Strategies for Optimizing Antiepileptic Drug Therapy in Elderly People

Thomas E. Lackner, Pharm.D., FASCP

Disclosures

Pharmacotherapy. 2002;22(3) 

In This Article

Traditional Antiepileptic Drugs

Phenytoin is the most widely prescribed AED in elderly patients, but it is difficult to dose, as suggested by a disproportionately high number of total SDCs outside the usual therapeutic range compared with other AEDs, and causes frequent adverse drug reactions.[5,11,189] In addition to its complex pharmacokinetic properties, phenytoin dosing in the elderly is complicated by variably decreased protein binding to plasma albumin (increased free fraction) and diminished activity of isozymes CYP2C9/19 that are primarily responsible for elimination.[199,203,204,239] These factors predispose to drug-drug interactions, decreased total body clearance, and a potentially altered therapeutic range.[1,69] For example, the anticipated pharmacologic effect of phenytoin in a patient with a total phenytoin concentration of 20 µg/ml and hypoalbuminemia of 2.5 g/dl is equivalent to that expected with a total phenytoin concentration of approximately 28 µg/ml when adjusted for the decreased albumin concentration. In this case, a 40% lower SDC would be necessary to achieve the same pharmacologic effect as in an individual with a normal albumin concentration of 4 g/dl. If measuring the unbound phenytoin concentration is not feasible, the expected impact of hypoalbuminemia on the pharmacologic effect, in terms of a normal total serum phenytoin concentration, can be estimated with the revised Winter-Tozer equation[240]: phenytoin (normalized; µg/ml) = phenytoin (measured; µg/ml)/[(0.25 x serum albumin; g/dl) + 0.1]

Although the total volume of distribution of phenytoin in elderly people is not different from that in younger adults, the volume of distribution of unbound drug is approximately 50% lower.[174] Since only unbound phenytoin crosses the blood-brain barrier, a lower than normal loading dose was hypothesized but remains unproved.

Phenytoin is eliminated primarily by hepatic oxidation. Its metabolism, largely by CYP2C9, generally becomes saturated (capacity limited) at SDCs no higher than usual therapeutic levels. Subsequently, CYP2C19 assumes the predominant role in phenytoin metabolism. Because of capacity-limited metabolism, a change in phenytoin maintenance dosage can result in a direct but disproportionate change in steady-state serum concentration. Since phenytoin has a low hepatic extraction ratio, its elimination is dependent on intrinsic hepatic clearance, which can be diminished in the elderly. Antipyrine clearance, a marker of metabolism by various CYP isozymes including those catalyzing phenytoin metabolism, decreases with advancing age, indicating the possibility of altered drug elimination.[241,242] In fact, in several clinical trials the maximum rate of phenytoin metabolism (Vmax) that reflects enzyme capacity was reduced in elderly subjects.[1]

An 84% lower clearance of unbound phenytoin and Vmax were observed in 34 elderly patients (aged 60-79 yrs) compared with 26 younger patients (aged 20-39 yrs) at steady-state conditions.[174] All patients received phenytoin monotherapy, had normal plasma albumin concentrations and liver function, and received no concomitant drugs known to modify hepatic metabolism. These findings indicate the need for a smaller initial dosage in elderly people taking phenytoin monotherapy than is usually recommended for younger adults.[1,174,242] In addition, because of the decrease in Vmax, a dosage increment of no more than 10% is recommended.[1,174,242] It is estimated that increasing the dosage of phenytoin sodium from 300 mg/day to 330 mg/day in a 70-kg elderly person would result in an average 67% increase in serum drug concentration.[174] It is unknown whether the dosage should be lower than usual in patients taking drugs that induce phenytoin metabolism. Useful products for small dosage adjustments are the 30-mg Dilantin Kapseal and the 50-mg Dilantin Infatab chewable tablet. Finally, as phenytoin clearance may be decreased, the assessment of maximum clinical response (steady state) should be deferred until 2-3 weeks after therapy is started or the dosage changed.[174] Because the concentration at which phenytoin metabolism becomes saturated is low in elderly people and metabolism is reduced, it is especially important to consider that phenytoin sodium (Dilantin Kapseal and intravenous) contains 8% less active phenytoin than the acid formulation (chewable tablet and suspension) when substituting one formulation, in whole or in part, for another.

An unexplained large intrapatient and interpatient fluctuation in serum phenytoin concentration of 50-150% was noted in elderly nursing home residents.[236,243] The fluctuation in SDC often is unrelated to known factors such as interacting drugs and influenza vaccine, phenytoin formulation, enteral tube feeding, decreased albumin or increased serum creatinine concentration, and liver impairment.[236] In some cases it may reflect an incorrect presumption of achievement of steady state that may be propagated by a delayed time to reach steady state in elderly people.[1,174,243] Until patients at high risk for this phenomenon can be identified, periodic routine SDC measurement (every 12 mo) and judicious clinical monitoring for adverse reactions and loss of disease control are advised.

