What Is Valproic Acid Toxicity?

Valproic acid is a colorless liquid. The molecular formula is C8H16O2, the molecular weight is 144.21100, the boiling point is 221 ° C, the relative density is 1.1 (24.5 / 4 ° C), the refractive index is 1.4250, and the flash point is 111 ° C. Hardly soluble in water. It is extremely harmful to water and toxic to fish. Do not let the product enter the water body. [1] Store in a cool, ventilated warehouse. Keep away from fire and heat sources. Packaging is sealed. It should be stored separately from oxidants and alkalis.

Valproic acid is a colorless liquid. The molecular formula is C8H16O2, the molecular weight is 144.21100, the boiling point is 221 ° C, the relative density is 1.1 (24.5 / 4 ° C), the refractive index is 1.4250, and the flash point is 111 ° C. Hardly soluble in water. It is extremely harmful to water and toxic to fish. Do not let the product enter the water body. [1] Store in a cool, ventilated warehouse. Keep away from fire and heat sources. Packaging is sealed. It should be stored separately from oxidants and alkalis.
Chinese name
Valproic acid
English name
Valproic Acid
nickname
2-propylvaleric acid dipropylacetic acid valproic acid A-propylvaleric acid di-n-propylacetic acid 2 [1]
Chemical formula
C8H16O2
Molecular weight
144.21 [1]
CAS Registry Number
99-66-1
EINECS registration number
202-777-3
Melting point
120- 130ºC
Boiling point
221ºC [1]
Water soluble
Very slightly soluble in water [1]
Density
0.904
Exterior
Colorless liquid
Flash point
232 ° F
Dangerous Goods Transport Number
UN 1230 3 / PG 2

Valproic acid compounds

Valproic acid basic information

Chinese name: Valproic acid
Chinese alias: 2-propylvaleric acid; 2-n-propyl-n-valeric acid; 2,2-di-n-propylacetic acid; A-propylvaleric acid; -propylvaleric acid;
English name: valproic acid
English alias: Mylproin; Ergenyl; 2-Propylpentanoic acid; VALPROIC ACID; Depakine;
CAS number: 99-66-1
Molecular formula: C 8 H 16 O 2
Molecular weight: 144.21100
Structural formula:
Exact mass: 144.11500
PSA: 37.30000
LogP: 2.28740 [2]

Valproic acid

Appearance and properties: transparent liquid
Density: 0.92
Melting point: 120-130ºC
Boiling point: 220 ° C (lit.)
Flash point: 232 ° F
Refractive index: n20 / D 1.425 (lit.)
Water solubility: slightly soluble
Stability: stable at normal temperature and pressure
Storage conditions: storeroom is ventilated, low temperature and dry, and stored separately from oxidants [2]

Valproic acid physical data

1. Properties: colorless liquid.
2. Density (g / mL, 20 ): 0.904
3. Relative vapor density (g / mL, air = 1): Not determined
4. Melting point (ºC): Not determined
5. Boiling point (ºC, normal pressure): 221
6. Boiling point (ºC, kPa): Not determined
7. Refractive index: 1.425
8. Flash point (ºC): 111
9. Specific rotation (º): Not determined
10. Spontaneous ignition point or ignition temperature (ºC): Not determined
11. Vapor pressure (mmHg, 25ºC): Not determined
12. Saturated vapor pressure (kPa, 25ºC): Not determined
13. Combustion heat (KJ / mol): Not determined
14. Critical temperature (ºC): Not determined
15. Critical pressure (KPa): Not determined
16. Logarithm of oil-water (octanol / water) partition coefficient: Not determined
17. Upper explosion limit (%, V / V): Not determined
18. Lower explosion limit (%, V / V): Not determined
19. Solubility: Very slightly soluble in water. [1]

Valproic acid toxicology data

Acute toxicity: oral LD5O in rats: 670mg / kg, oral LD5O in mice: 1098mg / kg, oral LD5O in guinea pigs: 824mg / kg [1]

Valproic acid ecological data

It is extremely harmful to water and toxic to fish. Do not let the product enter the water body. [1]

Valproic acid molecular structure data

1. Molar refractive index: 40.63
2. Molar volume (m3 / mol): 155.5
3. Isotonic specific volume (90.2K): 369.6
4. Surface tension (dyne / cm): 31.8
5. Dielectric constant:
6. Dipole distance (10-24cm3):
7. Polarizability: 16.10 [1]

Valuic acid calculated chemical data

1. Hydrophobic parameter calculation reference value (XlogP): None
2.Number of hydrogen-bonded donors: 1
3.Number of hydrogen bond acceptors: 2
4.Number of rotatable chemical bonds: 5
5.Number of tautomers: none
6. Topological molecular polar surface area 37.3
7.Number of heavy atoms: 10
8.Surface charge: 0
9.Complexity: 93.4
10.Number of isotope atoms: 0
11. Determine the number of atomic stereocenters: 0
12. Uncertain number of atomic stereocenters: 0
13. Determine the number of chemical bond stereocenters: 0
14. Uncertain number of chemical bond stereocenters: 0
15. Number of covalent bond units: 1 [1]

Valproic acid storage method

Store in a cool, ventilated warehouse. Keep away from fire and heat sources. Packaging is sealed. It should be stored separately from oxidants and alkalis. Use explosion-proof lighting and ventilation facilities. Prohibit the use of spark-prone machinery and tools. The storage area should be equipped with suitable materials to contain spills. [1]

