Pharmacologic management of epilepsy: an update.
This article has been approved for continuing education credit. Objectives are listed below. Test questions follow at the end of the article along with further directions.
1. Explain indications for selected antiepileptic drugs.
2. Identify nursing implications related to adverse effects of selected antiepileptic drugs.
Because epilepsy is one of the most common neurologic disorders, neuroscience nurses need to be knowledgeable of new developments in antiepileptic drug (AED) therapy. In addition they must understand the nature of epilepsy and its impact on daily living in order to assist people with epilepsy obtain optimal seizure control and quality of life. (These issues are covered well by other sources.[5,7,16,17,28]) The new AEDs offer potential for better achievement of these goals.
Many drugs have been developed for use in managing epilepsy over the past few decades, but only a few have demonstrated efficacy with acceptable side effects. In a survey of 760 people with epilepsy, 61% reported they experienced side effects from their medication.
Over the past two decades, investigators and pharmaceutical companies have made great efforts to develop AEDs that are effective, more tolerable and less likely to interact with other drugs. Until 1990, the last major AED to be approved was valproate (Depakene, then Depakote) in 1978. Since 1993, four new AEDs have been approved in the United States (Table 1).
Table 1. Approval Dates for Major
phenobarbital 1912 phenytoin 1938 ethosuximide 1950 primidone 1954 carbamazepine 1974 valproate 1978 felbamate 1993 gabapentin 1993 lamotrigine 1994 topiramate 1996
The chance discovery of valproate in animal models and subsequently in humans in the 1970s spurred development of other drugs with a similar property: enhancing the effect of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter in the brain. Other qualities were sought as well. An ideal AED would have high oral availability, no or low protein binding, a long half-life, linear kinetics (increases in dose yield proportionate increases in serum level), no active metabolites, no liver enzyme induction and no or few side effects.
Both old and new AEDs likely act through multiple mechanisms and multiple sites of activity. AEDs may disrupt one or more mechanisms involved in the genesis and spread of epileptic discharges. These include: 1) changes in voltage-regulated ion channels in neuronal membranes that lead to excessive depolarization or excessive action potential firing, 2) decreased inhibition allowing for excessive neuronal firing, 3) increased excitation mediated through glutamate receptors and 4) changes in extracellular concentrations of certain ions, such as potassium and calcium. Because all of the AEDs approved in this decade are indicated for the treatment of partial and generalized tonic clonic seizures, this article will focus on new and established AEDs for the treatment of these seizure types.
Established Antiepileptic Drugs
The established drugs for treatment of partial and generalized tonic clonic seizures are carbamazepine (Tegretol), phenobarbital, phenytoin (Dilantin), primidone (Mysoline) and valproate (Depakote).
Phenytoin (PHT) is indicated for the treatment of partial and both primary and secondarily generalized tonic clonic seizures. PHT acts by inducing voltage-and use-dependent blockade of sodium channels.
PHT is 900% bound to serum proteins. Protein binding displacement interactions are usually clinically irrelevant unless the displacing agent exerts an additional inhibitory effect on the metabolism of the target drug. When one drug is displaced from its binding sites on serum proteins by another drug, there is a transient rise in the free concentration. Compensatory increases in hepatic metabolism and renal elimination ensure that the new steady-state free concentration is similar to that which was present before the displacing drug was added. If, however, the displacing drug also inhibits metabolism of the original drug, free concentrations rise and neurotoxicity may occur. This phenomenon occurs when valproate is added to PHT.
The half life of PHT is about 24 hours, allowing for once a day dosing. However twice daily assures more constant serum levels. PHT has the unusual property of nonlinear kinetics. That is, the liver enzymes that metabolize PHT can become saturated as the dose increases. Therefore, small increments in dose can cause a large rise in serum concentration. A starting dose of 5 mg/kg of body weight raises serum concentrations within the target range of 10 to 20 mcg/ml. The recommend initial dose is 300 mg per day. In general the dose can be increased by 100 mg per day if the serum drug concentration is 8 mcg/ml or less. If the serum level is above 8 mcg/ml the dose should only be increased by 50 mg per clay. The therapeutic range of PHT is 10-20 mcg/ml.
