DRUG THERAPY: SPECIAL CONSIDERATIONS IN DIALYSIS PATIENTS
Use of Antiepileptic Drugs in Patients with Chronic Kidney Disease and End Stage Renal Disease Amar D. Bansal,* Chloe E. Hill,† and Jeffrey S. Berns* *Renal-Electrolyte and Hypertension Division, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, and †Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
ABSTRACT Epilepsy is a disorder with an approximate worldwide prevalence of 1%. Due to complexities of metabolism, protein-binding, renal elimination, and other pharmacokinetic parameters, the dosing of antiepileptic drugs (AEDs) in patients with chronic kidney disease (CKD) or end stage renal disease (ESRD) deserves special attention.
This is a review of the most commonly prescribed AEDs with special focus on their indication, pharmacokinetics, and unique considerations for use in patients with CKD and ESRD. A review of their renal toxicities is also included.
Epilepsy is a common, serious disorder with an approximate worldwide prevalence of 1% (1–4). While the exact combined prevalence of epilepsy and chronic kidney disease (CKD) or end stage renal disease (ESRD) is not well-established, the incidence of seizures has been reported to be 10% in patients with renal failure (5). Despite the fact that epilepsy is often a sequelae of cerebrovascular disease, which is common in patients with CKD, it remains unclear if there is a higher prevalence of epilepsy in patients with CKD as compared to the general population. We review the most commonly prescribed antiepileptic drugs (AEDs) with special focus on their indication, pharmacokinetics, and unique considerations for use in patients with CKD and ESRD, updating an earlier review in this journal (6). A review of their renal toxicities is also included. The purpose of this article is to not to offer a fully comprehensive description, but rather to provide a useful reference for nephrologists and neurologists by highlighting the key attributes of AEDs in relation to kidney disease. Careful attention is warranted when dosing AEDs in patients with ESRD or CKD. Decreased renal excretion can lead to toxicity. On the other hand,
failure to account for dialytic clearance can result in seizures precipitated by subtherapeutic drug levels. Furthermore, given that effective treatment of epilepsy often requires more than one AED, drugdrug interactions become especially important in this group. In addition to management of AEDs in patients with ESRD or CKD, acute kidney injury is also a setting in which nephrologists and neurologists are frequently called upon to manage seizures in acutely ill patients who are hospitalized (7). Although the newer AEDs have more favorable side effect profiles and fewer drug-drug interactions, (8) they also more frequently undergo renal clearance and therefore dosing considerations are quite relevant in the CKD and ESRD populations. The International League Against Epilepsy defines epilepsy as two or more unprovoked seizures more than 24 hours apart (9). Seizures can either be focal in onset, meaning they originate in one specific part of the brain (e.g. focal motor seizures or complex partial seizures) or generalized in onset, meaning the seizure is initiated by bilateral networks in the brain (e.g. primary generalized tonic-clonic seizures or absence seizures). This distinction is important since broad-spectrum AEDs are effective at treating both focal onset seizures and primary generalized seizures, whereas narrow-spectrum AEDs are more effective at treating focal onset seizures and may even exacerbate certain types of primary generalized seizures. Most AEDs work by enhancing GABAergic inhibitory activity or by inhibitory glutamatergic excitatory activity. The next considerations are the patient’s age, gender, comorbidities, medication list, and potential need for family planning so that a drug with the most tolerable side effect profile
Address correspondence to: Jeffrey S. Berns, MD, Renal-Electrolyte and Hypertension Division, Hospital of the University of Pennsylvania, 3400 Spruce St, 1 Founders Pavilion, Philadelphia, PA 19104, e-mail: [email protected]. Conflict of interest: None. Seminars in Dialysis—Vol 28, No 4 (July–August) 2015 pp. 404–412 DOI: 10.1111/sdi.12385 © 2015 Wiley Periodicals, Inc. 404
405
USE OF ANTIEPILEPTIC DRUGS IN PATIENTS WITH CKD AND ESRD