Valproic acid production method

1. Derived from dipropylmalonate by eliminating decarboxylation. Dipropylmalonic acid was put into the reaction pot and heated to 180 ° C, the reactants gradually melted, and a large amount of carbon dioxide gas was released. After the elimination reaction was completed, distillation was performed under reduced pressure, and a fraction of 112-114 ° C (0.93-1.06kPa) was collected, which was 2-propylvaleric acid, and the yield was 86%. [1]
2. Preparation method:
Dipropylmalonate: In a reaction flask equipped with a stirrer and a reflux condenser, add 122g (0.5mol) of diethyldipropylmalonate, 220mL of ethanol, and 400g of 4% potassium hydroxide. The reaction was refluxed for 4h. The ethanol was distilled off under reduced pressure. Cool to room temperature, slowly add concentrated hydrochloric acid, adjust to pH1, and precipitate a solid. Cool, suction filter, wash with water, and dry to obtain 75.0 g of yellow dipropylmalonate crystals, yield 80%, mp. 155-158 ° C. 2-propylvaleric acid: Add 75.0g (0.4mol) of dipropylmalonic acid to the reaction flask, slowly heat the oil bath to 180 ° C, the reactants gradually melt, and release a large amount of carbon dioxide gas, until no carbon dioxide gas escapes So far. Distillate under reduced pressure and collect a fraction of 120-123 ° C / 1.86kPa to obtain pale yellow 2-n-propyl acid 49.5 with a yield of 86% and nD141.4252. Note: It can also be prepared by reacting ethyl acetoacetate with n-bromopropane, followed by alkaline hydrolysis. [1]

Valproic acid uses

Used as pharmaceutical intermediate, organic synthesis. [1]

Valproic acid safety information

Dangerous Transport Code: UN 1230 3 / PG 2
Dangerous goods sign: T toxic Xn harmful
Safety identification: S26
Danger sign: R22 R36 / 37/38

Valproic acid pharmacology and toxicology

Valproate exerts its pharmacological effects mainly through the central nervous system. Animal studies have shown that it is resistant to many types of seizures.
Laboratory and clinical studies have shown that valproate produces anticonvulsant effects in two ways. The first mode of action is a direct pharmacological effect related to valproic acid concentration in plasma and brain. The second mode of action is indirect, which may be related to valproate metabolites in the brain, or to changes in neurotransmitters or direct membrane action. The widely accepted hypothesis is that taking valproate can cause an increase in -aminobutyric acid (GABA) levels in the body.
Valproate reduces the period of mid-sleep, while increasing slow-wave sleep. [3]

Valproic acid pharmacokinetics

Several pharmacokinetic studies of valproate have been carried out, and the results show that:
* Examination results using blood concentration as an index show that the bioavailability of oral drugs is close to 100%;
* Most drugs are distributed in the blood and there is a rapid exchange process with extracellular fluid. The drug can also be distributed in the cerebrospinal fluid (CSF) and the brain. The concentration of valproate in CSF is close to the concentration of free drug in plasma. The half-life of the drug is 15-17 hours. Children are usually shorter.
* The lower limit of serum drug concentration that produces a therapeutic effect is usually 40-50mg / L, and the range can be relaxed to 40-100mg / L. If it is determined that a higher blood concentration is necessary, a trade-off must be made between the efficacy and possible adverse effects, especially those related to the blood concentration. However, if the blood concentration level has been maintained above 150 mg / L, the dose needs to be reduced.
* The plasma concentration of the drug reaches steady state after 3-4 days of continuous administration.
* Valproate is excreted in the body through glucuronidation and -oxidation through the urine.
* Valproate can be dialyzed out, but hemodialysis only affects the plasma concentration of free drugs (about 10% of the plasma concentration). Valproate does not induce the enzymes involved in the CYP450 metabolic system. Compared with most other anti-epileptic drugs, it does not accelerate the degradation of itself and other drugs, such as estrogen-progestin and oral anticoagulants. Compared with valproate enteric preparations, the in vivo pharmacokinetics of the drug after taking this product at the same dose have the following characteristics:
* No absorption delay phase;
* Extended absorption phase;
* Same bioavailability;
* The peak of total plasma concentration and free plasma concentration decreased (Cmax decreased by about 25%, and showed a relatively stable plateau period between 4 and 14 hours after taking the drug); the blood concentration of valproic acid during the 24-hour period- The time curve shows a "smooth peak" phenomenon. The blood concentration of valproic acid is stable and lasts for 24 hours: after the same dose is taken twice a day, the change in the blood concentration of valproate is reduced by half.
* The linear relationship between the total plasma concentration and the free plasma concentration and the administered dose is better. [3]

Valproic acid indication

Valproic Epilepsy

It can be used as a monotherapy or as an additive treatment.
* For the treatment of generalized epilepsy: including absence episodes, myoclonus episodes, tonic-clonic episodes, tonic episodes and mixed episodes, special types of syndrome (West, Lennox-Gastaut syndrome), etc.
* For the treatment of partial epilepsy: local seizures, with or without generalized seizures.

Valproic mania

Used to treat manic episodes associated with bipolar disorder. [3]

Valproic acid specifications:

Each tablet contains 0.333g of sodium valproate and 0.145g of valproic acid (equivalent to 0.5g of sodium valproate). [3]

Valproic acid usage and dosage:

Valproic Epilepsy

This product is a sustained-release preparation. After taking the drug, the peak blood concentration in the body can be reduced, and at the same time, the blood concentration can be maintained at a normal level within 24 hours.
This dose is suitable for adults and children weighing more than 17 kg.
This dosage form is not suitable for children under 6 years of age. (There is a danger of accidentally entering the trachea)
Use this product to control seizures. Anti-epileptic drugs should not be discontinued abruptly in patients who are taking medications to prevent major seizures, because if they are abruptly discontinued, there is a high probability of a state of epilepsy with hypoxia and life threatening.