PHT can induce metabolism of many drugs. Likewise, drugs that inhibit metabolism of PHT can increase serum concentrations and produce toxic side effects. PHT interacts with many other drugs. These interactions are described in the Physician's Desk Reference (PDR).
Dose-related adverse effects of PHT include nystagmus, ataxia, dysarthria, drowsiness and mental slowing, which become increasingly likely when serum concentrations exceed 20 mcg/ml. Reversible cosmetic changes such as gum hypertrophy, acne, hirsutism and coarsening of facial features are more common in children and young adults.
Carbamazepine (CBZ) is indicated for the treatment of partial and generalized tonic clonic seizures. CBZ acts by decreasing the rate of repetitive firing of action potentials in depolarized neurons through voltage and use dependent blockade of sodium channels.
CBZ is 76% bound to serum proteins, which means it can be displaced from these binding sites by more highly bound drugs. CBZ is metabolized by the CYP 3A4 microenzymes in the liver. Therefore drugs that inhibit this enzyme will increase the CBZ serum level, leading to signs of CBZ toxicity. Drugs which induce the CYP 3A4 enzymes will lower the CBZ serum level, leading to seizure recurrence. The PDR describes the known drug interactions of CBZ.
CBZ induces its own metabolism, taking 3-5 weeks to stabilize if the dose remains unchanged. The half life of CBZ is 25-65 hours initially, decreasing to 12-17 hours after several days. Therefore treatment should be initiated slowly, usually at 200-400 mg daily. Dose increases of 200 mg increments should be made every few days. If increased too rapidly, toxic effects can occur. This is because the liver enzymes have not yet been synthesized to metabolize the drug, so more drug is in the circulation, and thus the brain. Dosages in adults can range from 600-1200 mg per day. Dosages are increased until seizures are controlled or until side effects develop. The therapeutic serum drug range is 4-12 mcg/ml. However, dosages should be determined by patient response, not the serum drug level. This is true of any AED.
The most frequent side effects of CBZ include nausea, headache, dizziness, tiredness, incoordination, vertigo and diplopia. Because CBZ has been associated with aplastic anemia agranulocytosis, complete blood counts should be performed at initiation of therapy and at regular intervals thereafter.
Carbamazepine, Extended Release
The manufacturers of CBZ designed a formulation that has a longer duration of action so that tid or qid dosing can be eliminated. Thus, an extended release CBZ tablet became available in 1996. The new formulation, CBZ-XR is comprised of an osmotic release delivery system (OROS). The tablet has a solid core, which contains CBZ and other compounds to enhance diffusion of CBZ out a single opening on one side of the tablet at a relatively constant rate once the tablet is exposed to water in the gastric cavity. This allows for the drug to be administered twice daily while achieving more constant mean serum drug concentrations than the original compound. It has comparable efficacy regarding seizure control. Crossover from CBZ to CBZ-XR can be achieved by using the same daily dose without loss of seizure control or increase in drug-related adverse experiences. CBZ-XR is available in 100 mg, 200 mg and 400 mg tablets. The tablets should not be chewed or crushed as this will disrupt the drug delivery mechanism.
Phenobarbital (PB) has been in use for over 80 years, longer than any currently used AED. It is as effective as CBZ and PHT in controlling generalized tonic clonic seizures but is less effective than these two drugs in controlling partial seizures. PB prolongs inhibitory postsynaptic potentials by increasing the mean chloride channel opening.
The half life of PB is very long, about 96 hours, which allows it to be taken once daily. PB is metabolized by the microsomal enzyme system in the liver and it induces this enzyme system, thereby increasing metabolism and lowering the effectiveness of drugs metabolized by this system. (Refer to PDR for list of drug interactions). PB is 50% bound to serum proteins.
