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Unit 3 D&D > DD 02-28-14 10-11am Antifungal Agents - French > Flashcards

DD 02-28-14 10-11am Antifungal Agents - French Flashcards

1
Q

Amphotericin B (Fungizone) - Mechanism of Action

A

Binds to ergosterol in fungal cell membrane

  • -> opens pores
  • -> results in leakage of cellular constituents (Na+, K+, and H+ ions) *
  • -> cell death (fungicidal)

-LESS selective toxicity b/c also binds cholesterol components in mammalian cells

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2
Q

Amphotericin B (Fungizone) - Pharmacokinetics

A
  • Poor oral absorption (used IV or topically)
  • Rapidly sequestered in tissues (liver, spleen, lymph nodes, lungs) - slowly released (little to CNS)
  • Slowly excreted by kidney, major route through biliary tract (terminal t1/2 about 15 days)
  • Also as bladder irrigation or intraventricularly / intracisternally / intralumbarly (fungal meningitis)
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3
Q

Amphotericin B (Fungizone) - Spectrum

A

Broad spectrum, in fungal infections including:

  • opportunistic (Candida, Aspergillus)
  • systemic (Histoplasma, Cryptococci, Blastomyces, Coccidioides)
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4
Q

Amphotericin B (Fungizone) - Clinical Uses

A
  • Drug of choice for nearly all life-threatening systemic fungal infections (commonly in immunosuppressed pts such as cancer patient with neutropenia)
  • Often used as initial induction therapy then replaced by newer, less toxic azoles
  • Deep candidiasis, aspergillosis, mucormycosis, cryptococcosis, extracutaneous sporotrichosis
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5
Q

Amphotericin B (Fungizone) - Adverse Rxns

A

VERY TOXIC DRUG!!!

  • Nephrotoxicity = major limiting factor
  • Infusion-related toxicities: Chills, fever, vomiting, rigor, hypotension with IV use
  • Anemia (75%) occurs secondary to bone marrow depression (via decreased erythropoeitin)
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6
Q

Nephrotoxicity w/ Amphotericin B

A
  • Occurs in nearly all patients
  • Attenuated somewhat w/ pretreatment saline infusion

Liposomal preps may reduce renal & infusion toxicities.

  • Lipid vehicle serves as amphotericin reservoir reducing non-specific binding to human cell membranes (in theory)
  • AmBisome, Abelcet
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7
Q

Infusion-related toxicities w/ Amphotericin B

A
  • premedicate w/ acetaminophen/diphenhydramine or administer w/ hydrocortisone
  • meperidine can shorten duration of rigors

Liposomal preps may reduce renal & infusion toxicities.

  • Lipid vehicle serves as amphotericin reservoir reducing non-specific binding to human cell membranes (in theory)
  • AmBisome, Abelcet
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8
Q

Nystatin (Mycostatin)

A
  • Similar to Amphotericin B
  • BUT toxicity limits use to topical treatment of Candidal infections of skin, mucous membranes, and GI tract
  • Safe & effective for this indication
  • No appreciable absorption from GI tract
  • Toxicities limited to mild and transient GI upset
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9
Q

Echinocandins - examples

A

Caspofungin (Cancidas),
Anidulafungin (Eraxis),
Micafungin (Mycamine)

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10
Q

Echinocandins - Mechanism of Action

A
  • Inhibits the synthesis of β (1,3)-D-glucan, an essential component of fungal cell walls
  • -> leads to disruption of cell wall assembly
  • High level of selective toxicity due to absence of these enzymes in mammalian cells
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11
Q

Echinocandins - Pharmacokinetics

A
  • IV infusion
  • Dosage reduction required for pts w/ hepatic insufficiency (NOT for anidulafungin)
  • No dosage reduction required in renal dysfunction
  • Dosage increase may be necessary if pt is also taking inducers of cytochrome P450 (phenytoin, rifampin, carbamazepine, certain HIV drugs)
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12
Q

