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PoD Exam 3 > Antifungals > Flashcards

Antifungals Flashcards

1
Q

Why are we seeing an increase in fungal infections?

A

ABX therapies, especially broad spectrum are opening the doors for fungal superinfections;
Also, predisposing procedures, treatments, and diseases (AIDS, Leukemia)

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2
Q

Why do we see a lot less antifungal drugs as compared to antibacterials?

A

Fungi are eukaryotes, so there are fewer exploitable differences.

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3
Q

What is an area frequently targeted by antifungals and why?

A

Cell wall; contains chitin and ergosterol which are different than human eukaryotic cells

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4
Q

What is the MOA of Amphotericin B?

A

It binds sterols (ergosterol) in fungal plasma membrane, making it more leaky, which allows K+ etc to leak–> leads to lysis and cell death

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5
Q

Is Amphotericin B fungicidal or fungistatic?

A

At low concentrations, Ampho B is FUNGISTATIC, but at high concentrations, it is FUNGICIDAL.

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6
Q

What is the distribution for Amphotericin B?

A

Poor CSF distribution unless given intrathecally.

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7
Q

What is the MAIN toxicity for Amphotericin B?

A

NEPHROTOXICITY
Up to ~80% patients
Usually reversible

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8
Q

How does Amphotericin B cause its main toxicity?

A

NEPHROTOXICITY
Directly causes afferent renal arteriole vasoconstriction, which decreases glomerular filtrations and decreases renal tubular blood flow.
K+, HCO3-, Mg2+ urine concentrations change (wasting) and decrease in erythropoietin occurs

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9
Q

What are other ADR to Amphotericin B?

A
  1. Anemia (due to decrease in erythropoietin afffecting RBC production)
  2. Electrolyte imbalance (K+ or Mg 2+ loss due to renal effects
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10
Q

Is Amphotericin B absorbed orally?

A

No.

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11
Q

What are the adverse effects to Amphotericin B infusion?

A

Shaking, Chills, fever, myalgia, and arthralgia

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12
Q

How can you reduce the ADR of Amphotericin B infusion?

A

By premedicating with NSAIDS, acetominophen, antihistamines, or meperidine (a narcotic) (for severe pain)

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13
Q

What is Spectrum of Activity for Amphotericin B?

A
  1. Aspergillosis
  2. Paracoccidioidomycosis
  3. Histoplasmosis
  4. Cryptococcus
  5. Blastomycosis
  6. Candida (when used topically)
  7. Coccidioidomycosis
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14
Q

What are the lipid formulations of Amphotericin B?

A

Ampho B Lipid Complex
Ampho B Colloidal Dispersion
Liposomal Ampho B

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15
Q

Why use a lipid formulation of Amphotericin B?

A

ABLC can be used in patients with aspergillosis who can’t tolerate conventional Ampho B.
With all three, there is less nephrotoxicity associated, but still as effective treatment.

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16
Q

Why might lipid formulations of Amphotericin B need higher doses than conventional?

A

Lipid forms are more likely to get stored in spleen/liver/lungs, etc., so won’t have as high of blood levels.

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17
Q

What is the MOA of Flucytosine (5-fluorocytosine)?

A

Flucytosine is an antimetabolite (inhibits pyrimidine metabolism).
It is converted to 5-fluorouracil by fungus-specific enzyme cytosine deaminase, which then interferes with DNA, RNA, and protein synthesis.

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18
Q

What is the distribution of Flucytosine?

A

Great CSF penetration! 60-100% penetration!

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19
Q

What are the adverse effects of Flucytosine?

A

Bone marrow depression, anemia, thrombocytopenia (more common in prolonged therapy or when in combo with Ampho B)
Elevated serum liver enzymes in about 5% pt (MONITOR IN PT)

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20
Q

What can Flucytosine be used to treat?

A
  1. Serious infections of candida and cryptococcus

2. Cryptococcal meningitis in AIDS patients (in combo with Ampho B)

21
Q

What is a concern when Flucytosine is used alone?

A

Resistance* (combination therapy is recommended)

22
Q

What are the two different types of Azoles?

A

Imidazoles (2 N in ring)

Triazoles (3 N in ring)

23
Q

What is the MOA of Azoles?

A

AFFECT CELL MEMBRANE STRUCTURE
by interfering with the fungal cytochrome P450 dependent enxyme that is responsible for demethylation of lanosterol and its conversion to ergosterol (the main sterol of fungal cell membrane)

24
Q

Can Azoles interfere with host metabolism?

A

Yes, because the fungal and mammalian are similar, BUT triazoles are a little better by having an increased affinity for fungal CYPs over mammalian.

