ChemicalBook > Product Catalog > API > Synthetic Anti-infective Drugs > Anti-tuberculous mycobacterium leprae drugs > Pyrazinamide
Basic information Anti-tuberculosis drug Drug Interactions Indications Dosage First aid treatment Adverse reactions and side effects Uses Safety Related Supplier
Pyrazinamide Chemical Properties
- Melting point:189-191 °C (lit.)
- Boiling point:229.19°C (rough estimate)
- Density 1.3260 (rough estimate)
- refractive index 1.5900 (estimate)
- Flash point:>110°(230°F)
- storage temp. 2-8°C
- solubility H2O: soluble50mg/mL
- form Crystalline Powder or Needles
- pka0.5(at 25℃)
- color White
- PH7 (H2O)
- Water Solubility 15 mg/mL
- Merck 14,7956
- BRN 112306
- CAS DataBase Reference98-96-4(CAS DataBase Reference)
- NIST Chemistry ReferencePyrazine carboxamide(98-96-4)
- EPA Substance Registry SystemPyrazinamide (98-96-4)
Pyrazinamide Usage And Synthesis
- Anti-tuberculosis drugPyrazinamide is a second-line anti-tuberculosis drug, also known as formamide pyrazine, carbamoyl pyrazine, and isonicotinic acid amine. At room temperature, it appears as a white crystalline powder and is slightly soluble in water and is odorless with slightly bitter taste. It has a good antibacterial effect against human type Mycobacterium tuberculosis with the strongest bactericidal effect at the range of pH value being between 5-5.5. It has especially optimal bactericidal effect against the Mycobacterium tuberculosis inside the slow-growing phagocytic cells in acidic environment. After pyrazinamide penetrates into the phagocytic cells and enter into the body of Mycobacterium tuberculosis, lactamase in vivo make it be de-amidated, being converted to pyrazine acid to play the antibacterial effect.
The in vivo inhibitory concentration is 12.5μg/ml with the concentration of 50 μg/ml being able to kill the Mycobacterium tuberculosis. The inhibitory concentration against Mycobacterium tuberculosis in vivo is 10 times lower than that in vitro with almost no inhibitory effect in a neutral, alkaline environment.
Its anti-bacterial effect is between streptomycin and paramisansodium. It has great toxicity and can easy to produce drug resistance and should be used in combination with other anti-TB drugs.
Pyrazinamide has similar chemical structure with nicotinamide and can interfere with the dehydrogenase through substitution of nicotinamide, therefore preventing the dehydrogenation and inhibiting the utilization of oxygen by Mycobacterium tuberculosis, causing death of the bacteria due to failure of normal metabolism.
It is oral easily absorbed and is widely distributed in body tissues and fluids including liver, lung, cerebrospinal fluid, kidney and bile. After 2 hours, its plasma concentration can reach peak. The concentration of cerebrospinal fluid is similar as blood concentrations. It can subject to hepatic metabolism to be hydrolyzed to the pyrazine acid that is a kind of metabolite having antimicrobial activity, then further being hydroxylated into inactive metabolites and excreted in urine after glomerular filtration. The t1/2 is about 8 to 10 hours. It can be used in combination with other kind of anti-TB drugs fro the treatment of some complex cases of tuberculosis and tubercular meningitis patients.
- Drug Interactions1, when being combined with allopurinol, colchicine, probenecid, and sulfinpyrazone, pyrazinamide can increase the serum uric acid concentration and further reduce the efficacy of the above drugs on gout. Therefore, when being combined with pyrazinamide, the above drugs should be subject to dose adjustment in order to control hyperuricemia and gout.
2, it can enhance the adverse reactions when combined with B sulfur isonicotinoyl amine.
3, when cyclosporine is used simultaneously with pyrazinamide, the blood concentration of the former drug may be reduced, and therefore the blood concentration needs to be monitored and we should adjust the dose if necessary.
4, it has synergistic effect when combined with isoniazid and rifampin and can delay the development of drug resistance.
The above information is edited by the chemicalbook of Dai Xiongfeng.
- IndicationsIt can be used in combination with other anti-TB drugs for the treatment of tuberculosis that failed to be cured by first-line anti-TB drugs (such as streptomycin, isoniazid, rifampicin and ethambutol).
This product is only valid against mycobacteria.
In the past, pyrazinamide was used as second-line drugs, commonly applied to the patients undergoing retirement due to failure to be cured by other anti-TB drugs. A large number of clinical studies have shown: the short course regimen containing this product is suitable for being applied to the newly diagnosed sputum-positive cases. It is generally applied for 2 to 3 months. This protocol can enable a significant reduction of the re-positive rate of Mycobacterium tuberculosis after the end of treatment.
This product has been well considered as the composition of triple or quadruple protocols in short course chemotherapy.
