Valproic acid is a commonly used antiepileptic drug that can cause toxicity at high doses. Symptoms of valproic acid toxicity range from mild drowsiness to profound coma and include central nervous system depression, electrolyte abnormalities, elevated liver enzymes, hyperammonemia, and hepatotoxicity. Management involves supportive care like activated charcoal, intravenous fluids, vasopressors, and mechanical ventilation in severe cases of respiratory depression or cerebral edema. Valproic acid toxicity has increased with wider use of the drug but cases have stabilized in recent years according to poison control center reports.

1. Valproic Acid Toxicity
Experimental general toxicology

2. (naturally produced by valerian,
Valeriana officinalis).
Valproic acid (2-propylvaleric
acid, 2-propylpentanoic acid or n-
dipropylacetic acid)
Derived from valeric acid

3. • was first synthesized in 1882 by Burton.
• It is a branched short-chain fatty acid, forming a clear liquid at room
temperature, and whose half-life is 9 to 16 hours.
• Valproate is a commonly used antiepileptic drug for the treatment of generalized
and partial seizures. It is safe for use in both adults and children more than three
years of age.

4. • It works by restoring the balance of certain natural substances
(neurotransmitters) in the brain.
• (valproic acid) has been widely used in the last decade and is now considered a
relatively safe and effective anticonvulsant agent.
It came to the market in 1978, and since then its use has broadened to include in the
treatment of bipolar and schizoaffective disorders, neuropathic pain, and
prophylactic treatment of migraines.

5. Valproic acid is available in different oral formulations such as solutions,
tablets, enteric-coated capsules and slow-release preparations.
Valproate toxicity can occur both accidentally and intentionally.
Toxicity can occur with dose adjustments to reach the therapeutic level, in patients
with metabolic derangements, with drug-drug interactions, or in attempts to cause
self-harm.

6. In patients with a severe overdose of valproate, patients can present with
hypotension, tachycardia, respiratory depression, metabolic acidosis,
cerebral edema, and valproate-related hyperammonemic encephalopathy
which may progress to coma and death, if not treated aggressively.
Acute valproate overdose usually presents with:
CNS depression/
encephalopathy
electrolyte
abnormalities such as
hypernatremia
elevated
transaminase levels
Hyperammonemia.
hepatoxicity

7. Prevalence
❑ The international frequency of valproic acid (VPA )toxicity is
unknown
❑ But according to the American Association of Poison Control
Center reports :
❖ Acute ingestion of VPA steadily increased around the turn of the 21st ,from 2717
exposures in 1994 to 8705 in 2005.
❖ A likely reason for the increase of exposures was the wider use of valproate for
mood stabilization
❖ More recently , acute ingestion of VPA cases has stabilized at a lower rate with
3211 cases in 2010 and 2996 cases reported in 2018.

8. Prevalence
❖ Although most acute VPA ingestions occur in :-
▪ persons older than 20 years,
▪ Children younger than 3 years who are on long-term valproate
therapy may be at increased risk for of VPA toxicity.
▪ children less than two years, there is a risk of fatal
hepatotoxicity with VPA exposure.

9. • Therapeutic serum concentrations of valproate
usually range from 50 to 100 mg/L.
• valproic acid concentrations should be obtained at
regular intervals (every 2 to 4 hours) until the serum
valproate level starts declining.
• When there is a steady decline in the level, it
suggests that a peak serum level has been reached.
• Patients with serum concentrations greater than 180
mg/dl have a central nervous system (CNS)
dysfunction.

10. A complete blood count (CBC) with differential -
thrombocytopenia and decreased in granulocyte
counts may be noted.
Laboratory testing — Routine laboratory evaluation of the
poisoned patient should include the following:
For women of childbearing age, pregnancy
testing is indicated.
Random blood glucose levels are necessary to rule out
hypoglycemia as the cause of altered mental status.

11. Serum AST and ALT levels can assess for hepatotoxicity.
Plasma ammonia levels are necessary for the patient
with a risk of encephalopathy.
Serum electrolytes and arterial blood gas analysis may show
hypernatremia, metabolic acidosis, and hypocalcemia.

