Pyrazinamide
McGraw-Hill Science & Technology Dictionary:
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pyrazinamide
(′pir·ə′zin·ə′mīd)
(pharmacology) C5H5N3O A crystalline compound with a melting point of 189-191°C; used as a drug in the treatment of tuberculosis.
Drug Info:
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Pyrazinamide, PZA
Chemical formula:
- Espa�ol:
- Pirazinamida, Tableta oral
Pyrazinamide Oral tablet
What is this medicine?
PYRAZINAMIDE (peer a ZIN a mide) is used for the prevention or treatment of tuberculosis (TB) infections. This medicine is usually used in combination with at least one other agent.
This medicine may be used for other purposes; ask your health care provider or pharmacist if you have questions.
What should I tell my health care provider before I take this medicine?
They need to know if you have any of these conditions:
•gout
•if you frequently drink alcohol containing drinks
•liver disease
•an unusual or allergic reaction to pyrazinamide, other medicines, foods, dyes or preservatives
•pregnant or trying to get pregnant
•breast-feeding
How should I use this medicine?
Take this medicine by mouth with a glass of water. Follow the directions on the prescription label. Take your medicine at regular intervals. Do not take your medicine more often than directed. For your therapy to work as well as possible, take each dose exactly as prescribed. Do not skip doses or stop your medicine even if you feel better. Skipping doses may make the TB resistant to this medicine and other medicines. Do not stop taking except on your doctor's advice.
Talk to your pediatrician regarding the use of this medicine in children. Special care may be needed.
Overdosage: If you think you have taken too much of this medicine contact a poison control center or emergency room at once.
NOTE: This medicine is only for you. Do not share this medicine with others.
What if I miss a dose?
If you miss a dose, apply it as soon as you can. If it is almost time for your next dose, use only that dose. Do not use double or extra doses.What may interact with this medicine?
•alcohol
This list may not describe all possible interactions. Give your health care provider a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use. Also tell them if you smoke, drink alcohol, or use illegal drugs. Some items may interact with your medicine.
What should I watch for while using this medicine?
Visit your doctor or health care professional for regular check ups. You will need blood work done regularly.
Alcohol may interfere with the effect of this medicine. Avoid alcoholic drinks.
This medicine can make you more sensitive to the sun. Keep out of the sun. If you cannot avoid being in the sun, wear protective clothing and use sunscreen. Do not use sun lamps or tanning beds/booths.
You may get a false-positive result for sugar in your urine while you are taking this medicine. Talk with your doctor.
What side effects may I notice from receiving this medicine?
Side effects that you should report to your doctor or health care professional as soon as possible:
•allergic reactions like skin rash, itching or hives, swelling of the face, lips, or tongue
•breathing problems
•dark urine
•fever
•general ill feeling or flu-like symptoms
•gout pain, joint swelling or pain
•light-colored stools
•loss of appetite, nausea
•right upper belly pain
•trouble passing urine or change in the amount of urine
•unusual bleeding or bruising
•unusually weak or tired
•yellowing of the eyes or skin
Side effects that usually do not require medical attention (report to your doctor or health care professional if they continue or are bothersome):
•aches and pains
•acne
•sensitivity to sun or ultraviolet light
•stomach pain
This list may not describe all possible side effects. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Where should I keep my medicine?
Keep out of the reach of children.
Store at room temperature between 15 and 30 degrees C (59 and 86 degrees F). Keep container tightly closed. Throw away any unused medicine after the expiration date.
Last updated: 7/1/2002
Important Disclaimer: The drug information provided here is for educational purposes only. It is intended to supplement, not substitute for, the diagnosis, treatment and advice of a medical professional. This drug information does not cover all possible uses, precautions, side effects and interactions. It should not be construed to indicate that this or any drug is safe for you. Consult your medical professional for guidance before using any prescription or over the counter drugs.
Oxford A-Z of Medicinal Drugs:
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pyrazinamide
A bactericidal antibiotic drug used in combination with other drugs for the treatment of tuberculosis, although it does not have a licence for this. It is effective only during the first two or three months but is particularly useful in treating tuberculous meningitis. It is available as tablets on prescription only.