and fewest drug-drug interactions can be chosen. Pharmacokinetics is a critical consideration in patients with hepatic or renal failure, or in patients who have difficulty with compliance. Once an appropriate AED is chosen, the typical approach is to start at a low dose and gradually escalate the dosage as guided by breakthrough seizures, side effect tolerability, and drug levels (this is not applicable to the emergent setting). The goal is treating the patient with the minimal number of drugs at the minimal dose necessary to maintain seizure freedom. Although monotherapy is preferred, about one-third of patients with epilepsy will require polytherapy for adequate seizure control (10). Once seizure control has been obtained and target AED levels have been established, therapy is monitored by periodic AED level checks. As many AEDs cause vitamin D deficiency that can lead to very significant loss of bone density, vitamin D and bone density are also monitored periodically and treated appropriately when clinically indicated. General Considerations for All AEDs Protein-binding of a drug is an important consideration for its pharmacokinetics since it is the free or unbound fraction of the drug that has pharmacological effect. If a drug is mainly protein-bound (>90%), hypoalbuminemia from any cause can result in a higher unbound drug level compared to what the level would be if the serum albumin concentration were normal. Hypoalbuminemia is very
prevalent in the CKD and ESRD populations. (11,12) Of the commonly prescribed AEDs, phenytoin and valproic acid both have >90% protein binding. (13–15) Special attention will also be given to metabolism, urinary excretion (which forms the basis for dose adjustment in reduced renal function), and renal toxicities. These are summarized in Table 1. Since the treatment of epilepsy frequently requires polytherapy, interactions among AEDs need monitoring. Although typically a neurologist will manage AED polypharmacy, it is important to understand that recommendations for dose adjustments in one agent can also affect therapeutic levels of another AED. For example, changes in phenobarbital dose can affect the carbamazepine level because phenobarbital induces CYP3A4 of the cytochrome P450 system (14), which also metabolizes carbamazepine. The nuances of interactions amongst various AEDs have been thoroughly reviewed and highlight the need for dedicated attention from an experienced neurologist (4,8,13–17). Table 2 has been included as a guide to typical AED dosing. Dose adjustments for various stages of CKD and dialysis supplementation are also included. Since values for therapeutic drug concentrations can differ among labs, they have not been included. Levetiracetam (Keppra) Levetiracetam is a very commonly used agent for generalized and focal epilepsy (18). It is typically very well-tolerated and does not require frequent
TABLE 1. Basic pharmacokinetics of AEDs AED
Protein binding
Metabolism
Urinary excretion
Levetiracetam
Use of Antiepileptic Drugs in Patients with Chronic Kidney Disease and End Stage Renal Disease Amar D. Bansal,* Chloe E. Hill,† and Jeffrey S. Berns* *Renal-Electrolyte and Hypertension Division, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, and †Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
ABSTRACT Epilepsy is a disorder with an approximate worldwide prevalence of 1%. Due to complexities of metabolism, protein-binding, renal elimination, and other pharmacokinetic parameters, the dosing of antiepileptic drugs (AEDs) in patients with chronic kidney disease (CKD) or end stage renal disease (ESRD) deserves special attention.
This is a review of the most commonly prescribed AEDs with special focus on their indication, pharmacokinetics, and unique considerations for use in patients with CKD and ESRD. A review of their renal toxicities is also included.
Epilepsy is a common, serious disorder with an approximate worldwide prevalence of 1% (1–4). While the exact combined prevalence of epilepsy and chronic kidney disease (CKD) or end stage renal disease (ESRD) is not well-established, the incidence of seizures has been reported to be 10% in patients with renal failure (5). Despite the fact that epilepsy is often a sequelae of cerebrovascular disease, which is common in patients with CKD, it remains unclear if there is a higher prevalence of epilepsy in patients with CKD as compared to the general population. We review the most commonly prescribed antiepileptic drugs (AEDs) with special focus on their indication, pharmacokinetics, and unique considerations for use in patients with CKD and ESRD, updating an earlier review in this journal (6). A review of their renal toxicities is also included. The purpose of this article is to not to offer a fully comprehensive description, but rather to provide a useful reference for nephrologists and neurologists by highlighting the key attributes of AEDs in relation to kidney disease. Careful attention is warranted when dosing AEDs in patients with ESRD or CKD. Decreased renal excretion can lead to toxicity. On the other hand,
