This document provides information on various antitubercular agents. It begins with background on tuberculosis (TB) caused by Mycobacterium tuberculosis bacteria. It then discusses first-line antitubercular drugs including isoniazid, rifampicin, pyrazinamide, ethambutol and streptomycin. For each drug, it summarizes uses, mechanisms of action and potential adverse effects. It also discusses second-line drugs including para-amino salicylic acid, ethionamide, cycloserine and thiacetazone. The document aims to inform readers about different drug options for treating TB.

1. ANTITUBERCULAR AGENTS
DR. MANJOOR AHAMAD SYED,
M.Pharm,Ph.D
Associate. Professor
Department of Medicinal Chemistry,
College of Public Health and Medical Sciences,
Mettu University, Mettu
Post Box No-318
Ethiopia.

2. ANTITUBERCULAR AGENTS
INTRODUCTION
Tuberculosis (TB) is an infectious disease usually caused by Mycobacterium
tuberculosis (MTB) bacteria. Tuberculosis (TB) is a bacterial infection spread through
inhaling tiny droplets from the coughs or sneezes of an infected person. It mainly
affects the lungs, but it can affect any part of the body, including the tummy (abdomen)
glands, bones and nervous system.

3. Symptoms of TB
Typical symptoms of TB include:
 A persistent cough that lasts more than three weeks and usually brings up phlegm, which
may be bloody
 Weight loss
 Night sweats
 High temperature (fever)
 Tiredness and fatigue
 Loss of appetite
 Swellings in the neck

4. Definition of Antitubercular drugs:
CLASSIFICATION
According to clinical utility the anti TB drugs can be divided into two classes.
The drugs which are used in the treatment of Tuberculosis are known as Antitubercular drugs.
FIRST line drugs [HRZSE]
• F Field defects causing drug i.e. Ethambutol [E]
• I Isoniazid (INH) [H]
• R Rifampicin [R]
• S Streptomycin [S]
• T Twice a day given drug i.e. Pyrazinamide [Z]
(All other first line antitubercular are given once a day)

5. SECOND line drugs
• S Salicylates like Para-amino salicylate
• E Ethionamide
• C Cycloserine
• O Old drug: Thioacetazone
• N Newer Drugs:
Quinolones e.g. Ciprofloxacin, Levofloxacin, gatifloxacin and
Moxifloxacin Macrolides e.g. Clarithromycin, Azithromycin
• D Drugs rarely used: Aminoglycosides e.g. Capreomycin, Kanamycin, and Amikacin
• Rifabutin

6. ISONIAZID (INH) [H]
Adverse Effects:
Mild increase Liver Function Tests (10-20%),
Peripheral neuropathy (dose related incidence, 10-20%
incidence with 10 mg/kg/d), Loss of appetite, Nausea,
Vomiting, Stomach pain, Weakness.
Dizziness, Slurred speech, Lethargy, Progressive liver
damage (increases with age; 2.3% in pts > 50 yrs),
Hyperreflexia. Agranulocytosis, Anemia, Megaloblastic
anemia, Thrombocytopenia, Seizure.
N
CONHNH2
pyridine-4-carbohydrazide
Synthesis:
N
CH3
4-methylpyridine
KMnO4
(O)
N
COOH
C2H5OH / H+
Esterification
N
COOC2H5
NH2 .NH2
Hydrazine
N
CONHNH2
pyridine-4-
carboxylic acid
ethyl pyridine-4-carboxylate
Isoniazid
USES:
1. Isoniazid is used with other medications to
treat active tuberculosis (TB) infections. It is
also used alone to prevent active TB
infections in people who may be infected
with the bacteria (people with positive TB
skin test).
2. Isoniazid is an antibiotic and works by
stopping the growth of bacteria.
3. This antibiotic treats only bacterial
infections. It will not work for viral
infections (such as common cold, flu).

7. Mechanism of Action:
Inhibits synthesis of mycolic acids – essential components of mycobacterial cell walls. Its prodrug activated by enzyme
catalase-peroxidase. The activated form of isoniazid - forms a covalent complex with an inh-A (Acyl carrier protein -AcpM)
and KasA, a ß-ketoacyl carrier protein synthetase, which blocks mycolic acid synthesis and kills the cell.