Side effects:
pyrazinamide may have adverse effects on the liver, including fever, loss of appetite, liver enlargement, and jaundice; other possible side effects are nausea, vomiting, muscle aches, and itching.
Precautions:
people taking pyrazinamide should report symptoms of liver toxicity, such as persistent nausea and vomiting, malaise, and jaundice, to their doctor.
Interactions with other drugs:
Probenecid its effects are antagonized by pyrazinamide.
Sulfinpyrazone: the effect of this drug in treating gout is reduced.
Proprietary preparation:
Rifater (combined with rifampicin and isoniazid).
| pumilio pine oil, psoriasis, pseudoephedrine | |
| pyridostigmine, pyridoxine, pyrimethamine |
Mosby's Dental Dictionary:
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pyrazinamide
n
trade name: generic; drug class: antitubercular; action: bactericidal interference with lipid, nucleic acid biosynthesis; use: tuberculosis, as an adjunct with other drugs.
Wikipedia on Answers.com:
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Pyrazinamide
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|---|---|
| Systematic (IUPAC) name | |
| pyrazine-2-carboxamide | |
| Clinical data | |
| Trade names | Rifater |
| AHFS/Drugs.com | monograph |
| MedlinePlus | a682402 |
| Pregnancy cat. | C |
| Legal status | ? |
| Routes | Oral |
| Pharmacokinetic data | |
| Bioavailability | >90% |
| Metabolism | Hepatic |
| Half-life | 9 to 10 hours |
| Excretion | Renal |
| Identifiers | |
| CAS number | 98-96-4  |
| ATC code | J04AK01 |
| PubChem | CID 1046 |
| DrugBank | DB00339 |
| ChemSpider | 1017 |
| UNII | 2KNI5N06TI |
| KEGG | D00144 |
| ChEBI | CHEBI:45285 |
| ChEMBL | CHEMBL614 |
| NIAID ChemDB | 007697 |
| Chemical data | |
| Formula | C5H5N3O |
| Mol. mass | 123.113 g/mol |
| SMILES | eMolecules & PubChem |
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Pyrazinamide is a drug used to treat tuberculosis. The drug is largely bacteriostatic, but can be bacteriocidal on actively replicating tuberculosis bacteria.
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Contents
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Abbreviations
The abbreviations PZA and Z are standard, and used commonly in the medical literature.
Dosing and presentation
- 20–25 mg/kg daily, or
- 50–70 mg/kg three times a week.
The British Thoracic Society guidelines are for 1.5 g daily for patients weighing less than 50 kg, and 2 g daily for patients weighing 50 kg or more.
Pyrazinamide is a generic drug and is available in a wide variety of presentations. Pyrazinamide tablets are usually 500 mg and form the bulkiest part of the standard tuberculosis treatment regimen. Pyrazinamide tablets are so large that some patients find them impossible to swallow: pyrazinamide syrup is an option for these patients.
Pyrazinamide is also available as part of fixed dose combinations with other TB drugs such as isoniazid and rifampicin (Rifater is an example).
Pharmacokinetics
Pyrazinamide is well absorbed orally. It crosses inflamed meninges and is an essential part of the treatment of tuberculous meningitis. It is metabolised by the liver and the metabolic products are excreted by the kidneys.
Pyrazinamide is routinely used in pregnancy in the UK and the rest of the world; the WHO recommend its use in pregnancy; and there is extensive clinical experience to show that it is safe. In the U.S., pyrazinamide is not used in pregnancy, citing insufficient evidence of safety.[1] Pyrazinamide is removed by haemodialysis and therefore doses should always be given at the end of a dialysis session.
Medical uses
Pyrazinamide is only used in combination with other drugs such as isoniazid and rifampicin in the treatment of Mycobacterium tuberculosis. It is never used on its own. It has no other indicated medical uses. In particular, it is not used to treat other mycobacteria; Mycobacterium bovis and Mycobacterium leprae are innately resistant to pyrazinamide. Pyrazinamide is used in the first two months of treatment to reduce the duration of treatment required.[2] Regimens not containing pyrazinamide must be taken for nine months or more.
