Anti tuberculosis drugs

Dr. Mozna Talpur

Classification
First line: Second line:
Isoniazid (INH) Streptomycin
Rifampin Ethionamide
Pyrazinamide (PZA) Capreomycin
Ethambutol Kanamycin
Flouroquinolone
Linzolid
Para amino salicylic
acid (PAS)
Cycloserine
Why use multiple drugs?
They grow very slowly, so long term therapy with
multiple drugs is required
Mycobacterium can also remain dormant thus killed
very slowly.
Lipid rich cell wall is impermeable to many anti
biotics
Intra cellular (macrophages) Pathogens have very
difficult penetration or very slow penetration of anti
biotics
Combination of drug is required to prevent resistance
Isoniazid (INH)
Structural resemblance with pyridoxine (Vit B6)
Bactericidal for actively growing bacteria (tubercular
bacillus)
Can penetrate macrophages so is useful for both
intracellular and extra cellular bacteria.
Pharmacokinetics
Drug is eliminated through acetylation.
Slow acetylators can develop more toxicity as they
acetylate the drug slowly.
Rapid acetylators may not even achieve the therapeutic
level in the blood as it is acetylated rapidly and
eliminated from body
Dose:
5-10mg/kg body weight or 300mg X O.D
Mechanism of action:
INH is a pro-drug which is activated through Kat G
protein present in the cell wall of M. tuberculosis.
Inactive INH Kat G Active INH
Active INH forms a covalent bond and inhibits beta-
keto-acyl carrier protein which is responsible for the
synthesis of mycolic acid.
INH inhibits the synthesis of mycolic acid which is
essential component of mycobacterial cell wall
Resistance
Cross resistance to Ethionamide also occur.
Over expression of inhA through mutation which
encodes NADPH dependant acyl carrier protein
reductase.
Mutation or deletion of Kat G gene.
Over production of ahpC gene which protects cell
from oxidative stress
Clinical Uses
5-10 mg\kg body weight in mycobacterium
tuberculosis infection along with rifampin, ethambutal,
and pyrazinamide.
Vit B6 supplement is also given with ATT for
prevention of Neuropathy.
Adverse reaction
Incidence and severity of side effects depends upon the
duration of treatment.
Immunological reaction:
Fever skin rashes
Drug induced lupus erythmatosis
Hepatotoxicity:
Inc liver enzymes
Nausea vomiting, loss of appetite.
Majority is asymptomatic.
Peripheral neuropathy:
Drug resembles Vit B6
Vit B6 deficiency anemia, tinnitus
CNS toxicity:
Loss of memory, psychosis, seizures.
 Treatment Vit B6 supplement

GI discomfort.
Rifampin
MOA:
Binds with β-subunit of DNA dependant RNA
polymerase and inhibits RNA synthesis.
Poorly penetrates BBB in rare cases of meningitis.
Resistance
Decrease binding due to point mutation in β-subunit of
bacterial DNA dependant RNA polymerase.
Clinical uses
15-20mg\kg in Mycobacterium tuberculosis infection
along with isoniazid, ethambutal, and pyrazinamide.
Meningococcal carrier stage
H.influenza infection.
Staphylococcal infection e.g prosthetic heart valve,
osteomylitis.
Adverse effects
Orange color of urine, saliva, sweat, contact lens and
other body secretions.
Rashes
Thrombocytopenia
Nephritis
Cholistatic jaundice
Flue like symptoms:
Fever myalgia, chills, sometimes acute tubular necrosis.
Drug interaction
CYP450 inducer.
Inc elimination of methadone, anti-coagulant,
cyclosporine, anti-convulsant, contraceptives.
Ethambutol
Synthetic drug.
Water soluble.
Heat stable.
Accumulates in renal failure.
Cross BBB during inflammation only.
Mechanism of action
Inhibits microsomal arybinosyl transferase which is
involved in polymerization reaction of arybinoglycans
which is also essential component of cell wall of
mycobacteria.
Resistance
Increase expression of emb gene products or with in
emb structure gene which is responsible for coding of
arybinosyl transferase
Clinical uses
15-25mg/kg with INH, rifampin, and pyrazinamide
Inc dose in meningitis.
Adverse Reaction
Red-green color blindness
Retrobulbar neuritis: loss of visual acquity.
Contraindicated in children.
Pyrazinamide
Relative of nicotinamide
Stable in heat
Slightly soluble in water
Inactive in neutral pH
Drug is taken up by macrophages and exerts its action
in acidic environment of lysosomes.
Mechanism of action
Inside the cell its converted to pyrazinoic acid.
Unknown mechanism of action.
Resistance
Impaired uptake
Impaired conversion to active form.
Clinical uses:
25mg/kg in mycobacterium tuberculosis infection
along with INH, Rifampin and ethambutol.
Sterilizing agent (kills bacteria inside the cell).
Adverse effects
Hepatotoxicity:
Nausea, vomiting, anorexia, jaundice
Drug fever
Hyperurecemia: Gouty attacks