Anti-Tubercular Agents Flashcards
Problems in TB Drug Therapy
1) Slow Growth of bacterium
- -Requires Long duration of treatment.
2) Intracellular bacterium (Access)
3) Resistance Development: Need for “Directly Observed Therapy” (DOT):
_MDRTB
_XDRTB
Latent TB Treatment
Should be treated in High-Risk Patients: _HIV _Receiving Immunosuppressive drugs _Younger than 5 yrs old _Diabetes _Chronic Renal Failure _Conversion to Positive Tuberculin Test within Past 2 years.
Primary Agents for TB
Isoniazid
Rifampin
Ethambutol
Pyrazinamide
(Streptomycin)
Mechanism of Action of Antimycobacterial Drugs
Isoniazid:
–Inhibits Mycolic Acid Synthesis (inhibits Cell Wall synthesis)
Rifampin:
–Inhibits RNA Synthesis by targeting RNA Polymerase
Ethambutol:
–Inhibits LAM synthesis (inhibits Cell Wall synthesis)
Pyrazinamide:
–Inhibits Cell Membrane Synthesis (by inhibiting Fatty Acid Synthesis)
Streptomycin:
(Aminoglycoside)
–Inhibits Protein Synthesis by targeting 30S Ribosomal Subunit
Fluoroquinolones:
–Inhibit DNA Gyrase, inhibiting DNA Synthesis
Ethionamide:
- -Peptide Synthesis
- -Similar to Isoniazid, but more toxic.
Isoniazid
Mechanism of Action:
_Active Metabolite
_Inhibits Mycolic Acid Synthesis (Cell Wall Synthesis)
Uses:
_Active Disease & Latent
_Prophylaxis
Disposition:
_Widely Distributed + CNS (crosses BBB)
_Fast Acetylation (half life: 1 hr) and *Slow Acetylation (half life: 3-4 hrs)
Adverse Effects: _*Peripheral Neuropathy (*Prevent with Pyridoxine) _*Hepatotoxicity _(Rash, Fever) _(Hemolysis with G6PD Deficiency)
Isoniazid increases elimination of Pyridoxine from the body. Give patient pyridoxine replacement during treatment.
(Pyridoxine = Vitamin B6)
Rifampin (Rifamycins)
Mechanism:
_*Inhibition of RNA Polymerase (inhibition of RNA synthesis)
Uses: _*Active _*Prophylaxis _*Other Mycobacteria infections _*Neisseria Meningitidis _*Legionella _*Haemophilus influenzae _*Other Gram Negative Bacilli
Disposition:
_*Widely Distributed + CNS
_Biliary Excretion
Adverse Effects:
_Red/Orange Discoloration of Urine/Sweat/Tears/Fluids
_CYT P450 Induction
(Thus, may see drug interaction with Anti-Retrovirals!)
_*Flu-like Syndrome (Fever, Nausea)
_Hepatotoxicity (Less frequent than Isoniazid)
Ethambutol
Mechanism:
_*Inhibits Cell Wall Synthesis
Adverse Effects:
_*Optic Neuritis (retrobulbar): red-green colorblindness +/- decreased visual acuity.
_Hyperuricemia (only an issue if pt has Gout)
Pyrazinamide
Mechanism of Action:
_Unknown;
_Converted to Active form by bacterium. (May inhibit plasma membrane synthesis)
Adverse Effects _*Hepatotoxicity (more severe than Isoniazid) (High Incidence) _Hyperuricemia
Streptomycin
Aminoglycoside
Mechanism:
_*Inhibits Protein Synthesis @ 30S Ribosome
Adverse Effects:
_Nephrotoxicity
_Ototoxicity
Secondary Agents
Fluoroquinolones: _*Moxifloxacin _Ciprofloxacin _Levofloxacin Often Effective in Resistant Strains.
*Linezolid:
_Last Resort for MDR strains
_Inhibits Protein Synthesis
_Bone Marrow Suppression, Neuropathy, MAO Inhibition
Bedaquiline:
_for MDR-TB
_Inhibits Mycobacterial ATP Synthase to reduce energy production
_No cross-resistance with other drugs
_Hepatotoxicity
_Increased Mortality in Clinical Trials (*Prolonged QT interval?)
_Nausea, Anorexia, Rash, Arthralgia, Chest pain
Cycloserine:
_Inhibits Cell Wall Synthesis
_May cause behavioral and Peripheral Neurotoxicity (Prevented by Pyridoxine)
Ethionamide:
_Similar mechanism to Isoniazid
_More severe GI and Neurotoxicity than Isoniazid
Capreomycin:
_Inhibits Protein Synthesis
_Often effective in MDR strains
_Neurotoxicity and Ototoxicity
Kanamycin and Amikacin
(Aminoglycosides):
_Amikacin is safer
Agents for Other Mycobacterium Infections
*Rifabutin:
_Mechanism similar to Rifampin
_Less CYT P450 induction than Rifampin
_Use: MAC in patients with advanced HIV
*Sulfones:
_Use: Mycobacterium leprae (Leprosy)
_Dapsone (DDS):
*Oral; *Long Half-life (1-2 Days); *Often used with Rifampin)
