Dr. Roane Antimycobacterials EXAM 3

Question 1

What is tuberculosis known for?

Answer 1

White plague (paleness of patients), consumption (pt lose weight)

Question 2

Synonym for Hansens disease

Answer 2

Leprosy

Question 3

Which patient population is associated with Mycobacterium Avium/intracellulare?

Answer 3

Immunocompromised patients

Question 4

What are the first-line drugs for Tuberculosis?

Answer 4

-Ethambutol
-Isoniazid
-Pyranizamide
-Rifampin/Rifapentine
-Streptomycin (aminoglycoside - only injectable)

Question 5

What does Rifampin, Rifabutin, Rifapentine have in common?

Answer 5

Similar structure

Question 6

Which diseases can be treated with Rifampin?

Answer 6

-Tuberculosis
-Leprosy

Question 7

Is Tuberculosis transmissible in latent patients?

Answer 7

No, but w/o treatment they may develop the disease at some point in their life

Question 8

What prevents the TB bacteria from spreading within the alveola tissue?

Answer 8

Granuloma contains of macrophages and other immune cells
-> When the Granuloma breaks open the TB bacteria multiplies and causes the disease

Question 9

Where in the body are TB bacteria found?

Answer 9

-In the lungs: pulmonary

-other parts of the body (via the bloodstream): Extrapulmonary

Question 10

Why is Mycobacterium tuberculosis hard to treat?

Answer 10

-mycolic acid (fatty acid, waxy) on the cell wall: less susceptible to antibiotics
-slow growing
-Resistance may occur -> more than one drug is required

Question 11

What are the important drug targets for Mycobacteria tuberculosis?

Answer 11

-Synthesis of Mycolic acid (fatty acid, waxy) on the outer cell wall

-Synthesis of the arabinogalactan (sugar-chain)

-Inhibition of protein synthesis

Question 12

How to test for tuberculosis?

Answer 12

-Mantoux test (skin test)
-A positive test means that the body has produced antibodies against tuberculosis (have been exposed to the bacteria; doesn’t mean you have the disease!

Question 13

How does the tuberculosis bacteria get to the brain?

Answer 13

Through lymphatics

-can infect any tissue in the body

Question 14

What does Granuloma look like on the tissues?

Answer 14

-Caesation: “cheese”-like tissue

Question 15

What is the recommended treatment for latent TB infections?

Answer 15

changed recently from long-term Monotherapy of Isoniazid to a short-course regimen

-Isoniazid + Rifapentine (3mo, 1xweekly)
-Rifampin (4mo, daily)
-Isoniazid - Rifampin (3mo, daily)

Question 16

What does TDR or XDR mean?

Answer 16

MDR: Multi-drug-resistant TB
TDR: Totally-drug-resistant tuberculosis
XDR: broadly drug-resistant TB

Question 17

How many drugs are required to treat TB?

Answer 17

-At least 2 bacteriocidal drugs
-usually Isoniazid and Rifampin
-compliance is an issue

Question 18

MOA of Isoniazid

Answer 18

-Inhibits bacterial enzymes
-The exact cidal MOA is unknown, more cidal when the bacteria is rapidly dividing
-pro-drug -> that is activated by bacterial enzymes -free radical is formed -> formation of an adduct -> inhibits mycolic acid

-disrupts the synthesis of mycolic acid (cell wall)

Question 19

Form of Resistance of Tuberculosis

Answer 19

-Failure to activate the pro-drug
-Neutralize active compound (catches free radicals and prevents its effect?)

Question 20

Which patient should be treated with caution when INH is used?

Answer 20

-Patients with liver disease

-INH itself also damages the liver

Question 21

Adverse effects of Isoniazid

Answer 21

-Hepatitis
->increases with age and rifampin
-> No alcohol allowed
-> Threshold for acetaminophen toxicity is lower

-Peripheral neuritis (tingling - corrected by pyridoxine V6 supplement)
-other neurological effects, rash, fever

Question 22

What is a major route of Metabolism of INH?

Answer 22

Hepatic acetylation
-Slow acetylators are common, more common
in Mediterainean peoples

Question 23

What part of the population is vulnerable to INH use?

Answer 23

-Hispanic, African-American

Question 24

How can the adverse effect of peripheral neuritis (pins and needle tingling) be treated?

Answer 24

pyridoxine V6 supplement (similar structure)

Question 25

Which enzyme is inhibited by Isoniazide and what is the effect?

Answer 25

-Monooxidase -anti-depressive effect

Question 26

Which INH-relative drug led to the discovery of Isocarboxazid?

Answer 26

-Iproniazid -Isocarboxazid (MOA inhibitor treating depression)

Question 27

Which disease is known to be treated with Rifampin?

