Metabolism Of Chlorpromazine

Metabolic Pathways Phenothiazine
Figure 12.6 • Some metabolic pathways for chlorpromazine.

Promazine. Promazine, 10-[3-(dimethylamino) propyl-(phenothiazine monohydrochloride (Sparine), was introduced into antipsychotic therapy after its 2-chloro-substituted relative. The 2H-substituent vis-à-vis the 2Cl substituent gives a milligram potency decrease as an antipsychotic, as encompassed in Gordon's rule. Tendency to EPS is also lessened, which may be significant, especially if it is decreased less than antipsychotic potency.

Triflupromazine Hydrochloride, USP. Trifluproma-zine hydrochloride, 10-[3-(dimethylamino)propyl]-2-(trifluo-romethyl)phenothiazine monohydrochloride (Vesprin), has a greater milligram potency as an antipsychotic, higher EPS, but lower sedative and hypotensive effects than chlorprom-azine. The 2-CF3 versus the 2-Cl is associated with these changes. Overall, the drug has uses analogous to those of chlorpromazine.

Thioridazine Hydrochloride, USP. Thioridazine hydrochloride, 10-[2-(1-methyl-2-piperidyl)ethyl]-2-(methyl-thio)phenothiazine monohydrochloride (Mellaril), is a member of the piperidine subgroup of the phenothiazines. The drug has a relatively low tendency to produce EPS. The drug has high anticholinergic activity, and this activity in the striatum, counterbalancing a striatal DA block, may be responsible for the low EPS. It also has been suggested that there may be increased DA receptor selectivity, which may be responsible. The drug has sedative and hypotensive activity in common with chlorpromazine and less antiemetic activity. At high doses, pigmentary retinopathy has been observed. Its major metabolites include n-demethylated, ring-hydroxylated, and s-oxidized products. Thioridazine is prominently converted to the active metabolite mesorid-azine (discussed next), which probably contributes to the antipsychotic activity of thioridazine.

Mesoridazine Besylate, USP. Mesoridazine besylate, 10-[2-(methyl-2-piperidyl)ethyl]-2-(methylsulfinyl)phe-nothiazine monobenzenesulfonate (Serentil), shares many properties with thioridazine. However, no pigmentary retinopathy has been reported.

Prochlorperazine Maleate, USP. Prochlorperazine maleate, 2-chloro-10-[3-(4-methyl-1-piperazinyl)propyl]phe-nothiazine maleate (Compazine), is in the piperazine subgroup of the phenothiazines, characterized by high-milligram antipsychotic potency, a high prevalence of EPS, and low sedative and autonomic effects. Prochlorperazine is more potent on a milligram basis than its alkylamino counterpart, chlorpromazine. Because of the high prevalence of EPS, however, it is used mainly for its antiemetic effect, not for its antipsychotic effect.

Perphenazine, USP. Perphenazine, 4-[3-(2-chlorophe-nothiazine- 10-yl)propyl]piperazineethanol; 2-chloro-10-[3-

[4-(2-hydroxyethyl)piperazinyl]propyl]phenothiazine (Trilafon), is an effective antipsychotic and antiemetic.

Fluphenazine Hydrochloride, USP. The member of the piperazine subgroup with a trifluoromethyl group at the 2-position of the phenothiazine system and the most potent antipsychotic phenothiazine on a milligram basis is fluphenazine hydrochloride, 4-[3-[2-(trifluoromethyl)phenazin-10-yl] propyl]-1-piperazineethanol dihydrochloride, 10[3-[4-(2-hydroxyethyl)piperazinyl]propyl]-2-trifluoromethylphen othiazine dihydrochloride (Permitil, Prolixin). It is also available as two lipid-soluble esters for depot intramuscular injection, the enanthate (heptanoic acid ester) and the dec-anoate ester. These long-acting preparations have use in treating psychotic patients who do not take their medication or are subject to frequent relapse.

Thiothixene, USP. The thioxanthene system differs from the phenothiazine system by replacement of the N-H moiety with a carbon atom doubly bonded to the propyli-dene side chain. With the substituent in the 2-position, Zand E-isomers are produced. In accordance with the concept that the presently useful antipsychotics can be superimposed on DA, the Z-isomers are the more active antipsychotic isomers. The compounds of the group are very similar in pharmacological properties to the corresponding phenothiazines. Thus, thiothixene (Z-N-dimethyl-9-[3-(4-methyl-1-piper-azinyl)propylidene]thioxanthene-2-sulfonamide (Navane), displays properties similar to those of the piperazine subgroup of the phenothiazines.

Clozapine Ring

Ring Analogs of Phenothiazines: Benzazepines, Dibenzoxazepines, and Dibenzodiazepines

Additional tricyclic antipsychotic agents are the benzazepines, containing a seven-membered central ring (6-7-6 system). These newer atypical antipsychotics include diben-

zodiazepines (clozapine with 2-Cl), dibenzoxazepines (loxapine with 2-Cl), thienobenzodiazepines (olanzapine without 2-substituent), and dibenzothiazepines (quetiapine without 2-substituent). These ring analogs of phenothiazines are structural relatives of the phenothiazine antipsychotics; therefore, most of them share many clinical properties with the phenothiazines. However, they have some important differences, notably low production of EPS and reduction of negative symptoms. These benzazepines and other atypical antipsychotics including risperidone, ziprasidone, and arip-iprazole block both D2 and 5-HT2A receptor, other DA and serotonin receptor subtypes, adrenergic, histamine, and muscarinic receptors. The low D2 receptor affinity and the high 5-HT2A receptor affinity of atypical antipsychotics including clozapine and olanzapine led to the proposal that 5-HT2A antagonism accounts for their lower EPS.

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