Chapter: Pharmacology of Cetirizine

1. Introduction/Overview

Cetirizine is a widely prescribed second-generation antihistamine, recognized as a cornerstone in the management of allergic conditions. As a piperazine derivative and a carboxylated metabolite of hydroxyzine, it represents a significant advancement over first-generation agents due to its improved receptor selectivity and reduced penetration of the blood-brain barrier. The clinical importance of cetirizine stems from its efficacy in alleviating symptoms associated with immunoglobulin E (IgE)-mediated hypersensitivity reactions, offering patients relief from pruritus, rhinorrhea, sneezing, and urticaria with a generally favorable side effect profile. Its established role in therapeutic guidelines for allergic rhinitis and chronic spontaneous urticaria underscores its relevance in both primary care and specialist settings.

Learning Objectives

Upon completion of this chapter, the reader should be able to:

• Describe the pharmacodynamic mechanism of cetirizine as a competitive histamine H₁-receptor antagonist and explain its selectivity profile.
• Outline the pharmacokinetic properties of cetirizine, including its absorption, distribution, minimal metabolism, and renal excretion, and relate these to dosing regimens.
• Identify the approved clinical indications for cetirizine and evaluate its role in the management of allergic rhinitis and urticaria.
• Analyze the common and serious adverse effect profile of cetirizine, contrasting it with first-generation antihistamines, particularly regarding central nervous system effects.
• Apply knowledge of cetirizine’s pharmacology to special populations, including pediatric and geriatric patients, and those with renal or hepatic impairment.

2. Classification

Cetirizine can be classified according to several pharmacological and chemical schemas, which inform its clinical behavior and therapeutic application.

Pharmacotherapeutic Classification

Cetirizine is primarily classified as a second-generation H₁-receptor antagonist (antihistamine). This classification distinguishes it from first-generation agents (e.g., diphenhydramine, chlorpheniramine) based on key characteristics. Second-generation antihistamines are characterized by high specificity for peripheral H₁ receptors, minimal anticholinergic activity, and a reduced propensity to cross the blood-brain barrier, thereby minimizing sedative effects. Within this class, cetirizine is often described as a “low-sedation” antihistamine, though its potential for causing somnolence, while lower than first-generation drugs, may be slightly higher than other second-generation agents like loratadine or fexofenadine in some individuals.

Chemical Classification

Chemically, cetirizine is designated as (±)-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acid. It is a racemic mixture. More informatively, it is a piperazine derivative and the principal active carboxylic acid metabolite of the first-generation antihistamine hydroxyzine. This carboxylation is a critical structural feature that increases its polarity, reducing its lipid solubility and thus its distribution into the central nervous system. Cetirizine is a zwitterion at physiological pH, possessing both a basic piperazine nitrogen and an acidic carboxyl group, which influences its pharmacokinetic properties.

3. Mechanism of Action

The therapeutic effects of cetirizine are predominantly mediated through competitive antagonism of histamine at the H₁-receptor, though additional anti-inflammatory properties may contribute to its clinical efficacy.

Histamine H₁-Receptor Antagonism

Cetirizine acts as a potent, selective, and competitive inverse agonist at the peripheral H₁-receptor. Histamine, released from mast cells and basophils during allergic reactions, binds to the H₁-receptor, a G-protein coupled receptor (GPCR). This binding activates phospholipase C, leading to the generation of inositol trisphosphate (IP₃) and diacylglycerol (DAG), culminating in increased intracellular calcium and the clinical manifestations of allergy: vasodilation, increased vascular permeability, smooth muscle contraction (e.g., in bronchi), sensory nerve stimulation (pruritus, pain), and glandular secretion.

Cetirizine binds with high affinity to the inactive conformational state of the H₁-receptor, stabilizing it and preventing histamine from inducing the active signaling state. By occupying the receptor binding site, it competitively inhibits histamine binding. As an inverse agonist, it may also suppress basal, constitutive receptor activity. This antagonism effectively blocks the downstream effects of histamine, leading to reduction in:

• Capillary dilation and edema (wheal and flare response).
• Pruritus and sneezing reflexes.
• Rhinorrhea and lacrimation.

