Chemotherapy for Tuberculosis

Lec. 7

Assistant. Prof. Dr. Inssaf IH. Al-Shemmary

 Chemotherapy for Tuberculosis
Tuberculosis (TB) is a bacterial disease caused by Mycobacterium
tuberculosis ((member of the genus Mycobacterium), can lead to
serious infections of the lungs,GIT, skeleton and meninges.
Mycobacterial infections are intracellular, this bacteria are slender,
rod-shaped and lipid-rich cell walls, also this organism grows
slowly and resistant. Therefore, multidrug therapy is employed
when treating tuberculosis (TB) to delay or prevent the resistant
strains.
Isoniazid, rifampin, ethambutol, and pyrazinamide are the
principal or so-called first-line drugs therapy for TB because of
their efficacy and acceptable degree of toxicity.The initial short
course chemotherapy for TB includes isoniazid, rifampin,
ethambutol, and pyrazinamide for 2 months (the intensive phase)
and then isoniazid and rifampin for the next 4 months (the
continuation phase).
Multidrug schedules for the treatment TB.
 First-line drugs Therapy
Isoniazid (INH)
Isoniazid (INH) is the hydrazide of isonicotinic acid, synthetic
analog of pyridoxine. It is the most potent of the antitubercular
drugs.

Mechanism of Action
Isoniazid inhibits synthesis of mycolic acids, which are essential
components of mycobacterial cell walls. Isoniazid is a prodrug
that is activated by the mycobacterial catalase-peroxidase (KatG).
The activated form of isoniazid forms a covalent complex with an
acyl carrier protein (AcpM) and a beta-ketoacyl carrier protein
synthetase, which blocks mycolic acid synthesis and kills the cell.
Antibacterial spectrum
INH is bacteriostatic for mycobacterium bacilli in the stationary
phase, but for rapidly dividing organisms, it is bactericidal. INH is
specific for treatment of M. tuberculosis.

Pharmacokinetics: Orally administered INH is readily

absorbed. Absorption is impaired if INH is taken with food. The
drug diffuses into all body fluids, cells, and caseous material
(necrotic tissue). Isoniazid undergoes N-acetylation and hydrolysis,
resulting in inactive products. Bimodal distribution of isoniazid
half-lives caused by rapid and slow acetylation of the drug.
Excretion is through glomerular filtration, predominantly as
metabolites.
Bimodal distribution of isoniazid half-lives caused by
rapid and slow acetylation of the drug.
Adverse effects
1. Peripheral neuritis: Peripheral neuritis (manifesting as
paresthesias of the hands and feet), which is the most common
adverse effect appears due to a relative pyridoxine (vitamin B6)
deficiency.
2. Hepatitis and idiosyncratic hepatotoxicity: Potentially fatal
hepatitis caused by a toxic metabolite.
3. Other adverse effects: Mental abnormalities, convulsions,
optic neuritis and hypersensitivity reactions have been observed.

Drug interactions: Because INH inhibits metabolism of

phenytoin, INH can potentiate the adverse effects of that drug.
 Rifampin
Rifampin which is derived from the soil mold Streptomyces, has a
broader antimicrobial activity than isoniazid and has found
application in the treatment of a number of different bacterial
infections.
Mechanism of Action: Rifampin binds to the β subunit of bacterial
DNA-dependent RNA polymerase and thus inhibits RNA synthesis.
Antimicrobial Spectrum: Rifampin is bactericidal for both
intracellular and extracellular mycobacteria, including M.
tuberculosis. It is effective against many gram-positive and gram-
negative organisms and is frequently used prophylactically for
individuals exposed to meningitis caused by meningococci or H.
influenzae.
Resistance: caused by a mutation in the affinity of the bacterial
DNA-dependent RNA polymerase for the drug or by decreased
permeability.
Pharmacokinetics: Absorption is adequate after oral
administration. Distribution of rifampin occurs to all body fluids
and organs. Adequate levels are attained in the CSF even in the
absence of inflammation. The drug is taken up by the liver and
undergoes enterohepatic cycling. Elimination of metabolites and
the parent drug is by the bile into the feces or by the urine.
Adverse effects: The most common adverse reactions include
nausea, vomiting, rash, hepatitis and a flu-like syndrome.
Drug interactions: Because rifampin can induce a number of
cytochrome P450 enzymes, it can decrease the half-lives of other
drugs (chlofibrate, digitoxin, ketoconazole).
Pyrazinamide
Pyrazinamide is a synthetic,orally effective,bactericidal,antitubercular
agent used in combination with isoniazid, rifampin, and ethambutol.
Pyrazinamide must be enzymatically hydrolyzed to pyrazinoic acid,
which is the active form of the drug. Resistance may be due to
impaired uptake of pyrazinamide or mutations that impair
conversion of pyrazinamide to its active form.
Pyrazinamide distributes throughout the body, penetrating the CSF. It
undergoes extensive metabolism. Major adverse effects of
pyrazinamide include hepatotoxicity (in 1–5% of patients), nausea,
vomiting, fever, and hyperuricemia.
 Ethambutol
Ethambutol is bacteriostatic. It inhibits arabinosyl transferase-an
enzyme that is important for the synthesis of the mycobacterial
arabinogalactan cell wall. Ethambutol can be used in combination
with pyrazinamide, isoniazid, and rifampin to treat TB.

Absorbed on oral administration, ethambutol is well distributed

throughout the body. Penetration into the CNS is therapeutically
adequate in tuberculous meningitis. Both parent drug and
metabolites are excreted by glomerular filtration and tubular
secretion.
Adverse Effect: The most important adverse effect is optic neuritis,
which results in diminished visual acuity and loss of ability to
discriminate between red and green. Visual acuity should be
periodically examined. Discontinuation of the drug results in reversal
of the optic symptoms. urate excretion is decreased by the drug; thus,
gout may be occur .

Alternate second-line drugs

Streptomycin, capreomycin, cycloserine, ethionamide,
fluoroquinolones, Macrolides. They are no more effective than the
first-line agents and their toxicities are often more serious
 Chemotherapy for Leprosy
Leprosy is a bacterial disease caused by Mycobacterium leprae.
Bacilli bacteria from skin lesions or nasal discharges of infected
patients enter susceptible individuals via abraded skin or the
respiratory tract.
The World Health Organization (WHO) recommends for the
treatment of leprosy by the triple-drug regimen of dapsone,
clofazimine, and rifampin for 6 -24 months.