Sodium valproate is a broad-spectrum anticonvulsant drug useful for treating generalized absence seizures, tonic-clonic seizures, and partial seizures. Therapeutic concentrations range from 50-100 μg/mL, and toxicity can occur at levels over 180 μg/mL. Its precise mechanism of action is unknown but it is thought to work by increasing GABA levels in the brain. It is available in various oral and parenteral formulations and is used for both acute and chronic treatment of seizures as well as bipolar disorder and migraines. Common side effects include nausea, vomiting, drowsiness, and rash.

1. SodiumValporate orValporic
Acid
• Sodium valproate as valproic acid in the bloodstream has a
broad spectrum of anticonvulsant activity, being useful in
generalised absence, generalised tonic–colonic and partial
seizures.
• Plasma concentration–response relationship
• There is no clear concentration–response relationship for
valproate, although a range of 50–100 mg/L is often quoted
as being optimal, with 50% of patients showing a response
at levels above 80 mg/L.

2. • Levels above 100 mg/L do not confer any
additional therapeutic benefits.
• Although there is no clear relationship
between plasma levels and toxic effects,
the rare hepatotoxicity associated with
valproate appears to be related to very
high levels of over 150 mg/L

3. Therapeutic and Toxic
Concentrations
Therapeutic concentration:
• General accepted Css for valproic acid is
50-100μg/mL
• For partial seizures range is >100mg/L
• For generalized seizures its 30-65mg/L

4. Toxic concentration
• Severe toxicity with valproic acid occur
when serum concentration exceed
180mg/L (Warner et al., 1998).

5. Mechanism of Action
• Precise mechanism of action for valproic
acid is unknown
• Antiepileptic effect is thought to result
from its ability to increase concentrations
of the neuroinhibitor γ-aminobutyric acid
(GABA)
• potentiate the postsynaptic response to
GABA,or to exert a direct effect on
cellular membranes

6. Indications for use
• generalized, partial, and absence (petit
mal) seizures
• for the acute treatment and chronic
prophylaxis of seizures.
• useful agent for the treatment of bipolar
affective disorders and the prevention of
migraine headaches
• It has the widest spectrum of activity
compared to the other currently
available antiepileptic drugs

7. Dosage Forms and Formulations
Available as three different entities
valproic acid
sodium valproate
divalproex sodium (a stable coordination
compound consisting of a 1:1 ratio of
valproic
acid and sodium valproate).

8. Dosage Forms
Parenteral form (100 mg/mL solution).
 Oral use,a syrup (50 mg/mL)
Soft capsule (250 mg)
Enteric coated capsules (125 mg, 250 mg,
and 500 mg)
Sustained-release tablets (250 mg and 500
mg)
Sprinkle capsule (125 mg,used to sprinkle
into foods)

9. Dosing
Indications Initiation dose
(mg/kg/day)
Dose to be
increased
(mg/kg/day)
Maximum
dose
(mg/kg/day)
Response
shown
at(mcg/ml)
Seizures 10-15mg 5-10
mg/kg/day
every week
50-
100mcg/ml
Acute
mania
750mg in divided
doses of delayed-
release tablets
60 mg/kg/day.
migraines 250 mg twice daily
of delayed-release
tablets,, using
extended release
tablets then 500-
1000mg once daily
1000 mg/day

10. Maintenance Dose
• typical maintenance dose 15 mg/kg/d
resulting in 1000 mg
• Because of age and coadministration of
other antiepileptic drugs
• 7.5 mg/kg/d for adults or 10 mg/kg/d for
children under 12 years(monotherapy)
• 15 mg/kg/d for adults or 20 mg/kg/d for
children )under 12 years of age (enzyme
inducers

11. • Distribution
• Valproate is extensively bound to plasma protein (90–95%),
• Unlike other drugs, it can saturate protein binding sites at
concentrations greater than 50 mg/L, altering the free
fraction of drug.
• Therefore, the apparent volume of distribution of valproate
varies from 0.1 to 0.5 L/kg.

12. • Elimination
• Elimination of valproate is almost entirely by hepatic
metabolism, with less than 5% being eliminated by the
kidneys.
• As a result of the saturation of protein binding sites and the
subsequent increase in the free fraction of the drug,
clearance of the drug increases at higher concentrations.
• Therefore, there is a non-linear change in plasma
concentration with dose

13. • Toxicity:
Oral, mouse: LD50 = 1098 mg/kg; Oral,
rat: LD50 = 670 mg/kg. Symptoms of
overdose may include
 coma
 extreme drowsiness
 and heart problems.

14. Idiosyncratic side effects
• Chronic VPA therapy may be associated
with non-dose-related (idiosyncratic)
toxicity like
hepatic failure
 hyperammonemia without hepatic failure
Alopecia
Leukopenia
thrombocytopenia and anemia

15. SIDE EFFECTS
• Nausea and vomiting
• Drowsiness –sedation
• Ataxia
• Rash
• Hyponatremia
• Weight gain or weight loss
• Teratogenicity
• Osteoporosis

16. DRUG-INTERACTIONS
Acetylsalicylic acid
Acetylsalicylic acid increases
the effect of valproic acid.
Carbamazepine Decreases the effect of valproic
acid
Felbamate
Felbamate,a CYP2C19 inhibitor,
may decrease the metabolism
of Valproic acid,
Erythromycin
The macrolide antibiotic,
Erythromycin,may increase the
serum concentratin of Valproic
acid..

17. Continued
Lamotrigine
Valproic acid may increase the
adverse effects of Lamotrigine by
increasing Lamotrigine serum
concentration
.
Lorazepam
Valproic acid may increase the
serum concentration of Lorazepam
by reducing Lorazepam metabolism.

18. • Practical implications
• In view of the lack of a clear concentration–response
relationship and the variable pharmacokinetics, there
are limited indications for the measurement of
valproate levels.
• In most cases, dosage should be based on clinical
response.
• Valproic acid can take several weeks to become fully
active, so adjustment of doses must not be made
quickly.

19. • In a few cases where seizures are not controlled at
high dosage, a plasma level may be helpful in
confirming treatment failure.
• If monitoring is to be undertaken, levels should be
drawn at steady state (2–3 days). A trough sample
will be the most useful, since wide fluctuations of
blood levels may occur during a dose interval.

20. • Lamotrigine, vigabatrin, gabapentin, tiagabine, topiramate,
pregabalin, lacosamide and levetiracetam
• These newer medicines are indicated for the treatment of a
range of types of epilepsy and some with additional
indications.
• All are used as adjunctive treatment with other
anticonvulsants, and some indicated for monotherapy.