What Is Pyrazinamide?

White or almost white crystalline powder; odorless or almost odorless, slightly bitter. Slightly soluble in water and very slightly soluble in ethanol. Melting point is 188 192 , it has better antibacterial effect on human tubercle bacillus, and its bactericidal effect is strongest at pH 5 ~ 5.5. In humans, the bacteriostatic concentration of 12.5 g / ml can kill Mycobacterium tuberculosis. The mechanism of action may be related to pyrazinate. After the pyrazinamide penetrates into phagocytes and enters the body of Mycobacterium tuberculosis, the amidase in the bacteria removes the amido group and converts it into pyrazinate to exert antibacterial effect. In addition, because pyrazinamide is similar in chemical structure to nicotinamide, it interferes with dehydrogenases by replacing nicotinamide, prevents dehydrogenation, prevents the use of oxygen by Mycobacterium tuberculosis, and affects the normal metabolism of bacteria and causes death ^[1] .

Chinese name: Pyrazinamide
nickname: Isonicotinamide
Chemical formula: C5H5N3O

Molecular weight: 123.11
Melting point: 188-192
Exterior: White or off-white crystalline powder
Pinyin: b qín xin àn

Introduction to pyrazinamide compounds

Pyrazinamide Basic Information

Chinese name: Pyrazinamide

English name: Pyrazinamide (Aldinamide, PZA)

Chinese aliases: carbamoylpyrazine, pyrazinecarboxamide, isonicotinamide

English alias: Aldinamide, Diazinamide, Eprazine, Isopyratsin, Piraldina, Pyrafat, Pyrazide, PyrazinoicAcidAmide, Tebrazid, Zinamide

CAS number: 98-96-4

Structural formula:

Molecular formula: C ₅ H ₅ N ₃ O

Molecular weight: 123.11

Exact mass: 123.04300

PSA: 68.87000

LogP: 0.27580

Pyrazinamide physicochemical properties

Appearance and properties: transparent to off-white crystalline powder

Density: 1.301g / cm ³

Melting point: 189-191 ° C (lit.)

Boiling point: 357.4ºC at 760 mmHg

Flash point: 169.9ºC

Water solubility: 15 mg / mL

Stability: Stable under normal temperature and pressure. Store in a closed container. Store in a cool, dry, well-ventilated area away from incompatible materials. Store below 40ºC.

Pyrazinamide Safety Information

Customs code: 2933599090

WGK Germany: 3

Danger category code: R11

Safety instructions: S22-S24 / 25

RTECS number: UQ2275000

Dangerous goods mark: F; C

Pyrazinamide uses

Used as anti-tuberculosis drugs ^[2] .

Pyrazinamide Pharmacopoeia Standard

Pyrazinamide source (name), content (potency)

This product is pyrazine formamide. Calculated on dry basis, containing C5H5N3O shall not be less than 99.0%.

Pyrazinamide traits

This product is white or off-white crystalline powder.

This product is slightly soluble in water and slightly soluble in methanol or ethanol.

Melting point

The melting point of this product (Appendix VIC of Part Two of the 2010 Pharmacopoeia) is 188 ~ 192 ° C.

Pyrazinamide identification

(1) Take 0.1g of this product, add 10ml of water to dissolve, add 1ml of ferrous sulfate test solution, the solution is orange-red; add sodium hydroxide test solution to make it alkaline, and then turn blue.

(2) Take this product, dissolve it with water and make a solution containing about 10g per 1ml as the test solution. (1) Determine by UV-visible spectrophotometry (Appendix IVA of Pharmacopoeia Part II of the 2010 edition) at 310nm There is maximum absorption at the wavelength of. Take the test solution (1) diluted with water to make a solution containing about 10 g per 1 ml. As the test solution (2), determine according to the ultraviolet-visible spectrophotometry (Appendix IV A of the second edition of the Pharmacopoeia of the 2010 edition). There is maximum absorption at a wavelength of 268 nm.

(3) The infrared light absorption spectrum of this product should be the same as that of the control ("Infrared Spectra of Drugs" 191).

Pyrazinamide test

acidity

Take this product, add water to dissolve and dilute it to make a solution containing about 15mg per 1ml, and measure it according to law (Appendix VI H of the second edition of the Pharmacopoeia, 2010 edition). The pH value should be 5.0 7.0.

Color of solution

Take 0.10g of this product and add 10ml of water to dissolve. The solution should be colorless.

