Idiosyncratic reactions to phenytoin are relatively rare. A skin rash may indicate hypersensitivity of the patient to the drug. Fever may also occur, and in rare cases, the skin lesions may be severe and exfoliative. Lymphadenopathy may rarely occur; this must be distinguished from malignant lymphoma. Hematologic complications are exceedingly rare, although agranulocytosis has been reported in combination with fever and rash.
MEPHENYTOIN, ETHOTOIN, & PHENACEMIDE
Many congeners of phenytoin have been synthesized, but only three have been marketed in the USA, and one of these (phenacemide) has been withdrawn. The other two congeners, mephenytoin and ethotoin, like phenytoin, appear to be most effective against focal and generalized tonic-clonic seizures. No well-controlled clinical trials have documented their effectiveness, and the drugs are rarely used. The incidence of severe reactions such as dermatitis, agranulocytosis, or hepatitis is higher for mephenytoin than for phenytoin. Mephenytoin is metabolized to 5-ethyl5-phenyl-hydantoin (nirvanol) via demethylation; nirvanol contributes most of the antiseizure activity of mephenytoin.
Gabapentin and pregabalin, known as “gabapentinoids,” are amino acid-like molecules that were originally synthesized as analogs of GABA but are now known not to act through GABA mechanisms. They are used in the treatment of focal seizures and various nonepilepsy indications, such as neuropathic pain, restless legs syndrome, and anxiety disorders.
Mechanism of Action
Despite their close structural resemblance to GABA, gabapentin and pregabalin do not act through effects on GABA receptors or any other mechanism related to GABA-mediated neurotransmission. Rather, gabapentinoids bind avidly to α2δ, a protein that serves as an auxiliary subunit of voltage-gated calcium channels but may also have other functions. The precise way in which binding of gabapentinoids to α2δ protects against seizures is not known but may relate to a decrease in glutamate release at excitatory synapses.
Gabapentin and pregabalin are effective in the treatment of focal seizures; there is no evidence that they are efficacious in generalized epilepsies. Indeed, gabapentin may aggravate absence seizures and myoclonic seizures. Gabapentin is usually started at a dose of 900 mg/d (in three divided doses), but starting doses as high as 3600 mg/d can be used if a rapid response is required. Some clinicians have found that even higher dosages are needed to achieve improvement in seizure control. The recommended starting dose of pregabalin is 150 mg/d, but a lower starting dose (50–75 mg/d) may avoid adverse effects that can occur on drug initiation; the effective maintenance dose range is 150 to 600 mg/d. Although comparative studies are lacking, gabapentinoids are generally considered less effective than other antiseizure drugs for the treatment of focal seizures. Gabapentinoids are frequently used in the treatment of neuropathic pain conditions, including postherpetic neuralgia and painful diabetic neuropathy, and in the treatment of anxiety disorders. Pregabalin is also approved for the treatment of fibromyalgia. Gabapentin and pregabalin are generally well tolerated. The most common adverse effects are somnolence, dizziness, ataxia, headache, and tremor. These adverse effects are most troublesome at initiation of therapy and often resolve with continued dosing. Both gabapentinoids can cause weight gain and peripheral edema.