Pharmacology: Pharmacodynamics: Mechanism of Action: Loratadine is a tricyclic antihistamine with long-acting selective peripheral H1 receptor antagonist activity. It does not readily cross the blood brain barrier.
Human histamine skin wheal studies following single and repeated 10 mg oral doses of loratadine have shown that the drug exhibits an antihistaminic effect beginning within 1 to 3 hours, reaching a maximum at 8 to 12 hours, and lasting in excess of 24 hours. There was no evidence of tolerance to this effect after 28 days of dosing with loratadine.
Pharmacokinetics: After oral administration, loratadine is rapidly and well absorbed, and undergoes extensive first pass metabolism, mainly by CYP3A4 and CYP2D6. The major metabolite - desloratadine (DL) - is pharmacologically active and responsible for a large part of the clinical effect. Loratadine and DL achieve maximum plasma concentrations (Tmax) between 1-1.5 hours and 1.5-3.7 hours after administration, respectively.
Increase in plasma concentrations of loratadine has been reported after concomitant use with ketoconazole, erythromycin, and cimetidine in controlled trials, but without clinically significant changes (including electrocardiographic).
Loratadine is highly bound to plasma proteins (97% to 99%), its active metabolite moderately bound (73% to 76%) to plasma proteins.
In healthy subjects, the plasma distribution half-lives of loratadine and its active metabolite are approx. 1 and 2 hours, respectively. The mean elimination half-lives in healthy adult subjects were 8.4 hours (range = 3 to 20 hours) for loratadine and 28 hours (range = 8.8 to 92 hours) for the major active metabolite.
Approximately 40% of the dose is excreted via urine and 42% in the faeces over a 10 day period and mainly in the form of conjugated metabolites. Approximately 27% of the dose is excreted in the urine during the first 24 hours. Less than 1% of the active substance is excreted unchanged in active form, as loratadine or DL.
The bioavailability parameters of loratadine and of the active metabolite are dose proportional.
The pharmacokinetic profile of loratadine and its metabolites is comparable in healthy adult volunteers and healthy geriatric volunteers.
Concomitant ingestion of food can delay slightly the absorption of loratadine but without influencing the clinical effect.
In patients with chronic renal impairment, both the AUC and peak plasma levels (Cmax) increased for loratadine and its metabolite as compared to the AUCs and peak plasma levels (Cmax) of patients with normal renal function. The mean elimination half-lives of loratadine and its metabolite were not significantly different from that observed in normal subjects. Haemodialysis does not have an effect on the pharmacokinetics of loratadine or its active metabolite in subjects with chronic renal impairment.
In patients with chronic alcoholic liver disease, the AUC and peak plasma levels (Cmax) of loratadine were double while the pharmacokinetic profile of the active metabolite was not significantly changed from that in patients with normal liver function. The elimination half-lives for loratadine and its metabolite were 24 and 37 hours, respectively, and increased with increasing severity of liver disease.
Loratadine and its active metabolite are excreted in the breast milk of lactating women.