Cetirizine -Zyrtec®
Cetirizine -Zyrtec®
Classification:
Antihistamines
Description: Cetirizine is the active metabolite of hydroxyzine, a piperazine H1-receptor antagonist. Cetirizine, however, differs from the parent compound by having greater affinity for the H1-receptor. Cetirizine has been demonstrated effective in the treatment of chronic idiopathic urticaria, perennial allergic rhinitis, and seasonal allergic rhinitis. Cetirizine has also been investigated for the treatment of allergic asthma, physical urticaria (triggered by physical stimuli) and for symptomatic relief of atopic dermatitis. Cetirizine, at recommended doses, may cause a higher incidence of somnolence than the non-sedating antihistamines fexofenadine and loratadine, although to a much lesser degree than older antihistamines. Like fexofenadine and loratadine, the cardiovascular safety of cetirizine has been demonstrated in drug-interaction studies, elevated-dose studies, and clinical trials. Cetirizine also appears well tolerated by pediatric and elderly patients. Cetirizine was initially FDA-approved for the treatment of allergic rhinitis and chronic urticaria on December 8, 1995; an expansion of labeling for use in infants as young as 6 months of age was FDA-approved in October 2002. A chewable tablet was FDA-approved in March 2004.
Mechanism of Action: Cetirizine has high affinity for histamine H1-receptors. It has less affinity, however, than terfenadine or hydroxyzine for calcium-channel, alpha-adrenergic, D2-dopamine, 5HT2-serotonin, and muscarinic receptors. In both atopic and normal human volunteers, cetirizine reduction of histamine wheal and flare is similar to that of clemastine, hydroxyzine, and terfenadine. The addition of the less lipophilic carboxyl group to the ethylamine side chain reduces the penetration of cetirizine into the CNS. Consequently, cetirizine produces a low incidence of sedation compared with older antihistamines. Drowsiness may, nevertheless, be dose-related.
The inflammatory response involves a number of mediators. Initial release of histamine from mast cells is followed by late-phase reactions involving a number of other cells. These include fibroblasts and epithelial cells, neutrophils, eosinophils (especially in conditions with raised IgE levels), macrophages, platelets, and lymphocytes. Cell adhesion can also be part of the inflammatory process. The action of cetirizine appears to involve a number of these mediators. Cetirizine’s effect on mast cells has generated conflicting reports. Some investigators found that cetirizine decreased prostaglandin D2, while others did not. Similarly, cetirizine may decrease leukotriene C4 production. Cetirizine plays a part in suppressing neutrophil migration in IgE-mediated reactions. Cetirizine reduces eosinophil infiltration to nasal mucosa in patients with seasonal allergic rhinitis. A similar effect is seen in patients with delayed-pressure urticaria. Cetirizine is not believed to affect the immune response, but it might affect cell adhesion. The mechanism of action may involve the inhibition of platelet-activating factor (PAF)-induced influx of eosinophils.
Chemical Structure For: Zyrtec
Pharmacokinetics: Cetirizine is administered orally. The bioavailability of the tablets and oral syrup is comparable. The drug has a rapid onset (i.e., time to Cmax 1 hour in adults) and a long duration of action. The overall bioavailability of cetirizine is not altered by the presence of food, although the rate of absorption can be slightly reduced. Penetration into the CNS is poor; CSF concentrations are less than 10% of peak serum concentrations.
Cetirizine is metabolized to limited extent via O-dealkylation to a metabolite with negligible activity; the enzyme(s) responsible for metabolism have not been determined. The elimination half-life of cetirizine in healthy volunteers ranges 6.5 - 10 hours (mean 8.3 hours). Overall recovery of an administered dose is roughly 70% in the urine, of which most (50%) of the radioactivity is unchanged drug (50%). Overall recovery from the feces is roughly 10%.
- Special Populations: Pharmacokinetic parameters have been investigated in pediatric and elderly patients, and those with impaired renal or hepatic function. Children exhibit greater weight-normalized apparent body clearances, with a 33 - 41% reduction in elimination half-life, when compared to adults. In general, elderly patients have decreased rates of clearance which correlate with age-associated reductions in creatinine clearance, and are not specifically age-related. Following a single, 10 mg oral dose, the elimination half-life was prolonged by 50% and the apparent total body clearance was 40% lower in 16 elderly subjects with a mean age of 77 years compared to 14 adult subjects with a mean age of 53 years. Dosage adjustment may be needed in patients 77 years of age and older (see Dosage). Patients with renal impairment exhibit a longer time to Cmax, decreased rates of clearance, and an increase in half-life up to 20 hours. Hemodialysis removes less than 10% of cetirizine from the blood. Dosing adjustment is necessary in patients with moderate or severe renal impairment (i.e., CrCl <= 30 ml/min) and in those on dialysis. Despite limited hepatic metabolism of cetirizine, patients with chronic liver disease (hepatocellular, cholestatic or biliary cirrhosis) have an altered pharmacokinetic profile, with a 50% increase in half-life along with a corresponding 40% decrease in clearance compared to healthy subjects; the changes may necessitate dosage adjustments.
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