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Understanding the drug interactions associated with antiepileptic drugs can avoid complications.
Epilepsy is one of the most common chronic neurologic disorders, with a prevalence rate between 0.5% and 1% in the Western population.1 It is characterized by recurrent and unprovoked seizures, a consequence of abnormal discharge of neurons in the brain. Seizure types are further subclassified based on both the patient’s symptoms and electroencephalography (EEG) characteristics.
While other treatment options exist, pharmacotherapy remains the standard of care in patients with epilepsy. Extensive drug therapies are available today due to the high demand, research, and approval of antiepileptic drugs (AEDs) in the last 2 decades.
AEDs work through a multitude of mechanisms of action. As a result, one can observe a myriad of different responses from different patients. Due to this variety of properties, AEDs must not be assumed to be appropriate for every epilepsy syndrome. Drugs such as valproic acid, lamotrigine, and topiramate are considered broad spectrum, and are effective for most seizure types and useful in patients with refractory seizures. Narrow spectrum antiepileptic drugs such as carbamazepine, phenytoin, and gabapentin treat partial seizures or secondary generalized tonicclonic seizures, but may worsen certain seizure types.
Most notably, carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin, tiagabine, and vigabatrin have been associated with exacerbating absence and myoclonic seizures. For these reasons, AEDs must be carefully selected for each individual patient and specific seizure disorder.1-3
AED therapy is effective for most patients; however, when to initiate therapy is a complex decision. The First Seizure Trial Group (FIRST) study indicates that waiting to initiate therapy until a second epileptic seizure has occurred has no long-term consequences, particularly with lowrisk patients.4 Regardless of when treatment is initiated, however, therapy with a single agent is the ideal treatment goal. Monotherapy has been shown to achieve seizure control in more than 70% of epileptic patients.5,6
When patients do not demonstrate satisfactory outcomes on monotherapy, physicians often prescribe additional AEDs. In these cases, polytherapy is employed in an attempt to reduce the number or severity of seizures. Optimal polytherapy involves combining drugs that differ in mechanism. This strategy aims to overlap mechanisms of action and allow for synergistic effects between drugs.7
Unfortunately, polytherapy usually results in improvement for only a minority of patients. Only an additional 10% will respond significantly to 2 medications, and even less will respond to 3.8 Marginal reductions in the number of seizures may increase quality of life. However, these benefits with polytherapy must always be weighed against the pitfalls of multiple medications including additional costs, adverse effects, drug interactions, and complicated regimens that hinder compliance.
The treatment of status epilepticus is complex, but pharmacists should be aware that newer AEDs with IV formulations, such as levetiracetam and lacosamide, are being studied and may replace older medications, such as phenytoin, for this indication.
AEDs are notorious for drug–drug interactions due to liver enzyme induction and inhibition, as well as complications in protein binding. Potent CYP450 enzymatic inducers include carbamazepine, phenytoin, and phenobarbital. A potent enzyme inhibitor is valproic acid. Interactions with these drugs can occur with other medications that heavily rely on hepatic metabolism. Concomitant administration of oral contraceptives with the inducers previously mentioned along with lamotrigine, oxcarbazepine, and topiramate may decrease their efficacy. 1 Some of the AEDs are also highly protein-bound, and thus compete with other protein-bound agents for binding sites (Table). This can lead to an unexpected increase in free concentrations of 1 or both drugs.
While it is common to utilize generic medications in many conditions, this practice is much more controversial in epilepsy. The requirements for generics to prove bioequivalence are stringent; however, many epileptologists believe that even minute disturbances may lead to devastating effects in epileptic patients. This belief is held despite data from a 2002 FDA study showing generics differed on average only 3.5% in bioavailability and a 2010 study noting no association between generics and poorer seizure control. It is thought that even small changes in plasma concentration can result in an increase in dose-dependent adverse reactions or a loss of seizure control. This concept is important because 1 additional seizure can lead to an injury or accident.2,6,9
For this reason, the American Academy of Neurology has issued strong statements against generic substitution unless the ordering physician consents.1,2,6 It is important for pharmacists to recognize that patients with epilepsy admitted to a hospital may receive either a generic substitution for a brand drug that they’ve been controlled on or a different manufacturer’s generic product— and that these substitutions may result in clinical sequelae.
AEDs and Comorbidities
Pharmacists are likely to encounter the use of AEDs in patients with both epilepsy and another condition such as stroke, asthma, hypertension, cancer, and mental health disorders.10 Pharmacists must review the use of these drugs with consideration that some may be problematic in certain chronic conditions or changes may be needed following exacerbations of these conditions.
For patients presenting with cardiovascular disease, the risk of phenytoininduced hypotension and arrhythmias is higher, particularly when using intravenous formulations (IV) of this drug. Additionally, the IV use of phenytoin’s prodrug, fosphenytoin, is contraindicated in patients with severe heart disease and second- or third-degree AV block. Valproic acid appears to be a safer alternative formulation in these instances, as there are fewer concerns of hemodynamic instability, particulary when infused at moderate rates, and it is available in an IV formulation. Levetiracetam is also available through this route, but less data exist for its use in emergent situations.11
Epilepsy patients with varying degrees of renal dysfunction also pose a challenge to practitioners. AEDs that are mainly eliminated hepatically, such as carbamazepine, phenytoin, lamotrigine, and valproic acid, are recommended over medications primarily eliminated through the kidney, such as levetiracetam, gabapentin, and pregabalin. Additionally, if there is concern for nephrolithiasis, topiramate and zonisamide should be avoided. In the case of hemodialysis, each AED is likely to be affected to a different degree, as properties such as protein binding and volume of distribution influence changes in concentrations during this process. For this reason, the pharmacist must be prepared to provide revised dosing regimens to patients undergoing hemodialysis.
