Assessment of Toxicity of

Anticonvulsant
VALPROIC ACID
 Introduction
Valproic acid is currently used to
– Treat various seizure disorders,
– Migraine prevention
– Psychiatric disorders
o Mania
o Anxiety
o Depression
o Psychosis
o Substance-abuse withdrawal
Carbamazepine Drug Interactions
CYP 3A4 inhibitors CYP 3A4 inducers
• Valproic acid
• Cimetidine • Carbamazepine
• Clarithromycin • Cisplatin
• Diltiazem • Felbamate
• Erythromycin
• Phenobarbital
• Fluoxetine
• Grapefruit juice • Phenytoin
• Isoniazid • Theophylline
• Verapamil
 MOA
• Increase production of GABA in the brain
• Enhance the effect of GABA that already
exists at receptors.
• Mimics the action of GABA, thus decreasing
the risk of having a seizure.
• Inhibition of Sodium and Calcium Channels
 PK
Protein binding
• Vd for VPA is------------- 0.1-0.5 L/kg
• At normal serum levels, protein binding for VPA is greater
than 80-95%.
• An overdose-------------protein-binding sites are
saturated,-------increasing the free fraction of VPA and Vd.
• At 40 mg/L VPA --------protein binding is 90%
• At 130 mg/L VPA--------binding is 81%.
• At > 150 mg/L VPA ------Binding below 70%.
• At > 450 mg/L VPA ---------serious intoxication, Binding is 29%
Protein binding may also be lowered in patients with uremia.
 PK
Metabolism
• VPA is primarily metabolized in the liver
• Less than 5% is excreted unchanged in the urine.
• Many of the metabolites are biologically active
and contribute to anticonvulsant action.
• Lag Effect (ongoing toxicity (eg, persistent coma)
even as serum VPA levels return to normal).
• VPA metabolites are not represented on serum
VPA screening.
 PK/DDI
VPA increases serum levels of carbamazepine,
phenobarbital, and primidone???????

Cimetidine and ranitidine increase VPA levels ?????

Drugs that slow the GI tract (eg, opiates and

antihistamines) may delay absorption of VPA during
co-ingestion.
 MOT
• Valproic acid-VPA---- increases GABA levels --------
prolongs the recovery of inactivated sodium channels
(CNS depressant).
• VPA--------disruption of the urea cycle---------cause
hepatotoxicity, Hyper-ammonemia cerebral edema
• Carnitine plays a critical role in energy production. It
transports long-chain fatty acids into the
mitochondria so they can be oxidized (“burned”) to
produce energy.
• VPA depletes carnitine levels---------- decreased
transport of fatty acids and their accumulation in the
cytoplasm--------fatty liver
 Clinical symptoms
Acute overdose
• GIT upset
• CNS depression (drowsiness, confusion, disorientation
to coma
• Hypotension (severe cases)
• Cardiac arrest(severe cases)
• Respiratory failure(severe cases)---endotracheal
intubation
• The pupils may be miotic, and the presentation may
mimic an opiate poisoning.
 Toxicity
• Patients at primary risk of fatal hepatic dysfunction are children under
the age of 2 years who are receiving multiple anticonvulsants
and also have significant medical problems in addition to severe
epilepsy.
• The risk is considerably lower for patients over the age of 2 years on
valproate monotherapy.
• Hepatitis-------- not dose related ------not usually seen after an acute
overdose.
• Pancreatitis ----non–dose-related effect.
• Alopecia, Red cell aplasia, thrombocytopenia, and neutropenia have
been associated with both acute and chronic valproic acid intoxication.
• Valproic acid is a known human teratogen.
• At very high serum levels (> 1000 mg/L) after large ingestions-------
metabolic and electrolyte abnormalities (hypocalcemia, and
hypernatremia).
THERAPEUTIC AND TOXIC PLASMA
CONCENTRATIONS cont…
 Hyperammonemia symptoms
Ammonia excess is toxic to the CNS.

Ammonia ---------increase glutamate levels --------

activates N-methyl-D-aspartate (NMDA)
receptors---------seizures.

Seizures (difficult to differentiate from the

pathology itself; epilepsy), can be misdiagnosed as
therapeutic failure instead of an ADR of VPA.
 THERAPEUTIC AND TOXIC PLASMA
CONCENTRATIONS cont…
Hyperammoneima symptoms
• Irritability.
• Depression.
• Drowsiness.
• Difficulty with word-finding.
• Poor short-term memory.
• Poor concentration.
• Confusion and disorientation.
• Insomnia.
 THERAPEUTIC AND TOXIC PLASMA
CONCENTRATIONS cont…
Hepatotoxicity & Hyperammonemia
encephalopathy (rare but lethal).
• The use of valproic acid in various
psychiatric disorders creates an
additional need for vigilance for
hyperammonemia.
• The symptoms of hyperammonemia
can be mistaken for altered mental
status associated with the disorders
being treated.
 L. Carnitine
• This amino acid derivative is
an important nutrient; 75%
comes from the diet,
particularly in red meat,
avocado, and dairy products.

