Valproik Asit (Convulex, Depakin)

Clinical Effects:

VALPROIC ACID
  • USES: Anticonvulsant for a broad spectrum of seizure disorders. Also used as a mood stabilizer in the treatment of bipolar affective disorder, used to treat chronic pain and as prophylaxis for migraine headaches. PHARMACOLOGY: Inhibits voltage-gated sodium channels (membrane stabilizing effects). Inhibits T-type calcium channels (excessive conductance causes seizures). Competitive antagonist of N-methyl-D-aspartic acid (NMDA) {excitatory} neuroreceptor. Inhibits GABA transaminase, increasing GABA (inhibitory neurotransmitter) concentrations in the brain. TOXICOLOGY: Causes CNS depression in overdose by extension of the pharmacologic mechanisms. Valproic acid depletes hepatic carnitine stores by forming valproylcarnitine, which inhibits the carnitine transported on the plasma membrane. Fatty acids cannot be metabolized due to lack of carnitine, resulting in chronic fatty liver. Valproic acid also depletes coenzyme A (CoA) stores in the liver by trapping CoA in the mitochondria by the valproic acid beta-oxidation metabolites. Depletion of CoA affects the activation of the carbamyl phosphate synthetase I (CPS I), which is needed for incorporating ammonia into the urea cycle, leading to hyperammonemia. EPIDEMIOLOGY: Poisoning is common with moderate severity. MILD TO MODERATE TOXICITY: Primary effect is CNS depression, generally lethargy and sedation, vomiting and tachycardia. SEVERE TOXICITY: Patients typically develop more severe CNS depression, coma, miotic pupils, tachycardia, hypotension, QTc prolongation, and respiratory depression following severe poisoning. Seizures and cerebral edema are less common. Laboratory abnormalities may include hypernatremia, hypocalcemia, and hyperammonemia. Bone marrow suppression may develop 3 to 5 days after massive overdose, and usually resolves spontaneously. Pancreatitis, acute hepatotoxicity, renal insufficiency, and acute lung injury are uncommon, but have been reported. Valproate-induced hyperammonemic encephalopathy can develop after overdose or therapeutic use. It is characterized by deterioration of mental status (i.e., lethargy, confusion, coma) AND an elevated ammonia concentration; it may also be associated with hepatotoxicity. ADVERSE EFFECTS: COMMON: Anorexia, nausea, alopecia, peripheral edema, rash, sedation, weight gain, and teratogenicity. IDIOSYNCRATIC: Pancreatitis, hepatotoxicity, thrombocytopenia, hyperammonemia, and encephalopathy.

Range of Toxicity:

VALPROIC ACID
  • TOXICITY: MILD: Greater than 200 mg/kg risk of CNS depression; MODERATE: Greater than 400 mg/kg risk of multiogran system toxicities; and SEVERE: Greater than 750 mg/kg potentially lethal. THERAPEUTIC DOSE: ADULTS and CHILDREN 10 years of age and older: Initial dose: 10 to 15 mg/kg/day, titrate as needed; maximum dose: 60 mg/kg/day.

Treatment:

VALPROIC ACID
  • Support: MANAGEMENT OF MILD TO MODERATE TOXICITY: Symptomatic and supportive care in all patients. Monitor for progression of sedation. Repeat valproic acid levels every 4 to 6 hours and consider multidose activated charcoal if the level is continuously rising. MANAGEMENT OF SEVERE TOXICITY: Resuscitation, symptomatic and supportive care in all patients. Early intubation in patient with declining level of consciousness. Hypotension: Treat with IV fluids, if no responses start vasopressors. Consider hemodialysis in patients with severe toxicity who are not responding to supportive care. Consider carnitine in patients with coma, elevated ammonia concentration, or a valproate concentration above 450 mcg/mL.
  • Decontamination: PREHOSPITAL: Ipecac-induced emesis is NOT recommended in the prehospital setting because of the potential for aspiration. In patients with valproic-induced coma and/or significant respiratory depression, naloxone may be considered in the prehospital setting. Activated charcoal may be considered in the prehospital setting by a healthcare professional only, if the patient is asymptomatic, the ingestion is recent, and there are no contraindications. HOSPITAL: Administer activated charcoal if the patient presents early after a significant ingestion, if the patient is awake and can protect their airway, or the airway is protected. Administer a second dose of charcoal in patients who have ingested a sustained release formulation, or in patients with rising serum concentrations despite therapy. MULTIDOSE ACTIVATED CHARCOAL: Consider if valproic acid level is continuously rising and gastrointestinal function is intact (Note: patients with severe toxicity often have depressed gastrointestinal motility and may not tolerate multiple dose charcoal).
  • Airway management: Endotracheal intubation should be considered early if the patient presents with altered level of consciousness, hemodynamic instability, or multiorgan toxicity.
  • Naloxone: Naloxone has been used to reverse valproic acid induced CNS depression and coma, with variable success. PREHOSPITAL: In patients with valproic-induced coma and/or significant respiratory depression, naloxone may be considered in the prehospital setting. HOSPITAL: Risk of naloxone administration is low, it is reasonable to administer in patients with significant CNS depression.
  • Antidote: L-CARNITINE: Orphan drug approved by FDA for the treatment of L-carnitine deficiency secondary to valproic acid toxicity. Appears effective in increasing survival in patients with valproate-induced hepatotoxicity and encephalopathy after therapeutic administration. INDICATION: Patients with coma, hyperammonemia, hepatotoxicity, or serum valproate concentration greater than 450 mcg/mL. While there are no controlled studies to support its use after acute overdose, there are several reports suggesting it lowers serum ammonia concentrations, and it is associated with few adverse effects. DOSE: IV 100 mg/kg over 30 minutes (maximum: 6 g) followed by 15 mg/kg IV every 4 hours until clinical improvement.
  • Enhanced elimination procedure: Hemodialysis and hemoperfusion are reserved for severe toxicity with failure of improvement or deterioration despite supportive management, especially with concomitant severe metabolic disturbance, and/or a serum valproic acid concentration of greater than 1000 mg/L. Because protein binding is saturated at high serum concentration (resulting in higher free valproate concentrations) hemodialysis appears to be useful in severe overdose.
  • Patient disposition: HOME CRITERIA: Asymptomatic patients with unintentional ingestion of less than 50 mg/kg can be observed at home. OBSERVATION CRITERIA: Symptomatic patients, those with deliberate ingestions, and those with unintentional ingestions of 50 mg/kg or more should be referred to a medical facility for evaluation and treatment. Obtain serial valproate concentrations every 2 to 3 hours. Patients should be observed until valproate concentrations are clearly declining on at least two sequential measurements, and symptoms have resolved. IMMEDIATE RELEASE: Patients should be observed for a minimum of 6 hours after immediate release valproate ingestions. EXTENDED RELEASE: Monitor patients for a minimum of 12 hours following extended release preparations and should be admitted if symptoms develop. ADMISSION CRITERIA: Patients with rising valproate concentrations and those developing CNS depression or other clinical or laboratory evidence of toxicity should be admitted. Patients with persistent altered mental status, abnormal vital signs, acidosis, renal or hepatic involvement should be admitted to the intensive care setting. CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity, or in whom the diagnosis is not clear.
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