Anti-Fungal Therapy Flashcards

1
Q

3 Types of Fungal Infections

A

1) SUPERFICIAL - skin/hair/nails
2) SUBCUTANEOUS - dermis/subcutaneous tissue/adjacent structures
3) SYSTEMIC - internal organs

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2
Q

What is the difference between superficial/subcutaneous and systemic fungal infections?

A

Superficial/subcutaneous - Can occur in healthy individuals
Systemic - Opportunistic fungal infections that occur in diseased/immunocompromised conditions
[HIV epidemic, cancer chemotherapy usage, organ Tx immunosuppressive therapy, autoimmune, widespread usage of antibiotics]

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3
Q

3 Anti-fungal Drug Classifications

A

1) SYSTEMIC (oral/IV)
2) SYSTEMIC drugs for MUCOCUTANEOUS infections
3) TOPICAL drugs

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4
Q

Anti-fungal Drug Targets (unique to fungi and absent in humans)

A

1) CELL WALL
2) CELL MEMBRANE (fungi use ERGOSTEROL instead of cholesterol in human cells)
3) DNA SYNTHESIS

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5
Q

Anti-fungal cell membrane targeting drugs:

A

Amphotericin B (used for systemic fungal infections)
Azoles (Imidazoles [K,C,M] + Triazoles [I,F,V,P])
Allylamines
Nystatin (NOT used for systemic fungal infections)

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6
Q

Anti-fungal cell wall targeting drug

A

Echinocandins (C,A,M)

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7
Q

Anti-fungal DNA synthesis targeting drug

A

Flucytosine

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8
Q

What is the structure of amphotericin B (most commonly used anti-fungal drug) AND nystatin?

A

Macrolide with an AMPHIPATHIC ring structure (hydrophilic + hydrophobic components)

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9
Q

What is the difference in medication usage between amphotericin B and nystatin?

A

Amphotericin B - used for systemic (opportunistic) infections
Nystatin - NOT used for systemic (opportunistic) infections

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10
Q

Mechanism of AMPHOTERICIN B + NYSTATIN

A

Amphipathic molecule:
NONPOLAR side: Binds SELECTIVELY to ergosterol (fungal cell membrane) and not cholesterol
POLAR side: Forms pores for ion efflux leakage -> Kills fungi

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11
Q

Which fungal species display intrinsic amphotericin B resistance?

A

Candida lusitaniae

Pseudallescheria boydii

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12
Q

What is the drug of choice for nearly ALL life-threatening systemic fungal infections?

A

Amphotericin B

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13
Q

Amphotericin B Clinical Usages

A

1) Life-threatening systemic infections - Often used as INITIAL treatment in critical cases -> TRIAZOLES (CHRONIC therapy/Relapse preventions)
2) Topical drops for mycotic corneal ulcer/keratitis
3) Local injection for fungal arthritis

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14
Q

Amphotericin B Administration

A

1) Suspension by IV (in deoxycholate lipophilic soln) - Since amphotericin B is INSOLUBLE in water
2) Oral - Only if it is a GI infection (poor drug absorption)

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15
Q

Preparation for reducing amphotericin B’s high toxicity

A

LIPOSOMAL PREPARATION - drug formulated in a lipid package

Enables higher doses with reduced nephrotoxicity

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16
Q

Most common problematic toxicity of Amphotericin B

A

RENAL DAMAGE (slower toxicity)

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17
Q

Acute (infusion-related) Toxicity of Amphotericin B __

How can this be managed?

A

Fever/chills/vomiting/headache/hypotension
Managed by:
1) Decreasing dose
2) Premedication with antipyretics (oral acetaminophen), antihistamins, meperidine, hydrocortisone

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18
Q

Slower toxicity of Amphotericin B

A

Renal Damage
Anemia
Occasional impaired liver function

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19
Q

Main precautionary element of drug interactions regarding Amphotericin B

A

Avoid administration if other nephrotoxic drugs are being administered as well (cyclosporine + aminoglycosides)

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20
Q

Mechanism of FLUCYTOSINE

A

1) Uptake by fungal cytosine permease
2) Conversion to 5-FU by cytosine deaminase
3) INHIBIT RNA synthesis: 5-FU converted to 5-FUTP
4) INHIBIT DNA synthesis: 5-FU converted to 5-FdUMP -> Inhibits thymidylate synthase

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21
Q

Selectivity of flucytosine: What can flucytosine target that human cells do not have?

A

CYTOSINE DEAMINASE: 5-flucytosine (5-FC)’s conversion to 5-FU by this enzyme
Mammalian cells poorly convert 5-FC to 5-FU

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22
Q

Resistance mechanisms of flucytosine

A

1) Loss of 5-FC permease
2) Loss of 5-FC conversion to 5-FU
3) Loss of 5-FU to 5-FdUMP conversion

23
Q

Does flucytosine have broad spectrum (like amphotericin B) or limited spectrum

A

Limited spectrum - ONLY Candida and Cryptococcus

24
Q

Due to the high resistance against flucytosine (5-FC), how is it often administered to patients? (i.e. what combination therapy is prescribed)

