Drug Monograph on Rifampicin - page 1

Keywords: rifampicin, drug monograph, pharmacology, efficay, therapeutic uses, pharmacodynamics, Prophylaxis of meningococcal meningitis rifampin rifadin SA infections tuberculosis essay on rifampicin pharmacokinetics absorption distribution matabolism excretion bmj referecing

By Einstein10 on 30/12/2009

Level: Foundation Degree

Page Number: 1 of 11 pages: 1 2 3 4 5 6 7 8 9 10 11

Introduction

Rifampicin is an antibacterial drug and belongs to a pharmacotherapeutic class of drugs known as naphthalenic rifamycins. It is a synthetic derivative of a natural antibiotic rifamycin B produced by Streptomyces mediterranei. 1
Rifampicin is recognised for its potency, broad spectrum antimicrobial activity and its high affinity to binding and thereby restricting bacterial DNA resistant RNA polymerase (RNAP). 2 Rifampicin was first introduced in 1968 and diffuses freely into living cells (lipophillic), tissues and bacteria making it extremely effective against intracellular pathogens like Mycobacterium Tuberculosis. 3 Like all antibiotics bacteria can develop resistance against Rifampicin and almost exclusively to the rpoB gene which codes for the β subunit of RNA polymerase. 4 It is also licensed for leprosy as well as widely used in the treatment of other infections 5 as it is active against Gram positive and Gram negative bacteria. 3

Drug Design

Drug Facts
Source Semisynthetic derivative of rifamycin B, a natural fermentation product of Nocardia mediterranei
Chemical Name 3-[[(4-Methyl-1-piperazinyl)imino]methyl]rifamycin
Chemical Group Macrocylic Antibiotic
Molecular formula C43H58N4O12

Molecular weight 822.94

Physical and chemical properties red/brown crystalline powder, slightly soluble in water, soluble in acetone and also alcohol 13

Formulations available capsules, syrup, intravenous infusion
In combined preparations available as tablets 14, 7.

pKa 7.9

Table 1.5, 6, 7. A table to show important drug facts about Rifampicin

RNA polymerase (RNAP) is a crucial enzyme involved in bacterial growth. This multi- subunit complex consists of a α2ββ – core enzyme which interacts with σ to form the holoenzyme 1.

Rifampicin interaction with RNAP (Rif-RNAP Complex)

When Rifampicin interacts with RNAP, a group of hydrophobic residues L391, L413, G414 AND I1452 shown above, line one side of the Rifampicin binding pocket and make van der Waals contact with the methyl group at C7 and the napthol ring (Figure 1). 3 The other side of the binding pocket is formed by direct interactions of the alkyl group of Q390 with C28 and C29 and the polar head of Q390 with Oxygen 5 of the Rifampicin molecule. Alongside this, 4 essential hydroxyl groups (circled in Figure 1) of the Rifampicin molecule position themselves to make hydrogen bonds with 5 proteins, R409, Q393, S411, D396 and H406 on the RNAP molecule. Oxygen 1 with R409, Oxygen 2 with S411 and Q393, and Oxygen 10 with H406. Oxygen’s 9, 10 and 11 are also in position to make hydrogen bonds with the backbone amide and carboxyl groups of F393. 4

Rifampicin inhibition of RNAP

RNAP is involved in synthesis of an RNA copy from a DNA template. After initial transcription

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Drug Monograph on Rifampicin- page 1

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