Fitz, TB Flashcards
(48 cards)
Why should fluoroquinolones NOT be used as first line treatment for TB in endemic areas?
They mask active TB and it promotes resistance of fluoroquinolones.
Signs and symptoms of TB
- Cough for 3 weeks or longer
- Hemoptysis
- Night sweats
- Weight loss
- Weakness
- Fever, chills
- Pain in chest
Name the three things that make TB treatment challenging.
- Primary lesion - caseating granuloma with TB inside macrophages
- Persistent mycobacteria in LYMPH NODES and LUNG
- CAVITATING LESIONS
Three goals of TB treatment
- Eradicate Mycobacterium TB
- Prevent drug resistance
- Prevent relapse
Name the four drugs used in standard therapy of ACTIVE TB and at what stages they’re used.
- Initial stage - Isoniazid, Rifampin, Ethambutol, Pyrazinamide
- Continuation phase - Isoniazid and Rifampin
Length of time in the initial stage of treatment of active TB and the GOAL.
- 8 weeks
- Goal - eradicate the large burden of REPLICATING bacteria
Length of time in the continuation stage of treatment of active TB and the GOAL.
- wk8 to wk26
- Goal - Infiltrate INTRACELLULARLY… non-cavitating lesions
What drug is used for TB patients that cannot take drugs PO?
Streptomycin - NOT a 1st line drug.
Administered parenteral.
Clearance of isoniazid, rifampin, ethambutol, pyrazinamide
Mixed hepatic/renal
Isoniazid spectrum
Narrow spectrum - mycobacteria TB.
BacteriCIDAL in GROWING mycobacteria.
MOA of isoniazid
Disrupts mycolic acid synthesis, making mycobacteria vulnerable to destruction.
What is mycolic acid?
Distinctive component of mycobacteria cell wall.
Describe the location and process of isoniazid activation
- Location: IN the mycobacterium
- Process: INH (prodrug) –> converted to activated metabolite by Catalase Peroxidase (KatG) –> activated metabolite binds to NAD, inhibiting enzymes (InhA and KasA) from forming functional mycolic acid for cell wall.
Describe the 2 mechanisms of resistance to isoniazid.
- Deletion of KatG –> resulting in insufficient metabolite
2. Overexpression/mutation in InhA or KasA (can work in presence of lower NAD levels)
Describe the metabolization process of isoniazid and what the toxic metabolite is.
INH –(NAT+acetylCoA)–> N-Acetyl-INH –> N-Acetyl-Hydrazine (this is toxic) or Isotonic acid
Describe the fast metabolization of INH and what’s excreted
- Fast acetylators (90% of Asians) = 90% of INH excreted as N-Acetyl-INH
Describe slow metabolization of ING and what’s excreted
- Slow acetylators (50% of Whites, Blacks, Hispanics) = 65% of INH excreted as N-Acetyl-INH, so MORE EXPOSURE TO N-Acetylhydralazine (toxic)
A person presents with hepatotoxicity after taking isoniazid. What type of metabolizer is this person and what metabolite is causing the hepatotoxicity?
- Slow acetylator
- N-acetylhadralazine
What are the clinical presentations of the two major adverse reactions to INH?
- Hepatotoxic (slow acetylators) - jaundice, elevated liver enzymes, hepatitis
- Neurologic (slow acetylators) - peripheral neuritis/parasthesias, convusions
Risk factors for N-Acetylhydralazine toxicity.
Age, alcoholism, drug abuse, drugs (liver enzyme inducers), liver disease.
The major molecule and mechanism in isoniazid neuropathy.
Pyridoxal-5-Phosphate is a co-factor for neurotransmitter synthesis (GABA). INH reacts with this and increases its urinary excretion, depleting pyridoxines.
Pyridoxine is aka…
Vitamin B6.
A person presents with peripheral neuropathy, parasthesias, and seizures after taking isoniazid. What type of metabolizer is this person and what metabolite is causing the isoniazid neuropathy?
Slow acetylator
- Vitamin B6/pyridoxine is depleted.
Rifampin spectrum
Broad spectrum - mycobacteria TB + other bacteria BacteriCIDAL extracellular (caseous lesions) and INTRACELLULAR (can get into macrophages in "continuation phase").
