ANTITUBERCULAR DRUGS 1 Anti TB Drugs

ANTITUBERCULAR DRUGS
(Ani TB Drugs)
What is Tuberculosis?
Tuberculosis (TB) is the most prevalent infectious disease in humans worldwide and a leading
killer caused by an infectious agent, that is, Mycobacterium tuberculosis. Mycbacterium spp. are
aerobic, Gram-positive, acid-fast, non-motile bacilli responsible for infections in humans, cattle,
rats and birds. Tuberculosis has been present in humans since ancient times.
According to World Health Organization (WHO) report, M. tuberculosis, currently infects over 2
billion people worldwide, with 30 million new cases reported every year. This infection accounts
for at least 3 million deaths annually.
Common Sites of Infection: Common infection sites of the tuberculosis are lungs (primary site),
brain, bone, liver, and kidney. In advanced cases, the infection may spread to lymphatic system,
pleura, genitourinary system, pericardium, middle ear and intestines.
The tuberculosis of lungs is called “pulmonary tuberculosis”, whereas, the tuberculosis of other
tissues/organs is called “extrapulmonary tuberculosis”.
Symptoms: The main symptoms are cough, fever, night sweats, tachycardia, cyanosis, weight loss,
fatigue and respiratory failure.
Most infections show no symptoms, in which case it is known as “latent tuberculosis (Latent
TB)”. Around 10% of latent infections progress to “active disease (Active TB)” in which the
patient feels sick and shows symptoms. If left untreated, Active TB will kill about half of those
affected. Active infection occurs more often in people with HIV/AIDS and in those who smoke.
Mode of Transmission: Tuberculosis is spread from one person to the next through the air when
people who have Active TB in their lungs cough, spit, speak, laugh or sneeze. People with Latent
TB do not spread the disease.
Pulmonary Tuberculosis: In pulmonary tuberculosis, after the pathogen gains entry into the
alveoli, they are ingested by the pulmonary macrophages. This results in stimulation of
surrounding fibroblasts to enclose the infection site leading to the formation of tubercles. The
infection, if contained, may lie dormant for years (Latent TB) and may reappear later (Active TB)
either through reactivation or through another invasion. In tuberculosis, there is extensive tissue
destruction and in advanced cases, virulent bacilli become isolated in cavities and debris of
necrotic tissue.
The tubercle formation and the tissue debris result in sub-lethal levels of chemotherapeutic agents
reaching the bacilli leading to emergence of resistant strains and multiple drug-resistant
tuberculosis (MDR-TB).
Diagnosis: Diagnosis of active TB is based on chest X-rays, as well as microscopic examination
and culture of body fluids. Diagnosis of Latent TB relies on the tuberculin skin test (TST) or blood
tests.
ANTITUBERCULAR DRUGS 2 Anti TB Drugs

Tuberculosis (TB) Management:

