isoniazid

Organic compound

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Isoniazid, also known as 4- pyridine Formyl hydrazine 、 Isonicotinic acid Hydrazine is a Organic compound , chemical formula is C six H seven N three O， It's isonicotinic Hydrazide , white Crystallinity Powder, and Li Fuping 、 Ethambutol and Pyrazinamide The same line Antituberculosis drug 。

On October 27, 2017, world health organization International Agency for Research on Cancer The published list of carcinogens was preliminarily sorted out for reference, and isoniazid (isoniazid) Category 3 carcinogens List.^[2]

Drug name: isoniazid^[4]
Foreign name: isoniazid^[4]
Alias: Isonicotinic hydrazide 、 4-Pyridinecarbohydrazide
Prescription medicine or not: yes
Main indications: tuberculosis
Main drug contraindications: Caution for patients with epilepsy, psychosis and liver dysfunction
Dosage form: Tablets, injections^[4-6]
Whether included in medical insurance: yes
Drug type: Antituberculosis drugs^[4-6]

chemical formula: C six H seven N three O
molecular weight: one hundred and thirty-seven point one four
CAS login number: 54-85-3
EINECS login number: 200-214-6
Melting point: 162 to 164 ℃
Density: 1.244 g/cm³
Appearance: White crystalline powder
Security description: S26；S36/37/39
Hazard symbol: Xn
Hazard description: R22；R36/37/38；R40

catalog

Action category

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Antituberculosis drugs 。

indication

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tuberculosis

taboo

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Patients with epilepsy, psychosis and poor liver function should be cautious.

character

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This product is colorless crystal, white or almost white crystalline powder, odorless; Gradual change in light.

This product is easily soluble in water, slightly soluble in ethanol, and very slightly soluble in ether.

melting point

The melting point of this product (general rule 0612) is 170~173 ° C.

Specifications

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Tablets: 50mg, 100mg, 300mg;

Injection: 2ml: 50mg, 2ml: 100mg.^[5-6]

Usage and dosage

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1. Oral: 0.1~0.3g once for adults, 0.2~0.6g per day Acute miliary pulmonary tuberculosis Or tuberculous meningitis, 0.2~0.3g once, three times a day.

2. Intravenous injection or intravenous drip: 0.3-0.6g once, plus 5% for more severe infiltrating tuberculosis, extrapulmonary active tuberculosis, etc Glucose Injection or Isotonic sodium chloride injection 20~40mL, slowly inject. Or add 250~500ml of intravenous infusion.

3、 Intramuscular injection : It is mostly used for patients who cannot take orally, and the dose is the same as that of oral administration.

4、 bacterial dysentery : 200mg once, three times a day, for 3-7 days.

5. Pertussis: 10~15mg/kg per day, divided into three times.

6. Wheaty swelling: 4~10mg/kg, divided into three times a day.

7. Local (intrapleural injection therapy Focal Tuberculosis, etc.): 50-200mg once.

Adverse reactions

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The treated amount of isoniazid has less adverse reactions, less toxicity, headache, dizziness and other minor reactions. Higher dose (more than 6mg/kg per day) common peripheral neuritis , paresthesia of limbs Reflection disappears , muscle Paresis and insane Therefore, those with epilepsy, alcoholism and mental illness history should use it carefully. These symptoms are related to vitamin B6 deficiency. Its mechanism may be that isoniazid is similar to vitamin B6 in structure, while competing for the same Enzyme system Or combined into hydrazone, excreted by urine, which reduces the utilization of vitamin B6 and causes amino acids Metabolic disorder And produce peripheral neuritis. When vitamin B6 is deficient glutamate generate GABA The central nervous system is blocked Inhibitory transmitter GABA reduction, resulting in Central excitation , insomnia, restlessness, and even convulsions , Induction Schizophrenia and Epilepsy 。 It can be treated or prevented by taking vitamin B6 together. High dose isoniazid can damage the liver, causing transaminase Temporary increase. Fast acetylation, over 35 years old and alcoholism are more likely to occur. Therefore, liver function should be checked regularly during medication, hepatopathy Patients should use it with caution hepatitis , it is strictly prohibited to continue using.

