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Orap (Pimozide) - Description and Clinical Pharmacology

 
 



DESCRIPTION

ORAP® (pimozide) is an orally active antipsychotic agent of the diphenylbutylpiperidine series. The structural formula of pimozide, 1-[1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl]-1, 3-dihydro-2H-benzimidazole-2-one is:

The solubility of pimozide in water is less than 0.01 mg/mL; it is slightly soluble in most organic solvents.

Each white ORAP tablet contains either 1 mg or 2 mg of pimozide and the following inactive ingredients: calcium stearate, microcrystalline cellulose, lactose anhydrous and corn starch.

CLINICAL PHARMACOLOGY

PHARMACODYNAMIC ACTIONS

ORAP (pimozide) is an orally active antipsychotic drug product which shares with other antipsychotics the ability to blockade dopaminergic receptors on neurons in the central nervous system. Although its exact mode of action has not been established, the ability of pimozide to suppress motor and phonic tics in Tourette's Disorder is thought to be a function of its dopaminergic blocking activity. However, receptor blockade is often accompanied by a series of secondary alterations in central dopamine metabolism and function which may contribute to both pimozide's therapeutic and untoward effects. In addition, pimozide, in common with other antipsychotic drugs, has various effects on other central nervous system receptor systems which are not fully characterized.

METABOLISM AND PHARMACOKINETICS

More than 50% of a dose of pimozide is absorbed after oral administration. Based on the pharmacokinetic and metabolic profile, pimozide appears to undergo significant first pass metabolism. Peak serum levels occur generally six to eight hours (range 4-12 hours) after dosing.

Pimozide is extensively metabolized, primarily by N-dealkylation in the liver. This metabolism is catalyzed mainly by the cytochrome P450 3A (CYP 3A) enzymatic system and to a lesser extent, by cytochrome P450 1A2 (CYP 1A2). Two major metabolites have been identified, 1-(4-piperidyl)-2-benzimidazolinone and 4,4-bis(4-florophenyl) butyric acid. The antipsychotic activity of these metabolites is undermined. The major route of elimination of pimozide and its metabolites is through the kidney.

The mean serum elimination half-life of pimozide in schizophrenic patients was approximately 55 hours. There was a 13-fold interindividual difference in the area under the serum pimozide level-time curve and an equivalent degree of variation in peak serum levels among patients studied. The significance of this is unclear since there are few correlations between plasma levels and clinical findings.

Effects of food and disease upon the absorption, distribution, metabolism and elimination of pimozide are not known. Effects of concomitant medication on pimozide metabolism are described in the CONTRAINDICATIONS section.

ANIMAL PHARMACOLOGY

A chronic study in dogs indicated that pimozide caused gingival hyperplasia when administered for several months at about 5 times the maximum recommended human dose. This condition was reversible after withdrawal.

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