 Tuberculosis management describes the techniques and procedures utilized for preventing and
treating tuberculosis.
 Those persons at high risk include household, workplace, and social contacts of people with
active TB. Antibiotic resistance is a growing problem, with increasing rates of multiple drug-
resistant tuberculosis (MDR-TB).
 Prevention of TB involves screening those at high risk, early detection and treatment of
cases, and vaccination with the Bacillus Calmette-Guérin (BCG) vaccine.
 Treatment (chemotherapy) requires the use of multiple anti-TB drugs over a long period of
time (six to twelve months). Patients must be isolated during the therapy until non-infectious.
 First-Line Therapy: The majority of the patients with tuberculosis are treated with first-line
drugs and show excellent results with a 6-month course of treatment. For the first 2 months
(high-intensity phase), isoniazid, rifampicin, ethambutol and pyrazinamide are given,
followed by isoniazid and rifampicin for the remaining 4 months (continuation phase,
consolidation phase or eradication phase).
 Second-Line Therapy: The second line drugs are only used to treat disease that is resistant to
first line therapy or to treat multidrug resistant M. tuberculosis infections (MDR-TB).
Classification of Antitubercular Drugs:
Drugs used in the treatment of tuberculosis can be divided into two major categories:
1. First-line drugs:
a. Isonicotinoyl hydrazides: Isoniazid (Isonicotinic acid hydrazide).
b. Pyrazines: Pyrazinamide.
c. Ethylenediamino butanols: Ethambutol.
d. Antibiotics:
i. Aminoglycosides: Streptomycin.
ii. Rifamycins: Rifampicin (Rifampin).
2. Second-line drugs:
a. Salicylic acid derivatives: p-Amino salicylic acid.
b. Thioamides: Ethionamide.
c. Antibiotics:
i. Fluoroquinolones: Ofloxacin, Ciprofloxacin, Moxifloxacin.
ii. Aminoglycosides: Amikacin, Kanamycin.
iii. Polypeptides: Viomycin, Capreomycin.
iv. Cycloserines: Cycloserine, Terizidone.
The majority of the patients with tuberculosis are treated with first-line drugs and shows excellent
results with a 6-month course of treatment. For the first 2 months (high-intensity phase),
isoniazid, rifampicin, ethambutol and pyrazinamide are given, followed by isoniazid and
rifampicin for the remaining 4 months (continuation phase, consolidation phase or eradication
phase).
The second line drugs are only used to treat disease that is resistant to first line therapy or to trat
multidrug resistant M. tuberculosis infections (MDR-TB).
ANTITUBERCULAR DRUGS 3 Anti TB Drugs

ISONIAZID (INH, H)
Isonicotinic Acid Hydrazide

Mode/Mechanism of Action of Isoniazid:

 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.
Uses of Isoniazid: Used in first-line therapy of tuberculosis in combination with other drugs.
Synthesis of Isoniazid:

PYRAZINAMIDE (PZA, Z)
(Pyrazine-2-carboxamide)

Mode/Mechanism of Action of Pyrazinamide:

Pyrazinamide is a prodrug and is activated by M. tuberculosis amidase enzyme to pyrazine
carboxylic acid, which has bactericidal activity (inhibition of the fatty acid synthetase-I).
Uses of Pyrazinamide:
 Pyrazinamide is used in first-line therapy in the short-term treatment of tuberculosis regimens
because of its tuberculocidal activity and comparatively less short-term toxicity.
 It is also used in meningitis.
ANTITUBERCULAR DRUGS 4 Anti TB Drugs

Synthesis of Isoniazid:

ETHAMBUTOL (EMB, E)
(Ethylenediamino Dibutanol)

Mode/Mechanism of Action of Ethambutol:

 It is a bacteriostatic drug that acts as mycobacterial cell wall synthesis inhibitor.
 It acts by inhibiting arabinosyl transferase enzyme involved in cell wall synthesis.
 It prevents the incorporation of mycolic acid into the mycobacterium cell wall.
Uses of Ethambutol:
 It is not recommended for use as a single drug, but used in combinations with other
antitubercular drugs in the chemotherapy of pulmonary tuberculosis.
 It is used as water soluble Ethambutol hydrochloride.
ANTITUBERCULAR DRUGS 5 Anti TB Drugs

Synthesis of Isoniazid:

RIFAMPICIN (RMP, R)
(Rifampin)

Mode/Mechanism of Action of Rifampicin:

 Rifamycins are macrocyclic antibiotics obtained from Streptomyces mediterranei.
 Rifampicin is a semisynthetic rifamycin derived from Rifamycin-B.
 It inhibits DNA-dependent RNA polymerase (DDRP) of mycobacteria by forming a stable
drug-enzyme complex, leading to suppression of initiation of chain formation in RNA synthesis.
 It acts as a bactericidal drug.
Uses of Rifampicin:
 Rifampicin is the most active agent in clinical use for the treatment of tuberculosis.
 It is used in first-line therapy only in combination with other antitubercular drugs.
 It is also used in the treatment of leprosy, endocarditis, osteomyelitis, and pneumonia.
ANTITUBERCULAR DRUGS 6 Anti TB Drugs

STREPTOMYCIN (STM, S)
(Streptomycin Sulphate)

Mode/Mechanism of Action of Streptomycin:

