eMedicine Specialties > Emergency Medicine > Toxicology

Toxicity, Valproate

Author: Timothy Wiegand, MD, Clinical Assistant Professor of Medicine, University of Vermont College of Medicine and Maine Medical Center; Associate Medical Director, Northern New England Poison Center
Coauthor(s): Kent R Olson, MD, FACEP, Clinical Professor of Medicine and Pharmacy, University of California San Francisco; Medical Director, San Francisco Division, California Poison Control System; Herbert E Hern Jr, MD, Assistant Clinical Professor, Department of Emergency Medicine, University of California, San Francisco; Residency Director, Department of Emergency Medicine, Highland General Hospital
Contributor Information and Disclosures

Updated: Jan 26, 2009

Introduction

Background

Ingestions of valproic acid (VPA) have become increasingly common since 1995, when the US Food and Drug Administration (FDA) approved valproic acid for the treatment of acute mania in patients with mood disorders. Although most cases of valproic acid overdose are benign, serious toxicity, including death, may occur after acute valproic acid ingestion.

Valproic acid is an 8-carbon 2-chain fatty acid used mainly for the primary and adjuvant control of simple and complex partial seizures, absence seizures, generalized tonic-clonic seizures, and myoclonic epilepsy. It was approved for use as an anticonvulsant in the United States in 1978. Valproic acid is also used for acute and maintenance therapy of bipolar disease, for migraine prophylaxis, more recently as adjunctive therapy to benzodiazepines for treatment of alcohol and other sedative-hypnotic withdrawal syndromes and occasionally for chronic pain syndromes.

Pathophysiology

Mechanism of action

Valproic acid increases levels of gamma-aminobutyric acid and prolongs the recovery of inactivated sodium channels. These properties may be responsible for its action as a CNS depressant. Valproic acid may also cause impairments in fatty-acid metabolism and disrupt the urea cycle, leading to hyperammonemia.

Valproic acid interacts with voltage-sensitive sodium channels. Its presence inhibits repetitive firing of neurons and is frequency dependent. In this way, its action is similar to those of phenytoin and carbamazepine. Despite this effect, sodium-channel blockade is not thought to underlie the anticonvulsant activity and it does not substantially contribute to the toxicity of valproic acid.

Valproic acid affects the action of gamma-aminobutyric acid (GABA). Unlike sedative-hypnotics that enhance the postsynaptic action of GABA (eg, phenobarbital, benzodiazepines), valproic acid appears to indirectly increase the amount of GABA available to the CNS. In vitro studies have shown that valproic acid increases GABA levels by increasing the activity of glutamic acid decarboxylase and by inhibiting GABA transaminase.

Valproic acid alters fatty-acid metabolism, impairs beta-oxidation (a mitochondrial process), and disrupts the urea cycle. This leads to hyperammonemia, among other metabolic derangements, and, ultimately, end-organ effects (hepatitis, pancreatitis, hemodynamic compromise) may be the result of severe toxicity due to these impaired metabolic processes.

Through several mechanisms, valproic acid depletes carnitine levels resulting in decreased transport of fatty acids and their accumulation in the cytoplasm. This process may result in development of fatty liver.

Pharmacokinetics

Absorption

Valproic acid is usually absorbed rapidly from the GI tract. Peak serum concentrations are recorded at 1-4 hours. In the United States, 5 preparations of valproic acid are available for oral administration. These products have been compared in fasting individuals at a 250-mg dose administration. Measurements including time to maximum concentration (T_max and C_max), which represent the rate of absorption, were obtained. Large differences were found (which may even increase, or change dramatically, in an overdose setting) from valproic acid syrup (34.2 mg/L, 0.9 h) and valproic acid capsule (31.4 mg/L, 2.2 h) to divalproex sodium enteric-coated delayed-release tablet (26.0 mg/L, 3.4 h) and finally, divalproex sodium extended-release (divalproex-ER) tablet (11.8 mg/L, 19.7 h). Clinically, the divalproex-ER tab has been found to cause the longest delays to peak levels in overdose setting.  

Serial measurements documenting declining valproic acid concentrations or prolonged observation are recommended to determine whether a patient is medically safe for discharge or psychiatric placement. In massive overdose of enteric-coated or extended-release valproic acid preparations, delays to peak concentrations have been reported out to nearly 20 hours. In one case with enteric-coated valproic acid, the patient presented 3 hours after ingestion, alert and asymptomatic with a nondetectable level.¹  She later became comatose. At 13 hours, her level was 1075 mg/L.

