Oxcarbazepine Chemische Eigenschaften,Einsatz,Produktion Methoden
Beschreibung
Oxcarbazepine is a new antiepileptic carbamazepine derivative, reportedly better
tolerated than carbamazepine. It appears to be most effective in partial epilepsy with
complex seizures.
Chemische Eigenschaften
Pale Yellow Powder
Verwenden
Oxcarbazepine is a sodium channel protein inhibitor. It is an anticonvulsant and mood-stab.
Definition
ChEBI: A dibenzoazepine derivative, having a carbamoyl group at the ring nitrogen, substituted with an oxo group at C-4 of the azepeine ring which is also hydrogenated at C-4 and C-5. It is a anticholinergic anticonvulsant and mood stabilizing drug, used primaril
in the treatment of epilepsy.
Biologische Funktion
Oxcarbazepine is chemically and pharmacologically
closely related to carbamazepine, but it has much less
capacity to induce drug-metabolizing enzymes. This
property decreases the problems associated with drug
interactions when oxcarbazepine is used in combination
with other drugs. The clinical uses and adverse effect
profile of oxcarbazepine appear to be similar to those of
carbamazepine.
Allgemeine Beschreibung
Oxcarbazepine, marketed under the trade name Trileptal
?, is an anticonvulsant developed and prescribed for treatment of epilepsy. In recent years, Oxcarbazepine has shown efficacy in treatment of mood disorders. This certified solution standard is suitable as starting material for the preparation of calibrators and controls in oxcarbazepine testing by GC/MS or LC-MS/MS.
Biologische Aktivität
Anticonvulsant; protects mice and rats against generalized tonic-clonic seizures induced by electroshock. Thought to act via inhibition of sodium channel activity.
Mechanism of action
Although oxcarbazepine is less potent that CBZ, its mechanism of action is similar. The majority of the pharmacological
activity for oxcarbazepine is attributed to its primary metabolite, 10-monohydroxycarbazepine (MHD), the plasma
levels of which may be ninefold higher than those for CBZ. Both oxcarbazepine and MHD produce a blockade of voltagedependent sodium channels, thus decreasing repetitive firing and spread of electrical activity. An additional action on calcium and potassium channels may contribute to the therapeutic effect. Like carbamazepine, oxcarbazepine may worsen juvenile
myoclonic or absence seizures.
Pharmakokinetik
Oxcarbazepine is completely absorbed, and food has no effect on its absorption. Unlike CBZ, it does not cause autoinduction of
its own metabolism. The metabolism of oxcarbazepine is different from that of CBZ. Oxcarbazepine is reduced by cytosolic
enzymes to MHD before its O-glucuronidation. More than 95% of its oral dose is excreted as conjugated metabolites, with
approximately 4% of the drug converted to inactive 10,11-dihydroxy CBZ. Unlike CBZ, no epoxide nor aromatic hydroxylation
metabolites are formed. The half-life is 2 hours for oxcarbazepine and 9 hours for the active 10-monohydroxy metabolite. In
patients with impaired renal function, the half-life for MHD is prolonged to 19 hours, with a doubling in its area under the
plasma concentration curve. Peak plasma concentration following an oral dose occurs at approximately 4.5 hours.
Oxcarbazepine induces CYP3A4/5 and UTP, and it also inhibits CYP2C19, producing significant effects on the plasma
concentration of other drugs. Therefore, oxcarbazepine decreases felodipine bioavailability and lowers plasma levels for
lamotrigine, CBZ, CBZ epoxide, calcium channel blockers, and oral contraceptives. Oxcarbazepine increases plasma levels
of phenobarbital and phenytoin. Unlike carbamazepine, oxcarbazepine has no effect on plasma levels of risperidone or
olanzepine. The plasma levels for oxcarbazepine or MHD are decreased by CBZ, phenobarbital, phenytoin, valproate,
and verapamil. Serum MHD may decrease during pregnancy but increase following delivery. Oxcarbazepine clearance is
decreased in renal impairment and the elderly. In children, a higher dose/kg for oxcarbazepine than in adults is required to
obtain an effective plasma concentration.
Clinical Use
Oxcarbazepine (Trileptal?) is the 10-keto analogue of carbamazepine. It is indicated as monotherapy or adjunctive
therapy for partial seizures in adults with epilepsy, as monotherapy for the treatment of partial seizures in children 4 years of
age or older, and as adjunct therapy in children 2 to 4 years of age.
Nebenwirkungen
Patients with hypersensitivity reactions to carbamazepine can be expected to show cross-sensitivity (e.g., rash) or related
problems to oxcarbazepine. The improved toxicity profile for oxcarbazepine when compared to CBZ may result from absence of
the epoxide or CBZ-iminoquinone metabolites. The most common side effects are headache, dizziness, nystagmus, blurred
vision, somnolence, nausea, ataxia, and fatigue. The incidence of adverse effects has been related to elevated serum MHD
concentrations. Adverse effects on cognitive status, hyponatremia, and serious dermatological reactions have been
reported, as has hyponatremia.
Synthese
Oxcarbazepine can be obtained in two different ways.
1) Reaction of 10-methoxy-5H-dibenz[b,f]azepine (1) with phosgene gives the 5- chlorocarbonyl compound, treatment with NH3 affords 10-methoxy-5H-dibenz[b,f ]azepine-5-carboxamide (2), which is hydrolyzed with diluted HCl to oxcarbazepine.
2) Nitration of 5-cyano-5H-dibenz[b,f ]azepine (3) with NaNO3 in acetic anhydride/acetic acid gives 5-cyano-10-nitro-5H-dibenz[b,f ]azepine (4), which is treated with BF3 and powdered iron in acetic acid.
Oxcarbazepine Upstream-Materialien And Downstream Produkte
Upstream-Materialien
Downstream Produkte
