Description

Simple

A medication used to control certain types of seizures.

Clinical

An anticonvulsant used to control complex partial seizures and both simple and complex absence seizures.

Overview

Valproic acid, or valproate, is an fatty acid derivative and anticonvulsant originally synthesized in 1881 by Beverly S. Burton.[26] It enjoyed use as a popular organic solvent in industry and pharmaceutical manufacturing for nearly a century. In 1963, a serendipitous discovery was made by George Carraz during his investigations into the anticonvulsant effects of khelline when he found that all of his samples, dissolved in valproic acid, exerted a similar degree of anticonvulsive activity. It first received approval on February 28, 1978 from the FDA under the trade name Depakene.[29]

Since then, it has been investigated for neuroprotective, anti-manic, and anti-migraine effects. It is currently a compound of interest in the field of oncology for its anti-proliferative effects and is the subject of many clinical trials in a variety of cancer types.

Pharmacology

Indication

**Indicated** for:[Label]

1) Use as monotherapy or adjunctive therapy in the management of complex partial seizures and simple or complex absence seizures.

2) Adjunctive therapy in the management of multiple seizure types that include absence seizures.

3) Prophylaxis of migraine headache... Read more

Pharmacodynamic

Valproate has been shown to reduce the incidence of complex partial seizures and migraine headaches.[FDA Label, Read more

Mechanism of action

The exact mechanisms by which valproate exerts it's effects on epilepsy, migraine headaches, and bipolar disorder are unknown however several pathways exist which may contribute to the drug's action.

Valproate is known to inhibit succinic semialdehyde dehydrogenase.[ Read more

Absorption

The intravenous and oral forms of valproic acid are expected to produce the same AUC, Cmax, and Cmin at steady-state.[label] The oral delayed-release tablet formulation has a Tmax of 4 hours. Differences in absorption rate are expected from other formulations but are not considered to be clinically... Read more

Protein binding

Protein binding is linear at low concentrations, 10% bound at 4 mcg/mL, but becomes non-linear at higher concentrations, increasing up to 18.5% bound at 135 mcg/mL.[label] This may be due to binding at separate high and low affinity sites on albumin proteins.[ Read more

Volume of distribution

11 L/1.73m2.[label]

Clearance

0.56 L/hr/m2[label]Pediatric patients between 3 months and 10 years of age have 50% higher clearances by weight. Pediatric patients 10 years of age or older approximate adult values.[FDA Label]

Half life

13-19 hours.[label]

The half-life in neonates ranges from 10-67 hours while the half-life in pediatric patients under 2 months of age ranges from 7-13 hours.

Route of elimination

Most drug is eliminated through hepatic metabolism, about 30-50%.[label] The other major contributing pathway is mitochondrial β-oxidation, about 40%. Other oxidative pathways make up an additional 15-20%. Less than 3% is excreted unchanged in the urine.

Toxicity

**LD50 Values**

Oral, mouse: 1098 mg/kg

Oral, rat: 670 mg/kg

**Overdose**

Symptoms of overdose include somnolence, heart block, deep coma, and hypernatremia. Fatalities have been reported, however patients have recovered from valproate serum concentrations as high as 2120 mcg/... Read more

Adverse Effects

Contraindications

  • Regions: US
  • Patient Conditions:
      • Name: Hepatic Disease
      • Drugbank Id: DBCOND0069929
  • Regions: US
  • Patient Conditions:
      • Name: Urea Cycle Disorders
      • Drugbank Id: DBCOND0032809
  • Regions: US
  • Below Age:
    • Amount: 2
    • Unit: year
  • Patient Conditions:
      • Name: POLG-related disorder
      • Drugbank Id: DBCOND0107606
  • Regions: US
  • Patient Conditions:
      • Name: Significant hepatic dysfunction
      • Drugbank Id: DBCOND0107604
  • Regions: US
  • Patient Conditions:
      • Name: Mitochrondrial disorders
      • Drugbank Id: DBCOND0107605

Food Interactions

  • Avoid alcohol.
  • Avoid milk and dairy products.
  • Take with food.

Interactions

Type in a drug name to check for interaction with Valproic acid
Type a drug name in the box above to get started
  • Paracetamol(acetaminophen)
  • Paxil(paroxetine)
  • Pamelor(nortriptyline)
  • Panadol(acetaminophen)
  • Patanol(olopatadine ophthalmic)
  • Pataday(olopatadine ophthalmic)
  • Parnate(tranylcypromine)
  • Pazeo(olopatadine ophthalmic)
(6R)-Folinic acid
The serum concentration of (6R)-Folinic acid can be decreased when it is combined with Valproic acid.
(6S)-5,6,7,8-tetrahydrofolic acid
The serum concentration of (6S)-5,6,7,8-tetrahydrofolic acid can be decreased when it is combined with Valproic acid.
(R)-warfarin
The serum concentration of (R)-warfarin can be increased when it is combined with Valproic acid.
(S)-Warfarin
The serum concentration of (S)-Warfarin can be increased when it is combined with Valproic acid.
2,5-Dimethoxy-4-ethylamphetamine
The risk or severity of serotonin syndrome can be increased when Valproic acid is combined with 2,5-Dimethoxy-4-ethylamphetamine.
2,5-Dimethoxy-4-ethylthioamphetamine
The risk or severity of adverse effects can be increased when Valproic acid is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
3-isobutyl-1-methyl-7H-xanthine
Valproic acid may increase the excretion rate of 3-isobutyl-1-methyl-7H-xanthine which could result in a lower serum level and potentially a reduction in efficacy.
4-Bromo-2,5-dimethoxyamphetamine
The risk or severity of adverse effects can be increased when Valproic acid is combined with 4-Bromo-2,5-dimethoxyamphetamine.
4-hydroxycoumarin
The metabolism of 4-hydroxycoumarin can be decreased when combined with Valproic acid.
4-Methoxyamphetamine
The risk or severity of adverse effects can be increased when Valproic acid is combined with 4-Methoxyamphetamine.
4-Oxoretinol
Valproic acid may increase the Pseudotumor Cerebri activities of 4-Oxoretinol.
5-methoxy-N,N-dimethyltryptamine
The risk or severity of adverse effects can be increased when Valproic acid is combined with 5-methoxy-N,N-dimethyltryptamine.
5-methyltetrahydrofolic acid
The serum concentration of 5-methyltetrahydrofolic acid can be decreased when it is combined with Valproic acid.
6-O-benzylguanine
Valproic acid may increase the excretion rate of 6-O-benzylguanine which could result in a lower serum level and potentially a reduction in efficacy.
7-Deazaguanine
Valproic acid may increase the excretion rate of 7-Deazaguanine which could result in a lower serum level and potentially a reduction in efficacy.
7-Nitroindazole
The risk or severity of adverse effects can be increased when Valproic acid is combined with 7-Nitroindazole.
7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline
The risk or severity of adverse effects can be increased when Valproic acid is combined with 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline.
7,9-Dimethylguanine
Valproic acid may increase the excretion rate of 7,9-Dimethylguanine which could result in a lower serum level and potentially a reduction in efficacy.
8-azaguanine
Valproic acid may increase the excretion rate of 8-azaguanine which could result in a lower serum level and potentially a reduction in efficacy.
8-chlorotheophylline
Valproic acid may increase the excretion rate of 8-chlorotheophylline which could result in a lower serum level and potentially a reduction in efficacy.
30 References
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  28. 28 . Depacon FDA Label (2006) Link
  29. 29 . Depakene FDA Link
  30. 30 . Depakene FDA Label (2019) Link