Whereas most of our knowledge of the pharmacodynamics of AEDs in elderly people comes from investigations of benzodiazepines (sedative and cognitive decline), a similar pharmacodynamic effect may be seen with other AEDs.[191] One study observed that elderly patients (age unspecified) receiving phenytoin experienced more changes in mental status at the same total phenytoin concentrations than younger persons (age unspecified).[8] However, since unbound SDCs were not measured, the possibility that this merely reflects a higher unbound SDC cannot be discounted.

Numerous drug-drug and drug-disease interactions are associated with phenytoin, but gingival hyperplasia is believed to be less common in elderly people than in younger adults. This may be due to a lower turnover rate of gingival connective tissue in elderly people.[244]

Since antacids can decrease the bioavailability of phenytoin, administration of the two should be separated by at least 2 hours, phenytoin preferably administered before the antacid. The bioavailability of phenytoin also may be impaired due to chemotherapy-induced gastrointestinal mucosal damage.[69] Especially in debilitated elderly people, folate supplementation often is required; however, it may decrease phenytoin SDCs, probably by increasing its metabolism.[69] This decrease is generally small, but an increase in seizure frequency is possible. The small amounts of folate in multivitamins and recent addition of folate to grain-based products in the United States do not affect serum phenytoin concentrations substantially. Conversely, long-term phenytoin therapy may decrease the concentration; however, megaloblastic anemia occurs in less than 1% of patients.[69] Although disputed, concomitant administration of phenytoin and enteral products through the same feeding tube may impair phenytoin bioavailability, with decreased or fluctuating serum phenytoin concentration and potential for loss of disease control, or toxicity especially on discontinuing or tapering tube feeding.[69,245,246] Pharmacodynamic interactions (opioids, valproate) should not be overlooked as a cause for neurotoxicity when a normal phenytoin unbound SDC excludes a pharmacokinetic etiology.[69]

Fosphenytoin, unlike phenytoin, can be administered intramuscularly for nonstatus seizures and short-term maintenance therapy. In addition, it can be administered intravenously for status epilepticus at a faster rate than phenytoin.[95] The pharmacokinetics of fosphenytoin, including its conversion to phenytoin by endogenous phosphatase enzymes, have not been studied in elderly people. When administered intramuscularly, the drug is rapidly absorbed and well tolerated, and permits treatment in a nursing facility as well as hospital.[95] Intravenous fosphenytoin (for status epilepticus and short-term maintenance therapy) is less likely than intravenous phenytoin to cause venous irritation, pain, and thrombophlebitis at the infusion site.[95] Other adverse effects including hypotension and cardiac arrhythmias are similar to those with phenytoin. Therefore, monitoring the electrocardiogram (ECG) and blood pressure is recommended.[53] Intravenous fosphenytoin can cause transient paresthesias and pruritus, especially in the face and groin.[53] When assessing phenytoin SDCs in patients of all ages, phlebotomy should be deferred for 4 hours or more after fosphenytoin administration to minimize the element of ex vivo conversion of fosphenytoin to phenytoin.[95]

Carbamazepine and its active metabolite carbamazepine 10,11-epoxide are bound to both AAG, a reactant serum protein, and to a lesser extent to albumin.[194,195] In contrast to albumin, AAG increases with advanced age, stroke, heart failure, infection, myocardial infarction, chronic obstructive pulmonary disease, and concurrent administration of enzyme-inducing AEDs[195,247] Increased binding of weakly basic and neutral AEDs such as carbamazepine and its epoxide metabolite to AAG can increase their total SDCs without effecting a change in the unbound SDC of parent drug or the metabolite.[248] In this case, reliance on total SDC may impede sufficient dosage to provide optimum disease control. However, this effect is less predictable since a lower plasma albumin concentration and related binding may partially offset the effect of AAG. In the case of altered protein binding, greater clinical attention to drug response and smaller dosage changes are essential. Measuring unbound carbamazepine or the 10,11-epoxide metabolite SDC may be useful but is not routinely performed in many clinical laboratories.

