Antipsychotic drugs metabolism

Antipsychotic drugs metabolic adverse effects (Chapter 6) Bisphosphonates osteonecrosis of the jaw (Chapter 49)... 

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. 

Other orthopramides have been shown to be resistant to in vivo hydrolysis. Thus, the gastrokinetic drug cisapride (4.80) was not hydrolyzed after oral administration to dogs and humans [51]. Similarly, sulpiride (4.81), an antidepressant and antipsychotic drug, did not undergo hydrolysis in humans and laboratory animals. These compounds are metabolized by other routes, and hydrolysis of the amide bond, when it occurs at all, is only a minor pathway. 

There are some clinically important pharmacodynamic drug-drug interactions to be mentioned. Antipsychotics will potentiate the central depressant effects of sedatives and of alcohol. They will also increase the risk of respiratory-depressant effects of opiates. Inducers of drug metabolic enzymes like for example rifampicin and several antiepileptics, may increase the elimination rate of antipsychotic agents and thus decrease their efficacy. 

Fang, J. and Gorrod, J.W (1999) Metabolism, pharmacogenetics, and metabolic drug-drug interactions of antipsychotic drugs. Cell Mol Neurobiol 19 491—510. 

Shen, W.W. (1999b) The metabolism of atypical antipsychotic drugs an update. Ann Clin Psychiatry 11 145-158. 

Taken with alcohol they potentiate the sedative effects and impairment of psychomotor performance. Hepatic enzyme induction by barbiturates or nicotine may reduce plasma levels. Cimetidine may increase levels by enzyme inhi bition. Some antipsychotic drugs may compete for similar metabolic pathways. 

Fluoxetine and paroxetine inhibit cytochrome CYP P-450 2D6 and thus may affect metabolism of some opioids, e.g. codeine, 0) codone and tramadol, that are partly metabolised by CYP2D6, many antipsychotic drugs and tricyclic antidepressants. 

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%. 

Recall that one of the key drug-metabolizing enzymes is the cytochrome P450 (CYP450) enzyme called 1A2. Two atypical antipsychotic drugs are substrates of 1A2, namely olanzapine and clozapine. That means that when they are given con-... 

Baptista T, Kin NM, Beaulieu S. Treatment of the metabolic disturbances caused by antipsychotic drugs. Clin Pharmacokinet 2004 43 1-15. 

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