Pharmacists must also be aware of the potential complications of AED therapy in the presence of hepatic dysfunction. Besides decreasing the clearance of medications, hepatic insufficiency may also lead to hypoalbuminemia. This becomes problematic with highly protein-bound drugs such as phenytoin which can become toxic due to an increase in the free fraction of the drug. In severe liver disease, drugs with minimal hepatic metabolism and low protein binding, such as gabapentin, levetiracetam, oxcarbazepine, pregabalin, and topiramate, are more appropriate.11 Valproic acid is usually avoided in the presence of liver injury as it is known to be hepatotoxic.
AEDs and Women
Women of child bearing age should be provided counseling on the potential risks associated with antiepileptic drugs before conception, as these drugs may pose harm in the early phases of pregnancy. Due to its high rate of teratogenicity, valproate is avoided in this population. It is recommended to give the lowest effective dose and as few medications as possible to maintain seizure control. Pregnant women taking AEDs should be given information about and enrolled in the Antiepileptic Drug Pregnancy Registry. Additionally, like the general population, women of reproductive age with epilepsy should aim for sufficient intake of folic acid.1,2,6
Pharmacists must also be prepared for fluctuations in plasma concentrations of AEDs for pregnant patients. Pregnancy may increase the clearance and decrease concentrations significantly for lamotrigine, phenytoin, and carbamazepine. Concentrations of these drugs should be monitored and dose adjustments made during pregnancy and after delivery.12
Recently, concerns about bone health have risen with the use of AEDs. Although the association and specific mechanism of this risk of antiepileptic drugs is not fully clear, it is suspected that long-term use of some of these drugs may predispose patients to low bone mineral density. Changes in the metabolism of vitamin D is only 1 of the suspected pathways of this irregularity. The older enzyme-inducing drugs are the agents most associated with a risk for mineral bone disease. The consensus on many of the newer medications is not clear. Therefore, pharmacists should counsel all patients on proper bone health including DXA screenings, adequate exercise, smoking cessation, and a sufficient intake of calcium and vitamin D.2,6,13
Role of the Pharmacist
Antiepileptic medications often pose significant clinical dilemmas and complexities. It is crucial that pharmacists understand the drug interactions associated with AEDs to anticipate and avoid complications. Additionally, formulary issues such as generic substitution are magnified in the epileptic population. Counseling patients on pregnancy risks with these drugs as well as proper maintenance of healthy bone density can lead to improved quality of care.
AEDs have a strong place in therapy in both epilepsy and many other chronic conditions. Pharmacists should be involved in patient care to decrease adverse effects and drug interactions as well as to aid in dose adjustments. This ensures safe and effective drug therapy.
1. AndersonJ, Moor C. Anti-epileptic drugs: a guide for the non neurologist. Clinical Medicine. 2010;10(1):54-58.
2. Chong DJ, Bazil CW. Update on anticonvulsant drugs. Curr Neurol Neurosci Rep. 2010; 10:308-318.
3. Perucca E, Gram L, Avanzini G, et al. Antiepileptic drugs as a cause of worsening seizures. Epilepsia. 2005;39(1):5-17.
4. Musicco M, Beghi E, Solari A, Viani F; First Seizure Trial Group (FIRST Group). Treatment of first tonic-clonic seizure does not improve the prognosis of epilepsy. Neurology. 1997;49(4):991-998.
5. National Institute for Health and Clinical Excellence. The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care. http://guidance.nice.org.uk/CG20. Updated January 11, 2012.
6. Perucca E, Tomson T. The pharmacological treatment of epilepsy in adults. Lancet. 2011;10:446-456.
7. Brodie MJ, Covanis A, Gil-Nagel A. Antiepileptic drug therapy: does mechanism of action matter? Epilepsy and Behavior. 2011;21:331-341.
8. RogersSJ, Cavazos JE. Epilepsy. In: Dipiro JT, Talbert RL, Yee GC, et al. Pharmacotherapy: A Pathophysiologic Approach. 7thed. New York, NY: McGraw-Hill; 2008:930.
9. Bialer M, Midha KK. Generic products of antiepileptic drugs: a perspective on bioequivalence and interchangeability. Epilepsia. 2010;51(6):941-950.
10. Tellez-Zenteno JF, Matijevic S, Wiebe S. Somatic comorbidity of epilepsy in the general population in Canada. Epilepsia. 2005;46(12):1955-1962.
11. Gimenez JR, Sanchez-Alvarez JC, Canadillas-Hidalgo F, et al. Antiepileptic treatment in patients with epilepsy and other comorbidities. Seizure. 2010;19:375-382.
12. Harden Cl, Pennell PB, Koppel BS. Management issues for women with epilepsy--focus on pregnancy (an evidence-based review): III: vitamin K, folic acid, blood levels, and breast-feeding: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Epilepsia. 2009;50(5):1247-1255.
13. Noe KH. Seizures: diagnosis and management in the outpatient setting. Seminars in Neurology. 2011;31(1):54-64.
About the Authors
Dr. Smith is a neuropsychiatry pharmacy resident, Ernest Mario School of Pharmacy, Rutgers University.
Dr. Wagner is an associate professor, Ernest Mario School of Pharmacy, Rutgers University.
Dr. Liu is a clinical assistant professor, Ernest Mario School of Pharmacy, Rutgers University.