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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.+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[(:cite:panayiotopoulos2005)].
 ===== Authorised indications ===== ===== Authorised indications =====
 UK-SmPC: In the treatment of generalized, partial or other epilepsy. UK-SmPC: In the treatment of generalized, partial or other epilepsy.
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 Valproate sodium injection is indicated as an intravenous alternative in patients for whom oral administration of valproate products is temporarily not feasible. Valproate sodium injection is indicated as an intravenous alternative in patients for whom oral administration of valproate products is temporarily not feasible.
 ===== Clinical applications ===== ===== 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), all syndromes of IGE and photosensitive epilepsy compared with any other drug so far, with the probable exception of levetiracetam. The efficacy of valproate has been well documented in long-term and worldwide clinical practice and controlled studies. +  * 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), all syndromes of IGE and photosensitive epilepsy compared with any other drug so far, with the probable exception of levetiracetam. 
-However, valproate is (1) far inferior to carbamazepine and some newer AEDs in the treatment of focal epilepsies and (2) has serious ADRs in women of child-bearing age and in patients of early childhood. +  * 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[(:ref:todo)].When seizure aggravation occurs with valproate, it is in a specific clinical context, such as overdose, encephalopathy, or hepatic or metabolic disorders. +  * Unlike many other AEDs, valproate appears to have a very low potential to aggravate seizures[(:ref:todo)].When seizure aggravation occurs with valproate, it is in a specific clinical context, such as overdose, encephalopathy, or hepatic or metabolic disorders.
 ==== Dosage and titration ==== ==== 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. **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.
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 Reference range (measures valproic acid): 50–100 mg/l (300–700 μmol/l). Reference range (measures valproic acid): 50–100 mg/l (300–700 μmol/l).
  
 +Also see: [[https://bnfc.nice.org.uk/drug/sodium-valproate.html|BNFc]]
 ==== Main ADRs ==== ==== Main ADRs ====
  
-Valproate is associated with serious ADRs, particularly in children and women. Acute liver necrosis and acute pancreatitis, which may be fatal, are rare and more likely to occur in children receiving polypharmacy. An estimated 1–2% risk of neural tube defects, predominantly spina bifida aperta, in babies of women on valproate is well established and the 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 syndrome290 and other endocrine ADRs makes the use of valproate in some women undesirable.+  * Valproate is associated with serious ADRs, particularly in children and women. Acute liver necrosis and acute pancreatitis, which may be fatal, are rare and more likely to occur in children receiving polypharmacy. 
 +  * 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.+**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.
  
-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**. 
-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 
-Hepatic failure resulting in fatalities is 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. The incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups (range 1/8000–1/10,000 between 3 and 20 years of age) and in monotherapy with valproate. Hepatic failure has 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.  +    * the risk is 1/600 before the age of 3 years. 
-However, this may not be helpful because: +    * incidence decreases considerably in progressively older patient groups (range 1/8000–1/10,000 between 3 and 20 years of age) and in monotherapy with valproate. 
-  * benign elevation of liver enzymes is common during valproate treatment +    * 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. 
-  * severe hepatotoxicity is not preceded by progressive elevation of liver enzymes. +    * Liver function tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first 6 months. However 
-Raised liver enzymes are common during treatment with valproate, particularly if used in conjunction with other AEDs. These are usually transient or respond to dose reduction. Patients with such biochemical abnormalities 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, requires withdrawal of valproate. Any concomitant use of salicylates should be stopped, since they employ the same metabolic pathway. +      * 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. 
-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. +      * 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, requires withdrawal of valproate. 
-Hyperammonaemic encephalopathy, which is sometimes fatal, has been reported following initiation of valproate therapy in patients with urea cycle disorders. When urea cycle enzymatic deficiency is suspected, metabolic investigations should be performed prior to treatment with valproate. +    * 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. 
-Thrombocytopenia and other haematological abnormalities:it is recommended that platelet counts and coagulation tests are performed before initiating therapy and at periodic intervals, because of reports of thrombocytopenia, inhibition of the secondary phase of platelet aggregation and abnormal coagulation parameters. Evidence of haemorrhage, bruising or a disorder of haemostasis/coagulation is an indication for reduction or withdrawal of valproate. +  * hyperammonaemic encephalopathy, which is sometimes fatal, has been reported following initiation of valproate therapy in patients with urea cycle disorders. When urea cycle enzymatic deficiency is suspected, metabolic investigations should be performed prior to treatment with valproate. 
- +  * Thrombocytopenia and other haematological abnormalities:it is recommended that platelet counts and coagulation tests are performed before initiating therapy and at periodic intervals, because of reports of thrombocytopenia, inhibition of the secondary phase of platelet aggregation and abnormal coagulation parameters. 
-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. +  * Evidence of haemorrhage, bruising or a disorder of haemostasis/coagulation is an indication for reduction or withdrawal of valproate. 
- +  * 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. +  * 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, dry mouth, stomatitis) and urogenital system (e.g. urinary incontinence, vaginitis, dysmenorrhoea, amenorrhoea and urinary frequency).
-Other ADRs concern the gastrointestinal system (e.g. anorexia, constipation, dry mouth, stomatitis) and urogenital system (e.g. urinary incontinence, vaginitis, dysmenorrhoea, amenorrhoea and urinary frequency).+
  
