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Pharm > Antifungal drugs > Flashcards

Antifungal drugs Flashcards

1
Q

Amphotericin B, a polyenes used to treat systemic antifungal infections, what makes it so good and what makes it so bad?

A

good: broadest spectrum
bad: significant adverse side effects
(there are newer liposomal formulations associated with increased efficacy and decreased toxicity)

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2
Q

How is amphotericin given, what is its mechanism of action?

A

IV

  1. binds to ergosterol in fungal membrane
  2. forms pore in the membrane thereby increasing membrane permeability
  3. efflux of essential molecules
  4. fungal death
    - binds only weakly to cholesterol
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3
Q

What is amphotericin B not active against?

A
  1. Candida Lusitaniae

2. Pseudallescheria boydii (scedosporium apiospermum)

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4
Q

When is amphotericin used?

A

initial induction therapy (usually 4 weeks) to reduce fungal burden, then replaced by newer less toxic AZOLE drugs for consolidation therapy and prevention of relapse

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5
Q

What is the ONLY antifungal agent that is approved in pregnant/ breast feeding women?

A

Amphotericin

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6
Q

What is amphotericin the treatment of choice for?

A

Zygomycosis/mucormycosis

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7
Q

What are the adverse infusion related effects for amphotericin a drug with a low therapeutic index ?

A
  1. infusion related
    - fever, chills, muscle spasms, vomiting, headache and hypotension
    a. slow rate/decrease dose
    b. preemptive meds like antipyretic,antihistamine, corticosteroids
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8
Q

What are the cumulative toxicities of amphotericin B?

A
  1. nephrotoxicity
    a. reversible-decreased renal perfusion via vasoconstriction
    - reduce by using saline drip (Na loading)
    b. non reversible
    - renal tubular injury(prolonged administration)
    - tubular acidosis and severe K+ and Mg2+ wasting
    - more common in presence of diuretics or other nephrotoxic meds eg. aminoglycosides/cyclosporine
  2. hepatotoxicity (occasional)
  3. anemia
    - reversible suppression of erythrocyte production due to decreased EPO
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9
Q

What are the bad parts of flucytosine and the good part?

A

bad:

  1. narrow spectrum of activity
  2. use is restricted by high incidence of resistance
    - mutations in cytosine permease, cytosine deaminase, uracil phosphoribosyl transferase or increase in cytosine synthesis

good:
good penetration into the CSF
-used for cryptococcal meningitis

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10
Q

Is flucytosine used alone?

A

no typically in combination with other antifungal drugs

  • especially ampho B and an azole
  • ampho enhances flucytosine permeability
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11
Q

How is flucytosine eliminated?

A

renally-dosage adjustment required in presence of renal insufficiency

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12
Q

What is the mechanism of action of flucytosine?

A
  1. taken up via cytosine permease
  2. fungal specific cytosine deaminase –>5 fluorouracil
  3. inhibits both DNA(thymidylate synthase) and RNA synthesis
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13
Q

What does flucytosine+amphotericin B treat?

A

cryptococcosis and candidiasis

-cryptococcal meningitis (good CSF penetration of flucytosine and ampho b enhances fungal uptake of flucytosine)

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14
Q

What does flucytosine + itraconazole treat?

A

chromoblastomycosis

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15
Q

What are the adverse effects of flucytosine?

A
  1. endogenous gut microflora express cytosine deaminase –>5 fluorouracil (antimetabolite)–>toxicity
  • GI: nausea, vomiting diarrhea
  • Bone marrow toxicity: anemia, leukopenia, thrombocytopenia

Tetratogenic

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16
Q

What is the prototype imidazole?

A

ketoconazole

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17
Q

What is the order of spectrum of activity for the triazoles?

A

Fluconazole

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18
Q

What is the mechanism of action of azoles?

A

Azoles are fungistatic/fungicidal

  1. Inhibit 14 alpha demethylase (CYP45) involved in biosynthesis of ergosterol from lanosterol
    - impairs membrane function
    - increases membrane permeability
    - decreases activity of membrane associated proteins
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19
Q

What are the common adverse side effects of all azoles?

