Link to 3.4.2.1 Sodium Valproate Teaching Resources
Link to Problems for Discussion

Sodium Valproate


DRUGS INCLUDED IN THIS CATEGORY


In Australia, 100 mg tablets of sodium valproate are normal release while all other strengths are enteric controlled release formulations. Divalproex sodium is converted to valproate in the small intestine and this is responsible for delayed peak concentrations.

OVERVIEW


Sodium valproate is an anti-epileptic medication that is also used bipolar & affective disorders with a consequent increase in presentations with self-poisoning. In the majority of patients the clinical course is benign and manifest as sedation only (in spite of numerous case reports of severe toxicity). In general, it is less toxic in overdose than either phenytoin or carbamazepine. Severe toxicity is unlikely to occur with doses less than 400 mg/kg, and almost never with doses < 200 mg/kg. However, in very large ingestions ingestions (> 400 mg/kg) significant clinical toxicity (metabolic acidosis, bone marrow failure, unconsciousness and circulatory collapse) can occur and death is a significant risk with massive ingestions of >1,000 mg/kg. Serious complications are more likely at concentrations > 5,900 micromol/L
(> 850 mg/L) and death is a significant risk at concentrations > 6,900 micromol/L (> 1,000 mg/L). Asymptomatic thrombocytopenia & leukopenia can occur.

MECHANISM OF TOXIC EFFECTS


Valproate is a drug with anticonvulsant activity against a wide range of seizure types and appears to be well tolerated at therapeutic doses. In therapeutic use valproate's action may be related to altered turnover of GABA and actions on voltage sensitive sodium channels. The mechanisms involved in toxicity are unclear. It appears to have teratogenic effects in therapeutic doses.

KINETICS IN OVERDOSE


Absorption

Peak plasma concentrations are achieved 1-2 h after standard release preparations. Peak concentrations were delayed > 10
hours in 15% of patients in one series. Bioavailability is high (~100%).

Distribution

In low therapeutic concentrations there is 90% protein binding (albumin). Protein binding saturates at 350 micromol/L (50
mg/L) so at concentrations greater than this the free fraction of valproate will increase. The apparent volume of
distribution is low (0.13 to 0.23 L/kg).

Metabolism - Elimination

Hepatic conjugation to glucuronides, some metabolites probably contribute to the therapeutic effects. 1-3% of the ingested
dose is excreted unchanged in the urine. The plasma half-life varies between 9 and 21 h with a mean of 12 - 13 h.

CLINICAL EFFECTS


Central nervous system effects

Patients are often described as lethargic, 2 - 3% develop coma. Seizures & cerebral oedema are occasionally reported in very
large overdoses (> 400 mg/kg).

Cardiac effects

Tachycardia (25 - 30%) and hypotension (2 - 3%) are the most common manifestations and are probably secondary to
vasodilatation or volume depletion. QT prolongation occurs and cardiac arrest has occurred in very large poisonings (> 400
mg/kg).

Haematological effects

Thrombocytopenia (5 - 8%) and leukopenia (1 - 3%) are concentration related transient events which are normally clinically
insignificant. In massive overdose, bone marrow failure can occasionally occur.

Other effects

Nausea & vomiting (10 - 15%). Metabolic acidosis can occur in very large or massive overdoses.
Cholestatic hepatitis & pancreatitis appears to be an idiosyncratic complication (1/10,000) occurring rarely in overdose &
therapeutically. In therapeutic use, severe liver toxicity, occasionally with a fatal outcome, is extremely rare. It appears
to be caused by an idiosyncratic reaction and usually occurs during the first 6 months of valproate therapy. It may be
related to metabolism to hepatotoxic metabolites occurring in some individuals and is not usually a problem in overdose.

INVESTIGATIONS


Biochemistry

FBC, electrolytes, and acid base estimation should be performed in clinically severe patients.