Valproic acid dose

The initial dose is usually 10-15 mg / kg daily, and then it is increased until the effect is satisfactory (see Initial Treatment). The general dose is 20 to 30 mg / kg daily. However, if seizure status cannot be controlled at this dose range, then increasing the dose can be considered, but the patient must be closely monitored.
When children take this product, the usual dose is 30mg / kg daily.
When adults take this product, the usual dose is 20-30mg / kg daily.
When taking this product in elderly patients, the dosage should be determined according to the control of the state of attack.
The daily dose should be determined according to the age and weight of the patient. At the same time, it should be taken into account that there are obvious individual differences in clinical sensitivity to valproate.
So far, the correlation between daily dose, blood concentration level and therapeutic effect is still not clear, and the dosage is mainly determined based on clinical efficacy. When the seizure is uncontrollable or suspected of adverse reactions, in addition to clinical monitoring, the determination of sodium valproate plasma levels should be considered. The effective range has been reported to be 40-100 mg / L (300-700 mol / L). [3]

Valproic acid medication method

oral. The daily dose should be taken in 1-2 times.
In cases where epilepsy has been well controlled, daily medication may be considered.
This product should be swallowed whole, can be taken halfway apart, but cannot be ground or chewed.
Initial treatment
* For patients newly diagnosed with epilepsy or who have not used other antiepileptic drugs, the drug dose is increased every 2 to 3 days, and the optimal dose is reached within 1 week.
* For patients taking other fast-acting sodium valproate and the condition has been well controlled, the recommended daily dose when using this product is still maintained.
* In patients who have previously received other antiepileptic drugs, the use of sodium valproate sustained-release tablets should be carried out gradually, reaching the optimal dose within 2 weeks, and other treatments gradually reduced to discontinuation. If other antiepileptic drugs are needed, they should be added gradually. (See [Drug Interactions])

Valproic mania

Oral administration. In patients who have not received other psychotropic drugs, the drug dose is increased every 2-3 days and the optimal dose is reached within 1 week. For patients with other psychotropic drugs, the dose is adjusted according to the characteristics of the drug action and the clinical response of the individual.

Valproic acid dose

Anti-mania should start with a small dose, the recommended starting dose is 500mg / day, divided into 2 doses, once in the morning and evening, the dose should be increased as soon as possible, 1000mg / day on the third day, the first weekend It reaches 1500mg / day. After that, the dose can be adjusted according to the condition and the blood concentration of Debakin. The maintenance dose range is 1000-2000mg / day, the maximum dose does not exceed 3000mg / day, and the therapeutic blood concentration is 50-125ug / mL Inside.
For children and young people under the age of 18, the safety and effectiveness of debakin in treating mania associated with bipolar disorder has not been studied. Elderly patients reduce as appropriate. [3]

Valproic acid adverse reactions

The incidence of adverse reactions was graded by OOMS frequency.
Very common 10%, common 1 and 10%, rare 0.1 and <1%, rare 0.01 and <0.1%, extremely rare <0.01%, unknown (cannot be estimated from available data).

Valproic gastrointestinal system:

Very common: nausea.
· Common: upper abdominal pain and diarrhea, which often occur at the beginning of treatment. These abnormalities usually disappear after several days of continued medication
Rare: pancreatitis, sometimes fatal cases. (See [Precautions])

Valproic hepatobiliary system:

· Common: Liver damage. (See [Precautions])

/ Congenital and familial / hereditary valproic acid :

Teratogenic risk (see [Medication for pregnant and lactating women]).

Valproate central nervous system:

Rare: Cases of cognitive dysfunction and concealed and progressive seizures, which can progress to complete dementia, and can be reversed weeks to months after stopping treatment.
· Common: tremor
Common: A few minutes after intravenous injection, extravertebral system disorders, stiffness, drowsiness, convulsions *, memory disorders, headaches, nystagmus, and dizziness may occur. The reaction will disappear automatically within minutes.
Rare: coma *, encephalopathy *, lethargy *, reversible Parkinson's disease, ataxia, and paresthesia.
Blurred consciousness: Some patients reported stiff or lethargy during sodium valproate treatment, sometimes leading to transient coma (encephalopathy). The above symptoms are isolated or associated with an increase in the incidence of convulsions during treatment, which will be reduced after discontinuation of valproate treatment or a reduction in dose. When combined therapy (especially with phenobarbital) or a sudden increase in valproate doses, these symptoms are reported more often.
· Common: Confusion, aggressive behavior *, emotional agitation *, attention disorder *
Rare: abnormal behavior *, hyperkinesis, learning disabilities
* These adverse reactions occur mainly in the pediatric population.

/ Valproic acid metabolism / nutrition system:

Common cases of hyponatremia.
Rare: Hyperaemia * (see "Precautions").
* Single and moderate hypernitrogenemia may not cause changes in liver function tests. It should not cause drug discontinuation. Hypernitrogenia related to neurological symptoms have also been reported. In this case, further research should be considered. (See "Precautions").
Few reports of non-severe peripheral edema.
· There have been reports in the literature about Fanconi syndrome (metabolic acidosis, hyperphosphatemia, amino acid urine, and diabetes). These reactions can be reversed after stopping taking valproic acid-containing drugs. However, the mechanism by which the above reactions occur is still unclear.
· Common: Weight gain. Weight gain is a risk factor for polycystic ovary syndrome, and patient weight should be closely monitored. (See [Precautions])
Benign, malignant, and unspecified tumors (including cysts and polyps)
Rare: Myelodysplastic Syndrome

Valproic urogenital system:

Reports of rare enuresis and urinary incontinence. Individual reports of kidney damage have been reported.
· Common: Dysmenorrhea
· Uncommon: menopause
· Rare: male infertility, polycystic ovary

Valproic blood lymphatic system:

· Common: Anemia, thrombocytopenia (see [Precautions]).
Rare: whole blood cells decrease, white blood cells decrease.
Rare: Bone marrow failure, including simple red cell aplasia, agranulocytosis, large cell anemia, large red cell disease.
· Rare: reduced coagulation factors (at least one), abnormal coagulation tests (such as prolonged prothrombin time, prolonged activation of prothrombin prokinase, prolonged thrombin time, INR) Medication for lactating women]).
Skin and subcutaneous tissue:
· Common: Hypersensitivity, temporary hair loss, and related to the dose administered.
* Rare: Angioedema, rash.
* Rare: toxic epidermal necrosis, Steven-Johnson syndrome and erythema polymorpha, drug-induced rash, drug rash with eosinophilia, and systemic symptoms (DRESS).

