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Rifampicin
Systematic (IUPAC) name
(7S,9E,11S,12R,13 S,14R,15R,16R,17S,18S,19 E,21Z)-2,15,17,27,29-pentahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-26-{(E)-[(4-methylpiperazin-1-yl)imino]methyl}-6,23-dioxo-8,30-dioxa-24-azatetracyclo[23.3.1.1 4,7.05,28]triaconta-1(28),2,4,9,19,21,25(29),26-octaen-13-yl acetate
Identifiers
CAS number 13292-46-1
ATC code J04AB02 QJ54AB02
PubChem 5360416
DrugBank APRD00207
ChemSpider 4529237
Chemical data
Formula C 43H58N4O12  
Mol. mass 822.94 g/mol
Synonyms 5,6,9,17,19,21-Hexahydroxy-23-methoxy-2,4,12,16,18,20,22-heptamethyl-8-[ N-(4-methyl-1-piperazinyl)formimidoyl]-2,7-(epoxypentadeca[1,11,13]trienimino)-naphtho[2,1- b]furan-1,11(2H)-dione 21-acetate
Physical data
Melt. point 183–188 °C (361–370 °F)
Pharmacokinetic data
Bioavailability 90 to 95%
Metabolism Hepatic and intestinal wall
Half life 6 to 7 hours
Excretion 15 to 30% renal
60% faecal
Therapeutic considerations
Pregnancy cat. C(AU)
Legal status Prescription Only (S4) (AU) POM (UK)
Routes Oral, IV

Rifampicin (INN) (pronounced /rɪˈfæmpəsɪn/) or rifampin (USAN) is a bactericidal antibiotic drug of the rifamycin group.[1] It is a semisynthetic compound derived from Amycolatopsis rifamycinica (formerly known as Amycolatopsis mediterranei and Streptomyces mediterranei).[2] Rifampicin may be abbreviated R, RMP, RD, RA, or RIF (US).

In 1957, a sample of soil coming from a pine wood on the French Riviera was brought for analysis to the Lepetit Pharmaceuticals research lab in Milan, Italy. There, a research group headed by Prof. Piero Sensi (1920-) discovered a new bacterium. This new species appeared immediately of great scientific interest since it was producing a new class of molecules with antibiotic activity. Because Prof. Sensi and some of his fellow researchers were particularly fond of the French crime story Rififi (about a jewel heist and rival gangs),[3] they decided to call these compounds "Rifamycins". After two years of attempts in order to obtain more stable semi-synthetic products, in 1959 a new molecule with high efficacy and good tolerability was produced and was named "Rifampicin".

It is also known as rifaldazine, R/AMP, and Rofact (in Canada). There are various types of rifamycins from which this is derived, but this particular form, with a 4-methyl-1-piperazinaminyl group, is by far the most clinically effective.

Contents

Indications

Rifampicin was introduced in 1967,[4] as a major addition to the cocktail-drug treatment of tuberculosis and inactive meningitis, along with isoniazid, ethambutol, pyrazinamide and streptomycin. It requires a prescription in industrial North America, but is not a controlled substance. It must be administered regularly daily for several months without break otherwise, the risk of drug-resistant tuberculosis is greatly increased.[4] In fact, this is the primary reason that it is used in tandem with the three aforementioned drugs, particularly isoniazid.[5] This is also the primary motivation behind directly observed therapy for tuberculosis.

Rifampicin resistance develops quickly during treatment and rifampicin monotherapy should not be used to treat these infections — it should be used in combination with other antibiotics.

Mycobacteria

Rifampicin is typically used to treat Mycobacterium infections, including tuberculosis and leprosy.

With multidrug therapy used as the standard treatment of leprosy, rifampicin is always used in combination with dapsone and clofazimine to avoid eliciting drug resistance.

Other bacteria

Rifampicin also has a role in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) in combination with fusidic acid. It is used in prophylactic therapy against Neisseria meningitidis (meningococcal) infection.

It is also used to treat infection by Listeria species, Neisseria gonorrhoeae, Haemophilus influenzae and Legionella pneumophila. For these non-standard indications, sensitivity testing should be done (if possible) before starting rifampicin therapy.

The Enterobacteriaceae, Acinetobacter, and Pseudomonas species are intrinsically resistant to rifampicin.

