Effects of smoking on haloperidol and reduced haloperidol plasma concentrations and haloperidol clearance

Jann, Michael W.; Saklad, Stephen R.; Ereshefsky, Larry; Richards, Ann L.; Harrington, Charles A.; Davis, Charlotte

doi:10.1007/bf00174062

Cited by 112 publications

(44 citation statements)

References 13 publications

(7 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A role for CYP1A2 has been suggested in haloperidol clearance but is controversial. 23,24 The accumulated evidence suggests that multiple enzymes are involved in haloperidol metabolism, therefore diluting any specific effect of CYP2D6 genotype on QT c pharmacodynamics in our study.…”

Section: Discussionmentioning

confidence: 77%

Pharmacokinetics and QT interval pharmacodynamics of oral haloperidol in poor and extensive metabolizers of CYP2D6

Desai

Tanus‐Santos

et al. 2003

Pharmacogenomics J

View full text Add to dashboard Cite

We studied the pharmacokinetics and QT interval pharmacodynamics of a single 10 mg dose of oral haloperidol in a randomized, double-blind, placebo-controlled, crossover trial of healthy poor (PMs) and extensive (EMs) metabolizers of CYP2D6. There was a statistically significant greater mean QT c on haloperidol (421.6720.1 ms) than on placebo (408.4718.5 ms, P ¼ 0.0053) occurring 10 h post haloperidol/placebo administration. Men and women had similar ranges of QT c changes from placebo. Despite a statistically significant greater mean elimination half-life (19.173.6 vs 12.974.0 h, P ¼ 0.04) and lower mean apparent oral clearance (12.874.1 vs 27.0711.3 ml/min/kg, P ¼ 0.02) of haloperidol in CYP2D6 PMs than in EMs, this exposure change did not translate into marked QT c changes from baseline that could be considered clinically important. Although the magnitude of the mean QT c prolongation on haloperidol relative to placebo is relatively small, it may assume significance in the presence of other risk factors for QT prolongation. The Pharmacogenomics Journal (2003) 3, 105-113. doi:10.1038/sj.tpj.6500160Keywords: haloperidol; CYP2D6 genotype; QT INTRODUCTION Schizophrenia is a common psychiatric disease with a lifetime prevalence of nearly 1% of the general population 1 that is associated with an increased risk of premature death. A recent meta-analysis revealed that schizophrenic patients are 1.5 times more likely of dying from all causes compared to an age-and gendermatched cohort of the general population. 2 While it is not known how much of this excess risk can be attributed to antipsychotic-induced cardiotoxicity, it is clear that many antipsychotics are arrhythmogenic. 3 Among the antipsychotic drugs, haloperidol remains one of the most widely used worldwide. Haloperidol-induced ventricular arrhythmias of the torsades de pointes (TdP) type have been reported with a range of doses starting as low as 4 mg 4 administered over a 24 h period and as high as 825 mg 5 over a 24-h period. Cardiac side effects at high doses likely involve excessive exposure to haloperidol. However, the extent to which low doses of haloperidol contribute to QT interval prolongation in the absence of risk factors 6 such as age, concomitant medications, electrolyte imbalances, ischemic heart disease, or congenitally prolonged QT intervals is less well characterized. Prolongation of the QT interval is a biomarker for the malignant ventricular arrhythmia of TdP.In vitro cardiac electrophysiology studies that we have conducted demonstrate that supratherapeutic concentrations of haloperidol prolong the heart rate corrected QT interval (QT c ) by approximately 26% in an isolated perfused feline heart model. 7 The mechanism of haloperidol-mediated QT prolongation

show abstract

Section: Discussionmentioning

confidence: 77%

Pharmacokinetics and QT interval pharmacodynamics of oral haloperidol in poor and extensive metabolizers of CYP2D6

Desai

Tanus‐Santos

et al. 2003

Pharmacogenomics J

View full text Add to dashboard Cite

show abstract

“…Smoking may also alleviate neuroleptic-induced extrapyramidal side effects (Decina et al 1990;Goff et al 1992;Sandyk 1993). Nicotine use increases haloperidol metabolism (Jann et al 1986;Miller et al 1990), requiring patients that smoke to take higher doses than non-smoking schizophrenics, often further increasing their smoking behavior (McEvoy et al 1995). Interestingly, clozapine, which does not induce the motor dysfunctions seen with typical neuroleptics, reduces smoking behavior (George et al 1995) and normalizes the electrophysiological deficit in schizophrenics .…”

