The effects of antiepileptic inducers in neuropsychopharmacology, a neglected issue. Part II: Pharmacological issues and further understanding

Abstract

Right click to open a feedback form in a new tab to let us know how this document benefits you.1 Resumen La literatura en epilepsia y el trastorno bipolar en los inductores está contaminada por falsos negativos. Esta es la segunda parte de una revisión exhaustiva de los fármacos antiepilépticos (FAE) con propiedades inductoras que aporta más material educativo a los clínicos acerca de la complejidad de interpretar sus interacciones medicamentosas.Se revisa la farmacología básica de inducción incluyendo los citocromos P450 (CYP), las enzimas de glucuronización (UGTs) y la glicoproteina P (P-gp). Los CYP2B6 y CYP3A4 son muy sensibles a la inducción. El CYP1A2 es moderadamente sensible. Los CYP2C9 y CYP2C19 son sólo levemente sensibles. El CYP2D6 no se puede inducir con los fármacos. La inducción de los enzimas metabólicos, los CYPs o las UGTs, y los transportadores, como la P-gp, se debe a un aumento en la síntesis de estas proteínas mediado por los receptores nucleares (receptores constitutivo androstano, de los estrógenos, de los glucocorticoides y de preganano X). Aunque la primer parte de este artículo describe factores de corrección para los antiepilépticos inductores, la extrapolación de estos valores desde un paciente promedio a un individuo concreto está influenciada por la ruta de administración, la carencia de la enzima metabólica debida a razones genéticas, y la presencia de inhibidores, u otros inductores. También pueden ser importantes las interacciones farmacológicas de los FAE a nivel de los mecanismos farmacodinámicos. Seis pacientes con una sensibilidad extrema los inductores antiepilépticos son descritos. AbstractThe literature on inducers in epilepsy and bipolar disorder is seriously contaminated by false negative findings. Part II of this comprehensive review on antiepileptic drug (AED) inducers provides clinicians with further educational material about the complexity of interpreting AED drug-drug interactions.The basic pharmacology of induction is reviewed including the cytochrome P450 (CYP) isoenzymes, the Uridine Diphosphate Glucuronosyltransferases (UGTs), and P-glycoprotein (P-gp).CYP2B6 and CYP3A4 are very sensitive to induction. CYP1A2 is moderately sensitive while CYP2C9 and CYP2C19 are only mildly sensitive. CYP2D6 cannot be induced by medications. Induction of UGT and P-gp are poorly understood. The induction of metabolic enzymes such as CYPs and UGTs, and transporters such as P-gp, implies that the amount of these proteins increases when they are induced; this is almost always explained by increasing synthesis mediated by the so-called nuclear receptors (constitutive androstane, estrogen, glucocorticoid receptors and pregnane X receptors). Although Part I provides correction factors for AEDs, extrapolation from an average to an individual patient may be influenced by administration route, absence of metabolic enzyme for genetic reasons, and presence of inhibitors or other inducers. AED pharmacodynamic DDIs may also be important. Six patients with extreme sensitivity to AED inductive ...

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