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Phenobarbital

Category II psychotropic drugs

Phenobarbital is an organic compound with chemical formula C twelve H twelve N two O three , listed as the second category of psychotropic drugs Product control^[1] 。

Phenobarbital is a barbital sedative and sleeping drug. Clinically, it is used for: ① sedation: anxiety, irritability, hyperthyroidism, hypertension, functional nausea, infantile pyloric spasm, etc.; ② Hypnosis: occasionally used for intractable insomnia, but after waking up, there are often residual effects such as fatigue and lethargy; ③ Anticonvulsant: It is often used to fight convulsions caused by central stimulant poisoning or high fever, tetanus, encephalitis, cerebral hemorrhage and other diseases; ④ Anti epilepsy: it is used for the treatment of grand mal and partial seizure, with quick effect, and can also be used for status epilepticus; ⑤ Administration before anesthesia; ⑥ It is used in combination with antipyretic and analgesic drugs to enhance its effect; ⑦ To treat neonatal hyperbilirubinemia.

On October 27, 2017, the list of carcinogens released by the International Agency for Research on Cancer of the World Health Organization (WHO) was preliminarily sorted out for reference, and phenobarbital was included in the list of Category 2B carcinogens.^[2]

Chinese name: Phenobarbital
Foreign name: phenobarbital
Alias: 5-Ethyl-5-phenyl-2,4,6 - (1 H ,3 H ,5 H ）-Pyrimidine trione
chemical formula: C twelve H twelve N two O three
molecular weight: two hundred and thirty-two point two three five
CAS login number: 50-06-6
EINECS login number: 200-007-0

Melting point: 174 ℃
Water solubility: Insoluble
Appearance: White crystalline powder
Security description: S36/37；S45；S53
Hazard symbol: T
Hazard description: R25；R40；R43；R61
UN dangerous goods number: two thousand eight hundred and eleven

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Compound Introduction

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essential information

Chemical name: 5-ethyl-5-phenyl-2,4,6 - (1 H ,3 H ,5 H ）-Pyrimidine trione

Chemical formula: C twelve H twelve N two O three

Molecular weight: 232.235

CAS No.: 50-06-6

EINECS No.: 200-007-0

Physical and chemical properties

Density: 1.234g/cm three

Melting point: 174 ℃

Flash point: 11 ℃

Appearance: white crystalline powder

Solubility: insoluble in water, soluble in ethanol, chloroform and ether^[3]

Molecular structure data

Molar refractive index: 43.84

Molar volume (cm three /mol）：122.0

Isotonic specific volume (90.2K): 337.5

Surface tension (dyne/cm): 58.5

Polarization (10 -24 cm three ）：17.38^[3]

Brief Introduction to Drugs

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pharmacology

Phenobarbital is a long-acting barbital drug, in which the central inhibitory effect varies with the dose. It has sedative, hypnotic and anticonvulsant effects. It can also resist epilepsy, and has good effect on grand mal, localized seizure and status epilepticus; The curative effect is poor for epileptic seizures; However, it is often ineffective for psychomotor attacks, and may aggravate the attacks when the drug is used alone. This product also has the effect of enhancing antipyretic and analgesic drugs, inducing liver microsomal glucuronosyltransferase activity, promoting the combination of bilirubin and glucuronic acid, reducing plasma bilirubin concentration, and treating neonatal hyperbilirubinemia (brain nuclear jaundice). Its sodium salt is easily absorbed after oral administration and injection. It can be distributed in various tissues and body fluids. Although it enters human brain tissue slowly, the concentration in brain tissue is the highest. It takes 0.5~1 hour for oral administration and 15 minutes for intravenous injection to take effect. The blood drug concentration reached the peak value in 2-18 hours. The effective blood drug is 10~40 µ g/mL. The average duration of the action was 10-12 hours, and the average plasma protein binding rate was 40%, t 1/2 50~144 hours for adults and 40~70 hours for children. 65% were metabolized in the liver, and some metabolites and their prototypes (about 30%) were excreted from the body through the kidney. Renal tubules have a reabsorption effect, which prolongs the duration of the effect.