8. ETHAMBUTOL
CH2
CH2
NH
NH
CH
C
H
CH2
C
H3
CH2
CH3
CH2 CH2
O
H
OH
2,2'-(ethane-1,2-diyldiazanediyl)di(butan-1-ol)
Synthesis:
CH2
CH2
Cl
Cl
+
C
H3
CH2
CH
CH2
O
H
NH2
2
1,2-dichloroethane
2-aminobutan-1-ol
Δ
-2HCl
CH2
CH2
NH
NH
CH
C
H
CH2
C
H3
CH2
CH3
CH2 CH2
O
H
OH
Ethambutol
Uses:
 Ethambutol is used with other medications to treat tuberculosis (TB).
 Ethambutol is an antibiotic and works by stopping the growth of bacteria.
 This antibiotic treats only bacterial infections.

9. Mechanism of Action:
Ethambutol inhibits mycobacterial arabinosyl transferases. Arabinosyl transferases are
involved in the polymerization reaction of arabinoglycan, an essential component of the
mycobacterial cell wall.
Adverse Effects:
Acute gout or hyperuricemia, Abdominal pain, Anaphylaxis, Confusion, disorientation,
Fever, Headache, LFT abnormalities, Malaise, Nausea, Optic neuritis; symptoms may
include decreased acuity, color blindness or visual defects (usually reversible with
discontinuation), Peripheral neuritis, Rash.

10. PYRAZINAMIDE
Synthesis:
Uses:
Pyrazinamide is used with other medications to treat tuberculosis (TB).
It is an antibiotic and works by stopping the growth of bacteria.
This antibiotic treats only bacterial infections.
It will not work for viral infections (such as common cold, flu).
N
N
NH2
O
pyrazine-2-carboxamide
NH2
NH2
benzene-1,2-diamine
+
CHO
CHO
oxaldehyde
N
N
quinoxaline
N
N
O
H
O
O
O
H
Oxidation
KmnO4
N
N
OH
O
OH
O
Selective
decarboxylation
N
N
OH
O
-CO2
NH3
N
N
NH2
O
Pyrazinamide

11. Mechanism of Action:
Pyrazinamide's exact mechanism of action is not known. Susceptible strains release
pyrazinamidase, which converts PZA to pyrazinoic acid (POA). POA decreases the pH
below that which retards the growth of M. tuberculosis and inhibiting the fatty acid
synthesis. Studies indicate that PZA is most effective in the initial stages of treatment, which
may be the result of diminished organism populations in macrophages early in therapy.
Adverse Effects:
Malaise, Nausea, Vomiting, Anorexia, Arthralgia, Myalgia.
Fever, Rash, Itching, Acne, Photosensitivity, Gout, Dysuria, Porphyria, Thrombocytopenia,
Hepatotoxicity, Interstitial nephritis.

12. RIFAMPICIN
Uses:
Rifampicin is used for the treatment of tuberculosis in combination with other antibiotics, such
as pyrazinamide, isoniazid, and ethambutol for the treatment of tuberculosis, it is administered
daily for at least 6 months. Combination therapy is used to prevent the development of
resistance and to shorten the length of treatment.
NH
O
CH3
CH3
C
H3
O
H
O
H
O CH3
C
H3
O
CH3
O
C
H3
O
CH3
O
OH
N
N
N
CH3
O
H
O
H
C
H3
Adverse Effects:
Elevated liver function test (LFT) results (up to 14%), Rash
(1-5%), Epigastric distress (1-2%), Anorexia (1-2%), Nausea
(1-2%), Vomiting (1-2%), Diarrhea (1-2%), Cramps (1-2%),
Pseudomembranous colitis (1-2%), Pancreatitis (1-2%)
Mechanism of Action:
Rifampin binds to the β subunit of bacterial DNA–dependent RNA
polymerase and thereby inhibits RNA synthesis.

13. STREPTOMYCIN
Adverse Effects:
Hypotension, Neurotoxicity, Drowsiness, Drug
fever, Skin rash, Nausea, Vomiting,
Eosinophilia, Arthralgia, Tremor, Ototoxicity
(auditory, vestibular), Nephrotoxicity.
O
O
H
C
H3
O
H
NH
CH3
O
O
CH3
O
H
OHC
O
O
H OH
N
NH2
N
H2
OH
N
N
H2
NH2
Mechanism of Action:
Irreversibly inhibits bacterial protein synthesis. Protein synthesis is inhibited in at least three
ways:
1. Interference with the initiation complex of peptide formation.
2. Misreading of mRNA, which causes incorporation of incorrect amino acids into the peptide,
resulting in a nonfunctional or toxic protein.
3. Breakup of polysomes into nonfunctional monosomes.

14. Uses:
Streptomycin is an antibiotic medication used to treat a number of bacterial infections. This
includes tuberculosis, Mycobacterium avium complex, endocarditis, brucellosis,
Burkholderia infection, plague, tularemia, and rat bite fever.
In veterinary medicine, streptomycin is the first-line antibiotic for use against gram negative
bacteria in large animals (horses, cattle, sheep, etc.). It is commonly combined with procaine
penicillin for intramuscular injection. Tularemia infections have been treated mostly with
streptomycin.