Blood concentrations Conversion factor

  • mg/L x 6.93 = micromol/L
  • micromol/L x 0.144 = mg/L
Serum sodium valproate concentrations (therapeutic range 350 - 700 micromol/L, 50 - 100 mg/L) confirm ingestion but probably
do not give a great deal of additional information to the clinical assessment. Very high concentrations > 5,900 micromol/L (>
850 mg/L) are associated with more severe toxicity and should prompt consideration of extracorporeal removal. Death is a
significant risk at concentrations > 6,930 micromol/L (> 1,000 mg/L) and extracorporeal elimination may be life-saving. For
very large (> 400 mg/kg) and particularly for massive ingestions (> 1,000 mg/kg) serum valproate should be measured
frequently (2nd hourly) as concentrations can rise precipitously. Patients with severe clinical toxicity and a concentration
of < 5,900 micromol/L (< 850 mg/L) should prompt a search for other contributing causes.

ECG

ECG should be done at baseline and repeated in patients with increasing concentrations or progressive clinical toxicity.

Other investigations

Moderate elevations in blood ammonia concentrations are fairly common during treatment with valproic acid and can occur in
overdose. The clinical importance of the hyperammonaemia is unclear and outcome is not predicted by its presence.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis should be directed towards other medications to which the patient may have access. Depending on
the underlying diagnosis this includes other anticonvulsants and psychiatric medication.

TREATMENT


Supportive

The treatment is primarily supportive. Adequate IV fluids are need to combat vasodilatation.

GI Decontamination

Single dose activated charcoal is the recommended gastrointestinal decontamination procedure for patients presenting within
1- 2 hours of overdose. Whole bowel irrigation should be considered for controlled release preparations of > 200 mg/kg and is
probably justified in ingestions > 400 mg/kg.

Treatment of specific complications

Seizures
Seizures should be treated with intravenous benzodiazepines (adults: diazepam 5 to 10 mg, repeated if necessary every 15 to
20 minutes). Seizures refractory to diazepam may require phenobarbitone (15 mg/kg).

Antidotes

L-carnitine
L-carnitine has been used in a number of case reports. There is evidence it reduces ammonia concentrations in acute valproate
overdose but the correlation between reducing ammonia concentrations and improving outcome is lacking.
A suggested dose is 100 mg/kg bolus, then 50 mg/kg/hr

Elimination enhancement

High Flux Haemodialysis and haemoperfusion enhance elimination. One recent case report and review of extracorporeal techniques in
valproate poisoning suggests that haemodialysis is more effective than haemoperfusion, although this may be limited by the
circulatory collapse that can occur. The recent case series of Spiller et al suggests that haemodialysis should not be used
for cases with peak levels < 5,900 micromol/L (< 850 mg/L) because all patients in that series with concentrations< 5.900
micromol/L recovered with supportive care.

Concentrations > 6,900 micromol/L (> 1,000 mg/L) are potentially life-threatening and extracorporeal removal may be
life-saving.

LATE COMPLICATIONS, PROGNOSIS - FOLLOW UP


No routine follow-up is required.

REFERENCES


Full Text

Isbister G, Balit C, Whyte I, Dawson A. Valproate overdose: a comparative cohort study of self poisonings Br J Clin Pharmacol,55 , 398–404 (Full Text)

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Meek MF, Broekroelofs J, Yska JP, Egbers PHM, Boerma EC, van der Voort PHJ. Valproic acid intoxication: sense and non-sense of haemodialysis. Neth J Med. 2004 Oct;62(9):333-336.

Thanacoody HKR. Chronic valproic acid intoxication: reversal by naloxone. Emerg Med J. 2007 Sep;24(9):677-678.

Engbersen R, Kramers C. Enhanced extracorporeal elimination of valproic acid in overdose. Neth J Med. 2004 Oct;62(9):307-308.

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Mayerhoff DI, Nurenberg J, Shah S, Schleifer SJ. Neurotoxicity associated with free valproic acid. Am J Psychiatry. 2005 Apr;162(4):810

Abstracts


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Graudins A & Aaron C. Delayed peak serum valproic acid in massive difalproex overdose - treatment with charcoal haemoperfusion. Clin Toxicol 1996; 34:335-341

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