VALPROIC ACID, VALPROATE SODIUM, DIVALPROEX SODIUM
Chemistry - Structurally unrelated to other anticonvulsant agents, valproic acid, valproate sodium, divalproex sodium are derivatives of carboxylic acid. Valproic acid occurs as a colorless to paleyellow clear liquid. It is slightly viscous, has a characteristic odor, a pKa of 4.8, is slightly soluble inwater and freely soluble in alcohol. It is also known as Dipropylacetic acid, DPA, 2-propylpentanoic acid, and 2-propylvaleric acid.
Valproate sodium occurs as a white, crystalline, saline tasting, very hygroscopic powder. It is verysoluble in water and in alcohol. The commercially available oral solution has a pH of 7-8.
Divalproex sodium is a stable compound in a 1:1 molar ratio of valproic acid and valproatesodium. It occurs as a white powder with a characteristic odor. It is insoluble in water and verysoluble in alcohol.
Animal studies have demonstrated that valproic acid inhibits GABA transferase and succinicaldehyde dehydrogenase causing increased CNS levels of GABA. Additionally, one study hasdemonstrated that valproic acid inhibits neuronal activity by increasing potassium conductance.
Uses, Indications - Because of its cost, apparent unfavorable pharmacokinetic profile, and potentialhepatotoxicity, valproic acid must be considered at this time to be a third-line drug in the treatmentof seizures in the dog. Some clinicians feel it is of benefit when added to phenobarbital in patientsnot adequately controlled with that drug alone. Additionally, it is less protein bound in dogs than inman, so the human serum therapeutic range of the drug (40 - 100 micrograms/ml) may be too highin dogs. The drug (free form) actually may concentrate in the CSF, and anticonvulsant effects maypersist even after valproate levels are non-detectable in CSF, leading to the prospect that serumlevels do not accurately reflect clinical efficacy. Clearly, additional studies are needed to determinethe clinical efficacy of this drug.
Valproic acid is rapidly distributed throughout the extracellular water spaces and plasma. It isapproximately 80-95% plasma protein bound in humans, and 78-80% plasma protein bound indogs. CSF levels are approximately 10% of those found in the plasma. Milk levels are 1-10% ofthose found in the plasma and it readily crosses the placenta.
Valproic acid is metabolized in the liver and is conjugated with glucuronide. These metabolicconjugates are excreted in the urine; only very small amounts of unchanged drug are excreted in theurine. The elimination half-life in humans ranges from 5-20 hours, and in dogs from 1.5-2.8 hours.
Contraindications/Precautions - Valproic acid is contraindicated in patients with significanthepatic disease or dysfunction, or exhibiting previous hypersensitivity to the drug. It should be usedwith caution in patients with thrombocytopenia or altered platelet aggregation function.
A 1-2% incidence of neural tube defects in children born of mothers taking valproic acid duringthe first trimester of pregnancy has been reported. Use in pregnant dogs only when the benefitsoutweigh the risks of therapy.
Other potential adverse effects include: CNS (sedation, ataxia, behavioral changes, etc), dermatologic (alopecia, rash, etc), hematologic (thrombocytopenia, reduced platelet aggregation, leukopenias, anemias, etc.), pancreatitis, and edema.
Overdosage - Severe overdoses can cause profound CNS depression, asterixis, motor restlessness, hallucinations, and death. One human patient recovered after a serum level of 2000 micrograms/ml(20 times over therapeutic) was measured. Treatment consists of supportive measures andmaintenance of adequate urine output is considered to be mandatory. Because the drug is rapidlyabsorbed, emesis or gastric lavage may be of limited value. Because of its delayed absorptivecharacteristics, the divalproex form may be removed by lavage or emesis if ingestion occurredrecently. Naloxone is reported to be of benefit in reversing some of the CNS effects of valproicacid, but may also reverse the anticonvulsant properties of the drug.
Valproic acid may increase serum levels of phenobarbital and primidone. Valproic acid mayhave effects on platelet aggregation; use with caution with other drugs that affect coagulation status(e.g., warfarin, ASA).
Salicylates may displace valproic acid from plasma protein sites, thus increasing valproic acidlevels.
The sedative effects of clonazepam may be enhanced by valproic acid and the anticonvulsantefficacy of both may be diminished.
Drug/Lab Interactions - A keto-metabolite of valproic acid is excreted into the urine and may yield false positive urine ketone tests. Altered thyroid function tests have been reported in humans with unknown clinical significance.
Valproate sodium occurs as a white, crystalline, saline tasting, very hygroscopic powder. It is verysoluble in water and in alcohol. The commercially available oral solution has a pH of 7-8.
Divalproex sodium is a stable compound in a 1:1 molar ratio of valproic acid and valproatesodium. It occurs as a white powder with a characteristic odor. It is insoluble in water and verysoluble in alcohol.