indication

1. Sedation: such as anxiety, irritability, hyperthyroidism, hypertension, functional nausea, children's pyloric spasm, etc;

2. Hypnosis: occasionally used for intractable insomnia, but after waking up, there are often residual effects such as fatigue and lethargy;

3. Anticonvulsive: It is often used to fight convulsions caused by central stimulant poisoning or high fever, tetanus, encephalitis, cerebral hemorrhage and other diseases;

4. Anti epilepsy: it is used for the treatment of grand mal and partial seizure, with quick effect, and can also be used for status epilepticus;

5. Pre anesthesia administration;

6. It is used in combination with antipyretic and analgesic drugs to enhance its effect;

7. To treat neonatal hyperbilirubinemia.

Adverse reactions

1. After medication, dizziness, drowsiness and other sequelae may occur. Long term use may lead to tolerance and dependence. Repeated use should be alert to accumulated poisoning.

2. A few patients may have allergic reactions such as rash, drug heat, exfoliative dermatitis, etc.

contraindication

It is prohibited for patients with allergy to this product, severe liver and kidney dysfunction, bronchial asthma, respiratory depression and porphyria.

matters needing attention

1. When it is used to treat epilepsy for a long time, the drug cannot be stopped suddenly, so as not to cause seizures, or even epileptic status.

2. Generally, 5~10 times of hypnotic dose can cause moderate poisoning, and 10~15 times of hypnotic dose can cause severe poisoning. When the blood concentration is higher than 8~10mg/100mL, life is in danger. The symptoms of acute poisoning are lethargy, then shallow breathing, greatly reduced ventilation, and finally respiratory failure and death.

3. Cautiously used for severe anemia, heart disease, diabetes, hypertension, hyperthyroidism, the elderly, pregnant women and lactating women.

4. The intravenous injection speed should not exceed 60mg per minute, which may cause respiratory depression.

5. If this product is taken during pregnancy, the newborn may suffer from prothrombin deficiency and bleeding. Vitamin K has therapeutic or preventive effects.

6. First aid for poisoning caused by this product or other barbiturates: For those who take this product orally for less than 3 hours, a large amount of warm normal saline or potassium permanganate solution of 1:2000 can be used for gastric lavage (pay attention to prevent liquid from flowing into the trachea to avoid inhalation pneumonia). After washing, use 10~15g sodium sulfate (avoid magnesium sulfate) for catharsis. Alkalize urine with sodium bicarbonate or sodium lactate to reduce reabsorption in renal tubules and accelerate drug excretion. Diuretics such as mannitol can also be used to increase urine output and promote drug excretion. In case of respiratory acidosis caused by respiratory inhibition, it can promote drugs to enter the center and aggravate the toxic reaction. Therefore, it is particularly important to ensure that the respiratory tract is unobstructed. If necessary, tracheotomy or tracheal intubation, oxygen inhalation or artificial respiration should be performed. Can also be properly given in, pivot stimulants. When the blood pressure is low, intravenous drip of glucose saline or low molecular dextran can be used.

Drug interaction

1. Combined with acetaminophen, it can cause liver toxicity.

2. When combined with acetaminophen, dicoumarin, hydrocortisone, dexamethasone, testosterone, estrogen, progesterone, oral contraceptives, chlorpromazine, chloramphenicol, doxycycline, griseofulvin, digoxin, digoxin, phenytoin sodium and cyclosporine, phenobarbital accelerates their metabolism and reduces the efficacy.

3. When combined, the drug action of cyclophosphamide in vivo is increased.

4. When used together, the blood concentration of ethylsuccinamine and carbamazepine is reduced, t 1/2 shorten.

5. When used together, sodium valproate was shortened, hepatotoxicity was increased, and the blood concentration of phenobarbital was increased.

