ANTI- TUBERCULAR AGENTS
By
S. RAVICHANDRA,
ASSISTANT PROFESSOR,
DEPARTMENT OF PHARMACEUTICAL CHEMISTRY,
CHEBROLU HANUMAIAH INSTITUTE OF
PHARMACEUTICAL SCIENCES,
GUNTUR.
INTRODUCTION
Tuberculosis
Infectious disease worldwide and a leading killer caused by a single
infectious agent
• Lungs
Common infection sites: • Kidne
y
ry System
rato
• Respi 2
Depending upon the site of infection: Disease can be categorized as;
Respiratory
Tract
Pulmonary tuberculosis
Genitourinary
Tract
Genitourinary tuberculosis
Nervous System
Tuberculous Meningitis Throughout Body
Milliary tuberculosis
3
• Many Potent Anti TB drugs drugs were developed in order:
Streptomycin
PASA
Isoniazid
Ethambutol
Rifampicin
Synthetic anti tubercular agents: Isoniozid*, Ethionamide, Ethambutol,
Pyrazinamide, Para amino salicylic acid.*
Anti tubercular antibiotics: Rifampicin, Rifabutin, Cycloserine
Streptomycine, Capreomycin sulphate.
4
• According to Clinical Utility of Anti TB drugs can be divided into two major
categories:
First Line Second Line
Agents Agents
- High Potency - Low Potency
- Low Toxicity - High Toxicity
Ethionamide
Isoniazid, p-Amino salicylic acid
Streptomycin Ofloxacin
Rifampicin Ciprofloxacin
Ethambutol Cycloserine Amikacin
Pyrazinamide Kanamycin, Viomycin
Capreomycin
5
Classification of drugs based on chemical structure
Basic nucleus Example
1) Salicylic acid derivatives Para amino Salicylic acid
2) Pyridine derivative Isoniazid, Ethionamide,
Prothionamide
3) Pyrazine derivative Pyrazinamide
4) Ethylene diaminobutanol Ethambutol
5) Antibiotics Streptomycin, Rifampicin,
Kanamycin
6) Miscellaneous class Ofloxacin, Ciprofloxacin,
Azithromycin & Clarithromicin 6
Classification based on toxicity
7
ISONIAZID (INH)
INH is first synthesized in 1952
First line synthetic anti-tubercular drug
8
Prodrug activated on the surface of M. tuberculosis by katG
enzyme to Isonicotinic acid.
katG enzyme: Catalase-peroxidase-heme enzyme.
Metabolism:
The major metabolite is N-acetyl isoniazid: Enzyme
responsible for acetylation-Cytosolic N-acetyl transferase.
Other metabolites include Isonicotinic acid, which is found in
the urine as a glycine conjugate and hydrazine.
10
• 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.
Bactericidal
Against rapidly multiplying organism
Bacteriostatic
Against resting cell
11
SAR
12
1. N-1 nitrogen in hydrazine side chain
should be unsubstituted.
2. N-2 Nitrogen can be substituted with
alkyl groups to get active compounds.
3. Replacement of pyridine nucleus with other aromatic ring
such as benzene or piperidine or thiazole ring diminished the
anti-tubertcular activity.
Iproniazid. 4. Isopropyl group is substituted at N2:
Isopropyl derivative named as Iproniazid
But not having Anti-tubercular activity.
It exhibit Psychomotor Stimulant activity.
N'-Isopropylisonicotinohydrazide
5. Numerous derivatives have been developed none of them have exhibited
activity superior to that of the parent drug.
16
14
Isoniazid: Side effects
1. Clumsiness or unsteadiness
2. Dark urine
3. Loss of appetite
4. Nausea and vomiting
5. Numbness, Tingling, Burning or pain in hands or feet
6. Unusual tiredness or weakness
7. Yellow eyes or skin
Ethambutol
SAR:
1. The presence of two amino moieties: Essential, Replacement of Amino
moieties by Acetyl, Sulphonyl or Nitrosoyl moieties: Inactive
2. Presence of small branched alkyl groups on the nitrogen atom also influences
the activity
3. Heteroatoms Oxygen, Sulphur in Ethylene moiety: Inactive derivatives
4. Increase or Decrease in ethylene chain length: Destroy the activity
Rifampicin
Antibiotic obtained from Streptomyces mediterranei
• Bactericidal to M. tuberculosis.
• Both extra- and intracellular organisms are affected.
• It can kill organisms that are poorly accessible to many other drugs.
• Rifampin binds to bacterial DNA-dependent RNA polymerase and
There by inhibits RNA synthesis.
MOA
Inhibits DNA-dependent RNA polymerase of mycobacterium
by forming a stable drug enzyme complex
Leading to suppression of initiation of chain formation in RNA
synthesis
Bactericidal
Double stranded DNA Single stranded mRNA
18
ETHIONAMIDE
It is Nicotinamide derivative, with antibacterial activity. Second line drug in
the therapy of Tuberculosis used only in combination Inhibit the synthesis
of mycolic acid, a saturated fatty acid found in the bacterial cell wall, thereby
inhibiting bacterial cell wall synthesis
SE: Hepatotoxicity, GI distress
19
RIFABUTIN
1. Semisynthetic structurally similar to Rifampicin.
2. Against M. avium, - causes of disseminated (spread over) infections, with
patients suffering with Human Immunodeficiency Virus (HIV).
3. Rifabutin lipophilic in nature and penetrate cell wall of organism more
effectively than other agents.
20
STREPTOMYCIN
1943 from Streptomyces griseus
Given in combination with Isoniazid, Rifampicin, and
Pyrazinamide Intramuscularly
Act by binding to the 30S ribosomal subunit of susceptible organisms and
disrupting the initiation and elongation steps in Protein Synthesis.
BACTERICIDAL
SE: Ototoxicity & Nephrotoxicity
21
Capreomycin
Capreomycin inhibit protein synthesis by binding to
the 70S ribosomal unit. Capreomycin 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.
Capreomycin is excreted largely unchanged in the urine.
Its lack of hepatic metabolism and known ototoxicity
and nephrotoxicity (which are dose-limiting) may
account for its lack of hepatotoxicity.
THANK YOU