15. COOH
OH
NH2
4-amino-2-hydroxybenzoic acid
COOH
NH2 HNO3 / H2SO4
COOH
NH2
NO 2
NaNO2 / HCl
COOH
N
+
NO2
N.Cl-
H2O
-N2 , HCl
COOH
OH
NO 2
2-aminobenzoi
c
acid
2-amino-4-nitro
benzoic acid
2-carboxy-5-nitrobenzen
e
-1-diazonium Chloride
2-hydroxy-4-nitro
benzoic acid
COOH
OH
NH2
Reduction Sn / HCl
PAS
PARA-AMINO SALICYLIC ACID:
Synthesis:
Uses:
4-Aminosalicylic acid, also known as Para-Amino Salicylic acid (PAS) is primarily used to
treat tuberculosis.
Specifically it is used to treat active drug resistant tuberculosis together with other
antituberculosis medications.
PAS has also been used in the treatment of inflammatory bowel disease, but has been
superseded by other drugs such as sulfasalazine and mesalazine.

16. Mechanism of action:
Aminosalicylic acid is a folate synthesis antagonist that is active almost exclusively against
mycobacterium tuberculosis. It is structurally similar to p-amino benzoic acid (PABA) and
the
Sulfonamides.
Adverse Effects:
Nausea, vomiting, diarrhea, abdominal pain, goiter with or without myxedema,
hypersensitivity (eg, fever, skin eruptions, leukopenia, thrombocytopenia, hemolytic
anemia, jaundice, hepatitis, encephalopathy, Loffler syndrome, vasculitis).

17. ETHIONAMIDE:
Synthesis:
Uses:
Ethionamide is used in combination with other antituberculosis agents as part of a second-
line regimen to treat tuberculosis (TB). The antimicrobial spectrum of ethionamide
includes M. tuberculosis, M. bovis and M. segmatis.
This antibiotic treats only bacterial infections. It will not work for viral infections (such as
common cold, flu).
N
S NH2
C2H5
2-ethylpyridine-4-carbothioamide
N
NH2
C2H5
HCN / HNO3
N
CN
C2H5
2-ethylpyridine-
4-carbonitrile
H2S / C2H5OH
N
S NH2
C2H5
Ethionamide

18. Mechanism of action:
Ethionamide is a prodrug which is activated by the enzyme ethA, a mono-oxygenase in
Mycobacterium tuberculosis, and then binds NAD+ to form an adduct which inhibits InhA
(enoyl acyl carrier protein reductase enzyme) in the same way as isoniazid. The mechanism
of action is thought to be through disruption of mycolic acid
Adverse Effects:
Disorder of gastrointestinal tract (50%), Postural hypotension, Dizziness, Drowsiness,
Headache
Peripheral neuropathy, Psychosis.

19. CYCLOSERINE
Synthesis:
Uses:
Cycloserine used exclusively to treat tuberculosis caused by mycobacterium tuberculosis
resistant to first line agents.
Cycloserine is also sometimes used to treat urinary tract and other types of infections that
have not responded to other treatments.
NH
O
O
N
H2
4-amino-1,2-oxazolidin-3-one
O
H COOH
NH2
2-amino-3-hydroxy
propanoic acid
O
H COOCH 3
NH3
+
Cl
-
CH3OH
HCl
PCl5
Cl COOCH 3
NH3
+
Cl
-
NH2OH
OH-
NH
O
O
N
H2
Cycloserine

20. Mechanism of action:
Cycloserine inhibits the incorporation of D- alanine into peptidoglycan pentapeptide by
inhibiting alanine racemase, which converts L-alanine to D- alanine, and D- alanyl-D –
alanine ligase (finally inhibits mycobacterial cell wall synthesis).
Adverse Effects:
Confusion, Dizziness, Headache, Somnolence, Seizure, Psychosis.

21. THIACETAZONE:
N
NH NH2
S
NH
C
H3
O
N-{4-[(E)-(2-carbamothioylhydrazinylidene)methyl]phenyl}acetamide
Mechanism of action:
Bacteriostatic- inhibits cyclopropanaton of cell wall mycolic acids.
Adverse Effects:
Hepatitis, exfoliative dermatitis, SJS, bone marrow depression rarely Common: Abdominal
discomfort, loose motions, rashes, mild anemia, anorexia.
Uses:
Thiacetazone is used in the treatment of tuberculosis. Thiacetazone is an antibiotic. It works
by slowing the growth of bacteria that causes tuberculosis.