CHAPTER 2-155: VALPROIC ACID

Valproic acid (Depakene or Depakote [divalproex sodium]) is a structurally unique anticonvulsant. It is used for the treatment of absence seizures, partial complex seizures, and generalized seizure disorders and is a secondary agent for refractory status epilepticus. It is also used commonly for the prophylaxis and treatment of acute manic episodes and other affective disorders, chronic pain syndromes, and migraine prophylaxis.

1. Valproic acid is a low–molecular-weight (144.21) branched-chain carboxylic acid (pKa = 4.8) that increases levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and prolongs the recovery of inactivated sodium channels. These properties may be responsible for its action as a general CNS depressant. Valproic acid also alters fatty acid metabolism, with impairment of mitochondrial beta-oxidation and disruption of the urea cycle, and can cause hyperammonemia, hepatotoxicity, metabolic perturbations, pancreatitis, cerebral edema, and bone marrow depression. Some of these effects may be associated with carnitine deficiency.

2. Pharmacokinetics

   1. Valproic acid is rapidly and completely absorbed from the GI tract. There is a delay in the absorption with the preparation Depakote (divalproex sodium) because of its delayed-release formulation as well as the intestinal conversion of divalproex to two molecules of valproic acid.

   2. At therapeutic levels, valproic acid is highly protein bound (80–95%) and confined primarily to the extracellular space, with a small (0.1–0.5 L/kg) volume of distribution (Vd). In overdose and at levels exceeding 90 mg/L, saturation of protein-binding sites occurs, resulting in a greater circulating free fraction of valproic acid and a larger Vd.

   3. Valproic acid is metabolized predominantly by the liver and may undergo some degree of enterohepatic recirculation. The elimination half-life is 5–20 hours (average, 10.6 hours). In overdose, the half-life may be prolonged to as long as 30 hours (there are case reports of up to 60 hours, but this may have been due to delayed absorption). A level exceeding 1,000 mg/L may not drop into the therapeutic range for at least 3 days. In addition, active metabolites (eg, the neurotoxic 2-en-valproic acid and the hepatotoxic 4-en-valproic acid) produced via beta-oxidation and omega-oxidation pathways may contribute to prolonged or delayed toxicity.

The usual daily dose for adults is 1.2–1.5 g to achieve therapeutic serum levels of 50–150 mg/L, and the suggested maximum daily dose is 60 mg/kg. Acute ingestions exceeding 200 mg/kg are associated with a high risk for significant CNS depression, and ingestions exceeding 400 mg/kg are associated with coma, respiratory depression, cerebral edema, and hemodynamic instability. The lowest published fatal dose is 15 g (750 mg/kg) in a 20-month-old child, but adult patients have survived after ingestions of 75 g.

1. Acute overdose

   1. Acute ingestion commonly causes GI upset, variable CNS depression (confusion, disorientation, obtundation, and coma with respiratory failure), and occasionally hypotension with tachycardia and a prolonged QT interval. The pupils may be miotic, and the presentation may mimic that of an opiate poisoning. Cardiorespiratory arrest has been associated with severe intoxication, and the morbidity and mortality from valproic acid poisoning seem to be related primarily to hypoxia and refractory hypotension.

   2. Paradoxical seizures may occur in patients with a pre-existing seizure disorder.

   3. Transient rises of transaminase levels have been observed without evidence of liver toxicity. Hyperammonemia with encephalopathy has been observed with therapeutic levels and in overdose without other evidence of hepatic dysfunction. Hyperammonemia may also be associated with a higher risk for cerebral edema.

   4. At very high serum levels (>1,000 mg/L) after large ingestions, other metabolic and electrolyte abnormalities may be observed, including an increased anion gap acidosis, hypocalcemia, and hypernatremia.

   5. Other complications or late sequelae (days after ingestion) associated with severe intoxication may include myelosuppression, optic nerve atrophy, cerebral edema, noncardiogenic pulmonary edema, anuria, and hemorrhagic pancreatitis.

2. Adverse effects of chronic valproic acid therapy include hepatic failure (high-risk patients are younger than 2 years of age, are receiving multiple anticonvulsants, or have other long-term neurologic complications) and weight gain. Hepatitis is not dose related and usually is not seen after an acute overdose. Pancreatitis usually is considered a non–dose-related effect but has been reported with acute fatal overdoses. Alopecia, red cell aplasia, thrombocytopenia, and neutropenia have been associated with both acute and chronic valproic acid intoxication.

3. Use in pregnancy. FDA Categories D & X (for migraine). Valproic acid is a known human teratogen.

Is based on the history of exposure and typical findings of CNS depression and metabolic disturbances. The differential diagnosis is broad and includes most CNS depressants. Encephalopathy and hyperammonemia may mimic Reye syndrome.

