Anti-Mycobacterial Pharmacology Flashcards
What organisms are in the Mycobacterium family?
M. Tuberculosis M. Avium complex -pulmonary -disseminated M. Leprae
What are common traits of Mycobacterium family?
Rod shaped Lipid rich cell wall Acid-fast stain, Can replicate IN macrophages Slow growing -Dormant within granulomas Gram stains poorly or not at all. may form filaments.
Why are mycobacterium so hard to treat?
Most drugs can only work when bacteria are fast growing. Mycos grow very slowly.
What is the most common form of TB in the body?
Latent TB. 90%
What is a latent TB infection?
Has inactive non-replicating Tuberculosis in their body. Will come up with a positive skin test and an Interferon-G test. Chest X ray is negative. Not infectious or symptomatic
What constitutes an active TB infection?
Active, multiplying bacteria. CXR is abnormal, IFN-G and skin test are positive. They ARE symptomatic with cough, fever, and weight loss. sputum smears are positive.
What are the obstacles to treating Tuberculosis?
Slow growing
Viable but dormant organism
Rapidly develops resistance
Can develop toxicity to TB drugs. (6-12 months of drugs which have bad side effects)
How do we get around these problems?
3-4 drug regimen
Need to take the drugs regulary (direct observed therapy)
Therapy must continue for sufficient time.
Drugs used to treat TB
Rifamycin, Isoniazid, Streptomycin, Pyrazinamide
What is the most active drug for TB treatment?
Isoniazid used for latent and active infections.
What is the M. Avium Complex?
Includes M. Avium and M. Intracellulare
Pulmonary disease in immunocompetent, and disseminated disease in AIDS patients.
Acquired through ingestion of contaminated food and water.
What 4 drugs are used for activeTB Treatment?
Isoniazid, Rifampin, Pyrazinamide, Embamutol
What drug is used for latent TB?
Isoniazid for 9 months
What features of Isoniazid make it so effective?
Penetrates into macrophages. Shares structural similarity to pyridoxine(B6)
MOA of Isoniazid?
Inhibits synthesis of Mycolic acid which is essential for cell walls.
How is resistance developed to Isoniazid?
Mutation in the Kat G gene(lack of prodrug activation)
Overexpression of the Inh A Protein(involved in mycolic acid synthesis)
Pharmacokinetics of Isoniazid?
Readily absorbed into GI tract
Peak plasma Conc. In 2 hrs.
INH is acetylated in liver bowel and kidney. people that are slower acetylators can develop toxicity(Longer half life)
What is a toxic effect of isoniazid?
Peripheral neuropathy (similar to vit B6). Hepatitis(more with alcoholism)
What are included in the Rifamyciin family?
Rifampin, Rifambutol
MOA of Rifampin?
Inhibits RNA synth
Binds to bacterial DNA dependant RNA pol
Penetrates most tissues and phagocytic cells.
Doesn’t effect mammalian RNA Pol.
How does resistance develop to Rifampin?
Point mutations in bacterial RNA pol. Needs to be combined with other drugs.
Adverse rxns of rifampin?
GI symptoms. Red/orange urine, feces, sweat, tears, etc.
What are the drug interactions associated with Rifampin?
Strong inducer of Cyt P450.
Increases elimination of many drugs, especially antiretrovirals.
What drug can be substituted for Rifampin if Patient is on antiretroviral treatment?
Rifambutol. reduced rxns
How does pyrazinamide work?
an analouge of nicotinamide which is important to bacteria.
What is MOA of Pyrazinamide?
Inhibits mycolic acid synthesis
Dependant on an acidic environment. WORKS WELL INSIDE MACROPHAGES!
What are the adverse reactions of Pyrazinamide?
Hepatotoxicity
Hyperuricemia(gout)
What is the MOA of Ethambutol?
Inhibits arabinosyl transferases. Cell wall synthesis.
Used for active TB and avium complex infections
What are rhe adverse reactions of Ethambutol?
Retrobulbar neurotis (impaired visual acuity, R/G colorblindness) Hyperuricemia (more often with pyrazinamide)
What drug is used when the 4 drug therapy fails?
Streptomycin(old drug).
What are the adverse Rxns assoaciated with Streptiomycin?
Ototoxic(vertigo, hearing loss permanent?)
Nephrotoxic
What is unique about streptomycin pharmacology that makes it a worse drug to use?
Injected, penetrates cells and tissues poorly
What else is Rifabutin used for besides M. TB?
M. Avium. It has a greater activity against MAC than Rifampin.
What drugs are used to treat M. Avium?
Macrolide(clarithromycin or azithromycin), rifampin, ethambutol
All 3 for disseminated infection(AIDS)
What are the different forms of M. Leprae?
Lepromatous form and Tuberculoid (more mild) form
What drugs are used to treat Leprosy?
Dapsone, Clofazamine, and rifampin. Long treatment!
What is the MOA of Dapsone?
Analog of para-amino-benzoic acid. Inhibitor of folic acid synthesis.
What are the adverse reactions to Dapsone
Hemolytic anemia in those with G6PD deficiency
What is the MOA of Clofazimine?
Poorly absorbed but highly lipophilic. Intercalates with the bacterial DNA? We’re not sure…(reddish-brown skin)