PB is less desirable than other AEDs because it causes sedation and can be fatal if taken in an overdose. To minimize the sedative effect, the starting dose should be low (60 mg in adults and 4 mg/kg of body weight in children) and increased gradually according to response. Dose-related adverse effects include nystagmus, dysarthia, incoordination and ataxia. Average adult doses range from 60-200 mg per day. The therapeutic range for PB is 15-30 mcg/ml.
Primidone (PRM) is an analogue of phenobarbital. It is metabolized to two active metabolites: phenobarbital and phenylethylmalonamide (PEMA). PEMA has low antiepileptic potency, therefore, phenobarbital contributes most of the antiepileptic properties of PRM. PRM is indicated for the treatment of partial and generalized tonic clonic seizures. Average adult doses range from 750-1500 mg per day. The therapeutic range for PRM is 5-12 mcg/ml. PRM is considered less efficacious than phenobarbital by some and is not considered an AED of first choice. For practical purposes, the pharmacokinetics and side effects of PRM can be considered to be similar to PB.
Valproate (VPA) has a broader range of efficacy than the other established AEDs. It is indicated for treatment of simple and complex absence seizures and as adjunctive treatment of multiple seizure types that include absence seizures. It has been used as adjunctive treatment of partial complex and generalized tonic clonic seizures as well. Investigators disagree about how it compares in efficacy to CBZ for partial seizures.[20,26] Valproic acid (Depakene) was the original formulation of VPA, but because it caused a high incidence of gastric upset, an enteric coated delayed-release formulation divalproex sodium (Depakote) was developed. Both medications dissociate to valproate in the gastrointestinal (GI) tract. VPA probably acts in several ways, by interfering with GABA degrading enzymes, thereby increasing the neurotransmitter-related fraction of the GABA pool, and by blocking sodium channels.
Protein binding of VPA is high, at about 90% and may displace other highly bound drugs such as PHT and CBZ. Protein binding is reduced in the elderly, in patients with hepatic disease, and in patients with renal impairment. Aspirin also reduces VPA protein binding and inhibits its metabolism. VPA can inhibit several hepatic metabolic processes, including oxidation, conjugation and epoxidation. The half life of VPA ranges from 9-16 hours, but it may be shorter in people taking enzyme-inducing drugs like CBZ, PHT and PB.
The therapeutic range is 50-100 mcg/ml, however there is no clear cut relation among serum concentration of VPA, its effect and toxicity. In addition, the daily variation in serum concentration is wide. The recommended initial dose is 15 mg/kg of body weight, increasing by 5-10 mg/kg per day until seizures are controlled or side effects occur.
Common side effects of VPA are dose-related tremor, weight gain, temporary thinning of hair and menstrual irregularities. VPA can cause rare, idiosyncratic hepatoxicity which is usually unaccompanied by fever, rash or other evidence of hypersensitivity. Three reviews of VPA-related hepatic fatalities in the United States confirmed the major risk factors for this adverse reaction: children under age 2 years, polypharmacy, developmental disability and metabolic disorders.[4,8,9]
New Antiepileptic Drugs
All of the new major AEDs have been approved in the 1990s and are indicated for the treatment of partial seizures. Three of the four are also indicated for treatment of secondarily generalized tonic-clonic seizures. The new AEDS have good to excellent bioavailability, more predictable and linear pharmacokinetics, lack of autoinduction of liver enzymes and reduced potential for drug interactions.
Felbamate (FBM) was approved in 1993, the first AED to be marketed since valproate in 1978. It is indicated for both primary monotherapy and adjunctive therapy for intractable complex partial seizures and secondarily generalized tonic-clonic seizures and for adjunctive therapy in Lennox Gastaut syndrome. However, because of unexpected fatalities in the post-marketing phase, FBM use has been severely restricted.
