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Pharm 2 - Exam 4 > Lecture 3 - AntiTB Drugs > Flashcards

Lecture 3 - AntiTB Drugs Flashcards

1
Q

What are some reasons why treating TB so difficult?

A

Cell wall is impermeable (d/t lipid rich - mycolic acid)

Abundance of efflux pump on cell membrane (responsible for responsible for intrinsic resistance)

Intracellular (macrophages —inaccessible)

Latent vs active infection

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2
Q

What drugs are approved for TB treatment?

A

Fluoroquinolone (levofloxacin)

Rifamycin

Streptomycin

Macrolides

Isoniazid and ethlonamide

Ethambutol

Pyrazinamide

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3
Q

What experimental drugs are being testing for TB treatment?

A

Bedaquiline (TMC-207)

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4
Q

What is the MOA of fluoroquinolone?

A

Inhibits DNA synthesis and supercoiling by targeting topoisomerase

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5
Q

What is the MOA of rifamycin?

A

Inhibits RNA synthesis by targeting RNA polymerase

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6
Q

What is the MOA of streptomycin?

A

Inhibits protein synthesis by targeting the 30S ribosomal subunit

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7
Q

What is the MOA of macrolides?

A

Target 23S ribosomal RNA, inhibiting peptidyl transferase

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8
Q

What is the MOA of isoniazid and ethionamide?

A

Inhibit mycolic acid synthesis

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9
Q

What is the MOA of ethambutol?

A

Inhibits cell wall synthesis

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10
Q

What is the MOA of pyrazinamide?

A

Inhibits cell membrane synthesis

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11
Q

What is the MOA of bedaquiline?

A

TMC-207

Inhibits ATP synthase

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12
Q

Streptomycin

A 
Oldest TB agent 
CanNOT enter cells 
Bactericidal 
Resistance led to new agents 
May be used in severe cases (ie. disseminated disease, meningitis) 
Ototoxicity/nephrotoxicity 
Risk in pregnancy
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13
Q

Isoniazid (INH)

A

PO
Prodrug
Renal clearance
Good CNS/CSF penetrance

Most effective Rx in susceptible strains

Penetrates macrophages
-effective against intra/extracellular organism

Bactericidal
Inhibits mycolic acid synthesis; inhibits dihydrofolate reductase

Isoniazid is a prodrug that needs catalase-peroxidase to form activated drug

Adverse effects: 
Hepatic toxicity (most common) 
(Age dependent >35 yr)
Peripheral neuropathy (d/t pyridoxne deficiency-vtB6) 
Not to be used in pregnancy

Drug-drug interaction:
Acetaminophen - CYP2E1 induction
Warfarin - CYP2C9 inhibition

Resistance:
KatG deletion/mutation
InhA overexpression

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14
Q

What is the MOA of isoniazid?

A

Bactericidal
Inhibits mycolic acid synthesis - inhibits dihydrofolate reductase

Prodrug that gets activated by catalase -peroxidase

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15
Q

What resistance is present with isoniazid?

A

KatG deletion/mutation

InhA overexpression

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16
Q

What is the SE of isoniazid?

A 
Hepatic toxicity (most common) 
-age dependent >35yo

Peripheral neuropathy
-d/t pyridoxine deficiency (vit B6)

Overdose: seizure/coma

17
Q

Drug drug interaction of isoniazid

A

Acetaminophen - CYP2E1 INDUCTION —> hepatotoxicity

Warfarin - CYP2C9 inhibition —> possibility of increased bleeding

18
Q

Pyrazinamide

A

PO
Renal clearance

Excellent distribution (including CNS) 
Synthetic analog of nicotinamide

Inactive at neutral pH, “active” at acidic pH
Penetrates macrophages

Prodrug:
Converted to pyraxinoic acid by mycobacterial pyrazinamidase (pncA)

Inhibition of FAS1 (decrease mycolic acid synthesis)
Bactericidal (pncA mutations - mechanism of resistance)

SE:
Hyperuricemia (100% - exacerbates gout)

CI: pregnancy

19
Q

What is the MOA of pyrazinamide?

A

Inactive at neutral pH, “Active” at acidic pH

Penetrates macrophages
Prodrug converted to pyrazinoic acid by mycobacterial pyrazinamidase (pncA)

Inhibition of FAS1 (decrease mycolic acid synthesis)

20
Q

What is the mechanism of resistance for pyrazinamide?

A

pncA mutations

21
Q

What are the SE of pyrazinamide?

A

Hyperuricemia

Exacerbates gout
Inhibits uric acid excretion

Hepatic toxicity

Risk can not be ruled out in pregnancy

22
Q

Ethambutol

A

PO
Renal clearance
CSF penetration w/ meningeal inflammation

Inhibits mycobacterial arbinosyl transferase (embAB operon)

  • enhances bacterial cell wall permeability
  • bacteriostatic

Resistance:
-embB mutations

SE:
Optic neuritis (red-green color blindness)
23
Q

What is the MOA of ethambutol?

A

Inhibits mycobacterial arbinosyl transferase (embAB operon)

-enhances bacterial cell wall permeability

24
Q

What is the mechanism of resistance for ethambutol?

A

EmbB mutations

25
Q

What are the SE of Ethambutol?

A

Optic neuritis

Red-green color blindness

CI: pregnancy

26
Q

Rifampin

A

PO
Hepatic clearance/primarily biliary excretion

Bactericidal in mycobacteria

Inhibits RNA synthesis: bind beta subunits of bacterial DNA dependent RNA polymerase (rpoB) - no effect on eukaryote RNA polymerase

Resistance:
RpoB mutations

SE:
N/V
Fever, rash
May turn urine, tears, and other body fluids reddish-orange

CI: pregnancy
Caution in pts with chronic liver disease/alcoholics

Drug-drug interaction:
Induces hepatic metabolism
Accelerates metabolism of the antiHIV cocktail (protease/rev T’criptase inhibitors)

Rifabutin is used in TB for pts taking protease inhibitors for HIV

27
Q

What is the MOA of rifampin?

A

Bactericidal in mycobacteria

Inhibits RNA synthesis: binds beta subunit of bacterial DNA dependent RNA polymerase (rpoB) - no effect on eukaryote RNA polymerase

28
Q

What is the mechanism of resistance of rifampin?

A

RpoB mutations

29
Q

What are the SE of rifampin?

A

N/V
Fever, rash
May turn urine, tears, and other body fluids reddish-orange

CI:
Pregnancy
Caution in pts with chronic liver disease/alcoholics

30
Q

What are the drug drug interactions with rifampin?

A

Induces hepatic metabolism

Accelerates metabolism of the anti HIV cocktail (protease/rev T’criptase inhibitors)

31
Q

Which rifamycin can be used when a TB pt is on protease inhibitors of HIV?

A

Rifabutiin

32
Q

What is the preferred TB treatment for active TB?

A 
2 months
INH
Rifampin
Pyrazinamide
Ethambutol if INH resistance is suspected

4 months
INH plus RIF

33
Q

What is the preferred TB treatment for latent TB?

A

INH (9 months) or RIF (4 months)

34
Q

What is the most common cause of TB tx failure?

A

Poor compliance

35
Q

Bedaquiline

A

PO
Tx: 24 weeks in combination w/ >/= 3 drugs
$30K

Inhibits mycobacterial ATP synthase
-enzyme essential for the generation of energy
Resistance:
AtpE (subunit c ATP synthase)

Metabolized by CYP3A4 (do NOT administer with CYP3A4 inducers like rifampin)

SE:
Monitor liver functions
BOXED warning —QT prolongation with sirturo

Pharm 2 - Exam 4 (9 decks)

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