A
  1. GI distress
  2. Hepatotoxicity-requires hepatic enzyme monitoring
  3. fetal abnormalities
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20
Q

When should itraconazole and voriconazole never be given to a patient?

A

when the patient is taking statins due to increased risk of developing rhabdomyolysis

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21
Q

What azoles have good CNS penetration?

A

fluconazole and voriconazole

22
Q

What azole needs real adjustment?

A

Fluconazole

23
Q

What limits ketoconazole use?

A
  • oral ketoconazole requires acidic environment for absorption
  • poor penetration into CSF and urine
  • many adverse effects due to inhibition of CYP450 enzymes involved in adrenal and gonadal steroid synthesis
  • ->decreased cortisol and decreased testosterone
  • –>gynecomastia, libido, impotence, menstrual irregularities, hypotension and fatigue

-many drug interactions of CYP450 3A4

  • rarely used now, largely replaced by itraconazole
  • still used topically to treat dermatophyte infections
24
Q

What is the spectrum of activity fluconazole?

A

Narrowest spectrum of activity of all azole drugs but

  • good oral bioavailability and EXCELLENT penetration into the CSF
  • fewest drug interactions of all azoles
25
Q

Does fluconazole have many adverse effects?

A

no only minor effects: nausea, headache, skin rash and GI, and alopecia (reversible, long/high dose)

26
Q

How is fluconazole eliminated?

A

80% of drug eliminated unchanged in the urine

-useful in treatment of fungal BLADDER infections

27
Q

What does fluconazole used to treat?

A
  1. Candida
    - mucocutaneous candids
    - poor activity toward C. glabrata and no activity against C. krusei
  2. TREATMENT OF CHOICE
    for cryptococcal meningitis
    -used as consolidation/maintenance therapy with ampho b/flucytosine
  3. good activity against coccidioides
  4. variable activity against endemic dimorphic fungi
    - less active than itraconazole against histoplasmosis, balstoplsmisis, sporotrichosis
    - only used if itraconazole not well tolerated
  5. dermatophytes
28
Q

What is fluconazole the therapy of choice for?

A
  1. Cryptococcal meningitis

2. coccidioidal meningitis

29
Q

What should itraconazole not be used for?

A
  • meningitis

- bladder infections

30
Q

HOw is the spectrum of activity of itraconazole vs. fluconazole?

A

broader spectrum but more adverse effects and many potential drug interactions

31
Q

What are the clinical uses of itraconazole?

A
  1. oral treatment of dermatophytes
  2. oral treatment of onychomycosis
  3. preferred agent for non-meningeal blastomyces/histoplasma/coccidioides
  4. effective against candida
    - but more adverse effects than fluconazole
  5. active against aspergillus
    - less effective than voriconazole
32
Q

What are the adverse effects of itraconazole?

A

Triad

  1. Hypertension
  2. Hypokalemia
  3. Peripheral edema

Can cause CHF in patients with ventricular dysfunction
-not be used if history of ventricular dysfunction or CHF

33
Q

What is the spectrum of voriconazole?

A

newer extended spectrum azole
-distributed into CSF (absorption inhibited by fatty meals, bioavailability is unpredictable and affected by genetic polymorphisms)

  • less toxic than ampho b but has unique side effects
  • non linear dosing
  • inhibitor of CYP2C19, 2c9, 3a4
34
Q

What is the spectrum of activity for voriconazole?

A
  1. Excellent activity against candida
    - even C. Glabrata and C. krusei
  2. good activity against dimorphic fungal infections
    - blastomycosis, histoplasmosis, sporothrix, coccidioidomycosis
  3. effective against pseudoallerischerideri boydii/scedosporium
  4. enhanced activity against aspergillus and fusarium
    - treatment choice for aspergillus
35
Q

What is voriconazole the drug of choice for?