• It is not a true vitamin

because it is also
biosynthesized
endogenously from dietary
amino acids (methionine,
lysine), especially in the liver
and in the kidneys.
 Causes of carnitine deficiency…
• In cirrhosis and chronic renal failure,
endogenous carnitine biosynthesis is impaired.

• Patients with renal disease also appear to lose

carnitine via haemodialysis treatment – a loss
that cannot be depleted simply by endogenous
biosynthesis and dietary intake.
 THERAPEUTIC AND TOXIC PLASMA
CONCENTRATIONS cont…
• Hepatotoxicity is a serious complication
of therapy and should be considered in
any patient with elevated liver
enzymes.
• It is believed that hepatotoxicity from
valproic acid is due to low
concentrations of L-carnitine in the
body.
• The use of IV L-carnitine has been
shown to halt the progression of liver
toxicity once it occurs and should be
considered when patients are
I. Emergency and supportive measures
II. Antidotes
III. Contamination
IV. Enhanced Elimination
I. Emergency and supportive measures
Treatment

• Maintain an open airway and assist ventilation if needed

• supplemental oxygen.
• Treat coma, hypotension, and seizures
• Corticosteroids, and osmotic agents-----------to treat
cerebral edema.
• Treat acidosis, hypocalcemia, or hypernatremia if they are
severe and symptomatic.
• 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.
 II. Antidote
There is no specific antidote.

• Naloxone ------------increase arousal

• L-Carnitine -------------valproic acid–induced hyper-
ammonemia
• Carnitine in the treatment of valproic acid-induced liver
toxicity.
 III.GI Decontamination
• Administer activated charcoal if available.
• Do not induce vomiting???
• Consider gastric lavage for large ingestions.
• The addition of whole-bowel irrigation----------------
• (helpful in large ingestions of SR DF such as divalproex
(Depakote or Depakote ER).

Repeat-dose activated charcoal.

• Theoretically, repeated doses of charcoal may enhance
clearance
• Enhanced gastrointestinal decontamination after large or
massive ingestion, since single doses of charcoal are
inadequate to adsorb all ingested drug.
 IV. Enhanced elimination
Although valproic acid is highly protein bound at therapeutic
serum levels, saturation of protein binding in overdose makes
valproic acid favorably disposed to enhanced removal
methods.

Hemodialysis and hemoperfusion.

Consider dialysis in patients with serum valproic acid levels
exceeding 850 mg/L, since these cases are associated with
higher morbidity and mortality.
Assessment of Toxicity of
Anticonvulsant
PHENOBARBITAL
 Introduction
• Phenobarbital is a long acting barbiturate, non selective
CNS depressant uses as
a. Sedatives.
b. Hypnotics, for the short-term treatment of insomnia.
c. Preanesthetics.
d. Long-term anticonvulsants for the treatment of generalized
tonic-clonic seizures.
• Route of administration:
– Oral
– IM
– IV
 TOXIC CONC
CNS depression (conc dependent)

Ataxia: mimic those of being drunk, such as slurred

speech, stumbling, falling, and incoordination
Headache
Unsteadiness
Sedation
Confusion
Lethargy
Coma, and respiratory arrest may result, especially
with rapid bolus or excessive doses.

At >60 μg/mL------------ stupor (a state of near-

unconsciousness or insensibility) and coma
 TOXIC CONC
• Long-term treatment -----------changes in
behavior, decreased cognitive function, and
osteomalacia
Side effects that are independent
of concentration --------- skin rashes and blood
dyscrasias (imbalance of four body
fluids: blood, bile, lymph, and phlegm).
Use in pregnancy.
• FDA category D (possible fetal risk).
• Phenobarbital readily crosses the placenta
• Chronic use may cause hemorrhagic disease
of the newborn
 TOXIC CONC

Concentrations in excess of 100

to 150 mg/L are considered
potentially Lethal although few
patients with higher
concentrations have survived.
 TOXIC CONC

Hypotension may result from rapid

IV administration--------This can be
prevented by limiting the rate of
administration to less than 50
mg/min
Phenobarbital has additive central nervous system
and respiratory depression effects with other
sedative drugs.

Hepatic enzyme induction with chronic use,

although this is not encountered with acute
phenobarbital dosing.

Extracorporeal removal techniques (eg,

hemodialysis, hemoperfusion, and repeat-dose
activated charcoal may enhance the clearance of
phenobarbital