ANTI TUBERCULAR AGENTS

Mycobacterium Tuberculosis

• Slow-growing bacillus • Dormant forms in

macrophages
 Incidence of TB
• WHO: infects 2 billion people world wide
• Intracellular infections kills 3 million people
annually
• Increase incidence due to HIV associated
Mycobateria
• Common site of infection: lungs (primary
site),brain, bone, liver and kidneys.
• The main symptoms are cough, tachycardia,
cyanosis and respiratory failure.
 Category of TB

Depending upon the site of infection, the disease can

be categorized as follows:

o Pulmonary tuberculosis (respiratory tract).

o Genitourinary tuberculosis (genitourinary tract).

o Tuberculous meningitis (nervous system).

o Miliary tuberculosis (a widespread infection).

Anti-tubercular Agents
History of Antitubercular Drugs
Classification of Anti-tubercular drugs
Second-line: This drugs are considered
First-line: drugs are only when – resistance to first-line agents –
failure of clinical response to conventional
those which exhibit therapy. Serious treatment-limiting adverse
drug reactions . Expert guidance to deal with
the toxic effects is required .
high efficacy and less There are six classes of second-line drugs
(SLDs) used for the treatment of TB.
toxicity
– Para amino salicylic acid
– Isoniazid – Cycloserine
– Ciprofloxacin {fluoroquinolones}
– Rifampicin – Levofloxacin
– Capreomycin {Polypeptides}
– Ethambutol – Streptomycin
– Kanamycin
– Pyrazinamide – Amikacin {Aminoglycosides}
– Ethionamide {Thioamines}
Classification of Anti-tubercular drugs

 Rifabutin
 Macrolides like clarythromycin
 Linezolid
 Thioacetazone
 Vitamin D
 Thioridazine
 Chemical Classification of Anti TB
drugs
• Antitubercular drugs are also classified on the basis of chemical moiety as:-
• Salicylic acid derivatives: Para amino salicylic acid.

• Pyridine derivatives:Isoniazid (Isonicotinic acid hydrazine) ,Ethionamide

2-ethyl-4-thiopyridylamide
Isonicotinc acid Hydrazide
 Chemical Classification of Anti TB
drugs contd
• Pyrazine derivatives:Pyrazinamide

Pyrazine-2 carboxamide
• Ethylenediaminobutanol derivatives: Ethambutol
 Chemical Classification of Anti TB
drugs contd
• Antitubercular Antibiotics:
Rifampicin
Rifabutin
Cycloserine
Streptomycine
Capreomycin sulphate
Fluoroquinolones
ISONIAZID
 Synthesis of Isoniazid

Or
4-methyl pyridine
Mechanism of action of Isoniazid
 Mechanism of action of Isoniazid :

• Isoniazid causes a decreased synthesis of mycolic acid.

• Mycolic acid is a constituent of mycobacterial cell responsible for the acid
fastness of the bacteria. If Mycolic acid synthesis inhibited, causing in loss
of some areas of outer membrane and thinning of the cell wall.

KatG is mycobacterial catalase (peroxidase),

AcpM is Acyl carrier protein,
KaSA is Beta ketoacyl carrier protein synthetase
 Mechanism of action
• Isoniazid is a prodrug that is activated on the surface of
M. tuberculosis by katG enzyme to isonicotinic acid.
Isonicotinic acid inhibits the bacterial cell wall mycolic
acid, thereby making M. tuberculosis susceptible to
reactive oxygen radicals. Isoniazid may be bacteriostatic
or bactericidal in action, depending on the concentration
of the drug attained at the site of infection and the
susceptibility of the infecting organism. The drug is active
against susceptible bacteria only during bacterial cell
division.
 Use of Isoniazid
Use: First line drug used primarily as a bacteriostatic on resting bacilli.
•Bactericidal for actively dividing m.tuberculosis.
• It remains the treatment of choice for chemotherapy of pulmonary
or extrapulmonary tuberculosis.
•Used alone for prophylaxis.
•Used in combination with other anti TB agents like rifampicin and
pyrazinamide for treatment.
• Pridoxine (Vit-B6) is given together with the isoniazid to correct the toxic
reactions of INH
Dose: Prophylaxis: 300 mg once daily. Active infection: 5 mg/kg daily;
max 300 mg once daily orally.
Combination therapy: INH,Rifampicin and Pyrazinamide for 2 months
followed by INH (15mg/kg orally ) with Rifampicin (10 mg /kg
upto 600 mg per dose )twice /week for 4 months.
Biotransformation of isoniazid
Isoniazid is metabolized in the liver via acetylation.
There are two forms of the enzyme responsible for acetylation,
so that some patients metabolize the drug more quickly than
others.
 SAR of Isoniazid
Subsitution of hydrazide porion of INH with alkyl and aryl substitution resulted in a
series of active and inactive derivatives.
SAR of Isoniazid Contd
 Ethionamide
•A second-line anti tubercular agent that
inhibits mycolic acid synthesis.
•For use in the treatment of pulmonary and
extrapulmonary tuberculosis when other
antitubercular drugs have failed.
2-ethyl-4-thiopyridylamide •It also be used for treatment of leprosy.
Ethambutol
 Mechanism of action of Ethambutol

