Valproic acid

Valproic acid is an anticonvulsant and is used to treat various types of seizure disorders, including epilepsy. It is also used in some cases to treat bipolar disorder and prevent migraines. Valproic acid belongs to a class of drugs known as valproate derivatives and may be available in a variety of forms including tablets, capsules, oral liquids and injectable solutions.

Indications Valproic acid

Valproic acid (or its salts, such as sodium valproate) is a drug that is used to treat a variety of medical conditions. Here are some of the main indications for valproic acid:

1. Epilepsy: Valproic acid is often used to control epileptic seizures in patients with various forms of epilepsy, including generalized and partial seizures.
2. Migraine: Sodium valproate can be used to prevent migraines in patients suffering from frequent and severe attacks.
3. Bipolar Disorder: Sodium valproate can be used as a mood stabilizer to treat bipolar affective disorder.
4. Prevention of side effects during treatment of bipolar disorder with lithium: Sodium valproate can be used as an additional drug to reduce the risk of side effects during treatment of bipolar disorder with lithium.
5. Central nervous system lesions: Valproic acid can sometimes be used to treat central nervous system lesions such as neuralgia and neuropathic pain.

Release form

Valproic acid is available in a variety of dosage forms, making it easy to administer depending on the individual patient's needs and doctor's recommendations.

The main dosage forms of valproic acid include:

1. Tablets: usually containing sodium valproate or valpromide, are one of the most common forms. Tablets can be either immediate-release or prolonged-release (extended-release).
2. Capsules: often contain microgranules for extended release, which helps to maintain a more stable level of the substance in the blood throughout the day. Capsules may be filled with either solid microgranules or liquid.
3. Syrup or solution: the liquid form of valproic acid makes it easier for children and adults who have difficulty swallowing tablets or capsules to take the medicine. The dosage in this form allows you to precisely regulate the amount taken.
4. Injection: solution for intravenous administration is used clinically, often for rapid control of a condition when oral administration is not possible or is ineffective.

Pharmacodynamics

The pharmacodynamics of valproic acid include several key mechanisms of action through which it exerts therapeutic effects on the central nervous system, especially in the treatment of epilepsy, bipolar disorder and in some cases for migraine prophylaxis.

Mechanisms of action of valproic acid:

1. Increase in GABA levels: Valproic acid increases the concentration of gamma-aminobutyric acid (GABA) in the brain. GABA is the main inhibitory neurotransmitter in the central nervous system. Valproic acid increases the synthesis of GABA and/or decreases its breakdown, and may enhance the action of GABA at postsynaptic receptors. This results in decreased nerve excitability and helps control seizures.
2. Inhibition of sodium channels: Valproic acid modulates ion channels, in particular blocks sodium channels, slowing the repolarization of neurons. This reduces the ability of neurons to generate high-frequency repetitive impulses, which is the mechanism underlying seizure activity.
3. Effect on calcium channels: Valproic acid may also have an effect on T-type calcium channels in neurons, which contributes to a decrease in neuronal excitability.
4. Effects on signaling pathways: Valproic acid is thought to affect various signaling pathways in neurons, including pathways regulated by proteins such as GSK-3 (glycogen synthase-3). This may play a role in its antimanic and mood-stabilizing effects.

Pharmacokinetics

The pharmacokinetics of valproic acid describes how it is absorbed, metabolized, and excreted from the body. Here are the main aspects of valproic acid pharmacokinetics:

1. Absorption: Valproic acid is usually well absorbed from the gastrointestinal tract after oral administration. However, absorption may vary depending on the form of the drug and associated factors such as the presence of food in the stomach.
2. Metabolism: Valproic acid is metabolized in the liver. The main pathways of metabolism are glucoronidation, beta-oxidation and cyclic hydrolysis. The major metabolite is 4-en-valproic acid.
3. Bioavailability: The bioavailability of valproic acid when taken orally may be about 80-90%. This may vary depending on individual patient characteristics and concomitant conditions.
4. Distribution: Valproic acid is widely distributed throughout the tissues of the body. It has low binding to plasma proteins, which favors its distribution in tissues.
5. Elimination: Elimination of valproic acid occurs mainly through the kidneys in the form of conjugated metabolites, as well as through the lungs and to a small extent through the intestine. In patients with normal renal function, the elimination half-life of valproic acid is about 9-16 hours.

