Med chem of antimycobacterial agent

Question 1

What is mycobacterium tuberculosis?
-May be dormant for a long time
-_______ (tubercles) form in the lungs

Answer 1

-Slow growing aerobic bacterium
-Relatively resistant to most antibiotics

-Granulomas

Question 2

What type of organism is mycobacterium tuberculosis?

Answer 2

Acid fast bacteria (AFB)
*Obligate aerobe
**Not gram (+) nor gram (-)

Question 3

The lipid rich cell wall of mycobacterium tuberculosis contains _____ and is impermeable to many drugs

**Causes both ____ and ____ infections

Answer 3

Mycolic acids

Latent and active

Question 4

Mycobacterium TB is a facultative ____ parasite

It is taken up by _______ and is maintained there, so it does not get degraded

Answer 4

Intracellular

Phagocytes

Question 5

Most common treatment of active Tb infections

Answer 5

RIPE: rifampin, isoniazid, pyrazinamide, and ethambutol

Question 6

Alternative tx for active Tb infection

Answer 6

Rifapentine, isoniazid, pyrazinamide, and MOXIFLOXACIN

Question 7

Why are combo drugs needed for Tb?

Answer 7

-Needs to combat dividing and dormant cells
-Tb rapidly develops resistance to individual drugs

Question 8

Isoniazid
-Specific for ____
-Bacteri_____
-Only active against ______
-Prodrug that is activated by _________

Answer 8

M. tb

Bactericidal

Only active against growing M. tb

Prodrug activated by M. tb KatG protein

Question 9

Isoniazid (INH) MOA

Answer 9

1. Activated by KatG
2. Forms adducts with NAD+ and NADP+
3. Inhibits enzymes that use NAD+ and NADP+
4. Activated isoniazid inhibits InhA (a component of fatty acid synthesis II that catalyzes the NADH-dependent reduction of fatty acids bound to acyl carrier proteins)
5. This causes a build up of C20 precursors (linked to CoA) which inhibit longer carbon chain cells
6. Blocks mycolic acid synthesis –> defective cell wall

Question 10

Isoniazid resistance

Answer 10

1. Overexpression of inhA (gives low level of resistance)
2. Mutation in KatG (higher level of resistance bc isoniazid will not be converted to its active form)

Question 11

Metabolism of Isoniazid

Answer 11

-Acetylated by liver N-acetyltransferase (NAT2)
-Some pts are slow metabolizers and some are rapid
-No therapeutic consequence if dosed daily, but can result in subtherapeutic levels if dosed weekly if a pt metabolizes quickly

Question 12

Difference between KatG and NAT2

Answer 12

KatG activates isoniazid from its prodrug to active form

NAT2 inactivates isoniazid and leads to renal excretion

Question 13

Isoniazid toxicity

Answer 13

Hepatitis
Peripheral neuropathy

Question 14

Isoniazid toxicity mechanism

Answer 14

-Acetylisoniazid can be converted to acetylhydrazine
-CYP2E1 converts acetylhydrazine –> hepatotoxic metabolites
-NAT2 can acetylate acetylhydrazine to nontoxic diacetylhydrazine
-Rapid acetylators will rapidly remove acetylhydrazine
-Slower acetylators will lead to more toxic metabolites
-Rifampin induces CYP2E1 & potentiates isoniazid heptotoxicity

Question 15

_____ and ____ lead to toxic metabolites of Isoniazid

Answer 15

CYP2E1
Rifampin (which induces CYP2E1)

Question 16

_____ and _____ lead to nontoxic metabolites of isoniazid

Answer 16

NAT2
Rapid acetylators

Question 17

Isoniazid can cause peripheral neuropathy which can be reversed by giving __________ via 2 mechanisms:
1. _____
2. _____

Answer 17

Pyridoxine (Vitamin B6)

1. Isoniazid competitively inhibits pyridoxine phosphokinase (converts the pyridoxine to pyridoxal phosphate = active form)
2. Isoniazid metabolites directly inactivate pyridoxine spp

Question 18

Pyrazinamide (Aldinamide)
-Shortened tx to ____
-Sterilizing agent against _____ (sometimes referred to as nonreplicating, persistent bacilli = NRPB)
-Structurally similar to _____
-Activity is pH dependent:
~Activated by ____ pH
~Inactive at ____ pH

Answer 18

6 months

residual intracellular bacteria

Nicotinamide

-low; neutral

Question 19

Pyrazinamide is a prodrug which requires conversion to ____ by _____

Answer 19

Pyrazinoic acid
pncA (mycobacterium enzyme)

Question 20

Normally, pncA converts nicotinamide into nicotinic acid + ammonia

With pyrazinamide, pncA converts it to pyrazinoic acid + ammonia which is active at pH < _____

Answer 20

5.5

Question 21

Pyrazinamide MOA

Answer 21

-Inhibition of panD leading to inhibition of Co-A synthesis

Question 22

Pyrazinamide (PZA) MOA
-panD converts L-aspartate to ____
-Pyrazinoic acid (POA) binds to panD which causes ____ not to bind
-PZA tx reduces accumulation of _____ after panD step which increases levels of ____ bc they don’t have the coenzyme

Answer 22

Alanine

PZA

Co-A; free fatty acids

Question 23

Pyrazinamide (PZA)
-panD binding affinity is _____
-POA (does/does not) inhibit panD efficiently
-Binding leads to degradation of panD which recruits _____ and decreases panD levels so that ____ cannot be made