Valproic musculoskeletal and connective tissue

Rare: decreased bone density, osteoporosis, osteoporosis and fractures in patients treated with this product for a long time. The mechanism by which this product affects bone metabolism has not been determined.
Rare: Systemic lupus erythematosus (see "Precautions").
Vascular abnormalities
Common: Bleeding
Rare: vasculitis

Valproic acid endocrine

Rare: Antidiuretic hormone secretion syndrome (SIADH)
Rare: Decreased thyroid function (see "Medications for pregnant and lactating women")

Valproic acid special sensory system

Common: Deafness. Respiratory, chest, and mediastinal systems
Rare: pleural effusion [3]

Valproic acid contraindications:

* Persons who are allergic to valproate, divalproate, valproamide or any of the ingredients in this product;
* Patients with acute hepatitis;
* Patients with chronic hepatitis;
* Persons with a history or family history of severe hepatitis, especially patients with hepatoporphyria associated with medication;
* Patients with disorders of the urea cycle. [3]

Valproic acid matters needing attention:

Valproic acid special tips:

In rare cases, the use of an antiepileptic drug treatment may result in an increase in the number of seizures, or the type of seizures that occur, and is different from the phenomenon observed in some types of epilepsy. When using valproate, the above-mentioned phenomena are mainly caused by the interaction between combined antiepileptic drug treatment or pharmacokinetics (see [Drug Interactions]), toxic reactions (liver disease or encephalopathy) (see [Caution Matters] and [adverse reactions] or drug overdose.
After taking this product, the drug is converted into valproic acid in the body, so you should not take other drugs containing active ingredients that can be converted into the same compound while taking this product to prevent excessive valproic acid in the body (such as double Valproate, valproamide, etc.).
* In some cases, if a patient and her therapist make an informed choice after careful evaluation of all relevant factors, TM is a suitable choice for women of childbearing age (see [Precautions] and [Pregnant women who are not breastfeeding] ). [3]

Valproic acid warning

1. Liver toxicity: Conditions of occurrence: Very rare severe liver damage including fatal cases are reported.
Experience with epilepsy treatment shows that the patients at greatest risk are infants, especially when combined with multiple anticonvulsants, children under 3 years of age and those with severe seizures, especially with brain damage, mental retardation and / or Congenital metabolic disease or degenerative disease. After 3 years of age, the situation decreased significantly, and gradually decreased with age. In most cases, this type of liver damage occurs during the first 6 months of treatment, usually between the second and the twelfth week and during multi-drug antiepileptic therapy. [3]

Valproic acid suggests symptoms:

Clinical symptoms are essential for early diagnosis. It should be considered especially if jaundice occurs in the following patients at risk:
* Non-specific symptoms: usually sudden onset, such as weakness, anorexia, weakness, and lethargy, sometimes associated with repeated vomiting and abdominal pain.
* Symptoms recur in patients with epilepsy. The patient (or the child's family) should be informed and the doctor should be reported as soon as this happens. Clinical examination and biological determination of liver function should be performed immediately. [3]

Valproic acid test:

