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Avanços na terapêutica farmacológica da hiperamonémia
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A hiperamonémia (HA) é uma condição metabólica caracterizada por níveis elevados de amónio e/ou amoníaco no sangue. Várias poderão ser as causas desta condição, incluindo alterações genéticas primárias que afetam o ciclo da ureia ou outras doenças hereditárias do metabolismo, como certas acidúrias orgânicas ou doenças ao nível da oxidação de ácidos gordos. O uso de certos medicamentos, nomeadamente antiepiléticos ou antitumorais, pode também estar associado a HA como efeito indesejado. Em muitos casos, a HA apenas é detetada, quando já evoluiu para encefalopatia hepática (HE, Hepatic Encephalopathy), que se associa frequentemente a uma função hepática comprometida. A HE é uma condição grave que pode resultar de um amplo e complexo espetro de alterações metabólicas em doentes com patologia hepática. A cirrose é a causa mais comum. A HE manifesta-se através de alterações no comportamento dos doentes, como confusão, desorientação, sonolência e ainda alterações ao nível da personalidade e do humor. Apesar de não se conhecer totalmente o mecanismo fisiopatológico da HE, existem três fatores relevantes para a mesma, sendo elas, a HA, a inflamação sistémica e o stress oxidativo. Assim, é de sublinhar que um objetivo central da terapêutica visa o aumento da excreção de amónio/amoníaco do organismo humano, devido à sua elevada neurotoxicidade. Existem, também, outros fatores que poderão agravar o estado clínico do doente, salientando-se as infeções bacterianas, as hemorragias do trato gastrointestinal e a obstipação. Os tratamentos aprovados e utilizados na HE contemplam laxantes, como a lactulose e o lactitol e antibióticos como a rifaximina. Como são escassos os tratamentos farmacológicos disponíveis, novas opções têm vindo a ser desenvolvidas nesta área, incluindo a utilização de aminoácidos, adsorventes de carbono, antagonistas do recetor GABA-A e antibióticos. Avanços têm sido também reportados na terapia celular, terapia génica, e ainda, na modulação da microbiota fecal ou de hormonas. Alguns destes tratamentos já têm sido aplicados em modelos animais ou em estudos clínicos, úteis quando o doente não responde à terapêutica padrão. No entanto, são necessários mais progressos em investigação, de forma a comprovar a sua verdadeira eficácia no tratamento da HE e subsequente recomendação para as guidelines de tratamento.
Hyperammonemia is characterized by high levels of ammonia in the blood. There may be several causes contributing to this condition, ranging from primary genetic defects disturbing the urea cycle as well as other inherited metabolic diseases such as specific organic acidurias or fatty acid oxidation disorders. The use of certain medications particularly antiepileptic drugs or antitumoral drugs may also associate with HA, as an unwanted effect. In many cases, hyperammonemia is only detected when it develops into hepatic encephalopathy (HE), mostly associated with compromised liver function. HE is a serious condition that can result from a broad and complex spectrum of metabolic changes in patients with liver disease. Cirrhosis is the most common cause. HE manifests through changes in the patient's behavior, signs of confusion, disorientation, drowsiness or changes in personality and mood, also. Although the pathophysiological mechanism of this condition is not fully understood, there are three factors of relevance: HA, systemic inflammation and oxidative stress. There are also other factors that can aggravate the clinical condition of the patient, and the most important ones are bacterial infections, bleeding in the gastrointestinal tract and constipation. The treatments that have been approved for HE includes laxatives such as lactulose and lactitol and antibiotics such as rifaximin. Since the available treatments are scarce, various other compounds have been studied to increase the therapeutic options. The goals of therapy are mainly centered on increasing the excretion of ammonia from the human body, due to its serious neurotoxicity, which triggers HE. Some novel treatment options have emerged in this area, namely the use of amino acids, carbon adsorbents, GABA-A receptor antagonists and antibiotics. Advances have also been reported in cell therapy, gene therapy, and in the modulation of fecal microbiota or hormones. Some of these treatments have already been applied in animal models or specific case reports, especially when the patient does not respond to standard therapy. However, more research is needed to prove their true effectiveness in treating HE and subsequent recommendation as part of the treatment guidelines.
Hyperammonemia is characterized by high levels of ammonia in the blood. There may be several causes contributing to this condition, ranging from primary genetic defects disturbing the urea cycle as well as other inherited metabolic diseases such as specific organic acidurias or fatty acid oxidation disorders. The use of certain medications particularly antiepileptic drugs or antitumoral drugs may also associate with HA, as an unwanted effect. In many cases, hyperammonemia is only detected when it develops into hepatic encephalopathy (HE), mostly associated with compromised liver function. HE is a serious condition that can result from a broad and complex spectrum of metabolic changes in patients with liver disease. Cirrhosis is the most common cause. HE manifests through changes in the patient's behavior, signs of confusion, disorientation, drowsiness or changes in personality and mood, also. Although the pathophysiological mechanism of this condition is not fully understood, there are three factors of relevance: HA, systemic inflammation and oxidative stress. There are also other factors that can aggravate the clinical condition of the patient, and the most important ones are bacterial infections, bleeding in the gastrointestinal tract and constipation. The treatments that have been approved for HE includes laxatives such as lactulose and lactitol and antibiotics such as rifaximin. Since the available treatments are scarce, various other compounds have been studied to increase the therapeutic options. The goals of therapy are mainly centered on increasing the excretion of ammonia from the human body, due to its serious neurotoxicity, which triggers HE. Some novel treatment options have emerged in this area, namely the use of amino acids, carbon adsorbents, GABA-A receptor antagonists and antibiotics. Advances have also been reported in cell therapy, gene therapy, and in the modulation of fecal microbiota or hormones. Some of these treatments have already been applied in animal models or specific case reports, especially when the patient does not respond to standard therapy. However, more research is needed to prove their true effectiveness in treating HE and subsequent recommendation as part of the treatment guidelines.
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2024, Universidade de Lisboa, Faculdade de Farmácia.
Palavras-chave
Hiperamonémia Encefalopatia hepática Amoníaco Fígado Doenças do ciclo da ureia Mestrado Integrado - 2024