Dosing and administration

The method of administration and dosage of valproic acid depend on the specific disease, the patient's age, weight and individual response to treatment. It is important to strictly follow the doctor's instructions and recommendations specified in the instructions for use of the drug. The following are general recommendations for the use and dosage of valproic acid, but remember that only your doctor can determine the optimal dosage based on your condition.

For the treatment of epilepsy:

• Adults and children weighing more than 20 kg: The initial dose is usually 10-15 mg/kg bodyweight per day, the dose is gradually increased until the desired effect is achieved. The maximum daily dose may be up to 60 mg/kg body weight, depending on the response to treatment and tolerability of the drug.
• Children under 20 kg: The dosage is calculated by the doctor individually, with special care to minimize the risk of side effects.

For the treatment of bipolar disorder:

• The starting dose for adults is usually 750 mg per day, divided into several doses. The dosage may be adjusted by a physician depending on clinical response and tolerability.

For migraine prevention:

• The recommended dosage for adults starts at 250 mg twice daily and may be adjusted by a physician until optimal effect is achieved.

General application guidelines:

• Valproic acid can be taken independently of meals, but taking it with food may help reduce stomach irritation.
• Abrupt discontinuation of valproic acid without consulting a physician should be avoided, as this may lead to a worsening of the condition.
• Regular medical supervision is important to monitor the effectiveness of treatment and to detect possible side effects.

Use Valproic acid during pregnancy

Valproic acid during pregnancy is a major concern because of the high risk of birth defects and adverse effects on fetal development. Studies have shown that the use of valproic acid during pregnancy, especially in the first trimester, significantly increases the risk of birth defects such as neural tube defects (e.g., spina bifida), facial anomalies, cardiovascular defects, and cognitive impairment and developmental delay in the child.

Because of these risks, valproic acid is generally not recommended for women of childbearing age and especially pregnant women, unless the potential benefits of the drug outweigh the risks to the fetus. If a woman is planning a pregnancy or is already pregnant, she should discuss possible alternatives to valproic acid with her doctor.

For women on valproic acid treatment who are planning a pregnancy, doctors may recommend:

1. Reassessing the treatment regimen: Changing the medication to a safer option or adjusting the dose of valproic acid if discontinuation of treatment is not possible.
2. Additional folic acid supplementation: Take before and during pregnancy to reduce the risk of neural tube defects, although folic acid does not guarantee complete protection against valproic acid-related birth defects.
3. Regular medical examinations and pregnancy monitoring: Including ultrasound for early detection of possible fetal abnormalities.

The use of valproic acid during pregnancy requires careful weighing of risks and benefits, and treatment decisions should be made in conjunction with a qualified medical professional specializing in pregnancy management and the treatment of epilepsy or bipolar disorder.

Contraindications

Valproic acid has several contraindications, and its use should be carried out under the strict supervision of a doctor. The main contraindications to the use of valproic acid are listed below:

1. Hypersensitivity or allergic reaction: Patients with a known allergy to valproic acid or any other ingredients of the drug should not use this drug.
2. Hepatic insufficiency: Valproic acid is metabolized in the liver, therefore its use may be contraindicated in patients with severe hepatic insufficiency or in patients with impaired hepatic function.
3. Porphyrin disease: The use of valproic acid may be contraindicated in patients with porphyrin disorders, as it may cause exacerbation of the disease.
4. Pregnancy: The use of valproic acid during pregnancy may be associated with an increased risk of birth defects in the fetus, therefore use should be strictly limited in pregnant women, especially in the first trimester.
5. Pancreatitis: The drug may be contraindicated in the presence of or predisposition to pancreatitis.
6. Diabetes Mellitus: Valproic acid may increase the risk of developing diabetes mellitus or worsen its course in patients with existing diabetes.
7. Children under 2 years of age: The use of valproic acid in children under two years of age may be contraindicated due to the risk of hepatic insufficiency.