Protein binding

At normal serum levels, valproic acid is greater than 80-95% protein bound. However, this percentage decreases during acute overdose, when protein-binding sites are saturated: About 90%, binding occurs at valproic acid concentrations of 40 mg/L, and at 81%, binding occurs at 130 mg/L. Concentrations greater than 150 mg/L saturate protein binding, which decreases to less than 70%. In one case report, protein binding was only 29% at valproic acid levels of 451 mg/L.² Protein binding may also be lowered in patients with uremia.

Metabolism

Valproic acid is metabolized primarily in the liver by means of conjugation to form a glucuronide ester and by means of oxidation by mitochondria. Less than 5% is excreted unchanged in the urine. Many of the metabolites are biologically active and contribute to anticonvulsant action. They may also be responsible for ongoing toxicity (eg, persistent coma) even as serum levels of valproic acid return to normal. Valproic acid metabolites are not represented on serum valproic acid screening.

Half-life

The elimination half-life varies from 5-20 hours. The half-life may be increased in neonates, in patients with liver disease, and in those ingesting an acute overdose, particularly with Divalproex ER. The half-life is 4-14 hours in children, 8-17 hours in adults, and up to 30 hours in those with an acute overdose. A large amount of inter-individual variation and variability exists, depending upon whether co-ingestants that may slow GI motility (eg, anticholinergic or opiate drugs) were involved. Valproic acid will cause decreased GI motility.

Dosing
 
Initial dosing can be as low as 10 mg/kg/d given in 2-3 divided doses. Maintenance therapy may be dosed as high as 60 mg/kg/d in 2-3 divided doses.

Therapeutic range

The therapeutic range is 350-690 µmol/L (50-100 mg/L). Control of symptoms may be improved with levels greater than 690 µmol/L (100 mg/L).

Toxic range 

Mild symptoms may occur when levels are in the therapeutic range (see above). Serious intoxication is likely at levels greater than 450 mg/L. Patients with levels greater than 850 mg/L uniformly present with coma, and 63% of them require intubation. Hemodynamic instability and metabolic acidosis may occur at levels greater than 850-1000 mg/L. Because of prolongation of half-life in overdose, a level greater than 1000 mg/L may not drop into the therapeutic range for over 3 days.

Conversion

To convert from traditional units or milligrams per liter into International System of Units (SI) units of micromoles per liter, multiply the traditional units by 6.934. To convert SI units to traditional units, divide by 6.934.

Drug interactions

Valproic acid increases serum levels of carbamazepine, phenobarbital, and primidone mainly by inhibiting various cytochrome P450 (CYP450) isoenzymes involved in their metabolism. Cimetidine and ranitidine increase valproic acid levels by inhibiting hepatic mixed-function oxidase (thereby decreasing VPA metabolism). Drugs (opiates, antihistamines) that slow the GI tract may delay absorption of valproic acid during co-ingestion.

Frequency

United States

Reported acute ingestions of valproic acid have steadily increased over the last decade. According to the 2005 Annual Report of the American Association of Poison Control Center's Toxic Exposure Surveillance System (TESS), 8705 acute exposures to valproic acid occurred. Of these exposures, 866 were in children younger than 6 years, and 5965 were in individuals older than 19 years. Major adverse outcomes were noted in 404 patients of this cohort, and 26 fatalities were reported.³ By comparison, in 1995, 4149 exposures (88 major adverse outcomes, 3 fatal) occurred, and in 1994, 2717 exposures (69 major adverse outcomes, 4 fatal) occurred. A likely reason for the increase of exposures is the increased use of valproate for mood stabilization, as opposed to its initial use predominantly as an anticonvulsant.

International

The international frequency of valproic acid toxicity is unknown.

Race

Outcomes after an acute valproic acid overdose do not depend on race.

Sex

Outcomes after an acute valproic acid overdose do not depend on sex.

Age

• Although most acute valproic acid ingestions occur in persons older than 19 years, age does not influence outcomes after an acute ingestion.
• Children younger than 3 years who are taking several anticonvulsant medications and who have coexistent medical illness may be at increased risk for fatal hepatotoxicity related to long-term valproic acid therapy; the incidence is 1 case in 500 patients. Additional sources suggest that children younger than 2 years are at significant risk (1:800) for developing an idiosyncratic, potentially fatal hepatotoxic syndrome, even in the absence of the previously mentioned risk factors.