Further, it has been used with Amphotericin B in largely unsuccessful attempts to treat primary amoebic meningoencephalitis caused by Naegleria fowleri.

Virus

Rifampicin has some effectiveness against vaccinia virus.[6][7]

Pharmacodynamics (mechanism of action)

Rifampicin inhibits DNA-dependent RNA polymerase in bacterial cells by binding its beta-subunit, thus preventing transcription to RNA and subsequent translation to proteins. Its lipophilic nature makes it a good candidate to treat the meningitis form of tuberculosis, which requires distribution to the central nervous system and penetration through the blood-brain barrier.

Rifampicin acts directly on messenger RNA synthesis. It inhibits only prokaryotic DNA-primed RNA polymerase, especially those that are Gram-stain-positive and Mycobacterium tuberculosis. Evidence shows that in vitro DNA treated with concentrations 5000 times higher than normal dosage remained unaffected; in vivo eukaryotic specimens' RNA and DNA polymerases suffered few problems as well.[5][8] Much of this acid-fast positive bacteria's membrane is mycolic acid complexed with peptidoglycan, which allows easy movement of the drug into the cell. Rifampicin interacts with the β subunit of RNA polymerase when it is in an α2β trimer. This halts mRNA transcription, therefore preventing translation of polypeptides.[5] It should be made clear, however, that it cannot stop the elongation of mRNA once binding to the template-strand of DNA has been initiated.[9] The Rifampin-RNA polymerase complex is extremely stable and yet experiments have shown that this is not due to any form of covalent linkage. It is hypothesized that hydrogen bonds and π-π bond interactions between naphthoquinone and the aromatic amino acids are the major stabilizers, though this requires the oxidation of naphthohydroquinone which is found most commonly in Rifampin. It is this last hypothesis that explains the explosion of multi-drug-resistant bacteria: mutations in the rpoB gene that replace phenylalanine, tryptophan, and tyrosine with non-aromatic amino acids result in poor bonding between Rifampin and the RNA polymerase.[5]

Rifampin-resistant bacteria produce RNA Polymerases with subtly different β subunit structures which are not readily inhibited by the drug.[10] In molecular biology research, plasmids containing rifampicin-resistant genes are often used for colony screening. Many plasmids containing these resistant genes are commercially available to researchers.

Adverse effects

The most serious adverse effect is related to rifampicin's hepatotoxicity, and patients receiving rifampicin often undergo baseline and frequent liver function tests to detect liver damage.

Rifampicin is an effective liver enzyme-inducer, promoting the upregulation of hepatic cytochrome P450 enzymes (such as CYP2C9 and CYP3A4), increasing the rate of metabolism of many other drugs that are cleared by the liver through these enzymes. As a consequence, rifampicin can cause a range of adverse reactions when taken concurrently with other drugs.[11] For instance, patients undergoing long term anticoagulation therapy with warfarin have to be especially cautious and increase their dosage of warfarin accordingly.[12] Failure to do so could lead to under-treating with anticoagulation resulting in serious consequences of thromboembolism. Likewise, it can also reduce the efficacy of hormonal contraception.

The more common unwanted effects include fever, gastrointestinal disturbances, rashes, and immunological reactions.

Taking rifampicin can cause certain bodily fluids, such as urine and tears, to become orange-red in color, a benign but sometimes frightening side-effect. This may permanently stain soft contact lenses. It also may be excreted in breast milk, therefore breast feeding should be avoided.

In short, adverse effects include:

Pharmacokinetics

Orally-administered Rifampin results in peak plasma concentrations in about 2 to 4 hours. Aminosalicyclic acid significantly reduce absorption of Rifampin,[13] and peak concentrations may not be reached. If these two drugs must be used concurrently, they must be given separately with an interval of 8 to 12 hours between administrations.

Rifampin is easily absorbed from the gastrointestinal tract; its ester functional group is quickly hydrolyzed in the bile; and it is catalyzed by a high pH and substrate-specific enzymes called esterases. After about 6 hours, almost all of the drug is deacetylated. Even in this deacetylated form, Rifampin is still a potent antibiotic; however, it can no longer be reabsorbed by the intestines and it is subsequently eliminated from the body. Only about 7% of the administered drug will be excreted unchanged through the urine, though urinary elimination accounts for only about 30% of the dose of the drug that is excreted. About 60% to 65% is excreted through the feces.

