Rifampicin Chemische Eigenschaften,Einsatz,Produktion Methoden
R-Sätze Betriebsanweisung:
R22:Gesundheitsschädlich beim Verschlucken.
R36/37/38:Reizt die Augen, die Atmungsorgane und die Haut.
R36/38:Reizt die Augen und die Haut.
S-Sätze Betriebsanweisung:
S26:Bei Berührung mit den Augen sofort gründlich mit Wasser abspülen und Arzt konsultieren.
S36:DE: Bei der Arbeit geeignete Schutzkleidung tragen.
S37/39:Bei der Arbeit geeignete Schutzhandschuhe und Schutzbrille/Gesichtsschutz tragen.
Beschreibung
Rifampicin is a semisynthetic derivative of rifamicin B, a macrolactam antibiotic and one
of more than five antibiotics from a mixture of rifamicins A, B, C, D, and E, which is called
a rifamicin complex, which is produced by actinomycetes Streptomyces mediteranei
(Nocardia mediteranei). It was introduced into medical practice in 1968. Synthesis of
rifampicin begins with an aqueous solution of rifamicin, which under the reaction conditions
is oxidized to a new derivative of rifamicin S (32.7.4), with the intermediate formation of rifamicin O (32.7.3). Reducing the quinone structure of this product with hydrogen using a
palladium on carbon catalyst gives rifamicin SV (32.7.5). The resulting product undergoes
aminomethylation by a mixture of formaldehyde and pyrrolidine, giving 3-pyrrolidinomethylrifamicin SV (32.7.6). Oxidizing the resulting product with lead tetracetate to an
enamine and subsequent hydrolysis with an aqueous solution of ascorbic acid gives
3-formylrifamicin SV (32.7.7). Reacting this with 1-amino-4-methylpiperazine gives the
desired rifampicin (32.7.8).
Chemische Eigenschaften
Red to Orange Crystalline Solid
Verwenden
Rifampicin is used to treat Tuberculosis and Tuberculosis-related mycobacterial infections. It is widely used as an antipruritic agent in the autoimmune cholestatic liver disease, primary biliary cirrhosis (PBC). It has been shown to cause hepatitis.
Indications
Rifampin (300 to 450 mg daily) is very effective in relieving the pruritus of
primary biliary cirrhosis, by inhibiting hepatic bile uptake and stimulating
mixed-function oxidases. Liver enzymes should be monitored to detect druginduced
hepatitis.
Definition
ChEBI: A member of the class of rifamycins that is a a semisynthetic antibiotic derived from Amycolatopsis rifamycinica (previously known as Amycolatopsis mediterranei and Streptomyces mediterranei)
Antimicrobial activity
It exhibits potent activity in vitro against Gram-positive cocci, including methicillin-resistant staphylococci (MIC <0.025–0.5 mg/L) and penicillinresistant pneumococci. Enterococci are less susceptible. Gram-positive bacilli, including Bacillus spp., Clostridium difficile, Corynebacterium spp. and Listeria monocytogenes, are highly susceptible (MIC 0.025–0.5 mg/L). The pathogenic Neisseria and Moraxella spp. are also highly susceptible.
Enteric Gram-negative bacteria are generally less sensitive (MIC 1–32 mg/L), but Bacteroides fragilis is highly susceptible. Among other Gram-negative bacilli, Haemophilus influenzae, H. ducreyi, Flavobacterium meningosepticum and Legionella spp. are highly susceptible (MIC <0.025–2 mg/L). Chlamydia trachomatis and Chlamydophila psittaci are inhibited by low concentrations (0.025–0.5 mg/L).
Most strains of M. tuberculosis, M. kansasii and M. marinum are inhibited by <0.01–0.1 mg/L, but M. fortuitum and members of the M. avium complex are resistant. M. leprae is highly sensitive.
Rifampicin is active against some eukaryotic parasites through inhibition of the prokaryote-like polymerase of kinetoplasts or mitochondria. Maturation of Plasmodium falciparum is inhibited by 2–10 mg/L; at higher concentrations Leishmania spp. are also inhibited.
High concentrations inhibit growth of a variety of poxviruses by interference with viral particle maturation; viral reverse transcriptase is unaffected.