Monitor liver function on a regular basis before and during the first 6 months of treatment.
In routine examinations, tests that reflect protein synthesis, especially prothrombin time, are most closely related. If it is determined that abnormally low prothrombin time is present, especially in combination with other biological abnormalities (fibrinogen and coagulation factor levels are significantly reduced; bilirubin concentration increases and transaminase increases, valproate treatment needs to be stopped)
(As a precaution, if salicylic acid derivatives are used in combination, the treatment of this product should also be stopped because this product has the same metabolic pathway as the latter.)
When this product is used in patients with a previous history of liver disease, more attention should be paid. For patients with multiple anticonvulsants, children, patients with congenital metabolic diseases, those with severe convulsions with mental retardation, and those with organic brain disorders This danger is particularly prominent.
2. Pancreatitis: Very few patients have reported severe or even fatal pancreatitis. The response is related to the patient's age and treatment cycle, and there may be a certain risk of the child's response.
Pancreatitis that causes adverse reactions is often observed in young children or patients with severe seizures, brain damage, or patients taking multiple antiepileptic drugs. If pancreatitis is accompanied by liver dysfunction, the risk of death is increased.
Patients and their guardians should be warned that abdominal pain, nausea, vomiting, and / or loss of appetite may be symptoms of pancreatitis. This requires an immediate medical evaluation. If pancreatitis has been diagnosed, the application of this product should be stopped under normal circumstances. According to clinical indications, other treatments should be performed for potential disease states.
3. Teratogenicity: According to published and unpublished reports, valproic acid may have teratogenic effects on the offspring of women who use the drug during pregnancy. Valproate may cause teratogenic effects such as neural tube defects (for example, spina bifida). Therefore, it can only be applied to women of childbearing age when the benefit of treatment is greater than the risk of harm to the fetus. (See [Medication for pregnant and lactating women])
This medicine should not be used in women of childbearing age, unless it is clearly needed (that is, if other treatments are ineffective or intolerable), this evaluation should be performed before the first prescription of this product or a treatment with this product Of women of childbearing age are planning to become pregnant while women of childbearing age must use effective contraception during treatment.
According to published and unpublished reports, valproic acid may have teratogenic effects on the offspring of women who use the drug during pregnancy. Valproate may cause teratogenic effects such as neural tube defects (for example, spina bifida). Therefore, it can only be applied to women of childbearing age when the benefit of treatment is greater than the risk of harm to the fetus. (See [Medication for pregnant and lactating women])
4. Urea circulation disorder (UCD): This product is not recommended for patients with urea cycle enzyme deficiency. Urea cycle disorders are a group of uncommon genetic abnormalities, particularly seen in the presence of ornithine carbamyltransferase deficiency. Sporadic cases of coma due to hyperammonemia have been reported in these patients.
In the following patients, UCD evaluation should be considered before starting this product. These patients are: 1) patients with a history of unexplained encephalopathy or coma, patients with a history of encephalopathy related to protein load, and patients with pregnancy Patients with a history of related encephalopathy or postpartum encephalopathy, patients with a history of elevated plasma ammonia or glutamate levels; 2) Those with periodic vomiting, occasional extreme excitability, motor ataxia, low urea nitrogen or protein Avoided patients; 3) Patients with a family history of UCD or patients with an unexplained family death (particularly boys); 4) Those with other UCD signs and symptoms. Patients with unexplained hematoammonia encephalopathy while receiving this product should be treated immediately (including stopping valproate therapy) and evaluated for potential urea cycle disorders.
5. Drowsiness in elderly patients: In elderly patients, the dosage should be increased more slowly, and fluid and nutrient intake, dehydration, lethargy, and other adverse events should be monitored regularly. (See [Dosage and Usage]).
6. Thrombocytopenia: Thrombocytopenia has been reported during divalproic acid treatment, due to the drug's second stage inhibition of platelet aggregation, and abnormalities in coagulation parameters (such as low fibrinogen) It is recommended to test platelet count and coagulation function before starting treatment and at periodic intervals.
7. Application in pregnant women: According to published and unpublished reports, valproic acid may have teratogenic effects on the offspring of women who use the drug during pregnancy.
In mothers receiving sodium valproate in the first trimester of pregnancy, the incidence of neural tube defects in their fetuses may increase. The United States National Centers for Disease Control (CDC) has determined that children with women exposed to valproic acid have a risk of spina bifida about 1% to 2%.
Other congenital anomalies (such as craniofacial defects, cardiovascular malformations, and abnormalities involving multiple body systems) have been reported. These congenital anomalies may or may not coexist with life. There is not enough data to determine the incidence of these congenital anomalies.
The high incidence of fetal congenital abnormalities in women with convulsive disorders treated with antiepileptic drugs cannot be considered a causal relationship. There are inherent methodological problems in obtaining sufficient data on drug teratogenicity from humans; genetic factors or epilepsy status itself may play a more important role than drug therapy in causing congenital malformations in the fetus.
Patients treated with sodium valproate may develop coagulopathy. If sodium valproate is used in pregnant women, coagulation parameters should be carefully monitored.
In the treatment and counselling of women of childbearing age, the prescribing physician will want to make a trade-off between the benefits and the risks of treatment. If the drug is to be used during pregnancy, or if the patient is going to become pregnant during the application of the drug, the patient should be informed of the potential danger to the fetus.
Antiepileptic drugs should not be abruptly discontinued in patients with antiepileptic medications to prevent major epileptic seizures because they may promote the development of a state of epilepsy with hypoxia and are life threatening. For some patients whose epilepsy severity and frequency are so low that stopping drug therapy does not pose a serious threat to the patient, it may be considered to discontinue drug therapy before and during pregnancy, although it is not guaranteed that epilepsy is small The attack does not pose some risks to the development of the embryo or fetus.
In pregnant women receiving sodium valproate, consideration should be given to the use of existing acceptable procedures to detect neural tube defects and other defects.
8. Suicide intentions and behaviors
There have been reports of suicidal intentions and behaviors following antiepileptic treatment in patients with treatment indications. A meta-analysis of a randomized placebo-controlled antiepileptic drug trial also showed a slight increase in suicidal intentions and behavioral risks. The mechanism of this action is unclear.
Therefore, patients should be monitored for signs of suicidal intentions and behavior, and appropriate treatment should be considered. If suicidal intentions and behavioral signs are found, patients (patient caregivers) should be advised to seek medical help immediately.
9.Carbapenems
The simultaneous use of sodium valproate and carbapenems is not recommended (see [Drug Interactions]). [3]

