Mycobacterium agents (Tuberculosis) Flashcards
Is isoniazid static or cidal?
Static for latent
Cidal for active/dividing bacteria
How does isoniazid work?
Inhibits mycolic acid production (which inhibits the waxy cell coat)
How is isoniazid excreted?
75-95% excreted as acetylated metabolite
Fast acetylators (eskimos) 70 minute t1/2 Slow acetylators (caucasians) 3.3 hr t 1/2
Which TB drug has dif half lives for dif populations
Isoniazid
75-95% excreted as acetylated metabolite
Fast acetylators (eskimos) 70 minute t1/2 Slow acetylators (caucasians) 3.3 hr t 1/2
How does isoniazid work in the body?
It is metabolically activated by bacterial catalase-perioxidase
How does resistance to isoniazid occur?
Resistance occurs by point mutation in DNA coding for activation enzyme
True or False: Isoniazid enters the CNS
True
What is isoniazid used for?
Prophylactic for TB - used alone
Active TB - used in combination
What are the adverse effects of Isoniazid?
Allergic reactions - lupus like syndrome
Hepatitis - increased risk in alcoholics/older age
Peripheral neuritis - pyridoxine deficiency
How to treat isoniazid toxicity?
Can only treat the peripheral neuritis Use pyridoxine (B6)
What happens with Isoniazid overdose?
Seizures, euphoria, psychosis, memory impairment, coma
Happens due to decreased pyridoxyl-5-phosphate reactions which decreases GABA
What drug interactions do you worry about with Isoniazid?
Potent inducer of CYP2C19, CYP3A4
Weak inhibitor of CYP2D6
Worry about theophylline, phenytoin, diazepam, APAP, etc
What do you use Rifampin for?
Rifampin, Rifapentine, and RIfabutin are all BROAD spectrum (gram + and gram -, used in all mycobacterium)
What are the semi-synthetic forms of rifamycin B?
Rifampin
Rifapentine
Rifabutine
How does Rifampin work?
Inhibits the DNA dependent RNA polymerase (forms complex with the enzyme)
No effect on human enzyme!
When is Rifampin used alone?
NEVER
Rapid tolerance can occur due to mutations in DNA repair enzymes
What is Rifampin used for?
Primary use is TB
Can also be used as prophylaxis for meningitis
Can also be used in endocarditis caused by gram - only
How is rifampin excreted?
Metabolized by microsomal-B-esterases and cholinesterases
What are the adverse effects of Rifampin?
Induces P450 enzymes so worry about antichoagulants, contraceptives, digoxin, etc
Jaundice, hepatitis (chronic liver disease)
Secretions are colored orange-tan (tears, sweat, urine)
Hypersensitivity - flu like symptoms in 20% of patients
GI disturbances
Which drug can cause secretions to turn orange-tan?
Rifampin
Which drug can cause flu like symptoms?
Rifampin
How does Pyrazinamide work?
It is converted to pyrazinic acid, activated at LOW pH at necrotic edges of cavities
Inhibits fatty acid synthesis (interferes with mycolic acid production)
Reduces pH
Disrupts membrane transport
Why do we use Pyrazinamide?
It decreases duration of the combined therapy
What are the adverse effects of Pyrazinamide?
Hepatitis (15%)
Inhibits uric acid excretion, all hyperuricemic, may induce gout
Nausea, vomiting, anorexia, arthralgias
Avoid in pregnancy
What drug can cause gout
Pyrazinamide
What drug should be avoided in pregnancy
Pyrazinamide
What causes resistance in Pyrazinamide?
Decreased conversion to pyrazinic acid
What is Ethambutol?
Bacteriostatic drug
Inhibits arabinosyl transferase 3 which disrupts mycolic acid incorporation into membranes
Weakens the cell wall to allow other agents better access
Why do we use Ethambutol?
It weakens the cell wall to allow other agents better access
Only use for 2 months
How is Ethambutol excreted?
75% excreted unchanged
Adjust dose in renal disease
What causes resistance in Ethambutol?
Resistance develops quickly if used alone, mutations in arabinosyl-transferase 3
What are the adverse effects of Ethambutol?
Visual disturbances (limited in children)
Decreased red green discrimination
Decreased visual acuity
Increased uric acid levels
What drug causes visual disturbances
Ethambutol
E=EYE
