Rifampin isoniazid

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Rifampin isoniazid
FDA Package Insert (RIFAMATE®)
Description
Clinical Pharmacology
Indications and Usage
Contraindications
Warnings and Precautions
Adverse Reactions
Overdosage
Dosage and Administration
How Supplied
Labels and Packages

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. 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.
  2. 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.
  3. 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
  4. 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.
  5. 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.
  6. 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.
  7. 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. 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.
  9. 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)
  10. 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)
  11. 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)
  12. PMID 19686043 (PMID 19686043)
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  13. Pharmacology, Harvey 4th edition. November 2009.