Valproic acid

Liver function should be measured before treatment (see [Contraindications]) and regularly monitored within 6 months before starting treatment, especially for dangerous patients (see [Precautions]).
As with most antiepileptic drugs, slight elevations in transaminase levels should be noted, especially at the beginning of treatment, but are usually transient and moderate and have no clinical significance.
More in-depth biological examinations (including prothrombin time) are recommended in these patients; dose adjustments may be considered when appropriate, and the above tests repeated.
Monotherapy is recommended when children use sodium valproate, but the potential benefits of sodium valproate should be weighed against the risk of liver damage or pancreatitis before starting treatment in such patients (see [Cautions]).
Blood tests (such as blood cell count, bleeding time, and agglutination test) should be performed before treatment, before surgery, or when spontaneous bruises or bleeding occur (see [Adverse Reactions]).
Due to the risk of hepatotoxicity and bleeding, children should avoid the combined use of acetylsalicylic acid in the treatment of epilepsy.
Patients with renal insufficiency may need to reduce the dose. Because plasma concentration monitoring can be misleading, doses should be adjusted based on clinical monitoring.
The diagnosis of pancreatitis must be considered when acute abdominal pain or gastrointestinal symptoms including nausea, vomiting and / or anorexia occur. For patients who have experienced elevated trypsin levels, treatment should be discontinued and necessary treatment measures should be implemented.
This product is not recommended for patients with urea cycle enzyme deficiency. Sporadic cases of coma due to serotoninemia have been reported in these patients.
Hepatic and gastrointestinal disorders of unknown etiology (such as anorexia, vomiting, cytolysis), depression or coma, children with mental retardation, or children with neonatal or infant deaths in the family who are receiving any valproate Metabolic indicators must be tested before acid salt treatment, especially fasting and postprandial blood ammonia levels.
Although immunological abnormalities are rarely observed during administration, patients with systemic lupus erythematosus should weigh the possible benefits and risks.
All patients should be aware of the risk of weight gain before receiving valproate and take appropriate steps to reduce it.
At the beginning of treatment, if the patient is a woman of childbearing age, it should be confirmed that she is not pregnant, and effective contraception is being used before starting treatment (see [Medication for pregnant and lactating women]).
Since valproic acid can be partially metabolized to ketone bodies, it should be noted that the results of ketone body excretion tests performed on diabetic patients suspected of ketoacidosis may have a false positive effect.
In the case of sodium valproate in the treatment of acute mania, no clinical trial data on the clinical safety and efficacy of this product has been obtained for a long time (more than 4 weeks). Therefore, if the treatment time of sodium valproate is prolonged, the clinical The need for continuous medication should be assessed on the patient's individual situation. [3]

Valproic acid hyperammonemia:

Hyperammonemia has been reported to be related to sodium valproate treatment, and even if liver function tests are normal, hyperammonemia can occur. In patients with unexplained drowsiness and vomiting or altered mental status, the possibility of hyperammonia encephalopathy should be considered, and blood ammonia levels should be measured. If blood ammonia is elevated, valproate therapy should be discontinued. Appropriate treatment for hyperammonemia should be initiated, and such patients should be examined to determine if they have a urea cycle disorder.
Increases in asymptomatic blood ammonia levels are more common. When asymptomatic blood ammonia levels are present, plasma ammonia levels need to be closely monitored. If blood ammonia continues to increase, then consideration should be given to stopping valproate therapy. In patients with unexplained drowsiness and vomiting or altered mental status, the possibility of hyperammonia encephalopathy should be considered and blood ammonia levels should be measured (see [Contraindications]).
Alcohol is not recommended during treatment with sodium valproate.
Impact on driving and machine operation capabilities: Patients should pay attention to the danger of drowsiness, especially the driver or machine operator. Pay special attention to this drowsiness response when taking multidrug anticonvulsant therapy or taking other drugs at the same time. [3]

Valproic acid for pregnant and lactating women:

Valproic acid women of childbearing age

This medicine should not be used in women of childbearing age unless explicitly needed (ie in cases where other treatments are ineffective or intolerable).
This assessment should be done before the first prescription of this product or when a woman of childbearing age who is treated with this product plans to become pregnant. Women of childbearing age must use effective contraception during treatment. [3]

Valproic pregnancy

Based on the data obtained, valproate is not recommended during pregnancy.
The risk of deformity induced by pregnant women taking sodium valproate is 3-4 times higher than that of the normal population, which is 3%.
The most common malformations are neurocatheter closure defects (about 2-3%), craniofacial defects, limb deformities, cardiovascular malformations, and multiple malformations including different human systems.
Obvious risk factors for the above-mentioned malformations when doses are greater than 1000 mg / day and in combination with other anticonvulsants.
Existing epidemiological data do not show a decrease in children's overall IQ when exposed to valproate in utero, however, a slight decrease in oral expression has been observed in these children and / or the need for speech The situation of adjuvant treatment has increased. Further results showed that there were scattered case reports of autism and related disorders in children exposed intrauterine to valproate. Further clinical studies are needed to confirm these results.
Children exposed to valproic acid in the womb also have autistic subgroup disorders.
Both valproate monotherapy and valproate multitherapy are associated with abnormal pregnancy. Available data indicate that antiepileptic multidrug therapy with valproate is at higher risk for abnormal pregnancy than valproate monotherapy.
In summary
The following recommendations should be considered: this drug should not be used during pregnancy and in women of childbearing age, unless explicitly needed (ie, if other treatments are ineffective or intolerable). This assessment should be done before the first prescription of this product or when a woman of childbearing age who is treated with this product plans to become pregnant. Women of childbearing age must use effective contraception during treatment. [3]

Valproic acid plan pregnancy:

If a woman is planning to become pregnant, regardless of the indication, the treatment of this product should be re-evaluated. Complete steps should be taken to consider whether other treatments are available.
When applied to indications of bipolar disorder, consideration should be given to discontinuing the use of this product. For any other indication, if the use of sodium valproate is considered unavoidable (or no other option), it is recommended that the daily dose be the lowest effective dose, while using a sustained release dosage form as far as possible. In the case of a delayed release dosage form, it can be considered in time Take the regular dosage form several times to avoid peak blood levels of valproic acid.
To date, there is no evidence to support the effectiveness of folic acid supplementation when women take sodium valproate during pregnancy. However, considering the beneficial effects in other cases, one can consider supplementing with folic acid one month before and two months after conception at a dose of 5 mg / day. Regardless of whether patients take folic acid or not, they need to be examined for the same deformity.

During valproic acid pregnancy:

If there is no alternative to continuous therapy with sodium valproate (there are no alternatives), a minimum effective dose is recommended. If possible, avoid doses above 1000 mg / day.

