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. Its actions are primarily mediated through four distinct G-protein-coupled receptor subtypes: H₁, H₂, H₃, and H₄. Antihistamines, more precisely termed histamine receptor antagonists, are pharmacological agents that competitively inhibit the binding of histamine to its receptors. The term “antihistamine” in common clinical parlance typically refers to H₁ receptor antagonists, which form the cornerstone of therapy for allergic disorders. The clinical relevance of these drugs is substantial, given the high global prevalence of allergic conditions such as allergic rhinitis, urticaria, and conjunctivitis. Beyond their anti-allergic properties, many first-generation agents exhibit significant effects on the central nervous system, leading to both therapeutic applications and undesirable sedation.

The development of antihistamines represents a pivotal advancement in pharmacotherapy. Since the introduction of the first compounds in the 1940s, the evolution from sedating, first-generation drugs to selective, non-sedating second-generation agents has markedly improved the risk-benefit profile for patients. Understanding the pharmacology of these agents—encompassing their molecular mechanisms, pharmacokinetic profiles, therapeutic applications, and adverse effect spectra—is essential for rational prescribing in medical and pharmacy practice.

Learning Objectives

• Classify H₁ antihistamines based on chemical structure, receptor selectivity, and sedative potential.
• Explain the molecular mechanism of action of H₁ receptor antagonists and differentiate it from the action of H₂ receptor antagonists.
• Analyze the pharmacokinetic properties of major antihistamine classes and relate these to dosing regimens and therapeutic outcomes.
• Evaluate the approved clinical indications, off-label uses, and limitations of antihistamine therapy.
• Identify common and serious adverse effects, major drug interactions, and special population considerations for antihistamine administration.

Classification

Antihistamines are systematically classified according to their primary receptor antagonism and their propensity to cause sedation. The most clinically significant division is between H₁ and H₂ receptor antagonists, which have distinct therapeutic roles. H₃ and H₄ receptor antagonists remain largely experimental or in early clinical development.

H₁ Receptor Antagonists

This class is further subdivided into first-generation (sedating) and second-generation (non-sedating or less-sedating) agents. The classification is based primarily on their ability to penetrate the blood-brain barrier.

• First-Generation (Classical) Antihistamines: These are lipophilic compounds that readily cross the blood-brain barrier, resulting in significant central nervous system effects, including sedation. They often exhibit poor receptor selectivity, with notable antimuscarinic, anti-α-adrenergic, and local anesthetic properties. Chemical classes within this group include:
  • Ethanolamines (e.g., diphenhydramine, dimenhydrinate, clemastine)
  • Ethylenediamines (e.g., pyrilamine, tripelennamine)
  • Alkylamines (e.g., chlorpheniramine, brompheniramine)
  • Piperazines (e.g., hydroxyzine, cyclizine, meclizine)
  • Phenothiazines (e.g., promethazine)
  • Piperidines (e.g., cyproheptadine)
• Second-Generation (Non-Sedating) 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. Key agents include:
  • Piperidines: Loratadine, desloratadine, fexofenadine
  • Piperazines: Cetirizine, levocetirizine
  • Phthalazinones: Azelastine (also available as a nasal spray)
  • Others: Olopatadine, ketotifen (often used in ophthalmic formulations)

H₂ Receptor Antagonists

These agents, such as cimetidine, ranitidine, famotidine, and nizatidine, selectively antagonize histamine H₂ receptors primarily located on gastric parietal cells. Their main therapeutic application is the inhibition of gastric acid secretion for the management of peptic ulcer disease and gastroesophageal reflux disease. Their pharmacology is distinct from H₁ antagonists and is typically covered in chapters dedicated to gastrointestinal drugs.

Mechanism of Action

The primary mechanism of H₁ antihistamines is reversible, competitive antagonism at the histamine H₁ receptor. These receptors are G-protein-coupled receptors (GPCRs) whose activation by histamine triggers the intracellular phosphoinositide pathway via G_q/11 proteins.

Receptor Interactions and Signal Transduction

Under physiological conditions, histamine binding to the H₁ receptor activates phospholipase C (PLC). PLC catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP₂) into inositol trisphosphate (IP₃) and diacylglycerol (DAG). IP₃ mobilizes intracellular calcium stores, while DAG activates protein kinase C (PKC). This cascade results in the characteristic effects of histamine: vascular smooth muscle relaxation (contributing to vasodilation and edema), increased vascular permeability, contraction of bronchial and gastrointestinal smooth muscle, stimulation of sensory nerve endings (causing pruritus and pain), and modulation of neurotransmitter release in the central nervous system.

Antihistamines bind to the H₁ receptor at or near the histamine-binding site, stabilizing the receptor in its inactive conformation. This prevents the conformational change required for G-protein coupling and subsequent signal transduction. The antagonism is surmountable; a sufficiently high concentration of histamine can displace the antagonist, which has implications for dosing in acute allergic reactions.