FBM inhibits N-methyl-D,L-aspartic acid (NMDA) excitatory responses and potentiates GABA action. It may also modulate sodium channel conductance. FBM is well absorbed and unaffected by food intake. it is metabolized by the liver, so it has potential for interactions with other drugs. FBM is only 25% bound to serum proteins. The half life is 20 hours, which is shortened with concomitant use of enzyme-inducing AEDS (CBZ, PB, PHT) and lengthened when used with VPA.
The side effect profile is different from the established AEDs. Insomnia and headache rather than sedation, ataxia and cognitive trouble are the major side effects. However, fatal cases of aplastic anemia and hepatotoxicity appeared after the drug was marketed and used in large numbers of people. In August 1994, the manufacturer of FBM issued a recommendation to practitioners to withdraw patients from FBM unless "in the physician's judgment, the patient's well being is so dependent upon continued treatment with Felbatol that abrupt withdrawal is deemed to pose an even greater risk." If patients are put on FBM they must sign a consent form acknowledging the risk of aplastic anemia and liver failure and the requirement to get laboratory studies at frequent intervals. Epileptologists have chosen, with consent of their patients, to continue FBM therapy in some cases.
The initial dose of FBM is 400 mg tid (1200 mg daily). Dosage can be increased to 2400-31/2 mg daily in weekly or biweekly increments of 600-1200 mg. For individuals taking concomitant CBZ or PHT, the dosage of these drugs should be decreased by 20-33%.
Gabapentin (GBP) became available in 1994 for adjunctive ther-apy in partial seizures, with and without secondary generalization. Its exact mechanism of action is unknown, but is thought to have a GABAergic effect by promoting release of GABA from presynaptic terminals and, increasing GABA synthesis.
The bioavailability of GBP is inversely related to dose, which means that increasing dosage of GBP provides only fractional increases in drug levels. The half life of GBP is only 9 hours, so it must be administered three times per day. Because GBP is not bound to serum proteins and is not metabolized in the liver, it does not interact with other drugs. However, the dosage must be lowered in people with renal insufficiency.
Somnolence, fatigue, dizziness and weight gain are the most frequent side effects. There have been no adverse effects on liver, bone marrow, or skin, so laboratory monitoring is not required.
Initiation of therapy requires titration to tid dosing, beginning with a single 300 mg capsule on day one, 300 mg bid on day two, followed by 300 mg tid for maintenance therapy. The package insert states the dosage can be increased to a total daily maximum dose of 2400 mg, however clinicians are using even higher doses.
Lamotrigine (LTG) was approved in 1994 for adjunctive therapy of partial seizures in people 16 years of age and older. The best understood mechanism of action is a use-dependent blocking effect on voltage sensitive sodium channels, resulting in inhibition of glutamate and aspartate release.
LTG is 55% bound to serum proteins. it does not induce liver enzymes, but it is metabolized in the liver by glucuronidation. The half life of LTG is 25 hours, but the half life is reduced to 15 hours in patients receiving enzyme-inducing AEDs and is doubled with concomitant use of valproate. The therapeutic window is wide. LTG does not interact with other AEDs, but other AEDs affect LTG, as mentioned previously.
The most commonly reported side effects are dizziness, headache, diplopia, ataxia, nausea, amblyopia, somnolence and rash. Most of these side effects are mild and transient. However, in 1997 the manufacturer of LTG added a warning to the prescribing information, stating that "severe, potentially life-threatening rashes have been reported in association with the use of Lamictal." The risk of rash is much higher in children under age 16 and is higher when LTG is used with valproate. Other risk factors are exceeding the recommended initial dose of LTG or exceeding the recommended dose escalation for LTG. Clinicians are advised to stop LTG therapy in anyone who develops a rash, as there are no reliable predictors of which type of rash in a given individual may become life-threatening.
