Pharmacology of Cetirizine

Pharmacodynamics

Cetirizine acts as a highly selective antagonist of histamine H1 receptors.The Ki values for the H1 receptor are approximately 6 nM for cetirizine, approximately 3 nM for levocetirizine, and approximately 100 nM for dexetirizine, indicating that the levo-enantiomer is the predominant active form.Cetirizine is 600-fold or more selective for H1 receptors over a variety of other sites, including muscarinic acetylcholine, serotonin, dopamine, and alpha-adrenergic receptors, among others.The drug is 20,000-fold or more selective for H1 receptors over the five muscarinic acetylcholine receptors and therefore does not exhibit anticholinergic effects.It showed negligible inhibition of hERG channels (IC50 > 30 μM) and no cardiotoxicity was observed at doses of cetirizine up to 60 mg/day, which is normal Six times the recommended dose[3] and the highest dose of cetirizine has been studied in healthy subjects.

Cetirizine crosses the blood-brain barrier only slightly, so it produces minimal sedation compared to many other antihistamines.A positron emission tomography (PET) study found that brain occupancy of H1 receptors was 12.6% for 10 mg cetirizine, 25.2% for 20 mg cetirizine, and 67.6% for 30 mg hydroxyzine. %.(A 10 mg dose of cetirizine is equivalent to approximately 30 mg of hydroxyzine in terms of peripheral antihistamine effects.) PET studies of antihistamines found that brain H1 receptor occupancy A rate of more than 50% is associated with a high prevalence of drowsiness and cognitive decline, whereas a brain H1 receptor occupancy of less than 20% is considered non-sedating.Thus, H1 receptor occupancy was strongly associated with subjective sleepiness with 30 mg hydroxyzine but not with 10 or 20 mg cetirizine.Thus, the brain penetration and brain H1 receptor occupancy of cetirizine are dose-dependent, thus, although no sedation or mild sedation was reported for cetirizine at doses of 5 to 10 mg,20 Higher doses of mg have been shown to cause significant drowsiness in other studies.

Cetirizine also exhibits anti-inflammatory properties independent of H1 receptors.This effect works by inhibiting the NF-κB pathway, modulating the release of cytokines and chemokines, thereby modulating the recruitment of inflammatory cells.It has been shown to inhibit eosinophil chemotaxis and LTB4 release.At a dose of 20 mg, Boone et al. It was found to inhibit the expression of VCAM-1 in patients with atopic dermatitis.

Pharmacokinetics

Absorb:

Cetirizine is rapidly and extensively absorbed after oral administration in tablet or syrup form.Cetirizine has an oral bioavailability of at least 70% and levocetirizine has an oral bioavailability of at least 85%.Regardless of formulation, cetirizine has a Tmax of approximately 1.0 hours.The pharmacokinetics of cetirizine have been found to increase linearly with dose in the range of 5 to 60 mg.A single dose Cmax of 257 ng/mL (10 mg) and 580 ng/mL (20 mg) has been found.Food has no effect on the bioavailability of cetirizine, but has been found to delay Tmax by 1.7 hours (ie approximately 2.7 hours) and reduce Cmax by 23%.Similar findings were found with levocetirizine, which delayed Tmax by 1.25 hours and decreased Cmax by about 36% when taken with a high-fat meal.Steady-state levels of cetirizine occurred within 3 days and there was no drug accumulation with long-term administration.After taking 10 mg cetirizine daily for 10 days, the mean Cmax was 311 ng/mL.

Distribution

The average plasma protein binding of cetirizine has been found to be 93% to 96%, ranging from 25 to 1,000 ng/mL, independent of concentration.Multiple studies have also reported plasma protein binding of 88% to 96%.The drug binds albumin with high affinity, whereas α1-acid glycoproteins and lipoproteins contribute much less to total plasma protein binding.The unbound or free fraction of levocetirizine has been reported to be 8%.The true volume of distribution of cetirizine is unknown but estimated to be 0.3 to 0.45 L/kg.Cetirizine has difficulty crossing the blood-brain barrier slowly, which is thought to be due to its chemical properties and its activity as a substrate for P-glycoprotein.

Metabolism

Cetirizine is not extensively metabolized.Notably, it is not metabolized by the cytochrome P450 system.Therefore, it does not significantly interact with drugs that inhibit or induce cytochrome P450 enzymes such as theophylline, erythromycin, clarithromycin, cimetidine, or alcohol.While cetirizine is not extensively metabolized or metabolized by cytochrome P450 enzymes, it does undergo some metabolism by other means, including oxidation and conjugation.The plasma radioactivity of unchanged cetirizine exceeded 90% at 2 hours, 80% at 10 hours, and 70% at 24 hours, indicating limited and slow metabolism.The enzyme responsible for the conversion of cetirizine has not been identified.

Elimination

Approximately 70% to 85% of cetirizine is excreted in urine and 10% to 13% in feces.Approximately 50% or 60% of cetirizine is excreted in the urine without change.It is excreted in the urine by an active transport mechanism.In healthy adults, the elimination half-life of cetirizine ranges from 6.5 to 10 hours, with a mean elimination half-life of approximately 8.3 hours across studies.Its duration of action is at least 24 hours.The elimination half-life of cetirizine is increased in the elderly (up to 12 hours), hepatic impairment (up to 14 hours), and renal impairment (up to 20 hours).