ANTI-

TUBERCULAR
DRUGS

Dr. Gita Paudel

Associate Professor
Department of Pharmacology
TUBERCULOSIS: AN
OVERVIEW
 Tuberculosis(TB) is an infectious disease caused
predominantly by Mycobacterium tuberculosis and
among the leading causes of mortality in the world . It
is a global pandemic, killing someone approximately
every 20 seconds — about 1.5 million every year.
 A major health problem in developing countries
 Pulmonary TB (Lungs) is the most common site for
pathological lesions but it also affects other sites
(especially the lymph nodes, gut, meninge, bone,
adrenal glands), which is called extrapulmonary TB.
TUBERCULOSIS: AN
OVERVIEW
 Chronic granulomatous disease
 Caused by Mycobacterium tuberculosis
 Other than M. tuberculosis are called non-tuberculous or
atypical mycobacteria.
 The infection is usually due to inhalation of infected droplets
 Symptoms: low grade fever in the evening, night sweats, malaise,
fatigue, weight loss and a blood streaked productive cough.
 M. avium complex (MAC) is an important and common cause of
disseminated TB type of pulmonary disease seen most commonly
in immunocompromised patients, eg, those with AIDS.
 Difficult to treat: a. Most tubercle bacilli becomes intracellular
and resides in macrophages b. drug resistance to any single drug
so combination of drugs are therefore needed.
CHEMOTHERAPY IN
TUBERCULOSIS
 Goals of anti-tubercular chemotherapy
 Kill dividing bacilli:
 Large number of actively multiplying
mycobacteria must be killed.
 Bactericidal action rapidly reduce bacillary load
in the patient and achieve quick sputum
negative so that patient becomes non-
contagious : transmission of TB is interrupted.
 Kill persisting bacilli: For the effective cure
and to prevent relapse.
 Prevent emergence of resistance: so that
the bacilli remain susceptible to the drugs.
Antitubercular drugs:
classification
 First line: High antitubercular efficacy as
well as low toxicity, cheaper, are used
routinely.
 Second line: Either low antitubercular
efficacy or higher toxicity or both, are
used as reserved drugs.
FIRST LINE DRUGS (NEW)
ESSENTIAL SUPPLEMENTARY
 Isoniazid (INH/H)  Rifabutin
 Rifampicin (R)  Rifapentine
 Pyrazinamide (Z)
 Ethambutol (E)
 SECOND LINE DRUGS :
CLASSIFICATION
 Four groups:
 (A) Fluoroquinolones: Levofloxacin(Lfx), moxifloxacin,
ofloxacin
 (B) Injectables:
 I) aminoglycosides: kanamycin(Km), amikacin (Am), and
streptomycin(S)
 II) injectable polypeptide capreomycin (Cm)

 (C)
Other oral agents: ethionamide, prothionamide,
cycloserine, terizidone, linezolid(Lzd), clofazimine(Cfz)

 (D) Add-on agents:

 Three subgroups:
 D1: the first-line drugs pyrazinamide, ethambutol, and high-
dose isoniazid
 D2: the two new drugs bedaquiline and delamanid
 D3: PAS, clarithromycin, imipenem-cilastatin, meropenem,
MYCOBACTERIAL CELL
WALL