6. When used together, it can enhance the antihypertensive effect of calcium antagonist.

Pharmacopoeia information

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source

This product is 5-ethyl-5-phenyl-2,4,6 (1 H ,3 H ,5 H ）-Pyrimidine trione, calculated as dry product, containing C twelve H twelve N two O three Not less than 98.5%.

character

This product is a white lustrous crystalline powder, odorless, acidic reaction in saturated aqueous solution.

This product is dissolved in ethanol or ether, slightly dissolved in chloroform, very slightly dissolved in water, and dissolved in sodium hydroxide or sodium carbonate solution.

melting point

The melting point of this product (general rule 0612 method 1) is 174.5~178 ° C.

identify

1. Take about 10mg of this product, add 2 drops of sulfuric acid and about 5mg of sodium nitrite, mix it, it will turn orange yellow, and then turn orange red.

2. Take about 50mg of this product, put it into a test tube, add 1mL of formaldehyde test solution, heat it, boil it, cool it, slowly add 0.5mL of sulfuric acid along the tube wall, make it into two liquid layers, and heat it in a water bath. The interface appears rose red.

3. The infrared absorption spectrum of this product should be consistent with the control spectrum (spectrum set 227 figure).

4. This product shows the identification reaction of malonylurea (general rule 0301).

inspect

acidity

Take 0.20g of this product, add 10mL of water, boil and stir for 1 minute, cool down, filter, take 5mL of filtrate, add 1 drop of methyl orange indicator solution, and it shall not appear red.

Clarity of solution

Take 1.0g of this product, add 5mL of ethanol, heat and reflux for 3min, and the solution should be clear.

Related substances

Determine according to the method of high performance liquid chromatography (general rule 0512).

Test solution: take this product, add mobile phase to dissolve and dilute it to make a solution containing about 1mg per 1mL.

Reference solution: precisely measure 1mL of the test solution, place it in a 200mL volumetric flask, dilute it with mobile phase to the scale, and shake it up.

Chromatographic conditions: octylsilane bonded silica gel is used as the filler, hexyl water (25:75) is used as the mobile phase, the detection wavelength is 220nm, and the injection volume is 5 µ L.

System applicability requirements: the number of theoretical plates shall not be less than 2500 based on phenobarbital peak, and the resolution between phenobarbital peak and adjacent impurity peak shall meet the requirements.

Determination method: Precisely measure the test solution and the reference solution, respectively inject them into the liquid chromatograph, and record the retention time of the chromatogram to three times of the main component peak.

Limit: If there are impurity bees in the chromatogram of the test solution, the peak area of a single impurity shall not be greater than the main peak area of the reference solution (0.5%), and the sum of the peak areas of each impurity shall not be greater than 2 times (1.0%) of the main peak area of the reference solution.

Neutral or alkaline substances

Take 1.0g of this product, put it into a separating funnel, add 10mL of sodium hydroxide test solution to dissolve it, add 5mL of water and 25mL of ether, shake for 1 minute, separate the ether layer, shake and wash it three times with water, 5mL each time, take the ether solution, filter it with dry filter paper, put the filtrate into an evaporating dish with constant weight at 105 ℃, evaporate it to dryness, dry it at 105 ℃ for 1 hour, and the residual residue shall not exceed 3mg.

Loss on drying

Take this product, dry it at 105 ℃ to constant weight, and the weight loss shall not exceed 1.0% (general rule 0831).

Ignition residue

Not more than 0.1% (general rule 0841).

Assay

Take about 0.2g of this product, weigh it accurately, add 40mL of methanol to dissolve it, add 15mL of newly prepared 3% anhydrous sodium carbonate solution, and titrate it with silver nitrate titrant (0.1mol/L) according to the potentiometric titration method (General Rule 0701). Every 1mL of silver nitrate titrant (0.1mol/L) is equivalent to 23.22mg of C twelve H twelve N two O three 。