#3: Drugs for TB

Question 1

What are the 3 major Tx challenges of TB

Answer 1

3I’s

1. Impermeable cell wall
2. Intrinsic resistance (d/t lot of efflux pumps)
3. Inaccessible (b/c intracellular in macrophages)

Question 2

Where is TB located in latent vs active phase, why does this matter

Answer 2

Latent phase –> inside macrophages

Active –> outside macrophage
- can be transmitted

Question 3

What are the 4 1st line drugs for txting TB?

Answer 3

1st line drugs for txting TB = “RIPE”

1. Rifampin
2. INH
3. Pyrazinamide
4. Ethambutol

Question 4

Which of the 1st line TB drugs are cell wall inhibitors? (3)

Answer 4

Cell wall inhibitors for TB

1. INH
2. Pyrazinamide
3. Ethambutol

Question 5

Which 2 cell wall synthesis inhibitors can penetrate macrophages

Answer 5

Cell wall synthesis inhibitors that penetrate macrophages

1. INH
2. Pyrazinamide

Question 6

Which cell wall synthesis inhibitor inhibits mycolic acid synthesis and dihydrofolate reductase

Answer 6

INH

Question 7

Which cell wall synthesis inhibitor is the MOST effective in susceptible strains of TB

Answer 7

INH

Question 8

What does INH’s t 1/2 depend on

Answer 8

INH’s t 1/2 depends on:

NAT2 polymorphisms/ acteylation rate

Question 9

INH Acteylation rate

1. what does fast acteylation mean for metab + result?
2. what does slow acetylation mean for metab + result?

Answer 9

INH Acteylation rate

1. Fast acteylation = fast metab –> drug ineff
2. Slow acteylation = slow metab –> toxicity

Question 10

INH AEs

• 4 major a/w this drug
• which is MC

Answer 10

INH AEs

1. Hepatic toxicity = MC
2. PN (Peripheral Neuropathy)
3. Rash, fever
4. OD

Question 11

INH AEs: Hepatic toxicity (+/- fatal)

1. what is it incr w/ (2 things)

Answer 11

INH AEs: Hepatic toxicity (+/- fatal)

1. incr w/ slow acteylators and age (> 35)

Question 12

INH AEs: PN (Peripheral Neuropathy)

1. what type of ppl it is incr in
2. what is it d/t
3. Tx for it

Answer 12

INH AEs: PN

1. incr in slow acteylators
2. d/t = Vit B6/Pyroxodine defic
3. Tx for it = Vit B6

Question 13

What 4 drugs have interactions w/INH

Answer 13

Drug interactions w/INH

1. Acetaminophen
2. Warfarin
3. Diazepam
4. Phenytoin

Question 14

Drug Interactions w/INH

1. Acetaminophen - what does CYP2E1 induction cause
2. Warfarin - what type of inhibition may cause incr bleedin
3. Diazepam - what type of inhibition leads to sedation/resp depression (2)
4. Phenytoin - what does CYP2C19 inhibition cause

Answer 14

Drug Interactions w/INH

1. Acetaminophen
   - CYP2E1 induction–> hepatotoxicity
2. Warfarin
   - CYP2C9 inhibition may–> incr bleedin
3. Diazepam
   - CYP3A/2C19 –> sedation/resp depression
4. Phenytoin
   - CYP2C19 inhibition–> neuro toxicity

Question 15

Cell Wall Synthesis Inhibitors: Pyrazinamide

1. what converts Pyrazinamide –> pyrazinoic acid (POA)
   (converts it from prodrug to active)
2. what does POA inhibit + then block the synthesis of

Answer 15

Cell Wall Synthesis Inhibitors: Pyrazinamide

1. pncA (myocbacterial pyrazinamidase) converts Pyrazinamide –> pyrazinoic acid (POA)
   (converts it from prodrug to active)
2. POA blocks FAS1 –> inhibits mycolic acid synthesis

Question 16

Cell Wall Synthesis Inhibitors: Pyrazinamide

1. at what pH is this drug active at
   - b/c of this where is it active

Answer 16

Cell Wall Synthesis Inhibitors: Pyrazinamide

1. active at acidic pH –> active in macrophages/TB lesions (acidic)

Question 17

Cell Wall Synthesis Inhibitors: Pyrazinamide

what types of mutations–> resistance

Answer 17

Cell Wall Synthesis Inhibitors: Pyrazinamide

pncA mutations –> resistance

Question 18

Cell Wall Synthesis Inhibitors: Pyrazinamide

• what are the 3 AEs a/w this drug

Answer 18

Cell Wall Synthesis Inhibitors: Pyrazinamide AEs

1. Hepatoxicity
2. Hyperuricemia (exacerbates gout)
3. Arthralgias

Question 19

Cell Wall Synthesis Inhibitors: Ethambutol

1. MOA: what does it inhibit that utimately stops the growth of the bacteria
2. What mutations lead to resistance
3. What is the major but rare AE

Answer 19

Cell Wall Synthesis Inhibitors: Ethambutol

1. MOA: it inhibits mycobacterial arabinosyl transferase (embAB operon) –> incr BACTERIAL cell wall permeability –> stop bacterial growth
2. embB mutations resistance
3. major but rare AE = Optic Neuritis

