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Respiratory II > Anti-TB Drugs > Flashcards

Anti-TB Drugs Flashcards

1
Q

What are the five first line agents agaist TB in order of preference?

A

Isoniazid, Rifampin, Pyrazinamide, Ethambutol, and Streptomycin

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2
Q

What is the MOA of isoniazid (INH)?

A

INH inhibits the synthesis of mycolic acids, which are essential in the cell wall. This is acheived by INH forming a complex with acyl carrier protein and ketoacyl carrier protein synthetase.

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3
Q

What are the four mechanisms of resistance (MOR) to INH?

A
  1. Overexpression of inhA encoding an NADH-dependent acyl carrier protein reductase –> low-level resistance
  2. Mutations or deletions of KatG gene –> high-level resistance
  3. Promoter mutations causing overexpression of ahpC which confers protection from oxidative stress
  4. Mutations of KasA (Ketoacyl protein carrier synthetase)
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4
Q

What are the four major side effects of Isoniazid?

A
  1. Hepatitis. Stop drug immediately. Age-dependent adverse effect. More likely in alcoholics, pregnancy, and post-partum.
  2. Peripheral neuropathy. Most common in slow-acetylators, malnutrition, alcoholics, AIDS, diabetes, and uremia.
  3. CNS toxicity presents with memory loss, psychosis, and seizures.
  4. Drug Induced SLE
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5
Q

What is the MOA of Rifampin?

A

Binds to the beta-subunit of DNA-dependent RNA polymerase inhibiting RNA synthesis. Does not interfere with human RNA synthesis.

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6
Q

What is the MOR of rifampin? Does cross-resistance exist?

A

Point mutations in rpoB gene confer resistance to binding of the beta-subunit of RNA polymerase. This doesn’t confer resistance to other drugs, except rifmycin derivatives.

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7
Q

Aside from mycobacterial infections, what are other indications for the use of rifampin?

A

Meningococcal infections
Deep-seated staphylococcal infections
Prophylaxis of heamophilus type B spread

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8
Q

What are possible adverse effects (6) of rifampin?

A
  1. CYP 450 inducer –> reduced half-lives of many drugs
  2. CYP 450 inducer –> caution in HIV + on anti-retroviral therapy
  3. Harmless red/orange color in the urine, sweat, tears, and saliva
  4. Rash and thrombocytopenia
  5. nephritis
  6. Flu-Like syndrome if poor regimen compliance
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9
Q

What is the MOA of pyrazinamide?

A

Taken up into macrophages and converted to pyrazinoic acid. Some of this is protonated to POAH. Specific mechanism is unknown, but it interferes with transport and cell membrane synthesis.

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10
Q

What are the two MOR for pyrazinamide? Is there cross-resistance?

A
  1. Decreased/impaired uptake of pyrazinamide
  2. Mutation of pncA (mycobacterial pyrazinamidase)

There is no cross-resistance to other TB drugs.

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11
Q

What are the adverse effects (4) of pyrazinamide?

A
  1. Hepatotoxicity (most hepatotoxic 1st line agent)
  2. GI Disturbances
  3. Rash
  4. Hyperuricemia
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12
Q

What is the MOA and associated operon for ethambutol?

A

Ethambutol inhibits arabinosyl transferases. These enzymes participate in the production of arabinoglycan, an integral component of the cell membrane. Arabinosyl transferases are encoded by the ethCAB operon.

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13
Q

What are the two MOR to ethambutol?

A
  1. overexpression of embB

2. mutation of embB

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14
Q

What is the adverse effect and related contraindication for ethambutol?

A

Can cause retrobulbar neuritis manifesting with loss of visual acuity and red/green colorblindness. This is a dose-dependent phenomenon. Due to these sequellae the drug is contraindicated in patients too young to allow visual asses-ment.

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15
Q

What is the MOA for streptomycin?

A

Streptomycin irreversible binds the S12 riboprotein of 30S subunit. However, the mechanism is unclear and the drug poorly penetrates cells.

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16
Q

What are the two MOR for streptomycin? What are the only three species which are susceptible?

A
  1. Mutations of rpsL gene which encodes S12 riboprotein
  2. Mutations of rrs gene, which encodes 16S rRNA. This rRNA modifies the drug binding site.j

M. Tuberculosis, m. Adium complex, m. Kansasii

17
Q

What are the two adverse effects of streptomycin and the related contraindication?