Section: Previous Studies Have Suggested That An Abnormality In Neuromentioning

confidence: 99%

Abnormal Regulation of High Affinity Nicotinic Receptors in Subjects with Schizophrenia

Breese

2000

Neuropsychopharmacology

305

215

View full text Add to dashboard Cite

Previous studies have suggested that an abnormality in neuronal nicotinic acetylcholine receptor expression or function may be involved in the neuropathophysiology of schizophrenia. [ 3 H]-nicotine and [ 3 H]-epibatidine binding were compared in postmortem brain from control and schizophrenic subjects with varying smoking histories. In control subjects, increased receptor binding was seen in hippocampus, cortex, and caudate with increasing tobacco use. In contrast, schizophrenic smokers had reduced nicotinic receptor levels in these brain regions compared to control smokers. Chronic haloperidol and nicotine treatment, in the rat, was used to assess neuroleptic effects on receptor up-regulation by nicotine. A significant increase in cortical nicotinic receptors was seen in both nicotine treated as well as haloperidol and nicotine co-treated animals, suggesting that the abnormal regulation of high affinity neuronal nicotinic receptors in schizophrenics followingPrevious studies have shown that high affinity nicotinic receptor numbers increase in the brains of human subjects who smoke (Benwell et al. 1988;Breese et al. 1997a;Court et al. 1998). This increase was shown to be dosedependent, based on the number of cigarettes smoked at death, and was reversible, with binding levels returning to control values in subjects who had quit smoking for at least two months prior to death (Breese et al. 1997a). The up-regulation of receptor numbers does not appear to be under transcriptional regulation (Marks et al. 1992). Rather, the increases may be related to changes in receptor turnover based on receptor desensitization, subunit composition, secondary structural changes in the receptor, or to modification of the receptor by protein kinases (Peng et al. 1994;Baenziger and Chew 1997;Eilers et al. 1997;Flores et al. 1997;Hsu et al. 1997;Xiao et al. 1998;Fenster et al. 1999).In spite of the high degree of nicotine self-administration in schizophrenics (Lohr and Flynn 1992;Ziedonis et al. 1994;de Leon et al. 1995), few studies have examined the effect of smoking or neuroleptic treatment on nicotinic receptor regulation in this disease (Dalack et al. 1998). It has been suggested that nicotine self-administration in schizophrenics may control a neuronal deficit. In this regard, it has been shown that abnormal electro- NO . 4 physiological and eye-tracking deficits can be normalized by cigarette smoking or nicotine administration (Adler et al. 1992(Adler et al. , 1993Olincy et al. 1998). Smoking may also alleviate neuroleptic-induced extrapyramidal side effects (Decina et al. 1990;Goff et al. 1992;Sandyk 1993). Nicotine use increases haloperidol metabolism (Jann et al. 1986;Miller et al. 1990), requiring patients that smoke to take higher doses than non-smoking schizophrenics, often further increasing their smoking behavior (McEvoy et al. 1995). Interestingly, clozapine, which does not induce the motor dysfunctions seen with typical neuroleptics, reduces smoking behavior (George et al. 1995) and normalizes the electrophysiologi...

show abstract

“…The plasma concentration of most typical antipsychotics is significantly reduced by smoking, [36][37][38][39][40][41] an established inducer of CYP1A2. 42 Conversely, the cessation of smoking was reported to increase chlorpromazine plasma concentration and adverse effects.…”

Section: Introductionmentioning

confidence: 99%

A functional polymorphism of the cytochrome P450 1A2 (CYP1A2) gene: association with tardive dyskinesia in schizophrenia

et al. 2000

View full text Add to dashboard Cite

Effects of smoking on haloperidol and reduced haloperidol plasma concentrations and haloperidol clearance

Cited by 112 publications

References 13 publications

Pharmacokinetics and QT interval pharmacodynamics of oral haloperidol in poor and extensive metabolizers of CYP2D6

Pharmacokinetics and QT interval pharmacodynamics of oral haloperidol in poor and extensive metabolizers of CYP2D6

Abnormal Regulation of High Affinity Nicotinic Receptors in Subjects with Schizophrenia

A functional polymorphism of the cytochrome P450 1A2 (CYP1A2) gene: association with tardive dyskinesia in schizophrenia

Contact Info

Product

Resources

About