Specification :

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

Indications
Rifampicin was introduced in
1967, as a major addition to the
cocktail-drug treatment of
tuberculosis and inactive
meningitis, along with isoniazid,
ethambutol, and streptomycin.
There is no generic form. 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. In fact, this is the
primary reason that it is used in
tandem with the three
aforementioned drugs,
particularly isoniazid.

Rifampicin is typically used to
treat Mycobacterium infections,
including the aforementioned
tuberculosis and leprosy; it 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.
Further, it has been used with
Amphotericin B in largely
unsuccessful attempts to treat
primary amoebic
meningoencephalitis caused by
Naegleria fowleri.

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.
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. With multidrug
therapy (MDT) used as the
standard treatment of leprosy,
rifampicin is always used in
combination with dapsone and
clofazimine.

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

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.

Rifampin acts directly on
messenger RNA synthesis. It
inhibits only prokaryotic DNA-
primed RNA polymerase, especially
those that are Gram-stain-
positive, such as Mycobacterium
tuberculosis, which is slightly
such. In fact, evidence shows
that in vitro DNA treated with
concentrations 5000 times higher
than normal dosage remained
unaffected; in vivo eukaryotic
specimen's RNA and DNA
polymerases suffered few problems
as well. Much of these Gram-
positive bacteria’s membrane is
mycolic acid complexed with
peptidoglycan which allows easy
movement of the drug into the
cell. Rifampicin interacts with
the ? subunit of RNA polymerase
when it is in an ?2? trimer. This
halts mRNA transcription,
therefore preventing translation
of polypeptides.[3] 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.
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 ?-? 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.

Rifampin-resistant bacteria
produce RNA Polymerases with
subtly different ? subunit
structures which are not readily
inhibited by the drug. In
molecular biology research,
plasmids containing Rifampicin
(abbrev. Rif) resistant gene are
often used for colony screening.
Many plasmids containing Rif
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. The dosage cannot
exceed 600mg (average for a
healthy adult) or the patient
risks developing hepatitis.

Rifampicin is an effective liver
enzyme-inducer, promoting the
upregulation of hepatic
cytochrome P450 enzymes (such as
CYP2D6 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. For instance, patients
undergoing long term
anticoagulation therapy with
warfarin have to be especially
cautious and increase their
dosage of warfarin accordingly.
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

Hepatotoxic - Hepatitis,
jaundice, liver failure in severe
cases.
Respiratory - breathlessness
Cutaneous - flushing, pruritus,
rash, redness and watering of
eyes.
Abdominal - nausea, vomiting,
abdominal cramps with or without
diarrhea
Flu-like symptoms - with chills,
fever, headache, arthralgia and
malaise
Pharmacokinetics
Orally administered Rifampin
results in peak plasma
concentrations in about 2 to 4
hours. Aminosalicyclic acid may
significantly reduce absorption
of Rifampin, 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 and
its ester functional group is
quickly hydrolyzed in the bile
and 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.

Preparations
In Bulgaria it is marketed as
Tubocin (by
Actavis/Balkanpharma), in Israel
as Rimactan (Sandoz) and in
Romania as Sinerdol (Sicomed). In
the UK marketed 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). In the U.S.
as Rifadin (Aventis), Rifater
combination with isoniazid and
pyrazinamide (Aventis), Rimactane
(Novartis). In India Rifampicin
is available as R-Cinex 600
(Lupin Ltd). Its a combination of
Rifampicin and Isoniazid. The
main Rifampicin API (active
pharmaceutical ingredient)
available from Hebei Xingang
Pharmaceutical Co., Ltd.