Neuroleptics pimozide

The role of fluonne in the development of CNS agents has been reviewed [14] Ruonnated phenothiazines, typified by fluphenazine (7[Pg.1121]

The administration of low doses of PCP to rodents induces hyperactivity and stereotypy (Chen et al. 1959 ). The observation that neuroleptics such as chlorpromazine, haloperidol, and pimozide, and adrenolytics such as alpha-methyl paratyrosine antagonize these behavioral effects of PCP suggests that they are mediated by facilitation of central dopaminergic neurotransmission (Murray and Horita 1979). The actions of PCP on central dopaminergic neurotransmission may be similar to amphetamine. A dose of PCP (2.5 mg/kg) in rats, which has no effects when given alone, enhances the behavioral effects of 1 and 3 mg/kg of d-amphetamine (Balster and Chait 1978). PCP, like dopamine, has also been shown to suppress plasma prolactin (Bayorh et al. 1983). However, the firm establishment of an excl usive relationship between dopamine neuro-transmission and PCP effects is difficult because of the prominent interactions of this drug with other neurotransmitter systems. 

Non-selective antagonists spiperone, amperozide, pimozide Possible clinical use of antagonists neuroleptics 5-HT,... 

Representatives of diphenylbutylpiperidines are pimozide, fluspirilene, and penfluridol, which belong to the powerful neuroleptic drugs with expressed antipsychotic properties similar to haloperidol. The principle distinctive feature of this series of drugs is their prolonged action. The mechanism of their action is not completely known however, it is clear that they block dopaminergic activity. 

Extrapyramidal symptoms (EPS) Dystonic reactions develop primarily with the use of traditional antipsychotics. EPS has occurred during the administration of haloperidol and pimozide frequently, often during the first few days of treatment. Neuroleptic malignant syndrome (NMS) A potentially fatal symptom complex sometimes referred to as NMS has been reported in association with administration of antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, rhabdomyolysis, and acute renal failure. 

Fluphenazine, a typical neuroleptic of the phenothi-azine class, has been less widely used for treatment of tics than haloperidol or pimozide. A controlled trial of haloperidol, fluphenazine, and trifluoperazine found comparable tic-reducing efficacy, but greater sedation and extrapyramidal side effects for haloperidol fluphenazine was the best tolerated (Borison et al., 1982). In an open-label trial with 21 subjects who had an unsatisfactory response to haloperidol, fluphenazine had a superior side effect profile to that of haloperidol in the dose range employed (mean dose of fluphenazine, 7 mg/day, range 2-15 mg/day) (Goetz et al., 1984). In this group selected for an unsatisfactory response to haloperidol, 11 of the 21 subjects (52%) had a better response to fluphenazine than haloperidol, 6 subjects had a comparable response, and 2 subjects preferred haloperidol. 

The side effects of typical neuroleptics are extensively discussed in Chapters 26 and 41 in this volume. Given its potent calcium channel blocking properties, additional considerations apply to the use of pimozide. The use of pimozide requires caution regarding the possibility of QT prolongation, and we typically obtain an electrocardiogram (EKG) to measure the QTc interval at baseline, and obtain a repeat EKG during the dose... 

Pimozide is FDA-labeled for Tourette s disorder and is particularly interesting in that it is a highly specific DA antagonist that may produce fewer adverse effects than haloperidol. In open studies with adequate doses, this agent has demonstrated efficacy for acute schizophrenia. Several double-blind trials comparing pimozide with other neuroleptics also found it to be an equally effective maintenance therapy ( 34, 35, 36, 37 and 38). We consider this agent to be as effective as the other standard agents, with the same, but perhaps less severe, side effects. 

Figure 11.5. Correlation between the average daily dose of various neuroleptics and their affinity for D2 receptors. (l)=promazine (2)=chlorpromazine (3)=thio-ridazine (4)=clozapine (5)=triflupromazine (6)=penfluridol (7)=trifluoperazine (8)=fluphenazine (9)=haloperidol (10)=pimozide (ll)=fluspirilene (12)=benper-idol (13)=spiroperidol (spiperone).

The neuroleptics that are widely available may be divided into two general categories, those with low potency (such as chlorpromazine and thioridazine) and those with high potency (exemplified by haloperidol, trifluoperazine and pimozide). The former groups have a lower propensity to cause extrapyramidal side effects but are more sedative and likely to cause postural hypotension and have anticholinergic side effects. In vitro studies have shown that chlorpromazine has an affinity for all five types of dopamine receptor and has some preference for D2 and D3 receptors. By contrast, haloperidol is more potent than chlorpromazine for the D2, D3 and D4 receptors with a low affinity for the D and D5 receptors. 

