Page 444 - Basic _ Clinical Pharmacology ( PDFDrive )

430 SECTION V Drugs That Act in the Central Nervous System

side effects, trimethadione and the related oxazolidinediones para- Norclobazam has antiseizure activity, although it is weaker than
methadione and dimethadione, the major metabolite of trimetha- clobazam. Nevertheless, because norclobazam levels are so much
dione, are now rarely used. higher at steady state, seizure protection during chronic therapy is
likely mainly due to norclobazam. Clobazam is a moderate inhibi-
DRUGS EFFECTIVE FOR tor of CYP2D6 and has been shown to significantly increase the
levels of drugs metabolized by this isoenzyme such as phenytoin
MYOCLONIC SEIZURES SUCH AS and carbamazepine. Reduced dosing may be required when these
IN THE SYNDROME OF JUVENILE antiseizure drugs are used in combination with clobazam.
MYOCLONIC EPILEPSY
RUFINAMIDE
Valproate is the drug of first choice for the treatment of myoclonic
seizures. Other drugs effective in the treatment of this seizure type Rufinamide is a triazole derivative identified by screening in
are levetiracetam, zonisamide, topiramate, and lamotrigine. animal seizure models. It is effective for atonic seizures in Lennox-
Gastaut syndrome, but there is also some evidence of efficacy in
DRUGS EFFECTIVE FOR ATONIC the treatment of focal seizures. In the USA and Europe, rufin-
SEIZURES SUCH AS IN THE amide is only approved for treatment of seizures associated with
the Lennox-Gastaut syndrome.
LENNOX-GASTAUT SYNDROME
F
Valproate in combination with lamotrigine and a benzodiazepine N
is the most widely used treatment for atonic seizures. Topiramate, N N
felbamate, and lamotrigine are used in the treatment of Lennox-
Gastaut syndrome; clinical trials have shown improvement in F NH
atonic seizures. The sodium channel-blocking antiseizure drugs O 2
phenobarbital and vigabatrin should be used with caution because Rufinamide
they may worsen atonic seizures. Clobazam and rufinamide, dis-
cussed in this section, are also used in the treatment of seizures
associated Lennox-Gastaut syndrome and have been demon- Mechanism of Action
strated in clinical trials to reduce the frequency of atonic seizures. In mice and rats, rufinamide is protective in the MES test and,
at higher doses, in the PTZ test. Its only known action that is
CLOBAZAM relevant to seizure protection is as a blocker of voltage-gated
sodium channels.
Clobazam is widely used for the treatment of focal seizures in
many countries, although it is not approved for that indication Clinical Uses
in the United States, where its only approved use is for treatment In the Lennox-Gastaut syndrome, rufinamide is effective against
of seizures associated with Lennox-Gastaut syndrome in patients all seizure types but especially against atonic seizures. Some clinical
2 years of age or older. Clobazam is a 1,5-benzodiazepine and data suggest it may be effective against focal seizures. Treatment in
structurally different from other marketed benzodiazepines, which children is typically started at 10 mg/kg/d in two equally divided
are 1,4-benzodiazepines. Like the 1,4-benzodiazepines, however, doses and gradually increased to 45 mg/kg/d to a maximum of
clobazam is a positive allosteric modulator of GABA receptors 3200 mg/d. Adults can begin with 400–800 mg/d in two equally
A
and has similar pharmacologic activities and adverse effects. In divided doses up to a maximum of 3200 mg/d as tolerated. The
addition, while tolerance occurs to clobazam in animal models drug should be given with food. The most common adverse events
within days to weeks of chronic administration, retrospective are somnolence and vomiting.
studies assessing the extent of tolerance in the clinical setting have
suggested that tolerance is not a prominent issue in clinical treat- Pharmacokinetics
ment. Side effects that occur in a dose-dependent fashion include
somnolence and sedation, dysarthria, drooling, and behavioral Rufinamide is well absorbed, and plasma concentrations peak
changes, including aggression. Withdrawal symptoms may occur between 4 and 6 hours. The half-life is 6–10 hours, and minimal
with abrupt discontinuation. Clobazam has a half-life of 18 hours plasma protein binding is observed. Although cytochrome P450
and is effective at dosages of 0.5–1 mg/kg/d. Clobazam is enzymes are not involved, the drug is extensively metabolized
metabolized in the liver by CYP and non-CYP transformations, to inactive products. Most of the drug is excreted in the urine;
with up to 14 metabolites; however, the major metabolite is des- an acid metabolite accounts for about two-thirds of the dose.
methylclobazam (norclobazam). With long-term administration Most drug-drug interactions are minor except that valproate may
of clobazam, levels of norclobazam, which has a longer half-life decrease the clearance of rufinamide; dosing with valproate, par-
than clobazam, are 8- to 20-times higher than those of the parent. ticularly in children, may need to be decreased, typically by 50%.