Loratadine, properties

CUssold SP, Sorkin EM, Goa KI. Loratadine a preliminary review of its pharmacodynamic properties and therapeutic efficacy. Drugs 1989 1 42-57. 

The signal characteristic of the second-generation antihistamines is their freedom from sedation (2,16). The relative lack of sedative properties in the second-generation antihistamines has been ascribed to their relative hydrophi-licity. Little is known about intracerebral concentrations of antihistamines and their metabohtes, but positron emission tomography has shown that the first-generation antihistamine chlorphenamine occupied a larger fraction of brain histamine Hi receptors than terfenadine (SEDA-20,164). Differential affinity for, or different actions on, central and peripheral Hi receptors (SEDA-21,171) could also explain variations in sedative effect, but differences in receptor binding have only been shown for loratadine in vitro (45). 

Muscarinic effects, mediated by acetylcholine, the primary transmitter of the autonomic nervous system ganglia, are inhibited by the anticholinergic effects exerted by antihistamines. Anticholinergic side effects include dry mouth, urinary retention, blurred vision, and constipation. Because first-generation antihistamines also distribute into the CNS, sedation is a prominent side effect. The development of second-generation antihistamines, such as loratadine and fexofenadine, lack anticholinergic activity and do not distribute into the CNS (Table 31-1). Hence, they are not typically associated with sedation and do not possess antiemetic properties. 

In the discovery phase, metabolite identification is usually performed with a combination of in vitro and in vivo experiments using samples from different species in order to compare metabolite exposures. The structural identification of major circulating metabolites formed in nonclinical animal models as well as the metabolites formed in human in vitro systems is needed for the metabolites to be synthesized and their pharmacological activities and/or toxicological implications to be determined [25], In addition, metabolite identification can lead to the discovery of candidates with satisfactory clearance/PK properties and/or improved safety profile. Following are some examples of metabolites that were later developed as drugs desloratadine from loratadine, acetaminophen from phenacetin, morphine from codeine, minoxidil sulfate from minoxidil, fexofenadine from terfenadine, and oxazepam from diazepam. 

The most common side effect of the antihistaminics is sedation, and all of them cause it to varying degrees. For example, diphenhydramine, dimenhydrinate, and promethazine cause marked sedation, but pyrilamine produces only moderate sedation. Chlorpheniramine, meclizine, and cyclizine have mild sedative properties, while terfenadine, astemizole, loratadine, and cetirizine are nonsedating. 

Second-Generation Piperidines (Prototype Terfena-dine). Terfenadine and astemizole were withdrawn from the market. Current drugs in this class include loratadine, deslor-atadine, and fexofenadine. These agents are highly selective for Hi receptors, lack significant anticholinergic actions, and penetrate poorly into the CNS. Taken together, these properties appear to account for the low incidence of side effects of piperidine antihistamines. 

The second-generation ( nonsedating ) Hj antagonists e.g., loratadine, cetirizine, and fexofenadine) are largely excluded from the brain when given in therapeutic doses because they do not cross the blood-brain barrier. An interesting and useful property of certain Hj antagonists is the capacity to counter motion sickness see Chapters 7 and 37). This effect was first observed with dimenhydrinate and subsequently with diphenhydramine (the active moiety of dimenhydrinate), various piperazine derivatives, and promethazine. 

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