Baron S (ed.) Medical Microbiology. 4th edition. Chapter 33

Antitubercular drugs: isoniazid(H)
Mechanism of action
 Isoniazid inhibits synthesis of mycolic
acids, which are essential components
of mycobacterial cell walls.
 Isoniazid,a prodrug, enters bacilli by
passive diffusion.
 Gets activated by mycobacterial enzyme:
catalase-peroxidase ( KatG)
  Inhibition of synthesis of mycolic acid,
an essential component of the
mycobacterial cell wall, leading to cell
death
Antitubercular drugs: isoniazid
ADR
 Hepatotoxicity: serious side effect
 Peripheral neuritis
 preventedand treated by pyridoxine in a
dosage as low as 10 mg/day
 CNS toxicity: memory loss, psychosis,
ataxia, and seizures.
 Rash, fever, arthralgia, lupus like
syndrome
Antitubercular drugs: rifampicin (R)
Mechanism of action
 Rifampicin binds to the β subunit of
bacterial DNA-dependent RNA
polymerase (encoded by rpoB gene) 
inhibition of RNA synthesis in bacteria 
affect protein synthesis.
 Mammalian RNA polymerase does not
bind to the drug, so the RNA synthesis
of the host cells is therefore unaffected.
 RIFAMPICIN: ADR
 Least toxic antitubercular drug
 Safest drug in pregnancy.
 Hepatitis: Dose related, occur in patients with
preexisting liver disease, chronic alcoholic
 development of jaundice requires drug discontinuation
 Orange discoloration of urine, sweat, and tears
 Harmless
 Cutaneous syndrome: skin rash, flushing,
pruritus, redness and watering of eyes
 Flu like syndrome (fever, chills,
myalgias,headache)
 Abdominal syndrome: nausea,vomiting, cramps
 Anemia, thrombocytopenia, hemolysis rarely
Antitubercular drugs: pyrazinamide (Z)
Mechanism of action
 Passively diffuses into mycobacterial
cells  converted to pyrazinoic acid
(active form) by mycobacterial
pyrazinamidase (encoded by pncA
gene).
 Pyrazinoic acid(PA) gets accumulated in
acidic medium and probably inhibit
mycolic acid synthesis, but by
interacting with a different fatty acid
synthase. It also disrupts mycobacterial
cell membrane metabolism and
transport functions  cell death.
 Antitubercular drugs: pyrazinamide (Z)
ADR
 Hepatotoxicity (in 1–5% of patients)
 Hyperuricemia (asymptomatic)
 Non-gouty arthralgia (in 40%)
 GI upset: nausea, vomiting
 Drug fever, photosensitivity
 Loss of glycemic control
 Contraindicated in:
 Liver disease
 Ethambutol:
Mechanism of action
 Ethambutol inhibits mycobacterial
arabinosyl transferases (encoded by the
embAB genes) thereby disrupting
arabinogalactan biosynthesis, an
essential component of the
mycobacterial cell wall.
Ethambutol: ADR
 The most common serious ADR is retrobulbar
neuritis, resulting in loss of visual acuity and red-
green color blindness.
 Dose dependent and reversible
 Baseline and monthly visual acuity and color
discrimination testing recommended
 Because children are unable to report early visual
impairment, this drug is relatively contra-
indicated in children.
 Hyperuricemia
 peripheral neuritis.
 Requires dose adjustment in renal failure.
 Rarely hypersensitivity
 Safe in pregnancy
 STREPTOMYCIN
 Tuberculocidal aminoglycoside.
 It is not absorbed orally and must be administered
by i.m injection.
 It is active only against extra-cellular bacteria.
 Ototoxicity and nephrotoxicity are major ADR.
 Contraindicated in pregnancy (X)
 Dose: 15mg/kg/day
PRINCIPLES OF ANTITUBERCULAR
CHEMOTHERAPY
 Only combination anti-TB therapy is currently
recommended
 Multidrugtherapy prevents resistance and reduces
the duration of therapy.
 Standard Antitubercular regimens are divided
into an intensive (bactericidal) phase and a
continuation (sterilizing) phase
 Fixed dose combination tablets recommended
over separate drug formulations.
 Recently WHO has recommended that TB
treatment in all cases be administered daily
(rather than thrice or twice a week)
 DOTS strategy is followed to ensure compliance.
DOTS STRATEGY
 Directly Observed Treatment Short course
(DOTS)
 Patient takes every dose of medicine under
the direct observation of a health worker or a
volunteer
 Recommended by WHO in 1995
 Most effective strategy for tuberculosis
control.
 Itensures patient takes the right drug in right
dose at right intervals and for right duration.
 Improves adherence
 Around 5000 DOTS treatment centres in
Nepal
BLISTER PACKS
 Blister packs are currently used for
treatment of TB in Nepal. A single blister
pack contains 28 tablets. The number of
tablets to give to each patient is based
on their weight band and the number of
blister packs to be given depends on the
number of tablets each patient takes,
and the number of days supplied
TB TREATMENT REGIMENS
(SHORT COURSE REGIMENS)
 WHO introduced 6–8 month multidrug
‘short course’ regimens in 1995 under
the DOTS programme.
 Multi drug therapy given in two phases:
 Initial
Intensive phase
 Continuation phase
 Initial Intensive phase (IP) (2
months)
 3-4/5 drugs
 Rapidly kill majority of the bacilli.
 Minimise the chance of developing
resistance
 Bring about sputum conversion
 patient becomes noninfectious

 Symptomatic relief
 Continuation phase (CP)(4 months)

 Eliminationof the remaining bacilli

 To minimize the chance of relapse
TB TREATMENT REGIMEN (NEPAL) 2019
Treatment regimen
Treatment category
Intensive Continuation
phase phase

Adult and Childhood 2HRZE 4HR

New - Bacteriological or clinically
case diagnosed
s - Pulmonary or extra-
pulmonary
Complicated/Severe EP 2HRZE 7-10 HRE
cases (CNS TB, TB
Pericarditis, Musculoskeletal
TB, Miliary TB etc.)
Retreatment cases 2HRZE 4HR
(Previously treated Patients who
have received 1 month or more of
anti-TB drugs in the past)
New cases: Patients who have never been treated for TB or have taken
anti- TB drugs for less than one month
NATIONAL TB MANAGEMENT
GUIDELINES 2019: KEY FEATURES
 Category II treatment previously used for
retreatment cases is no longer used and
is no longer recommended.
 All TB patients must be treated using
Fixed Dose Combination (FDC) drugs
and treatment must be given daily dose
under direct observation.
 All treatment must be directly supervised
or observed by a treatment provider
(DOTS ensured)
 MARCH 24
 WORLD TB DAY