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Valproic Acid; Uses, Dosage, Side Effects, Drug Interactions

Valproic Acid is a synthetic derivative of propylpentanoic acid with antiepileptic properties and potential antineoplastic and antiangiogenesis activities. In epilepsy, valproic acid appears to act by increasing the concentration of gamma-aminobutyric acid (GABA) in the brain. This agent’s antitumor and antiangiogenesis activities may be related to the inhibition of histone deacetylases and nitric oxide synthase, which results in the inhibition of nitric oxide synthesis.

Valproic acid supplied as the sodium salt valproate semisodium or divalproex sodium is a fatty acid with anticonvulsant properties used in the treatment of epilepsy & primarily used to treat epilepsy and bipolar disorder and to prevent migraine headaches. It is useful for the prevention of seizures in those with absence seizures, partial seizures, and generalized seizures. The mechanisms of its therapeutic actions are not well understood. It may act by increasing gamma-aminobutyric acid levels in the brain or by altering the properties of voltage-dependent sodium channels.

Mechanism of Action of Valproic Acid

Valproic Acid dissociates to the valproate ion in the gastrointestinal tract and then binds to and inhibits GABA transaminase. The drug’s anticonvulsant activity may be related to increased brain concentrations of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter in the CNS, by inhibiting enzymes that catabolize GABA or block the reuptake of GABA into glia and nerve endings. Valproic Acid may also work by suppressing repetitive neuronal firing through inhibition of voltage-sensitive sodium channels. It is also a histone deacetylase inhibitor. Valproic acid has also been shown to be an inhibitor of an enzyme called histone deacetylase 1 (HDAC1). HDAC1 is needed for HIV to remain in infected cells. A study published in August 2005 revealed that patients treated with valproic acid in addition to highly active antiretroviral therapy (HAART) showed a 75% reduction in latent HIV infection.

Valproic acid (VPA), a widely prescribed drug for seizures and bipolar disorder, has been shown to be an inhibitor of histone deacetylase (HDAC). /A/ previous study has demonstrated that VPA pretreatment reduces lipopolysaccharide (LPS)-induced dopaminergic (DA) neurotoxicity through the inhibition of microglia over-activation. The aim of this study was to determine the mechanism underlying VPA-induced attenuation of microglia over-activation using rodent primary neuron/glia or enriched glia cultures. Other histone deacetylase inhibitors (HDACIs) were compared with VPA for their effects on microglial activity. We found that VPA induced apoptosis of microglia cells in a time- and concentration-dependent manner. VPA-treated microglial cells showed typical apoptotic hallmarks including phosphatidylserine externalization, chromatin condensation, and DNA fragmentation. Further studies revealed that trichostatin A (TSA) and sodium butyrate (SB), two structurally dissimilar HDACIs, also induced microglial apoptosis. The apoptosis of microglia was accompanied by the disruption of mitochondrial membrane potential and the enhancement of acetylation levels of the histone H3 protein. Moreover, pretreatment with SB or TSA caused a robust decrease in LPS-induced pro-inflammatory responses and protected DA neurons from damage in mesencephalic neuron-glia cultures. Taken together, /these/ results shed light on a novel mechanism whereby HDACIs induce neuroprotection and underscore the potential utility of HDACIs in preventing inflammation-related neurodegenerative disorders such as Parkinson’s disease

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Indications of Valproic Acid

Bipolar disorder
Epilepsy
Seizure prevention
Cluster-Tic syndrome
Hyperekplexia
Mania
Migraine prevention
Schizoaffective disorder
Seizures
Epilepsies
A migrainous headache
Schizophrenic disorders
Acute manic episode
For treatment and management of seizure disorders, mania, and prophylactic treatment of a migraine headache. In epileptics, valproic acid is used to control absence seizures, tonic-clonic seizures (grand mal), complex partial seizures, and the seizures associated with Lennox-Gastaut syndrome.

Contra Indications of Valproic Acid

High amount of ammonium in the blood
Low amount of albumin proteins in the blood
Porphyria
Decreased blood platelets
Having thoughts of suicide
Depression
Organic mental disorder
Liver problems
Acute inflammation of the pancreas
Pregnancy
Ornithine carbamoyltransferase deficiency
Poisoning by drug valproic Acid
Hereditary disease causing neurologic dysfunction
Urea cycle disorder

The Dosage of Valproic Acid

Strengths: 125 mg; 200mg; 500 mg ;100 mg/mL; 250 mg; 250 mg/5 mL

Epilepsy

Complex partial seizures

Initial dose: 10 to 15 mg/kg orally or IV daily; increase by 5 to 10 mg/kg per week if necessary according to clinical response
Maintenance dose: 10 to 60 mg/kg daily
Maximum dose: 60 mg/kg daily

