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MED234 Respiratory > Fitz, TB > Flashcards

Fitz, TB Flashcards

1
Q

Why should fluoroquinolones NOT be used as first line treatment for TB in endemic areas?

A

They mask active TB and it promotes resistance of fluoroquinolones.

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2
Q

Signs and symptoms of TB

A
  • Cough for 3 weeks or longer
  • Hemoptysis
  • Night sweats
  • Weight loss
  • Weakness
  • Fever, chills
  • Pain in chest
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3
Q

Name the three things that make TB treatment challenging.

A
  • Primary lesion - caseating granuloma with TB inside macrophages
  • Persistent mycobacteria in LYMPH NODES and LUNG
  • CAVITATING LESIONS
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4
Q

Three goals of TB treatment

A
  1. Eradicate Mycobacterium TB
  2. Prevent drug resistance
  3. Prevent relapse
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5
Q

Name the four drugs used in standard therapy of ACTIVE TB and at what stages they’re used.

A
  • Initial stage - Isoniazid, Rifampin, Ethambutol, Pyrazinamide
  • Continuation phase - Isoniazid and Rifampin
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6
Q

Length of time in the initial stage of treatment of active TB and the GOAL.

A
  • 8 weeks

- Goal - eradicate the large burden of REPLICATING bacteria

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7
Q

Length of time in the continuation stage of treatment of active TB and the GOAL.

A
  • wk8 to wk26

- Goal - Infiltrate INTRACELLULARLY… non-cavitating lesions

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8
Q

What drug is used for TB patients that cannot take drugs PO?

A

Streptomycin - NOT a 1st line drug.

Administered parenteral.

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9
Q

Clearance of isoniazid, rifampin, ethambutol, pyrazinamide

A

Mixed hepatic/renal

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10
Q

Isoniazid spectrum

A

Narrow spectrum - mycobacteria TB.

BacteriCIDAL in GROWING mycobacteria.

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11
Q

MOA of isoniazid

A

Disrupts mycolic acid synthesis, making mycobacteria vulnerable to destruction.

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12
Q

What is mycolic acid?

A

Distinctive component of mycobacteria cell wall.

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13
Q

Describe the location and process of isoniazid activation

A
  • Location: IN the mycobacterium
  • Process: INH (prodrug) –> converted to activated metabolite by Catalase Peroxidase (KatG) –> activated metabolite binds to NAD, inhibiting enzymes (InhA and KasA) from forming functional mycolic acid for cell wall.
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14
Q

Describe the 2 mechanisms of resistance to isoniazid.

A
  1. Deletion of KatG –> resulting in insufficient metabolite

2. Overexpression/mutation in InhA or KasA (can work in presence of lower NAD levels)

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15
Q

Describe the metabolization process of isoniazid and what the toxic metabolite is.

A

INH –(NAT+acetylCoA)–> N-Acetyl-INH –> N-Acetyl-Hydrazine (this is toxic) or Isotonic acid

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16
Q

Describe the fast metabolization of INH and what’s excreted

A
  1. Fast acetylators (90% of Asians) = 90% of INH excreted as N-Acetyl-INH
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17
Q

Describe slow metabolization of ING and what’s excreted

A
  1. Slow acetylators (50% of Whites, Blacks, Hispanics) = 65% of INH excreted as N-Acetyl-INH, so MORE EXPOSURE TO N-Acetylhydralazine (toxic)
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18
Q

A person presents with hepatotoxicity after taking isoniazid. What type of metabolizer is this person and what metabolite is causing the hepatotoxicity?

A
  • Slow acetylator

- N-acetylhadralazine

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19
Q

What are the clinical presentations of the two major adverse reactions to INH?

A
  1. Hepatotoxic (slow acetylators) - jaundice, elevated liver enzymes, hepatitis
  2. Neurologic (slow acetylators) - peripheral neuritis/parasthesias, convusions
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20
Q

Risk factors for N-Acetylhydralazine toxicity.

A

Age, alcoholism, drug abuse, drugs (liver enzyme inducers), liver disease.

21
Q

The major molecule and mechanism in isoniazid neuropathy.

A

Pyridoxal-5-Phosphate is a co-factor for neurotransmitter synthesis (GABA). INH reacts with this and increases its urinary excretion, depleting pyridoxines.

