The document discusses anti-tubercular drugs used to treat tuberculosis. It describes first line drugs like isoniazid, rifampin, pyrazinamide, ethambutol and streptomycin that are used initially. However, these often fail and lead to drug resistant strains. Second line drugs discussed include fluoroquinolones, aminoglycosides, cycloserine, ethionamide, para-aminosalicylic acid and capreomycin, which are used to treat multidrug resistant tuberculosis but have more side effects. The mechanisms of action and important properties of several first and second line anti-tubercular drugs are also summarized.

1. Anti-tubercular Drugs
By
Dr. Nidhi Gupta
MM College of Pharmacy
Mullana, Ambala, Haryana.

4. • Tuberculosis (TB) is caused by infection with Mycobacterium tuberculosis, which is transmitted
through inhalation of aerosolized droplets. TB mainly attacks the lungs, but can also affect other
parts of the body. TB is highly contagious during the active stage of the disease and can infect an
individual through inhalation of as few as 10 Mycobacterium tuberculosis (MTB) bacteria. After
inhalation, these bacteria are mainly captured by the alveolar macrophages, but they can evade
the host immune system and remain in the dormant stage for a long period of time, at which point
they can reactivate to a virulent form under immune-compromised conditions of the host. This is
possible because M. tuberculosis can persist in slow growing as well as in fast growing stages
which makes treatment challenging.
• Almost all of the antibiotics that can be used to treat TB work when the bacteria are actively
dividing. In the intensive phase of TB treatment, the antibiotics mainly kill rapidly growing bacteria,
which causes rapid sputum conversion, and the eradication of clinical symptoms. However, in
order to kill the persistent or slow growing strains of MTB, the continuation phase of the treatment
is essential.

5. • TB can be treated effectively by using first line drugs (FLD) isoniazid (INH), rifampin (RIF),
pyrazinamide (PZA), ethambutol (EMB) and streptomycin (SM). However, this first line therapy often
fails to cure TB for several reasons. Relapse and the spread of the disease contribute to the
emergence of drug resistant bacteria.
• The emergence of multidrug resistant TB (MDR-TB), i.e. which is resistant to at least isoniazid (INH)
and rifampicin (RIF), is of great concern, because it requires the use of second-line drugs that are
difficult to procure and are much more toxic and expensive than FLDs. Therefore, the detection and
treatment of drug susceptible or single drug resistant TB is an important strategy for preventing the
emergence of MDR-TB. M. tuberculosis strains with extensively drug resistant-TB (XDR-TB), that is
resistant to either isoniazid or rifampicin (like MDR tuberculosis), any fluoroquinolone, and at least one
of three second-line antituberculosis injectable drugs—i.e., capreomycin, kanamycin, and amikacin
have also been reported.

6. First Line drugs Second Line drugs
1. Rifampicin
2. Isoniazid
3. Pyrazinamide
4. Ethambutol
5. Streptomycin
1. Fluroquinolones
2. Amikacin
3. Cyclosporin
4. Ethionamide
5. Para-amino salicyclic
acid
6. Capreomycin
Classification of Anti-tubercular drugs

9. • Isoniazid, also known as isonicotinic acid hydrazide (INH), is an antibiotic used for
the treatment of tuberculosis.
• For active tuberculosis it is often used together with rifampicin, pyrazinamide, and
either streptomycin or ethambutol.[3] For latent tuberculosis it is often used by itself.
• It may also be used for atypical types of mycobacteria, such as M. avium, M. kansasii,
and M. xenopi.
• It is usually taken by mouth but may be used by injection into muscle.
• Common side effect include increased blood levels of liver enzymes and numbness in
the hands and feet.
• Serious side effects may include liver inflammation and acute liver failure.[2] It is unclear
if use during pregnancy is safe for the baby.
• Use during breastfeeding is likely safe. Pyridoxine may be given to reduce the risk of
side effects. Isoniazid works in part by disrupting the formation of the bacteria's cell
wall which results in cell death.

14. SAR of ISONIAZID

15. Synthesis of Isoniazid

17. • Rifampicin, also known as rifampin, is an antibiotic used to treat several
types of bacterial infections, including tuberculosis, Mycobacterium
avium complex, leprosy, and Legionnaires’ disease.
• It is almost always used together with other antibiotics with two notable
exceptions when given as a second-line treatment for latent TB and to
prevent Haemophilus influenzae type b and meningococcal disease in people
who have been exposed to those bacteria.
• Before treating a person for a long period of time, measurements of liver
enzymes and blood counts are recommended.
• Rifampicin may be given either by mouth or intravenously.