- DosageWhen used in combination therapy with other anti-TB drugs, the common dose of adult oral administration is: every 6 hours according to the weight 5-8.75mg/kg, or every eight hours according to the weight 6.7-11.7mg/kg; the highest value is 3 g daily.
Upon treatment of the infection of isoniazid resistant bacteria, you can increase the dose to 60 mg/kg daily.
Children should take with caution, the necessary reference amount should be: 20-25mg/kg daily, it should be separately orally administrated in 3 times with the maximum dose being 2 g daily, the treatment course is generally 2 to 3 months, it can not be more than six months.
- First aid treatment1. Misusage patients should be immediately subject to gastric lavage and catharsis.
2. If liver dysfunction occurs during the course of treatment, the drug should be discontinued and routine liver-protection therapy should be applied.
3. Patients of gout should be given 0.25g/time probenecid (carboxymethyl benzene with oral administration in 3 times daily and being able to promote the excretion of uric acid.
4. Allergic patients should be given treatment with antihistamines and corticosteroids.
- Adverse reactions and side effectsLong-term or high-dose application of the product is easy to cause liver damage and increased blood uric acid and can also cause gastrointestinal irritation and allergic reactions.
For patients of relative high incidence: loss of appetite, fever, unusual fatigue or weakness, yellowing of the eyes or skin (liver toxicity).
Persons of low incidence: chills, joint pain (especially in the big toe, the condyle, knee) or diseased joints skin taut fever (acute gouty joint pain).
During the treatment course of this drug, the blood uric acid can increase and can cause acute gout that should be subject to determination of serum uric acid.
Adverse reactions are dose-related. After current application of conventional dosage, adverse reactions have been rarely observed.
Hepatic impairment: administration of drug for 3g daily with about 15% of patients getting liver damage, hepatomegaly, tenderness, elevated transaminases and jaundice. Currently upon applying 1.5 g daily for a 3-month treatment course, reactions of liver toxicity are rare.
Joint pain: PZA metabolites can inhibit the excretion of uric acid, causing hyperuricemia and gout-like performance with resumption after stopping drug.
Gastrointestinal reactions: loss of appetite, nausea, vomiting.
Allergies: occasionally fever and rash, and even jaundice.
Skin reactions: in some individual cases, the patients are light sensitive with the exposed parts of the skin being bright red brown. Patients subject to the long-term medication have their skins be bronze that can be gradually restored after the withdrawal of the drug. For diabetic patients taking pyrazinamide, it is difficult to control the level of blood sugar.
- UsesIt is a kind of anti-tuberculosis drugs.
- DescriptionPyrazinamide was synthesized in 1952, and it is the nitrogen-analog of nicotinamide. It exhibits hepatotoxicity. Synonyms of this drug are dexambutol, miambutol, esnbutol, ebutol, and others.
- Chemical PropertiesCrystalline Solid
- UsesAn antibacterial agent used to study liver toxicity prevention
- UsesAntibacterial (tuberculostatic)
- IndicationsPyrazinamide is a synthetic analogue of nicotinamide. Its exact mechanism of action is not known, although its target appears to be the mycobacterial fatty acid synthetase involved in mycolic acid biosynthesis. Pyrazinamide requires an acidic environment, such as that found in the phagolysosomes, to express its tuberculocidal activity. Thus, pyrazinamide is highly effective on intracellular mycobacteria. The mycobacterial enzyme pyrazinamidase converts pyrazinamide to pyrazinoic acid, the active form of the drug.A mutation in the gene (pncA) that encodes pyrazinamidase is responsible for drug resistance; resistance can be delayed through the use of drug combination therapy.
- Antimicrobial activityIt is principally active against actively metabolizing intracellular bacilli and those in acidic, anoxic inflammatory lesions. Activity against M. tuberculosis is highly pH dependent: at pH 5.6 the MIC is 8–16 mg/L, but it is almost inactive at neutral pH. Other mycobacterial species, including M. bovis, are resistant. Activity requires conversion to pyrazinoic acid by the mycobacterial enzyme pyrazinamidase, encoded for by the pncA gene, which is present in M. tuberculosis but not M. bovis. A few resistant strains lack mutations in pncA, indicating alternative mechanisms for resistance, including defects in transportation of the agent into the bacterial cell.
- Acquired resistanceDrug resistance is uncommon and cross-resistance to other antituberculosis agents does not occur. Susceptibility testing is technically demanding as it requires very careful control of the pH of the medium, but molecular methods for detection of resistance-conferring mutations are available.