Question 20

Cell Wall Synthesis Inhibitors: Ethambutol AEs

- what are the 2 manif of Optic Neuritis

Answer 20

Cell Wall Synthesis Inhibitors: Ethambutol AEs: 2 manif of Optic Neuritis

1. Loss of visual acuity
2. red-green color blindness

Question 21

What is the prototype drug for Rifamycins

Answer 21

prototype drug for Rifamycins = Rifampin

Question 22

Rifampin

1. does it penetrate macrophages
2. bacteriostatic or cidal

Answer 22

Rifampin

1. yes it penetrates macrophages
2. bacteriocidal

Question 23

What is the general MOA for Rifampin

Answer 23

general MOA for Rifampin = inhibit RNA synthesis

Question 24

MOA for Rifampin: inhibits RNA synthesis

1. how does it inhibit RNA synthesis (what does it bind to)
   - why is that important

Answer 24

MOA for Rifampin

1. inhbits RNA synthesis by binding to DNA dep RNA polyermase –> ONLY in bacterial cells (doesnt effect host)

Question 25

Rifampin 1. what is mutations lead to resistance 2. what is the major AE of this drug

Answer 25

Rifampin 1. rpoB mutations lead to resistance 2. major AE = turns urine, tears other body fluids red-orange

Question 26

Rifampin: Drug Interactions 1. what does it induce the hepatic metabolism of 2. What types of HIV drugs does it incr metab of 3. if it decr the t 1/2/incr metab of many drugs what does this lead to

Answer 26

Rifampin: Drug Interactions 1. induces the hepatic metabolism of MOST CYPs 2. incr metab of PIs and RT inhibitors (HIV drugs) 3. It decr t 1/2 of many drugs --> therapeutic failure (drugs ineff)

Question 27

Preferred TB Tx Regimens 1. for Latent TB 2. for Active TB

Answer 27

Preferred TB Tx Regimens 1. for Latent TB --> INH (+ Vit B6) for 9 months 2. for Active TB --> RIPE x 2 months --> RI x 4 months

Question 28

DOT and TB 1. why is it recommended 2. what 4 groups/types of Tx is it recommended for

Answer 28

DOT 1. recommended b/c MC cause of TB Tx failure = non-compliance (length of Tx) 2. recommended for - intermittent Tx, active TB Tx, Kids - daily Tx, drug resis TB

Question 29

What drug is approved for MDR (multi drug resistant) TB

Answer 29

Bedaquiline/Sirturo = for MDR TB

Question 30

Bedaquiline/Sirturo and MDR TB 1. what does it inhibit (MOA) 2. AEs: what does it incr the levels of 3. what CYP does it interact w/ and therefore you cant give it w/ _______

Answer 30

Bedaquiline/Sirturo and MDR TB 1. inhibits myocbacterial ATP synthase (stops NRG production in bacteria) 2. AE: incr levels of hepatic transaminases 3. interacts w/CYP34A ---> CANT GIVE W/RIFAMPIN

Question 31

Bedaquiline/Sirturo and MDR TB - what are the 2 BBW for it

Answer 31

Bedaquiline/Sirturo and MDR TB: BBW 1. incr risk of death 2. QT prolongation `

Question 32

2nd line Tx for TB: Aminoglycosides what is the main drug in this class Note: other not discussed = Amikacin

Answer 32

2nd line Tx for TB: Aminoglycosides drug = Streptomycin

Question 33

2nd line Tx for TB: Aminoglycosides (Streptomycin) 1. what is this not 1st line 2. what type of TB infxn can it only be used for + why (note used only for severe cases) 3. what are the 2 major AEs

Answer 33

2nd line Tx for TB: Aminoglycosides (Streptomycin) 1. not 1st line b/c of resistance to it 2. ONLY for ACTIVE TB infxn b/c it cant enter cells (note used only for severe cases) 3. 2 major AEs - oto/nephrotoxicity - risk in pregnancy

Question 34

What 2 other types of drugs used as 2nd line Tx for TB

Answer 34

2nd line Tx for TB 1. Fluoroquinolones (Levo) 2. Cycloserine

Question 35

XDR (Extremely drug resistant) TB - what 4 drugs is it resistant to

Answer 35

XDR TB: resistant to 1. INH 2. Rifampin 3. Fluoroquinolone 4. 1 IV 2nd line drug (ex: aminoglycoside)

Question 36

What is the Atypical Mycobacterium | - how are TB drugs affected by it

Answer 36

Atypical Mycobacterium = non TB infxn | - TB drugs less effective

Question 37

Atypical Mycobacterium: MAC | - what is the 3 drug regimen for it

Answer 37

Atypical Mycobacterium: MAC Tx 1. Rifampin 2. Ethambutol 3. MACrolides "Return of thE MAC"

Question 38

Leprosy/Hansen's Dz (caused by M.leprae) 1. why is multi drug Tx needed 2. what is the 3 drug tx regimen

Answer 38

Leprosy/Hansen's Dz (caused by M.leprae) 1. multi drug Tx needed to avoid resistance 2. 3 drug tx regimen - Rifampin - Dapsone - Clofazimine "Hansen Really Didnt wanna Catch Leprosy"