Phenothiazines piperidine

Low-potency piperidine phenothiazines (e.g., thioridazine), clozapine, and ziprasidone are more likely to cause ECG changes. 

The piperidine phenothiazines, as exemplified by the most widely used member of this series thioridazine, are approximately equivalent to the aliphatic phenothiazines but tend to be more sedative. Members of this series are therefore widely used for the more agitated, anxious psychotic patient. As their ability to cause parkinsonism appears to be less than with the other phenothiazines, possibly because of their potent central anticholinergic effects and slightly greater selectivity for mesocortical dopamine receptors, they are widely used to treat elderly psychotic patients. 

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). 

Thioridazine, a piperidine phenothiazine derivative, is much less potent and less selective for dopamine (D,) receptors than is fluphenazine, a piperazine derivative. Thus, thioridazine is likely... 

The phenothiazine duoperone (5) combines structural elements found in phenothiazine and buty-rophenone antipsychotic agents. Alkylation of substituted piperidine 1 with 3-chloropropanol affords the intermediate 2 treatment of this with thionyl chloride converts the terminal hydroxyl to chloride. Alkylation of the phenothiazine 4 with halide 3 affords the antipsychotic agent duoperone (5) [1]. 

To a stirred and refluxing suspension of 4.95 parts of 4-piperidinecarboxamide, 1 part of sodium iodide and 8.4 parts of potassium carbonate in 40 parts of butanone there are added in the course of 30 minutes9.3 parts of 2-chloro-10-( y"Chloropropyl)phenothiazine in 40 parts of butanone. Stirring and refluxing are continued for 12 hours after which the mixture is cooled and filtered. The filtrate is concentrated under vacuum to give a residue which is recrystallized from a mixture of 2-propanol and petroleum ether. The 1-[ y-(2 -chloro-10 -phenothiazinelpropyl] piperidine-4-carboxamide thus obtained melts at approximately 139°C. 

Brompheniramine maleate Chlorpheniramine maleate Dexchlorpheniramine maleate Ethanolamine class, nonselective Carbinoxamine maleate Clemastine fumarate Diphenhydramine hydrochloride Ethylenediamine class, nonselective Pyrilamine maleate Tripelennamine hydrochloride Phenothiazine class, nonselective Promethazine hydrochloride Piperidine class, nonselective Cyproheptadine hydrochloride Phenindamine tartrate... 

This group of drugs is subdivided into three subgroups depending on the type of substitution on the nitrogen atom of the phenothiazine ring. The subgroups are phenothiazines with an aliphatic side chain (chlorpromazine, promazine, triflupromazine), piperazine derivatives (acetophenazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine), and piperidines (mesoridazine, thioridazine). 

Piperazine derivatives inherent presence of stimulatory components.Phenothiazines with an aliphatic side chain and piperidine substituents have more of a sedative effect than piperazine derivatives. 

A number of different compounds of the piperidine and piperazine series with p-fluorobuty-rophenone group substitutions at the nitrogen atom display significant neuroleptic activity (haloperidol, trifluperidol, droperidol, methorin). There is a considerable interest in butyrophenone derivatives as antipsychotic agents as well as in anesthesiology. They exhibit pharmacological effects and a mechanism of action very similar to that of phenothiazines and thioxanthenes in that they block dopaminergic receptors. However, they are more selective with respect to D2 receptors. 

Hj histamine receptor blockers can be grouped according to their chemical structures ethanolamine derivatives (diphenhydramine, clemastine) ethylenediamine derivatives (tripe-lennamine, pyrilamine) alkylamines (chloropheniramine, dexchlorpheniramine, brompheniramine) piperazines (cycUzine, meclizine, hydroxizine) phenothiazines (promethazine, trimeprazine) piperidines (cyproheptadine, diphenylpyraline) and others that do not belong to a specific chemical classification (terfenadine, astemizole). 

Phenothiazine antipsychotics can be divided in the aliphatic phenothiazines with a dimethylamino-propyl group, those with a piperazine structure and agents with a piperidine structure. 