Side effects Valproic acid

Here are some of the most common side effects:

Common side effects:

• Nausea and vomiting: Some of the most common side effects, especially during the initial phase of treatment.
• Weight gain: May occur due to changes in appetite or metabolism.
• Tremor (shaking of the hands): Often occurs at high doses.
• Alopecia (hair loss): Usually temporary and reversible.
• Drowsiness and fatigue: Especially at the beginning of treatment.

Serious side effects:

• Hepatotoxicity (liver damage): May be serious and potentially life-threatening. Requires regular monitoring of liver function.
• Pancreatitis: Inflammation of thepancreas, which can be serious and require immediate intervention.
• Thrombocytopenia (low platelet count): May increase the risk of bleeding.
• Hyperammonemia: Elevated levels of ammonia in the blood, can cause changes in mental state.
• Teratogenicity: May cause birth defects if taken during pregnancy, so it is important to discuss contraception and family planning with your doctor.

Rare but serious side effects:

• Encephalopathy: May manifest as confusion, cognitive decline.
• DRESS syndrome(drug reaction with eosinophilia and systemic symptoms): A rare but serious condition requiring immediate discontinuation of the drug.

Overdose

Valproic acid overdose can lead to serious and potentially dangerous consequences. Symptoms of an overdose can vary depending on the level of excess drug in the body and individual patient characteristics. Here are some of the possible symptoms of valproic acid overdose:

1. Drowsiness and decreased wakefulness.
2. Dizziness and loss of coordination.
3. Cramping and shaking.
4. Swelling and breathing problems.
5. Vomiting and nausea.
6. An increase or decrease in blood pressure.
7. Mental disturbances, including agitation, anxiety, or hallucinations.
8. Increased levels of ammonia in the blood (hyperammonemia).

If an overdose of valproic acid is suspected, medical attention should be sought immediately. Treatment of overdose includes maintaining vital functions, monitoring the cardiovascular system and breathing, and taking measures to reduce the level of the drug in the body, such as gastric lavage, administration of activated charcoal and symptomatic therapy.

Interactions with other drugs

Valproic acid may interact with other medications, which may alter their effectiveness or increase the risk of side effects. Here are some of the most significant interactions with other medicines:

1. Drugs that increase the risk of bleeding: Drugs such as aspirin, anticoagulants (e.g. Warfarin) or platelet antiaggregants (e.g. Clofibrate) may increase the risk of bleeding when taken concomitantly with valproic acid.
2. Drugs affecting liver function: Drugs such as carbamazepine, phenytoin, phenobarbital and other inducers of hepatic microsomal enzymes may increase the metabolism of valproic acid, which may lead to a decrease in its concentration in the blood and reduced efficacy.
3. Drugs that decrease valproic acid concentration: Some drugs such as carbapenems (e.g., imipenem, meropenem) may increase the metabolism of valproic acid, which may also decrease its concentration in the blood and reduce its effectiveness.
4. Drugs that increase the concentration of valproic acid: Some drugs, such as lamotrigine, may increase the concentration of valproic acid in the blood, which increases the risk of side effects.
5. Sedative drugs: When valproic acid is combined with other sedative drugs (e.g., sleeping pills, antidepressants, or antihistamines), sedation may be increased.

Storage conditions

Valproic acid storage conditions should be followed according to the manufacturer's instructions and your doctor's recommendations. The following conditions are generally considered optimal for storage of valproic acid:

1. Temperature: Store valproic acid at room temperature, approximately 20°C to 25°C. Avoid overheating of the drug and extreme temperatures.
2. Protection from light: It is important to store valproic acid in the original package or in a dark container protected from direct sunlight. Light can destroy the active ingredients of the drug.
3. Dryness and protection from moisture: During storage, make sure that the preparation is not exposed to humid conditions. Store it in a dry place to prevent decomposition and change of properties of the preparation.
4. Children and pets: Keep valproic acid out of the reach of children and pets. This is important to prevent accidental use and to ensure the safety of others.
5. Original packaging: Keep the drug in its original package or container to avoid accidental confusion with other medicines.

Shelf life

Watch the expiration date of valproic acid and do not use it after the expiration date. Also observe the instructions for use dates after opening the package.