Additional Pharmacodynamic Properties

Many first-generation antihistamines possess significant affinity for other receptor systems, which accounts for their broader side effect profile. Antimuscarinic effects (dry mouth, urinary retention, blurred vision) are common with ethanolamines and ethylenediamines. Anti-α-adrenergic activity can lead to orthostatic hypotension and reflex tachycardia. Several agents, particularly those of the ethanolamine and phenothiazine classes, exhibit local anesthetic properties by blocking voltage-gated sodium channels. Some second-generation agents, such as cetirizine and azelastine, are reported to have additional anti-inflammatory properties, including inhibition of mediator release from mast cells and downregulation of adhesion molecule expression, though the clinical significance of these effects may be modest.

Pharmacokinetics

The pharmacokinetic profiles of antihistamines vary widely between classes and individual agents, influencing their onset of action, duration of effect, and suitability for different patient populations.

Absorption

Most H₁ antagonists are well absorbed following oral administration, with peak plasma concentrations (C_max) typically achieved within 1 to 3 hours. Bioavailability can be variable. 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 organic anion transporting polypeptide (OATP) transporters in the gut. The absorption of some agents, like cetirizine and levocetirizine, is not significantly affected by food.

Distribution

Distribution characteristics are the primary determinant of a drug’s sedative potential. First-generation agents are generally lipophilic and widely distributed throughout the body, including facile penetration of the blood-brain barrier. Their volume of distribution (V_d) is often large. Second-generation agents are designed to be more hydrophilic or are substrates for efflux transporters like P-glycoprotein at the blood-brain barrier, limiting their central nervous system penetration. Protein binding varies; cetirizine is approximately 93% bound to plasma proteins, while fexofenadine is 60-70% bound.

Metabolism

Hepatic metabolism via the cytochrome P450 (CYP) system is a major route of elimination for many antihistamines. Loratadine is metabolized extensively by CYP3A4 and, to a lesser extent, CYP2D6 to its active metabolite, desloratadine. Similarly, rupatadine is metabolized by CYP3A4. This creates potential for significant drug-drug interactions with CYP inhibitors (e.g., ketoconazole, erythromycin) or inducers. Fexofenadine and cetirizine undergo minimal hepatic metabolism; fexofenadine is excreted largely unchanged, and cetirizine is primarily cleared renally, with a small fraction metabolized. The metabolism of first-generation agents like diphenhydramine involves multiple CYP isoforms, including CYP2D6.

Excretion

Elimination pathways are drug-specific. Renal excretion of unchanged drug is significant for cetirizine, levocetirizine, and fexofenadine. Biliary and fecal excretion contributes to the elimination of loratadine and its metabolites. The elimination half-life (t_1/2) dictates dosing frequency:

• Short-acting (t_1/2 < 6 hours): Diphenhydramine (~4-8 hours), chlorpheniramine (~20 hours, but often dosed every 4-6 hours due to historical practice).
• Intermediate-acting (t_1/2 6-24 hours): Cetirizine (~8 hours), loratadine (~8 hours, but active metabolite extends effect).
• Long-acting (t_1/2 > 24 hours): Desloratadine (~27 hours), fexofenadine (~14 hours).

Dosing considerations must account for these parameters. For example, agents with long half-lives are suitable for once-daily dosing, improving adherence. Dose adjustment is often required in patients with hepatic or renal impairment, particularly for drugs cleared by these routes.

Therapeutic Uses/Clinical Applications

H₁ antihistamines are employed in the management of a variety of conditions, primarily those mediated by histamine release.

Approved Indications

• Allergic Rhinitis: This is the most common indication. Antihistamines effectively reduce symptoms of sneezing, rhinorrhea, nasal pruritus, and ocular symptoms (itching, tearing). Second-generation oral agents and intranasal formulations (e.g., azelastine, olopatadine) are first-line therapies.
• Chronic Spontaneous Urticaria: H₁ antagonists are the cornerstone of symptomatic treatment for wheals and pruritus. Up-dosing (up to four times the standard dose) of second-generation agents is recommended in treatment guidelines before considering add-on therapies.
• Allergic Conjunctivitis: Topical ophthalmic preparations (e.g., olopatadine, ketotifen, azelastine) provide rapid relief from itching and redness.
• Acute Urticaria and Anaphylaxis Adjunct Therapy: While not first-line for anaphylaxis (epinephrine is), parenteral first-generation antihistamines like diphenhydramine are used as adjunctive therapy to control cutaneous symptoms (urticaria, angioedema) and pruritus.
• Motion Sickness and Vertigo: First-generation agents with antimuscarinic properties, such as dimenhydrinate, meclizine, and promethazine, are effective prophylactic agents for motion sickness and in the management of vestibular disorders like Ménière’s disease.
• Insomnia (Short-term): The sedating effect of first-generation agents like diphenhydramine and doxylamine is exploited in over-the-counter sleep aids. Their use is generally recommended only for short-term management due to tolerance, anticholinergic effects, and potential cognitive impairment.
• Nausea and Vomiting: Phenothiazines (e.g., promethazine) are used for their antiemetic properties, particularly in postoperative nausea and vomiting or chemotherapy-induced nausea, though they have been largely superseded by more selective antiemetics.