Acquired resistance
Most large bacterial populations contain resistant mutants, which readily emerge in the presence of the drug and can emerge during treatment. The mutation rate to resistance in Staph. aureus, Str. pyogenes, Str. pneumoniae, Esch. coli and Proteus mirabilis is about 10–7 and that to M. tuberculosis and M. marinum 10–9–10–10. Primary resistance in M. tuberculosis remained low for many years, but is increasing.
Resistance is of the one-step type, and several classes of mutants exhibiting different degrees of resistance can be selected by exposing a large population to a relatively low concentration of the drug. Some of these mutants may be susceptible to other rifamycin derivatives.
Resistance is due to a change in a single amino acid of the β subunit of DNA-dependent RNA polymerase, which no longer forms a stable complex with rifampicin. It is not transferable and there is no cross-resistance with any other antibiotic class. The susceptible strains of the gastrointestinal flora become rapidly resistant during rifampicin treatment without alteration in the flora composition, and revert to susceptibility within a few weeks of cessation of treatment.
Allgemeine Beschreibung
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Pharmazeutische Anwendungen
Rifampin (USAN). Molecular weight: 822.95.
A semisynthetic derivative of rifamycin SV, available for oral administration or intravenous infusion and in several combined formulations with other antimycobacterial drugs. It is poorly soluble in water, but soluble in organic solvents.
Mechanism of action
Rifampin is a semisynthetic macrocyclic antibiotic produced
from Streptomyces mediterranei. It is a large lipidsoluble
molecule that is bactericidal for both intracellular
and extracellular microorganisms. Rifampin binds
strongly to the β-subunit of bacterial DNA-dependent
RNA polymerase and thereby inhibits RNA synthesis.
Rifampin does not affect mammalian polymerases.
Pharmakologie
Rifampin is well absorbed orally, and a peak serum concentration
is usually seen within 2 to 4 hours. Drug absorption is impaired if rifampin is given concurrently
with aminosalicylic acid or is taken immediately after a
meal. It is widely distributed throughout the body, and
therapeutic levels are achieved in all body fluids, including
cerebrospinal fluid. Rifampin is capable of inducing
its own metabolism, so its half-life can be reduced
to 2 hours within a week of continued therapy.
The deacetylated form of rifampin is active and undergoes
biliary excretion and enterohepatic recirculation.
Most of the drug is excreted into the GI tract and a
small amount in the urine.Moderate dose adjustment is
required in patients with underlying liver disease.
Clinical Use
Tuberculosis (in combination with other antituberculosis agents; see Ch. 58)
Leprosy (in combination with other antileprotic agents; see Ch. 57)
Serious infection with multiresistant staphylococci and pneumococci (in combination with a glycopeptide)
Elimination of nasopharyngeal carriage of Neisseria meningitidis and H. influenzae.
Nebenwirkungen
Rifampicin is relatively non-toxic, even when administered for a long period (as in the treatment of tuberculosis). However, several unwanted effects, including pink staining of soft contact lenses, are associated with its use. Other reactions can be divided into those associated with daily or intermittent administration, and those found only with intermittent therapy.
Sicherheitsprofil
Suspected carcinogen with experimental neoplastigenic and teratogenic data. Poison by intraperitoneal and intravenous routes. Moderately toxic to humans by ingestion. Moderately experimentally toxic by ingestion and subcutaneous routes. Human systemic effects by ingestion: conjunctiva irritation, iritis (inflammation of the iris), other eye effects, dermatitis. Experimental reproductive effects. Human mutation data reported. When heated to decomposition it emits toxic fumes of NOx.
läuterung methode
This macrolide antibiotic crystallises form Me2CO in red-orange plates. It has UV max at 237, 255, 334, and 475nm ( 33,200, 32,100, 27,000 and 15,400) at pH 7.38. It is stable in Me2SO and H2O and is freely soluble in most organic solvents but slightly soluble in H2O at pH <6. [Binda et al. Arzneim.-Forsch 21 1907 1971.] It inhibits cellular RNA synthesis without affecting DNA [Calvori et al. Nature 207 417 1965].
Rifampicin Upstream-Materialien And Downstream Produkte
Upstream-Materialien
Downstream Produkte
