The liver is the principal organ of drug metabolism. Some drugs are absorbed from the gut, delivered to the liver and undergo first-pass metabolism prior to reaching the systemic circulation. Metabolism of these drugs is significantly affected by hepatic vascular supply; if hepatic blood flow is reduced, first-pass metabolism is decreased and more drug reaches the systemic circulation. Other drugs reach the systemic circulation before being delivered to the liver for metabolism; hepatocyte function is more important than the blood supply for their metabolism.
Cytochrome P450 enzymes are involved in Phase I metabolism (non-synthetic metabolism which includes oxidation, reduction and hydrolysis). There is substantial genetic polymorphism within these enzymes, and people may be slow or fast metabolizers. These enzymes are also frequently induced or inhibited by drugs, including anti-epileptic drugs. Phenytoin, phenobarbital and carbamazepine are well-known enzyme inducers (Table Effects of liver disease on specific anti-epileptic drugs).
Table Effects of liver disease on specific anti-epileptic drugs (AEDs)
|AED||Protein bound (%)||Half-life (h)||Liver disease|
|Carbamazepine||80||36; 16-24 with repeated doses; 9-10 with enzyme inducers||Reduced protein binding; reduced metabolism|
|Felbamate||25||Potentially hepatotoxic; inadvisable to use in liver disease|
|Lamotrigine||50||24-34; doubled with valproate; 15 with enzyme inducers||Slight reduction in clearance and prolonged half-life but considered clinically insignificant in trials|
|Oxcarbazepine||40 of active metabolite||Parent drug, 2; active metabolite, 9||No need to alter dose|
|Phenobarbital||40-50||55-118||Prolonged half-life; reduced metabolism; reduce dose and increase time between doses|
|Phenytoin||>90||22-36||Reduced metabolism, therefore accumulates and may become toxic quickly; reduced protein binding; increase in free fraction; monitor free levels|
|Tiagabine||96||5-8||Prolonged half-life; increased free fraction; reduce dose; increase time between doses|
|Topiramate||<20||18-23||Reduced clearance; prolonged half-life; felt to be clinically insignificant|
|Valproate||85-95||12-16||Reduced protein binding; rarely hepatotoxic|
|Vigabatrin||0||5-8||Not affected; however, some reports of liver damage|
|Zonisamide||40||50-70; 30 with enzyme inducers||Reduced metabolism; prolonged half-life; increase interval between dose adjustments|
The liver is also involved in protein production; impaired protein production reduces the amount of drug that is protein bound, increasing the free fraction. This is relevant for phenytoin, valproate, tiagabine and carbamazepine, which are highly protein bound. The true plasma concentration of phenytoin in a patient with low albumin can be calculated by Equation 2.
All anti-epileptic drugs except levetiracetam, gabapentin, pregabalin and vigabatrin have some hepatic metabolism, therefore hepatic disease may affect pharmacokinetics of most of the anti-epileptic drugs (Table Drugs that induce or inhibit hepatic enzymes). Additionally, patients with liver disease may be encephalopathic and have altered pharmacodynamics, having a lower seizure threshold as well as being more vulnerable to the central nervous system (CNS) adverse reactions of anti-epileptic drugs.
Seizures occur frequently after liver transplantation. Immunosuppressants are mainly metabolized by the liver, as are most anti-epileptic drugs. In addition, many anti-epileptic drugs may induce or inhibit hepatic metabolism. These factors make management of epilepsy difficult in patients with a liver transplant. Levetiracetam may be a good choice of anti-epileptic drug in such patients because of its predominantly renal metabolism and excretion, low protein binding, lack of enzyme induction, lack of drug interactions and broad-spectrum use in different seizure types.
A number of anti-epileptic drugs may rarely be hepatotoxic; the most common culprit is valproate, which is contraindicated in patients with hepatic failure. However, other anti-epileptic drugs, including phenytoin, may cause an acute drug-induced hepatitis. These reactions are idiosyncratic and usually occur soon after commencing the drug. Hepatic toxicity should prompt immediate discontinuation of the offending drug and substitution of an alternative anti-epileptic drug.
As gabapentin, pregabalin and levetiracetam are not significantly protein bound or metabolized by the liver, these are good choices for long-term anti-epileptic drug in patients with hepatic disease. If a patient with liver disease has an acute seizure, benzodiazepines may be used, although there is an increased risk of respiratory depression.
Table Drugs that induce or inhibit hepatic enzymes
|Enzyme inducers||Enzyme inhibitors|
|Anti-epileptic drugs||Anti-epileptic drugs||Antifungals|
|Antibiotics||Ciprofloxacin||Proton pump inhibitors|
|Histamine 2 blockers||Monoamine oxidase inhibitors|
Selections from the book: “Therapeutic Strategies in Epilepsy” (2008)