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A teratogenicidade associada aos fármacos antiepiléticos: que progressos?
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Abstract(s)
A epilepsia é uma doença que pode afetar mulheres em idade fértil, e em caso de gravidez, na sua maioria será necessário manter a terapêutica farmacológica para controlar a situação clínica. Porém, existem vários estudos que nos demonstram que os fármacos antiepiléticos (AEDs) podem causar malformações físicas ao feto e/ou défices neurocognitivos a longo prazo.
A teratogenicidade provocada pela toma de AEDs constitui um problema sério, sendo urgente perceber quais os fármacos que apresentam maior e menor risco de causar malformações, para que a terapêutica possa ser ajustada. Para além disso, durante o período pré-concecional e durante a gestação a mulher deve ser aconselhada a tomar cerca de 4-5 mg/dia de ácido fólico, pois está comprovado que este reduz os efeitos adversos provocados por AEDs. Por outro lado, é importante conhecer o mecanismo de teratogenicidade dos AEDs, pois permite o desenvolvimento de estratégias para impedir a ocorrência de danos. A maioria dos estudos realizados têm tido como foco os efeitos teratogénicos do ácido valpróico, suportando a ideia de que este pode associar-se a stress oxidativo, atuar como inibidor da histona deacetilase e alterar a expressão de transportadores na placenta.
A placenta é um órgão materno-fetal essencial para as trocas entre a mãe e o feto. O transporte de moléculas através desta ocorre por difusão simples ou facilitada, transporte ativo e endocitose. A maioria dos AEDs consegue atravessar a barreira placentária, o que implica que quantidades significativas de AEDs entrem em contacto com o feto. De maneira a contornar o problema, estão a ser estudados processos alternativos de administração dos fármacos AEDs para evitar a sua passagem placentária, que serão revistos ao longo deste trabalho.
Na mulher com epilepsia, a terapêutica não farmacológica como a cirurgia, neuroestimulação e o consumo de alimentos/suplementos contendo compostos biologicamente ativos, também demonstraram ser uma importante possibilidade. Estas opções terapêuticas podem levar à liberdade total de crises convulsivas e à retirada dos AEDs ou diminuição da sua respectiva dose.
Epilepsy is a disease that can affect women during fertile age, and in case of pregnancy most of them need to maintain a drug therapy to control her clinical condition. However, several studies show that antiepileptic drugs (AEDs) can cause physical malformations to the fetus and/or neurocognitive deficits at long term. The teratogenicity caused by the intake of AEDs is a serious problem and it is crucial to understand which drugs have the highest and lowest risk of causing malformations, so that the therapy can be adjusted. In addition, during the preconception period and during pregnancy, women should be advised to take about 4-5 mg/day of folic acid, as this supplementation has been shown to reduce the adverse effects caused by AEDs. On the other hand, it is important to elucidate the teratogenicity mechanisms of AEDs, as this allows to promote the development of strategies to prevent the occurrence of damages. Most studies have been focusing on valproic acid effects, suporting the idea that it can be associated with oxidative stress, act as a histone deacetylase inhibitor and alter the expression of carriers and molecules transport at the placental level. The placenta is an essential maternal-fetal organ for exchanges between the mother and the fetus. Transport processes through the placenta include simple or facilitated diffusion, active transport and endocytosis. Most AEDs may cross the placental barrier, causing exposure of the fetus to significant amounts of AEDs. In order to overcome this problem, other alternative modes of administering these drugs are being studied to prevent placental exchange of AEDs, that will be reviewed in this monography. In women with epilepsy, non-pharmacological therapy such as surgery, neurostimulation and the consumption of food/supplements containing biologically active compounds, also proved to be an important possibility. These therapeutic options can lead to complete absence of seizures crises and withdrawal of AEDs or decrease of respective dose.
Epilepsy is a disease that can affect women during fertile age, and in case of pregnancy most of them need to maintain a drug therapy to control her clinical condition. However, several studies show that antiepileptic drugs (AEDs) can cause physical malformations to the fetus and/or neurocognitive deficits at long term. The teratogenicity caused by the intake of AEDs is a serious problem and it is crucial to understand which drugs have the highest and lowest risk of causing malformations, so that the therapy can be adjusted. In addition, during the preconception period and during pregnancy, women should be advised to take about 4-5 mg/day of folic acid, as this supplementation has been shown to reduce the adverse effects caused by AEDs. On the other hand, it is important to elucidate the teratogenicity mechanisms of AEDs, as this allows to promote the development of strategies to prevent the occurrence of damages. Most studies have been focusing on valproic acid effects, suporting the idea that it can be associated with oxidative stress, act as a histone deacetylase inhibitor and alter the expression of carriers and molecules transport at the placental level. The placenta is an essential maternal-fetal organ for exchanges between the mother and the fetus. Transport processes through the placenta include simple or facilitated diffusion, active transport and endocytosis. Most AEDs may cross the placental barrier, causing exposure of the fetus to significant amounts of AEDs. In order to overcome this problem, other alternative modes of administering these drugs are being studied to prevent placental exchange of AEDs, that will be reviewed in this monography. In women with epilepsy, non-pharmacological therapy such as surgery, neurostimulation and the consumption of food/supplements containing biologically active compounds, also proved to be an important possibility. These therapeutic options can lead to complete absence of seizures crises and withdrawal of AEDs or decrease of respective dose.
Description
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2021, Universidade de Lisboa, Faculdade de Farmácia.
Keywords
Epilepsia Gravidez Teratogenicidade Antiepiléticos Malformações Mestrado integrado - 2021