27. • Streptomycin is an antibiotic medication used to treat a number of bacterial infections.[3] This
includes tuberculosis, Mycobacteriumavium complex, endocarditis, brucellosis, Burkholderia infe
ction, plague, tularemia, and rat bite fever.
• For active tuberculosis it is often given together with isoniazid, rifampicin, and pyrazinamide.[4] It
is given by injection into a vein or muscle.[3]
• Common side effects include vertigo, vomiting, numbness of the face, fever, and rash.[3] Use
during pregnancy may result in permanent deafness in the developing baby.[3] Use appears to be
safe while breastfeeding.[4] It is not recommended in people with myasthenia gravis or
other neuromuscular disorders.[4] Streptomycin is an aminoglycoside.[3] It works by blocking the
ability of 30S ribosomal subunits to make proteins, which results in bacterial death.[3]
• Streptomycin was discovered in 1943 from Streptomyces griseus.[5][6] It is on the World Health
Organization's List of Essential Medicines.[7] The World Health Organization classifies it as
critically important for human medicine.

31. • 4-Aminosalicylic acid, also known as para-aminosalicylic acid (PAS) and sold under the
brand name Paser among others, is an antibiotic primarily used to treat tuberculosis.
• Specifically it is used to treat active drug resistant tuberculosis together with
other antituberculosis medications.
• It has also been used as a second line agent to sulfasalazine in people with inflammatory
bowel disease such as ulcerative colitis and Crohn's disease. It is typically taken by mouth.
• Common side effects include nausea, abdominal pain, and diarrhea.Other side effects may
include liver inflammation and allergic reactions. It is not recommended in people with end
stage kidney disease. While there does not appear to be harm with use during pregnancy it
has not been well studied in this population. 4-Aminosalicylic acid is believed to work by
blocking the ability of bacteria to make folic acid.

34. • Ethionamide (ETH, 2-ethylisonicotinamide) is a derivative of isonicotinic acid and has been
used as an antituberculosis agent since 1956.
• Ethionamide and the similar drug prothionamide (PTH, 2-ethyl-4-pyridinecarbothioamide)
act as pro-drugs, like isoniazid. Which is activated by EtaA/EthA (a mono-oxygenase) and
inhibits the same target as INH, the InhA of the mycolic acid synthesis pathway. Once
delivered into the bacterial cell, ethionamide undergoes several changes. Its sulfo group is
oxidized by flavin monooxygenase, and the drug is then converted to 2-ethyl-4-
aminopyridine.

35. Cycloserine
• Cycloserine (CS) is an antibiotic that is used to treat TB. The exact
mechanism of action of cycloserine is unknown, but it is thought to
prevent the tuberculosis bacteria from making substances called
peptidoglycans, which are needed to form the bacterial cell wall. This
results in the weakening of bacteria’s cell wall, which then kills the
bacteria.
• Cycloserine possesses high gastric tolerance (compared with the other
drugs) and lacks cross-resistance to other compounds. But it causes
adverse psychiatric effects; which is its main drawback. So, psychiatric
interrogation is necessary before prescribing cycloserine drug.
Cycloserine is one of the cornerstones of treatment for MDR and XDR
tuberculosis.

36. Fluoroquinolones
• The fluoroquinolones (FQs) have broad-spectrum antimicrobial activity and so are widely
used for the treatment of bacterial infections of the respiratory, gastrointestinal and
urinary tracts, as well as sexually transmitted diseases and chronic osteomyelitis.
• In contrast to many other antibiotics used to treat bacterial infections, the FQs have
excellent in vitro and in vivo activity against M. tuberculosis. FQs include ciprofloxacin,
ofloxacin, levofloxacin, and moxifloxacin. So, FQs are currently in use as second-line
drugs in the treatment of TB.
• Adverse effects are relatively infrequent (0.5–10% of patients) and include
gastrointestinal intolerance, rashes, dizziness, and headache. Most studies of
fluoroquinolone side effects have been based on relatively short-term administration for
bacterial infections, but trials have now shown the relative safety and tolerability of
fluoroquinolones administered for months during TB treatment in adults.

37. Mode of Action:
The cellular target of FQs in M. tuberculosis is DNA gyrase, a type II topoisomerase consisting of
two A and two B subunits encoded by gyrA and gyrB genes, respectively. Mutations in a small
region of gyrA, called quinolone resistance-determining region (QRDR) and, less frequently,
in gyrB are the primary mechanism of FQ resistance in M. tuberculosis.

38. Aminoglycosides (kanamycin, amikacin and capreomycin)
• The aminoglycosides amikacin (AMK)/kanamycin (KAN) and the cyclic polypeptide
capreomycin (CAP) are important injectable drugs in the treatment of multidrug-resistant
tuberculosis. Although belonging to two different antibiotic families, all exert their activity at
the level of protein translation.
• Renal toxicity occurs from these drugs. Regular monitoring of hearing and renal function is
recommended.
• AMK and KAN are aminoglycosides that have a high level of cross-resistance between them.