The half-life of Rifampin ranges from 1.5 to 5 hours, though hepatic impairment will significantly increase it. Food consumption, on the other hand, inhibits absorption from the GI tract, and the drug is more quickly eliminated.

Distribution of the drug is high throughout the body, and reaches effective concentrations in many organs and body fluids, including the CSF. This high distribution is the reason for the orange-red color of the saliva, tears, sweat, urine, and feces. About 60% to 90% of the drug is bound to plasma proteins.[9]

Preparations

Rifampicin is available in:

  • Bulgaria as Tubocin (by Actavis/Balkanpharma)
  • Israel as Rimactan (Sandoz)
  • Romania as Sinerdol (Sicomed)
  • UK as Rifadin (Aventis), Rimactan (Sandoz), Rifater a combination with isoniazid and pyrazinamide (Aventis), Rifinah a combination with isoniazid (Aventis), and Rimactazid a combination with isoniazid (Sandoz)
  • U.S. as Rifadin (Aventis), Rifater combination with isoniazid and pyrazinamide (Aventis), Rimactane (Novartis)
  • India R-Cinex 600 (Lupin Ltd), a combination of rifampicin and isoniazid
  • Australia as Rimycin (Alphapharm)

References

  1. ^ Masters, Susan B.; Trevor, Anthony J.; Katzung, Bertram G. (2005). Katzung & Trevor's pharmacology. New York: Lange Medical Books/McGraw Hill, Medical Pub. Division. ISBN 0-07-142290-0.  
  2. ^ Sensi P, Margalith P, Timbal MT (1959). "Rifomycin, a new antibiotic—preliminary report". Farmaco Ed Sci 14: 146–147.  
  3. ^ "When I Use a Word . . .I Mean It". British Medical Journal 1999;319(7215):972 (9 October). http://www.bmj.com/cgi/content/extract/319/7215/972. Retrieved 2009-07-10.  
  4. ^ a b Long, James W. (1991). Essential Guide to Prescription Drugs 1992. New York: HarperCollins Publishers. pp. 925–929. ISBN 0-06-273090-8.  
  5. ^ a b c d 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.
  6. ^ Charity JC, Katz E, Moss B (March 2007). "Amino acid substitutions at multiple sites within the vaccinia virus D13 scaffold protein confer resistance to rifampicin". Virology 359 (1): 227–32. doi:10.1016/j.virol.2006.09.031. PMID 17055024. PMC 1817899. http://linkinghub.elsevier.com/retrieve/pii/S0042-6822(06)00687-8.  
  7. ^ Sodeik B, Griffiths G, Ericsson M, Moss B, Doms RW (February 1994). "Assembly of vaccinia virus: effects of rifampin on the intracellular distribution of viral protein p65". J. Virol. 68 (2): 1103–14. PMID 8289340. PMC 236549. http://jvi.asm.org/cgi/pmidlookup?view=long&pmid=8289340.  
  8. ^ Coulson, Christopher J. "Bacterial RNA-Polymerase - Rifampin as Antimycobacterial." Molecular Mechanisms of Drug Action. 2nd ed. Bristol, PA: Taylor Francis, 1994. pp. 40-41.
  9. ^ a b Hardman, Joel G., Lee E. Limbird, and Alfred G. Gilman, eds. "Rifampin." The Pharmacological Basis of Therapeutics. 10th ed. United States of America: The McGraw-Hill Companies, 2001. pp. 1277-1279.
  10. ^ O'Sullivan DM, McHugh TD, Gillespie SH (May 2005). "Analysis of rpoB and pncA mutations in the published literature: an insight into the role of oxidative stress in Mycobacterium tuberculosis evolution?". J. Antimicrob. Chemother. 55 (5): 674–9. doi:10.1093/jac/dki069. PMID 15814606.  
  11. ^ Collins, R Douglas. Atlas of Drug Reactions. New York, NY: ChurchillLivingstone, 1985. pp. 123.
  12. ^ Stockley, Ivan H. "Anticoagulant Drug Interactions." Drug Interactions. 3rd ed. Boston: Blackwell Scientific Publications, 1994. pp. 274-275.
  13. ^ G Curci, A Ninni, A.D'Aleccio (1969) Atti Tavola Rotonda Rifampicina, Taormina, page 19. Edizioni Rassegna Medica, Lepetit, Milano

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