A

Invasive aspergillus/fusarium

36
Q

What the side effects to voriconazole?

A
  1. periostitis (bone pain-associated with long term therapy)
    - inflammation of the periosteum
  2. transient vision changes-visual blurring
    - flashes of light
    - changes in color vision
    - -affects 30% of patients
    - -seen after first dose/diminishes with time
  3. photosensitivity/rash-rarely Stevens Johnson syndrome

associated with high concentrations >5.5

  1. visual/auditory hallucinations
  2. seizures
37
Q

Posaconazole is the newest azole what is its spectrum of azole family?

A

broadest spectrum

-maybe poor penetration to CSF and urine

38
Q

What is posaconazole used for?

A
  1. treatment of invasive fungal infections
    - candida and aspergillus
  2. antifungal prophylaxis in neutropenia
  3. salvage therapy for mucormycosis
    * *****only azole effective against zygomycosis/mucormycosis
39
Q

How do echinocandins work?

A

cidal
-competitively inhibit B 9(1-3) D glucan synthase complex involved in biosynthesis of the principal building block of the fungal wall

  • impairs structural integrity of fungal wall
  • increases osmotic instability leading to cell wall death
40
Q

Does echinocandins penetrate the CSF do they inhibit CYP450?

A

no

41
Q

What is the spectrum of activity for echinocandins?

A
  1. Candida (including glabrata and krusei)
    - fungicidal with minimal effects
  2. aspergillus
    - used in salvage therapy for invasive aspergillosis that fail initial treatment with ampho b or voriconazole

-NO Significant activity toward cryptococcus or dimorphic fungi

42
Q

What are systemic antifungal drugs for cutaneous infections?

A

griseofulvin and terbinafine

43
Q

What does grisoefulvin treat?

A 
mycotic infections of skin, nail, and hair due to:
dermatophytes
-microsporum
-epidermophyton
-trichophyton

no activity against any other fungi

44
Q

What are the side effects of griseofulvin?

A
  1. nervous system; headache, lethargy, vertigo and blurred vision
  2. skin: urticaria, photosensitivity, rash and skin eruptions
  3. hepatotoxicity (rare)
  4. leukopenia, neutropenia and monocytosis (rare)
  5. fetal abnormalities

-inducer of CYP450

45
Q

What is the mechanism of action of griseofulvin? IS it static or cidal

A

static
-binds to fungal microtubules preventing the formation of mitotic spindles inhibiting fungal mitosis

-treatment needs to be continued until affected tissue is completely replaced by new tissue

46
Q

Terbinafine an oral antifungal agent deposits where? What is its activity and clinical use?

A

deposits in the skin, nail hair and fat

  • activity is limited to dermatophytes and candida albicans
  • cure rate is 90% effective-MORE effective than griseofulvin or itraconazole!
47
Q

What is the mechanism of action of terbinafine?

A

inhibition of fungal squalene epoxidase

  1. increased squalene–>toxic products
  2. impaired fungal membrane function
48
Q

What is nystatin? What is its MOA? What does it treat?

A

topical antifungal

  • similar to Amho B-binds to ergosterol and forms pores in the fungal membrane
  • -to toxic for IV administration
  • not significantly absorbed from sin, mucus membrane or GI tract
  • NOT active against dermatophytes
  • used in the treatment of oral candidiasis (swish and swallow)
49
Q

What are the topical azoles?

A

clotrimazole, miconazole, terconazole

creams, lozenges, suppositories
treat:
1. oral and vulvovaginal candidiasis
2. dermatophyte infections

50
Q

What are topical allylamines and benzylamines? WHat is the MOA?

A
  1. Allylamines-terbinafine and naftifine
  2. Benzylamines-butenafine

act like terbinafine to inhibit squalene epoxidase

  • spectrum of activity limited to
    1. candida albicans
    2. dermatophytes

-used in the treatment of tinea cruris, tinea corporis, and tinea pedis

Pharm (36 decks)

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