Carbamazepine is eliminated predominately from the body by hepatic metabolism (CYP3A4). Whereas evidence suggests an age-related decline in the activity of CYP3A4, a single-dose study of five healthy elderly volunteers (aged 66-74 yrs) compared with six younger volunteers (aged 20-25 yrs) failed to detect a significant difference in elimination rate and area under the serum concentration-time curve between groups.[200,201,249] However, a retrospective study of carbamazepine total body clearance in seven elderly nursing home patients (mean age 82.3 yrs) during maintenance dosing documented a significantly lower (40%) apparent oral clearance (41 ± 19.6 ml/kg/hr) in elderly than in younger patients (71.4 ± 35.8 ml/kg/hr).[1] In another prospective study, carbamazepine apparent oral clearance was approximately 25% lower in 14 ambulatory elderly people (age ≥ 70 yrs) than in 815 younger individuals.[168] Lower carbamazepine clearance may permit less frequent dosing in the elderly.[1] It is not known whether autoinduction of carbamazepine is altered in the elderly; the usual time to maximum induction in young adults approximates 10 days. Until more definitive data are available, it may be prudent to begin therapy with a smaller than usual dosage.

Carbamazepine is associated with numerous adverse reactions.[163] Skin rash is more common in elderly than in younger adults.[12] The SIADH and hyponatremia from carbamazepine may occur more often in the elderly, especially with higher SDCs.[250] Recognizing this effect can be difficult, since some symptoms of hyponatremia such as lethargy, weakness, and confusion can be mistaken for carbamazepine CNS toxicity as well as various medical conditions that are prevalent in elderly people. Although hyponatremia usually is mild and without serious clinical consequences, patients can suffer worsening seizures, cardiac arrhythmia, and coma with brain injury. Together with monitoring for hyponatremia symptoms, baseline and periodic routine electrolyte panels including serum sodium are advised.[250] Management consists of fluid restriction as low as 500 ml/day in asymptomatic patients with a serum sodium 115 mEq/L or higher. In symptomatic patients or in those with a lower serum sodium concentration, fluid restriction plus demeclocycline 600-1200 mg/day is advised. As a matter of convenience, substituting carbamazepine with another AED should be considered in lieu of adding demeclocycline as long-term therapy.

Aplastic anemia and other serious idiosyncratic reactions are uncommon and not known to be age related.[251] Baseline and periodic routine monitoring of the complete blood count and liver function tests are advised, although the benefit of routine monitoring is disputed.[251] In any case, clinical monitoring and prompt attention to symptoms of hematologic and hepatic dysfunction are essential.[251] Therefore, pretreatment assessment should include a complete blood count with differential and platelet count, liver enzymes, serum sodium, thyroid function, and ECG. With the exceptions of ECG and liver enzymes, these values should be reassessed periodically.

Oral antineoplastics that damage the gastrointestinal mucosa can decrease the bioavailability of carbamazepine.[69] The drug is a potent CYP inducer of many agents, including itself (autoinduction). In young adults auto-induction is characterized by a pseudo-steady state after 2-4 days, followed by a gradual decline in SDC until secondary steady state is achieved in approximately 3-4 weeks.[252] It is not known whether autoinduction is altered in elderly people. A pharmacodynamic interaction with carbamazepine resulting in neurotoxicity (lethargy, muscle weakness, ataxia, tremor, hyperreflexia) was reported with lithium, opioids, and lamotrigine and should be considered with numerous other pharmacokinetic interactions.[69]

A new treatment option for acute repetitive seizures is a diazepam rectal gel.[85,87] Its onset of effect is approximately 10 minutes, similar to that of intravenous diazepam.[85,87,88] Unlike administering the injectable formulation of diazepam rectally using a syringe and tubing, this agent is a self-contained, ready-to-use product but is considerably more expensive.[85,87] It should be administered with caution in elderly people at a dose of 0.2 mg/kg, with the calculated dose rounded down to a commercially available dose using fixed, unit-doses of 5, 10, 15, or 20 mg up to 20 mg.[93] A second dose, if necessary, may be given 4-12 hours after the first one.[93] Adverse reactions with rectal diazepam are infrequent and usually mild, with somnolence being the most common.[85,87,88,93] Rectal lorazepam is also well tolerated but is absorbed more slowly (time to maximum concentration 68 min) than rectal diazepam and consequently has no role in treatment.[253,254]

Valproate is highly protein bound to albumin. Its binding is saturable at an approximate average SDC of 80 µg/ml (within the usual valproate serum concentration range). Therefore, a decrease in albumin plasma concentration or serum valproate concentration exceeding approximately 80 µg/ml can cause an increase in percentage of unbound valproate.[255,256] The drug is nearly entirely eliminated from the body by hepatic metabolism. Results of three small studies consistently showed lower protein binding (40-67% higher unbound valproate concentrations) and 65% lower unbound valproate clearance in elderly than in younger adults; however, the decreased unbound clearance is fully compensated by lower protein binding, so total valproate SDCs are similar to those in younger adults.[257,258,259] Consequently, the desired clinical response might be achieved at a dosage approximately 50% of that required in younger adults with a normal albumin concentration.