cardiovascular system

There have been reports that may cause Nodular vasculitis , and into Erythema nodosum , accompanied by Arthralgia 、 fever and Purpura 、 Gastrointestinal bleeding as well as Renal failure 。

respiratory system

because Vasculitis Caused by asthma Or lung damage is rare. China reported a case of asthma on the third day after taking 300mg of the drug daily, and the asthma disappeared on the second day after stopping the drug. Another case reported that Lufreu's syndrome occurred 13 days after medication.

nervous system

Peripheral neuritis is more common in patients with slow acetylation, and has a significant relationship with the dose. The incidence rate was 1%~2%, which most often occurred in the third week after treatment. Symptoms often start from the feet and lower limbs, with abnormal sensation first, Muscle strength Hypoplasia, numbness, hyporeflexia, subsequent pain, severe cases Muscular atrophy and Ataxia ， central nervous system The symptoms of infringement are dizziness, headache, restlessness, euphoria, insomnia Retrobulbar neuritis , red and green Color vision disorder , Brain Dysfunction And convulsions. Temporary excitability, moodiness, anxiety, euphoria, depression, separation of concept from reality may also occur, alcoholism Patients are more common.

digestive system

except anorexia , nausea and mild epigastric pain, no serious reaction. Oral mucosal reaction is rare after the addition of vitamin B6. Sometimes the patient is constipated because he is in bed. The adverse liver reactions caused by this product are not uncommon, and are related to age, dose, acetylation type, combined medication and other factors. Can happen to those who take medicine for a long time Fatty liver 。

urinary system

It may cause nodular vasculitis and invade the kidney, and may also occur Glomerulonephritis 。 Renal insufficiency Eighty five percent of patients need good dose control and renal function examination.

hemopoietic system

A few reports due to lack of 5- phosphoric acid Vitamin B6 causes iron utilization disorder (Sidero astric) anemia. Over the years, China has reported individual cases. There are also individual occurrences Antinuclear antibody A positive report.

Endocrine and metabolism

diabetes People should use this product for treatment, especially at the same time Adrenocortical hormone Close observation and control shall be carried out. Otherwise, diabetes will worsen. Occasionally, it is reported that due to this product Gonadotropin The formation of Cushing syndrome , accompanied by increased appetite, overweight and Purple stripe 。 There are also female breast and female breast after several months of treatment Menstrual disorder And amenorrhea.

Anaphylactic reaction

Rashes (2%), fever (1-2%) jaundice (0.6%). Isoniazid can cause rheumatic syndrome, which is manifested as Arthralgia And ankylosis, often starting from the proximal finger joint and later invading Metacarpophalangeal joint , wrist, elbow and others Large articulation And the spine. Erythema caused by isoniazid Lupus like syndrome The serious symptoms of arthritis 、 rheumatic fever Or accompanied by fever, pleurisy and leukopenia, and drug withdrawal is required.

Drug interaction

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1. Drinking alcohol every day when taking isoniazid is easy to cause the liver induced by this product Toxic reaction And accelerate the metabolism of the product. Therefore, the dosage of the product must be adjusted and closely observed Hepatotoxicity sign. Patients should be advised to avoid alcoholic beverages during medication.

2. And Adrenocortical hormone (In particular Prednisolone ）When used together, it can increase the metabolism and excretion of the product in the liver, resulting in Blood concentration The effect of reduction is more significant in fast acetylation patients, and the dosage should be adjusted appropriately.

3、 Anticoagulant (e.g coumarin Or ninhydrin diketone derivatives) when used together with this product, the anticoagulant effect is enhanced due to inhibition of the enzyme metabolism of anticoagulants.

4. Isoniazid is Vitamin B6 Of Antagonist It can increase the output of vitamin B6 through the kidney, which is easy to cause peripheral neuritis. Those taking vitamin B6 at the same time should increase the dosage as appropriate.

5. It should not be used together with other neurotoxic drugs to avoid increasing neurotoxicity 。

6. And Cycloserine Can be increased when used together central nervous system Adverse reactions (such as dizzy or Lethargy ）, the dosage should be adjusted, and the central nervous system should be closely observed Systemic toxicity Signs, especially for patients engaged in work requiring high sensitivity.

