DRUG MECHANISM OF ACTION
ISONIAZID Prodrug
Activated by mycobacterial
KatG catalase peroxidase
Coupled with reduced
nicotinamide adenine
dinucleotide (NADH)
isonicotinic acyl-NADH
complex
Blocking of mycobacterial
ketoenoylreductase (InhA)
inhibition of FA synthesis and
INHIBITION of MYCOLIC ACID
SYNTHESIS
KatG activation = free radical
release = antimycobacterial
activity (Nitric Oxide)
MIC:
M. tuberculosis: < 0.1 mcg/mL
M. kansaii: 0.5 2 mcg/mL
PHARMACOKINETICS
Half-life:
- Fast acetylators: 30 90
minutes lower serum
levels
- Slow acetylators: 3 4
hours higher serum
levels more toxicity
Peak serum levels: 3 5
mcg/mL (30min 2 hrs after
ingestion)
Good distribution even in
CFS
Metabolized in the liver via
acetylation by N-acetyl-
transferase 2 (NAT2) and
hydrolysis
Enzyme inhibitor (CYP 450)
INH and metabolized are
unchanged and excreted in
urine
DOSE CLINICAL USE RESISTANCE ADVERSE EFFECT
Adults: 5mg/kg INH + Rifampin = mainstay 1. KatG Interacts with the ff. drugs
Children: 10 20 mg/kg Excellent bactericidal activity: - Catalase peroxidase Warfarin CBZ
Max: 300 mg intracellular M. tuberculosis gene BZD Paracetamol
Clopidogrel Maraviroc
Intermittent: and extra-cellular actively 2. InhA
- mycobacterial keto- Dronedarone salmeterol
- Adults: 2x a week dividing organisms
Tamoxifen Phenytoin
- 15 mg/kg Bacteriostatic: slowly dividing enoylreductase gene
Eplerenone Stavudine -
- Max: 900 mg organisms 3. KasA
neurotoxic
No required dose First Line Agent LTBI - Mycolic acid elongation
adjustments in renal dse - Daily or intermittently (2x - Loss of NADH
Induced liver injury
12 dose 3 month weekly weekly) DOT for 9 months dehydrogenase 2
PEIPHERAL NEUROPATHY
LTBI regimen - 9 mos > 6 mos (efficacy) activity
- Pyridoxine (B6) deficiency
- 15 mg/kg - Extension to 12 mos no 4. Efflux pump genes
- Excretion of Pyridoxine is
- Max: 900 mg more further protection - efpA
promoted by INH
- Coadministered with - 6 months: acceptable - mmpL7
- Interference of pyridoxine
Rifapentine second line therapy - mmr
metabolism
TB disease: combined with - p55
- 2% (5mg/kg dosing)
other agents 5. Rv1258c
- Prophylactic pyridoxine
- Std Regimen: R I P E - Tap-like gene
(25 50 mg/d)
Given together with Asymptomatic transient
PYRIDOXINE (25 50mg)
elevation of aminotransferases
Prevention of PERIPHERAL
(Hepatic adaptation)
NEUROPATHY
INH-induced hepatitis
DISCONTINUE: - Idiosyncratic
- Hepatitis symptoms or - Incidence increases w/ age,
jaundice
daily alcohol consumption,
- ALT 3x upper limit of normal
within 3 months postpartum
- Absent symptoms but ALT
Routine hepatic ALT testing >
5x upper limit of normal
35 years of age optional