Valproate

The oxa2ohdinedione trimethadione [127-48-0] C H NO (50), at one time the dmg of choice for the treatment of absence sei2ures, has been replaced by ethosuximide (41) and valproate (49). (50) has a distinct profile from that of phenytoin but causes photophobia and night blindness in approximately 30% of the patients taking it and has the CNS and sedative properties seen for other anticonvulsants together with moderate neutropenia, hepatitis, and skin rashes (13). Trimethadione does not appear to produce its effects via modulation of GABA-mediated responses. 

Martin, M.L. Regan, C.M. (1988). The anticonvulsant sodium valproate specifically induces the expression of a rat glial heat shock protein which is identified as the collagen type IV receptor. Brain Res. 459, 131-137. 

The first mood stabilizer was lithium (its antimanic action being discovered in 1948) more recently the anticonvulsant drugs carbamazepine and valproate have been found to be effective in acute mania. Unfortunately these mood stabilizers are only successful in controlling mania to a limited extent and few patients are well enough to leave hospital at the end of 3 weeks of treatment using these drugs as monotherapy. It is increasingly common for combination treatment to be advocated, in which an antipsychotic dmg is combined with lithium or an anticonvulsant. 

In the case of carbamazepine the evidence suggests that its prophylactic efficacy is less than that of lithium (Greil and Kleindienst, 1999). For valproate there is no placebo-controlled evidence as yet to support its efficacy in the prophylaxis of bipolar disorder. The only large-scale study designed to elucidate this action was a failed trial in which neither lithium nor valproate was more effective than placebo in maintenance treatment over 2 years (Bowden et al, 2000). 

The total costs are likely to reflect the efficacy of treatment. In one industry-sponsored study (Keck et al, 1996b) treatment with lithium or valproate was compared in relation to classical, mixed and rapid-cycling disorder. Treatment with lithium was associated with lower costs than treatment with valproate for classical bipolar disorder, but treatment with valproate was associated with lower costs than treatment with lithium for mixed and rapid-cycling disorders. This is in keeping with the evidence that valproate is more effective than lithium for certain patients with rapid-cycling disorder and probably also for certain patients with mixed affective states. However, these associations are a guide to predicting response to treatment but are not very specific. 

The evidence base for clinical decisions based on cost-effectiveness for the affective disorders is less clear than for schizophrenia. In bipolar disorder the primary effectiveness of the mainstay treatments, lithium and anticonvulsant pharmacotherapy, is undergoing considerable revision (Bowden et al, 2000). Until this is clarified, cost-effectiveness studies are probably premature. Nevertheless the cost burden in bipolar disorder is qualitatively similar to that in schizophrenia, with in-patient costs being the primary burden and associated social costs in treated patients. The drug costs are even less than those for schizophrenia. In Chapter 5 John Cookson suggests there is little economic evidence to drive prescribing decisions. The in-patient burden does not seem to have altered with the introduction of lithium. The only drug-related study (Keck et al, 1996) showed an obvious difference in treatment costs only when lithium was compared with sodium valproate. Since these are both cheap drugs this is unlikely to influence clinical decisions. The main question is what impact... 

Sodium valproate GM PM 6 also 1 Inhibition of GABA metabolism... 

Introduced initially for absence seizures, this drug is now known to be effective in and used to treat tonic lonic seizures and most types of epilepsy. It was found to inhibit GABA transaminase and so elevate GABA concentrations and inhibition. This is achieved, however, over a slower time-course than its anti-seizure effect, especially experimentally, which is now thought to be due to its phenytoin-like, use-dependent block of sodium channels. Since, unlike phenytoin, the full effect of valproate takes some weeks to develop, its slower effect on GABA metabolism and activity should not be ignored. 

Newer AEDs do have some advantages in that they tend to have fewer effects on the metabolism of each other or other drugs. By contrast, phenobarbitone is one of the most potent inducers of the microsomal enzyme system (cytochrone T 450) responsible for the metabolism of drugs. Phenytoin and carbamazepine have a similar but less marked effect while valproate inhibits the system. 

Some AEDs, especially phenytoin and valproate, are highly bound to plasma proteins. When interpreting a reported concentration for these drugs, it is important to remember that the value represents the total (i.e., bound and unbound) concentration in the blood. Because of differences in the metabolism of these drugs, the clinical effects of altered protein binding are different for different drugs. 

When valproate protein binding is altered, the risk for severe dose-related adverse effects is much less compared to phenytoin. Michaelis-Menten metabolism is not a factor with valproate, so hepatic enzymes are able to efficiently metabolize the additional unbound portion. 

Outside of the evidence-based guidelines, other pharmacologic treatments are commonly used or avoided. For initial treatment of absence seizures, ethosuximide and valproate are commonly used, not only in the United Kingdom, but also in the United States. Zonisamide may be also used for initial treatment of absence and myoclonic seizures. In absence and myoclonic seizures, carbamazepine, oxcarbazepine, gabapentin, tiagabine, and pregabalin should be avoided, as they have been associated with an exacerbation of these types of seizures. 

Myoclonic Not mentioned Lamotrigine Valproate Valproate Topiramate (children with severe myoclonic epilepsy of infancy) Second-line Clobazam6 Clonazepam Lamotrigine Levetiracetam Piracetam6 Topiramate... 

Phenobarbital Phenytoin Topiramate Valproate Oxcarbazepine Topiramate Second-line Clobazam6 Gabapentin Levetiracetam Phenytoin Tiagabine... 

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