- General DescriptionPyrazinecarboxamide (PZA) occurs as a white crystalline powder that is sparingly soluble in water and slightly soluble in polar organic solvents. Its antitubercular properties were discovered as a result of an investigation of heterocyclic analogs of nicotinic acid, with which it is isosteric. Pyrazinamide has recently been elevated to first-line status in short-term tuberculosis treatment regimens because of its tuberculocidal activity and comparatively low short-term toxicity. Since pyrazinamide is not active against metabolically inactive tubercle bacilli, it is not considered suitable for long-term therapy. Potential hepatotoxicity also obviates long-term use of the drug. Pyrazinamide is maximally effective in the low pH environment that exists in macrophages (monocytes). Evidence suggests bioactivation of pyrazinamide to pyrazinoic acid by an amidase present in mycobacteria.
- General DescriptionWhite powder. Sublimes from 318°F.
- Air & Water ReactionsWater soluble.
- Reactivity ProfilePyrazinamide is a carbamate ester. Incompatible with strong acids and bases, and especially incompatible with strong reducing agents such as hydrides. May react with active metals or nitrides to produce flammable gaseous hydrogen. Incompatible with strongly oxidizing acids, peroxides, and hydroperoxides.
- Pharmaceutical ApplicationsLike isoniazid, pyrazinamide is a synthetic nicotinamide analog, although its mode of action is quite distinct.
- PharmacologyPyrazinamide is well absorbed from the GI tract and is widely distributed throughout the body. It penetrates tissues, macrophages, and tuberculous cavities and has excellent activity on the intracellular organisms; its plasma half-life is 9 to 10 hours in patients with normal renal function. The drug and its metabolites are excreted primarily by renal glomerular filtration.
- PharmacokineticsOral absorption: >90%
Cmax 20–22 mg/kg oral: 10–50 mg/L after 2 h
Plasma half-life: c. 9 h
Plasma protein binding: c. 50%
It readily crosses the blood–brain barrier, achieving CSF concentrations similar to plasma levels. It is metabolized to pyrazinoic acid in the liver and oxidized to inactive metabolites, which are excreted in the urine, although about 70% of an oral dose is excreted unchanged.
- Clinical UseTuberculosis (a component of the early, intensive phase of short-course therapy)
- Clinical UsePyrazinamide is an essential component of the multidrug short-term therapy of tuberculosis. In combination with isoniazid and rifampin, it is active against the intracellular organisms that may cause relapse.
- Side effectsHepatotoxicity is the major concern in 15% of pyrazinamide recipients. It also can inhibit excretion of urates, resulting in hyperuricemia. Nearly all patients taking pyrazinamide develop hyperuricemia and possibly acute gouty arthritis. Other adverse effects include nausea, vomiting, anorexia, drug fever, and malaise. Pyrazinamide is not recommended for use during pregnancy.
- Side effectsIt is usually well tolerated. Moderate elevations of serum
transaminases occur early in treatment. Severe hepatotoxicity
is uncommon with standard dosage, except in patients with
pre-existing liver disease.
Its principal metabolite, pyrazinoic acid, inhibits renal excretion of uric acid, but gout is extremely rare. An unrelated arthralgia, notably of the shoulders and responsive to analgesics, also occurs.
Other side effects include anorexia, nausea, mild flushing of the skin and photosensitization.
- Chemical SynthesisPyrazinamide, pyrazincarboxamide (34.1.11), is synthesized from quinoxaline (34.1.7) by reacting o-phenylendiamine with glyoxal. Oxidation of this compound
with sodium permanganate gives pyrazin-2,3-dicarboxylic acid (34.1.8). Decarboxylation
of the resulting product by heating gives pyrazin-2-carboxylic acid (34.1.9). Esterifying
the resulting acid with methanol in the presence of hydrogen chloride and further reaction
of this ester (34.1.10) with ammonia gives pyrazinamide.
Pyrazinamide was synthesized in 1952, and it is the nitrogen-analog of nicotinamide. It exhibits hepatotoxicity. Synonyms of this drug are dexambutol, miambutol, esnbutol, ebutol, and others.
- Purification MethodsThe amide crystallises from water, EtOH or 1:1 hexane/EtOH in four modifications viz -form, -form, -form and form. [R. & S.rum Acta Cryst 28B 1677 1972, Beilstein 25 III/IV 772.]
Pyrazinamide Preparation Products And Raw materials
- Raw materialsPhenylhydrazine
- LUMICHROME 6-METHYLPTERINE 2,3-PYRAZINEDICARBOXAMIDE MIA 6-hydroxymethylpterin 5-(N,N-DIMETHYL)-AMILORIDE HYDROCHLORIDE BENZAMIL HYDROCHLORIDE Glipizide 3',5'-DICHLOROFOLIC ACID 6-Biopterin 5-(N,N-HEXAMETHYLENE)-AMILORIDE 6-CHLORO-3,5-DIAMINO-2-PYRAZINECARBOXAMIDE Lumazine 2-AMINO-4-HYDROXYPTERIDINE-6-CARBOXYLIC ACID Amiloride hydrochloride ALLOXAZINE Pyrazinamide Pyrazine
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