A

Synergistic Effect with AMPHOTERICIN B + ITRACONAZOLE

25
Q

Administration of flucytosine

A

ORAL - rapid absorption from GI

26
Q

Mechanism of flucytosine toxicity

A

Gut bacteria actually convert 5-FC to 5-FU in the intestinal tract

27
Q

Flucytosine Toxicity Effects

A

Decrease in bone marrow function (Leukopenia/thrombocytopenia)
Rash/GI effects

28
Q

Main precautionary element of adminstering FLUCYTOSINE regarding drug interactions

A

Avoid administering flucytosine with drugs that suppress bone marrow

29
Q

2 Subcategories within Anti-fungal azoles

A

1) IMIDAZOLE (2 N’s in 5-member rings)

2) TRIAZOLE (3 N’s in 5-member rings)

30
Q

Diff between Imidazole and Triazole compound AZOLE anti-fungal drugs

A

IMIDAZOLES - first generation, ONLY used topically
(Systemic infn usage is DISCONTINUED due to toxicity)
TRIAZOLE - Later generation, Broader spectrum, Less side effects
Mainly used for systemic infections

31
Q

Which azole sub-class of drugs CAN be used for systemic fungal infections?

A

TRIAZOLE

Not imidazole - due to high toxicity

32
Q

Mechanism of AZOLES

A

NON-COMPETITIVE Inhibition of p450 enzyme lanosterol demethylase (ERG11) -> BLOCKS ergosterol biosynthesis ->
RESULT 1: Limit important fungal membrane component -> Weaken membrane structure
RESULT 2: Accumulation of TOXIC methylsterols -> Bind and Inhibit membrane Enz

33
Q

Mechanisms of AZOLE drug resistance:

A

1) PUMP overexpression - increased drug efflux
2) Target alteration/overexpression - e.g. reduced drug binding capacity
3) Downstream enzyme of ergosterol biosynthesis (ERG3) LOF

34
Q

Selectivity of AZOLE drugs for targeting fungi rather than humans

A

Azoles bind specifically to fungal p450 enzymes (ERG) rather than mammalian p450s -> target egolesterol biosynthesis

35
Q

Are azole drugs Broad spectrum (like amphotericin B) or Limited spectrum (like flucytosine)

A

BROAD

36
Q

Precautionary element with administering AZOLE drugs regarding drug interactions

A

Avoid administering azole drugs with other drugs that get metabolized through p450 (cyclosporine, warfarin, buspirone, dihydropyridine)

37
Q

3 IMIDAZOLE DRUGS

A

Ketoconazole - first ORAL but has been replaced by triazoles
Miconazole - ONLY TOPICAL
Clotrimazole - ONLY TOPICAL

“KETO, MICO, CLOT”

38
Q

What is the most potent azole drug (Triazole)?

A

Itraconazole

“IT”

39
Q

Administration of Itraconazole

Toxicity of Itraconazole

A

ORAL

GI distress + TERATOGEN

40
Q

Precautionary elements when administering itraconazole regarding drug interactions

A

1) Avoid with H2 and proton pump inhibitors that would DECREASE gastric acidity -> since this drug’s oral absorption is INCREASED by gastric acidity
2) Avoid with other drugs that require liver p450 enzymes for metabolism (cyclosporine, warfarin, etc)

41
Q

3 TRIAZOLE DRUGS

A

Itraconazole
Fluconazole
Voriconazole
Posaconazole - BROADEST SPECTRUM

42
Q

Main advantages of FLUCONAZOLE

A

Oral adminstration with NO problem of gastric acidity

LEAST effects with p450 microsomal enzymes (less drug interactions)

43
Q

Which triazole drug has the broadest spectrum?

A

Posaconazole

44
Q

3 Echinocandin Drugs

A

Capsofungin
Anidulafungin
Micafungin

45
Q

Structure of echinocandins

A

Water-soluble Lipopeptide derivative of Pneumocandin B

46
Q

Mechanism of CAPSOFUNGIN (echinocandin)

A

BINDS and INHIBITS beta (1,3) - glucan synthase (FKS1) -

Membrane enz used to make carbohydrate component of fungal cell wall necessary for viability

47
Q

What fungal infections (2) is CAPSOFUNGIN primarily used for?

A

1) CANDIDA

2) Invasive ASPERGILLOSIS when amphotericin B did not work

48
Q

Mechanism of resistance for CAPSOFUNGIN (although it’s highly selective)

A

Mutation in FKS1

49
Q

Synthetic ALLYLAMINE (anti-fungal cell membrane targeting) for MUCOCUTANEOUS infections

A

Terbinafine

50
Q

Mechanism of TERBINAFINE (allylamine)

A

Inhibits SQUALENE EPOXIDASE (ERG1) -> Blocks FIRST STEP of ergosterol biosynthesis
Similar mechanism to azole’s inhibition of downstream ERG11 -> Blocks ergosterol biosynthesis -> Accumulate toxic methylsterols + weaken fungal cell membrane

51
Q

What class of drugs is TERBINAFINE (alyllamine) synergistic with?

A

TRIAZOLE drugs (block a different ERG enzyme of the same biosynthetic pathway for ergosterol synthesis)

52
Q

TOPICAL anti-fungal drugs

A

1) Nystatin - mainly used for Candida infections
2) Terbinafine - mainly used against dermatophyte-caused tinea
3) Clotrimazole + Miconazole - mainly for dermatophyte infections

53
Q

Fungi that are known to cause diseases in humans

A

Mycoses