R. Pinder, R. N. Brogden, T. Speight
Feb 1, 1977
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Influential Citations
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Drugs
Abstract
SummarySodium valproate1 has a broad spectrum of anticonvulsant activity, but is structurally unrelated to conventional antiepileptic drugs. Its proposed mode of action is mediated through effects on the function of brain γ-aminobutyric acid (GABA). However, the elevations in brain and cerebellar GABA, and the concomitant reductions in levels of cyclic guanosine monophosphate, occur in animals at dose levels which are unlikely to be achieved during the treatment of epileptic patients. Pharmacodynamic studies have shown that sodium valproate does not affect the autonomic nervous system, and it lacks significant cardiovascular, renal or respiratory effects. Its effects on the EEG are uncertain, but it does seem to reduce or abolish spike-and-wave activity consistently in epileptic patients. Sodium valproate may have an intrinsic hypnotic action, for a controlled trial in normal subjects has shown the drug to be significantly more sedative than placebo and additive with phenobarbitone. In clinical practice, however, the drug seems to produce increased awareness and alertness in many epileptic patients, possibly as a result of the reduced dosage of other antiepileptic drugs with sedative side-effects although the same effect is also noticed in patients who are on sodium valproate alone. Sodium valproate had no psychotropic properties during a controlled trial in patients with aggressive behavioural problems. Pharmacokinetic studies: Sodium valproate is rapidly absorbed after oral administration, reaching peak blood levels within 1 to 4 hours. A good correlation has not yet been established between daily dose, plasma levels and therapeutic effects, due, among other reasons, to wide interindividual variations. The serum half-life is about 7 to 9 hours, but may be longer in cases of overdosage and shorter in epileptic patients receiving long-term therapy with some other antiepileptic drugs. Therapeutic blood levels appear to be about 50 to 100µg/ml in most patients, associated with an adult daily dose of 1,200 to 1,500mg. Delayed-release forms of dipropylacetic acid may offer some advantages in terms of smoothing out fluctuations in inter-dose serum levels, but have to be administered with care due to large individual variations in release. Sodium valproate is rapidly distributed, reaching the brain of animals in a few minutes, but it is likely that most of the drug, which is strongly bound (90%) to human plasma proteins, is restricted to the circulation and rapidly exchangeable extracellular water. The white matter is reached at a later period. Placental transfer occurs, and the drug produces dysmorphogenic effects in animals. Elimination is rapid, principally in the urine with minor amounts in the faeces and expired air. Renal excretion of unchanged sodium valproate is very small, and animal and human studies suggest that it is metabolised rapidly to a glucuronide conjugate and to products of omega-side-chain oxidation. Therapeutic trials: There are few controlled trials of sodium valproate in the treatment of epilepsy, and evidence of its efficacy comes mainly from open studies. In general, the drug has been given to patients already receiving but usually refractory to other antiepileptic medication, which in some cases has been subsequently reduced in dosage or withdrawn completely. Sodium valproate raises the plasma levels of other antiepileptic drugs, particularly phenobarbitone and primidone, though long-term studies have suggested that these levels may return to normal if treatment is continued. Nevertheless, sodium valproate is effective alone in many patients, either as the drug first used in treatment or as a gradual replacement for previously ineffective medication. There is little evidence for the development of tolerance to its antiepileptic effects in long-term studies.Controlled trials have shown that sodium valproate is significantly superior to placebo when added to the previous antiepileptic medication of patients with various types of epilepsy. In one trial, the drug was indistinguishable from ethosuximide when either drug was given alone or added to other antiepileptic drugs in children with typical absence seizures. Sodium valproate is more effective in the generalised than in the partial epilepsies, and is particularly effective in patients with 3 cycle per second spike-and-wave discharges in the EEG. It may play a useful role in the management of grand mal, mixed grand mal and petit mal, drug-refractory temporal lobe epilepsy, and myoclonic