Haloperidol metabolism

Based on published data in humans, concomitant medications were classified as potential inhibitors (cimetidine, fluoxetine, levopromazine, paroxetine, and thioridazine) or inducers of haloperidol metabolism (carbamazepine, phenobarbital, and phenytoin). 

Yasui N, Kondo T, Otani K, Furukori H, Mihara K, Suzuki A, Kaneko S, Inoue Y. Effects of itraconazole on the steady-state plasma concentrations of haloperidol and its reduced metabolite in schizophrenic patients in vivo evidence of the involvement of CYP3A4 for haloperidol metabolism. J Clin Psychopharmacol 1999 19(2) 149-54. 

Fluvoxamine inhibits liver drug-metabolizing enzymes. Dosages of alprazolam, theophylline, and warfarin must be reduced if any of these drugs are given concomitantly with fluvoxamine. Nefazodone may also decrease the metabolism of benzodiazepines, and venlafaxine may inhibit haloperidol metabolism. The answer is (B). 

Escitalopram. Escitalopram is an inhibitor of the eytoehrome P450 isoenzyme CYP2D6, and may therefore inhibit haloperidol metabolism The manufacturers say that consideration should be given to reducing the dose of haloperidol. ... 

The effect of PCP-like drugs was also studied in vivo. In these experiments, the ability of these drugs to enhance haloperidol-induced DA metabolism was assessed by measuring DA and homovanil-11c acid (HVA) concentrations in the striatum. In this paradigm, saline or drug was administered (SC) immediately after the administration of 0.1. mg/kg ha 1 operido 1. The rats were killed 45 minutes later, and DA and HVA levels were estimated fluorometri-tal ly (Snel 1 et al. 1984). 

Iwahashi K, Anemo K, Nakamura K, Fukunishi 1, Igarashi K. 2001. Analysis of the metabolism of haloperidol and its neurotoxic pyridinium metabolite in patients with drug-induced parkinsonism. Neuropsychobiology 44 126. 

The work that has been done with chlorpromazine, haloperidol, and pimozide suggests that these drugs are metabolized more rapidly in children than in adults (Morselli et ah, 1982 Sallee et ah, 1987 Furlanut et ah, 1990). In addition, it appears that larger doses of chlorpromazine and haloperidol per body weight are needed in young people to achieve the same plasma concentrations as those in adults (Morselli et ah, 1979 Rivera-Calimlim et ah, 1979). 

There are several antipsychotics that are substrates to CYP2D6 (von Bahr et ah, 1991 Jerling et ah, 1996 Ring et ah, 1996 (Fang and Gorrod, 1999 Flockhart and Oesterheld, 2000) (Table 26.3). Moreover, several antipsychotics may act as inhibitors of CYP2D6-mediated biotransformation. These include thioridazine, chlorpromazine, haloperidol, fluphenazine, and pimozide (Desta et ah, 1998 Shin et ah, 1999). Of particular salience is the fact that the serotonin selective reuptake inhibitors (SSRIs) fluoxetine and paroxetine are metabolized to a significant extent by this isoenzyme. 

Oxcarbazepine is a keto derivative of carbamazepine but offers several advantages over carbamazepine. Oxcarbazepine does not require blood cell count, hepatic, or serum drug level monitoring. It causes less cytochrome P450 enzyme induction than does carbamazepine (but may decrease effectiveness of oral contraceptives containing ethinyl estradiol and levonorgestrel). As opposed to carbamazepine, oxcarbazepine does not induce its own metabolism. These properties, combined with its similarity to carbamazepine, led many clinicians to use this medication for the treatment of bipolar disorder. Randomized controlled trials suggested efficacy in the treatment of acute mania compared with lithium and haloperidol, but these trials were quite small and did not include a placebo control (Emrich 1990). 

Limited evidence indicates that carbamazepine plus an antipsychotic may also benefit some schizophrenic patients. This is an interesting possibility in view of the similar antimanic properties of lithium and carbamazepine (375). This area requires further research, especially to clarify the indications for combining anticonvulsants with an antipsychotic. For example, mania complicated by psychotic features may benefit from lithium, valproate, or carbamazepine augmented by antipsychotics. Because carbamazepine induces the metabolism of at least some antipsychotics (e.g., haloperidol, thiothixene), dose adjustment based on TDM may be necessary to achieve the optimal effect. 

Ichikawa J, Meltzer HY. Differential effects of repeated treatment with haloperidol and clozapine and dopamine release and metabolism in the striatum and the nucleus accumbens. J Pharmacol Exp Ther 1991 256 348-357. 

Most antipsychotic drugs are readily but incompletely absorbed. Furthermore, many undergo significant first-pass metabolism. Thus, oral doses of chlorpromazine and thioridazine have systemic availability of 25-35%, whereas haloperidol, which has less first-pass metabolism, has an average systemic availability of about 65%. 

Haloperidol Blockade of D2 receptors >> 5HT2A receptors Some a blockade, but minimal M receptor blockade and much less sedation than the phenothiazines Schizophrenia (alleviates positive symptoms), bipolar disorder (manic phase), Huntington s chorea, Tourette s syndrome Oral and parenteral forms with metabolism-dependent elimination Toxicity Extrapyramidal dysfunction is major adverse effect... 

Lately it has been found that it takes ten times as much haloperidol to relieve schizophrenic symptoms in Caucasians as it does in the inhabitants of Taiwan. And when using propanolol for the control of blood pressure, men of Chinese descent metabolize it more efficiently than Caucasians and could use lower doses for comparable effects. 

Glucose metabolism has been studied in 10 patients taking haloperidol none had impaired glucose tolerance and only one had a glycemic peak delay (476). 

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