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====== Valproate ====== | ====== Valproate ====== | ||
+ | Valproic acid (2-propyl pentanoic acid, 2-propyl valeric acid) is a short-chain branched fatty acid. Prior to the serendipitous discovery of its anti-epileptic activity in 1963, valproic acid was used as an organic solvent[(: | ||
+ | ===== Authorised indications ===== | ||
+ | UK-SmPC: In the treatment of generalized, | ||
+ | FDA-PI: (1) monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures that occur either in isolation or in association with other types of seizures and (2) use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types which include absence seizures. | ||
+ | |||
+ | Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized epileptic discharges without other detectable clinical signs. Complex absence is the term used when other signs are also present. | ||
+ | |||
+ | Valproate sodium injection is indicated as an intravenous alternative in patients for whom oral administration of valproate products is temporarily not feasible. | ||
+ | ===== Clinical applications ===== | ||
+ | * Valproate is one of the most effective broad-spectrum AEDs for all types of seizures and epilepsies | ||
+ | * It has superior efficacy in all types of generalised seizures (idiopathic and symptomatic), | ||
+ | * However, valproate is far inferior to carbamazepine and some newer AEDs in the treatment of focal epilepsies | ||
+ | * valproate has serious ADRs in women of child-bearing age and in patients of early childhood. | ||
+ | * Unlike many other AEDs, valproate appears to have a very low potential to aggravate seizures[(: | ||
+ | ==== Dosage and titration ==== | ||
+ | **Adults:** start treatment with 200 mg/day in two equally divided doses for 3 days. Titrate in increments of 200 mg/day every 3 days to a maintenance dose of usually 1000–1500 mg/day (maximum 3000 mg/day) given in two equally divided doses. Higher initial dosage and faster titration rates are usually well tolerated. | ||
+ | |||
+ | **Children: | ||
+ | |||
+ | **Combined therapy:** it may be necessary to increase the dose by 30–50% when used in combination with enzymeinducing AEDs, such as phenytoin, phenobarbital and carbamazepine. On withdrawal of these AEDs, it may be possible to reduce the dose of valproate. | ||
+ | |||
+ | **Dosing:** twice or three-times daily, and once daily for slow-release formulations. | ||
+ | |||
+ | **TDM:** often not useful, because of poor correlation between valproate dose and plasma levels. However, because of significant drug interactions, | ||
+ | |||
+ | Reference range (measures valproic acid): 50–100 mg/l (300–700 μmol/l). | ||
+ | |||
+ | Also see: [[https:// | ||
+ | ==== Main ADRs ==== | ||
+ | |||
+ | * Valproate is associated with serious ADRs, particularly in children and women. Acute liver necrosis and acute pancreatitis, | ||
+ | * An estimated 1–2% risk of neural tube defects, predominantly spina bifida aperta, in babies of women on valproate is well established | ||
+ | * overall risk of major teratogenic effects with valproate is two to three-times higher than the background prevalence of major non-syndromic congenital anomalies. This together with polycystic ovary syndrome and other endocrine ADRs makes the use of valproate in some women undesirable. | ||
+ | |||
+ | **CNS-related ADRs: | ||
+ | * in contrast with other older AEDs, valproate is not usually associated with drowsiness and fatigability or significant dose-related effects on cognition or behaviour. | ||
+ | * Valproate encephalopathy is exceptional. | ||
+ | * Tremor is the more troublesome CNS adverse effect of valproate. There is great individual susceptibility to the development of tremor, which is usually mild, but may become very intense, socially embarrassing and disabling. It is reversible and declines when the dose is lowered. | ||
+ | |||
+ | **Systemic: | ||
+ | * the most serious are **fatal hepatotoxicity** and **acute haemorrhagic pancreatitis**. | ||
+ | * **fatal hepatotoxicity** | ||
+ | * primarily age-dependent and occurs mainly in children receiving polypharmacy and with organic brain disease | ||
+ | * the risk is 1/600 before the age of 3 years. | ||
+ | * incidence decreases considerably in progressively older patient groups (range 1/ | ||
+ | * usually occurred during the first 6 months of treatment. The diagnosis is based on clinical criteria with non-specific symptoms, such as malaise, weakness, lethargy, facial oedema, anorexia, vomiting and loss of seizure control. | ||
+ | * Liver function tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first 6 months. However | ||
+ | * benign elevation of liver enzymes is common during valproate treatment, particularly if used in conjunction with other AEDs. These are usually transient or respond to dose reduction | ||
+ | * severe hepatotoxicity is not preceded by progressive elevation of liver enzymes. | ||
+ | * patients with raised LFTs should be reassessed clinically and liver function tests should be performed more frequently. | ||
+ | * an abnormally low prothrombin level, particularly in association with other relevant abnormalities, | ||
+ | * any concomitant use of salicylates should be stopped, since they employ the same metabolic pathway. | ||
+ | * **acute haemorrhagic pancreatitis** with markedly increased amylase and lipase levels is another rare, but serious, adverse effect of valproate treatment. It develops within the first 3 months of treatment, is more prevalent in children and with polytherapy. | ||