22
Q

Pyridoxine is aka…

A

Vitamin B6.

23
Q

A person presents with peripheral neuropathy, parasthesias, and seizures after taking isoniazid. What type of metabolizer is this person and what metabolite is causing the isoniazid neuropathy?

A

Slow acetylator

- Vitamin B6/pyridoxine is depleted.

24
Q

Rifampin spectrum

A 
Broad spectrum - mycobacteria TB + other bacteria
BacteriCIDAL extracellular (caseous lesions) and INTRACELLULAR (can get into macrophages in "continuation phase").
25
Q

Rifampin MOA

A

Inhibits PROkaryotic RNA polymerase/gene transcription, resulting in zero mRNA.
- Intracellular penetration by rifampin is high. Reaches intracellularly during “continuation” treatment.

26
Q

Adverse effect of Rifampin

A

Stains RED - urine, contacts, sweat, etc.

27
Q

A woman on oral contraceptives should not take what TB drug? Why?

A

Major rifampin-drug interaction is CYP450 INDUCTION. So any drug (i.e. OCP) metabolized by this will be cleared faster.

28
Q

Two major Rifampin-drug interactions.

A
  1. Induces CYP450

2. Increases clearance of HIV protease inhibitors and non-nucleoside transcriptase inhibitors.

29
Q

A HIV pt is dx with TB. Do you tx TB or HIV first and what drug should you substitute?

A

Deal with TB infection first. Substitute RIFABUTIN for Rifampin because Rifampin will increase clearance of HIV protease inhibitors.

30
Q

Pyrazinamide spectrum

A

Narrow spectrum - mycobacteria TB at ACIDIC pH’s

31
Q

Pyrazinamide MOA

A

Reaches intracellular pathogens and is bacteriCIDAL only at acidic pH - “sterilizing” agent.

32
Q

Metabolism of pyrazinamide

A

Hepatic, CYP450

33
Q

Toxicity of pyrazinamide

A
  • Hepatotoxic
  • Renal –> Gout
  • **Do not give to pregnant women - possible teratogenicity)
34
Q

If a patient has severe liver disease or gout, what TB drug should be avoided and how should the drug regimen be changed?

A

Avoid pyrazinamide.

Same duration of Initiation Phase, but extend Continuation Phase.

35
Q

Ethambutol spectrum

A

Narrow - only mycobacteria

36
Q

Ethambutol MOA

A

Inhibits arabinosyl transferase which makes (sugar) arabinogalactin in cell wall.

37
Q

Mechanisms of resistance to rifampin (2).

A
  1. Mutation in RNA polymerase

2. Drug permeability (?)

38
Q

Mechanism of resistance to ethambutol.

A

Mutation of arabinosyl transferase.

39
Q

Adverse effects of ethambutol (2).

A
  1. Visual - optic neuritis and color disturbance.

2. Renal - gout

40
Q

Pyrazinamide/Ethambutol Renal reactions and results.

A

Block tubular secretion of uric acid and cause retention, resulting in hyperuricemia and urate crystals.

41
Q

What is the drug regiment for latent TB (less mycobacteria)?

A

Isoniazid and rifapentine 1/week for 12 weeks.

42
Q

12-dose regimen is not recommended in what types of populations?

A

Children less than 2yo
Pregnant women
HIV postive

43
Q

Drug regimen in pregnant women.

A

Isoniazid, Rifampin, Ethambutol

44
Q

Four caveats for people with HIV and TB.

A

TB is #1 killer of HIV patients.

  1. Initiate TB treatment first, then HIV.
  2. Avoid weekly INH-rifapentine
  3. Avoid twice weekly INH-rifampin if CD4 less than 100.

Give rifabutinin..

45
Q

What drugs is MDR-TB resistant to?

A

Isoniazid and rifampin.

46
Q

WHO recommendation of MDR-TB treatment.

A

20 months of second line drugs (**fluoroquinolones, ethionamide, aminoglycosides, PAS, ethionamide)

47
Q

What drug is used for MDR-TB that inhibits ATP synthesis in mycobacteria?

A

Bedaquiline.

Inhibits mycobacterial ATP synthase = bacteriCIDAL.

48
Q

Regimen if bedaquline is used.

A

Used in combo with 3 other drugs that the MDR-TB is susceptible to.

MED234 Respiratory (15 decks)

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