Echinocandins - Spectrum / Clinical Uses

A
  • Indicated for treatment of invasive aspergillosis in pts refractory / intolerant to other therapies (amphotericin B, itraconazole)
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13
Q

Echinocandins - Adverse Rxns

A

Histamine-mediated symptoms

  • rash
  • facial swelling
  • pruritus

Other effects:

  • fever
  • n/v
  • H/A
  • phlebitis
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14
Q

Types of Azoles

A

Triazoles and Imidazoles

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15
Q

Triazoles - Examples

A

Fluconazole (Diflucan)
Itraconazole (Sporanox)
Voriconazole (Vfend)
Terconazole (Terazole) is topical only

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16
Q

Triazoles - Mechanism of Action

A
  • Highly selective inhibition of fungal cytochrome P450 (14α-demethylase) reducing normal sterol synthesis
    = FUNGISTATIC
  • Greater selectivity for fungal vs mammalian cytochrome enzymes than seen W/ imidazoles (ketoconazole)
  • -> less hepatotoxicity, fewer hepatic enzyme interactions, & wider therapeutic index
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17
Q

Triazole Pharmacokinetics

A
  • Oral bioavailability is 90-99%

- T1/2 of 30-40 hrs allows once daily dosing of each

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18
Q

Triazole Pharmacokinetics - Itraconazole

A
  • absorbed best with food

- eliminated primarily by hepatic metabolism

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19
Q

Triazole Pharmacokinetics - Fluconazole

A
  • cleared primarily by renal excretion of unchanged drug (80%) requiring dosage reduction in impaired renal function
  • can enter CSF for treatment of meningitis
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20
Q

Triazole Clinical Uses - Fluconazole [& Itraconazole]

A
  • Vaginal candidiasis in pts who fail treatment w/ topical agents
  • Oropharyngeal & esophageal candidiasis
  • also used in Itraconazole has potential benefit in treatment of aspergillosis, histoplasmosis, sporotrichosis
  • Agent of choice in dermatophytoses & onychomycosis if systemic therapy chosen
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21
Q

Triazole Clinical Uses - Voriconazole

A
  • new agent
  • useful in serious invasive aspergillosis
  • less toxicity than amphotericin
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22
Q

Triazoles - Adverse Effects

A
  • Reported more frequently in HIV pts
  • Overall very well tolerated
Most common: GI distress most common
Also;
- H/A
- allergic rash
- elevation of liver enzymes
- transient visual changes (voriconazole)
  • No inhibition of mammalian CYP450 steroid biosynthesis
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23
Q

Triazoles - Drug Interactions - Itraconazole & Fluconazole

A
  • Interference w/ drug metabolism by itraconazole is similar to ketoconazole
  • Inhibition by fluconazole somewhat less, but possible
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24
Q

Triazoles - Drug Interactions - Voriconazole

A

Voriconazole levels reduced by CYP450 inducers

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25
Q

Imidazoles - examples

A

Ketoconazole (Nizoral) - systemic (PO, IV) & topical use

Clotrimazole (Lotrimin / Mycelex) - topical only*

Miconazole (Monistat) - topical only*

  • topical only due to extreme systemic toxicity
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26
Q

Imidazoles - Mechanism of Action

A

Inhibits P450-dependent enzyme (14α-demethylase)

  • -> results in decreased levels of ergosterol
  • -> Disruption in synthesis of cell membrane sterols leads to alterations in membrane permeability
  • Fungistatic / Fungicidal depending on concentration
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27
Q

Imidazoles (Only Ketoconazole used systemically) - Pharmacokinetics

A
  • Poorly absorbed, max absorption with low pH
  • Well-distributed, but enters CNS poorly (5%)
  • Crosses placenta & Excreted in breast milk
  • Eliminated by hepatic metabolism (primarily by oxidation)
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28
Q