The initial dose of LTG in patients not taking valproate is 50 mg once a day for 2 weeks, followed by 50 mg bid for 2 weeks. The dose can be escalated by 100 mg/day every week, to total dose of 300 to 500 mg per day in two divided doses. Initial, escalation and maintenance dosages for patients taking valproate are about half the usual dosages.
Topiramate (TPM) is the most recently approved AED. TPM is indicated for adjunctive therapy of intractable partial seizures with or without secondary generalization. The exact mechanism of action is unknown, but it appears to modulate sodium channels, enhance GABA activity and inhibit an excitatory glutamate receptor, all of which reduce neuronal excitability.
The half life of TPM is 21 hours after single or multiple doses and has linear kinetics. TPM is only 15% bound to serum proteins. overall, the potential for drug interaction is low, but some precautions are necessary. The dosage of TPM may need to be adjusted when an enzyme-inducing AED, such as PHT or CBZ, is added or withdrawn. The efficacy of oral contraceptives may be compromised by TPM, so patients taking oral contraceptives may require a contraceptive agent containing a higher level of estrogen. Digoxin dosage may need adjusting, as TPM can reduce digoxin levels. Because TPM is a weak carbonic anhydrase inhibitor, the risk of kidney stones is higher if it is used with other carbonic anhydrase inhibitors. In clinical trials the incidence of nephrolithiasis was approximately 1.5%.
The side effects of TPM, which do not appear to be dose-related, are somnolence, dizziness, ataxia, speech disorders, psychomotor slowing, nystagmus and paresthesia. The most common dose-related side effects are fatigue, nervousness, difficulty with concentration or attention, confusion, depression, anorexia, language problems, anxiety, mood problems, cognitive problems, weight loss and tremor. Adverse events which lead to discontinuing therapy in 9% of patients in one clinical trial included dizziness, fatigue, anxiety, cognitive difficulty, headache, ataxia, somnolence, nystagmus, paresthesia and diplopia increased at doses higher than 400 mg per day.
The recommended daily dosage of TPM is 400 mg per day in two divided doses. Therapy should be initiated at 50 mg per day followed by slow titration (increase by 50 mg weekly over a period of 8 weeks) to prevent adverse side effects.
Selection of Antiepilectic Drugs
Several considerations besides efficacy are important in selecting an appropriate AED: adverse effects, drug interactions, compliance and cost. The frequency and severity of the adverse effects vary with the dose, method and duration of administration, coadministration of other drugs and patient population, but certain adverse effects are characteristic of each drug. Side effects occurring with initiation of treatment often subside with prolonged use. Idiosyncratic reactions often occur within the first few months of therapy but can occur after a few years of therapy in rare cases. Leukopenia frequently follows the initiation of treatment with any of the established AEDs but is rarely severe enough to cause discontinuation of the drug. Fatal hepatoxicity has occurred with VPA and FBM, and fatal aplastic anemia has occurred with FBM. With the exception of FBM, the newer AEDs do not require routine laboratory monitoring.
Drug interactions are an important consideration in starting or changing AED therapy. Protein binding and liver enzyme induction properties of AEDS can influence the blood levels of other drugs as well as other AEDS. Drugs that induce liver enzyme production (Table 2) and have high protein binding (Table 3) are more likely to cause drug interactions.
