Strategies for Optimizing Antiepileptic Drug Therapy in Elderly People

Thomas E. Lackner, Pharm.D., FASCP

Disclosures

Pharmacotherapy. 2002;22(3) 

In This Article

Adverse Reactions with AEDs

More than 50% of persons, including the elderly, treated with traditional AEDs experience short-term, long-term, and idiosyncratic adverse effects including impaired cognition, decreased bone mineral density, osteomalacia and osteoporosis, gait disturbance, falls and fractures, and occasionally urinary incontinence.[163] Phenytoin was associated with 6% of probable or definite adverse drug reactions in nursing home residents and 9% of severe reactions (≥ 2 physician visits, hospitalization, prolongation of hospitalization, death).[5] According to an FDA survey, AEDs account for 9% of all adverse drug reactions in elderly people.[4] A survey of elderly nursing home residents revealed that AEDs were the fourth leading cause of such reactions.[189] Further complicating this situation is the fact that adverse AED reactions in elderly people can be severe (neurotoxicity) and sometimes difficult to distinguish from other conditions (neurologic deficits, mental confusion, Parkinson's disease, essential tremor, dizziness, behavioral distur-bances, urinary incontinence, hypothyroidism, anemia, falls, anorexia) and untoward effects of other drugs such as psychopharmacologic agents.[5,7,8,9,190,191,192]

Variably altered AED pharmacokinetics (primarily distribution and elimination) and pharmacodynamics (usual therapeutic total SDC range may be lower and narrower) associated with advanced age, together with insufficient dosage information, particularly for individuals 85 years of age and older, polypharmacy, and the complex pharmacokinetics of traditional AEDs predispose to both excessive dosage and adverse reactions or underdosage and suboptimal patient response.[1,4,5,6,163,164,190] For example, the plasma albumin concentration tends to decrease with advanced age, poor nutrition, renal insufficiency, hepatic disease, and rheumatoid arthritis.[193,194] With this decline, the binding of weakly acidic AEDs such as phenytoin can decrease, lowering the total SDC, while the unbound SDC remains unchanged (assuming unaltered clearance), albeit the percentage of unbound AED is increased.[194,195,196,197] Highly protein-bound AEDs such as phenytoin have an intrinsic clearance that is much less than liver blood flow. Consequently, hepatic metabolism is restricted to unbound drug, and changes in unbound SDC elicit a nearly proportional change in clearance. In this case, the AED dosage may be erroneously increased based on a lower than usual total SDC. In addition, an adverse AED reaction may be discounted incorrectly because of a total SDC within the usual therapeutic range.[198]

Failing to consider possible advanced age-related changes in AED elimination also increases the risk for adverse reactions. For example, the activity of cytochrome P450 (CYP) isozymes 3A4 and 2C9/19, primarily responsible for elimination of several AEDs, may be reduced in advanced age.[199,200,201,202,203,204] Gabapentin, levetiracetam, and topiramate are primarily eliminated from the body by renal excretion and may require a dosage reduction in elderly people even without overt renal dysfunction.[58,59,61] Zonisamide is contraindicated with a creatinine clearance less than 50 ml/minute.[52]

Some AEDs (benzodiazepines, topiramate, zonisamide) can impair cognitive function, especially with higher dosages and SDCs and during coadministration of a drug with this same effect, whereas the effects of other AEDs (phenytoin, carbamazepine, oxcarbazepine, tiagabine, valproate) on cognition are equivocal.[49,52,60,61,205,206,207,208,209,210] Evidence for cognitive impairment from AEDs is even more limited for elderly people than for the overall population.[206,207] A small randomized, single-blind study evaluated elderly patients (median age 77 yrs) with new-onset epilepsy, 20 taking phenytoin monotherapy (mean dosage 247 mg/day, mean SDC 31 µmol/L) and 18 valproic acid monotherapy (mean dosage 688 mg/day, mean SDC 396 µmol/L) for the first time.[206] Only minimal effects were reported on attention, concentration, psychomotor speed, and memory in 38 of 47 patients completing 6 weeks of treatment. Generally, no significant differences were seen in the effect of either agent on any tests of cognitive function (visual, verbal, digit memory, motor speed, information processing, coordination). Although phenytoin less adversely affected tests of mental attention than valproic acid to a small but statistically significant extent after 6 weeks and after 3 months of treatment, these differences did not persist at 6-month and 1-year assessments. The findings were similar after treatment for 1 year; however, because of a high rate of treatment discontinuation the number of evaluable subjects was small. However, only one patient was withdrawn due to mental confusion.