Its affinity for the H₁-receptor is high, with a dissociation constant (K_d) in the nanomolar range. Importantly, cetirizine exhibits minimal affinity for muscarinic cholinergic, alpha-adrenergic, or serotonin receptors at therapeutic doses, accounting for its low incidence of anticholinergic side effects such as dry mouth, urinary retention, or blurred vision.

Additional Anti-inflammatory Properties

Beyond receptor blockade, evidence suggests cetirizine possesses anti-inflammatory activities that are not solely dependent on H₁ antagonism. These effects, observed at higher concentrations or with prolonged use, may explain its superior efficacy in some models compared to pure receptor antagonists. Proposed mechanisms include:

• Inhibition of Inflammatory Cell Recruitment: Cetirizine may reduce the expression of adhesion molecules (e.g., ICAM-1) on endothelial cells, impairing the migration and infiltration of eosinophils, neutrophils, and other inflammatory cells into allergic reaction sites.
• Modulation of Mediator Release: Some in vitro studies indicate a potential to inhibit the release of histamine and other pro-inflammatory mediators (e.g., leukotrienes, cytokines) from mast cells and basophils, though the clinical significance of this effect remains uncertain.
• Antioxidant Effects: A free radical scavenging activity has been demonstrated, which could mitigate oxidative stress associated with allergic inflammation.

These ancillary properties might contribute to its effectiveness in conditions like chronic urticaria, where multiple inflammatory pathways are involved.

4. Pharmacokinetics

The pharmacokinetic profile of cetirizine is characterized by rapid oral absorption, limited distribution, minimal hepatic metabolism, and predominant renal excretion of the unchanged drug.

Absorption

Cetirizine is rapidly and extensively absorbed following oral administration. Peak plasma concentrations (C_max) are typically achieved within 1 hour (t_max ≈ 1 h) in fasted adults. The presence of food may delay the rate of absorption, prolonging t_max by approximately 1.5 hours and reducing C_max by about 23%, but the overall extent of absorption (measured by area under the curve, AUC) is not significantly altered. The oral bioavailability is estimated to be high, likely exceeding 70%. The absorption kinetics generally follow first-order processes.

Distribution

Cetirizine exhibits a moderate volume of distribution (V_d ≈ 0.5 L/kg), indicating distribution largely within the extracellular fluid. Its zwitterionic nature and relatively low lipophilicity limit its penetration into the central nervous system. The concentration of cetirizine in cerebrospinal fluid is approximately 10-20% of plasma levels, which correlates with its reduced sedative potential compared to more lipophilic first-generation antihistamines. Plasma protein binding is consistent at approximately 93%, primarily to albumin. Cetirizine crosses the placenta and is excreted into breast milk, considerations relevant for use in pregnancy and lactation.

Metabolism

Cetirizine undergoes minimal hepatic metabolism. Unlike many drugs, it is not a substrate for the cytochrome P450 enzyme system to a clinically significant degree. A small fraction (less than 10-14% of the administered dose) may be oxidized via CYP3A4 and, to a lesser extent, CYP2C19, but this pathway is not a major route of elimination. The lack of significant metabolism reduces its potential for pharmacokinetic drug interactions mediated by enzyme induction or inhibition. Cetirizine is not converted to active metabolites; it is itself the active metabolite of hydroxyzine.

Excretion

The primary route of elimination for cetirizine is renal excretion of the unchanged drug. Approximately 70% of an orally administered dose is recovered in the urine as parent compound over 96 hours. A smaller proportion (about 10%) is eliminated in the feces. The renal clearance of cetirizine (≈ 30 mL/min) is less than the glomerular filtration rate, suggesting a component of active tubular secretion, likely via organic cation transporters (OCTs), alongside glomerular filtration. The elimination half-life (t_1/2) in adults with normal renal function is approximately 8-10 hours. This allows for once-daily dosing in most patients.