Off-Label Uses

• Pruritus of Non-Allergic Origin: Used in conditions like atopic dermatitis, though their efficacy is often limited, and sedation from first-generation agents may be the primary mechanism for nocturnal itch relief.
• Anxiety: Hydroxyzine, a first-generation agent, is sometimes used for its anxiolytic properties, which are attributed to its antihistaminic and possibly antimuscarinic effects in the CNS.
• Appetite Stimulation: Cyproheptadine has been used to stimulate appetite in underweight patients due to its antiserotonergic effects.
• Parkinsonism and Drug-Induced Dystonias: Diphenhydramine’s central antimuscarinic action can provide temporary relief for acute dystonic reactions, such as those induced by antipsychotic medications.

Adverse Effects

The adverse effect profile differs markedly between first- and second-generation antihistamines.

Common Side Effects

• First-Generation Agents:
  • Central Nervous System: Sedation, drowsiness, fatigue, impaired cognitive and psychomotor performance are dose-dependent and can be profound. Paradoxical excitation (restlessness, insomnia) may occur in children and some adults.
  • Antimuscarinic Effects: Dry mouth, blurred vision, urinary retention, constipation, and tachycardia.
  • Gastrointestinal: Nausea, epigastric distress, changes in appetite.
• Second-Generation Agents:
  • These are generally well-tolerated. Headache is the most frequently reported side effect. Mild somnolence may occur in a small subset of patients, particularly with cetirizine. Dry mouth and fatigue are also occasionally reported.

Serious/Rare Adverse Reactions

• Cardiac Toxicity: Certain second-generation antihistamines that were withdrawn from the market (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). The currently available second-generation agents (loratadine, desloratadine, fexofenadine, cetirizine) carry a negligible risk of this effect at recommended doses.
• Hypersensitivity Reactions: Rare cases of urticaria, anaphylaxis, and photosensitivity have been reported.
• Blood Dyscrasias: Agranulocytosis, thrombocytopenia, and hemolytic anemia are extremely rare idiosyncratic reactions.
• Seizures: Overdose of first-generation agents, particularly in children, can lower the seizure threshold.

No black box warnings are currently mandated for commonly prescribed second-generation H₁ antihistamines. However, promethazine carries a black box warning regarding severe tissue injury, including gangrene, following intravenous or intra-arterial administration.

Drug Interactions

Antihistamines can participate in pharmacokinetic and pharmacodynamic interactions.

Major Drug-Drug Interactions

• CNS Depressants: First-generation antihistamines potentiate the sedative effects of alcohol, benzodiazepines, opioids, barbiturates, and other sedative-hypnotics, significantly impairing alertness and motor coordination.
• CYP3A4 Inhibitors: Potent inhibitors like ketoconazole, itraconazole, erythromycin, and clarithromycin can dramatically increase plasma concentrations of metabolized antihistamines (e.g., loratadine, rupatadine). While the risk of cardiotoxicity with modern agents is low, the increased exposure can amplify other side effects like sedation.
• Anticholinergic Drugs: Concurrent use with other agents possessing antimuscarinic activity (e.g., tricyclic antidepressants, antipsychotics, antispasmodics) can lead to an additive anticholinergic burden, increasing the risk of urinary retention, constipation, blurred vision, and cognitive dysfunction, particularly in the elderly.
• Monoamine Oxidase Inhibitors (MAOIs): MAOIs may potentiate the anticholinergic and sedative effects of first-generation antihistamines.
• P-glycoprotein Inhibitors: Drugs like verapamil and cyclosporine may increase the central nervous system penetration of fexofenadine by inhibiting its efflux at the blood-brain barrier, though the clinical impact appears minimal.

Contraindications

• Narrow-Angle Glaucoma: The antimuscarinic effects of first-generation agents can precipitate an acute attack by causing mydriasis and increasing intraocular pressure.
• Severe Prostatic Hyperplasia or Bladder Neck Obstruction: Anticholinergic effects can exacerbate urinary retention.
• Severe Respiratory Conditions (e.g., asthma with significant bronchial secretions): Anticholinergic drying of secretions can lead to mucus plugging.
• Concurrent Use of QT-Prolonging Drugs: While low risk, caution is advised when using antihistamines with other drugs known to prolong the QT interval (e.g., certain antiarrhythmics, macrolide antibiotics, antipsychotics) in patients with underlying cardiac disease or electrolyte disturbances.
• Neonates and Premature Infants: Contraindicated due to increased risk of CNS and cardiovascular effects.