7. And Ethionium 、 Pyrazinamide 、 Li Fuping When other antituberculosis drugs with hepatotoxicity are used together, the hepatotoxicity of the product can be increased, especially for those with liver function damage or those with fast and slow acylation of isoniazid. Therefore, it should be avoided to use together or closely follow up for signs of hepatotoxicity in the first three months of the course of treatment.

8. Suppressable carbamazepine The metabolism of, make its blood drug concentration increase, cause toxic reaction; Carbamazepine can induce isoniazid microsome Metabolism, forming an intermediate with hepatotoxicity metabolite Increase.

9. And Acetaminophen When used together, isoniazid can induce Hepatocyte Pigment P-450 increases the amount of toxic metabolites formed by the former, which can increase the hepatotoxicity and Nephrotoxicity 。

10. And Alfentanil When used together, isoniazid is Hepatic drug enzyme inhibitor , can prolong the effect of alfentanil; And Disulfiram Combined use can enhance the role of the central nervous system, resulting in dizziness, uncoordinated movement, irritability, insomnia, etc; And Enflurane Combined use can increase the formation of inorganic fluoride metabolites with nephrotoxicity.

11. Not suitable for Tong Kangzuo or Miconazole When used together, the blood concentration of the latter two drugs can be reduced.

12. With phenytoin sodium or aminophylline When used together, it can inhibit the metabolism of both in the liver, resulting in Phenytoin sodium Or the blood concentration of aminophylline increases, so the dosage of phenytoin sodium or aminophylline should be properly adjusted when the product is used successively or in combination with both.

13. Inaccessibility ephedrine 、 belladonna Take it at the same time to avoid or increase adverse reactions.

Pharmacology and toxicology

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pharmacology

Antituberculosis

yes Mycobacterium tuberculosis It has inhibitory and killing effects Biomembrane Penetrability Good. It is the first choice because of its good curative effect, low toxicity, low price and convenient oral administration Antituberculosis drug 。 Oral administration of isoniazid absorptivity 90%; 1-2 hours after taking Serum drug concentration Reachable peak; V d It is 0.61 ± 0.11L/kg, and the protein binding rate is very low. This product is mainly used in the body Acetylation At the same time, it is partially hydrolyzed and metabolized. because Genetic differences The population can be divided into fast acetylators and slow acetylators. their half life yes significant difference , average of fast acetylators t 1/2 1.1 hours. Slow acetylation lasted for 3 hours. The product is easy to pass blood brain barrier 。 Mainly used for various types pulmonary tuberculosis It can also be used for Tuberculous meningitis And others Extrapulmonary tuberculosis Etc. This product often needs to be mixed with others Antituberculosis drugs Combined application to enhance efficacy and overcome Drug resistant bacteria 。 In addition dysentery 、 pertussis 、 Hordeolum It also has certain curative effect.

Antidepressant

Isoniazid is also the first Antidepressants However, it was withdrawn from the market due to its strong hepatotoxicity.

Antibacterial

Isoniazid Mycobacterium tuberculosis It is highly selective and has strong antibacterial effect. The concentration of 0.025-0.05mg/L in the test tube can inhibit bacteria, and the higher concentration of 10mg/L can inhibit bacteria Breeding period Bacteria Bactericidal action 。 For tubercle bacillus in quiescent period, increasing drug concentration or prolonging contact time can also have bactericidal effect. It has the same killing effect on Mycobacterium tuberculosis both inside and outside the cell. Isoniazid is easy to produce drug resistance when used alone, and can be delayed when used in combination Drug resistance And enhance the curative effect. Isoniazid and other anti tuberculosis drugs Cross resistance 。