25
Q

Are Azoles fungistatic or fungicidal?

A

They are either depending on concentration (like Ampho B)

26
Q

What are the adverse effects for Azoles?

A
  1. Nausea/Vomitting
  2. Dose-dependent depression of testosterone and ACTH [ketoconazole is used in Cushing’s syndrome]
  3. Hepatitis (RARE)
  4. Increased aminotransferases (NOT RARE)–transient, monitor LFTs
27
Q

What drug interaction occurs between Antacids, PPIs, & H2 antagonists and Azoles?

A

These drugs decrease acidity of stomach, leading to decreased absorption of Azoles.

28
Q

What Azoles are not affected by the drug interaction with Antacids, PPIs, and & H2 antagonists?

A

Voriconazole** and Fluconazole!**

29
Q

What drug interactions occur between Cyclosporine and Azoles?

A

Increased concentration of Cyclosporine, because of decreased metabolism from Azole interference with CYP450.

30
Q

What drug interactions occur between Warfarin and Azoles?

A

Increased anticoagulation effect because of build up of warfarin from decreased metabolism due to Azole interference with CYP450.

31
Q

What are the individual Imidazoles?

A
  1. Ketoconazole

2. Miconazole

32
Q

What are the individual Triazoles?

A
  1. Fluconazole
  2. Itraconazole
  3. Voriconazole
  4. Posaconazole
33
Q

What is the absorption of Ketoconazole?

A

Rapidly absorbed from GI tract

pH dependent bioavailability (if pH is increased, absorption is decreased)

34
Q

What is the spectrum of activity for Ketoconazole?

A 
(Largely replaced by itraconazole these days)
HBCCTV
1. Histoplasmosis
2. Blastomycosis
3. Coccidiomycosis
4. Candidiasis
5. Tinea
6. Vulvovaginal candidiasis
35
Q

What is the absorption of Fluconazole?

A

Rapidly absorbed from GI tract
F > 90% which is awesome
and Oral dosing has same bioavailability as IV

36
Q

Is Fluconazole affected by stomach pH or food?

A

No! (That’s why antacids, etc don’t interact)

37
Q

How is Fluconazole distributed?

A

Well distributed! Even into the CSF! (50-94% plasma)

38
Q

How is Fluconazole eliminated?

A

Renally, it is excreted 60-80% unchanged in urine

39
Q

What does Fluconazole treat?

A
  1. Cryptococcal infections (especially meningitis) FLUCONAZOLE IS DRUG OF CHOICE FOR CRYPTOCOCCAL MENINGITIS
  2. Coccidioidomycosis (pulmonary or disseminated)
  3. Candidiasis (oropharyngeal, esophageal, systemic–C. glabrata [Torulopsis] and C. krusel RESISTANT though)
  4. Prophylaxis of candidiasis
40
Q

How is Itraconazole distributed?

A

Wide distribution, but poorly distributed into CSF

41
Q

What advantage can Itraconazole have over Ampho B?

A

It can be given orally (useful in histo/blasto)and with less adverse effects and is used quite a bit (but Ampho B should still be used if life-threatening and then switched after clinical improvement)

42
Q

What does Itraconazole treat?

A
  1. Aspergillosis**
  2. Cryptococcal infections
  3. Coccidiomycosis
  4. Hisoplasmosis
  5. Blastomycosis
  6. Sporotrichosis
  7. Dermatophytosis
  8. Tinea unguium (onychomycosis)
43
Q

What is absorption for Voriconazole?

A

Absorption is decreased by high fat meals

But otherwise, great bioavailability (96%!)

44
Q

How is Voriconazole eliminated?

A

Eliminated by liver

Half life is about 6 hours

45
Q

Why does Voriconazole cause drug interaction?

A

Voriconazole interferes with several (especially important) CYP450s, particularly CYP4503A4 (metabs ~50% all drugs undergoing metab) (affects statin, cyclosporine)

46
Q

When is Voriconazole contraindicated?

A 
With Rifampin (increases CYP450 activity  so Voriconazole is too rapidly cleared)
With Sirolimus and Quinidine (Voriconazole increases these drugs' concentrations in the body, by reducing CYP450 metab)
47
Q

What are the adverse effects of Voriconazole?

A
  1. VIsual disturbances* – blurred vision, color changes in about 30% of pt)
  2. Rash (~6% pt)
  3. Increased LFTs (~13% pt)
48
Q

What is Voriconazole used for?

A
  1. Invasive Aspergillosis
  2. Candidiasis
  3. May also be used in patients with therapy-limiting toxicity associated with conventional regimens

PoD Exam 3 (2 decks)

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