Although nonlinear protein binding of valproate is not considered to be clinically relevant in younger adults, because of a relatively wide therapeutic concentration range, this may not be the case in elderly people with decreased albumin concentrations and unbound clearance and a total concentration above 80 µg/ml, when an even greater disparity between total serum concentration and clinical response may exist. Therefore, measuring unbound valproate serum concentration should be considered in case of hypoalbuminemia or discord between total SDC and clinical response.[260] The serum elimination half-life was twice as long in elderly volunteers as in younger adults in one trial, whereas no difference was seen between elderly and younger adults in another.[259] Therefore, extending the dosing interval may be permitted as guided by SDCs and patient response. Since the time to steady state may be doubled, a corresponding postponement in documenting the steady-state SDC is recommended.

Idiosyncratic hepatotoxicity is a serious but rare (~1/117,000) adverse reaction in adults. It primarily affects individuals receiving several AEDs; those with preexisting hepatic dysfunction, history of alcohol abuse, or pancreatitis; or developmentally disabled persons.[261] Due to the rare and insidious nature of hepatotoxicity, the optimal frequency of blood monitoring (baseline and follow-up liver function tests, serum chemistries, complete blood cell count with differential) is uncertain, and the need for routine monitoring in patients at low risk is questioned.[261]

Pancreatitis is also a rare adverse effect of valproate. Potentially fatal, but generally reversible with drug discontinuation, acute hemorrhagic pancreatitis symptoms may be confused with dose-dependent gastrointestinal toxicity that occurs especially early in therapy.[262]

Because valproate, especially with SDCs greater than 110 µg/ml, may cause thrombocytopenia (usually mild and self-limited) it should be avoided or prescribed with caution in patients receiving other drugs that can cause platelet dysfunction (salicylates, clopidogrel, dipyridamole, ticlopidine).[67,234] With the possibility of diminished hematopoietic activity in elderly people, close monitoring of platelet count and clinical evidence of bruising and bleeding are indicated.

An extended-release formulation of divalproex may cause fewer gastrointestinal adverse effects and sedation than delayed-release divalproex and allows once/daily dosing.[234]

The bioavailability of valproate may be diminished by gastrointestinal damage caused by oral antineoplastics.[69] In a complex interaction with phenytoin, valproate both displaces and decreases the intrinsic clearance of phenytoin, resulting in an increased, decreased, or unchanged total phenytoin SDC, and increased unbound phenytoin SDC and percentage unbound. In addition to protein-binding displacement interactions, many other drug-drug interactions with valproate have been identified.[69] Valproate can interact with lamotrigine, causing potentially life-threatening skin rashes and neurotoxicity.

Depacon is a valproate formulation indicated as an intravenous alternative in patients for whom oral administration of valproate products is temporarily not feasible (for complex partial seizures, simple and complex absence seizures, adjunctive therapy in various seizure types that include absence seizures).[263] As Depacon cannot be administered intramuscularly because of tissue necrosis, its utility in long-term care facilities, most of which cannot administer drugs intravenously, will be limited.

The total plasma clearance of phenobarbital is 50% lower in patients older than 40 years versus those aged 15-40 years.[264] Therefore, a reduction to one-half the usual starting dosage and smaller dosage increments are suggested in the elderly.[1,264] Reduced clearance also can delay the time to assess steady-state response and prolong the time before the SDC should be monitored. Phenobarbital causes numerous adverse effects including paradoxic irritability, restlessness, agitation, falls, and confusion and is not advised in the elderly.[6,44,46]

The agent is an inducer of the metabolism of many drugs, and its own metabolism is altered by numerous drugs, notably valproate, which results in a need to decrease the usual initial pheno-barbital dosage by up to 50%.[69] A pharmaco-dynamic interaction with opioids can result in neurotoxicity.[69]

The plasma clearance and elimination half-life of primidone in young adults are not significantly different from those in elderly people.[265] A 30% lower renal clearance was observed in elderly patients compared with young adults, although its clinical significance is unknown.[265] The need for a dosage reduction is possible in very old patients, who were not included in this study, or in individuals with severe renal impairment, especially since the clearance of phenobarbital, primidone's principal metabolite, is significantly decreased in the elderly. In assessing the pharmacologic response, monitoring SDCs of both phenobarbital and primidone is recommended.

Adverse reactions of primidone are similar to those of phenobarbital.[163] The same drugs that interact with phenobarbital also may interact with primidone. However, the effect of both CYP inducers and inhibitors on the primidone metabolite phenobarbital will be the opposite of that observed with phenobarbital. Inducers of primidone decrease the SDC of primidone but increase the SDC of phenobarbital.[69] Inhibitors of primidone increase the SDC of primidone but decrease the phenobarbital SDC.[69]

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