The interaction of tricyclic antipsychotics with (Na +-K +)-ATPase

Abstract

Tricyclie antipsychotics currently used for therapeutic purposes include phenotbiazine and tbioxanthene derivatives. The pharmacological properties of these drugs are complex and intriguing; they can modify many different physiological functions in the central and autonomic nervous system and can produce also endocrine alterations (Byck, 1975). They have moreover been shown to inhibit numerous biochemical processes in vitro and in vivo (Decsi, 1965). Such diversity of effects could suggest that these drugs do not interact with specific receptors but bind to biological structures rather nonspecifically. However, recent advances in physicochemical studies have shown that the molecules of tricyclic antipsychotics combine many distinct physical and chemical properties that are conceivably responsible for their different pharmacological effects. For example, due to their redox properties these agents interfere with various oxidation-reduction processes. The high lipophilicity and surface activity are responsible for the anaesthetic-like action on cellular membranes. Their structural kinship to certain neurotransmitters (catecholamines, acetylcholine, histamine and serotonin) accounts for some of the central and autonomic effects. The biochemical and pharmacological actions of phenothiazines have been admirably summarized by Domino et al. (1968) in relation to their structure and physicochemical properties. Although meager data are still available for thioxanthenes, the physicochemical properties and structure-activity relationship of these drugs appear quite similar to those of the phenothiazines. Information concerning both types of tricyclic antipsychotics, including a critical appraisal of (Na ÷K+)-ATPase inhibition, can be found in the more recent and also valuable review of Zirkle and Kaiser (1974). Tricyclic antipsychotics inhibit many membranebound and soluble enzymes but the relevance of these effects to their pharmacological actions has not yet been assessed. A good correlation has been found between the inhibitory potency of phenothiazines on (Na+-K +) ATPase from rat brain and their antipsychotic activity (Davis & Brody, 1966). The only notable exception was represented by thioridazine whose inhibitory potency was much higher than would be expected from its antipsychotic activity. This discrepancy is frequently found in the enzymatic studies in vitro and may be explained considering the high lipophilicity of thioridazine (Zirkle & Kaiser, 1974). However, a good correlation between a biochemical and a clinical effect does not necessarily prove that the former represents the pharmacologically relevant site of action. The finding (to be published) that the cis (Z) and t r a m (E) isomers of the thioxanthene derivative flupenthixol are about equipotent inhibitors of (Na+-K+)-ATPase seems to exclude the possibility that this biochemical effect is related to the neuroleptic action, as Moiler-Nielsen et al. (1973) have shown that the trans isomer is much less active in animal tests (cf. also Zirkle & Kaiser, 1974). Nevertheless, this consideration does not diminish pharmacological interest in the inhibition of (Na+-K+)-ATPase, since this biochemical effect, brought about by therapeutically significant concentrations of tricyclic antipsychotics (Domino et al.. 1968), may have profound effects on numerous activities of cerebral cells. The fact that Gubitz et al. (1977) found no alteration of (Na ' -K ' ) -ATPase activity in brain homogenates after systemic administration of chlorpromazine is consistent with the reversibility of the inhibition (see below). Inhibition of the sodium pump is likely to alter the excitability of nerve cells. A relationship seems in fact to exist between (Na ÷K+)-ATPase activity and electrical activity of the brain (Abdel-Latif et al., 1967). A reduction in (Na ÷-' K ÷)-ATPase activity, and hence in ATP requirement, will, in addition, increase the cellular adenylate energy charge and, consequently, depress all the energy-producing reactions (Atkinson, 1968). In view of the coupling between (Na ' -K + )-ATPase and the active transport of amino acids and biogenic amines (Schwartz et al., 1972) it cannot be excluded that the inhibition of this enzyme may have an influence on the synaptic transmission. If the recent observation of Hesketh et al. (1977) that depressive illness is associated with a reduction in {Na'-K*)-ATPase activity is confirmed, then the inhibition of (Na+-K+) ATPase might also give an explanation for the severe mood depression produced by long-acting p r_eparations of tricyclic antipsychotics (de Alarcon &' Carney, 1969). The study of the interaction between tricyclic antipsychotics and (Na*-K+)-ATPase can moreover provide general information on the physicochemical principles that govern the binding of these