LEPQUITY

Indications

• Epilepsy
• Migraine prophylaxis
• Bipolar disorder

Dosage

Children: Refer to BNF for Children for specific dosing guidance.

Adults: Refer to BNF for specific dosing recommendations based on indication and patient factors.

Mechanism of action

Valproate exerts its effects by inhibiting succinic semialdehyde dehydrogenase, leading to increased levels of succinic semialdehyde which inhibits GABA transaminase, thereby increasing GABA levels and enhancing inhibitory neurotransmission. Additionally, valproate may suppress voltage-gated sodium channels and activate the extracellular signal-related kinase (ERK) pathway, promoting neurogenesis and neural plasticity through increased expression of brain-derived neurotrophic factor (BDNF) and other downstream targets.

Pharmacodynamics

Valproate is effective in reducing the incidence of complex partial seizures, alleviating migraine headaches, and controlling symptoms of bipolar mania. Its neuroprotective properties contribute to the prevention of neural degeneration in these conditions. However, it poses risks of hepatotoxicity and teratogenicity due to its genomic effects. There are also mixed findings regarding its role in the clearance of HIV when used with antiretroviral therapy.

Pharmacokinetics

Valproate is absorbed rapidly from the gastrointestinal tract, with peak plasma concentrations typically reached within 1 to 4 hours post-administration. It has a large volume of distribution and is highly protein-bound, primarily to albumin. The drug undergoes extensive hepatic metabolism, primarily via glucuronidation and beta-oxidation. Its elimination half-life can vary significantly but generally ranges from 8 to 20 hours, depending on individual patient factors.

Contra-indications

• Known hypersensitivity to valproate or any component of the formulation
• Liver disease or significant hepatic dysfunction
• Urea cycle disorders

Adverse effects

• Hepatotoxicity
• Teratogenic effects
• Gastrointestinal disturbances (nausea, vomiting, diarrhea)
• Weight gain
• Sedation
• Tremors
• Hair loss
• Pancreatitis
• Hyperammonemia

Interactions

• May interact with other antiepileptic drugs, leading to altered plasma levels
• Increased risk of hepatotoxicity when used with other hepatotoxic drugs
• May enhance the effects of central nervous system depressants
• Potential to alter the metabolism of drugs metabolized by the liver

Precautions

• Monitor liver function tests before and during treatment
• Use with caution in patients with a history of hepatic disease
• Assess for signs of pancreatitis
• Consider possible teratogenicity in women of childbearing age
• Avoid abrupt withdrawal to prevent seizure exacerbation

Pregnancy

Valproate is associated with a high risk of teratogenic effects, including neural tube defects and other malformations. It should be avoided during pregnancy unless absolutely necessary.

Breast-feeding

Valproate is excreted in breast milk. Caution is advised if the mother requires valproate while breastfeeding.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Valproic acid oral tablets
• Valproic acid oral solution
• Valproate semisodium extended-release tablets
• Valproate semisodium injection

Mechanism of action

The exact mechanisms by which valproate exerts it's effects on epilepsy, migraine headaches, and bipolar disorder are unknown however several pathways exist which may contribute to the drug's action. Valproate is known to inhibit succinic semialdehyde dehydrogenase. This inhibition results in an increase in succinic semialdehyde which acts as an inhibitor of GABA transaminase ultimately reducing GABA metabolism and increasing GABAergic neurotransmission. As GABA is an inhibitory neurotransmitter, this increase results in increased inhibitory activity. A possible secondary contributor to cortical inhibition is a direct suppression of voltage gated sodium channel activity and indirect suppression through effects on GABA. It has also been suggested that valproate impacts the extracellular signal-related kinase pathway (ERK). These effects appear to be dependent on mitogen-activated protein kinase (MEK) and result in the phosphorylation of ERK1/2. This activation increases expression of several downstream targets including ELK-1 with subsequent increases in c-fos, growth cone-associated protein-43 which contributes to neural plasticity, B-cell lymphoma/leukaemia-2 which is an anti-apoptotic protein, and brain-derived neurotrophic factor (BDNF) which is also involved in neural plasticity and growth. Increased neurogenesis and neurite growth due to valproate are attributed to the effects of this pathway. An additional downstream effect of increased BDNF expression appears to be an increase in GABA_A receptors which contribute further to increased GABAergic activity. Valproate exerts a non-competitive indirect inhibitory effect on myo-inosital-1-phophate synthetase. This results in reduced de novo synthesis of inositol monophosphatase and subsequent inositol depletion. It is unknown how this contributed to valproate's effects on bipolar disorder but [lithium] is known to exert a similar inositol-depleting effect. Valproate exposure also appears to produce down-regulation of protein kinase C proteins (PKC)-α and -ε which are potentially related to bipolar disorder as PKC is unregulated in the frontal cortex of bipolar patients. This is further supported by a similar reduction in PKC with lithium. The inhibition of the PKC pathway may also be a contributor to migraine prophylaxis. Myristoylated alanine-rich C kinase substrate, a PKC substrate, is also downregulated by valproate and may contribute to changes in synaptic remodeling through effects on the cytoskeleton. Valproate also appears to impact fatty acid metabolism. Less incorporation of fatty acid substrates in sterols and glycerolipids is thought to impact membrane fluidity and result in increased action potential threshold potentially contributing to valproate's antiepileptic action. Valproate has been found to be a non-competitive direct inhibitor of brain microsomal long-chain fatty acyl-CoA synthetase. Inhibition of this enzyme decreases available arichidonyl-CoA, a substrate in the production of inflammatory prostaglandins. It is thought that this may be a mechanism behind valproate's efficacy in migraine prophylaxis as migraines are routinely treated with non-steroidal anti-inflammatory drugs which also inhibit prostaglandin production. Finally, valproate acts as a direct histone deactylase (HDAC) inhibitor. Hyperacetylation of lysine residues on histones promoted DNA relaxation and allows for increased gene transcription. The scope of valproate's genomic effects is wide with 461 genes being up or down-regulated. The relation of these genomic effects to therapeutic value is not fully characterized however H3 and H4 hyperacetylation correlates with improvement of symptoms in bipolar patients. Histone hyperacetylation at the BDNF gene, increasing BDNF expression, post-seizure is known to occur and is thought to be a neuroprotective mechanism which valproate may strengthen or prolong. H3 hyperacetylation is associated with a reduction in glyceraldehyde-3-phosph

Pharmacodynamics

Valproate has been shown to reduce the incidence of complex partial seizures and migraine headaches. It also improves symptom control in bipolar mania. Although the exact mechanisms responsible are unknown, it is thought that valproate produces increased cortical inhibition to contribute to control of neural synchrony. It is also thought that valproate exerts a neuroprotective effect preventing damage and neural degeneration in epilepsy, migraines, and bipolar disorder. Valproate is hepatotoxic and teratogenic. The reasons for this are unclear but have been attributed to the genomic effects of the drug. A small proof-of concept study found that valproate increases clearance of human immunodeficiency virus (HIV) when combined with highly active antiretroviral therapy (HAART) by reactivating the virus to allow clearance, however, a larger multicentre trial failed to show a significant effect on HIV reservoirs when added to HAART. The FDA labeling contains a warning regarding HIV reactivation during valproate use..