Anti-Tuberculosis

drugs

BABAN S THAWKAR
 Tuberculosis is a chronic granulomatous disease and a major health problem in
developing countries.
 About 1/3rd of the world’s population is infected with Mycobact. tuberculosis,
out of which 10–15% develop the disease over their life time.
 As per WHO statistics for 2014,$ there were 9.6 million new TB cases globally, to
which India was the highest contributor with 2.2 million cases.
 600 people die from TB every day. Thus, TB kills more adults in India than any
other infectious disease.
 A new dimension got added in the 1980s due to spread of HIV with high
prevalence of tuberculosis and Mycobact. avium complex (MAC) infection among
these patients.
 Emergence of ‘multidrug resistant’ (MDR) TB which now accounts for ~ 20% of
previously treated, and 3.3% of new TB cases worldwide is a major challenge in
antitubercular chemotherapy.
 Mycobacterium tuberculosis can cause latent tuberculosis infection (LTBI) and
the disease known as tuberculosis (TB).
According to their clinical utility the anti-TB drugs can be divided into
 First line: These drugs
have high antitubercular
efficacy as well as low
toxicity; are used
routinely.
 Second line: These
drugs have either low
antitubercular efficacy
or higher toxicity or
both; and are used when
first line drugs cannot be
used, or to supplement
them
Chemotherapy for Tuberculosis
 TB treatment generally includes four first-line drugs.
 Second-line drugs are typically less effective, more toxic, and less extensively
studied. They are used for patients who cannot tolerate the first-line drugs or
who are infected with resistant TB.
 M. tuberculosis is slow-growing and requires treatment for months to years.
LTBI can be treated for 9 months with isoniazid (INH) monotherapy or with
12 once-weekly higher doses of INH and rifapentine.
 In contrast, active TB disease must be treated with several drugs.
 Treatment for drug-susceptible TB lasts for at least 6 months, while treatment of
multidrug-resistant TB (MDR-TB) typically lasts for about 2 years.
 First line
Isoniazid [eye-so-NYE-a-zid], along with ➢ Resistance follows chromosomal
rifampin, is one of the two most important TB mutations, including 1) mutation or
drugs. deletion of KatG (producing mutants
➢ Mechanism of action: incapable of prodrug activation), 2)
varying mutations of the acyl carrier
 Isoniazid is a prodrug activated by a proteins, or 3) overexpression of the
mycobacterial catalase–peroxidase (KatG). target enzyme InhA.
 Isoniazid targets the enzymes acyl carrier ➢ Pharmacokinetics:
protein reductase (InhA) and β-ketoacyl-
ACP synthase (KasA), which are essential for ▪ Isoniazid is readily absorbed after oral
the synthesis of mycolic acid. administration.

 Inhibiting mycolic acid leads to a disruption ▪ The drug diffuses into all body fluids,
in the bacterial cell wall. cells, and caseous material
Pharmacokinetics cont….
 Isoniazid undergoes N-
acetylation and hydrolysis,
resulting in inactive products.
 Isoniazid acetylation is
genetically regulated, with fast
acetylators exhibiting a 90-
minute serum half-life, as
compared with 3 to 4 hours
for slow acetylators (
ADR
 Hepatitis is the most  Isoniazid inhibits the metabolism of
serious adverse effect carbamazepine and phenytoin
 The incidence increases  isoniazid can potentiate the adverse effects of
with age (greater than 35 these drugs (for example, nystagmus and
years old), among patients
who also take rifampin, or ataxia).
among those who drink
alcohol daily.
 Peripheral neuropathy,
manifesting as paresthesia
of the hands and feet,
appears to be due to a
relative pyridoxine
deficiency caused by
isoniazid.
Rifamycins: rifampin, rifabutin, and rifapentine
 Rifampin, rifabutin, and rifapentine are all considered rifamycins, a group of
structurally similar macrocyclic antibiotics, which are first-line oral agents for
tuberculosis.