Answer 23

Low

Does not

ClpC1

CoA

Question 24

Pyrazinamide (PZA) resistance
-Generated _____, but suppressed when used in combo
-Primarily due to mutations in _____
-Genome sequencing of resistance strains: RpsA, panD, and ClpC1 (hard to screen bc many different mutation strains)

Answer 24

easily

pncA

Question 25

Pyrazdinamide toxicity -_____ is the most common SE -_____ is the most dangerous *** Pts must undergo studies of ____ function before tx ***Hydroxylated POA is cause of toxicity

Answer 25

Joint pain (arthralgia) Hepatitis *** hepatic

Question 26

Ethambutol -Bacteri____ inhibitor of M. Tb

Answer 26

Bacteriostatic

Question 27

Ethambutol MOA

Answer 27

Inhibits mycobacterial arabinosyl transferases which are involved in the polymerization of arabinogalactan (layer in cell wall) -Results in buildup of precursor (arabinan) -Inhibits formation of arabinogalactan and lipoarabinomannan (LAM)

Question 28

Recap: -Isoniazid messes up the _____ layer -Ethambutol messes up the ____ layer

Answer 28

Mycolic acid Arabinogalactan

Question 29

Ethambutol -Synergistic with ____ to increase penetration into the cell -Resistance is due to overexpression of/mutations in ________ -Not recommended for use alone due to resistance

Answer 29

Rifampin Arabinosyl transferase

Question 30

Ethambutol toxicity -MOST IMPORTANT: _______

Answer 30

Optic neuritis *can be irreversible if tx is not D/C

Question 31

Rifampin -Semisynthetic derivative of _____ -Reduced length of tx from 18 months --> 9 months -Most effective ____ line agent (high sterilizing activity & rapidly renders patients non-infectious) -Penetrates most tissues and phagocytic cells -Active against _____ (but most effective when ___ is happening) -Can kill M. tb that is inaccessible to many other drugs

Answer 31

Rifamycin B FIRST growing and stationary cells with low metabolic activity (cell division)

Question 32

Rifampin -Bacteri______ -Optimize AUC/MIC or Cmax/MIC Rifapentine is a derivative of _____ -More _____ -Longer _____

Answer 32

cidal Rifampin Lipophilic Half-life

Question 33

Rifampin MOA

Answer 33

-Binds RNA polymerase deep within the DNA/RNA channel -Binds ALLOSTERICALLY -Blocks the path of the elongation of nucleotides on RNA

Question 34

Rifampin ADR

Answer 34

-Colors urine, tears, and sweat orange (can permanently stain contact lenses) -Potent inducer of CYP450 (lots of DDI) -Increase in CYP enzymes increases elimination of other drugs metabolized by these enzymes

Question 35

FQ: moxifloxacin MOA -MOA -Bacteri_____

Answer 35

-Traps topo II (gyrase) on DNA ternary complex--> prevents resolution of supercoiled DNA-->disrupts DNA replication -Bactericidal -Reduces tx from 6 months --> 4 months -MOX is preferred due to better PK (penetration from plasma to tissues & better at reducing and/or killing M. tb in lesions)

Question 36

Toxicity associated with anti-TB drugs -Hepatitis from: _____ -Eye damage (loss of visual acuity & red-green color blindness) from: ______ -Orange discoloration of the urine from: _____ -Pts should be monitored at least ____ for ADR

Answer 36

1. Isoniazid, pyrazinamide, rifampin 2. Ethambutol 3. Rifampin 4. monthly

Question 37

Mechanisms of resistance for Anti-TB drugs

Answer 37

Drug exported from cell wall

Question 38

BPaL regimen -NOT first line (only if failed prior tx) -Combo therapy containing: _____ -For tx of _____ or ______

Answer 38

-Bedaquiline, pretomanid, linezolid -Extensively drug resistance TB (XDR-TB) -Treatment-intolerant or non-responsive multidrug-resistance TB (MDR-TB)

Question 39

Bedaquiline -_____ administration -Bacteri______ against actively growing and dormant bacilli (has sterilizing activity) -Metabolized by _____

Answer 39

Oral Bactericidal CYP3A4

Question 40

Bedaquiline MOA Resistance due to mutations in _____

Answer 40

-Inhibits ATP synthase (cell cannot make ATP --> toxic) -atpE (target enzyme)

Question 41

Nitroimidazole (Pretomanid) -Prodrug activated by ____

Answer 41

M. tb deazaflavin-dependent nitroreductase (Ddn)

Question 42

Pretomanid in aerobic conditions

Answer 42

Forms reactive intermediate metabolite that inhibits mycolic acid production (and likely other pathways)

Question 43

Pretomanid in anaerobic, nonreplicating, persistent bacilli conditions

Answer 43

-Generates reactive nitrogen species such as NO -Direct poisoning of the respiratory complex --> ATP depletion -Increases killing of mycobacterium by innate immune system

Question 44

Second line agents -Active anti-tubercular agents are ___ tolerated -_____ incidence of SE -Usually considered only if ____

Answer 44

Not well tolerated Increased 1. Resistance to first line agents 2. Failure of clinical response to first line agents 3. Intolerance to first line agents 4. Expert guidance available to deal with toxic side-effects

Question 45

Second line agent names

Answer 45

Streptomycin Ethionamide Para-aminosalicylic acid Cycloserine (similar to vanc and beta lactams) Capreomycin