Seizures may occur in uraemic encephalopathy, dialysis disequilibrium syndrome and dialysis encephalopathy. In addition, renal insufficiency and dialysis may both have effects on anti-epileptic drug pharmacokinetics. Renal impairment can alter the fraction of anti-epileptic drug absorbed, volume of distribution, protein binding and renal drug clearance.
Renal impairment may alter the gastric pH, cause small intestinal bacterial overgrowth, gastrointestimal tract oedema and impaired gastrointestinal motility. These factors may cause reduced ionization of some drugs and reduce drug absorption.
The volume of distribution of drugs may be increased in patients with end-stage renal failure, resulting in lower total plasma levels. However, protein binding of acidic drugs may be significantly reduced in renal impairment; total plasma levels of anti-epileptic drugs may therefore be misleading. A total drug level may appear within the therapeutic range, despite a toxic-free level. For anti-epileptic drugs metabolized by the liver, changes in protein binding will affect the steady-state plasma concentration, but the free concentration will remain unchanged. For these reasons, it is often more useful to measure free concentrations of anti-epileptic drugs which are highly protein bound, such as phenytoin and valproate.
Renal impairment may affect drug clearance depending on the extent of renal clearance, drug filtration and tubular secretion and resorption. Gabapentin, topiramate, pregabalin and levetiracetam are almost exclusively cleared by the kidneys. These drugs have reduced elimination and prolonged half-lives in patients with renal impairment and dosages should be adjusted accordingly. For other anti-epileptic drugs such as phenytoin, carbamazepine and tiagabine, renal excretion is minimal, and unless creatinine clearance is below 25ml / min there is no need to adjust the dose (Table Effect of renal disease on specific anti-epileptic drugs).
Table Effect of renal disease on specific anti-epileptic drugs (AEDs)
|AED||Protein binding (%)||Half-life (h)||Effect of renal disease|
|Carbamazepine||80||36; 16-24 with repeated doses; 9-10 with enzyme inducers||Anti-diuretic effect, may increase fluid retention|
|Felbamate||25||Reduced clearance; prolonged half-life|
|Gabapentin||0||5-9||Reduced clearance; significantly removed by HD; company advises 200-300 mg bolus post HD|
|Lamotrigine||50||24-34; doubled with valproate; 15 with enzyme inducers||Prolonged half-life; reduce dose; 20%removed by HD|
|Levetiracetam||<10||6-8||Reduced clearance; 50%removed by HD; company advise giving 250-500 mg bolus post HD|
|Oxcarbazepine||40 of active metabolite||Parent drug, 2; active metabolite, 9||Reduced clearance; reduce dose|
|Phenobarbital||40-50||55-118||Removed by HD; reduce dose|
|Phenytoin||>90||22-36||Reduced total concentration but increased free fraction; only 2-4% removed by HD; monitor free levels|
|Pregabalin||0||6||Reduced clearance, prolonged half-life; reduce dose; significantly removed by HD; supplement dose post HD|
|Topiramate||<20||21||Reduced clearance; reduce dose; significantly removed by HD; company advise loading before HD to avoid sub-therapeutic levels. Note: risk of renal stones|
|Valproate||85-95||12-16||Reduced protein binding; reduced total concentration but increased free fraction; 20%removed by HD|
|Vigabatrin||0||5-8||Reduced clearance; reduce dose|
|Zonisamide||40||50-70; 30 with enzyme inducers||Reduced clearance; some is removed by HD|
Several methods have been proposed to calculate anti-epileptic drug dose based on creatinine clearance, volume of distribution and other variables. However, these are complex and the actual drug concentration may vary considerably from that calculated. In patients with renal impairment, anti-epileptic drugs should be slowly initiated at low doses and clinical assessment and drug level monitoring are necessary.
Haemodialysis (HD) may clear anti-epileptic drugs from the circulation depending on their molecular size, water solubility, protein binding, volume of distribution and dialysis conditions. Drugs such as ethosuximide, gabapentin, levetiracetam, phenobarbital, pregabalin and topiramate which are highly water soluble, not protein bound and with a small volume of distribution are readily removed by HD. Carbamazepine, clonazepam, phenytoin, tiagibine and valproate have a low risk of removal, although even these will have some removal during HD.
The kidney is the most commonly transplanted organ, usually as a result of hypertensive disease, diabetes or glomerulonephritis, all of which cause uraemia and may be associated with seizures. The immunosuppressant agents most often used in renal transplantation are cyclosporine, tacrolimus, azathioprine and mycophenolate; most patients are also on steroids. Cyclosporine and tacrolimus are well known to be associated with posterior leukoencephalopathy and seizures. Cyclosporine has also been shown to reduce seizure threshold. These immunosuppressants are mainly metabolized by the liver. Enzyme-inducing anti-epileptic drugs such as phenytoin, carbamazepine and phenobarbital may reduce the plasma concentration of cyclosporine; it is therefore particularly important to monitor cyclosporine levels in such patients. It has been reported that phenytoin and phenobarbital reduce renal allograft survival, possibly due to increased metabolism of immunosuppressive agents. Owing to fewer effects on the cytochrome P450 system and fewer drug interactions, some of the second-generation anti-epileptic drugs are in renal transplant patients with epilepsy; however, gabapentin has been reported in association with acute renal dysfunction in an allograft.
If transplant patients with epilepsy have breakthrough seizures, it is important to consider aetiologies other than their epilepsy as the cause. In particular, uraemic encephalopathy, metabolic derangement, opportunistic infection or leukoencephalopathy should be considered.
In summary, gabapentin and levetiracetam may accumulate in patients with renal failure. Valproate, carbamazepine, oxcarbazepine and tiagabine are less likely to cause toxicity, although their protein binding will be affected.
Selections from the book: “Therapeutic Strategies in Epilepsy” (2008)