Special Considerations

Pregnancy and Lactation

Treatment decisions require careful risk-benefit analysis. Most antihistamines are classified as FDA Pregnancy Category B (animal studies have not demonstrated risk, but no adequate human studies exist) or C (risk cannot be ruled out). Chlorpheniramine and loratadine are often considered first-line options for allergic rhinitis in pregnancy based on accumulated observational data suggesting a low risk of teratogenicity. Diphenhydramine is also used but may have greater sedative effects. Cetirizine and levocetirizine are considered alternatives. During lactation, first-generation agents are generally not preferred as they can cause sedation and irritability in the infant. Loratadine and cetirizine, which have low milk-to-plasma ratios and minimal sedative effects, are often recommended if antihistamine therapy is necessary.

Pediatric Considerations

Second-generation agents are preferred in children due to their favorable side effect profile. Dosing is typically based on weight or age. Sedating antihistamines can impair learning and school performance and may cause paradoxical excitation. The use of over-the-counter cough and cold products containing antihistamines is not recommended in children under 4-6 years of age due to lack of proven efficacy and risk of serious adverse effects, including overdose.

Geriatric Considerations

Older adults are particularly sensitive to the adverse effects of first-generation antihistamines. The anticholinergic effects can precipitate or worsen cognitive impairment, delirium, constipation, urinary retention, dry mouth leading to dental caries, and postural hypotension with risk of falls. These agents are strongly discouraged in this population. Second-generation agents are the treatment of choice. Furthermore, age-related decline in renal and hepatic function may necessitate dose reduction for agents cleared by these pathways (e.g., cetirizine in renal impairment, loratadine in hepatic impairment).

Renal and Hepatic Impairment

• Renal Impairment: For drugs primarily excreted renally (cetirizine, levocetirizine, fexofenadine), dose reduction is required. For example, the dose of cetirizine is typically halved in patients with moderate to severe renal impairment (creatinine clearance < 30 mL/min).
• Hepatic Impairment: For agents extensively metabolized by the liver (loratadine, desloratadine, hydroxyzine), clearance may be reduced, and lower doses or extended dosing intervals are recommended. The pharmacokinetics of fexofenadine are not significantly altered in mild to moderate hepatic impairment.

Summary/Key Points

• H₁ antihistamines function as competitive antagonists at the histamine H₁ receptor, blocking the downstream effects of histamine release, which include vasodilation, increased vascular permeability, smooth muscle contraction, and pruritus.
• The major classification divides H₁ antagonists into first-generation (sedating, lipophilic, less receptor-selective) and second-generation (non-sedating, hydrophilic or P-gp substrates, more selective) agents.
• Pharmacokinetic properties, especially lipophilicity and susceptibility to hepatic metabolism, determine central nervous system penetration, duration of action, and drug interaction potential. Second-generation agents like fexofenadine and cetirizine have favorable profiles with minimal CYP450-mediated interactions.
• The primary therapeutic applications are allergic rhinitis, urticaria, and allergic conjunctivitis. First-generation agents have additional roles in motion sickness, insomnia, and as antiemetics, but their use is limited by adverse effects.
• Adverse effects are class-dependent: first-generation agents cause significant sedation, cognitive impairment, and antimuscarinic effects, while second-generation agents are generally well-tolerated with headache being most common.
• Significant drug interactions exist with CNS depressants, CYP3A4 inhibitors (for metabolized agents), and other anticholinergic drugs.
• Special population management is critical: second-generation agents are preferred in pediatric, geriatric, and pregnant/lactating patients, with dose adjustments required in renal or hepatic impairment.

Clinical Pearls

• For chronic allergic conditions, second-generation antihistamines are first-line due to superior safety and minimal impact on daily functioning.
• In acute anaphylaxis, H₁ antihistamines are adjunctive only; epinephrine remains the life-saving first-line treatment.
• The sedative effects of first-generation antihistamines can persist into the next day (“hangover” effect) and significantly impair driving ability equivalent to or greater than alcohol.
• Up-dosing of second-generation antihistamines (e.g., up to four times standard dose) is an accepted strategy in refractory chronic urticaria before advancing to third-line therapies like omalizumab or cyclosporine.
• When selecting an agent, consider comorbidities: avoid anticholinergic agents in patients with benign prostatic hyperplasia, glaucoma, or cognitive impairment, and prefer renally cleared drugs in patients with significant liver disease.

References

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