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drug has significant sedative and hypotensive properties, possibly reflecting central and peripheral ^-adrenergic blocking activity, respectively. As with the other phenothiazines, the effects of the other CNS-depressant drugs, such as sedatives and anesthetics, can be potentiated.90 Chlorpromazine is a minor substrate of CYP1A2 and 3A4 and a major substrate of CYP2D6.91 Chlorpromazine also is a strong inhibitor of CYP2D6 and a weak inhibitor of CYP2E1. Inhibitors of the CYP2D6 enzyme may increase the levels/effects of chlorpromazine and chlorpromazine may increase the levels/effects of CYP2D6 substrates. Chlorpromazine may also decrease the bioactivation of CYP2D6 prodrug substrates.91

Figure 13.5 • Trans-(A) versus c/s-(B) isomers in the thiothixenes.

Figure 13.5 • Trans-(A) versus c/s-(B) isomers in the thiothixenes.

Chlorpromazine has strong anticholinergic and sedative effects and is a potent antiemetic. It is considered a low-potency neuroleptic agent and therefore the associated incidence of EPS is low. The incidence of sedative, anticholinergic, and cardiovascular side effects is high, however. It is indicated for the symptomatic relief of nausea, vomiting, hiccups, and por-phyria; for preoperative sedation; and for the treatment of psychotic disorders.

Thioridazine Hydrochloride, USP. Thioridazine hydrochloride, 10- [2-( 1 -methyl-2-piperidyl)ethyl] -2-(methylthio)phenothiazine (Mellaril), is a member of the piperidine subgroup of the phenothiazines. Thioridazine occurs as a white or slightly yellow, crystalline or micronized powder, which is odorless or has a faint odor and is practically insoluble in water and freely soluble in dehydrated alcohol (pKa = 9.66). Thioridazine has relatively low tendency to produce EPS. The drug has sedative and hypoten-sive activity in common with chlorpromazine and less antiemetic activity. At high doses, pigmentary retinopathy has been observed. Thioridazine has similar activity toward the CYP450 family of enzymes as chlorpromazine. Thioridazine is indicated for the treatment of schizophrenic patients who fail to respond adequately to treatment with other antipsychotic drugs.

Perphenazine, USP. Perphenazine, 2-[4-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]piperazin-1-yl]ethanol. Perphenazine is a minor substrate of CYP1A2, 2C9, 2C19, and 3A4 and a major substrate for 2D6. Perphenazine is indicated for use in the management of the manifestations of psychotic disorders and for the control of severe nausea and vomiting in adults.

Trifluoperazine Hydrochloride, USP. Trifluoperazine hydrochloride, 10- [3-(4-Methyl-1 -piperazinyl)propyl- [2-(trifluoromethyl)phenothiazine dihydrochloride (Stelazine). The absorption of trifluoperazine is erratic and variable and it is widely distributed into tissues. The excretion of trifluoperazine occurs 50% via kidneys and the other 50% is through enterohepatic circulation. The metabolism and drug interactions of trifluoperazine are the same as with the other phenothiazines. Trifluoperazine does not show any specific drug interactions. Trifluoperazine is indicated for the management of schizophrenia and short-term treatment of nonpsychotic anxiety.

Thiothixene, USP. Thiothixene, N,N-dimethyl-9-[3-(4-methyl-1-piperazinyl)propylidene]thioxanthene-2-sulfonamide (Navane). The absorption of thiothixene is erratic because of its high lipophilicity. Thiothixene is widely distributed into tissues and it is more than 90% bound to plasma proteins. Thiothixene has a similar metabolic pathway as the phenothiazines. Thiothixene is a major substrate of CYP1A2, and CYP1A2 inducers may decrease the levels/effects of thiothixene, whereas CYP1A2 inhibitors may increase the levels/effects of thiothixene. Thiothixene is also a weak inhibitor of CYP2D6. As with other antipsychotic agents, some patients who are resistant to previous medications have responded favorably to thiothixene. Thioxanthenes may also be of value in the management of withdrawn, apathetic schizophrenic patients.

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