1. Antimycobacterial drugsBy
Bohlooli S, PhD
School of Medicine, Ardabil University of Medical Sciences

2. Drugs Used in Tuberculosis
First Line Agents
Isoniazid (INH)
Rifampine
Pyrazinamide
Ethambutol
Streptomycin
Second Line Agents
Amikacin
Aminosalicylic acid
Capreomycin
Ciprofloxacin
Clofazimine
Cycloserine
Ethionamide
Levofloxacin
Rifabutin
Rifapentine

3. Isoniazid (INH) Most active drug Water soluble Similar to pyridoxine
Good penetration to phagocytic cells

5. Isoniazid (INH): Mechanism of Action
Prodrug: activated by KatG (Catalase proxidase)
Active form bind to Acyl carrier protein (AcpM),and KasA (beta-ketoacyl carrier protein synthase), covalently
Inhibits synthesis of mycolic acid

6. Isoniazid (INH): Basis of Resistance
Mutation or deletion of KatG
Overexpression of inhA (encodes acyl carrier protein reducatase)
Overexperssion of ahpC, oxidative stress protection
Resistance mutants occur in 1 in 106

7. Isoniazid (INH): Pharmacokinetics
Good absorption from GIT
Readily distribute to tissues and body fluids
Ratio in CFS: 20 to 100%
Metabolism by N-acetyltransferase
Rapid acetylator: hepatoxicity
Slow acetylator: neuropathy

8. Isoniazid (INH): Clinical Use
Single agent in latent tuberculosis
In combination with second agent in active form
Use pyridoxine in conditions predisposing to neuropathy

9. Isoniazid (INH): Adverse Reactions
Allergic reactions
Fever, skin rashes
Drug induced systemic lupus erythematosus
Direct toxicity
Hepatitis: loss of appetite, nausea, vomiting, Jaundice, right upper quadrant pain
In 1% patients and fatal
Depend on age
Neuropathy: higher in slow acetylators
CNS effects: memory loss, psychosis, seizure
Drug interaction: phenytoin

10. Rifampin Active against: Mechanism: Resistance:
gram positive and gram negative cocci,
some enteric bacteria
Mycobacteria
Chlamydia
Mechanism:
Binds to DNA dependent RNA polymerase
Resistance:
Point mutation in rpoB gene
Prevent binding of rifampin to RNA polymerase

11. Rifampin: Pharmacokinetic
Well absorption
Enterohepatic cycle
Good distribution to body fluids and tissues and phagocytic cells
Adequate level in meningeal inflammation

12. Rifampin: Clinical use
Together with other drugs for prevention of resistance
Atypical mycobacterial infections
Leprosy
Alternative to INH
Prophylaxis in H. influemzae type b contacts
Staphylococcal infections
highly penicillin-resistant strain of pneumococci

13. Rifampin: adverse reactions
Orange color urine, sweat, tears, contact lens
Rashes, thrombocytopenia, nephritis
Hepatitis
Light chain proteinuria
Flu-like syndrome: fever, chills, myalgias, anemia, thrombocytopenia, acute tubular necrosis
Enzyme inducer

14. Chemical Sructure

15. Ethambutol Synthetic, water soluble, heat stable compound
An inhibitor of arabinosyl transferase and polymerization of arabinoglycan
Resistance due to mutations resulting in overexpression of emb gene products and occur rapidly
Good absorption from GIT
Elimination: 50% unchanged in Urine

16. Ethambutol Clinical use Adverse reaction
In combination with isoniazid or rifampin
Adverse reaction
Retrobulbular neurotitis, loss of visual acuity, red green blindness
Hypersensivity reactions

17. Chemical Structure

18. Pyrazinamide Relative of nicotinamide
Inactive in neutral pH but active in acidic pH
Drug taken up by macrophages
Converted to pyrazinoic acid by bacterial pyrazinamidase
Mechanism is unknown
Clinical use: together with insoniazid or rifampin
Resistance is fairly readily acquired
Adverse reaction: hepatotoxicity, nausea, vomiting, drug fever, hyperuricemia

19. Streptomycin
Resistance is due to point mutation in gene rpsL, encoding S12 ribosomal protein or rrs, encoding 16S ribosomal rRNA
Active against extracellular form of tubercle bacille
Employed when injectable drug is needed

20. Alternative second-line drugs for tuberculosis
In the case of resistance to the drug of first choice
In the case of failure of clinical response
When expert guidance is available to deal with the toxic effects.