Zyrtec Mechanism of Action

Pharmacotherapeutic group: Antihistamines for systemic use, piperazine derivatives. ATC Code: R06AE07.
Pharmacology: Pharmacodynamics: Mechanism of Action and Pharmacodynamic Effects: Cetirizine, a human metabolite of hydroxyzine, is a potent and selective antagonist of peripheral H₁-receptors. In vitro receptor binding studies have shown no measurable affinity for other than H₁-receptors.
Ex vivo experiments in mice have shown that systemically administered cetirizine does not significantly occupy the cerebral H₁-receptors.
In addition to its anti-H₁ effect, cetirizine was shown to display anti-allergic activities: at a dose of 10 mg once or twice daily, it inhibits the late phase recruitment of inflammatory cells, notably eosinophils, in the skin and conjunctiva of atopic subjects submitted to antigen challenge, and the dose of 30 mg/day inhibits the influx of eosinophils in the bronchoalveolar lavage fluid during a late-phase bronchial constriction induced by allergen inhalation in asthmatic subjects. Moreover, cetirizine inhibits the late-phase inflammatory reaction induced in chronic urticaria patients by intradermal administration of kallikrein. It also down-regulates the expression of adhesion molecules, such as ICAM-1 and VCAM-1, which are markers of allergic inflammation.
Studies in healthy volunteers show that cetirizine, at doses of 5 and 10 mg strongly inhibits the wheal and flare reactions induced by very high concentrations of histamine into the skin, but the correlation with efficacy is not established. The onset of activity after a single 10 mg dose occurs within 20 minutes in 50% of the subjects and within one hour in 95%. This activity persists for at least 24 hours after a single administration.
In a six-week, placebo-controlled study of 186 patients with allergic rhinitis and concomitant mild to moderate asthma, cetirizine 10 mg once daily improved rhinitis symptoms and did not alter pulmonary function. This study supports the safety of administering cetirizine to allergic patients with mild to moderate asthma.
In a placebo-controlled study, cetirizine given at the high daily dose of 60 mg for seven days did not cause statistically significant prolongation of QT interval.
At the recommended dosage, cetirizine has demonstrated that it improves the quality of life of patients with perennial and seasonal allergic rhinitis.
In a 35-day study in children aged 5 to 12, no tolerance to the antihistaminic effect (suppression of wheal and flare) of cetirizine was found. When treatment with cetirizine is stopped after repeated administration, the skin recovers its normal reactivity to histamine within 3 days.
Pharmacokinetics: Absorption: The steady-state peak plasma concentration is approximately 300 ng/ml and is achieved within 1.0 ± 0.5 h.
The distribution of pharmacokinetic parameters such as peak plasma concentration (C_max) and area under the curve (AUC), is unimodal.
The extent of absorption of cetirizine is not reduced with food, although the rate of absorption is decreased. The extent of bioavailability is similar when cetirizine is given as solutions, capsules or tablets.
Distribution: The apparent volume of distribution is 0.50 l/kg. Plasma protein binding of cetirizine is 93 ± 0.3%. Cetirizine does not modify the protein binding of warfarin.
Metabolism and Elimination: Cetirizine does not undergo extensive first pass metabolism. About two-thirds of the dose is excreted unchanged in urine. The terminal half-life is approximately 10 hours and no accumulation is observed for cetirizine following daily doses of 10 mg for 10 days. Cetirizine exhibits linear kinetics over the range 5 to 60 mg.
Special patient populations: Children: The half-life of cetirizine was about 6 hours in children of 6-12 years and 5 hours in children 2-6 years.
Elderly: Following a single 10 mg oral dose, half-life increased by about 50% and clearance decreased by 40% in 16 elderly subjects compared to the younger subjects. The decrease in cetirizine clearance in these elderly volunteers appeared to be related to their decreased renal function.
Renal impairment: The pharmacokinetics of the drug was similar in patients with mild impairment (creatinine clearance higher than 40 ml/min) and healthy volunteers. Patients with moderate renal impairment had a 3-fold increase in half-life and 70% decrease in clearance compared to healthy volunteers.
Patients on haemodialysis (creatinine clearance less than 7 ml/min) given a single oral 10 mg dose of cetirizine had a 3-fold increase in half-life and a 70% decrease in clearance compared to normals. Cetirizine was poorly cleared by haemodialysis. Dosing adjustment is necessary in patients with moderate or severe renal impairment.
Hepatic impairment: Patients with chronic liver diseases (hepatocellular, cholestatic, and biliary cirrhosis) given 10 or 20 mg of cetirizine as a single dose had a 50% increase in half-life along with a 40% decrease in clearance compared to healthy subjects.
Dosing adjustment is only necessary in hepatically impaired patients if concomitant renal impairment is present.
Toxicology: Non-Clinical Information: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.