Answer 27

-Leprosy -also: May treat mycobacterium avium-intracellulare, seen in AIDS patients

Question 28

MOA of Rifampin

Answer 28

Blocks prokaryotic DNA-dependent RNA polymerase

Question 29

Where is Rifampin derived from?

Answer 29

-Soil Streptomyces -belongs to the family of rifamycins (rifapentine, rifabutin and rifaximin)

Question 30

Mechanism of Resistance of the Bacteria against Rifampin

Answer 30

Mutations -> lowering of the affinity -Not All or one, varies in affinity for the target

Question 31

Pharmacokinetics and side effects of Rifampin

Answer 31

-Penetrates tissues well -Active orally -Enterohepatic circulation -Major p450 induction -Urine, feces, tears, and sweat are colored orange-red

Question 32

What is a characteristic of rifampin's metabolism?

Answer 32

It accelerates its own metabolism by inducing CYP450, as well as the metabolism of other drugs -dose may have to be increased?? does CYP450 metabolism lead to more metabolites, hence more side effects?? -patients are often concerned about the efficacy of oral contraceptives when taking Rifampin

Question 33

What are the side effects of Rifampin?

Answer 33

-Fever, rash, N/V, liver damage -Caution in patients with liver problems, alcoholics, elderly

Question 34

How does Pyrazinamide (PZA) work in the body?

Answer 34

-orally synthetic agent -needs to be activated by the bacteria -> converted into pyrazonic acid with bacterial pyrazinamidase -resistant bacteria lack pyrazinamidase

Question 35

What can be caused by the intake of PZA, INH, and Rifampin?

Answer 35

-liver dysfunction in 1-5% of patients -gout (elevation of uric acid)

Question 36

How does Ethambutol work?

Answer 36

-orally active -bacteriostatic -inhibits arabinogalactans synthesis in the cell wall -no resistance when used in Combination

Question 37

What are the side effects of Ethambutol?

Answer 37

-Optic neuritis (eye pain) -Blurred vision -Loss of red/green color discrimination

Question 38

Other drugs to treat Mycobacteria

Answer 38

-Streptomycin and other Aminoglycosides -Capreomycin (a cyclic peptide) -Macrolides (azithromycin) -Fluoroquinolones (ciprofloxacin or others)

Question 39

Which anti-TB drug showed promising results when tested against MDR tuberculosis strains in a study?

Answer 39

-Tebepenem, oral carbapenem -alone: MIC range of 0.125 to 8 μg/ml -with clavulanate: 2 μg/ml or less

Question 40

Which drugs are recommended by a recent protocol for patients with a low bacterial count?

Answer 40

Rifapentine and Moxifloxacin

Question 41

Which drug is the first new anti TB drug in 40 years?

Answer 41

Betaquiline (Sirturo) -MOA: inhibts mycobacterial ATP synthetase -T1/2= about 55 days

Question 42

Which drug would lower the plasma level of Betaquiline due to drug interaction with CYP3A4?

Answer 42

Rifampin: CYP3A4-inducer decrease Betaquiline leves by 50%

Question 43

Which drug would increase the plasma level of Betaquiline due to drug interaction with CYP3A4?

Answer 43

Ketoconazole: CYP-inhibitor increase Betaquiline leves by 25%

Question 44

What is in the Black Box Warning of Betaquiline?

Answer 44

prolonged QT interval -> Also for FQ and clofazamine

Question 45

What is the new drug Pretomanid used for?

Answer 45

- txt of MDR-TB in combination with Linezolid and betaquiline -Pretomanid inhibits mycolic acid synthesis -Betaquiline inhibits bac. ATP synthetase -Linezolid inhibits protein synthesis at the ribosome

Question 46

What is BPaL referred to?

Answer 46

combination of Pretomanid, betaquiline, and Linezolid

Question 47

What is Leprosy?

Answer 47

-not highly contagious infection of M. leprae -multi-drug therapy: 6-24 months -Hansen's Disease

Question 48

Which drugs are used to treat Leprosy?

Answer 48

-Dapsone (sulfonamide-like PABA-antagonist) -Clofazimine -Rifampin -in combination for 6-24 months

Question 49

Side effect of Dapsone

Answer 49

-hemolytic anemia (red blood cell die), especially in patients with G6P-DH deficiency -G6P-DH is involved in making ribose sugars and NADPH

Question 50

Side effect of Clofazimine

Answer 50

-phenazine dye, produces toxic free radical that inhibits DNA template function -dyes patient to reddish-brown (Rifampin colors fluids red)

Question 51

What is the consequence of Leprosy?

Answer 51

Sensory nerve damage -> patients can't feel injuries -> infection -> Lost body parts