Storage, Stability, Compatibility
Valproic acid capsules should be stored at room temperature(15-30°C) and in tight containers; avoid freezing. Valproate sodium oral solution should be storedat room temperature and in tight containers; avoid freezing. Divalproex sodium enteric-coatedtablets should be stored at room temperature in tight, light resistant containers.Pharmacology - VALPROIC ACID, VALPROATE SODIUM, DIVALPROEX SODIUM
The mechanism of the anticonvulsant activity of valproic acid is not understood.Animal studies have demonstrated that valproic acid inhibits GABA transferase and succinicaldehyde dehydrogenase causing increased CNS levels of GABA. Additionally, one study hasdemonstrated that valproic acid inhibits neuronal activity by increasing potassium conductance.
Uses, Indications - Because of its cost, apparent unfavorable pharmacokinetic profile, and potentialhepatotoxicity, valproic acid must be considered at this time to be a third-line drug in the treatmentof seizures in the dog. Some clinicians feel it is of benefit when added to phenobarbital in patientsnot adequately controlled with that drug alone. Additionally, it is less protein bound in dogs than inman, so the human serum therapeutic range of the drug (40 - 100 micrograms/ml) may be too highin dogs. The drug (free form) actually may concentrate in the CSF, and anticonvulsant effects maypersist even after valproate levels are non-detectable in CSF, leading to the prospect that serumlevels do not accurately reflect clinical efficacy. Clearly, additional studies are needed to determinethe clinical efficacy of this drug.
Pharmacokinetics - VALPROIC ACID, VALPROATE SODIUM, DIVALPROEX SODIUM
Sodium valproate is rapidly converted to valproic acid in the acidic environment of the stomach where it is rapidly absorbed from the GI tract. The bioavailability reportedin dogs following oral administration is approximately 80% and peak levels occur in approximatelyone hour. Food may delay absorption, but does not alter the extent of it. Divalproex in its entericcoated form has an approximately 1 hour delay in its oral absorption. Patients who exhibit GI(nausea, vomiting) adverse effects may benefit from this dosage form.Valproic acid is rapidly distributed throughout the extracellular water spaces and plasma. It isapproximately 80-95% plasma protein bound in humans, and 78-80% plasma protein bound indogs. CSF levels are approximately 10% of those found in the plasma. Milk levels are 1-10% ofthose found in the plasma and it readily crosses the placenta.
Valproic acid is metabolized in the liver and is conjugated with glucuronide. These metabolicconjugates are excreted in the urine; only very small amounts of unchanged drug are excreted in theurine. The elimination half-life in humans ranges from 5-20 hours, and in dogs from 1.5-2.8 hours.
Contraindications/Precautions - Valproic acid is contraindicated in patients with significanthepatic disease or dysfunction, or exhibiting previous hypersensitivity to the drug. It should be usedwith caution in patients with thrombocytopenia or altered platelet aggregation function.
A 1-2% incidence of neural tube defects in children born of mothers taking valproic acid duringthe first trimester of pregnancy has been reported. Use in pregnant dogs only when the benefitsoutweigh the risks of therapy.
Adverse Effects, Warnings
Because of the limited experience with this agent, the followingadverse effects may not be complete nor totally valid for dogs: Gastrointestinal effects consisting ofnausea, vomiting, anorexia, diarrhea are the most common adverse effects seen in people and alsoapparently in dogs. Hepatotoxicity is the most serious potential adverse (human) reaction reportedand must be also considered for canine patients. Dose related increases in liver enzymes may beseen and, rarely, hepatic failure and death may occur. In humans, incidences of hepatotoxicty aregreater in very young (<2 yrs old) patients, those on other anticonvulsants, or with multiplecongenital abnormalities.Other potential adverse effects include: CNS (sedation, ataxia, behavioral changes, etc), dermatologic (alopecia, rash, etc), hematologic (thrombocytopenia, reduced platelet aggregation, leukopenias, anemias, etc.), pancreatitis, and edema.
Overdosage - Severe overdoses can cause profound CNS depression, asterixis, motor restlessness, hallucinations, and death. One human patient recovered after a serum level of 2000 micrograms/ml(20 times over therapeutic) was measured. Treatment consists of supportive measures andmaintenance of adequate urine output is considered to be mandatory. Because the drug is rapidlyabsorbed, emesis or gastric lavage may be of limited value. Because of its delayed absorptivecharacteristics, the divalproex form may be removed by lavage or emesis if ingestion occurredrecently. Naloxone is reported to be of benefit in reversing some of the CNS effects of valproicacid, but may also reverse the anticonvulsant properties of the drug.
Drug Interactions
VPA may enhance the CNS depressant effects of other CNS active drugs.Valproic acid may increase serum levels of phenobarbital and primidone. Valproic acid mayhave effects on platelet aggregation; use with caution with other drugs that affect coagulation status(e.g., warfarin, ASA).
Salicylates may displace valproic acid from plasma protein sites, thus increasing valproic acidlevels.
The sedative effects of clonazepam may be enhanced by valproic acid and the anticonvulsantefficacy of both may be diminished.
Drug/Lab Interactions - A keto-metabolite of valproic acid is excreted into the urine and may yield false positive urine ketone tests. Altered thyroid function tests have been reported in humans with unknown clinical significance.