• An antitubercular agent that inhibits the transfer of mycolic acids into the cell wall
of the tubercle bacillus.

• It causes inhibition of mycobacterial arabinosyl transferases which is involved in

polymerization reaction of arabinoglycan, which is an essential component of
mycobacterial cell wall. By inhibiting this enzyme, the bacterial cell wall complex
production is inhibited. This leads to an increase in cell wall permeability.
•
Mechanism of action of Ethambutol
SAR of Ethambutol
 Use of Ethambutol
Use:
• Ethambutol is found to be more effective against
M. tuberculosis and M. kansasii.
• It can be used for Tuberculous meningitis
• As an adjunct, in the treatment of pulmonary
tuberculosis.

• Its usual dose is 15-25mg/kg/day.

Pyrazinamide
Pyrazinamide

Nicotinamide
Mechanism of action
Pyrazinamide diffuses into the granuloma of
M. tuberculosis, where the tuberculosis
enzyme pyrazinamidase converts
pyrazinamide to the active form pyrazinoic
acid.
- Under acidic conditions of pH 5 to 6, the
pyrazinoic acid that slowly leaks out converts
to the protonated conjugate acid, which is
thought to diffuse easily back into the bacilli
and accumulate. The net effect is that more
pyrazinoic acid accumulates inside the bacillus
at acid pH than at neutral pH.
- Pyrazinoic acid was thought to inhibit the
enzyme fatty acid synthase-I (FAS), which is
required by the bacterium to synthesize fatty
acids.
- Pyrazinoic acid was proposed to bind to the
ribosomal protein S1 (RpsA) and inhibit
translation process
Mechanism of action of Pyrazinamide
 Use of Pyrazinamide
• Used as a front line drug in combination with
Rifampicin and INH.
• For the initial treatment of active tuberculosis
in adults and children when combined with
other antitubercular agents.

• Dose: Daily administered dose is 20–35

mg/kg in 3–4 equally spaced doses and
maximum is 3 g daily
Para- Amino Salicylicacid
 Mechanism of Action
• Para amino salicylic acid acts as an inhibitor of bacterial
folate mechanism.
 P-amino aminosalicylic acid inhibits folic acid synthesis.
 P-amino salicylic acid is a structural analogue of PABA.
 The binding of para-aminobenzoic acid (PABA) to pteridine
synthetase acts as the first step in folic acid synthesis.
 P-aminosalicylic acid binds pteridine synthetase with
greater affinity than para-aminobenzoic acid, effectively
inhibiting the synthesis of folic acid.
• Also acts by inhibiting the synthesis of the cell wall
component, mycobactin, thus reducing iron uptake by M.
Tuberculosis.
P-Amino Salicylic Acid
SAR of p-amino Salicylic Acid
 SAR of p-amino Salicylic Acid
• The pharmacophore consisted of free amino
group, free phenol and free acid .
• Amino group at position 4 is essential for the
tuberculostatic activity and must be
unsubstituted.
• Hydroxyl group at postition 2 is also essential
for the activity.
 Use of p-amino Salicylic Acid
• P-Aminosalicylic acid is an anti-mycobacterial
agent used with other anti-tubercular drugs
(most often isoniazid) for the treatment of all
forms of active tuberculosis due to
susceptible strains of tubercle bacilli.
Rifampicin
 Rifampicin
Rifampicin is a semisynthetic derivative of Rifamycin B
Mechanism of Action
 Mechanism of Action contd

