Anti-Mycobacterial Pharmacology

Question 1

What organisms are in the Mycobacterium family?

Answer 1

M. Tuberculosis
M. Avium complex
-pulmonary
-disseminated
M. Leprae

Question 2

What are common traits of Mycobacterium family?

Answer 2

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.

Question 3

Why are mycobacterium so hard to treat?

Answer 3

Most drugs can only work when bacteria are fast growing. Mycos grow very slowly.

Question 4

What is the most common form of TB in the body?

Answer 4

Latent TB. 90%

Question 5

What is a latent TB infection?

Answer 5

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

Question 6

What constitutes an active TB infection?

Answer 6

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.

Question 7

What are the obstacles to treating Tuberculosis?

Answer 7

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)

Question 8

How do we get around these problems?

Answer 8

3-4 drug regimen
Need to take the drugs regulary (direct observed therapy)
Therapy must continue for sufficient time.

Question 9

Drugs used to treat TB

Answer 9

Rifamycin, Isoniazid, Streptomycin, Pyrazinamide

Question 10

What is the most active drug for TB treatment?

Answer 10

Isoniazid used for latent and active infections.

Question 11

What is the M. Avium Complex?

Answer 11

Includes M. Avium and M. Intracellulare
Pulmonary disease in immunocompetent, and disseminated disease in AIDS patients.
Acquired through ingestion of contaminated food and water.

Question 12

What 4 drugs are used for activeTB Treatment?

Answer 12

Isoniazid, Rifampin, Pyrazinamide, Embamutol

Question 13

What drug is used for latent TB?

Answer 13

Isoniazid for 9 months

Question 14

What features of Isoniazid make it so effective?

Answer 14

Penetrates into macrophages. Shares structural similarity to pyridoxine(B6)

Question 15

MOA of Isoniazid?

Answer 15

Inhibits synthesis of Mycolic acid which is essential for cell walls.

Question 16

How is resistance developed to Isoniazid?

Answer 16

Mutation in the Kat G gene(lack of prodrug activation)

Overexpression of the Inh A Protein(involved in mycolic acid synthesis)

Question 17

Pharmacokinetics of Isoniazid?

Answer 17

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)

Question 18

What is a toxic effect of isoniazid?

Answer 18

Peripheral neuropathy (similar to vit B6).
Hepatitis(more with alcoholism)

Question 19

What are included in the Rifamyciin family?

Answer 19

Rifampin, Rifambutol

Question 20

MOA of Rifampin?

Answer 20

Inhibits RNA synth
Binds to bacterial DNA dependant RNA pol
Penetrates most tissues and phagocytic cells.
Doesn’t effect mammalian RNA Pol.

Question 21

How does resistance develop to Rifampin?

Answer 21

Point mutations in bacterial RNA pol. Needs to be combined with other drugs.

Question 22

Adverse rxns of rifampin?

Answer 22

GI symptoms. Red/orange urine, feces, sweat, tears, etc.

Question 23

What are the drug interactions associated with Rifampin?

Answer 23

Strong inducer of Cyt P450.

Increases elimination of many drugs, especially antiretrovirals.

Question 24

What drug can be substituted for Rifampin if Patient is on antiretroviral treatment?

Answer 24

Rifambutol. reduced rxns

Question 25

How does pyrazinamide work?

Answer 25

an analouge of nicotinamide which is important to bacteria.

Question 26

What is MOA of Pyrazinamide?

Answer 26

Inhibits mycolic acid synthesis | Dependant on an acidic environment. WORKS WELL INSIDE MACROPHAGES!

Question 27

What are the adverse reactions of Pyrazinamide?

Answer 27

Hepatotoxicity | Hyperuricemia(gout)

Question 28

What is the MOA of Ethambutol?

Answer 28

Inhibits arabinosyl transferases. Cell wall synthesis. | Used for active TB and avium complex infections

Question 29

What are rhe adverse reactions of Ethambutol?

Answer 29

``` Retrobulbar neurotis (impaired visual acuity, R/G colorblindness) Hyperuricemia (more often with pyrazinamide) ```

Question 30

What drug is used when the 4 drug therapy fails?

Answer 30

Streptomycin(old drug).

Question 31

What are the adverse Rxns assoaciated with Streptiomycin?

Answer 31

Ototoxic(vertigo, hearing loss permanent?) | Nephrotoxic

Question 32

What is unique about streptomycin pharmacology that makes it a worse drug to use?

Answer 32

Injected, penetrates cells and tissues poorly

Question 33

What else is Rifabutin used for besides M. TB?

Answer 33

M. Avium. It has a greater activity against MAC than Rifampin.

Question 34

What drugs are used to treat M. Avium?

Answer 34

Macrolide(clarithromycin or azithromycin), rifampin, ethambutol All 3 for disseminated infection(AIDS)

Question 35

What are the different forms of M. Leprae?

Answer 35

Lepromatous form and Tuberculoid (more mild) form

Question 36

What drugs are used to treat Leprosy?

Answer 36

Dapsone, Clofazamine, and rifampin. Long treatment!

Question 37

What is the MOA of Dapsone?

Answer 37

Analog of para-amino-benzoic acid. Inhibitor of folic acid synthesis.

Question 38

What are the adverse reactions to Dapsone

Answer 38

Hemolytic anemia in those with G6PD deficiency

Question 39

What is the MOA of Clofazimine?

Answer 39

Poorly absorbed but highly lipophilic. Intercalates with the bacterial DNA? We're not sure...(reddish-brown skin)