+ | * hyperammonaemic encephalopathy, | ||
+ | * Thrombocytopenia and other haematological abnormalities: | ||
+ | * Evidence of haemorrhage, | ||
+ | * Weight gain occurs in 20% of patients and is some-times marked; women are more vulnerable. This is usually reversible if valproate is withdrawn early. | ||
+ | * Hair loss and changes in hair texture or colour are relatively rare; they usually occur in the early months of valproate treatment and may resolve spontaneously despite continuation of the drug. | ||
+ | * Other ADRs concern the gastrointestinal system (e.g. anorexia, constipation, | ||
+ | |||
+ | FDA warning: All patients who are currently taking or starting on valproate for any indication should be monitored for notable changes in behaviour that could indicate the emergence or worsening of suicidal thoughts or behaviour or depression. | ||
+ | |||
+ | === Considerations in women === | ||
+ | |||
+ | **Pregnancy: | ||
+ | |||
+ | **Breastfeeding: | ||
+ | |||
+ | **Interaction with hormonal contraception: | ||
+ | |||
+ | ==== Main mechanisms of action ==== | ||
+ | The main mechanism of action is unknown and a combination of several mechanisms may be responsible: | ||
+ | |||
+ | * reduction of sustained, repetitive, high-frequency firing by inhibiting voltage-sensitive sodium channels | ||
+ | * activating calcium-dependent potassium conductance | ||
+ | * possibly by direct action on other ion channels | ||
+ | * valproate has a GABAergic effect through elevation of brain GABA by various mechanisms, such as | ||
+ | * inhibiting GABA-transaminase (GABA-T) | ||
+ | * enhancing GABA-synthesising enzymes | ||
+ | * increasing GABA release | ||
+ | * inhibiting GABA uptake. | ||
+ | * However, this GABAergic action is observed only at high valproate levels and may explain its efficacy in other, but not absence, seizures. | ||
+ | * GABAergic drugs that affect GABAB receptors have a pro-absence action because they potentiate absences. Another explanation for the effect of valproate on absence seizures is that this drug, like ethosuximide, | ||
+ | ==== Pharmacokinetics ==== | ||
+ | **Oral bioavailability: | ||
+ | |||
+ | **Protein binding:** valproate is highly protein bound (about 90%). However, if the plasma level of valproic acid rises above 120 mg/l or if the serum albumin concentration is lowered, the binding sites may become saturated, causing the amount of free drug to rise rapidly, out of proportion to any increase in dosage. Valproate may displace phenobarbital or phenytoin from plasma protein-binding sites. | ||
+ | |||
+ | **Metabolism: | ||
+ | |||
+ | The major elimination pathway is via glucuronidation (40–60%). The remainder is largely metabolised via oxidation pathways, β-oxidation accounting for 30–40% and ω-oxidation, | ||
+ | |||
+ | **Elimination half-life: | ||
+ | |||
+ | **Drug interactions** | ||
+ | There are numerous drug interactions with valproate because: | ||
+ | * its metabolism is sensitive to enzymatic induction | ||
+ | * it inhibits the metabolism of other drugs | ||
+ | * it has a high affinity for serum proteins; it may be displaced or displace other drugs. | ||
+ | **Effect of other AEDs on valproate: | ||
+ | * The addition of ethosuximide may reduce the plasma concentration of valproate. | ||
+ | **Effects of valproate on other AEDs: | ||
+ | * valproate does not interact with most of the newer AEDs. A notable exception is lamotrigine.Valproate is a potent inhibitor of UGT-dependent metabolism of lamotrigine, | ||
+ | * The addition of valproate to ethosuximide or phenobarbital may double the plasma concentration of these AEDs with concomitant toxicity. | ||
+ | * There is evidence of severe CNS depression, with or without significant elevations of barbiturate or valproate plasma concentrations. | ||
+ | * All patients receiving concomitant barbiturate therapy should be closely monitored for neurological toxicity. | ||
+ | * Plasma barbiturate concentrations should be measured, if possible, and the barbiturate dosage decreased, if appropriate. | ||
+ | * Plasma levels of carbamazepine decrease to around 17%, while those of carbamazepine-10, | ||
+ | * Valproate displaces phenytoin from its plasma albumin-binding sites and inhibits its hepatic metabolism. Valproate significantly increases the free fraction of phenytoin and reduces its total plasma concentration. | ||
+ | * Valproate does not interact with hormonal contraception. | ||
+ | |||
+ | ==== Disadvantages ==== | ||
+ | Particularly unsuitable for: | ||
+ | * women, because of hormonal changes, weight gain and teratogenicity | ||
+ | * for focal epilepsis in young children since the doses of valproate required to be effective are much higher in focal than generalised epilepsies. Besides there are other, more effective and safer drugs for focal seizures | ||
+ | |||
+ | ==== History ==== | ||
+ | Valproic acid (VPA; valproate; di-n-propylacetic acid, DPA; 2-propylpentanoic acid, or 2-propylvaleric acid) was first synthesized in 1882, by Burton[(: | ||
+ | |||
+ | Two colleagues, H. Meunier and Y. Meunier, working for a small company, Berthier Laboratories, | ||
+ | |||
+ | It was first released as antiepileptic drug in France in 1967 after the publication of preclinical studies by Carraz et al. in 1964[(: | ||
+ | ==== References ==== | ||
+ | ~~REFNOTES~~ |