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Chapter: Basic & Clinical Pharmacology : Antiseizure Drugs

Management of Epilepsy

For many years, the choice of drugs for partial and tonic-clonic seizures was usually limited to phenytoin, carbamazepine, or bar-biturates.



For many years, the choice of drugs for partial and tonic-clonic seizures was usually limited to phenytoin, carbamazepine, or bar-biturates. There was a strong tendency to limit the use of sedative antiseizure drugs such as barbiturates and benzodiazepines to patients who could not tolerate other medications; this trend led, in the 1980s, to increased use of carbamazepine. Although car-bamazepine and phenytoin remain widely used, most newer drugs (marketed after 1990) are effective against these same seizure types. With the older drugs, efficacy and long-term adverse effects are well established; this creates a confidence level in spite of questionable tolerability. Most newer drugs have a broader spec-trum of activity, and many are well tolerated; therefore, the newer drugs are often preferred to the older ones. Although some data suggest that most of these newer drugs confer an increased risk of nontraumatic fractures, choosing a drug on this basis is not yet practical.


The issues (described above) related to choosing between old and new drugs apply to the generalized group of seizures as well.The drugs used for generalized tonic-clonic seizures are the same as for partial seizures; in addition, valproate is clearly useful.At least three drugs are effective against absence seizures. Two are nonsedating and therefore preferred: ethosuximide and val-proate. Clonazepam is also highly effective but has disadvantages of dose-related adverse effects and development of tolerance. Lamotrigine and topiramate may also be useful.Specific myoclonic syndromes are usually treated with val-proate; an intravenous formulation can be used acutely if needed. It is nonsedating and can be dramatically effective. Other patients respond to clonazepam, nitrazepam, or other benzodiazepines, although high doses may be necessary, with accompanying drowsiness. Zonisamide and levetiracetam may be useful. Another specific myoclonic syndrome, juvenile myoclonic epilepsy, can be aggravated by phenytoin or carbamazepine; valproate is the drug of choice followed by lamotrigine and topiramate.

Atonic seizures are often refractory to all available medications, although some reports suggest that valproate may be beneficial, as may lamotrigine. Benzodiazepines have been reported to improve seizure control in some of these patients but may worsen the attacks in others. Felbamate has been demonstrated to be effective in some patients, although the drug’s idiosyncratic toxicity limits its use. If the loss of tone appears to be part of another seizure type (eg, absence or complex partial seizures), every effort should be made to treat the other seizure type vigorously, hoping for simul-taneous alleviation of the atonic component of the seizure. The ketogenic diet may also be useful.


The treatment of infantile spasms is unfortunately limited to improvement of control of the seizures rather than other features of the disorder, such as retardation. Most patients receive a course of intramuscular corticotropin, although some clinicians note that prednisone may be equally effective and can be given orally. Clinical trials have been unable to settle the matter. In either case, therapy must often be discontinued because of adverse effects. If seizures recur, repeat courses of corticotropin or corticosteroids can be given, or other drugs may be tried. A repository corticotro-pin for injection is now approved in the USA for the treatment of infantile spasms, either of cryptogenic or symptomatic etiology. Other drugs widely used are the benzodiazepines such as clonaze-pam or nitrazepam; their efficacy in this heterogeneous syndrome may be nearly as good as that of corticosteroids. Vigabatrin is effective and is considered the drug of choice by many pediatric neurologists. The mechanism of action of corticosteroids or corti-cotropin in the treatment of infantile spasms is unknown but may involve reduction in inflammatory processes.


There are many forms of status epilepticus. The most common, generalized tonic-clonic status epilepticus, is a life-threatening emergency, requiring immediate cardiovascular, respiratory, and metabolic management as well as pharmacologic therapy. The lat-ter virtually always requires intravenous administration of antisei-zure medications. Diazepam is the most effective drug in most patients for stopping the attacks and is given directly by intrave-nous push to a maximum total dose of 20–30 mg in adults. Intravenous diazepam may depress respiration (less frequently, cardiovascular function), and facilities for resuscitation must be immediately at hand during its administration. The effect of diaz-epam is not lasting, but the 30- to 40-minute seizure-free interval allows more definitive therapy to be initiated. Some physiciansprefer lorazepam, which is equivalent to diazepam in effect and perhaps somewhat longer acting. For patients who are not actually in the throes of a seizure, diazepam therapy can be omitted and the patient treated at once with a long-acting drug such as phenytoin.

Until the introduction of fosphenytoin, the mainstay of con-tinuing therapy for status epilepticus was intravenous phenytoin, which is effective and nonsedating. It can be given as a loading dose of 13–18 mg/kg in adults; the usual error is to give too little. Administration should be at a maximum rate of 50 mg/min. It is safest to give the drug directly by intravenous push, but it can also be diluted in saline; it precipitates rapidly in the presence of glucose. Careful monitoring of cardiac rhythm and blood pressure is necessary, especially in elderly people. At least part of the cardio-toxicity is from the propylene glycol in which the phenytoin is dissolved. Fosphenytoin, which is freely soluble in intravenous solutions without the need for propylene glycol or other solubiliz-ing agents, is a safer parenteral agent. Because of its greater molecular weight, this prodrug is two thirds to three quarters as potent as phenytoin on a milligram basis.In previously treated epileptic patients, the administration of a large loading dose of phenytoin may cause some dose-related tox-icity such as ataxia. This is usually a relatively minor problem during the acute status episode and is easily alleviated by later adjustment of plasma levels.For patients who do not respond to phenytoin, phenobarbital can be given in large doses: 100–200 mg intravenously to a total of 400–800 mg. Respiratory depression is a common complication, especially if benzodiazepines have already been given, and there should be no hesitation in instituting intubation and ventilation.Although other drugs such as lidocaine have been recom-mended for the treatment of generalized tonic-clonic status epi-lepticus, general anesthesia is usually necessary in highly resistant cases.For patients in absence status, benzodiazepines are still drugs of first choice. Rarely, intravenous valproate may be required.

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