Simple and complex absence seizures

Initial dose: 15 mg/kg orally or IV daily; increase by 5 to 10 mg/kg per week if necessary according to clinical response
Maintenance dose: 10 to 60 mg/kg daily
Maximum dose: 60 mg/kg daily

Pediatric Epilepsy

10 years or older

Initial dose: 10 to 15 mg/kg orally or IV daily; increase by 5 to 10 mg/kg per week if necessary according to clinical response
Maintenance dose: 10 to 60 mg/kg daily
Maximum dose: 60 mg/kg daily

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Simple and complex absence seizures

Initial dose: 15 mg/kg orally or IV daily; increase by 5 to 10 mg/kg per week if necessary according to clinical response
Maintenance dose: 10 to 60 mg/day

Side Effects of Valproic Acid

The most common

nausea, vo miting, stomach pain, indigestion, constipation, diarrhea;
fever, flu symptoms, cough, sore throat, sneezing, runny nose;
nervousness, depression, sleep problems (insomnia);
headache, dizziness, drowsiness, memory problems, unusual thoughts;
rash, hair loss, bruising;
weakness, tremors, problems with balance or walking;
swelling in your hands or feet;
vision problems, ringing in your ears; or
changes in appetite, weight gain.

More common

Black, tarry stools
bleeding gums
bloating or swelling of the face, arms, hands, lower legs, or feet
blood in the urine or stools
confusion
cough or hoarseness
crying
delusions
dementia
depersonalization
diarrhea
difficult or labored breathing
dysphoria
euphoria
fever or chills

Less common

Abnormal dreams
absence of or decrease in body movement
anxiety
bloody nose
bloody or cloudy urine
blurred vision
burning, crawling, itching, numbness, prickling, “pins and needles”, or tingling feelings
change in personality
change in walking and balance
changes in patterns and rhythms of speech
chest pain
lack of appetite
lack of coordination
large, flat, blue or purplish patches in the skin
leg cramps
lip smacking or puckering
loss of bladder control

Drug Interactions of Valproic Acid

Valproic Acid may interact with following drug, suppliments, & may change the efficasy of drugs

antihistamines (e.g,. cetirizine, doxylamine, diphenhydramine, hydroxyzine,loratadine)
antiseizure medications e.g., clobazam, levetiracetam, phenobarbital, phenytoin, , valproic acid, zonisamide)
aripiprazole
“azole” antifungals (e.g., itraconazole, ketoconazole, voriconazole)
benzodiazepines (e.g., alprazolam, diazepam, lorazepam)
beta-adrenergic blockers (e.g., atenolol, propranolol, sotalol)
calcium channel blockers (e.g., amlodipine, diltiazem, nifedipine, verapamil)
captopril
celecoxib
chloroquine
cholecalciferol
cyclosporine
dantrolene
domperidone
“gliptin” diabetes medications (e.g., linagliptin, saxagliptin, sitagliptin)
gabapentin
H2 antagonists (e.g., famotidine, ranitidine)
mirabegron
montelukast
non-steroidal anti-inflammatory medications (NSAIDs;e.g., diclofenac, ibuprofenserotonin antagonists (anti-emetic medications;, naproxen)
phosphodiesterase 5 inhibitors (e.g., sildenafil, tadalafil, vardenafil)
quinolone antibiotics (e.g., levofloxacin, norfloxacin, moxifloxacin)
selective serotonin reuptake inhibitors (SSRIs; e.g., paroxetine, fluoxetine,citalopram)
e.g., granisetron,ondansetron)
“statin” anti-cholesterol medications (e.g., atorvastatin, lovastatin,simvastatin)
theophylline
thiazide diuretics (water pills; e.g., hydrochlorothiazide, indapamide, metolazone)
tramadol
tricyclic antidepressants (e.g., amitriptyline, clomipramine, desipramine,

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Pregnancy & Lactation of Valproic Acid

Valproate was initially Pregnancy Category D, but it is now Category X

Pregnancy

There is an increased risk of birth defects for a child whose mother takes valproic acid during pregnancy. Although rare, valproic acid may cause a defect of the spine called spina bifida or slowed or reduced mental development. Before becoming pregnant, women with epilepsy should speak to their doctor about options for seizure medications. If you become pregnant while taking this medication, contact your doctor immediately.

Lactation

This medication passes into breast milk. If you are a breastfeeding mother and are taking valproic acid it may affect your baby. Talk to your doctor about whether you should continue breastfeeding. As a general rule, women who are taking valproic acid should not breastfeed.