In another small controlled study of the cognitive effects of AED monotherapy in 23 elderly patients (median age 70 yrs) with epilepsy, no substantial changes were noted in cognition (attention, reaction time, finger tapping, memory) for any drugs (carbamazepine, valproate, phenytoin) and placebo when dosages were modestly increased, often producing SDCs in the upper portion of their usual therapeutic ranges.[207]

The AEDs most strongly implicated should be avoided in individuals with preexisting dementia and other cognitive disorders. The risk may be reduced with AED monotherapy, maintaining the lowest effective dosage and SDC, and avoiding concomitant agents that can impair cognition.[211,212] Acute cognitive impairment from tiagabine and topiramate can be minimized by starting with a low dosage and gradual escalation.[60,61,210]

Possibly as a result of potential effects on mental alertness, gait, vision, and perhaps posture (osteoporosis), AEDs may predispose to bone fractures and falls in the elderly.[6,47,213] In a case control study of 174 nursing home (5.9%) and community-dwelling (94.1%) elderly women (median age 80 yrs, range 55-103 yrs), therapy with long-acting barbiturates was a significant risk factor for hip fracture related to a fall (OR 5.2, 95% CI 0.6-45).[6] Phenytoin was significantly associated with a first nonvertebral fracture in community-dwelling elderly women (adjusted OR 2.93, 95% CI 1.04-8.30).[213,214,215] Plausible explanations for this effect are CNS effects with an increased risk of falls and/or altered bone density. In another study, elderly nursing home residents with decreased serum 25-hydroxyvitamin D and elevated serum parathyroid hormone concentrations, an untoward effect of enzyme-inducing AEDs, fell more often than those without this abnormality.[216] Except for seizure prophylaxis, AEDs generally should be avoided in individuals predisposed to falling. If necessary, valproate and carbamazepine may pose a lower risk of falling than other traditional AEDs.[217]

Several studies, some including elderly individuals, suggest that traditional AEDs may cause decreased bone mineral density (BMD), osteomalacia, and osteoporosis[214,218,219,220,221,222]; however, results are equivocal.[223] The risk of osteoporosis from AEDs may be compounded in elderly patients by the high prevalence of comorbid conditions known to decrease BMD (menopause, andropause, decreased mobility, low dietary intake of calcium and vitamin D).[224] In a case control study of 91 community-dwelling men (median age 64 yrs) with previous vertebral fractures and 91 age-matched controls, a significantly increased independent risk of new vertebral fractures was seen with traditional AEDs (OR 6.1, 95% CI 1.3-28.4) as well as with corticosteroids, current smoking, consumption of large amounts of alcohol, and family history of bone disease.[214] After adjusting for fractures and calcaneal bone density, the risk of first hip fracture doubled during an average 4.1 years of follow-up in 9516 community-dwelling Caucasian women aged 65 years and older taking traditional AEDs (RR 2.0, 95% CI 0.8-4.9).[215] None of the 7 fractures occurring in 105 individuals taking an AED were related to seizures or loss of consciousness. In an epidemiologic cohort study of community-dwelling women aged 65 years and older phenytoin was significantly (adjusted OR 2.93, 95% CI 1.04-8.30) associated with a first nonvertebral fracture.[213] Whereas precise causes of fractures were uncertain, decreased BMD and CNS effects of phenytoin were identified as potential factors.

A small case control study examined the relationship between BMD measured by dual-energy x-ray absorptiometry (DXA) bone densitometry and long-term traditional AED monotherapy in 78 middle-aged and elderly individuals (median age 58 yrs) with epilepsy and matched controls.[218] Therapy with an AED was independently associated with decreased BMD at the femoral neck. Unlike findings in a study of younger adults, the duration of treatment was not independently related to decreased BMD.[222] The mean serum vitamin D concentration was significantly lower in patients taking enzyme-inducing AEDs than in controls, but not in those taking nonenzyme-inducing AEDs. However, BMD did not differ significantly between AED subtypes and was lower in both cohorts at the femoral neck and lumbar spine than in controls.

