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PIIVIOZiDE:

PHARMACOLOGY AND CLINICAL USE

Pharmacodynamics

In man, the pharmacological effects of pimozide are essentially those affecting the central nervous system.

doses of 20mg daily were not well accepted by normal prison volunteers, requests for removal from the study corning

from days 16 to 20 because of nervousness, restlessness, insomnia, drowsiness, listlessness,

doses in psychotic patients have failed to produce a similar incidence. In chronic schizophrenic

in those patients showing positive

clinicalresponse. There is still some dispute, however, as to whether the EEG effects of pimozide differ or are similar

tion of the EEG is decreased, together with enhanced a-index (cortical activation),

High

oral

and fatigue.

Maintenance

patients, desynchronisa-

to those of the antipsychotic phenothiazines; a double-blind trial detected no difference between pimozide and triflu-

operazine, both marginally increasing amplitude variability.

subjective euphoric response to subsequent intravenousjnjections of amphetamine in abusers of the drug.

vascular changes have been insignificant in most therapeutic trials with occasional incidences of both mild hyper- and hypotension and non-specific T-wave changes in the EEG of a few subjects. There have been few reports of autonomic activity, except for occasional dryness of mouth.

Single oral doses of pimozide, 5 to 20mg, reduced the

Cardio-

Pharmacokinetics

Following oral dosage of 0.86mg tritiated pimozide to

stable maintenance therapy of 2 to 4mg pimozide daily, peak plasma levels of about 5JJ.g/1 OOml were achieved after

about 8 hours followed by a decline over several days.

radioactivity was still detectable in the plasma after

female prison inmates, who received a single dose of 2mg tritiated pimozide. The pattern

identical for tablets or liquid concentrate, was similar to that in the psychotic patients, except that peak levels of 18 to

3 patients with chronic schizophrenia, who were already on

Half-peak levels were maintained for 24 to 48 hours, and

14 days.

Similar results were observed in studies in healthy

of absorption, which was

20}J.g/100ml were reached in about 3 to 6 hours. Plasma half-life in normal volunteers was about

18 hours.

In human volunteers, the peak of urinary excretion of radioactivity occurred 2 to 6 hours after oral administration

of 2mg tritiated pimozide, with approximately 45% of the dose being recovered in the urine over 96 hours. About

38% of the dose in chronic schizophrenic patients was excreted in the urine over 9 days, of which less than

1%

was unchanged pimozide and two-thirds was 4-bis-(4-fluorophenyl) butyric acid. Faecal excretion in schizophrenic

patients consisted mainly of unchanged pimozide, with about 5% being excreted as the butyric acid derivative.

Therapeutic trials

In most controlled trials of pimozide as maintenance therapy in chronic schizophrenia,

generally been found between pimozide and other antipsychotic drugs, possibly because of the small patient groups involved. Pimozide was significantly superior to placebo in most controlled studies. There appears to be no relationship

between patient response and diagnostic category, sex, age, duration of illness, or previous antipsychotic therapy.

pimozide is more effective in the

The only positive correlation has been between response and symptomatology, that apathetic, withdrawn type of patient than it is in the hyperactive, aggressive type.

requirement for antiparkinsonian drugs have yet to be substantiated in suitably designed controlled trials.

no significant difference has

is

Claims that pimozide reduces the

Variations in the criteria for patient selection and evaluation, and the wide dose ranges used in some studies, make inter-trial comparison very difficult. However, double-blind trials comparing pimozide with other antipsychotic

drugs as daily maintenance therapy, and using both matched group and crossover analysis, have failed to find a significant

difference between: pimozide (2.5

pimozide (7.5mg) and perphenazine (28mg) in 42 patients over 6 weeks; pimozide (2 to 16mg) and thioridazine (75 to

375mg) in 30 patients over 24 weeks; pimozide (3 to 8mg) and flupenthixol (6

and pimozide (1.5

30 weeks. Pimozide (3 to 6mg) was significantly superior to haloperidol (7 to

to 2lmg) and chlorpromazine (75 to 450mg) in 51

to

patients over 24 weeks;

12mg) in

12 patients over 30 weeks;

to lOmg) and fluphenazine (2.5

to 2lmg) in a total of 144 patients in 5 separate trials lasting 8 to

14mg) in a trial in 20 patients over

12 weeks.

INPHARMA 21st August,

1976 p17

The general consensus of opinion in controlled trials is that maintenance doses of pimozide are indistinguishable from those of trifluoperazine, though they may be superior in improving psychomotor retardation and emotional withdrawal and some trials have indicated a significant overall advantage for pimozide.

There is no evidence that pimozide is effective in acute schizophrenia or in the control of hyperactive and aggressive patients. Some investigators, however, feel that the doses used have been too low and that therapeutic effects may not

be apparent until dose levels of up to 60mg are reached.

drug may be effective in treating behavioural disorders and schizophrenic-like symptomatology.

Umited studies in children aild adolescents suggest that the

Though significantly superior to placebo in patients with anxiety neurosis, pimozide has no advantages over currently available anxiolytic drugs, either in terms of efficacy or incidence of side-effects. Addition of pimozide to a therapeutic regimen of chlordiazepoxide did not result in a more rapid anxiolytic effect, an enhanced effect, a sparing of chlordiaze- poxide dosage, or a reduced incidence of side-effects. Claims for a specific effect against anxiety associated with psychosis or disturbed personality traits remain unproven.

Pilot triais suggest

excessive dopaminergic stimulation in the brain, including the tardive oral

antipsychotic drugs. Pimozide may be useful in generalised lipodystrophy.

thal

pimozidc may be of value in treating Huntington's chorea and other dyskinesias which involve

dyskii1esias

associated with

long-leon

use of

Side-effects

Extrapyramidal reactions such as akathisia and Parkinsonian symptoms are the most frequently

pimozide therapy, occurring in about

administration of anti parkinsonian drugs. Sedation is uncommon. Other effects such as insomnia, anorexia, weight

loss and autonomic effects have been reported less frequently, and there have been rare instances of rashes, hypotension and glycosuria. Laboratory tests have failed to show any drug-related abnormality, and slit-lamp examinations have shown no changes in ocular pigmentation. Pimozide may lower the seizure threshold in both epileptic and non-epileptic patients. Overdosage has been rarely reported, but both adults and infants who have ingested the drug have recovered

uneventfully in the absence of excessive extrapyramidal reactions following ingestion of 60 to

observed side-effects of

or

10 to

15% of patients. They are readily reversed by reduction in dosage

l OOmg of pimozide.

Pinder, R.M. et al.:

Drugs

12:

1-40 (No

1,

1976)

[130 references]

INPHARMA 21st August,

1976 p18