epilepsy. In new patients with typical absence seizures, sodium valproate may become the drug of first choice. Its relative lack of sedative effects leaves intellectual performance unimpaired, which is important in childhood epilepsy. Infantile spasms and the Lennox-Gastaut syndrome respond somewhat less effectively to sodium valproate than they do to the benzodiazepines, though sodium valproate is more effective in myoclonic epilepsy where it may be combined with nitrazepam but not clonazepam. The drug may have a role in the prophylaxis of febrile convulsions. Side-effects: Sodium valproate is remarkably free of side-effects, in the general context of antiepileptic drugs. Gastrointestinal effects (nausea, vomiting, abdominal cramp, diarrhoea) are the most commonly reported reactions, occurring in about 9 to 16 % of adults and about 22% of children. These effects have usually been transient and have only rarely required withdrawal of drug. CNS effects include transient drowsiness and sedation, which can usually be corrected by a reduction in the dosage of other antiepileptic drugs given to the patient and may not therefore be strictly attributable to sodium valproate. Both increased and decreased appetite, with appropriate changes in weight, may occur, and there may be a temporary loss of hair in some patients. Patients receiving sodium valproate, particularly children already on barbiturates, may show worsened behaviour with aggressiveness and hyperactivity which usually disappears on withdrawal of the barbiturate. However, most patients tend to feel more lively and alert. Sodium valproate inhibits the secondary phase of blood platelet aggregation, and this has been reflected in some isolated cases, mainly in children, of prolonged bleeding times and thrombocytopenia. Precautions: There are no specific contra-indications to sodium valproate, and there have been no reports of significant hepatic, cardiac or renal abnormalities attributable to the drug. It has been shown to be dysmorphogenic in animals (but no more so than phenytoin) and it probably should be used in women of child-bearing age only in severe cases of epilepsy or in those who are resistant to other treatment, though this is a matter for clinical judgement. There are no reports of dysmorphogenic effects in humans. Introduction of sodium valproate to existing medication may require concomitant reduction in the dosage of other drugs, especially phenobarbitone and primidone, due to the possibility of raised plasma levels and enhanced sedative effects. Sodium valproate may potentiate the effects of MAO inhibitors and thymoleptics, the dosages of which should be reduced accordingly. Caution should be exercised when the drug is administered with others that may affect blood coagulation or when surgery is contemplated in epileptic patients. Sodium valproate is partly eliminated in the form of ketone bodies, which may result in false positives when testing the urine of diabetic patients. Dosage: Sodium valproate may be introduced alone or added to existing medication, but dosage is individual. Treatment should begin with 600mg daily in divided doses, increasing by 200mg daily at 3-day intervals until control is achieved. This is generally within the range 1,000 to 1,600mg daily. If adequate control has not been achieved after two weeks, the dose may be further increased by stages to a maximum of 2,600mg daily, though some severe cases may require doses in excess of this recommended maximum. An alternative drug may be gradually substituted, initially at low dosage, though combination therapy should be considered only if individual drugs fail to produce adequate control. The same pattern of introduction of sodium valproate should be followed in patients already receiving other antiepileptic drugs. If increased sedation is observed, dosages of barbiturates or other drugs should be reduced as sodium valproate is increased. The dosage of both should be adjusted during the stabilisation period to give optimum control at the lowest combined dosage level. In some cases it may be possible to withdraw other medication entirely, allowing optimum control with sodium valproate alone. Initial dosage in children over 20kg should be 400mg/day irrespective of weight, in divided doses, with spaced increases until control is achieved. This is usually within the range of 20 to 30mg/kg of body weight per day. Children under 20kg and infants should be given 20mg/kg of body weight per day; in severe cases up to 50mg/kg/day. A dose of 50mg/kg should be exceeded only in patients in whom plasma levels are measured; plasma levels of 200μg/ml should be exceeded only with caution, and with monitoring of haematological function.