 It is an aminoglycoside antibiotic obtained from Streptomyces griseus.
 Streptomycin functions as bacterial protein synthesis inhibitor.
 It binds to bacterial ribosomes on 30S and 50S subunits as well as the interface leading to
codon misreading, inhibition of protein synthesis, and ultimately death of the cell.
 It acts as a bactericidal drug.
Uses of Streptomycin:
 It was the first effective drug for the treatment of tuberculosis.
 It is used in first-line therapy usually in combination with other antitubercular drugs such as
Ethambutol, Rifampicin and Isoniazid in the treatment of pulmonary tuberculosis.
 It is also used in the treatment of endocarditis, plague and tularemia (rabbit fever).

PARA-AMINO SALICYLIC ACID (PAS)

ANTITUBERCULAR DRUGS 7 Anti TB Drugs

Mode/Mechanism of Action of p-Amino Salicylic Acid:

 p-Aminosalicylic acid is a synthetic drug structurally similar to p-amino benzoic acid (PABA).
 Para-aminosalicylic acid is an inhibitor of bacterial folate metabolism in a manner similar to
the sulphonamide antibacterials.
 It acts as a bacteriostatic drug.
Uses of p-Amino Salicylic Acid:
 It is used in second-line therapy usually in combination with other antitubercular drugs such
as Streptomycin and Isoniazid in the long-term treatment of tuberculosis.
Synthesis of p-Amino Salicylic Acid:

ETHIONAMIDE
(2-ethylisothionicotinamide)

Mode/Mechanism of Action of Ethionamide:

 Ethionamide is a prodrug which is activated by the enzyme ethA, a mono-oxygenase in
Mycobacterium tuberculosis.
 It inhibits the mycobacterial mycolic acid synthesis thus inhibiting cell wall formation.
 It acts as a bacteriostatic drug.
Uses of Ethionamide:
 It is used in second-line therapy used in combination with other antitubercular drugs such as
Rifampicin and Isoniazid in the treatment of pulmonary tuberculosis.
 It is usually co-administered with pyridoxine to reduce neurological side effects.
 It is also used in the treatment of leprosy.
ANTITUBERCULAR DRUGS 8 Anti TB Drugs

Synthesis of Ethionamide:

CYCLOSERINE

Mode/Mechanism of Action of Cycloserine:

 Cycloserine is an antibiotic obtained from Streptomyces orchidaceus.
 Cycloserine is similar in structure to the amino acid D-alanine and works by interfering with
the formation of the bacteria's cell wall by inhibiting two enzymes; alanine racemase and D-
alanine ligase.
Uses of Cycloserine:
 It is used in second-line therapy used in combination with other antitubercular drugs in the
treatment of active drug resistant tuberculosis.
 It is usually co-administered with pyridoxine to reduce CNS side effects.
 It also finds its application for the control and management of acute UTIs caused by susceptible
microorganisms.
Synthesis of Cycloserine:
ANTITUBERCULAR DRUGS 9 Anti TB Drugs

FLUOROQUINOLONES

Ciprofloxacin Moxifloxacin Ofloxacin

Mode/Mechanism of Action of Fluoroquinoles:

 Fluoroquinolones are the synthetic antibacterials that inhibit the action of bacterial DNA
gyrase enzyme.
 This enzyme is responsible for supercoiling and compacting bacterial DNA molecules in the
bacterial cell during replication.
 This action is accomplished by modifying the topology of DNA via supercoiling and twisting
of these macromolecules to permit DNA replication or transcription.
 Thus, Fluoroquinolones interfere with DNA replication by preventing bacterial DNA from
unwinding and duplicating.
Uses of Fluoroquinoles:
 Fluoroquinolones like ciprofloxacin, ofloxacin, and moxifloxacin are found to be active against
M. tuberculosis.
 They are used in second-line therapy of tuberculosis.
 Fluoroquinolones are also used in the treatment of upper and lower respiratory tract infections,
gonorrhea, bacterial gastroenteritis, skin and soft tissue infections, urinary tract infections,
bone and joint infections.