The piperidines, e.g. thioridazine, pipothiazine and pericyazine, have the lowest potential to cause extrapyramidal effects. Thioridazine is one of the most sedative phenothiazines. It may decrease the inotropic activity of digitalis by its quinidine-like action, which can cause myocardial depression, decreased efficiency of repolarization, and increased risk of tachyarrhythmias. With thioridazine drug induced sexual dysfunction and especially cardiotox-icity with prolongation of the QT-interval are more frequently seen than with other phenothiazines. For the above reasons thioridazine is withdrawn from the market in many countries. 

Phenothiazines are classified on fhe basis of fheir chem-isfry, pharmacological acfions, and pofency. Chemical classifications include the aliphatic (e.g., chlorproma-ztne T/iorazme), piperidine (e.g., thioridazine Me//an7), and piperazine subfamilies. The piperazine derivatives are generally more potent and pharmacologically selective than the others. The thioxanthenes (e.g., thiothixene Navane) are chemically related to the phenothiazines and have nearly equivalent potency. The... 

Phenothiazines, piperidine mesoridazine besylate pericyazine pipotiazine palmitate thioridazine hydrochloride... 

The reduced basicity of phenothiazine nitrogen requires that even acylation proceed via the anion. The amide (34-2) from the methyl thioether (34-1) can be prepared, for example, by sequential reaction with sodium amide and acetic anhydride. Oxidation of that intermediate with peracid proceeds preferentially on the more electron-rich alkyl thioether to give the sulfone this affords the phenothiazine (34-3) on hydrolysis of the amide. Complex side chains are most conveniently incorporated in a stepwise fashion. The first step in the present sequence involves reaction of (34-3) as its anion with l-bromo-3-chloropropane to give (34-4). The use of that halide with alkylate piperidine-4-carboxamide (34-5) affords the antipsychotic agent metopimazine (34-6) [35]. 

Because the tardive syndromes that develop in adults are often irreversible and have no satisfactory treatment, care must be taken to reduce the likelihood of their occurrence. Antipsychotic medication should be prescribed only when necessary and should be withheld periodically to assess the need for continued treatment and to unmask incipient dyskinesia. Thioridazine, a phenothiazine with a piperidine side chain, is an effective antipsychotic agent that seems less likely than most to cause extrapyramidal reactions, perhaps because it has little effect on dopamine receptors in the striatal system. Finally, antimuscarinic drugs should not be prescribed routinely in patients receiving neuroleptics, because the combination may increase the likelihood of dyskinesia. 

Three subfamilies of phenothiazines, based primarily on the side chain of the molecule, were once the most widely used of the antipsychotic agents. Aliphatic derivatives (eg, chlorpromazine ) and piperidine derivatives (eg, thioridazine ) are the least potent. These drugs produce more sedation and weight gain. Piperazine derivatives are more potent (effective in lower doses) but not necessarily more efficacious. Perphenazine, a piperazine derivative, was the typical antipsychotic drug used in the CATIE study described in the following text. The piperazine derivatives are also more selective in their pharmacologic effects (Table 29-1). 

Lin, G., Chu, K.-W., Damani, L. A., Hawes, E. M. Identification of lactams as in vitro metabolites of piperidine-type phenothiazine antipsychotic drugs. J. Pharmacol. Biomed. Anal. 1996,14, 727-738. 

In CONCLUSION, the use of the "classical" neuroleptics, as exemplified by the phenothiazines, thioxanthines, butyrophenones and diphenylbutyl-piperidines, has been a landmark in the pharmacotherapy of schizophrenia and psychotic disorders. The efficacy of such drugs in the alleviation of the symptoms of schizophrenia is universally accepted. However, it is also evident that they have a spectrum of adverse effects that frequently renders their long-term use problematic. Side effects such as akathisia, Parkinsonism, tardive dyskinesia and the all too frequent changes in peripheral autonomic activity are largely predictable from the structure of the molecules and the basic animal pharmacology data. Such adverse effects, and the difficulties encountered when attempting to reduce their frequency and severity by concurrent medication, has stimulated the development of "atypical" neuroleptics such as clozapine and risperidone which, hopefully, will combine efficacy with a reduction in side effects. 

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