Strategies for Optimizing Antiepileptic Drug Therapy in Elderly People

Thomas E. Lackner, Pharm.D., FASCP

Disclosures

Pharmacotherapy. 2002;22(3) 

In This Article

Acute Repetitive Seizures and Status Epilepticus

Although not evaluated in the elderly, diazepam rectal gel or the less expensive but more cumbersome rectal administration of parenteral diazepam is the first choice treatment for acute repetitive seizures, also known as cluster seizures.[85,86,87] Onset of effect of diazepam rectal gel is approximately 10 minutes, similar to that of intravenous diazepam.[85,87,88] Diazepam or lorazepam (unlabeled use) administered intravenously is also effective, but potentially serious respiratory depression, hypotension, and cardiac arrhythmias limit both agents to hospitalized patients without contraindications. In addition, many nursing homes cannot administer drugs intravenously. If neither rectal nor intravenous administration of diazepam is feasible, oral diazepam solution is a second option; however, the maximum effect is not achieved for 30 minutes and it may be difficult and dangerous to administer when a patient is convulsing.[89,90] Oral diazepam solution is preferred over oral lorazepam because of faster onset of effect. Intramuscular administration of diazepam or lorazepam is not advised because of unacceptably slow (both drugs) and erratic (diazepam) absorption, and possible tissue necrosis at the injection site (diazepam).[85,91] Infrequent, nonemergency seizures are managed with oral diazepam or lorazepam solution or intramuscular lorazepam.[85] Total body clearance of lorazepam, predominantly by hepatic glucuronidation, is not altered significantly by advanced age, whereas oxidative metabolism of diazepam and its active metabolite is diminished in elderly people and requires a smaller than usual dosage.[92,93]

Rectal diazepam is not intended for maintenance therapy, and administration more frequently than recommended and long-term therapy are not advised because of potential for cyclic recurrence of seizures, possibly related to a fluctuating SDC.[94] If necessary, fosphenytoin may be administered intramuscularly or intravenously concomitantly with rectal or oral diazepam to maintain seizure control.[85,87,93,95]

The incidence of status epilepticus of 86/100,000/year in elderly people exceeds that in any other adult age group and is nearly twice that in the general population.[33] It is typically longer in duration and exacts a higher mortality (38-50%) than in younger adults (26%).[33,96] In adults of any age, pharmacotherapy generally is started with intravenous diazepam or lorazepam for rapid termination of status epilepticus and fosphenytoin to prevent recurrence.[53,97] To minimize sedation, some clinicians advocate starting therapy with intravenous fosphenytoin rather than a benzodiazepine in a patient who is not actively convulsing, and giving a benzodiazepine only if seizures occur during or after fosphenytoin infusion.[98] Lorazepam is considerably longer acting (12-24 hrs) than diazepam (15-30 min) and was significantly more effective than diazepam in terminating status epilepticus in young adults.[99] However, it may depress consciousness for a longer period of time. A randomized, double-blind trial compared efficacy and safety of intravenous lorazepam, phenytoin, combined diazepam and phenytoin, and phenobarbital for initial control of generalized status epilepticus in 570 patients, including many elderly individuals (median age 58.6 yrs in overt convulsive status, 62 yrs in subtle convulsive status).[100] Lorazepam was significantly more effective than phenytoin in terminating overt generalized status epilepticus. There were no significant differences in serious hypotension, respiratory depression, and cardiac arrhythmias among treatments. In that study, patients refractory to initial therapy were unlikely to respond (7% with overt status) to a different standard drug.[101] Therefore, refractory status epilepticus in the elderly may have to be treated with general anesthetic agents such as midazolam as well as ventilatory support and hemodynamic and EEG monitoring in an intensive care unit.[101,102]

Midazolam is effective in younger adults, with rapid onset of effect but short duration of action (brief depressed consciousness). In addition, hypotension is less evident than with barbiturates. Disadvantages are tachyphylaxis and high cost.[102] Midazolam is administered as an intravenous loading dose of 0.2 mg/kg as a slow bolus injection followed by an infusion of 0.1-2 mg/kg/hour according to EEG effect for at least 12-24 hours or longer if seizures recur. When intravenous access is not feasible, midazolam can be given intramuscularly. However, absorption and onset of anticonvulsant activity are more variable than with intravenous administration.[102] Diazepam is highly lipophilic, with an increased volume of distribution in elderly people.[103,104] This pharmacokinetic effect ordinarily would suggest the need for a larger loading dose; however, because elderly people may be more sensitive to the same SDC than younger adults (pharmacodynamic effect), no dosage adjustment is indicated.[105] Whereas no advanced age-specific guidelines are available for infusion rate of fosphenytoin, a smaller than usual loading dose should be considered for the elderly.[53,95]

An intravenous formulation of valproic acid is a promising option for managing status epilepticus in elderly people. It was associated with low frequencies of hypotension, respiratory depression, and sedation in a pilot study including several elderly patients and in a retrospective study of predominantly elderly patients (mean age 74.4 yrs) with hypotension or cardiac instability.[106,107] Controlled comparative trials are required to confirm its role and optimal dosage for status epilepticus in the elderly.

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