Although the mechanism of action of isoniazid has been studied in detail, it is not very clear. One is that isoniazid is converted into isoniazid nicotinic acid ， Isonicotinic acid Nicotinic Antimetabolite , instead of niacin, bound to NAD + , Deceived NAD + It cannot catalyze normal redox reaction. Another argument is that isoniazid inhibits C by blocking the action of desaturase twenty-four And C twenty-six Saturated fatty acid conversion to C twenty-four And C twenty-six Unsaturated fatty acids, which are most likely to be Mycotic acid Mycoic acid, the precursor of mycotic acid, is a key component of bacterial cell wall. Inhibiting the biosynthesis of mycotic acid will lead to the loss of acid resistance of bacteria. This mechanism fully demonstrates the selectivity of isoniazid on the role of cell wall of Mycobacterium tuberculosis.

clinical

This product is for treatment tuberculosis It is the first choice drug for all types of tuberculosis, such as tuberculosis of lung, lymph, bone, kidney, intestine, tuberculous meningitis pleurisy and peritonitis Etc. In order to prevent and delay the emergence of drug resistance, it should be combined with other first-line anti tuberculosis drugs. For acute Miliary tuberculosis And tuberculous meningitis should be increased. If necessary Intravenous drip 。 Isoniazid can be used for prevention and Active pulmonary tuberculosis People contacted by patients.

Toxicology

1. Mild Gastrointestinal reactions , such as loss of appetite, nausea, vomiting, abdominal pain, constipation, etc., pregnant women should use with caution.

2. There is often peripheral neuritis.

3. Do not use if there is liver damage or poor liver function.

4. Allergic reaction, drug fever and rash may occur.

5. Hematological symptoms: anemia, leukopenia, eosinophilia.

6. Endocrine disorders, male feminization of breast, lactation, irregular menstruation, impotence, etc.

matters needing attention

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1. The adverse reaction has gastrointestinal symptoms (such as Anorexia , nausea, vomiting abdominal pain , constipation, etc.); Blood system Symptoms（ anemia 、 Leukopenia 、 Eosinophil Increase Blood sputum 、 hemoptysis 、 Epistaxis 、 Eyeground hemorrhage Etc.); Liver damage; Allergy（ rash Or others); Endocrine disorder (Men Feminization Breasts lactation 、 Irregular menstruation 、 Impotence Etc.); Central symptom（ headache , insomnia, fatigue Memory loss , mental excitement, irritability, euphoria, hyperreflexia, hallucinations, convulsions dysuria , coma, etc.); Peripheral neuritis (manifested as Muscle spasm , limbs Paresthesia 、 Optic neuritis 、 Optic atrophy Etc.). Most of the above reactions occur in large doses or long-term applications. Slow acetylation is more likely to cause blood system endocrine system And neuropsychiatric responses; Fast acetylation is more likely to cause liver damage.

2、 Vitamin B6 Preventable nervous system For the occurrence of reaction, the daily dosage shall be 10-20mg, which shall be taken once or twice, but it shall not be used as a routine. Meet isoniazid acute poisoning A large dose of vitamin B6 can be antagonized, and other symptomatic treatment is required.

3. You can also take 300mg once a day or twice a week, 0.6-0.8g once Administration The method can improve the curative effect and reduce the incidence of adverse reactions.

4. Can be strengthened coumarin Anti coagulation drugs, some antiepileptic 、 hypotensor 、 Anticholinergic drug , Sanhuan antidepressant Attention shall be paid to the function of, etc.

5. Pay attention to inspection during medication liver function 。 People with poor liver function mental disease and epilepsy Patients with medical history should use it with caution.

6. Pregnant women should use it with caution.

7、 Antacid in especial Aluminium hydroxide It can inhibit the absorption of the product and should not be taken together.

A brief history of research

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In 1912, isoniazid was originally Bragg Of Charles University Hans Meyer and Josef Mally, graduate students of the Department of Chemistry (then Germany), synthesized it in 1912 when they were doing their doctoral thesis. They are totally unaware of the great medicinal value of their products. After being forgotten for about 40 years, researchers from Ross and Squibb in the United States and Bayer in West Germany independently found that isoniazid has extremely strong resistance Tuberculosis bacteria Activity.

In 1951, the clinical trial of isoniazid began in New York in 1951.

In 1952, isoniazid was first listed in the United States by Roche, Trade name Remifeng.