In recent years traditional neuroleptics, as exemplified by chlorpromazine, have been structurally modified to produce drugs with greater affinity for dopamine receptors while retaining some of their activity on other receptor systems (e.g. on alpha] adrenoceptors, 5-HT2 receptors and histamine] receptors). In the non-phenothiazine series, a high degree of specificity for the D2 receptors has been achieved with sulpiride and pimozide, with haloperidol showing antagonistic effects on the 5-HT2 and alpha] adrenoceptors in addition to its selectivity for D2 receptors. The czs-(Z) isomers of the thioxanthines are potent neuroleptics that, in addition to... 

With the typical neuroleptics in wide clinical use (e.g. chlorpromazine, thioridazine, haloperidol, pimozide, flupenthixol and clopenthixol), there would appear to be a correlation between their D2 antagonistic potency and their clinical potency presumably the ability of these drugs to block 5-HT2 receptors to varying extents is also evidence that the serotonergic system is involved in their clinical activity in some way. 

The serum concentrations of "classical neuroleptics and their metabolites vary considerably in patients, even when the dose of drug administered has been standardized. Such interindividual variation may account for the differences in the therapeutic and side effects. High interindividual variations in the steady-state plasma levels have been reported for pimozide, fluphenazine, flupenthixol and haloperidol, some of these differences being attributed to differences in absorption and metabolism between patients. 

The diphenylbutylpiperidines are structurally related to the butyrophenones and have essentially similar properties. Pimozide is the most well-established member of this series and is a potent neuroleptic that, like other potent neuroleptics, is likely to cause extrapyramidal side effects. 

Neuroleptics are the drugs of choice in the treatment of tic disorders but they should only be considered in situations where the life of the child is seriously affected and when behavioural treatments have failed. Of the classical neuroleptics which have been used, haloperidol and pimozide have shown success but so far there have been no adequately controlled trials of any neuroleptic to objectively validate their efficacy. It would appear that only low doses of haloperidol are necessary (2-3mg/day) to obtain a significant reduction in tic frequency. It would seem reasonable to consider the use of the atypical antipsychotics for these disorders but, to date, there is no evidence of their efficacy in children. Recently there have been studies in which clonidine was used in the effective treatment of motor tics. The side effects are similar to those seen in the adult and include sedation, headache, irritability and sinus bradycardia. 

Die specificity of the dopamine receptor was further studied with a series of dopaminergic antagonists of well known pharmacological activity. The 30-40% inhibitory effect of 10 nM dopamine was completely reversed by the addition of increasing concentrations of the potent neuroleptics (+)butaclamol (Kp = 1.5 nM) and (-)sulpiride (Kp = 0.5 nM) while their pharmacologically weak enantiomers (-)butaclamol and (+)sulpiride were 86 and 167 times less potent, respectively. The neuroleptics spiroperidol, thioproperazine, domperidone, haloperidol, fluphenazine and pimozide completely reversed the inhibitory effect of dopamine at low Kp values ranging from 0.02 to 0.8 nM (41). 

A variety of drugs that block DA receptors are available for clinical use, and even more for experimental purposes. These drugs, also referred to as neuroleptics, include phenothiazines (e.g., chlorpromazine), thioxanthenes (e.g., chlorprothixene), butyrophenones (e.g., haloperidol), diphenylbutylpiperidines (e.g., pimozide), and dibenzodiazepines (e.g., clozapine). The major medical applications for these drugs are in the treatment of severe psychiatric illnesses, certain movement disorders, emesis and intractable hiccough. 

Wise RA, Spindler J, deWit H, Gerberg GJ (1978) Neuroleptic induced anhedonia in rats pimozide blocks reward quality of food. Science 207 262-264. 

An in vitro technique, claimed to assess the relative risks of neuroleptic drug-induced seizures, was reported to produce striking differences between neuroleptic drugs in spike activity in hippocampal slices. Tentatively, molindone, pimozide, and butaclamol were the safest compounds, based on these in vitro experiments (172). 

In another study there were large differences in fatality from overdosage between different neuroleptic drugs (614). Pimozide had the lowest fatality index (the number of deaths divided by the number of prescriptions) and loxapine the highest. 

Pimozide is a diphenylbutylpiperidine neuroleptic drug, structurally similar to the butyrophenones. 

---