Before valproic acid :

Patients treated with sodium valproate may develop coagulopathy. If sodium valproate is used in pregnant women, the mother should be tested for coagulation before birth, including platelet counts, fibrinogen levels, and clotting time (aPTT). [3]

Valproic acid newborn:

This product may cause neonatal bleeding syndrome unrelated to vitamin K deficiency.
This type of bleeding syndrome is associated with thrombocytopenia, fibrinogen deficiency, and / or other coagulation factors. Fibrinogen deficiency has also been reported and can be fatal. However, this syndrome must be distinguished from a decrease in vitamin K-dependent clotting factors, which is induced by phenobarbital and enzyme inducers.
Routine hematological testing of the mother does not fully reflect the possibility of neonatal hematological abnormalities. The newborn's platelet count, fibrinogen level, coagulation test, and coagulation factors should be checked.
There have been cases of neonatal hypoglycemia, and their mothers took valproate during the last trimester of pregnancy.
There have been cases of neonatal hypothyroidism in which their mother took valproate during pregnancy.

Valproic acid breastfeeding:

The valproic acid concentration in milk is very low, only 1% to 10% of the maternal serum concentration. Although no clinical abnormalities have been reported in breastfeeding children monitored during the neonatal period, breastfeeding is not a contraindication to taking valproate. The trade-off should be based on various factors. [3]

Valproic acid for children:

Monotherapy is recommended when children use sodium valproate, but the potential benefits of sodium valproate should be weighed against the risk of liver damage or pancreatitis before starting treatment in such patients (see [Precautions]).
Due to the risk of liver toxicity and bleeding, children should avoid acetylsalicylic acid when taking this product.
Hepatic and gastrointestinal disorders of unknown etiology (such as anorexia, vomiting, cytolysis), depression or coma, children with mental retardation, or children with neonatal or infant deaths in the family who are receiving any of Metabolic indicators must be tested before acid salt treatment, especially fasting and postprandial blood ammonia levels.
For children and young people under the age of 18, the safety and effectiveness of sodium valproate in the treatment of mania associated with bipolar disorder has not been studied. [3]

Valproic acid medication for the elderly:

The ability of older patients (aged over 68 years) to clear sodium valproate has decreased and the incidence may have increased compared to younger adult patients, so the starting dose should be reduced in these patients. At the same time, the dose should increase more slowly, and regular monitoring of fluid and nutrient intake, dehydration, lethargy, and other adverse events is needed. When the patient's food and fluid intake declines, or the patient experiences excessive drowsiness, then the dose of sodium valproate should be reduced or the treatment of sodium valproate should be stopped. The final therapeutic dose should be determined based on tolerance and clinical response. See related content under other items in this manual, or follow the doctor's advice. [3]

Valproic acid drug interactions:

Careful consideration should be given when taking this product along with drugs that induce seizures, or drugs that reduce the threshold of seizures, based on the severity of the potential risk, which can be determined not to be used or disabled. These drugs mainly include most antidepressants (imipramine, SSRI), tranquilizers (phenothiazine and phenone drugs), melquinine (see later chapters), buspirone, tramadol Wait.

Valproic acid banned combined application

Combination with melquinine: When combined with epilepsy patients, melquinine may lead to increased valproic acid metabolism and its own seizure-inducing effect, making it at risk of seizures.
Combination with St. John's Wort: risk of reduced blood concentration and reduced anticonvulsant efficacy. [3]

Attention joint application of valproic acid

Combined with aztreonam, imipenem, and meropenem: there is a risk of a spastic response caused by a decrease in valproic acid blood levels. During the treatment of anti-infective drugs, clinical monitoring, blood concentration measurement and timely adjustment of the dose of anticonvulsant drugs should be performed. Monitoring should still be performed after stopping the drug.
Carbamazepine: It can increase the blood concentration of the active metabolite of carbamazepine, leading to an overdose reaction. At the same time, due to the induction of liver metabolism by carbamazepine, the blood concentration of valproic acid can be reduced. Therefore, clinical drug monitoring is recommended to determine the blood concentrations of the two anticonvulsants and adjust their doses.
Lamotrigine: Increased risk of severe skin reactions (Lyell's syndrome). Valproic acid can increase the plasma concentration of lamotrigine by inhibiting the liver metabolism of lamotrigine. If it must be taken in combination, it should be closely monitored in the clinic.
Felbamate: Increases the plasma concentration of valproic acid, creating a risk of overdose.
Monitoring of clinical and biochemical indicators and adjustment of valproate doses should be performed during treatment with felbamate. The above observation measures should still be taken after stopping the drug.
  1. Phenobarbital and Pumipone: Due to the inhibitory effect of valproic acid on liver metabolism, the blood concentration of phenobarbital or Pumipone can increase, and the phenomenon of overdose appears in children. At the same time, the blood concentration of valproic acid can be reduced due to the induction of liver metabolism by phenobarbital or primidone. Clinical monitoring should be performed during the first 15 days of combination therapy, and any sedative symptoms should be promptly reduced in the dose of phenobarbital or pumipone. In particular, the blood concentrations of the two anticonvulsants should be monitored.
  2. Phenytoin (and can be extrapolated to phosphoryl phenytoin): can cause changes in the plasma concentration of phenytoin. At the same time, due to the induction of liver metabolism by phenytoin, the blood drug concentration of valproic acid may be reduced. Clinical monitoring and blood concentration determination should be carried out, and the dose of the two anticonvulsants should be adjusted appropriately.
  3. Topiramate: There is a risk of hyperammonemia or encephalopathy, usually caused by taking valproate while taking topiramate. Clinical monitoring and laboratory monitoring should be added at the beginning of treatment, and attention should be paid to the signs of the reaction.
  4. Cimetidine and erythromycin: Taken at the same time, may increase serum valproic acid concentration.
  5. Acetylsalicylic acid: Babies and young children with temperature regulation disorders should not take medicines containing valproic acid and acetylsalicylic acid at the same time. Only under the guidance of a doctor, adolescents with disordered temperature regulation can take it.
  6. Benzodiazepines, barbiturates and stabilizers, monoamine oxidase inhibitors and antidepressants: When used in combination, valproic acid can increase the central inhibitory effect of these drugs. Patients should be closely monitored when combined with the above drugs, and dose adjustments of the drugs should be made if necessary.
  7. Zidovudine: Valproic acid can increase the serum drug concentration of zidovudine and may cause an increase in zidovudine toxicity. Anticoagulants and antiplatelet aggregation drugs: Concomitant use with valproic acid-containing drugs may cause an increased tendency to bleed. Therefore, routine monitoring of blood coagulation during combination therapy is recommended.
  8. Stability: The results of studies in healthy subjects show that valproic acid can displace diazepam from its plasma protein binding site and inhibit its metabolism. Plasma concentration of free diazepam in the body may increase, and plasma clearance and volume of distribution of free diazepam may decrease (reduced by 25% and 20%, respectively). However, the half-life remains unchanged. The results of studies in healthy subjects show that valproate and laurazepam can reduce the blood concentration of laurazepam by up to 40% when taken at the same time. In children, serum phenytoin levels may increase after taking clonazepam and valproic acid at the same time.
  9. Nimodipine (administered orally and intravenously): Due to the metabolic inhibition of valproic acid, it may lead to an increase in the blood concentration of nimodipine and promote the hypotensive response of nimodipine.
  10. Rifampicin may reduce the blood concentration of valproate, leading to reduced efficacy. Therefore, when used in combination with rifampicin, it is necessary to adjust the dose of valproate. [3]

