Epilepsy valproic acid

As with several other AEDs, it is difficult to ascribe a single mechanism of action to valproic acid. This compound has broad anticonvulsant activity, both in experimental studies and in the therapeutic management of human epilepsy. Valproic acid has been shown to block voltage-dependent sodium channels at therapeutically relevant concentrations. In several experimental studies, valproate caused an increase in brain GABA the mechanism was unclear. There is evidence that valproate... 

Phenobarbitone was the first AED and was introduced in 1912. It was largely replaced in 1932 by phenytoin for the management of tonic-xilonic seizures and partial and secondary epilepsy. Carbamazepine followed, then ethosuximide for absence seizures and valproic acid. These remained, apart from the introduction of the benzodiazepines, the mainstay of therapy until the last decade. They were introduced solely on their ability to control experimentally induced seizures. Their mechanisms of action were unknown and no thought was given to the possibility of NT modification and in fact subsequent research has shown that with the exception of the benzodiazepines none of them work primarily through NT manipulation. They act directly on neuronal excitability. 

Epilepsy is a clinical disorder characterized by spontaneous, recurrent seizures arising from excessive electrical activity in certain parts of the brain [51]. Currently available drugs, such as phenytoin, carbamazepine, valproic acid, lamotrigine, and topiramate (for molecular structures see Fig. 6), provide symptomatic seizure suppression in only 60-70% of those receiving treatment [52-54]. These drugs are also associated with unwanted side... 

Valproic acid (dipropylacetic acid) is a single branched chain carboxylic acid that is structurally unlike any of the other drugs used in the treatment of bipolar disorder or epilepsy. The amide derivative, valproamide, is available in Europe as a more potent form of valproate. Valproate was first developed in Erance as an antiepileptic agent in 1963. As an antiepileptic agent, it was shown to be active against a variety of epilepsies without causing marked sedation. 

Valproic acid, like the succinimides, is nsed for epilepsy in the absence of attacks, but its clinical efficacy exceeds that of the succinimides. 

Valproic acid has become a major AED against several seizure types. It is highly effective against absence seizures and myoclonic seizures. In addition, valproic acid can be used either alone or in combination with other drugs for the treatment of generalized tonic-clonic epilepsy and for partial seizures with complex symptoms. 

Convulsions associated with fever often occur in children 3 months to 5 years of age. Epilepsy later develops in approximately 2 to 3% of children who exhibit one or more such febrile seizures. Most authorities now recommend prophylactic treatment with anticonvulsant drugs only to patients at highest risk for development of epilepsy and for those who have multiple recurrent febrile seizures. Phenobarbital is the usual drug, although diazepam is also effective. Phenytoin and carba-mazepine are ineffective, and valproic acid may cause hepatotoxicity in very young patients. 

Birnbaum AK, Hardie NA, Conway IM, et at Valproic acid doses, concentrations, and clearances in elderly nursing home residents. Epilepsy Res 2004 62 157-162. 

Davis, R., Peters, D.H., and McTavish, D. (1994) Valproic acid. A reappraisal of its pharmacological properties and clinical efficacy in epilepsy. Drugs 47 332-372. 

Tanindi, S., Akin, R., Koseoglu, V., Kurekci, A.E., Gokcay, E., and Ozcan, O. (1996) The platelet aggregation in children with epilepsy receiving valproic acid. Thromb Res 8L471-476. 

Kastner et al. (1993) evaluated valproic acid in 18 children and adults (mean age, 19.7 years) with self-injury or aggression, irritability, sleep disorder, and evidence of cycling. Fourteen (78%) responded positively as assessed by the CGI in this uncontrolled study. The authors found that 11 subjects with established or suspected epilepsy responded significantly better than participants with no evidence of epilepsy. 

The discovery of benzodiazepines is a story of serendipity and certainly one that is difficult to predictably reproduce as part of a drug discovery program. Regrettably (or fortuitously), this story of the benzodiazepines is not an isolated example. Valproic acid, an agent used to treat epilepsy, migraine, chronic pain, and bipolar affective disorder, was also discovered by accident. 

Luef G, Abraham I, Haslinger M, Trinka E, Seppi K, Unterberger I, Alge A, Windisch J, Lechleitner M, Bauer G. Polycystic ovaries, obesity and insulin resistance in women with epilepsy. A comparative study of carba-mazepine and valproic acid in 105 women. J Neurol 2002 249(7) 835-41. 

Wirrell EC. Valproic acid-associated weight gain in older children and teens with epilepsy. Pediatr Neurol 2003 28 126-9. 

Valproic acid (Depakene, Depakote, other trade names) is classified as a carboxylic acid, and is used primarily to treat absence seizures or as a secondary agent in generalized tonic-clonic forms of epilepsy. This drug is also used to treat bipolar disorder (manic-depression), especially during the acute manic phase (see Chapter 7). 

The effects of concomitant carbamazepine, phenytoin, sodium valproate, and zonisamide on the steady-state serum concentrations of clonazepam have been investigated in 51 epileptic in-patients under 20 years of age (14). Serum concentrations of clonazepam correlated positively with the dose of clonazepam and negatively with the doses of carbamazepine and valproic acid, but not with phenytoin or zonisamide. These results confirm that as the oral doses of carbamazepine and sodium valproate increase, the serum concentration of clonazepam falls, but there is no interaction with either phenytoin or zonisamide. In the case of carbamazepine the mechanism of action is thought to be enzyme induction, increasing the metabolism of clonazepam. It is not known what the mechanism is with sodium valproate. In patients with epilepsy, the co-administration of either sodium valproate or carbamazepine will reduce the serum concentration of clonazepam and increase the risk of a seizure. When... 

A comparison of social skills in individuals with intellectual disability and epilepsy treated with carbamazepine, valproic acid, and phenytoin showed less positive social skills in those who received phenytoin (30). 

Other drugs are also used for the treatment of epilepsy, phenytoin, 59, carbomazepine, 60, and valproic acid, 61 are well-known anticonvulsants. 

Low bone density leads to an increased risk of fractures. There was a 30% increased risk of non-seizure-related fractures in 348 non-institutionalized patients with epilepsy compared with a large control population (129). For non-seizure-related fractures the crude fracture rate was 1.6 fractures per 100 patient-years of observation a similar rate (1.4) has been found in men with epilepsy (122). In addition, in children with epilepsy, treatment with valproic acid and/or lamotrigine for more than... 

Morris RG, Black AB, Lam E, Westley IS. Clinical study of lamotrigine and valproic acid in patients with epilepsy using a drug interaction to advantage Ther Drug Monit 2000 22(6) 656-60. 

Cisplatin caused subtherapeutic carbamazepine and valproic acid concentrations in a 38-year-old woman with epilepsy undergoing cytotoxic cancer chemotherapy with doxorubicin and cisplatin, resulting in tonic-clonic seizures the mechanism was not clear (266). 

A child with developmental delay and epilepsy developed glycosuria about 16 months after starting to take valproic acid (90). Laboratory evaluation showed global defects in proximal tubule function, consistent with the De Toni-Debre-Fanconi syndrome. The authors reviewed the literature on this rare complication, which is reversible on valproate withdrawal. 

Coulter DL, Wu H, Allen RJ. Valproic acid therapy in childhood epilepsy. JAMA 1980 244(8) 785-8. 

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