Mechanisms underlying AED-induced osteopathies are probably multifactorial. In elderly women, hepatic enzyme induction by phenobarbital, primidone, phenytoin, and carbamazepine increases hydroxylation of vitamin D metabolism and may result in decreased BMD and possibly osteoporosis.[223] However, even with normal serum 25-hydroxy vitamin D concentrations, accelerated bone turnover was documented in adults including a small unspecified number of elderly people.[225,226] The AEDs that increase sex hormone-binding globulin (phenytoin, phenobarbital, carbamazepine) lower the ratio of free to total sex hormone (pharmacologically active hormone). This causes an increased level of interleukin-6 with excessive osteoclastogenesis and inadequate osteoblasto-genesis (ability of marrow to form osteoblast precursors may be impaired in elderly people), resulting in reduced BMD.[227,228,229] In in vitro studies both phenytoin and carbamazepine inhibited proliferation of human osteoblast-like cells. A carbamazepine cell culture concentration of 10 mg/L resulted in a 52% decrease in proliferation of osteoblast-like cells, and a 50% reduction was found at a similar concentration of phenytoin. Even greater inhibition of cell proliferation occurred with higher AED concentrations.[226] Another proposed mechanism of osteopathy is AED-mediated inhibition of parathyroid hormone-induced release of calcium from bone.

Elderly patients receiving AEDs should be evaluated for osteoporosis. Since bone loss may be related to treatment duration, AED therapy should be limited to the shortest time possible. Although unproved, newer AEDs with less capacity to induce CYP hepatic enzymes may be less likely to cause osteoporosis.[230,231] Although no specific guidelines are available for managing AED-induced osteomalacia and osteoporosis, in high-risk elderly (institutionalized, ≥ 80 yrs with an additional risk factor for osteoporosis), supplemental elemental calcium up to the recommended daily intake of 1500 mg/day and vitamin D 400-800 U/day are suggested as minimal therapies.[221,222,232] If feasible, the need for additional therapy may be guided by DXA testing.[232] Whereas antiresorptive bisphosphonates such as alendronate and risedronate prevent and treat glucocorticoid-induced osteoporosis, they have not been studied specifically in AED-induced osteopathies. The benefit of other therapies such as estrogen replacement therapy and calcitonin is unknown.

Urinary incontinence, an infrequent adverse effect of many AEDs, easily can be overlooked considering its high prevalence in the elderly.[56,57,63,64,65,66,67] At usual therapeutic dosages, symptoms of urge and overflow urinary incontinence may occur, and stress urinary incontinence was reported with phenytoin, which relaxes the internal bladder sphincter by blocking a-adrenergic receptors.[56,57,63,64,65,66,67,190] Central nervous system depressants such as benzodiazepines and barbiturates may decrease intravesical internal pressure by relaxing the external bladder sphincter and causing uninhibited bladder contractions. Functional urinary incontinence may result from excessive sedation. Carbamazepine may prolong parasympathetic stimulation of the detrusor, causing overflow incontinence.[63] The lowest effective AED dosage and dosage reduction or discontinuation of concomitant agents that can enhance these effects may mitigate the disorder. If urinary incontinence persists, a different AED may be necessary as determined by risk:benefit analysis.

Strategies to minimize dose-related adverse events are starting an AED at approximately one-half the usual starting dosage in younger adults with gradual escalation.[1,210,233] In the event of a suspected dose-related adverse reaction, doses can be withheld. If this is not feasible, the AED concentration can be measured. If the SDC is no higher than a previous concentration at which toxicity was not evident, symptoms may be unrelated to the AED or not be dose related. An AED dose can be withheld and the dosage decreased, or a different AED substituted if necessary. Gastrointestinal toxicity may be relieved by administration with food (when appropriate) or prescription of a sustained-release AED such as divalproex sodium extended-release in place of valproate.[234] Gastrointestinal distress and CNS adverse effects often can be alleviated by a small and gradual dosage escalation.[210] A small dosage reduction or administering a larger portion of the total daily dose at bedtime may be helpful if the patient has only a transient adverse CNS effect such as postdose tremor. Long-term adverse reactions may be minimized by administering the lowest effective dosage or SDC for the shortest time necessary, and discontinuing unnecessary drugs that can exaggerate toxicity. In addition, because symptoms of various medical conditions can fluctuate throughout the course of a disease, reassessment of continued need for the AED and potential drug-disease interactions is important.

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