Lacosamide is approved for the treatment of focal onset seizures in patients age 17 years and older. In clinical trials with more than 1300 patients, lacosamide was effective at doses of 200 mg/d and had greater and roughly similar overall efficacy at 400 and 600 mg/d, respectively. Although the overall efficacy was similar at 400 and 600 mg/d, the higher dose may provide better control of focal-to-bilateral tonic-clonic (secondarily generalized) seizures; however, this dose is associated with a greater incidence of adverse effects. Adverse effects include dizziness, headache, nausea, and diplopia. The drug is typically administered twice daily, beginning with 50-mg doses and increasing by 100-mg increments weekly. An intravenous formulation provides short-term replacement for the oral drug. The oral solution contains aspartame, which is a source of phenylalanine and could be harmful in people with phenylketonuria.
Oral lacosamide is rapidly and completely absorbed in adults, with no food effect. Bioavailability is nearly 100%. The plasma concentrations are proportional to oral dosage up to 800 mg. Peak concentrations occur from 1 to 4 hours after oral dosing, with an elimination half-life of 13 hours. There are no active metabolites, and protein binding is minimal. Lacosamide does not induce or inhibit cytochrome P450 isoenzymes, so drug interactions are minimal.
Phenytoin, first identified to have antiseizure activity in 1938, is the oldest nonsedating drug used in the treatment of epilepsy. It is prescribed for the prevention of focal seizures and generalized tonic-clonic seizures and for the acute treatment of status epilepticus. Phenytoin was identified by testing in laboratory animals in a search for better tolerated barbiturates.
Phenytoin, sometimes referred to as diphenylhydantoin, is the 5,5-diphenyl-substituted analog of hydantoin. Hydantoin is a five-membered ring molecule similar structurally to barbiturates, which are based on a six-member ring. Phenytoin free base (pKa = 8.06–8.33) is poorly water soluble, but phenytoin sodium does dissolve in water (17 mg/mL). Phenytoin is most commonly prescribed in an extended-release capsule containing phenytoin sodium and other excipients to provide a slow and extended rate of absorption with peak blood concentrations from 4 to 12 hours. This form differs from the prompt phenytoin sodium capsule form that provides rapid rate of absorption with peak blood concentration from 1.5 to 3 hours. In addition, the free base is available as an immediate-release suspension and chewable tablets. Phenytoin is available as an intravenous solution containing propylene glycol and alcohol adjusted to a pH of 12. Absorption after intramuscular injection is unpredictable, and some drug precipitation in the muscle occurs; this route of administration is not recommended.
With intravenous administration, there is a risk of the potentially serious “purple glove syndrome” in which a purplish-black discoloration accompanied by edema and pain occurs distal to the site of injection. Fosphenytoin is a water-soluble prodrug of phenytoin that may have a lower incidence of purple glove syndrome. This phosphate ester compound is rapidly converted to phenytoin in the plasma and is used for intravenous administration and treatment of status epilepticus. Fosphenytoin is well absorbed after intramuscular administration, but this route is rarely appropriate for the treatment of status epilepticus.
Mechanism of Action
Phenytoin is a sodium channel-blocking antiseizure drug that acts in a similar fashion to carbamazepine and other agents in the class.