A
  1. Ototoxicity manifesting with hearing loss and vertigo
  2. Hepatotoxicity

Note: Toxicity is dose-dependent

Contraindicated in pregnancy to avoid hearing loss in the newborn.

18
Q

What is the MOA and related first-line agent, if any, of ethionamide?

A

Inhibits mycolic acid synthesis

Similar to Isoniazid

19
Q

What is the MOA and related first-line agent, if any, of capreomycin?

A

Inhibits protein synthesis

similar to streptomycin

20
Q

What is the MOA and related first-line agent, if any, of cycloserine?

A

Inhibitor of cell wall synthesis

similar to isoniazid?

21
Q

What is the MOA and related first-line agent, if any, of aminosalicylic acid (PAS)?

A

Inhibitor of folate synthesis

no related agent

22
Q

What is the MOA and related first-line agent, if any, of kanamycin/amikacin?

A

Inhibit protein synthesis

related to streptomycin

23
Q

What is the MOA and related first-line agent, if any, of fluoroquinolones?

A

Inhibit DNA synthesis

no related agent

24
Q

What is the MOA and related first-line agent, if any, of linezolid?

A

Protein synthesis inhibitor

no related agent?

25
Q

What is the MOA and related first-line agent, if any, of rifabutin/rifapentine?

A

Both are RNA synthesis inhibitors derived from rifampin. They possess similar drug interaction profiles.

Note: Rifapentine is long-acting

26
Q

Describe the reasoning for employing combination therapy in the treatment of TB.

A

1 in 10^6 bacteria are resistant to a single therapy. 1 in 10^12 bacteria are resistant to a dual-therapy. Elimination of infection is most likely with a dual-therapy.

27
Q

What is the most effective therapy for TB treatment? How can this therapy be augmented to shorten duration? What is the four-drug regimen and its clinical purpose?

A

The most effective therapy is the combination of rifampin and INH for 9 months. This can be shortened to 6 months if placed on pyrazinamide for the initial 2 months.

Note: rifampin is the most important drug in anti-TB therapy

Four-drug therapy consists of INH, rifampin, and pyrazinamide along with ethambutol or streptomycin. This is used until drug susceptibility can be determined.

28
Q

How should an INH resistant strain be treated?

A

Treat with rifampin, pyrazinamide, and ethambutol for 6 months

29
Q

how should rifamycin resistance be treated?

A

Treat with isoniazid, ethambutol, and fluorquinolone for 12 months. First 2 months should include pyrazinamide.

30
Q

What is a Multidrug-Resistant TB strain?

A

A strain resistant to atleast rifampin and isoniazid

31
Q

What is an extensively drug-resistant TB strain?

A

A strain resistant to rifampin, isoniazid, a fluorquinolone, and atleast one 2nd line aminoglycoside (capreomycin, amikacin, kanamycin)

32
Q

What is the treatment regimen for individuals with an HIV infection and a latent TB infection (LTBI)?

A

Isoniazid for 9 months

33
Q

What is the treatment regimen for individuals with an HIV infection and an active TB infection? What is the caveat to this regimen?

A

Rifampin, isoniazid, ethambutol, and pyrazinamide .

Patient’s on anti-retroviral therapy must be checked for drug interactions due to the CYP inducing effects of rifamycins.

Note: All HIV patients with active TB should be placed on anti-retroviral therapy

34
Q

Describe the approach to LTBI when prescribing immunomodulators like a TNF-alpha inhibitor.

A

Patients starting on an immunomodulator should be screened for LTBI. If an LTBI is found, immunomodulator should stop immediately and start Anti-TB regimen.

35
Q

How should the treatment approach to TB change for pregnancy in relation to LTBI, active TB, and HIV (+)?

A

LTBI in pregnancy should have treatment delayed until 2-3 months post-partum to avoid hepatotoxicity. Treatment will be the standard care. Active TB or HIV (+) pregnant patients should be started on treatment immediately. Treatment consists of ethambutol, isoniazid, and rifampin.

Note: All pregnant and post-partum women receiving isoniazid and their breastfeeding children should ingest pyridoxine.

36
Q

What drugs should be avoided in treatment of TB during pregnancy due to potential to cause congenital hearing loss?

A

All aminoglycosides: streptomycin, capreomycin, kanamycin, amikacin

Respiratory II (4 decks)

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