 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. 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 === === Considerations in women ===
-Valproate treatment in women raises many issues. 
  
 **Pregnancy:** category D.Valproate is teratogenic. It crosses the placenta and causes a spectrum of congenital anomalies, such as neural tube defects, craniofacial malformations and skeletal defects. The incidence of these anomalies is much higher when valproate is given as co-medication with other AEDs. **Pregnancy:** category D.Valproate is teratogenic. It crosses the placenta and causes a spectrum of congenital anomalies, such as neural tube defects, craniofacial malformations and skeletal defects. The incidence of these anomalies is much higher when valproate is given as co-medication with other AEDs.
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 **Interaction with hormonal contraception:** none. **Interaction with hormonal contraception:** none.
- 
-Other issues: see endocrine abnormalities. 
  
 ==== Main mechanisms of action ==== ==== Main mechanisms of action ====
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     * increasing GABA release     * increasing GABA release
     * inhibiting GABA uptake.     * 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, reduces a low threshold (T-type) calcium-channel current[(:ref:todo)]but this effect has not been supported by other studies[(:ref:todo)].+  * 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, reduces a low threshold (T-type) calcium-channel current[(:ref:todo)]but this effect has not been supported by other studies[(:ref:todo)].
 ==== Pharmacokinetics ==== ==== Pharmacokinetics ====
 **Oral bioavailability:** almost complete. Absorption of valproate varies according to the formulation used. Absorption is rapid and peak levels are reached within 2 hours after oral administration of syrup or uncoated tablets. This is longer (3–8 hours) with enteric-coated tablets. **Oral bioavailability:** almost complete. Absorption of valproate varies according to the formulation used. Absorption is rapid and peak levels are reached within 2 hours after oral administration of syrup or uncoated tablets. This is longer (3–8 hours) with enteric-coated tablets.
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 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, which is CYP dependent. Only 1–3% of the ingested dose is excreted unchanged in the urine. 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, which is CYP dependent. Only 1–3% of the ingested dose is excreted unchanged in the urine.
  
-Elimination half-life: this is variable, but generally appears to be 8–12 hours (range 4–16 hours). It is shorter in patients receiving enzyme-modifying AEDs or in long-term valproate treatment of children and adults. Many antipsychotic and antidepres sant drugs result in competitive metabolism or enzyme inhibition when given as a co-medication with valproate.+**Elimination half-life:** this is variable, but generally appears to be 8–12 hours (range 4–16 hours). It is shorter in patients receiving enzyme-modifying AEDs or in long-term valproate treatment of children and adults. Many antipsychotic and antidepres sant drugs result in competitive metabolism or enzyme inhibition when given as a co-medication with valproate.
  