Sulfate

Take 0.30g of this product and check it according to law (Appendix B of Part II of the Pharmacopoeia 2010), compared with the control solution made from 1.0ml of standard potassium sulfate solution, it must not be more concentrated (0.033%).

relative substance

Take about 20mg of this product, dissolve and dilute with water to make a solution containing about 0.4mg per 1ml, as a test solution; take a precise amount, dilute with water quantitatively to make a solution containing about 0.8g per 1ml, as a control Solution. As determined by high performance liquid chromatography (Appendix VD of Part Two of the Pharmacopoeia, 2010 edition), octadecylsilane bonded silica gel was used as a filler; water (pH adjusted to 3.0 with glacial acetic acid)-methanol (92: 8) was used as Mobile phase; detection wavelength is 268nm. Take an appropriate amount of pyrazinamide, dissolve it with water and dilute it quantitatively to make a solution containing about 0.04mg per 1ml. Take 4ml of the solution and 1ml of hydrochloric acid, mix well, and heat in a water bath for 5 minutes to partially hydrolyze the pyrazinamide to pyrazinate. , Let cool, as a system suitability test solution. Take 20l into the liquid chromatograph and record the chromatogram. The number of theoretical plates calculated from the pyrazinamide peak is not less than 3000. The resolution of the maximum degradation product, pyrazinic acid peak and pyrazinamide peak, should be greater than 3.0. Take 20l of the control solution, inject it into the liquid chromatograph, adjust the detection sensitivity so that the peak height of the main component chromatographic peak is about 25% of the full range, and then accurately measure 20l each of the test solution and the control solution, and inject them into the liquid chromatography. Instrument, record the chromatogram to the main component peak retention time twice. If there is an impurity peak in the chromatogram of the test solution, the sum of the area of each impurity peak must not be greater than the main peak area (0.2%) of the control solution.

Loss on drying

Take this product and put it in a phosphorus pentoxide dryer to dry under reduced pressure to constant weight, and the weight loss should not exceed 0.5% (Appendix L of Pharmacopoeia Part II of 2010 Edition).

Residue on ignition

Must not exceed 0.1% (Appendix N of Part Two of the 2010 Pharmacopoeia).

Heavy metal

Take 0.50g of this product, add 2ml of acetate buffer solution (pH 3.5) and 23ml of water. After heating and dissolving, check according to law (Appendix H of the second edition of the Pharmacopoeia of 2010 Edition H first method), containing no more than two parts per million. ten.

Determination of pyrazinamide

Take about 0.10g of this product, accurately weigh it, add 50ml of acetic anhydride to dissolve it, then use potentiometric titration method (Appendix A of Pharmacopoeia Part II of 2010 Edition), titrate with perchloric acid titrant (0.1mol / L) The results were corrected with a blank test. Each 1ml of perchloric acid titration solution (0.1mol / L) is equivalent to 12.31mg of C ₅ H ₅ N ₃ O ^[3-5] .

Pyrazinamide category

Anti-TB drugs.

Pyrazinamide storage

Shaded and sealed.

Pyrazinamide laboratory analysis

Method name: Pyrazinamide API-Determination of Pyrazinamide-Neutralization Titration

Application range: This method uses the titration method to determine the content of pyrazinamide in the pyrazinamide drug substance.

This method is applicable to pyrazinamide APIs.

Principle of the method: add water and 40% sodium hydroxide solution into the distillation bottle for the test product, and add 4% boric acid solution as the absorption solution, and add the methyl red-bromocresol green mixed indicator solution. Titrate with hydrochloric acid titration solution after the distillation is complete. The titration results were corrected with a blank test, and the content of pyrazinamide was calculated based on the amount of titrant used.

Reagent: 1. 40% sodium hydroxide solution

2. 4% boric acid solution

3. Hydrochloric acid titration solution (0.1mol / L)

4. Methyl red-bromocresol green mixed indicator liquid

5. Reference anhydrous sodium carbonate

equipment:

Sample preparation: 1. Hydrochloric acid titration solution (0.1mol / L)

Preparation: Take 9mL of hydrochloric acid, slowly inject an appropriate amount of water, cool to room temperature, add water to dilute to 1000mL, and shake well.

Calibration: Take about 0.15g of reference anhydrous sodium carbonate dried to constant weight at 270 ~ 300 , accurately weigh, add 50mL of water to dissolve, add 10 drops of methyl red-bromocresol green mixed indicator liquid, titrate with this liquid When the solution changes from green to purple, boil for 2 minutes, cool to room temperature, and continue titration until the solution changes from green to dark purple. Each 1mL hydrochloric acid titration solution (0.1mol / L) is equivalent to 5.30mg of anhydrous sodium carbonate. Calculate the concentration of this solution based on the consumption of this solution and the amount of anhydrous sodium carbonate taken.

2. Methyl red-bromocresol green mixed indicator liquid

Take 20 mL of 0.1% methyl red ethanol solution, add 30 mL of 0.2% bromocresol green ethanol solution, and shake well.

