Lecture 3 - AntiTB Drugs Flashcards by Indy P

What are some reasons why treating TB so difficult?

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

How well did you know this?

Not at all

Perfectly

What drugs are approved for TB treatment?

Fluoroquinolone (levofloxacin)

Rifamycin

Streptomycin

Macrolides

Isoniazid and ethlonamide

Ethambutol

Pyrazinamide

How well did you know this?

Not at all

Perfectly

What experimental drugs are being testing for TB treatment?

Bedaquiline (TMC-207)

How well did you know this?

Not at all

Perfectly

What is the MOA of fluoroquinolone?

Inhibits DNA synthesis and supercoiling by targeting topoisomerase

How well did you know this?

Not at all

Perfectly

What is the MOA of rifamycin?

Inhibits RNA synthesis by targeting RNA polymerase

How well did you know this?

Not at all

Perfectly

What is the MOA of streptomycin?

Inhibits protein synthesis by targeting the 30S ribosomal subunit

How well did you know this?

Not at all

Perfectly

What is the MOA of macrolides?

Target 23S ribosomal RNA, inhibiting peptidyl transferase

How well did you know this?

Not at all

Perfectly

What is the MOA of isoniazid and ethionamide?

Inhibit mycolic acid synthesis

How well did you know this?

Not at all

Perfectly

What is the MOA of ethambutol?

Inhibits cell wall synthesis

How well did you know this?

Not at all

Perfectly

What is the MOA of pyrazinamide?

Inhibits cell membrane synthesis

How well did you know this?

Not at all

Perfectly

What is the MOA of bedaquiline?

TMC-207

Inhibits ATP synthase

How well did you know this?

Not at all

Perfectly

Streptomycin

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

How well did you know this?

Not at all

Perfectly

Isoniazid (INH)

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

How well did you know this?

Not at all

Perfectly

What is the MOA of isoniazid?

Bactericidal
Inhibits mycolic acid synthesis - inhibits dihydrofolate reductase

Prodrug that gets activated by catalase -peroxidase

How well did you know this?

Not at all

Perfectly

What resistance is present with isoniazid?

KatG deletion/mutation

InhA overexpression

How well did you know this?

Not at all

Perfectly

What is the SE of isoniazid?

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

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

Overdose: seizure/coma

Drug drug interaction of isoniazid

Acetaminophen - CYP2E1 INDUCTION —> hepatotoxicity

Warfarin - CYP2C9 inhibition —> possibility of increased bleeding

Pyrazinamide

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

What is the MOA of pyrazinamide?

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)

What is the mechanism of resistance for pyrazinamide?

pncA mutations

What are the SE of pyrazinamide?

Hyperuricemia

Exacerbates gout
Inhibits uric acid excretion

Hepatic toxicity

Risk can not be ruled out in pregnancy

Ethambutol

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)

What is the MOA of ethambutol?

Inhibits mycobacterial arbinosyl transferase (embAB operon)

-enhances bacterial cell wall permeability

What is the mechanism of resistance for ethambutol?

EmbB mutations

What are the SE of Ethambutol?

Optic neuritis Red-green color blindness CI: pregnancy

Rifampin

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

What is the MOA of rifampin?

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

What is the mechanism of resistance of rifampin?

RpoB mutations

What are the SE of rifampin?

N/V Fever, rash May turn urine, tears, and other body fluids reddish-orange CI: Pregnancy Caution in pts with chronic liver disease/alcoholics

What are the drug drug interactions with rifampin?

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

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

Rifabutiin

What is the preferred TB treatment for active TB?

``` 2 months INH Rifampin Pyrazinamide Ethambutol if INH resistance is suspected ``` 4 months INH plus RIF

What is the preferred TB treatment for latent TB?

INH (9 months) or RIF (4 months)

What is the most common cause of TB tx failure?

Poor compliance

Bedaquiline

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