12. Screening for other anticonvulsants, aspirin, and acetaminophen
should be done as patients may frequently take these drugs with
valproate.
| Structures and 100 ppm SERS of (A) acetaminophen, (B) aspirin, and (C) ibuprofen.

13. Electrocardiography:
12 lead EKG should be obtained, and it
can show AV conduction block.
Sometimes severe valproate toxicity is
associated with atrial tachycardia.
Imaging studies:
Head CT is necessary when the patient
presents with signs of focal
neurological deficits, profound CNS
depression, and suspicion for cerebral
edema.

14. Etiology
Valproate toxicity may occur when :
1. increasing the dose more than the desired therapeutic effect.
2. when there is a normal total valproate concentration, but the free/
unbound drug becomes elevated, as in the cases of :-
➢ The elderly individuals,
➢ In the presence of hypoalbuminemia,
➢ Pregnancy,
➢ Renal dysfunction with GFR<50 mL/min/1.73m,
➢ Liver disease and concomitant use of medications that compete for albumin
binding sites.

15. Valproate toxicity may occur when
3) For patients who have bipolar disease or mood disorder, suicidal
attempts are possible with an intentional overdose of valproate.
!Note
The Valproate does not have increasingly significant toxicity
when compared to other mood stabilizers.
Etiology

16. ❑ VPA toxicity occurs by the following means:
" Intentional ingestions in attempted suicide
" Accidental ingestions
" Intentional poisoning of another person
❑ Mild symptoms may occur when levels are in the therapeutic range.
❑ Serious intoxication is likely when levels exceed 450 mg/L.
! Patients with levels above 850 mg/L uniformly present with coma, and 63% of
them require intubation.
! Hemodynamic instability and metabolic acidosis may occur at levels higher than
850-1000 mg/L.
! Because of the prolonged half-life in overdose, it may take longer than 3 days for
levels exceeding 1000 mg/L to drop into the therapeutic range.
Toxicity and Mortality

17. ❑ Altered vital signs that may be seen in VPA overdose include the following:
❖ Hyperthermia/hypothermia
❖ Tachycardia
❖ Hypotension (with severe overdose)
❖ Cardiac arrest (with severe overdose)
❖ Respiratory depression necessitating intubation
❑ CNS findings in cases of VPA overdose may include the following:
• Coma
• Confusion
• Somnolence
• Worsened seizure control
• Dizziness
• Hallucination
• Irritability
• Headache
• Ataxia
• Cerebral edema
Toxicity and Mortality

18. ❑ CNS depression is the most common manifestation of toxicity, ranging in
severity from
▪ mild drowsiness to
▪ profound coma and
▪ fatal cerebral oedema .
❑ Usually severe CNS depression develops in patients who ingest more than 200
mg/kg VPA and/or have plasma concentrations greater than 180 μg/ml
❑ In such severe cases, cerebral oedema becomes clinically apparent 12 hours to
4 days after the overdose
Toxicity and Mortality

19. ❑ Additional physical findings that may be noted include the
following:
❖ Alopecia (with severe and chronic overdose)
❖ Anorexia, nausea, and vomiting (the most common symptoms in acute toxicity)
❖ Renal failure (rare), anuria, and enuresis
❖ Tremors and chorea
❖ Miosis and nystagmus
Toxicity and Mortality

20. Management of acute VPA intoxication
❑ Management of acute VPA intoxication is largely supportive.
❑ GIT decontamination with a single dose of activated charcoal.
❑ Other interventions may involve :
❑ blood pressure support with IV fluids and vasopressors,
❑ correction of electrolyte abnormalities or acid-base disorders (commonly an
anion gap metabolic acidosis).
❑ Mechanical ventilation in patients who require airway protection or who
develop cerebral oedema or respiratory depression.
Toxicity and Mortality

21. THE END
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Experimental Toxicology Presentation
Dr. Awatif Omran