Pharmacokinetic Parameters and Dosing Considerations

The standard adult and pediatric (≥6 years) dose is 5-10 mg once daily, typically administered in the evening if sedation is a concern. The linear pharmacokinetics over the therapeutic dose range allow for predictable plasma concentrations. The relationship between dose (D), clearance (CL), and steady-state concentration (C_ss) can be described by the fundamental pharmacokinetic equation: C_ss = (F × Dose) ÷ (CL × τ), where F is bioavailability and τ is the dosing interval. Given its renal clearance, the most critical factor altering cetirizine’s pharmacokinetics is impaired renal function. In patients with moderate to severe renal impairment (creatinine clearance < 30 mL/min) or on hemodialysis, the elimination half-life is prolonged significantly (up to 18-21 hours), and dose reduction (e.g., 5 mg every other day) is required to prevent accumulation and increased risk of adverse effects. Hepatic impairment has a less pronounced effect, but caution is still advised in severe liver disease.

5. Therapeutic Uses/Clinical Applications

Cetirizine is indicated for the symptomatic relief of conditions mediated by histamine release. Its efficacy is well-established in large-scale clinical trials and meta-analyses.

Approved Indications

• Seasonal Allergic Rhinitis (Hay Fever): Cetirizine effectively reduces symptoms of sneezing, rhinorrhea, nasal pruritus, and ocular symptoms (itching, redness, tearing) associated with seasonal allergens such as pollen.
• Perennial Allergic Rhinitis: It is similarly effective for year-round symptoms triggered by indoor allergens like dust mites, mold, and animal dander.
• Chronic Spontaneous Urticaria (Chronic Idiopathic Urticaria): Cetirizine is a first-line therapy for reducing pruritus and decreasing the number, size, and duration of wheals (hives) in chronic urticaria. Its anti-inflammatory properties may be particularly relevant in this condition.
• Allergic Conjunctivitis: While often used systemically, it alleviates ocular itching and redness associated with allergies.
• Other Allergic Dermatoses: It is useful in managing pruritus associated with atopic dermatitis and other allergic skin conditions, though it is not a primary treatment for the underlying inflammation.

Off-Label Uses

Several off-label applications are supported by clinical evidence, though they are not formally approved in all jurisdictions.

• Acute Urticaria: Often used for symptomatic relief in acute allergic reactions presenting with hives.
• Physical Urticarias: Such as dermatographism or cold urticaria, where cetirizine may provide prophylactic benefit.
• Mast Cell Activation Syndromes: May be used as part of a regimen to control histamine-mediated symptoms.
• Pruritus of Non-Allergic Origin: Occasionally employed for pruritus in conditions like polycythemia vera or chronic kidney disease, with variable results.
• Adjunct in Anaphylaxis: While never a substitute for intramuscular epinephrine, cetirizine may be used adjunctively to manage cutaneous symptoms after the acute, life-threatening phase is controlled.

The efficacy of cetirizine in these conditions is typically assessed using symptom score reductions, quality-of-life questionnaires, and objective measures like histamine-induced wheal and flare suppression.

6. Adverse Effects

Cetirizine is generally well-tolerated, with a side effect profile markedly improved over first-generation antihistamines. Most adverse reactions are mild to moderate in severity and often transient.

Common Side Effects

The incidence of common side effects, as observed in placebo-controlled trials, is often only marginally higher than with placebo. The most frequently reported effects include:

• Sedation/Somnolence: Reported in approximately 10-15% of patients, compared to 6% on placebo. This is the most common dose-related adverse effect. While significantly less than with diphenhydramine (≈ 50%), it remains more frequent than with some other second-generation agents like loratadine or fexofenadine. The effect is usually mild and may diminish with continued use.
• Fatigue and Asthenia: A feeling of tiredness or lack of energy may occur independently of overt sedation.
• Dry Mouth: Occurs in approximately 5% of patients, a consequence of very weak anticholinergic activity at high doses.
• Headache: Reported at an incidence similar to placebo.
• Gastrointestinal Disturbances: Nausea, dyspepsia, and abdominal pain occur infrequently.
• Pharyngitis and Cough: These upper respiratory symptoms have been reported in some studies.