Pyrazinamide in conjunction with rifampin is a preferred treatment for latent tuberculosis.[3]
Pyrazinamide is a potent antiuricosuric drug[4] and consequently has an off-label use in the diagnosis of causes of hyperuricemia and hyperuricosuria.[5] It acts on URAT1.[5]
Mechanism of action
Pyrazinamide is a prodrug that stops the growth of Mycobacterium tuberculosis.
Pyrazinamide diffuses into M. tuberculosis, where the enzyme pyrazinamidase converts pyrazinamide to the active form pyrazinoic acid. Under acidic conditions, the pyrazinoic acid that slowly leaks out converts to the protonated conjugate acid, which is thought to diffuse easily back into the bacilli and accumulate. The net effect is that more pyrazinoic acid accumulates inside the bacillus at acid pH than at neutral pH.[6]
Pyrazinoic acid was thought to inhibit the enzyme fatty acid synthase (FAS) I, which is required by the bacterium to synthesise fatty acids[7] although this has been discounted.[8] It was also suggested that the accumulation of pyrazinoic acid disrupts membrane potential and interferes with energy production, necessary for survival of M. tuberculosis at an acidic site of infection. Further studies reproduced the results of FAS I inhibition as the putative mechanism first in whole cell assay of replicating M. tuberculosis bacilli which have shown that pyrazinoic acid and its ester inhibit the synthesis of fatty acids.[9] This study was followed by in vitro assay of tuberculous FAS I enzyme that tested the activity with pyrazinamide, pyrazinoic acid and several classes of pyrazinamide analogs. Pyrazinamide and its analogs inhibited the activity of purified FAS I.[10] Pyrazinoic acid binds to the ribosomal protein S1 (RpsA) and inhibits trans-translation. This may explain the ability of the drug to kill dormant mycobacteria.[11]
Mutations in the pncA gene, which encodes a pyrazinamidase, is responsible for the appearance of most pyrazinamide resistant M. tuberculosis strains.[12] A few pyrazinamidase resistant strains with mutations in the rpsA gene have also been identified.[11]
Side effects
The most common (approximately 1%) side effect of pyrazinamide is joint pains (arthralgia), but this is not usually so severe that patients need to stop taking the pyrazinamide.[13][14] The arthralgia can be distressing to patients, but is never harmful.[citation needed]
The most dangerous side effect of pyrazinamide is hepatotoxicity, which is dose related. The old dose for pyrazinamide was 40–70 mg/kg daily and the incidence of drug-induced hepatitis has fallen significantly since the recommended dose has been reduced. In the standard four-drug regimen (isoniazid, rifampicin, pyrazinamide, ethambutol), pyrazinamide is the most common cause of drug-induced hepatitis.[15] It is not possible to clinically distinguish pyrazinamide-induced hepatitis from hepatitis caused by isoniazid or rifampicin; test dosing is required (this is discussed in detail in tuberculosis treatment)
Other side effects include nausea and vomiting, anorexia, sideroblastic anemia, skin rash, urticaria, pruritus, hyperuricemia, dysuria, interstitial nephritis, malaise; rarely porphyria, and fever.
Chemical synthesis
Pyrazinamide can by synthesized from o-phenylenediamine and glyoxal:[16]
See also
References
- ^ American Thoracic Society, Centers for Disease Control, Infectious Diseases Society of America (2003). "Treatment of Tuberculosis". Am J Respir Crit Care Med 167 (602–662).
- ^ Hong Kong Chest Service, Medical Research Council (1981). "Controlled trial of four thrice weekly regimens and a daily regimen given for 6 months for pulmonary tuberculosis". Lancet 1 (8213): 171–4. doi:10.1016/S0140-6736(02)95623-0. PMID 6109855.
- ^ Centers for Disease Control and Prevention (2000). "Targeted tuberculin testing and treatment of latent tuberculosis infection". MMWR 49 (RR–6): 31–32. PMID 10881762.
- ^ Spaia S, Magoula I, Tsapas G, Vayonas G (2000). "Effect of pyrazinamide and probenecid on peritoneal urate transport kinetics during continuous ambulatory peritoneal dialysis". Perit Dial Int 20 (1): 47–52. PMID 10716583. http://www.pdiconnect.com/cgi/pmidlookup?view=long&pmid=10716583.
