Chapter 197: Anticonvulsants

INTRODUCTION

Anticonvulsants, or antiepileptics, are used to treat acute seizures and prevent convulsions in patients with epilepsy. The first generation of antiepileptics was developed between 1939 and 1980 (Table 197-1). Since 1993, 15 additional agents have been introduced into clinical use, termed the "second and third generation" of antiepileptic drugs. In general, these new anticonvulsants have fewer serious adverse side effects and fewer drug interactions than the first-generation agents. The first-generation drugs have an established therapeutic range for serum levels that can guide therapy during long-term management and that correlate with acute toxicity from an overdose. Consistent therapeutic levels have not been established for the second and third-generation anticonvulsants, and serum levels are not a useful guide to therapy.

This chapter reviews the pharmacology, clinical features, and treatment for commonly used anticonvulsants. Disposition recommendations depend on the resolution of clinical toxicity, but patients with intentional overdose need mental health evaluation in the ED before discharge.

PHENYTOIN AND FOSPHENYTOIN

Phenytoin is a primary anticonvulsant for partial and generalized tonic-clonic seizures. It is useful in the treatment of non–drug-induced status epilepticus in conjunction with rapidly acting anticonvulsants.¹ Pheny-toin has been used to prevent seizures due to head trauma (in the immediate post-traumatic period) and in the management of some chronic pain syndromes. Serious complications are extremely rare after intentional phenytoin overdose if supportive care is provided. Most phenytoin-related deaths have been caused by rapid IV administration or hypersensitivity reactions.

Phenytoin is available in oral and injecTable forms. Phenytoin has poor solubility in water, so the vehicle for the parenteral formulation is 40% propylene glycol and 10% ethanol, adjusted to a pH of 12 with sodium hydroxide. The acute cardiovascular toxicity seen with IV phenytoin infusion has frequently been ascribed to the propylene glycol diluent. Other limitations with parenteral phenytoin are the irritating nature of the vehicle and a tendency to precipitate in IV solutions. Fosphenytoin (a disodium phosphate ester of phenytoin) is a prodrug that is converted to phenytoin by phosphatases in the body with a conversion half-life of 10 to 15 minutes. The advantage with parenteral fosphenytoin is that it is soluble in aqueous solutions, is buffered to a pH of 8.8, is nonirritating to the tissues, and can be given by IM injection.²

PATHOPHYSIOLOGY

Mechanism of Action

Phenytoin exerts its anticonvulsant effect by blocking voltage-sensitive and frequency-dependent sodium channels in the neurons, suppressing repetitive neuronal activity, and preventing the spread of a seizure focus.³ At higher concentrations, phenytoin ...