Table 2. Enzyme Inducing Antiepileptic Drugs
Carbamazepine Phenytoin Phenobarbital Primidone Table 3. Procedural Instructions Elevate the head of the patient's bed to at least 70 degrees. Support the hemiplegic side with a pillow. Present bites/sips in this order (stop if the patient struggles at any step): 1. Give 1/2 teaspoon Italian Ice, placing at midline of tongue. 2. Give 1 teaspoon Italian Ice, placing at midline of tongue. 3. Give 1 teaspoon peaches. Repeat a second teaspoon. 4. Pour apricot into a cup, filling at least 1/2 full. Give patient 1 teaspoon size sip (nurse should control sip size). If successfully swallowed, give the patient the cup and allow the second sip to be an uncontrolled size. 5. If the thick liquid was successful, repeat the procedure above using the cranberry juice. 6. Give the patient a graham cracker and ask to take a bite, chew and swallow. If successful, offer the rest of the cracker. Records Results on the Nutrition and Swallowing Screen and forward copies to appropriate departments. Table 3. Percent of Protein Binding of Antiepileptic Drugs Phenytoin Valproate Carbamazepine 76% Lamotrigine 55% Phenobarbital 50% Felbamate 25% Topiramate 15% Gabapentin 0%
Compliance with AED therapy is a constant challenge, as it is with any chronic medication regimen. One factor that enhances compliance is simplifying the regimen to once or twice daily dosing rather than multiple daily dosing. Drugs with a longer half life can be given once or twice a day. In general, drugs should be dosed at intervals no longer than their half life. PB can be administered once a day because of its very long half life, whereas gabapentin must be given three times a day. Table 4 lists the half lives of the AEDs.
Table 4. Half Life of Antiepileptic Drugs Phenobarbital 96 hrs Lamotrigine 24 hrs (* **) Phenytoin 24 hrs Topiramate 21 hrs Felbamate 20 hrs(*) Carbamazepine 12-17 hrs Valproate 9-16 hrs Gabapentin 9 hrs
(*) Half life is shortened with concomitant use of enzyme inducing AEDs.
(**) Half life lengthened with concomitant use of valproate.
A final factor in selecting an AED is cost. The established AEDs are less expensive than the new AEDS. Phenobarbital is by far the least expensive AED. The newer AEDS are the most costly because of the expense of conducting research and development of these compounds.
While many patients can be successfully treated with a single AED, some require more than one drug to achieve seizure control. Selection of rational combination therapy requires consideration of several factors: mechanisms of drug actions, adverse effects, therapeutic index and drug-drug interactions. Use of drugs with different mechanisms of action theoretically provides a broader spectrum of antiepileptic activity, thereby enhancing seizure control. Drugs with a low incidence of adverse effects (eg, GPB, LTG) may be preferred over ones with high incidence (eg, PB) or intermediate incidence (eg, CBZ, FBM, PHT, VPA, TPM) of adverse effects in patients whose quality of life is impaired due to drug side effects. Related to incidence of adverse effects is the therapeutic index of a drug, which is the relationship of the effective dose of a drug to its toxic dose. Drugs with a low therapeutic index (eg, PB) produce side effects at or near doses that are effective, whereas drugs with a high therapeutic index (eg, FBM, GBP, LTG) tend to have effective doses that are much lower than the doses that produce side effects.
Drug interactions must be considered when combining AEDs. Potential mechanisms of interactions include liver enzyme induction and displacement of AEDS from protein binding sites. AEDS with high drug interaction potential include PHT, CBZ, PB and FBM. GBP has the lowest drug interaction potential.
A fifteen-year hiatus separated the availability of established AEDs and the new AEDs, after which the 1990s brought four new AEDs on the market. The new AEDs offer many alternatives that were unavailable before this decade for people with refractory epilepsy. Because AED clinical trials are usually based on efficacy in refractory patients, new drugs have an indication only for adjunctive therapy in people with poorly controlled seizures. In spite of their indication as adjunctive therapy, the new AEDS may eventually prove to be useful in monotherapy and even initial therapy of partial and secondarily generalized seizures. Although none of the new AEDs met all the criteria of an ideal AED, namely high oral bioavailability, rapid absorption, linear kinetics, negligible protein binding, long half life, renal excretion and low potential for drug interactions, they represent significant advances over the established AEDs. The only major barrier to broader use of the new AEDs appears to be cost.
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|Title Annotation:||includes CE test|
|Publication:||Journal of Neuroscience Nursing|
|Date:||Oct 1, 1997|
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