 **Drug interactions** **Drug interactions**
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 **Effect of other AEDs on valproate:** enzyme inducers, particularly those that elevate levels of UGTs, such as phenobarbital, phenytoin and carbamazepine, may increase the clearance of valproate, thus reducing plasma valproate levels by 30–50%. **Effect of other AEDs on valproate:** enzyme inducers, particularly those that elevate levels of UGTs, such as phenobarbital, phenytoin and carbamazepine, may increase the clearance of valproate, thus reducing plasma valproate levels by 30–50%.
   * The addition of ethosuximide may reduce the plasma concentration of 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, and doubles or triples its plasma half-life.+**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, and doubles or triples its plasma half-life. 
 +  * 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-10,11-epoxide increase by 45% on co-administration with valproate. 
 +  * 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.
  
-The addition of valproate to ethosuximide or phenobarbital may double the plasma concentration of these AEDs with concomitant toxicity.+==== 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
  
-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.+==== History ==== 
 +Valproic acid (VPA; valproate; di-n-propylacetic acid, DPA; 2-propylpentanoic acid, or 2-propylvaleric acid) was first synthesized in 1882, by Burton[(:cite:burton1882>Burton BS (1882) On the propyl derivatives and decomposition products of ethylacetoacetate. Am Chem J3: 385–395)].Its anticonvulsant activity was fortuitously discovered by Pierre Eymard in France in 1962 while working at the Firma Berthier laboratories in Grenoble. Because valproic acid is a liquid, it was used as a lipophilic vehicle to dissolve water-insoluble compounds during preclinical drug testing. As part of his thesis in 1962, Eymard had synthesized a number of khelline derivatives in the laboratory of G. Carraz at the School of Medicine and Pharmacy in Grenoble, France[(:cite:13935231>{{pmid>long:13935231}})].
  
-Plasma levels of carbamazepine decrease to around 17%, while those of carbamazepine-10,11-epoxide increase by 45% on co-administration with valproate.+Two colleagues, H. Meunier and Y. Meunier, working for a small company, Berthier Laboratories, in Grenoble, had used valproate for a long time as a vehicle for dissolving of a bismuth salt. So the three scientists Eymard, Meunier and Meunier had the idea to use this vehicle also for dissolving some of the khelline derivatives synthesized by Eymard. In order to evaluate the pharmacological activities of the khelline derivatives, Carraz proposed to test the most active derivative in the pentylenetetrazole (PTZ) seizure test. By doing this, the researchers found that the vehicle, valproate, alone exerted an anticonvulsant effect[(:cite:loscher1999>Löscher W. (1999) The discovery of valproate. In: Löscher W. (eds) Valproate. Milestones in Drug Therapy. Birkhäuser, Basel)].
  
-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. +It was first released as antiepileptic drug in France in 1967 after the publication of preclinical studies by Carraz et al. in 1964[(:cite:carraz1964>Carraz G, Fau R, Chateau R, Bonnin J (1964) Communication à propos des premiers essais cliniques sur l’activité anti-épileptique de l’acide n-dipropylacétiques (sel de Na). Ann Med Psychol (Paris) 122: 577–585)]. During 1970, it received license to other European countries, but in the USA it was not licensed before 1978. 
- +==== References ==== 
-Valproate does not interact with hormonal contraception. +~~REFNOTES~~
- +
-==== Main disadvantages ==== +
-The superior efficacy of valproate in generalised seizures is hindered by serious acute and chronic ADRs. It is particularly unsuitable for: +
-  * women, because of hormonal changes, weight gain and teratogenicity +
-  * young children, particularly those Valproate is the superior AED for generalised epilepsies, but its use in focal epilepsies is of very limited value, because: the doses of valproate required to be effective are much higher in focal than generalised epilepsies +
-there are other, more effective and safer drugs for focal seizures+
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