Cetizal 5 Mechanism of Action

Pharmacotherapeutic group: Antihistamine for systemic use, piperazine derivative.
Pharmacology: Levocetirize, the (R) enantiomer of Cetirizine, is a potent and selective antagonist of peripheral H₁-receptors. Levocetirizine has high affinity for human H₁-receptors. Levocetirizine dissociates from H₁-receptors with a half-life of 115 ± 38 min. After single administration, Levocetirizine shows a receptor occupancy of 90% at 4 hours and 57% at 24 hours.
Pharmacokinetics: The pharmacokinetics of Levocetirizine are linear with dose- and time-independent with low inter-subject variability. The pharmacokinetic profile is the same when given as the single enantiomer or when given as Cetirizine. No chiral inversion occurs during the process of absorption and elimination.
Absorption: Levocetirizine is rapidly and extensively absorbed following oral administration. In adults, peak plasma concentrations are achieved 0.9 hour after dosing. The extent of absorption is dose-independent and is not altered by food, but the peak concentration is reduced and delayed.
Distribution: No tissue distribution data are available in humans, neither concerning the passage of Levocetirizine through the blood-brain-barrier.
Levocetirizine is 90% bound to plasma proteins. The distribution of Levocetirizine is restrictive, as the volume of distribution is 0.4 L/Kg.
Metabolism: The extent of metabolism of Levocetirizine in humans is less than 14% of the dose and therefore differences resulting from genetic polymorphism or concomitant intake of enzyme inhibitors are expected to be negligible. Metabolic pathways include aromatic oxidation, N- and O- dealkylation and taurine conjugation. Dealkylation pathways are primarily mediated by CYP 3A4 while aromatic oxidation involved multiple and/or unidentified CYP isoforms. Levocetirizine had no effect on the activities of CYP isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 at concentrations well above peak concentrations achieved following a 5 mg oral dose.
Due to its low metabolism and absence of metabolic inhibition potential, the interaction of Levocetirizine with other substances, or vice-versa, is unlikely.
Elimination: The plasma half-life in adults is 7.9 ± 1.9 hours. The half-life is shorter in small children.
The major route of excretion of Levocetirizine and metabolites is via urine, accounting for a mean of 85.4% of the dose. Excretion via feces accounts for only 12.9% of the dose. Levocetirizine is excreted both by glomerular filtration and active tubular secretion.
Special population: Renal impairment: The apparent body clearance of Levocetirizine is correlated to the creatinine clearance. It is therefore recommended to adjust the dosing intervals of Levocetirizine, based on creatinine clearance in patients with moderate and severe renal impairment. In end-stage renal disease subjects, the total body clearance is decreased by approximately 80% when compared to normal subjects.
Pediatric population: In children 6 to 11 years of age, C_max and AUC volumes were about 2 fold greater than in adults. Total body clearance was 30% greater and elimination half-life was 24% shorter when compared with adults.
Elderly: The disposition of racemic Cetirizine is dependent on renal function rather than on age. This finding would also be applicable for Levocetirizine, as Levocetirizine and Cetirizine are both predominantly excreted in urine. Therefore, the Levocetirizine dose should be adjusted in accordance with renal function in elderly patients.
Gender: Half-life was slightly shorter in women than in men. However, the body-weight adjusted oral clearance in women appeared to be comparable with that in men. The same daily dosage and dosing intervals are applicable for men and women with normal renal function.
Race: The effect of race on Levocetirizine has not been studied. As Levocetirizine is primarily renally excreted, and there are no important racial differences in creatinine clearance, pharmacokinetic characteristics of Levocetirizine are not expected to be different across races. No race-related differences in the kinetics of racemic Cetirizine have been observed.
Hepatic impairment: The pharmacokinetics of Levocetirizine in hepatically impaired subjects have not been tested. Patients with chronic liver diseases (hepatocellular, cholestatic, and biliary cirrhosis) given 10 or 20 mg of the racemic compound Cetirizine as a single dose had a 50% increase in half life along with a 40% decrease in clearance compared to healthy subjects.
Pharmacokinetic/pharmacodynamic relationship: The action on histamine-induced skin reactions is out of phase with the plasma concentrations.