- ^ a b Ichida K, Hosoyamada M, Hisatome I, Enomoto A, Hikita M, Endou H, Hosoya T (January 2004). "Clinical and molecular analysis of patients with renal hypouricemia in Japan-influence of URAT1 gene on urinary urate excretion". J. Am. Soc. Nephrol. 15 (1): 164–73. doi:10.1097/01.ASN.0000105320.04395.D0. PMID 14694169. http://jasn.asnjournals.org/cgi/pmidlookup?view=long&pmid=14694169.
- ^ Zhang Y, Mitchison D (January 2003). "The curious characteristics of pyrazinamide: a review". Int. J. Tuberc. Lung Dis. 7 (1): 6–21. PMID 12701830. http://openurl.ingenta.com/content/nlm?genre=article&issn=1027-3719&volume=7&issue=1&spage=6&aulast=Zhang.
- ^ Zimhony O, Cox JS, Welch JT, Vilchèze C, Jacobs WR (2000). "Pyrazinamide inhibits the eukaryotic-like fatty acid synthetase I (FASI) of Mycobacterium tuberculosis" (abstract). Nature Medicine 6 (9): 1043–47. doi:10.1038/79558. PMID 10973326. http://www.nature.com/nm/journal/v6/n9/abs/nm0900_1043.html;jsessionid=AFEEF16483CA23196C7729EBE644297C.
- ^ Boshoff HI, Mizrahi V, Barry CE (2002). "Effects of Pyrazinamide on Fatty Acid Synthesis by Whole Mycobacterial Cells and Purified Fatty Acid Synthase I". Journal of Bacteriology 184 (8): 2167–72. doi:10.1128/JB.184.8.2167-2172.2002. PMC 134955. PMID 11914348. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=134955.
- ^ Zimhony O, Vilcheze C, Arai M, Welch J, Jacobs WR pi. Pyrazinoic acid and its n'Propyl Ester Inhibit Fatty Acid Synthase I in Replicating Tubercle Bacilli. Antimicrob Agents Chemother. 2007 51 752-754
- ^ Ngo SC., Zimhony O, Chung WJ Sayahi, H, Jacobs WR. and JT. Welchpi. Inhibition of Isolated Mycobacterium tuberculosis Fatty Acid Synthase I by Pyrazinamide Analogs. Antimicrob Agents Chemother AntimicrobAgents Chemother. 2007; 1 2430-5
- ^ a b Shi W, Zhang X, Jiang X, Yuan H, Lee JS, Barry CE et al. (2011). "Pyrazinamide inhibits trans-translation in Mycobacterium tuberculosis". Science 333 (6049): 1630–1632. doi:10.1126/science.1208813. PMID 21835980.
- ^ Scorpio A, Zhang Y (1996). "Mutations in pncA, a gene encoding pyrazinamidase/nicotinamidase, cause resistance to the antituberculous drug pyrazinamide in tubercle bacillus". Nature Medicine 2 (6): 662–7. doi:10.1038/nm0696-662. PMID 8640557.
- ^ East and Central African/Medical Research Council Fifth Collaborative Study (1983). "Controlled clinical trial of 4 short-course regimens of chemotherapy (three 6-month and one 9-month) for pulmonary tuberculosis". Tubercle 64 (3): 153–166. doi:10.1016/0041-3879(83)90011-9. PMID 6356538.
- ^ British Thoracic Society (1984). "A controlled trial of 6 months chemotherapy in pulmonary tuberculosis, final report: results during the 36 months after the end of chemotherapy and beyond". Br J Dis Chest 78 (4): 330–336. doi:10.1016/0007-0971(84)90165-7. PMID 6386028.
- ^ Yee D et al. (2003). "Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active tuberculosis". Am J Resp Crit Care Med 167 (11): 1472–7. doi:10.1164/rccm.200206-626OC. PMID 12569078. http://ajrccm.atsjournals.org/cgi/content/full/167/11/1472.
- ^ Kushner, S.; Dalalian, H.; Sanjurjo, J. L.; Bach, F. L.; Safir, S. R.; Smith, V. K.; Williams, J. H. (1952). Journal of the American Chemical Society 74 (14): 3617. doi:10.1021/ja01134a045.
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