Antimycobacterial drugs Flashcards
1
Q
First line drugs
A
- Isoniazid
- Rifampin
- Rifabutin (1st line in HIV +ve patients)
- Ethambutol
- Pyrazinamide
2
Q
Second line drugs
A
- Streptomycin
- Ethionamide
- Levofloxacin
- Amikacin
3
Q
Isoniazid
A
- Synthetic analog of pyridoxine
- First-line agent
- Most potent antitubercular drug
- PART OF COMBINATION THERAPY
- Sole drug in treatment of latent infection
MOA
- Pro-drug (activated by a mycobacterial catalase- peroxidase - KatG)
- Targets enzymes involved in mycolic acid synthesis:
- enoyl acyl carrier protein reductase (InhA)
- Beta-ketoacyl-ACP synthase (KasA)
- Bacteriostatic effects against bacilli in stationary phase
- Bactericidal against rapidly dividing bacilli
- Specific for M.tuberculosis
- If used alone resistant organisms rapidly emerge
Resistance
- Chromosomal mutations resulting in:
- mutation of deletion of KatG
- mutations of acyl carrier proteins
- overexpression of inhA
- Cross-resistance between other anti-tuberculosis drugs DOES NOT OCCUR
PK
- Oral, IV & IM
- Diffuses into all body fluids, cells & caseous material
4
Q
Isoniazid - Adverse
A
- Peripheral neuritis: corrected by pyridoxine supplementation
- Hepatotoxicity: clinical hepatitis & idiosyncratic
- CYP P450 inhibitor: important for HIV + Pt on multiple meds
- Lupus-like syndrome: rare
- Safe in pregnancy (however, hepatitis risk is increased, pyridoxine supplementation is recommended)
5
Q
Rifamycins
A
- Rifampin, rifabutin
- First-line drugs for treatment of all susceptible forms of TB
- PART OF COMBINATION THERAPY
- Bactericidal
- Resistant strains rapidly emerge
- USUALLY GIVEN IN COMBINATION
MOA
- Blocks transcription by binding to beta subunit of bacterial DNA-dependent RNA polymerase -> leading to inhibition of RNA synthesis
- Effective against Gram-positive & Gram-negative organisms but reserve rifampin for Mtb so resistance does not occur
Clinical applications
- TB
- Latent TB in INH intolerant patients
- Leprosy
- Prophylaxis for individuals exposed to meningitis
- **MRSA (with vancomycin) **
Resistance
- Point mutations in rpoB, the gene for the beta subunit of RNA polymerase -> decreased affinity of bacterial DNA-dependent RNA polymerase for drug
- Decreased permeability
PK
- Oral & parenteral
- Well distributed (including CSF)
- Excreted mainly into feces
- Strong CYP P450 inducer
6
Q
Rifampin - Adverse
A
- Light chain proteinuria
- GI distress
- Occasional effects: thrombocytopenia, rashes, nephritis, liver dysfunction
- Imparts harmless orange/red color to bodily fluids
- Strongly induces most CYP P450 isoforms
- SAFE IN PREGNANCY
7
Q
Rifabutin
A
- Preferred drug for use in HIV patients (due to lesser effects on CYP enzymes)
- Rifampin substitute to those that are intolerant
- Insufficient data to recommend use in pregnancy
8
Q
Ethambutol
A
- First-line agent for treatment of all susceptible forms of TB
- Specific for most strains of M.tuberculosis & M.kansasii
- Inhibits arabinosyl transferases
- Used in combination with pyrazinamide, izoniazid & rifampin
- Resistance occurs rapidly if used alone (mutations in emb gene)
9
Q
Ethambutol - Adverse
A
- Dose-dependent visual disturbances (eg, red/green color blindness) – cannot be used in children too young to receive sight tests
- Headache, confusion, hyperuricemia, peripheral neuritis (rare)
- Safe in pregnancy
10
Q
Pyrazinamide
A
- First-line agent
- Used in combination with isoniazid, rifampin & ethambutol
- Must be enzymatically hydrolysed to active pyrazinoic acid
- Resistant strains lack pyrazinamidase or have increased efflux of drug
PK
- Well absorbed orally & well distributed (including CSF)
- Renal or hepatic insufficiency may require dosage adjustment
11
Q
Pyrazinamide - Adverse
A
- Nongouty polyarthralgia (~ 40%)
- Acute gouty arthritis (rare unless predisposed)
- Hyperuricemia
- Hepatotoxicity, myalgia, GI irritation, porphyria, rash, photosensitivity
- Recommended for use in pregnancy when benefits outweigh risks
12
Q
Streptomycin
A
Used for drug-resistant strains
Used in drug combinations for treatment of life-threatening tuberculous disease:
- meningitis
- miliary dissemination
- severe organ tuberculosis
Increasing frequency of resistance to streptomycin limits use of drug
13
Q
Standard Regimens for empiric treatment of pulmonary TB:
A
Initial Phase
- 8 weeks: Isoniazid, Rifampin, Pyrazinamide, Ethambutol
- 8 weeks: Izoniazid, Rifampin, Ethambutol
Continuation Phase
- 18 weeks: Isoniazid, Rifampin
- 31 weeks: Isoniazid, Rifampin
14
Q
Standard Regimens for empiric treatment of drug-resistant strains
A
Mtb Drug Resistance to Isoniazid (+/- Streptomycin)
- Suggested regimen: Rifampin, pyrazinamide, ethambutol (can add fluoroquinolone to strengthen treatment) for 6 months
Isoniazid & rifampin (+/- Streptomycin)
- Suggested regimen: Fluoroquinolone, pyrazinamide, ethambutol + injectable agent +/- second-line agent for 18 to 24 months
Isoniazid, rifampin (+/- streptomycin), + ethambutol or pyrazinamide
- Suggested regimen: Fluoroquinolone (ethambutol or pyrazinamide if active) + injectable agent +/- two second-line agents for 24 months
Rifampin
- Suggested Regimen: Isoniazid, ethambutol, fluoroquinolone, supplemented with pyrazinamide for first 2 months for 12 to 18 months
15
Q
Leprosy
A
- aka Hansen’s disease
- Caused by Mycobacterium leprae & Mycobacterium lepromatis
- Primarily granulomatous disease of peripheral nerves & mucosa of upper respiratory tract
- ~ 70 % cases are in India
Drugs: 3 drugs to be used in combination: Dapsone, Clofazimine, Rifampin