Clinical

History

Few historical features are suggestive of valproic acid poisoning. As in most poisonings, a clinical history of the ingestion, including the amount and exact time of ingestion, are helpful. Adequate documentation of previous medical and psychiatric problems is essential.

• Medical and psychiatric diagnoses and medications
  • Prescription and nonprescription medications (including over-the-counter drugs and drugs of abuse) may contribute or mask symptoms of overdose. Adequate documentation of all medications is necessary.
  • Consider herbal and natural remedies as co-ingestants.
• Exact description of the type and amount of overdose
  • The formulation of valproic acid (eg, capsules, sprinkles, syrup, extended-release tablets) taken should be noted, as should the exact amount taken. In particular, Divalproex and the extended-release form may cause significant delays in peak concentration during overdose.
  • Count the remaining or unused portion in the prescription bottle. Subtract this count from the original amount dispensed from the pharmacy. A discrepancy between the number missing and the number that should be missing if the prescribed regimen was followed provides a rough estimate of the amount the patient may have taken.
  • Record the exact time of the overdose.
• Previous suicide attempts
  • Previous suicidal attempts are important because they can lead the clinician to consider referring the patient to a psychiatrist.
  • If a patient continues to have suicidal ideation, holding the patient for psychiatric evaluation on legal grounds may be warranted.
• Domestic violence
  • Remember to screen for domestic violence in all patients with valproic acid overdose.
  • Because domestic violence is widely underreported, be aware of other indications of such abuse, including assault, depression, or suicide attempts.

Physical

Physical examination may provide clues to the nature of the poisoning. Physical findings may reveal the severity of the overdose, but they are not specific for valproic acid (VPA) overdose. GI upset with nausea and vomiting is the most common presentation of patients with valproic acid overdose, closely followed by CNS symptoms of decreased level of consciousness and confusion.

• Vital signs: Vital signs are highly variable in patients with valproic acid poisoning.
• Fever and hypothermia have been reported.
• Hypotension has been reported with severe overdoses. Many case reports of severe valproic acid overdose discuss hypotension refractory to aggressive use of intravenous fluids and pressor agents. In a large multicenter review of 134 patients (80 of whom had VPA levels in the toxic range), 3% of patients had hypotension in association with acute valproic acid ingestion, and 25% of patients with levels greater than 850 mg/L had hypotension.⁴  Levels greater than 1000 mg/L may be associated with refractory hypotension. (Despite that hypotension hemodialysis is often recommended for these patients to rapidly increase elimination as these levels are associated with severe morbidity and mortality. Hemodialysis is often effective and may produce dramatic improvements for these patients. (See elimination discussed in Emergency Department Care).
• Cardiac arrest has been reported in severe valproic acid overdoses. The clinical condition of patients with valproic acid overdose can worsen dramatically as the drug is being absorbed. Patients with massive overdose can develop apnea and cardiac arrest.
• Respiratory depression requiring intubation occurs with increasing frequency as valproic acid levels rise.
• CNS: In a large multicenter review of 134 patients (80 with VPA levels in the toxic range), 71% of patients presented with lethargy, and 15% were comatose.⁴ All patients with serum levels greater than 850 mg/L were comatose, and 63% of these patients needed intubation. CNS findings may include the following:
• Coma
• Confusion
• Somnolence
• Worsened seizure control
• Dizziness
• Hallucinations
• Irritability
• Headache
• Ataxia
• Cerebral edema: This well-documented manifestation usually occurs 48-72 hours after ingestion, even as serum levels are decreasing. It has been suggested that elevated serum ammonia (NH₃) levels can produce encephalopathy via the inhibition of glutamate uptake by astrocytes, which may lead to potential neuronal injury and perhaps cerebral edema. It has also been suggested that hyperammonemia may lead to a disruption of the osmotic gradient, which is thought to precipitate the edema.
• Dermatologic findings: Alopecia has been reported in severe and chronic overdose.
• GI findings: Anorexia, nausea, and vomiting are the most common symptoms in acute toxicity.
• Genitourinary (GU) findings: Renal failure is rare. Case reports describe renal failure in patients with serum levels of greater than 1000 mg/L. Anuria and enuresis may be noted.
• Musculoskeletal findings: Patients may present with tremors and chorea.
• Ocular findings: Miosis and nystagmus may be observed.

Causes

• Intentional ingestions in attempted suicide
• Accidental ingestions
• Intentional poisoning of another person

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