Operation steps: accurately weigh about 0.25g of the test sample, put it in a distillation flask, add 200mL of water, carefully add 50mL of 40% sodium hydroxide solution along the bottle wall to form a liquid layer, connect the distillation device, and take another 40% of 4% boric acid solution as Add 10 drops of methyl red-bromocresol green mixed indicator solution to the absorption solution, gently rotate the distillation flask to mix the solution evenly, and heat and distill. After the distillation is complete, the absorption solution is titrated with hydrochloric acid titration solution (0.1mol / L). The titration results are corrected with a blank test. Each 1mL hydrochloric acid titration solution (0.1mol / L) is equivalent to 12.31mg of C5H5N3O.

Note: "Precision weighing" means that the weighed weight should be accurate to one thousandth of the weighed weight. "Precision measuring" means that the accuracy of measuring the volume should meet the accuracy requirements of the volume pipette in national standards ^[6] .

Pyrazinamide Drug Description

Use of pyrazinamide

The structure of this product is similar to nicotinamide, which can kill bacteria when entering the cell. Under the condition of low pH, the antibacterial activity is strong.

Pyrazinamide Tuberculosis drugs, which have no cross-resistance with other anti-tuberculosis drugs, are mainly used in cases where first-line drug treatment fails. This product alone is prone to drug resistance and needs to be combined with other anti-TB drugs.

Pyrazinamide pharmacological effects

This product only has a killing effect on Mycobacterium tuberculosis and has no antibacterial activity against other bacteria. Its anti-tuberculosis effect is closely related to the pH of the environment.

Pyrazinamide At pH 5 to 5.5, the antibacterial activity was the strongest; at pH 7, the antibacterial effect was significantly weakened. Animal experiments have confirmed that this product can enter the cell and is used in combination with isoniazid, which has a significant synergistic effect, and is also effective for extracellular tuberculosis bacteria in acidic environments. There is no cross-resistance between the product and other anti-tuberculosis drugs, and the drug alone is extremely prone to drug resistance. The mechanism of action may be that PZA penetrates into macrophages containing Mycobacterium tuberculosis and is converted into pyrazinate to exert antibacterial effect. This product is a derivative of nicotinamide, which has antibacterial or bactericidal effects, depending on drug concentration and bacterial sensitivity. This product has antibacterial activity only when the pH is acidic.

Pyrazinamide pharmacokinetics

It is quickly absorbed by the gastrointestinal tract after oral administration. After oral administration of 1g, the peak plasma concentration can reach 45mg / L after 2h, and about 10mg / L after 15h.

Pyrazinamide The drug concentration can be maintained for a longer period of time than when taken in divided doses. The product is widely distributed to the whole body tissues after oral administration, and the blood-brain barrier is well penetrated. The drug concentration in liver, lung and cerebrospinal fluid is similar to the blood concentration in the same period. The product is mainly metabolized in the liver, and 4% to 14% of the original drug is excreted by the urine within 24 hours after taking the drug. The plasma protein binding rate of the product is 50%, and the half-life is about 9 hours.

Pyrazinamide indications

It is used in combination with other anti-tuberculosis drugs in the treatment of tuberculosis that is not effective with first-line anti-tuberculosis drugs (such as streptomycin, isoniazid, rifampicin, and ethambutol). this

Pyrazinamide capsules The product is only effective for mycobacteria. This product has been used as a second-line drug in the past and is often used in re-treatment patients who have failed other antituberculosis drugs. A large number of clinical studies have shown that the short-term treatment plan containing this product is suitable for newly treated cases with positive sputum bacteria, and is generally applied for 2 to 3 months. After the treatment, the rejuvenation rate of sputum bacteria is significantly reduced. This product has been recognized as one of the triple or quadruple regimens in short-course chemotherapy.

Pyrazinamide usage dosage

oral. Commonly used amount for adults, combined with other anti-tuberculosis drugs, 5 to 8.75 mg / kg body weight every 6 hours, or 6.7 to 11.7 mg / kg body weight every 8 hours, up to 3 g per day. In the treatment of isoniazid resistant bacteria infection, it can increase to 60mg / kg per day. Unless necessary for children, it is usually not appropriate

Pyrazinamide tablets use. When it must be applied, the pros and cons should be fully weighed. Pyrazinamide can also be administered intermittently, twice a week, 50 mg / kg each time. When pyrazinamide is used alone to treat tuberculosis, bacteria are prone to drug resistance, so it is often used in combination with other anti-TB drugs. The course of treatment may take 1-2 years, or even apply for several years or indefinitely. Pyrazinamide is usually not recommended for patients with hypothyroidism unless necessary. Renal hypofunction need not be reduced when applied. Adults take 30 to 35 mg / kg daily, and those who weigh less than 50 kg will be given 1.5 g daily; those who weigh more than 50 kg will be given 2 g daily; and those who are more than 75 kg will be given 2.5 g daily. Children 20 to 25 mg / kg daily.