1. Specific levels. Obtain a stat serum valproic acid level. Serial valproic acid level determinations should be obtained, particularly after ingestion of divalproex-containing preparations (Depakote), because of the potential for delayed absorption. Peak levels have been reported up to 18 hours after Depakote overdose and can be reached even later after ingestion of the extended-release formulation, Depakote ER.

   1. In general, serum levels exceeding 450 mg/L are associated with drowsiness or obtundation, and levels greater than 850 mg/L are associated with coma, respiratory depression, and metabolic perturbations. However, there appears to be poor correlation of serum levels with outcome. Moreover, assays may or may not include metabolites.

   2. Death from acute valproic acid poisoning has been associated with peak levels ranging from 106 to 2, 728 mg/L, but survival was reported in a patient with a peak level of 2, 120 mg/L.

2. Other useful laboratory studies include electrolytes, glucose, BUN, creatinine, calcium, ammonia (note: use oxalate/gray-top blood tube to prevent false elevation of ammonia due to in vitro amino acid breakdown), liver aminotransferases, bilirubin, prothrombin time, lipase or amylase, serum osmolality and osmol gap (see Table I–21; serum levels >1, 500 mg/L may increase the osmol gap by ≥10 mOsm/L), arterial blood gases or oximetry, ECG monitoring, and CBC. Valproic acid may cause a false-positive urine ketone determination.

1. Emergency and supportive measures

   1. Maintain an open airway and assist ventilation if needed. Administer supplemental oxygen.

   2. Treat coma, hypotension, and seizures if they occur. There are anecdotal reports of the use of corticosteroids, hyperventilation, barbiturates, and osmotic agents to treat cerebral edema.

   3. Treat acidosis, hypocalcemia, and hypernatremia if they are severe and symptomatic.

   4. Monitor patients for at least 6 hours after ingestion and for up to 12 hours after ingestion of Depakote (divalproex sodium) because of the potential for delayed absorption.

2. Specific drugs and antidotes. There is no specific antidote. Naloxone has been reported to increase arousal, but inconsistently, with the greatest success in patients with serum valproic acid levels of 185–190 mg/L. L-Carnitine has been used to treat valproic acid–induced hyperammonemia and hepatotoxicity. Although data on clinical outcomes are not conclusive, it appears to have a safe adverse reaction profile.

3. Decontamination

   1. Administer activated charcoal orally if conditions are appropriate (see Table I–38). Gastric lavage is not necessary after small-to-moderate ingestions if activated charcoal can be given promptly.

   2. Moderately large ingestions (eg, >10 g) theoretically require extra doses of activated charcoal to maintain the desired charcoal-to-drug ratio of 10:1. The charcoal is not given all at once but in repeated 25- to 50-g quantities over the first 12–24 hours.

   3. The addition of whole-bowel irrigation may be helpful in large ingestions of sustained-release products such as divalproex (Depakote or Depakote ER).

4. Enhanced elimination. Although valproic acid is highly protein bound at therapeutic serum levels, saturation of protein binding in overdose (binding decreases to as low as 15% at levels exceeding 1,000 mg/L) makes valproic acid amenable to enhanced removal methods. These procedures should be considered in patients with high serum levels (eg, >850 mg/L) associated with severe intoxication (eg, coma, respiratory failure, hyperammonemia, hemodynamic instability).

   1. Hemodialysis and hemoperfusion. Hemodialysis may result in a 4- to 10-fold decrease in elimination half-life in overdose patients and is the method of choice. Dialysis also corrects metabolic disturbances, removes valproic acid metabolites and ammonia, and is associated with a rise in free carnitine levels. It is uncertain if use of high-efficiency and/or high-flux dialyzers is more advantageous. Charcoal hemoperfusion (alone and in series with hemodialysis) has also been used with clearances similar to those observed with hemodialysis and is subject to column saturation. However, the availability of hemoperfusion columns may be limited.

   2. Continuous renal replacement therapy (CRRT), such as continuous arteriovenous hemofiltration (CAVH), continuous venovenous hemofiltration (CVVH), and continuous venovenous hemodiafiltration (CVVHDF), is sometimes preferred for hemodynamically unstable patients but achieves lower reported clearances.

   3. Repeat-dose activated charcoal. Theoretically, repeated doses of charcoal may enhance clearance by interrupting enterohepatic recirculation, but no controlled data exist to confirm or quantify this effect. Another benefit is enhanced GI decontamination after a large or massive ingestion because single doses of charcoal are inadequate to adsorb all ingested drug.