• It inhibits DNA-dependent RNA polymerase

activity by forming a stable complex with the
enzyme.
• It thus suppresses the initiation of RNA
synthesis.
• Leading to a suppression of RNA synthesis and
cell death.
SAR of Rifampicin
 Use of Rifampicin
• Rifampicin is the first line drug in the treatmet of tuberculosis.
• Rifampicin is bactericidal, and acts on both intracellular and
extracellular organisms.
• It has a broad antibacterial spectrum, including activity against
several forms of Mycobacterium.
• Rifampicin is used in combination with Isoniazid, pyrazinamide and
ethambutol for the treatment of tuberculosis.
• Used in treatment of leprosy along with dapsone and clofazimine.
• Also used in the treatment of brucellosis and staphylococcal
endocarditis.
• Used for the prophylaxis of meningococcal and Haemophilus
influenzae meningitis.
 Rifabutin

Rifampicin
Rifabutin

•Rifabutin is a semi synthetic

derivative of rifamycin S.
•Structurally similar to Rifampicin.
 Rifabutin
MOA: Rifabutin is an antibiotic that inhibits
DNA-dependent RNA polymerase activity in
gram-positive and some gram-negative
bacteria, leading to a suppression of RNA
synthesis and cell death.
Use: A broad-spectrum antibiotic that is being
used as prophylaxis against disseminated
Mycobacterium avium complex infection in
HIV-positive patients.
 Streptomycin

• Streptomycin was isolated from a strain of Streptomyces griseus.

Streptomycin
streptomycin

Streptidine

Streptobiosamine
 streptomycin
• Streptomycin is a triacidic base and posess
aldehydic carbonyl group.
Posess 3 structural unit of Aminoglycoside
antibiotics :
• Streptidine : (Diguanyl compound
corresponding to streptamine)
• Streptose:
• N-methyl- L glucosamine: connected through
glycosidic linkage.
Mechanism of Action
 Mechanism of Action
• It acts by “irreversibly" binding to the specific
30S ribosomal subunit of susceptible
organisms and disrupting the initiation and
elongation steps in protein synthesis.
• It possess bactericidal action.
 Use
• For the treatment of tuberculosis in combination
with other antitubercular drugs.
• Alternative to gentamycin and used in
combination with penicillin to treat endocarditis .
• Streptomycin is effective for the treatment of
tularemia (Francisella tularensis), plague (Yersia
pestis).
• Also used in severe M. avium complex infections.
 Cycloserine

D-Alanine(2-aminopropanoic acid)

4-amino-1,2-oxazolidin-3-one

• Cycloserine is an analogue of the amino acid D-alanine with broad-

spectrum antibiotic activity.

Use: Cycloserine is a broad spectrum antibiotic used as a second line

agent for treatment of drug resistant tuberculosis, always in
combination with other antituberculosis agents.
Mechanism of Action
 Mechanism of Action
•Cycloserine is an analog of the amino acid D-alanine.
• It interferes with an early step in bacterial cell wall synthesis in the
cytoplasm by competitive inhibition of two enzymes, L-alanine
racemase, which forms D-alanine from L-alanine, and D-alanylalanine
ligase, which incorporates D-alanine into the pentapeptide necessary
for peptidoglycan formation and bacterial cell wall synthesis.
• Ultimately it inhibits the bacterial cellwall synthesis. The walls of the
bacteria become weak and it results in the death of the bacteria.
 Use
• Used in combination with up to 5 other drugs
as a treatment for Mycobacterium avium
complex (MAC) and is also used to treat
tuberculosis (TB).
• Cycloserine, a broad-spectrum antibiotic, may
be bactericidal or bacteriostatic, depending on
its concentration at the site of infection and
the susceptibility of the organism.
 Capreomycin

Cyclic peptide antibiotic produced by Streptomyces capreolus.

Used in the treatment of tuberculosis in combination with other
drugs.
Mechanism of Action
 Mechanism of Action
• Capreomycin inhibit protein synthesis by
binding to the 70S ribosomal unit.
• It also binds to components in the bacterial
cell which result in the production of
abnormal proteins. These proteins are
necessary for the bacteria's survival. Therefore
the production of these abnormal proteins is
ultimately fatal to the bacteria.
 Pulmonary TB
Initial phase –
• INH+Pyridoxine
• Rifampicin 2 months
• Ethambutol
• Pyrazinamide

Continuation phase –
• INH+Pyridoxine
4 months
• Rifampicin
 Anti-TB therapy
• Multiple drugs are used to reduce the
emergence of resistance

• Given as combination tablets

• Taken 30 min before the breakfast as

absorption of rifampicin is influenced by food
Directly observed therapy (DOT) -To improve the compliance
New Drugs