Terfenadine, sedative properties

Iatrogenic Reactions broadly refer to any adverse reactions that are unintentionally produced by physicians in their patients. For example, one of the side effects of many antihistaminic preparations (Hj antagonists) such as ethanolamine derivatives (prototype diphenhydramine) is heavy sedation. Although sedation may be desirable for some patients, it may interfere with daytime activities, and this needs to be considered when prescribing such medications. Other antihistaminic preparations (also 11 antagonists) such as piperidine derivatives (prototypes terfenadine or astemizole) have no sedative properties (Figure 3.2). 

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). 

In recent years H,-antagonists which do not readily cross the blood-brain barrier have been developed in an attempt to reduce the well-known sedative properties associated with this class of compounds. These include terfenadine (7) [70,71], astemizole (8) [72], mequitazine (9) [73-75] and temelastine (10) [76] whose structures are given in Figure 2.2. It is striking that for most of these compounds, particularly astemizole and terfenadine, the onset of action is slow and the duration of action is exceptionally long [70, 72]. For example, studies... 

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. 

The potentiation of sedative effects from benzodiazepines when combined with centrally acting drugs with antihistamine properties (for example first-generation antihistamines, tricyclic antidepressants, and neuroleptic drugs) can pose problems (143). Antihistamines that do not have central actions do not interact with benzodiazepines as in the case of mizolastine and lorazepam (144), ebastine and diazepam (145), and terfenadine and diazepam (143). 

Launched as a peripherally acting antihistamine with Uttle sedative activity, terfenadine largely fulfiUed this promise, but proved to have cardiotoxic properties, which led to restrictions on its use (SEDA-17, 196) (SEDA-18, 182) (SEDA-18, 186) (SEDA-19, 176) (SEDA-20, 163) (SEDA-21,177) (SEDA-22,179). 

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