failure to account for dialytic clearance can result in seizures precipitated by subtherapeutic drug levels. Furthermore, given that effective treatment of epilepsy often requires more than one AED, drugdrug interactions become especially important in this group. In addition to management of AEDs in patients with ESRD or CKD, acute kidney injury is also a setting in which nephrologists and neurologists are frequently called upon to manage seizures in acutely ill patients who are hospitalized (7). Although the newer AEDs have more favorable side effect profiles and fewer drug-drug interactions, (8) they also more frequently undergo renal clearance and therefore dosing considerations are quite relevant in the CKD and ESRD populations. The International League Against Epilepsy defines epilepsy as two or more unprovoked seizures more than 24 hours apart (9). Seizures can either be focal in onset, meaning they originate in one specific part of the brain (e.g. focal motor seizures or complex partial seizures) or generalized in onset, meaning the seizure is initiated by bilateral networks in the brain (e.g. primary generalized tonic-clonic seizures or absence seizures). This distinction is important since broad-spectrum AEDs are effective at treating both focal onset seizures and primary generalized seizures, whereas narrow-spectrum AEDs are more effective at treating focal onset seizures and may even exacerbate certain types of primary generalized seizures. Most AEDs work by enhancing GABAergic inhibitory activity or by inhibitory glutamatergic excitatory activity. The next considerations are the patient’s age, gender, comorbidities, medication list, and potential need for family planning so that a drug with the most tolerable side effect profile
Address correspondence to: Jeffrey S. Berns, MD, Renal-Electrolyte and Hypertension Division, Hospital of the University of Pennsylvania, 3400 Spruce St, 1 Founders Pavilion, Philadelphia, PA 19104, e-mail: [email protected]. Conflict of interest: None. Seminars in Dialysis—Vol 28, No 4 (July–August) 2015 pp. 404–412 DOI: 10.1111/sdi.12385 © 2015 Wiley Periodicals, Inc. 404
405
USE OF ANTIEPILEPTIC DRUGS IN PATIENTS WITH CKD AND ESRD
and fewest drug-drug interactions can be chosen. Pharmacokinetics is a critical consideration in patients with hepatic or renal failure, or in patients who have difficulty with compliance. Once an appropriate AED is chosen, the typical approach is to start at a low dose and gradually escalate the dosage as guided by breakthrough seizures, side effect tolerability, and drug levels (this is not applicable to the emergent setting). The goal is treating the patient with the minimal number of drugs at the minimal dose necessary to maintain seizure freedom. Although monotherapy is preferred, about one-third of patients with epilepsy will require polytherapy for adequate seizure control (10). Once seizure control has been obtained and target AED levels have been established, therapy is monitored by periodic AED level checks. As many AEDs cause vitamin D deficiency that can lead to very significant loss of bone density, vitamin D and bone density are also monitored periodically and treated appropriately when clinically indicated. General Considerations for All AEDs Protein-binding of a drug is an important consideration for its pharmacokinetics since it is the free or unbound fraction of the drug that has pharmacological effect. If a drug is mainly protein-bound (>90%), hypoalbuminemia from any cause can result in a higher unbound drug level compared to what the level would be if the serum albumin concentration were normal. Hypoalbuminemia is very
prevalent in the CKD and ESRD populations. (11,12) Of the commonly prescribed AEDs, phenytoin and valproic acid both have >90% protein binding. (13–15) Special attention will also be given to metabolism, urinary excretion (which forms the basis for dose adjustment in reduced renal function), and renal toxicities. These are summarized in Table 1. Since the treatment of epilepsy frequently requires polytherapy, interactions among AEDs need monitoring. Although typically a neurologist will manage AED polypharmacy, it is important to understand that recommendations for dose adjustments in one agent can also affect therapeutic levels of another AED. For example, changes in phenobarbital dose can affect the carbamazepine level because phenobarbital induces CYP3A4 of the cytochrome P450 system (14), which also metabolizes carbamazepine. The nuances of interactions amongst various AEDs have been thoroughly reviewed and highlight the need for dedicated attention from an experienced neurologist (4,8,13–17). Table 2 has been included as a guide to typical AED dosing. Dose adjustments for various stages of CKD and dialysis supplementation are also included. Since values for therapeutic drug concentrations can differ among labs, they have not been included. Levetiracetam (Keppra) Levetiracetam is a very commonly used agent for generalized and focal epilepsy (18). It is typically very well-tolerated and does not require frequent
TABLE 1. Basic pharmacokinetics of AEDs AED
Protein binding
Metabolism
Urinary excretion
Levetiracetam
