Page 445 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 24 Antiseizure Drugs 431

DRUGS EFFECTIVE FOR DRAVET’S agents. The mechanism of action of ACTH and corticosteroids in
SYNDROME the treatment of infantile spasms is unknown.

Dravet’s syndrome (severe myoclonic epilepsy of infancy) is a rare VIGABATRIN
genetic epileptic encephalopathy characterized by diverse generalized
and focal seizure types, including myoclonic seizures, tonic-clonic Vigabatrin is an analog of GABA, designed as an inhibitor of
seizures, absence seizures, atonic seizures, and one-sided hemi- GABA transaminase (GABA-T), the enzyme responsible for the
convulsive and focal seizures. Mutations of the SCN1A gene encoding metabolism of synaptically released GABA. Vigabatrin is effective
Na 1.1 voltage-dependent sodium channels cause 79% of diagnosed in the treatment of focal seizures (but not generalized seizures) and
v
cases of Dravet’s syndrome. Although drugs such as clobazam, valpro- in the treatment of infantile spasms. Because it may cause irre-
ate, and topiramate are used, none of these is very effective. Stiripentol versible visual loss, it is usually reserved for patients with seizures
is not approved in the USA but is widely used in Europe. In patients refractory to other treatments.
with SCN1A gene mutations, sodium channel-blocking antiseizure
drugs are contraindicated because they worsen seizures. OH
H

STIRIPENTOL O CH 2
NH 2
Stiripentol is an aromatic allylic alcohol that has activity in the
treatment of Dravet’s syndrome. Clinical studies indicate that NH 2
it reduces the frequency of prolonged seizures in children with O CH 2
this condition. Stiripentol is often used in conjunction with
clobazam or valproate; whether it has activity by itself has not OH H
been studied in clinical trials. The drug has various actions on Vigabatrin enantiomers
GABA-mediated neurotransmission including acting as a positive
allosteric modulator of GABA receptors. It is a potent inhibitor
A
of CYP3A4, CYP1A2, and CYP2C19 and dramatically increases Mechanism of Action
the levels of clobazam and its active metabolite norclobazam; it Vigabatrin is a specific, irreversible inhibitor of GABA-T, pro-
also inhibits valproate metabolism. These drug-drug interactions ducing a sustained increase in the extracellular concentrations of
have been proposed as the basis for the clinical effectiveness of GABA in the brain. This paradoxically leads to inhibition of syn-
stiripentol, and elevations in concomitant drugs likely contribute aptic GABA receptor responses, but also prolongs the activation
A
to some extent to efficacy. However, stiripentol has activity in of extrasynaptic GABA receptors that mediate tonic inhibition.
A
various animal seizure models, indicating that it has antiseizure Vigabatrin is effective in a wide range of animal seizure models.
activity in its own right. Dosing is complex, typically beginning Vigabatrin is marketed as a racemate; the S(+) enantiomer is active
with a reduction in concomitant medications. Stiripentol is then and the R(−) enantiomer appears to be inactive.
started at 10 mg/kg/d and is increased gradually as tolerated. The
most frequent adverse effects are sedation/drowsiness, reduced Clinical Uses
appetite, slowing of mental function, ataxia, diplopia, nausea, and
abdominal pain. Stiripentol exhibits nonlinear pharmacokinetics, Vigabatrin is useful in the treatment of infantile spasms, especially
decreasing in clearance as the dose increases. when associated with tuberous sclerosis. The drug is also effective
against focal seizures. The half-life is approximately 6–8 hours,
but the pharmacodynamic activity of the drug is more prolonged
DRUGS EFFECTIVE FOR INFANTILE and not well correlated with the plasma half-life because recovery
SPASMS (WEST’S SYNDROME) from the drug requires synthesis of replacement GABA-T enzyme.
In infants, the dosage is 50–150 mg/kg/d. In adults, vigabatrin is
Infantile spasms are treated with adrenocorticotropic hormone started at an oral dosage of 500 mg twice daily; a total of 2–3 g/d
(ACTH) by intramuscular injection or oral corticosteroids such may be required for full effectiveness. The most important adverse
as prednisone or hydrocortisone. Vigabatrin is also often used and effect of vigabatrin is irreversible retinal dysfunction. Patients
is particularly effective in cases associated with tuberous sclerosis. may develop permanent bilateral concentric visual field constric-
Other antiseizure medications that may be helpful are valproate, tion that is often asymptomatic but can be disabling. Minimal
topiramate, zonisamide, or a benzodiazepine such as clonazepam evidence also suggests that vigabatrin also can damage the central
or nitrazepam. ACTH and corticosteroids are associated with retina. The onset of vision loss can occur within weeks of start-
substantial morbidity, and vigabatrin, as discussed below, has a ing treatment or after months or years. Other adverse effects are
risk of permanent loss of vision. The goal of treatment is cessation somnolence, headache, dizziness, and weight gain. Less common
of seizures, and this generally requires ACTH, corticosteroids, or but more troublesome adverse effects are agitation, confusion, and
vigabatrin and is not generally achieved with the safer antiseizure psychosis; preexisting mental illness is a relative contraindication.