 Rifampin [ri-FAM-pin] has broader antimicrobial activity than isoniazid and can
be used as part of treatment for several different bacterial infections.
➢ Mechanism of action
 Rifampin blocks RNA transcription by interacting with the β subunit of
mycobacterial DNA-dependent RNA polymerase.
➢ Antimicrobial spectrum
 Rifampin is bactericidal for both intracellular and extracellular mycobacteria,
including M. tuberculosis, and NTM, such as M. kansasii and Mycobacterium
avium complex (MAC). Rifampin also is highly active against M. leprae.
➢ Resistance to rifampin is caused by  Elimination of rifampin and its
mutations in the affinity of the bacterial metabolites is primarily through the
DNA-dependent RNA polymerase gene bile and into the feces; a small
for the drug. percentage is cleared in the urine.
➢ Pharmacokinetics:  Urine, feces, and other secretions have
an orange-red color, so patients should
 Absorption is adequate after oral be forewarned. Tears may even stain
administration. Distribution of rifampin soft contact lenses orange-red.
occurs to all body fluids and organs.
 The drug is taken up by the liver and
undergoes enterohepatic recycling.
Rifampin can induce hepatic
cytochrome P450 enzymes and
transporters
ADR and Drug interactions
 The most common adverse reactions include
nausea, vomiting, and rash.
 Hepatitis and death due to liver failure are rare.
However, the drug should be used judiciously in
older patients, alcoholics, or those with chronic
liver disease.
 There is a modest increase in the incidence of
hepatic dysfunction when rifampin is co-
administered with isoniazid and pyrazinamide.
➢ Drug-drug interactions:
 Because rifampin induces several phase I
cytochrome P450 enzymes and phase II enzymes ,
it can decrease the half-lives of co-administered
drugs that are metabolized by these enzymes.
 Rifabutin [rif-a-BYOO-tin],  Rifapentine [rih-fa-PEN-teen] has a longer
a derivative of rifampin, is half-life than that of rifampin.
preferred for TB patients
coinfected with the human  In combination with isoniazid, rifapentine
immunodeficiency virus may be used once weekly in patients with
(HIV) who are receiving LTBI and in select HIV-negative patients with
protease inhibitors or minimal pulmonary TB.
several of the
nonnucleoside reverse
transcriptase inhibitors.
 Rifabutin is a less potent
inducer (approximately
40% less) of cytochrome
P450 enzymes, thus
lessening drug interactions.
Pyrazinamide
 It [peer-a-ZIN-a-mide] is a synthetic, orally effective short-course agent used in
combination with isoniazid, rifampin, and ethambutol.
 Pyrazinamide must be enzymatically hydrolyzed by pyrazinamidase to
pyrazinoic acid, which is the active form of the drug.
 Some resistant strains lack the pyrazinamidase enzyme. Pyrazinamide is active
against tuberculosis bacilli in acidic lesions and in macrophages.
 The drug distributes throughout the body, penetrating the CSF. Pyrazinamide
may contribute to liver toxicity. Uric acid retention is common.
 Most of the clinical benefit from pyrazinamide occurs early in treatment.
Therefore, this drug is usually discontinued after 2 months of a 6-month
regimen.
Ethambutol
 It [e-THAM-byoo-tole] is bacteriostatic and specific for mycobacteria.
 Ethambutol inhibits arabinosyl transferase—an enzyme important for the
synthesis of the mycobacterial cell wall.
 Ethambutol is used in combination with pyrazinamide, isoniazid, and rifampin
pending culture and susceptibility data.
 Both the parent drug and its hepatic metabolites are primarily excreted in the
urine.
 The most important adverse effect is optic neuritis, which results in diminished
visual acuity and loss of ability to discriminate between red and green.
 Uric acid excretion is decreased by ethambutol, and caution should be exercised
in patients with gout.
 Streptomycin [strep-toe-MY-sin], para-aminosalicylic [a-mee-noe-sal-i-SIL-ik]
acid, capreomycin [kap-ree-oh- MYE-sin], cycloserine [sye-kloe-SER-een],
ethionamide [e-thye-ON-am-ide], bedaquiline [bed-AK-wi-leen],
fluoroquinolones, and macrolides are second-line TB drugs.
 In general, these agents are less effective and more toxic than the first-line
agents.
 Drug-sensitive TB This is treated by 1st line ATDs as per regimens summarized
in table
➢ For new patients
 the initial treatment with 4 drugs including 3 bactericidal drugs (RHZ) and
one bacteriostatic drug (E) rapidy brings down the bacillary load and reduces
the risk of selecting resistant bacilli, especially in the face of increasing primary
H resistance which is now upto 18%.
 After 2 months Z is discontinued and the remaining 3 (RHE) are continued for
another 4 months to eliminate all bacilli from the body.
Treatment regimens* for new patients and previously treated patients of pulmonary TB
presumed to be drug-sensitive