Pyrazinamide adverse reactions

Higher incidence: loss of appetite, fever, abnormal weakness or weakness, yellow eyes or skin (hepatotoxicity), lower incidence: chills, joint swelling and pain (especially big toe, palate, knee) or lesion Joint skin tension and fever (acute gouty joint pain). Serum uric acid is often increased during the application of this product, which can cause acute gout attacks. Serum uric acid measurement must be performed. Adverse reactions are related to the course of dose. After the application of conventional doses, adverse reactions are rare. 1. Liver damage: When taking 3g of medicine daily, about 15% of patients have liver damage, hepatomegaly, tenderness, elevated transaminase, jaundice, etc. With 1.5g daily for 3 months, liver toxicity is rare. If transaminase is elevated or even jaundice, it is related to the dosage of the drug, and the drug can be discontinued and active liver protection treatment. 2, joint pain: PZA metabolites can inhibit the excretion of uric acid, leading to hyperuricemia and gout-like performance, can be recovered after stopping the drug. Symptoms, such as gout, occur more than 1 month to 2 months after administration. Pyrazinamide promotes renal tubular reabsorption of uric acid and increases serum uric acid. 3. Gastrointestinal reactions: loss of appetite, appetite, nausea, and vomiting. 4, allergic reactions: fever, rash, photosensitivity. 5. It is difficult to control the blood sugar of diabetics. 6. Allergic reactions. Such as fever and rash, anti-allergic treatment should be discontinued. Individual patients are sensitive to light, and the exposed part of the skin is bright reddish brown, which can be recovered after stopping the drug. 7, occasionally anemia, induced ulcer attacks, dysuria, etc. ^[7] .

1 Liver damage is most common, and liver function should be checked regularly during medication. Therefore, liver dysfunction and children under 3 years old are disabled.

2 Can cause joint pain, symptoms such as gout, patients with gout quality are contraindicated.

3 Allergic reactions, occasional fever and rash, and even jaundice.

4 Skin reactions, individual sensitive to light, exposed parts of the skin are bright reddish brown. Those who take the medicine for a long time have a bronzed skin, which can gradually recover after stopping the medicine.

5 Gastrointestinal reactions, including loss of appetite, nausea, and vomiting.

Pyrazinamide contraindications

Patients who are allergic to cross-allergy and are allergic to ethionamide, isoniazid, niacin, or other similar chemical structures may also be allergic to this product. Use with caution in patients with diabetes, gout, or severe liver dysfunction. This product is relatively toxic and should not be used by children. Hepatic hypofunction is usually not recommended unless necessary. Disabled for pregnant women. Not used for children under 3 years old. Diabetes, gout, and liver dysfunction should be used with caution. Check liver function regularly during medication.

Pyrazinamide considerations

(1) Cross-allergies. Patients who are allergic to ethionamide, isoniazid, nicotinic acid or other similar chemical structures may also be allergic to this product.

(2) Interference to diagnosis: This product can interact with sodium nitrocyanide to produce reddish brown, which affects the results of uroketone measurement; can increase the measured values of alanine aminotransferase, aspartate aminotransferase and blood uric acid .

(3) Patients with diabetes, gout or severe liver function should be used with caution.

(4) Serum uric acid is often increased during the application of this product, which can cause acute gout attacks. Serum uric acid measurement must be performed.

(5) This product can also be used intermittently, 50 mg / kg each time. This product is relatively toxic and should not be used by children. It must be decided after weighing the advantages and disadvantages when it must be applied. Pregnant women with tuberculosis can be treated with isoniazid, rifampicin and ethambutol for 9 months. If they are resistant to any of the above drugs and may be sensitive to the product, consider using the product. This product belongs to the FDA pregnancy medication category C.

Store in a light-proof and sealed container.

Pyrazinamide drug interactions

1. Used in combination with allopurinol, colchicine, probenecid, and sulfazone, pyrazinamide can increase blood uric acid concentration and reduce the effect of the above drugs on gout. Therefore, when the above drugs are combined with pyrazinamide, the dosage should be adjusted in order to control hyperuricemia and gout.

2, when combined with ethionamide, can enhance adverse reactions.

3. When the cyclosporine and pyrazinamide are used together, the blood concentration of the former may decrease, so the blood concentration needs to be monitored to adjust the dose accordingly.

4, Synergistic effect with isoniazid and rifampicin, and can delay the development of drug resistance ^[1] .