Imidazoles - Ketoconazole - Clinical Uses

A
  • Decline in systemic use of ketoconazole due to availability of safer agents
  • Chronic mucocutaneous candidiasis & other systemic fungal infections (ketoconazole, oral)
  • less toxic than Amphotericin B but also less effective
  • May antagonize amphotericin effect by preventing synthesis of ergosterol binding targets.
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29
Q

Imidazoles - topical Miconazole & Clotrimazole - Clinical Uses

A
  • Oral & vaginal candidiasis (miconazole / clotrimazole, topically as creams and troches as high systemic toxicity occurs if these agents are given parenterally)
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30
Q

Imidazoles - Ketoconazole (systemic) - Adverse Rxns

A

*Side effect profile leading to decline in use
Most Common: Anorexia, n/v
- tolerance improves by taking w/ food or at bedtime

Pruritus, rash, and dizziness can occur

Hepatotoxicity (usually mild jaundice, can be serious/fatal rarely)
- generally avoid if preexisting liver dysfunction

Avoid in pregnancy (teratogenic in rat)

Can inhibit mammalian testosterone synthesis

  • -> impotence, decreased libido, & gynecomastia
  • due to greater propensity to inhibit mammalian CYP450 than triazole antifungal agents

High doses may also inhibit adrenal steroidogenesis & decrease plasma cortisol concentrations

31
Q

Imidazoles - Ketoconazole - Drug Interaction

A
  • Antacids / Cimetidine: Elevation of pH leads to decreased oral absorption
  • Cyclosporine / Phenytoin / Anticoagulants: Ketoconazole is strong inhibitor of CYP3A4 drug metabolism leading to increased drug effect (or toxicity)
  • Rifampin: Decreases effect of ketoconazole by inducing metabolism
32
Q

Terbinafine (Lamisil)

A

Synthetic allylamine antifungal

33
Q

Terbinafine (Lamisil) - Mechanism of action

A
  • Interferes w/ ergosterol synthesis by inhibiting squalene oxidase
  • Toxic effects also from accumulation of squalene
  • Fungicidal
  • Accumulates in keratin (like griseofulvin)
34
Q

Terbinafine (Lamisil) - Pharmacokinetics / Clinical Uses

A
  • Agent of choice in once daily oral dose for toe / finger nail infections (onychomycosis)
  • Topical for athlete’s foot (tinea cruris, tinea corporis)
35
Q

Terbinafine (Lamisil) - Adverse effects

A
  • GI upset, rash, headache, taste disturbances

- Interference with CYP450 metabolism

36
Q

Flucytosine (Ancobon) - Mechanism of action

A
  • Converted in fungal cell into 5-fluorouracil (via cytosine deaminase)
  • -> interferes w/ DNA synthesis
  • -> leads to cell death

-High selective toxicity (mammalian cells lack deaminase)

37
Q

Flucytosine (Ancobon) - Resistance

A
  • Resistance in fungi that lack cytosine deaminase
38
Q

Flucytosine (Ancobon) - Pharmacokinetics

A
  • Well absorbed after oral administration
  • Given in 4 equally spaced doses
  • Excellent distribution to tissues (including CNS)
  • 90% excreted unchanged in urine
  • Requires decreased dosage if diminished renal function
39
Q

Flucytosine (Ancobon) - Spectrum / Clinical Uses

A

Effective agent, but rarely given alone
- given w/ Amphotericin B due to resistance development

Used for serious infections of cryptococcosis, candidiasis, and chromoblastomycosis

40
Q

Flucytosine (Ancobon) - Adverse Rxns

A

Nausea, vomiting, skin rashes occasionally

Prolonged high levels 
--> bone marrow depression
--> abnormal liver function
--> hair loss.
Probably due to bacterial conversion of flucytosine to 5-FU in intestine
41
Q

Griseofulvin (Fulvicin) - Mechanism of action

A
  • Binds to microtubules inhibiting fungal mitosis & interfering w/ processing of new cell wall components
  • FUNGISTATIC
42
Q

