Could there be a genetically predisposing factor explaining abnormal reactions to loratadine and ca

Fråga: Could there be a genetically predisposing factor explaining abnormal reactions to loratadine and caffeine in the same patient? Background: A 40-year-old man with allergic asthma was prescribed loratadine (Clarityn) and levocabastine (Livostin nasal spray). After two tablets of loratadine 10 mg he developed a depressive reaction including astenia, impaired concentration and fatigue. The symptoms persisted for four months. The patient says that he reacts in a similar (but less severe) way to caffeine in coffee or coca cola. He has also reacted with agressivness to other, not specified, medications.

Sammanfattning: There is no apparent mechanism to explain a similar, abnormal reaction to loratadine and caffeine.

Svar: Loratadine, with a chemical structure similar to tricyclic antidepressants, is an antihistamine which has been claimed to have a high selectivity for peripheral H1-receptors and little penetrance to the central nervous system (CNS) hence minimal mental side-effects (1). The bioavailability is low due to high first pass metabolism, but the clinical effect is largely exerted by the main metabolite. Loratadine is mainly metabolised by the liver enzyme CYP 3A4 and to a lesser extent by CYP2D6. The importance of the CYP2D6 pathway may increase if the CYP3A4 activity is inhibited (2).

CNS side-effects to loratadine have previously been discussed in a Drugline document (3). In short, CNS symptoms have been reported, though unfrequently. A case report has been published concerning a 14-year-old boy who developed aggressive behaviour, headache and vomiting during long term loratadine treatment. The authors point out the possibility of accumulation of loratadine or its metabolite. There is a large variation in the half-lifes of the two substances (3-26 and 11-137 hours respectively) (4).

Caffeine has a complicated metabolic pattern involving several enzymes, where CYP1A2 catalysis a major pathway. Other enzymes identified are CYP2E1, CYP3A4 (minor importance), N-acetyltransferase and xantinoxidase (5). Caffeine is thought to act by way of adenosine receptor antagonism in the CNS (6).

Thus, there is no apparent, common factor in the action on receptor level or in the metabolism of loratadine and caffeine. As the patient in the present case had taken only two tablets of loratadine, and as the reaction lasted for several months, drug accumulation seems less likely to be the cause.

If the patient has reacted unfavourably to antidepressants or neuroleptics it is possible to genotype the CYP 2D6 gene, which is responsible for the metabolism of many of these drugs, and where a polymorphism has been shown (7).