After years of use, it has been found that isoniazid has strong bactericidal power, high selectivity and few side effects. In particular, it is cheap and can be affordable for people in some poor areas. The sterilization characteristic of isoniazid is that it can inhibit the synthesis of mycotic acid components in the wall of tuberculosis bacteria, so that Mycobacterium tuberculosis Loss of multiple abilities (acid resistance, proliferation, Hydrophobicity ）When death occurs, isoniazid can also interact with tuberculous bacteria coenzyme Combination, interference Deoxyribonucleic acid and Ribonucleic acid Synthesis, so as to achieve the purpose of killing tuberculosis. The study also found that isoniazid had a stronger effect on tuberculosis bacteria with strong metabolic activity.

In this nearly 50 year history of use, although some patients infected with tuberculosis have developed drug resistance, the vast majority of doctors still believe that it is an indispensable main drug for the treatment of tuberculosis.

Compound Introduction

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essential information

Chemical formula: C six H seven N three O

Molecular weight: 137.14

CAS No ：54-85-3

EINECS No.: 200-214-6

Physical and chemical properties

Density: 1.244g/cm three

Melting point: 162-164 ℃

Appearance: white crystalline powder^[1]

Molecular structure data

Molar refractive index: 36.86

Molar volume (cm three /mol）：110.1

Isotonic specific volume (90.2K): 303.8

Surface tension (dyne/cm): 57.8

Polarization (10 -24 cm three ）：14.61^[1]

Calculate chemical data

Reference value for drainage parameter calculation (XlogP): None

Number of hydrogen bond donors: 2

Number of hydrogen bond receptors: 3

Number of rotatable chemical bonds: 1

Number of tautomers: 4

Topological molecular polar surface area: 68

Number of heavy atoms: 10

Surface charge: 0

Complexity: 120

Number of isotope atoms: 0

Determine the number of atomic structure centers: 0

Number of uncertain atomic structure centers: 0

Determine the number of chemical bond structure centers: 0

Number of uncertain chemical bond structure centers: 0

Number of covalent bond units: 1^[1]

Overtreatment

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performance

In addition to the above adverse reactions, the main manifestations are convulsions, confusion, coma, etc., which may occur if not handled in time Acute liver necrosis 。

processing method

1. Discontinue medication.

2. Keep respiratory tract unobstructed.

3. Adopt short effect Barbital Preparations and vitamin B 6 Intravenous administration. The dose of vitamin B6 is 1mg of vitamin B6 for every 1mg of isoniazid. If the dose of isoniazid is unknown, 65g of vitamin B can be given every 30 minutes until the convulsion stops and the patient regains consciousness. Then gastric lavage should be carried out within 2-3 hours after taking the product.

4. Take blood immediately to measure blood gas electrolyte 、 Urea nitrogen , blood sugar, etc.

5. Immediate intravenous administration sodium bicarbonate , correct Metabolic acidosis , repeat if necessary.

6. Adopt Osmotic diuretic And continue to use it after the clinical symptoms have been improved to promote the excretion of isoniazid and prevent the recurrence of poisoning symptoms.

7. Patients with severe poisoning should be given blood as soon as possible Hemodialysis When hemodialysis is not available peritoneal dialysis , shared at the same time diuretic 。

8. Take effective measures to prevent hypoxia hypotension and Aspiration pneumonia 。

identify

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1. Take about 10mg of this product, put it in a test tube, add 2mL of water to dissolve it, and then add ammonia to make silver nitrate Test solution 1mL, bubbles and black turbidity will occur, and a silver mirror will be generated on the tube wall.

2. In the chromatogram recorded under the content determination item, the retention time of the main peak of the test solution should be consistent with the retention time of the main peak of the reference solution.

3. The infrared absorption spectrum of this product should be consistent with the control spectrum (spectrum set 166 figure).

inspect

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Take 0.50g of this product, add 10mL of water to dissolve it, and then measure according to the law (general rule 0631). The pH value should be 6.0~8 0。

Clarity and color of solution

Take 1.0g of this product and add 10mL of water to dissolve it. The solution should be clear and colorless. If it appears turbid Turbidity standard solution (General Rule 0902, the first method) shall not be more concentrated. If color is developed, it shall be compared with the control solution of the same volume (for color comparison potassium dichromate Liquid 3.0mL for color comparison copper sulphate Liquid 0.10mL, diluted with water to 250mL), and shall not be deeper.