Griseofulvin (Fulvicin) - Pharmacokinetics

A

Poor oral absorption generally

  • can be improved by reducing particle size (microsize/ultramicrosize)
  • can be improved by administration with fatty foods

-Topical use has little effect

  • Little griseofulvin present in body fluids or tissues
  • Excreted chiefly in feces
43
Q

Griseofulvin (Fulvicin) - affects of skin

A

Absorbed drug has affinity for diseased skin

  • binds to keratin
  • -> makes it resistant to fungal growth
  • as keratinized structures shed, tend to be replaced by uninfected ones
44
Q

Griseofulvin (Fulvicin) - Clinical uses

A

Indicated for severe dermatophytosis (superficial) involving:

  • skin and hair (3-6 weeks)
  • fingernails (3-6 months)
  • toenails (6-12 months)

*Infrequently used, replaced by shorter course of therapy with itraconazole or terbinafine (3 months)

45
Q

Griseofulvin (Fulvicin) - Adverse effects

A
  • Hypersensitivity rxns most common (skin rashes, urticaria, angioneurotic edema)
  • Occasionally headache (can be severe), GI distress, mental confusion
46
Q

Pentamidine (Pentam) - Mechanism of Action

A

Inhibits protein and nucleic acid synthesis

47
Q

Pentamidine (Pentam) - Pharmacokinetics

A
  • Usually given IV/IM
  • inhalation can produce higher levels & lower toxicity in treating P. jirovici (carinii) pneumonia (common opportunistic fungal infection in AIDS patients)
48
Q

Pentamidine (Pentam) - Clinical Uses

A
  • Effective against wide variety of protozoa (concentrated in organisms)
  • Agent of choice in treatment of P. jirovici (carinii) pneumonia in AIDS patients (or trimethoprim / sulfamethoxazole [Bactrim])
  • Bactrim preferred for treatment in non-AIDS patients & for prophylaxis in all patients
49
Q

Pentamidine (Pentam) - Adverse Reactions

A
  • Severe toxicities often limit use w/ 50% of patients receiving pentamidine show some adverse effect
  • Leukopenia, hypoglycemia, hypotension (IV use)
  • Nephrotoxicity / hepatotoxicity more common, less severe
50
Q

Background on Fungal Infections

A
  • Uncommon in healthy, immunocompetent individuals w/ exception of mucosal candidiasis & dermatophyte skin infections (e.g., athlete’s foot)
  • Affect 10-20% of population at any given time
  • Account for > 2 million office visits a year
51
Q

Superficial fungal infections - examples

A

[pityriasis versicolor, tinea nigra, black piedra, white piedra]

52
Q

Superficial fungal infections - overview

A
  • Limited to outermost layers of the skin & hair that do not elicit a cellular response from the host
  • Usually produce only cosmetic problems that are easily diagnosed & treated.
53
Q

Superficial fungal infections - treatment

A
  1. Removal from the skin w/ keratolytic agents (selenium, salicylic acid)

AND / OR

  1. Topical azole-antifungal agents
    - ketoconazole (cream-shampoo-gel-foam)
    - miconazole
    - clotrimazole
54
Q

Cutaneous-Mucocutaneous Fungal Infections - 2 types

A

Dermatophytes

Candida (esp. albicans)

55
Q

Dermatophytes (Cutaneous-Mucocutaneous Fungal Infections) - examples

A 
Microsporum
Tricophyton
Epidermophyton, e.g. ...
- tinea corporis (ringworm)
- tinea pedis (Athlete’s Foot)
- tinea cruris (Jock Itch)
- tinea capitis (scalp)
- tricophyton rubrum (nails)
56
Q

Dermatophytes (Cutaneous-Mucocutaneous Fungal Infections) - overview

A
  • Includes infections that are deeper in the epidermis & its integuments, the hair and nails
  • Generally restricted to keratinized layers of integument & its appendages
  • Clinical manifestations of these infections are referred to as ringworm or tinea
57
Q