Serious/Rare Adverse Reactions

Serious adverse events are uncommon with cetirizine monotherapy at recommended doses.

• Hypersensitivity Reactions: Rare cases of anaphylaxis, angioedema, bronchospasm, and severe cutaneous adverse reactions (e.g., Stevens-Johnson syndrome) have been reported. Immediate discontinuation is required.
• Cardiovascular Effects: At very high doses (significantly exceeding therapeutic recommendations), some H₁-antihistamines have been associated with QT interval prolongation. While cetirizine has a very low affinity for cardiac potassium channels, extreme overdoses could theoretically pose a risk. At standard doses, it is considered to have no significant cardiac effects.
• Central Nervous System Effects: Paradoxical CNS stimulation, including nervousness, insomnia, tremor, or seizures, has been reported rarely, particularly in children.
• Hepatobiliary Disorders: Isolated cases of hepatitis and elevated liver enzymes have been documented.

There are no black box warnings issued by regulatory authorities for cetirizine when used at recommended doses.

7. Drug Interactions

The low metabolic liability of cetirizine results in a relatively low risk for pharmacokinetic drug interactions. However, pharmacodynamic interactions and considerations related to its renal excretion are important.

Major Drug-Drug Interactions

• CNS Depressants: Alcohol, benzodiazepines, barbiturates, opioid analgesics, sedating antidepressants, and other sedating antihistamines. Concomitant use may lead to additive CNS depression, impairing cognitive and motor performance. Patients should be cautioned about driving or operating machinery.

Theophylline: High doses of theophylline (≥ 400 mg every 6 hours) have been reported to decrease the clearance of cetirizine by approximately 16%, potentially increasing cetirizine plasma levels. The clinical significance of this interaction is likely minimal at standard theophylline doses.

• Drugs Competing for Renal Tubular Secretion: Since cetirizine undergoes active renal secretion, co-administration with other drugs eliminated by the same transport systems (e.g., procainamide, metformin, cimetidine) could theoretically reduce cetirizine clearance and increase its plasma concentration. In practice, such interactions are seldom clinically significant at therapeutic doses.
• Anticholinergic Agents: Concomitant use with drugs possessing strong anticholinergic properties (e.g., tricyclic antidepressants, oxybutynin, first-generation antihistamines) may theoretically increase the risk of anticholinergic side effects like dry mouth, urinary retention, or constipation, though cetirizine itself has minimal intrinsic anticholinergic activity.

Contraindications

Absolute contraindications to cetirizine are few but important:

• Hypersensitivity: Known hypersensitivity to cetirizine, hydroxyzine, or any component of the formulation. Cross-reactivity with other piperazine derivatives may be possible.
• Severe Renal Impairment: A contraindication exists only if appropriate dose adjustment is not implemented. Use of the standard 10 mg dose in patients with a creatinine clearance < 10 mL/min is contraindicated.
• Concomitant Use with Alcohol or Other CNS Depressants: While not an absolute contraindication, it is strongly discouraged due to additive impairment.

8. Special Considerations

The use of cetirizine requires tailored approaches in specific patient populations due to altered pharmacokinetics, pharmacodynamics, or safety profiles.

Pregnancy and Lactation

Pregnancy (FDA Category B): Animal reproduction studies have not demonstrated a risk to the fetus, but adequate and well-controlled studies in pregnant women are lacking. Cetirizine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It may be considered when antihistamine therapy is required, as some epidemiological data have not shown an increased risk of major malformations.