Other forms of valproic acid interaction:

With lithium: This product has no effect on serum lithium levels.
And oral contraceptives: Since valproic acid has no enzyme-inducing activity, it does not reduce the effect of hormonal contraceptives taken by women on estrogen-progestin. Phenobarbital and Pumipone: Due to the inhibitory effect of valproic acid on liver metabolism, the blood concentration of phenobarbital or Pumipone can increase, and the phenomenon of drug overdose occurs frequently in children. At the same time, the blood concentration of valproic acid can be reduced due to the induction of liver metabolism by phenobarbital or primidone.
Clinical monitoring should be performed during the first 15 days of combination therapy, and any sedative symptoms should be promptly reduced in the dose of phenobarbital or pumipone. In particular, the blood concentrations of the two anticonvulsants should be monitored.
Phenytoin (and can be extrapolated to phosphoryl phenytoin): can cause changes in the plasma concentration of phenytoin. At the same time, due to the induction of liver metabolism by phenytoin, the blood drug concentration of valproic acid may be reduced. Clinical monitoring and blood concentration determination should be carried out, and the dose of the two anticonvulsants should be adjusted appropriately.

Topiramate: There is a risk of hyperammonemia or encephalopathy, usually caused by taking valproate while taking topiramate. Clinical monitoring and laboratory monitoring should be added at the beginning of treatment, and attention should be paid to the signs of the reaction.
Cimetidine and erythromycin: Taken at the same time, may increase serum valproic acid concentration.
Acetylsalicylic acid: Babies and young children with temperature regulation disorders should not take medicines containing valproic acid and acetylsalicylic acid at the same time. Only under the guidance of a doctor, adolescents with disordered temperature regulation can take it.
Benzodiazepines, barbiturates and stabilizers, monoamine oxidase inhibitors and antidepressants: When used in combination, valproic acid can increase the central inhibitory effect of these drugs. Patients should be closely monitored when combined with the above drugs, and dose adjustments of the drugs should be made if necessary.
Zidovudine: Valproic acid can increase the serum drug concentration of zidovudine and may cause an increase in zidovudine toxicity. Anticoagulants and antiplatelet aggregation drugs: Concomitant use with valproic acid-containing drugs may cause an increased tendency to bleed. Therefore, routine monitoring of blood coagulation during combination therapy is recommended.
Stability: The results of studies in healthy subjects show that valproic acid can displace diazepam from its plasma protein binding site and inhibit its metabolism. Plasma concentration of free diazepam in the body may increase, and plasma clearance and volume of distribution of free diazepam may decrease (reduced by 25% and 20%, respectively). However, the half-life remains unchanged. The results of studies in healthy subjects show that valproate and laurazepam can reduce the blood concentration of laurazepam by up to 40% when taken at the same time. In children, serum phenytoin levels may increase after taking clonazepam and valproic acid at the same time.
Nimodipine (administered orally and intravenously): Due to the metabolic inhibition of valproic acid, it may lead to an increase in the blood concentration of nimodipine and promote the hypotensive response of nimodipine. [3]

Valproic acid overdose:

When taking acute overdose, common symptoms include coma with low muscle tone, low reflexes, dilated pupils, respiratory dysfunction, and metabolic acidosis. Clinical symptoms can vary, and there are reports of seizures when blood levels are too high. Cases of intracranial hypertension associated with cerebral edema have also been reported.
The treatment of overdose should be based on symptoms: gastric lavage for diarrhea, urine secretion, and cardiopulmonary monitoring. In very severe cases, hemodialysis can be used for treatment if necessary. It has been reported that naloxone can reverse the central nervous system inhibitory effect caused by sodium valproate overdose. Since in theory naloxone also reverses the anti-epileptic effect of divalproex sodium, more attention should be paid when using naloxone in patients with epilepsy. The prognosis is usually good. But scattered deaths have been reported. [3]

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