Page 431 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 24 Antiseizure Drugs 417

and phenobarbital, may decrease steady-state concentrations of eslicarbazepine but the conversion occurs more rapidly and it is
carbamazepine through enzyme induction. These interactions nearly completely to the S(+) form, with only a small amount of
may require dosing changes. No clinically significant protein- the R(−) isomer (5%) formed by chiral inversion. Whether there
binding interactions have been reported. is a benefit to the more selective conversion to S(+)-licarbazepine
is uncertain, especially since both enantiomers act similarly on
Adverse Effects voltage-gated sodium channels. The effective half-life of S(+)-
licarbazepine following oral administration of eslicarbazepine
Carbamazepine may cause dose-dependent mild gastrointestinal acetate is 20–24 hours so the prodrug can be administered once
discomfort, dizziness, blurred vision, diplopia, or ataxia; sedation daily, which is a potential advantage. The drug is administered at
occurs only at high doses, and rarely, weight gain can occur. The a dosage of 400–1600 mg/d; titration is typically required for the
diplopia often occurs first and may last less than an hour during higher doses. S(+)-Licarbazepine is eliminated primarily by renal
a particular time of day. Rearrangement of the divided daily dose excretion; dose adjustment is therefore required for patients with
can often remedy this complaint. A benign leukopenia occurs in renal impairment. Minimal pharmacokinetic effects are observed
many patients, but there is usually no need for intervention unless with coadministration of carbamazepine, levetiracetam, lamotrig-
3
neutrophil count falls below 1000/mm . Rash and hyponatremia ine, topiramate, and valproate. The dose of phenytoin may need
are the most common reasons for discontinuation. Stevens- to be decreased if used concomitantly with eslicarbazepine acetate.
Johnson syndrome is rare, but the risk is significantly higher in Oral contraceptives may be less effective with concomitant eslicar-
patients with the HLA-B*1502 allele. It is recommended that bazepine acetate administration.
Asians, who have a 10-fold higher incidence of carbamazepine-
induced Stevens-Johnson syndrome compared to other ethnic
groups, be tested before starting the drug. LACOSAMIDE

OXCARBAZEPINE OCH 3
O H
Oxcarbazepine is the 10-keto analog of carbamazepine. Unlike NH
3
carbamazepine, it cannot form an epoxide metabolite. Although H C NH
it has been hypothesized that the epoxide is associated with carba- O
mazepine’s adverse effects, little evidence is available to document Lacosamide
the claim that oxcarbazepine is better tolerated. Oxcarbazepine
is thought to protect against seizures by blocking voltage-gated Lacosamide is a sodium channel-blocking antiseizure drug
sodium channels in the same way as carbamazepine. Oxcarbaze- approved for the treatment of focal seizures. It has favorable phar-
pine itself has a half-life of only 1–2 hours; its antiseizure activity macokinetic properties and good tolerability. The drug is widely
resides almost exclusively in the active 10-hydroxy metabolites, prescribed.
S(+)- and R(–)-licarbazepine (also referred to as monohydroxy
derivatives or MHDs), to which oxcarbazepine is rapidly con-
verted and both of which have half-lives similar to that of car- Mechanism of Action
bamazepine (8–12 hours). The bulk (80%) of oxcarbazepine is Early studies suggested that lacosamide enhances a poorly
converted to the S(+) form. The drug is mostly excreted as the understood type of sodium channel inactivation called slow
glucuronide of the 10-hydroxy metabolite. inactivation. Recent studies, however, contradict this view and
Oxcarbazepine is less potent than carbamazepine, both in animal indicate that the drug binds selectively to the fast inactivated
tests and in patients; clinical doses of oxcarbazepine may need to state of sodium channels—as is the case for other sodium
be 50% higher than those of carbamazepine to obtain equivalent channel-blocking antiseizure drugs, except that the binding is
seizure control. Some studies report fewer hypersensitivity reactions much slower.
to oxcarbazepine, and cross-reactivity with carbamazepine does
not always occur. Furthermore, the drug appears to induce hepatic Clinical Uses
enzymes to a lesser extent than carbamazepine, minimizing drug
interactions. Although hyponatremia may occur more commonly Lacosamide is approved for the treatment of focal onset seizures
with oxcarbazepine than with carbamazepine, most adverse effects in patients age 17 years and older. In clinical trials with more than
of oxcarbazepine are similar to those of carbamazepine. 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
ESLICARBAZEPINE ACETATE 400 and 600 mg/d, the higher dose may provide better control
of focal-to-bilateral tonic-clonic (secondarily generalized) seizures;
Eslicarbazepine acetate, a prodrug of S(+)-licarbazepine, pro- however, this dose is associated with a greater incidence of adverse
vides an alternative to oxcarbazepine, with some minor differ- effects. Adverse effects include dizziness, headache, nausea, and
ences. Like oxcarbazepine, eslicarbazepine acetate is converted to diplopia. The drug is typically administered twice daily, beginning