Phenothiazines piperazine

The most complex side chain of the piperazine phenothiazines is to be found on chlorimpiphenine (86). The side chain is prepared by first alkylating monocarbethoxypiperazine with the chlorobenzimidazole 83 [itself attainable by alkylation of methylbenzimidazole with a dihalide). Removal of the carbethoxy group affords the substituted piperazine, 85. Alkylation of this base with the chloropropyl phenothiazine, 58, affords finally the desired compound (86). ... 

Contraindications Coma, myelosuppression, hypersensitivity to other piperazine phenothiazines, severe cardiovascular disease, severe CNS depression, subcortical brain damage... 

Brand Name(s) Compazine, Compazine Spansule, Compro, Procot Chemical Class Piperazine phenothiazine derivative... 

Mechanism of Action A piperazine phenothiazine that acts centrally to block dopamine receptors in chemoreceptor trigger zone in central nervous system (CNS). Tiicr-apeutic Effect Relieves nausea and vomiting. 

Other piperazine phenothiazines acetophenazine, perphenazine, carphenazine, prochlorperazine, trifluoperazine. 

The piperazine phenothiazines, as exemplified by fluphenazine, are the most potent members of the phenothiazine group, being at least 50 times more potent than chlorpromazine. Because of the structure of their side chain, members of this series lack anticholinergic, antihistaminic, adrenolytic and sedative effects. However, they are more likely to cause extrapyramidal side effects. 

It has been suggested that the less potent sedative neuroleptic drugs (aliphatic or piperidine phenothiazines) lower the convulsive threshold more than the potent neuroleptic drugs (piperazine phenothiazines) (170). Variable and unpredictable effects on seizure activity related to butyrophenones have been reported (171). 

Hepatotoxicity may be as frequent with piperidine and piperazine phenothiazines as with chlorpromazine, despite previous suggestions that the toxicity of these compounds is less. 

The classical antipsychotic (see p. 380) drugs block dopamine receptors and their antipsychotic activity relates closely to this action, which notably involves the Dj-receptor, the principal target in Parkinson s disease. It comes as no surprise, therefore, that these drugs can induce a state whose clinical features are very similar to those of idiopathic Parkinson s disease. The piperazine phenothiazines, e.g. trifluoperazine, and the butyrophenones, e.g. haloperidol, are most commonly involved. In one series of 95 new cases of parkinsonism referred to a department of geriatric medicine, 51% were associated with prescribed drugs and half of these required hospital admission. After withdrawal of the offending drug most cases resolved completely in 7 weeks. But... 

Fig. 11 General structure of piperazine phenothiazine derivatives with neuroprotective and/or neurotrophic effects on the central and/or peripheral nervous system...

The manufacture of a phenothiazine-based medicament with neuroprotective and/or neurotrophic effects on the central and/or peripheral nervous system was recently patented [138]. The starting substances were piperazine phenothiazine derivatives, and their pharmaceutically acceptable salts or esters. One of the compounds included in the patent is flufenazine. 

The general formula of the piperazine phenothiazine derivatives under study is presented in Fig. 11. In the structure of I, A = (un)branched C2—6 alkylene separating N atoms linked thereto by at least two carbon atoms R1 = H, halo, lower alkyl, lower alkoxy, etc. R2, R3, R4 and R5 = H, Me or Et R6 = H, lower alkyl, hydroxy lower alkyl, etc. 

The dihydroindolone molindone, though structurally different from the phenothiazine and butyrophenones, shares most of their antipsychotic properties and side effects. Its clinical effects resemble those of the piperazine phenothiazines. The drug s specific advantages, if any, are not readily apparent. 

Haloperidol is a butyrophenone derivative with antipsychotic action similar to that of piperazine phenothiazines such as fluphenazine. Haloperidol (0.5 to 2 mg t.i.d.) is indicated in the management of psychotic disorders in Tourette s disorder for the control of tics and vocal utterances in severe behavioral problems of children with combative and explosive nature in hyperactive impulse disorder in children associated with aggression, low fmstration tolerance, and impulsive behavior, and in elderly subjects with senile dementia (see also Table 9). 

Molindone (50 to 75 mg/day) is indicated in the management of the manifestations of psychotic disorders. Molindone is strncturally nnrelated to the phenothiazines, butyrophenones, or thioxanthenes, but it resembles the piperazine phenothiazines in its clinical action. It causes sedation, possesses anticholinergic properties and, similar to flnphenazine, produces movement disorders. Molindone is metabolized, and the metabolites are excreted in the nrine. It lowers the seizure threshold and may cause seizures in patients with epilepsy and other seizure disorders. Concomitant nse with sympathomimetics, including epinephrine, phenylephrine, phenylpropanolamine, and ephedrine (often fonnd in nasal sprays), or appetite suppressants may decrease their stimulatory and pressor effects. Becanse of its alpha-blocking potential, molindone may canse epinephrine reversal—a hypotensive response to epinephrine. 

Piperazine, phenothiazine, and levamisole are anthelmintics that may cause allergic contact dermatitis. Allergic contact dermatitis to nitrofurazone has been reported. This anticoccidian is used in cattle feed. Formaldehyde is the allergen in nitrofurazone. Allergic contact dermatitis to 3,5 dinitro-o-toluamide, an anticoccidian used in chicken feeds, has been reported [149]. 

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