Liver antipsychotic drugs

Shin, J.G., Soukhova, N. and Flockhart, D.A. (1999) Effect of antipsychotic drugs on human liver cytochrome P-450 (CYP) isoforms in vitro preferential inhibition of CYP2 D6. Drug Metabolism and Disposition, 27 (9), 1078-1084. 

Macrolides can cause drug interactions, through inactivation of liver enzymes, with antiarrhythmic dmgs, anticoagulants, antipsychotic drugs, anxiolytics and antiepileptic drugs. Erythromycin in particular can increase the risk of myopathy if taken in combination with lipid-lowering statins. Such combinations should be avoided. 

Most antipsychotic drugs as well as tricyclic antidepressants (TCAs) are inhibitors of the chytochrome P450 liver catabolic enzymes, thus potentially increasing each other s serum levels. Chlorpromazine increases imipramine serum levels. Levomepromazine can cause a significant increase in clomipramine serum levels. Perphenazine has been reported to increase the serum levels of amitriptyline, desipramine, imipramine, and nortriptyline. Thioridazine has also been shown to increase TCA serum levels (mainly desipramine). Marked extrapyramidal side-effects have been reported in a few cases with fluphenazine or perphenazine when fluoxetine was added to the regimen. The mechanism is not known. A mutual increase in serum levels of both thioridazine and paroxetine is evident when these agents are... 

The antipsychotics are contraindicated in patients with known hypersensitivity to the drug s, in comatose patients, and in those who are severely depressed, have bone marrow depression, blood dysera ias, Parkinson s disease (haloperidol), liver impairment, coronary artery disease, or severe hypotension or hypertension. 

Many antipsychotics show great interindividual variation in plasma levels and so analysis of therapeutic levels can be important clinically as well as in the research laboratory. In addition, nonresponse to the drugs may actually be due to excessive levels of neuroleptics, a paradoxical situation that requires analysis to identify (Rockland, 1986). Several methods using FID were cited in the previous edition of the Handbook of Neurochemistry but ECD and NPD have both shown utility for the typically low therapeutic levels (Cooper, 1988). GC-FID has been used to analyze levels of clozapine in blood, gastric, and urine samples in fatal cases of overdose with this drug (Ferslew et al., 1998), and olanzapine has been measured in blood and urine samples by GC-NPD in overdoses (Stephens et al., 1998). 4-(4-Chlorophenyl)-4-hydroxypiperidine, a metabolite of haloperidol, was analyzed in urine, plasma, brain, and liver from haloperidol-treated rats by GC-ECD, after derivatization with PFBC under aqueous conditions (Fang et al., 1996). 

Metabolism of antipsychotics is through two mechanisms conjugation with glucuronic acid and oxidation by hepatic microsomal enzymes. Both mechanisms of metabolism and subsequent inactivation take place in the liver. Some degree of enzyme induction may occur because of prolonged use of antipsychotics, which may be responsible for increasing the rate of metabolism of these drugs. 

The antipsychotic chlorpromazine is a prototype heptotoxicant for production of cholestasis. Pleiotropic effects of chlorpromazine on membrane permeability and associated ion gradients and microfilament-mediated canalicular contraction have been attributed to detergent effects. Valproic acid, an anticonvulsant, is associated with microvesicular steatosis. Inhibition of mitochondial fatty acid (S-oxidation is an important component of this toxic effect and is apparently related to carnitine availability as evidenced by the protection afforded by L-carnitine supplements. The hypolipidemic drugs clofibrate, fenofibrate, and gemfibrozil are peroxisome prolif-erators in rodent liver, but not in humans. Isoniazid, an antibiotic used to treat tuberculosis, exhibits an approximately 1 % incidence of hepatotoxicity. Although toxicity is known to be metabolism-dependent and protein adduction has been well-... 

Tramadol, phenothiazine antipsychotics and the majority of antidepressants, as well as a number of other drugs, can lower the seiznre threshold and are associated with an increased risk of convnlsions [6]. Again, these drugs may accumulate in patients with liver impairment such as cirrhosis or acute liver failure, and care must be taken if choosing to use them. This is especially important in alcoholics, who have an increased risk of seizures from acute alcohol withdrawal [7]. Examples of drugs that can lower the seizure threshold and should be used with caution/avoided are ... 

A mild jaundice, typically occurring early in therapy, may be seen in some patients receiving chlorpromazine. Pruritus is rare. The reaction probably is a manifestation of hypersensitivity, because eosinophilia and eosinophilic infiltration of the liver occur. For uninterrupted drug therapy in a patient with neuroleptic-induced jaundice, it probably is safest to use low doses of a potent, dissimilar agent. Hepatic dysfunction with other antipsychotic agents is uncommon. Clozapine can cause potentially severe ileus and sialorrhea. 

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