Antimycobacterial drugs
By
Bohlooli S, PhD
School of Medicine, Ardabil University of Medical Sciences
Drugs Used in Tuberculosis
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First Line Agents
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Isoniazid (INH)
Rifampine
Pyrazinamide
Ethambutol
Streptomycin
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Second Line Agents
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Amikacin
Aminosalicylic acid
Capreomycin
Ciprofloxacin
Clofazimine
Cycloserine
Ethionamide
Levofloxacin
Rifabutin
Rifapentine
Isoniazid (INH)
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Most active drug
Water soluble
Similar to pyridoxine
Good penetration to phagocytic cells
Isoniazid (INH): Mechanism of Action
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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
Isoniazid (INH): Basis of Resistance
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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
Isoniazid (INH): Pharmacokinetics
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Good absorption from GIT
Readily distribute to tissues and body fluids
Ratio in CFS: 20 to 100%
Metabolism by N-acetyltransferase
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Rapid acetylator: hepatoxicity
Slow acetylator: neuropathy
Isoniazid (INH): Clinical Use
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Single agent in latent tuberculosis
In combination with second agent in active
form
Use pyridoxine in conditions predisposing to
neuropathy
Isoniazid (INH): Adverse Reactions
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Allergic reactions
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Fever, skin rashes
Drug induced systemic lupus erythematosus
Direct toxicity
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Hepatitis: loss of appetite, nausea, vomiting, Jaundice, right
upper quadrant pain
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In 1% patients and fatal
Depend on age
Neuropathy: higher in slow acetylators
CNS effects: memory loss, psychosis, seizure
Drug interaction: phenytoin
Rifampin
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Active against:
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Mechanism:
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gram positive and gram negative cocci,
some enteric bacteria
Mycobacteria
Chlamydia
Binds to DNA dependent RNA polymerase
Resistance:
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Point mutation in rpoB gene
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Prevent binding of rifampin to RNA polymerase
Rifampin: Pharmacokinetic
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Well absorption
Enterohepatic cycle
Good distribution to body fluids and tissues
and phagocytic cells
Adequate level in meningeal inflammation
Rifampin: Clinical use
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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
Rifampin: adverse reactions
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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
Chemical Sructure
Ethambutol
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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
Ethambutol
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Clinical use
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In combination with isoniazid or rifampin
Adverse reaction
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Retrobulbular neurotitis, loss of visual acuity, red
green blindness
Hypersensivity reactions
Chemical Structure
Pyrazinamide
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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
Streptomycin
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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
Alternative second-line drugs for
tuberculosis
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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.