Free hydrazine

mirror Thin layer chromatography (General Rule 0502) Test.

Solvent: acetone -Water (1:1).

Test solution: Take an appropriate amount of this product, add solvent to dissolve it and dilute it quantitatively to prepare a solution containing about 0.1g per 1mL.

Reference solution: Take Hydrazine sulfate A proper amount of reference substance is dissolved in solvent and diluted quantitatively to prepare a solution containing about 80 µ g (equivalent to 20 µ g of free hydrazine) per 1mL.

System suitability solution : Take appropriate amount of isoniazid and hydrazine sulfate, add solvent to dissolve and dilute them to prepare a mixed solution containing 0.1g of isoniazid and 80 µ g of hydrazine sulfate per 1mL.

Chromatographic conditions: silica gel G Laminate , with Isopropanol -Acetone (3:2) is the developing agent.

System suitability requirements: the spots of free hydrazine and isoniazid shown in the system suitability solution should be completely separated, the ruler value of free hydrazine is about 0.75, and the ruler value of isoniazid R f The value is approximately 0.56.

Determination method: take 5 µ L each of the test solution, the reference solution and the system suitability solution, dab them on the same thin-layer plate, develop them, dry them in the air, and spray them with ethanol P-Dimethylaminobenzaldehyde Test solution, check after 15 minutes.

Limit: No yellow spots shall appear in front of the main spot of the test solution and the corresponding position of the main spot of the reference solution.

Related substances

mirror High performance liquid chromatography Method (General Rule 0512).

Test solution: take a proper amount of this product, add water to dissolve and dilute it to make a solution containing about 0.5mg per 1mL.

Reference solution : Accurately measure 1mL of the test solution, place it in a 100mL volumetric flask, dilute it with water to the scale, and shake it well.

Chromatographic conditions: Octadecyl silane bonded silica gel As filler, use 0.02 mol/L Disodium hydrogen phosphate Solution (with phosphoric acid Adjust the pH value to 6.0)- methanol (85:15) is mobile phase The detection wavelength is 262nm, and the injection volume is 10 µ L.

System suitability requirements: Theoretical plate number Not less than 4000 calculated according to isoniazid peak.

Determination method: Precisely measure the test solution and the reference solution and inject them into the liquid chromatograph respectively, and record the retention time of the chromatogram to the main component peak 3.5 times.

Limit: If there is an impurity peak in the chromatogram of the test solution, the area of a single impurity peak shall not be greater than 0.35 times (0.35%) of the main peak area of the reference solution, and the sum of the areas of each impurity peak shall not be greater than the main peak area of the reference solution (1.0%).

Loss on drying

Take the product and dry it at 105 ° C to constant weight, and the weight loss shall not exceed 0.5% (general rule 0831).

Ignition residue

Take 1.0g of this product and check it according to the law (general rule 0841). The residual residue shall not exceed 0.1%.

heavy metal

Take the residue left under the item of burning residue and check it according to law (the second method of General Rule 0821). The content of heavy metals shall not exceed 10% per million.

sterile

Take the product, dissolve it with suitable solvent, and then apply the film Filtration method Treatment and inspection according to law (general rule 1101) shall meet the requirements. (For sterile subpackaging)

Assay

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

Test solution

Take an appropriate amount of this product, weigh it precisely, add water to dissolve it and dilute it quantitatively to prepare a solution containing about 0.1mg per 1mL.

Reference solution

Take an appropriate amount of isoniazid reference substance, weigh it precisely, add water to dissolve it and dilute it quantitatively to prepare a solution containing about 0.1mg per 1mL.

Chromatographic conditions and system suitability requirements

See related substances.

Assay

Accurately measure the test solution and the reference solution, respectively inject them into the liquid chromatograph, and record the chromatogram. Calculate by peak area according to external standard method.