Oxcarbazepine

Abstract

Summary:The success of carbamazepine (,CBZ) as a broadspectrum antiepileptic drug (AED) has led to its use as first-line therapy in children and adults for partial and generalized tonicclonic seizures. The limitations of CBZ include toxicity in sensitive individuals, autoinduction, which requires dose adjustment when therapy is initiated, and chronic hepatic induction, producing drug interactions when CBZ is used with AEDs and other drugs that undergo hepatic metabolism. One of two main products of CBZ microsomal metabolism, CBZ-I 0,ll -epoxide (formed by oxidation of the double bond between C-10 and C-1 l), appears to provide antiepileptic efficacy but contributes significantly to clinical toxicity. The most common adverse effects of CBZ are central nervous system (CNS) symptoms, followed by gastrointestinal, hepatic, endocrine disturbances, and teratogenic effects. Oxcarbazepine (OXC) was developed to provide a compound chemically similar enough to CBZ to mimic its efficacy and overall safety while improving its side- PHARMACOLOGY ChemistryOxcarbazepine (OXC, 10,11 -dihydro-10-0x0-carbamazepine) is a keto analogue of carbamazepine (CBZ). Like CBZ, it has a dibenzazepine nucleus bearing the 5-carboxamide substituent but is structurally different in the 10,11-position (Fig. 1). OXC is a neutral lipophilic compound with very low aqueous solubility. In humans, OXC is almost immediately converted to the main active metabolite, a 10-monohydroxy derivative, 10,ll ,dihydro-lO-hydroxy-5H-dibenzo( b,flazepine-5-carboxamide (MHD). Mechanism of actionBecause OXC is similar to CBZ in chemical structure and efficacy in animal models, the pharmacologic mechanisms of action may be similar. Inhibition of sustained, high-frequency, repetitive firing of voltagesensitive sodium action potentials has been investigated using intracellular recordings of spinal cord neurons in cell culture. Both MHD and OXC (EC,, = 2-5 x M, respectively) limited repetitive neuronal firing elicited by intracellularly applied depolarizing currents at stable membrane potentials (Em -49 to -55 mV) (1-3). These effects were seen at concentrations much lower than plasma concentrations in patients treated with OXC. Furthermore, the limitation of repetitive firing was found to be frequency-dependent. The V,,, of the neuronal action potentials decreased with successive firing rates, and the percent of stimuli that elicited action potentials decreased significantly as the frequency was increased from 1 to 100 Hz in the presence of M OXC or MHD. These results suggest that blockade of voltagesensitive sodium channels could contribute to the antiepileptic efficacy of OXC and MHD.Blockade of penicillin-induced bursts in hippocampal slices has also been investigated as a measure of antiepileptic efficacy through an effect on potassium channels. MHD was shown to reduce the discharge frequency, and the effect was antagonized by co-application of 4-aminopyridine, a potassium channel blocker ( 1).Thus, MHD appears to have an additional effect on the potassium-dependen...

Lack of Pharmacokinetic Interaction between Oxcarbazepine and Lamotrigine

“…Conversely, oxcarbazepine is generally regarded as a weak enzyme-inducer (Tecoma, 1999); and its effects on lamotrigine pharmacokinetics are largely unknown. Two reports indicate that induction of glucuronidation pathways by oxcarbazepine may affect the metabolism of lamotrigine (May et al, 1999;Kramer et al, 2003) and another describes higher MHD concentrations in the presence of lamotrigine compared to oxcarbazepine monotherapy (Guenault et al, 2003).…”

Treatment of epilepsy: existing therapies and future developments

“…Oxcarbazepine (10,11-dihydro-10-oxo-5H-dibenz(b,f)azepine-5-carboxamide; Figure 5) reportedly has equivalent efficacy to its structural analog carbamazepine, its tolerability is at least equal to that of other AEDs (373,374), and it is less toxic than carbamazepine (375). It can be considered a prodrug, being rapidly metabolized to a hydroxyl derivative.…”

Sodium Channel Blockers for the Treatment of Neuropathic Pain

“…For example, oxcarbazepine, a carbamazepine derivative, is also a sodium channel blocker, and it was developed to retain the anticonvulsant efficacy of carbamazepine while avoiding the hepatic enzyme induction believed to be associated with an epoxide metabolite. 37,38 Oxcarbazepine has given positive results in two controlled, painful diabetic neuropathy trials, as well as a number of open label studies. 39,40 Similarly, lamotrigine, whose pharmacology includes NMDA receptor antagonism, as well as sodium channel blockade, has been efficacious in painful diabetic neuropathy, central poststroke pain, HIV-related painful neuropathy, and in spinal cord injury patients with incomplete (but not complete) transections.…”