphenhydramine are generally considered to have a longer history of use and are often preferred when an antihistamine is necessary during pregnancy, though they are not without risk. Loratadine and cetirizine are second-generation agents for which considerable observational data have not shown a clear increase in major birth defects, and they are frequently recommended. All antihistamines are excreted in breast milk. First-generation agents may cause irritability or sedation in the nursing infant. Second-generation agents, particularly loratadine and cetirizine, are considered compatible with breastfeeding due to low relative infant doses.

Pediatric Considerations

Children may exhibit paradoxical excitation (central nervous system stimulation) to first-generation antihistamines. Dosing is typically based on weight or body surface area. Second-generation agents are preferred for allergic conditions due to their better safety profile regarding sedation and cognitive impairment, which can affect learning. The use of over-the-counter cough and cold products containing antihistamines in children under 2 years of age is not recommended due to risks of serious adverse effects and lack of proven efficacy.

Geriatric Considerations

Older adults are particularly sensitive to the adverse effects of first-generation antihistamines. Age-related reductions in hepatic metabolism and renal excretion can lead to drug accumulation. The anticholinergic effects increase the risk of confusion, dry mouth leading to dental caries, constipation, urinary retention, and blurred vision. Furthermore, strong anticholinergic burden is associated with an increased risk of dementia. Second-generation antihistamines are strongly preferred in this population. The Beers Criteria, a guideline for medication use in older adults, explicitly recommends avoiding first-generation H₁ antagonists due to their high anticholinergic activity.

Renal and Hepatic Impairment

Dose adjustment is often necessary. For agents primarily excreted renally unchanged (e.g., cetirizine, levocetirizine, hydroxyzine), doses should be reduced in patients with moderate to severe renal impairment (creatinine clearance < 30 mL/min). For agents extensively metabolized by the liver (e.g., loratadine, desloratadine), dose reduction may be necessary in significant hepatic impairment, as decreased first-pass metabolism can lead to increased bioavailability and prolonged half-life. Fexofenadine, which is minimally metabolized, may require dose adjustment in severe renal impairment due to its partial renal excretion.

Summary/Key Points

• H₁ receptor antagonists are classified as first-generation (sedating, with anticholinergic effects) or second-generation (non-sedating, more receptor-selective), a distinction critical to their therapeutic index.
• The mechanism of action involves high-affinity binding to the H₁ receptor, functioning as inverse agonists to stabilize its inactive conformation and antagonize the effects of histamine on smooth muscle, vasculature, and sensory nerves.
• Pharmacokinetic properties, particularly lipophilicity, metabolism by CYP450 enzymes, and routes of excretion, determine dosing frequency, drug interaction potential, and suitability for special populations.
• The primary therapeutic applications include allergic rhinitis, urticaria, allergic conjunctivitis, and as adjuncts in anaphylaxis. First-generation agents retain roles in sedation, antiemesis, and motion sickness prophylaxis.
• Adverse effects range from common sedation and anticholinergic symptoms (first-generation) to rare but serious cardiac arrhythmias (associated with withdrawn agents). Second-generation agents offer a markedly improved safety profile for allergic disorders.
• Significant drug interactions occur primarily via CYP450 inhibition (increasing levels of metabolized agents) and pharmacodynamic synergy with other CNS depressants and anticholinergic drugs.
• Special population management mandates caution: second-generation agents are preferred in the elderly and children; choice in pregnancy and lactation requires careful risk-benefit analysis; and dose adjustments are frequently necessary in renal or hepatic impairment.

Clinical Pearls

• For allergic conditions, a second-generation antihistamine should be the default first-line oral therapy due to superior safety and equivalent efficacy.
• In chronic urticaria unresponsive to standard doses, guidelines support increasing the dose of a second-generation agent up to fourfold before considering add-on therapies.
• The sedative effect of first-generation antihistamines exhibits tolerance with continued use, reducing efficacy for sleep induction over time while anticholinergic risks persist.
• When prescribing, always inquire about over-the-counter sleep aids and cold medications, as these often contain sedating antihistamines that contribute to anticholinergic burden and interaction risk.
• In anaphylaxis, antihistamines are a secondary treatment to epinephrine; they do not treat airway obstruction or shock and should never delay the administration of epinephrine.

References

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