Lactation: Cetirizine is excreted into human breast milk. The milk-to-plasma ratio is approximately 0.9-1.4. The estimated daily infant dose via milk is 0.1-0.3% of the maternal weight-adjusted dose. While this amount is considered low, caution is advised. Potential effects on the nursing infant, such as sedation or irritability, should be monitored. Some guidelines suggest that loratadine may be preferred during breastfeeding due to even lower milk excretion.

Pediatric Considerations

Cetirizine is approved for children 6 months and older in syrup formulation, with dosing based on age and weight. For children aged 6 months to 5 years, the recommended dose is typically 2.5 mg once daily, which can be increased to 2.5 mg every 12 hours if needed. For children 6-11 years, the dose is 5-10 mg once daily. Efficacy in relieving allergic symptoms is similar to that in adults. The side effect profile is also comparable, though children may be more susceptible to paradoxical excitation (e.g., nervousness, insomnia). Long-term safety studies in children have not raised major concerns.

Geriatric Considerations

Elderly patients (≥65 years) may experience increased sensitivity to antihistamines. Age-related decline in renal function is a key consideration. Since creatinine clearance decreases with age, even in the absence of overt renal disease, the elimination half-life of cetirizine may be prolonged. A lower starting dose (5 mg daily) is often recommended. Furthermore, elderly patients are more susceptible to the CNS effects (dizziness, sedation), anticholinergic effects (dry mouth, potential urinary retention), and are at higher risk of falls. Concomitant use with other CNS-active medications, which is common in this population, requires careful review.

Renal and Hepatic Impairment

Renal Impairment: Dose adjustment is mandatory. For mild impairment (CrCl 50-79 mL/min), a maximum dose of 10 mg daily may be given. For moderate impairment (CrCl 30-49 mL/min), the dose should be reduced to 5 mg daily. For severe impairment (CrCl 10-29 mL/min), the dose is 5 mg every other day. In end-stage renal disease (CrCl < 10 mL/min) or patients on hemodialysis, cetirizine is contraindicated at standard doses; use is not recommended as it is not significantly removed by dialysis.

Hepatic Impairment: In patients with hepatic impairment but normal renal function, no dose adjustment is typically required. However, in cases of severe hepatic impairment, a reduction to 5 mg daily may be prudent due to potential alterations in protein binding and the minor metabolic pathway.

9. Summary/Key Points

Cetirizine is a fundamental therapeutic agent in the management of histamine-mediated allergic disorders, distinguished by its pharmacologic profile and clinical utility.

Bullet Point Summary

• Cetirizine is a second-generation, piperazine-derived, competitive inverse agonist at the peripheral H₁-histamine receptor, with additional anti-inflammatory properties.
• Its pharmacokinetics are defined by rapid oral absorption, minimal metabolism, and predominant renal excretion of unchanged drug, yielding a half-life of 8-10 hours.
• Primary indications include seasonal/perennial allergic rhinitis and chronic spontaneous urticaria, where it effectively reduces core symptoms.
• The adverse effect profile is favorable, with somnolence being the most common dose-related effect; serious reactions are rare.
• Significant drug interactions are limited, primarily to additive CNS depression with other sedating agents.
• Dose adjustment is critical in renal impairment but generally not required in hepatic impairment. Caution is advised in the elderly, and use in pregnancy/lactation requires benefit-risk assessment.

Clinical Pearls

• For patients experiencing sedation, administering the dose in the evening can improve tolerability while maintaining 24-hour efficacy.
• In chronic urticaria, regular daily dosing is more effective than “as-needed” use for suppressing wheal formation.
• Lack of response to one second-generation antihistamine does not predict failure of another; switching agents (e.g., to loratadine or fexofenadine) may be warranted if sedation is problematic.
• Always calculate creatinine clearance in elderly patients before initiating therapy to guide appropriate dosing.
• While cetirizine is effective for allergic ocular symptoms, topical ocular antihistamine/mast cell stabilizer combinations may provide more rapid and targeted relief for isolated eye symptoms.

References

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