Dermatophytes (Cutaneous-Mucocutaneous Fungal Infections) - treatment

A
  • Generally conservative w/ use of topical antifungal agents (clotrimazole, miconazole, butenafine, terbinafine)

Hair infections: griseofulvin PO

Nail infections (onychomychosis)

  • Generally requires systemic therapy of 6 wks - 6 mos duration (itraconazole, terbinafine)
  • Topical therapy (ciclopirox) is of low efficacy
  • Fingernail infections will usually always clear
  • Toenail infections respond in ~60-70 % of cases
58
Q

Candida (Cutaneous-Mucocutaneous Fungal Infections) - overview

A
  • esp. albicans
  • Part of normal human flora
  • Includes disease that affect mucosal surfaces of mouth, vagina, esophagus, & bronchial tree
  • Also diseases of skin & nails that mimic dermatophyte infections
59
Q

Candida (Cutaneous-Mucocutaneous Fungal Infections) - treatment

A
  • Topical nystatin, clotrimazole, butoconazole, terconazole for mucocandidiasis
  • Can try fluconazole via systemic (oral) route if no response
60
Q

Subcutaneous Fungal Infections - examples

A

Sporotrichosis
Chromoblastomycosis
*relatively rare

61
Q

Subcutaneous Fungal Infections - Overview

A
  • Infections that involve the dermis, subcutaneous tissues, muscle, & fascia
  • Characterized by development of lesions on skin surface
  • Usually sites of trauma where organism is implanted in tissue
62
Q

Subcutaneous Fungal Infections - Treatment

A
  • Oral itraconazole

- Parenteral amphotericin B (severe systemic infection)

63
Q

Systemic Fungal Infections - Examples

A

Blastomycosis
Coccidioidomycosis
Cryptococcosis
Histoplasmosis

64
Q

Systemic Fungal Infections - Overview

A
  • Infections that originate primarily in lung but may spread to many organ systems
  • Causative organisms are inherently virulent & cause disease in healthy humans
  • Respiratory infections are generally asymptomatic
  • Secondary spread to other organs causes pt to seek medical attention
  • Host’s immune status determines severity of disease, which can be life-threatening in immunocompromised patients if therapy not rapid
65
Q

Systemic Fungal Infections - Treatment

A
  • Long term therapy w/ systemic amphotericin B infusions generally required
66
Q

Systemic Fungal Infections - Treatment of Blastomycosis

A

amphotericin B > itraconazole > voriconazole > fluconazole > ketoconazole

67
Q

Systemic Fungal Infections - Treatment of Coccidiodomycosis

A
  • amphotericin B

- maintenance w/ fluconazole or itraconazole

68
Q

Systemic Fungal Infections - Treatment Cryptococcosis

A

amphotericin B ± flucytosine, fluconazole

69
Q

Systemic Fungal Infections - Treatment of Histoplasmosis

A

amphotericin B

itraconazole 

70
Q

Opportunistic Fungal Infections - Examples

A

Candida albicans
Aspergillus fumigatus
Pneumocystis carinii

71
Q

Opportunistic Fungal Infections - overview

A
  • Host debilitation increases susceptibility to fungal infections
  • Becoming more common & medically significant due to AIDS and increased use of radiation & cytotoxic drug therapy in cancer & transplant patients
72
Q

Opportunistic Fungal Infections - Treatment of Candidiasis (disseminated)

A

fluconazole
micafungin-caspofungin
posaconazole

73
Q

Opportunistic Fungal Infections - Treatment of Aspergillosis

A

amphotericin B
caspofungin
voriconazole
itraconazole

74
Q

Opportunistic Fungal Infections - Treatment of Pneumocystis pneumonia

A

TMP-SMX

pentamidine

Unit 3 D&D (18 decks)

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