Rifampin isoniazid
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, M.B.B.S [2]
Overview
Rifampin
Rifampin was introduced in 1967,[1] as a major addition to the cocktail-drug treatment of tuberculosis and inactive meningitis, along with pyrazinamide, isoniazid, ethambutol and streptomycin ("PIERS"). It requires a prescription in North America. It must be administered regularly daily for several months without break; otherwise, the risk of drug-resistant tuberculosis is greatly increased.[1] In fact, this is the primary reason it is used in tandem with the three aforementioned drugs, particularly isoniazid.[2] This is also the primary motivation behind directly observed therapy for tuberculosis.
Isoniazid
Isoniazid also known as isonicotinylhydrazine (INH), is an organic compound that is the first-line medication in prevention and treatment of tuberculosis. The compound was first synthesized in the early 20th century,[3] but its activity against tuberculosis was first reported in the early 1950s, and three pharmaceutical companies attempted unsuccessfully to simultaneously patent the drug[4] (the most prominent one being Roche, which launched its version, Rimifon, in 1952). The drug was first tested at Many Farms, a Navajo community, due to the Navajo reservation's dire tuberculosis problem and the fact that the population was naïve with respect to streptomycin, the main tuberculosis treatment at the time.[5] With the introduction of isoniazid, a cure for tuberculosis was first considered reasonable.
Category
Antimycobacterial
US Brand Names
RIFAMATE®
FDA Package Insert
Description | Clinical Pharmacology | Microbiology | Indications and Usage | Contraindications | Warnings and Precautions | Adverse Reactions | Overdosage | Clinical Studies | Dosage and Administration | Compatibility, Reconstitution, and Stability | How Supplied | Labels and Packages
Mechanisms of Action
Rifampin
Rifampin inhibits bacterial DNA-dependent RNA synthesis by inhibiting bacterial DNA-dependent RNA polymerase.[6]
Crystal structure data and biochemical data indicate that rifampicin binds to RNA polymerase at a site adjacent to the RNA polymerase active center and blocks RNA synthesis by physically preventing extension of RNA products beyond a length of 2-3 nucleotides ("steric-occlusion" mechanism).[7][8]
Resistance to rifampin arises from mutations that alter residues of the rifampin binding site on RNA polymerase, resulting in decreased affinity for rifampin.[8] Resistant mutations map to the rpoB gene, encoding RNA polymerase beta subunit.
Isoniazid
Isoniazid is a prodrug and must be activated by a bacterial catalase-peroxidase enzyme that in M. tuberculosis is called KatG.[9] KatG couples the isonicotinic acyl with NADH to form isonicotinic acyl-NADH complex. This complex binds tightly to the enoyl-acyl carrier protein reductase known as InhA, thereby blocking the natural enoyl-AcpM substrate and the action of fatty acid synthase. This process inhibits the synthesis of mycolic acid, required for the mycobacterial cell wall. A range of radicals are produced by KatG activation of isoniazid, including nitric oxide,[10] which has also been shown to be important in the action of another antimycobacterial prodrug PA-824.[11]
Isoniazid is bactericidal to rapidly dividing mycobacteria, but is bacteriostatic if the mycobacteria are slow-growing.[12]
Isoniazid inhibits the CYP450 system.[13]
References
- ↑ 1.0 1.1 Long, James W. (1991). Essential Guide to Prescription Drugs 1992. New York: HarperCollins Publishers. pp. 925–929. ISBN 0-06-273090-8.
- ↑ Erlich, Henry, W Ford Doolittle, Volker Neuhoff, and et al. . Molecular Biology of Rifomycin. New York, NY: MSS Information Corporation, 1973. pp. 44-45, 66-75, 124-130.
- ↑ Meyer H, Mally J (1912). "On hydrazine derivatives of pyridine carbonic acids". Monatshefte Chemie verwandte Teile anderer Wissenschaften (in German). 33: 393&ndash, 414. doi:10.1007/BF01517946.PDF fulltext
- ↑ Hans L Riede (2009). "Fourth-generation fluoroquinolones in tuberculosis". Lancet. 373 (9670): 1148&ndash, 1149. doi:10.1016/S0140-6736(09)60559-6. PMID 19345815.
- ↑ Jones, David (2002). "The Health Care Experiments at Many Farms: The Navajo, Tuberculosis, and the Limits of Modern Medicine, 1952-1962". Bulletin of the History of Medicine. 76 (4): 749–790.
- ↑ Calvori, C.; Frontali, L.; Leoni, L.; Tecce, G. (1965). "Effect of rifamycin on protein synthesis". Nature. 207 (995): 417–8. doi:10.1038/207417a0. PMID 4957347.
- ↑ Campbell, E.A., Korzheva, N., Mustaev, A., Murakami, K., Nair, S., Goldfarb, A., Darst, S.A. (2001). "Structural mechanism for rifampicin inhibition of bacterial RNA polymerase". Cell. 104 (6): 901–12. doi:10.1016/S0092-8674(01)00286-0. PMID 11290327.
- ↑ 8.0 8.1 Feklistov, A., Mekler, V., Jiang, Q., Westblade, L.F., Irschik, H., Jansen, R., Mustaev, A., Darst, S.A., Ebright, R.H. (2008). "Rifamycins do not function by allosteric modulation of binding of Mg2+ to the RNA polymerase active center". Proc Natl Acad Sci USA. 105 (39): 14820–5. doi:10.1073/pnas.0802822105. PMC 2567451. PMID 18787125.
- ↑ Suarez J, Ranguelova K, Jarzecki AA; et al. (2009). "An oxyferrous heme/protein-based radical intermediate is catalytically competent in the catalase reaction of Mycobacterium tuberculosis catalase-peroxidase (KatG)". The Journal of Biological Chemistry. 284 (11): 7017–29. doi:10.1074/jbc.M808106200. PMC 2652337. PMID 19139099. Unknown parameter
|month=ignored (help) - ↑ Timmins GS, Master S, Rusnak F, Deretic V (2004). "Nitric oxide generated from isoniazid activation by KatG: source of nitric oxide and activity against Mycobacterium tuberculosis". Antimicrobial Agents and Chemotherapy. 48 (8): 3006–9. doi:10.1128/AAC.48.8.3006-3009.2004. PMC 478481. PMID 15273113. Unknown parameter
|month=ignored (help) - ↑ Singh R, Manjunatha U, Boshoff HI; et al. (2008). "PA-824 kills nonreplicating Mycobacterium tuberculosis by intracellular NO release". Science. 322 (5906): 1392–5. doi:10.1126/science.1164571. PMC 2723733. PMID 19039139. Unknown parameter
|month=ignored (help) - ↑ PMID 19686043 (PMID 19686043)
Citation will be completed automatically in a few minutes. Jump the queue or expand by hand - ↑ Pharmacology, Harvey 4th edition. November 2009.