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Pharmacology > Antifungal Drugs > Flashcards

Antifungal Drugs Flashcards

1
Q

What is the MOA of the azole drugs? How is CYP450 involved? CYP3A4?

A
  • Avidly combine with P450 (14-alpha demethylase) and inhibit oxidative removal of C-32 of lanosterol, causing depletion of ergosterol and accumulation of 14-methylsterols in fungal membrane
  • This change in sterol composition disrupts membrane function -> growth inhibition and death of fungal cells
  • All of these drugs are capable of inhibiting CYP3A4, the major metabolic pathway for prescription medications, so these drugs can inhibit concurrent medications (concerns about effects on hepatic metabolism not paramount)
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1
Q

What are the AE’s associated with Terbinafine?

A
  • No effects on CYP activity
  • Generally well tolerated
  • Transient lymphopenia and neutropenia with oral drug
    1. Avoid in immunosuppressed patients (opportunistic infections)
    2. Routine CBC’s
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2
Q

What are the basic characteristics of the echocandins?

A
  • Drug names end in fungin
  • Inhibit beta-1,3 glucan synthesis, leading to loss of fungal cell membrane structure and integrity
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2
Q

What are the two topical azoles? Briefly describe their use.

A
  • Clotrimazole and miconazole
  • Candidiasis (oropharyngeal, mucocutaneous, vulvovaginal)
  • Available OTC (pleasant tasting oral clotrimazole an alternative to Nystatin)
  • Negligible absorption; rare adverse effects
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2
Q

What is a common mechanism of resistance to Terbinafine?

A

Efflux

MOA: ergosterol synthesis (squalene epoxidase)

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3
Q

Why has the FDA moved to limit widespread use of Ketoconazole?

A
  • Produces hepatic damage that is sometimes irreversible, is strongly associated with cardiac arrythmogenic events, and can also cause adrenal insufficiency (not cause by the other azoles)
  • At higher doses than those required for antifungal use, KETO inhibits synthesis of adrenal steroids, leading to reduction in aldosterone, cortisol, and testosterone (via 3 enzymes: chol side chain cleavage enzyme, 17-alpha-hydroxylase, and 17,20-lyase)
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4
Q

Describe the MOA, AE’s, and administation of Caspofungin and Micofungin.

A
  • Beta-1,3 glucan synthesis inhibitors; cell wall disruption
  • Used IV against Aspergillus and Candida sp.
  • Very well tolerated if used alone
    1. Minor GI upset
    2. Infusion reaction; chills, fever, flushing, headache
    3. Rare elevation of hepatic enzyme levels
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4
Q

What are the pregnancy and cardiac implications with azole use?

A
  • FLU and VORI should be both be avoided in pregnancy (cat. D); the others are labeled as category C
  • FLU, POSA, and VORI prolong QT (associated with a pro-arrythmogenic event; can facilitate arrythmias in presence of concurrent cardio active drugs, particularly because they may have an impact the metabolism of these other drugs via CYP3A4)
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4
Q

What are some common mechanisms of resistance to KETO, FLU, and Itraconazole?

A

Efflux, demethylase alteration, bypass, overproduction

MOA: ergosterol synthesis (demethylase)

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6
Q

List some risk factors for fungal infections in the ICU.

A
  • Chemotherapy
  • Renal replacement therapy
  • Malnutrition
  • Comorbid diabetes
  • Total perenteral nutrition
  • Corticosteroids
  • Immunosuppression
  • Surgery
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6
Q

What is a mechanism of resistance to Nystatin and Amphotericin B?

A

Sterol modification

MOA: cytoplasmic membrane pores

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7
Q

What are the three general categories of MOA for antifungals? Which is most common?

A
  1. Alteration in cell membrane function
  2. Mitotic spindle inhibition
  3. Antimetabolite
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9
Q

Describe the MOA of Amphotericin B? This drug is first-line therapy for which infections?

A
  • Amphipathic molecule (double-bond rich, hydrophobic side and hydroxyl rich, hydrophilic side) administered IV, binds membrane ergosterol, forms pores in membrane
    1. Organ-specific toxicity for kidney (80% of pts) b/c also binding to human membrane sterols: azotemia (elevated BUN and serum creatinine), renal failure, and hypokalemia
  • Sporotrichosis, histoplasmosis, cryptococcus, blastomycosis (severe), mucormycosis (in combo for all except this one)
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10
Q

What are the common AE’s associated with Flucytosine?

A
  • Good oral absorption and extensive distribution
  • Renal elimination: toxicity increased in renal impairment
  • Hematologic toxicities: anemia, leukopenia, and thrombocytopenia
  • Cell-cycle INH in normally dividing cells populations, i.e., GI
  • Temporary elevation of hepatic enzymes
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11
Q

Are there any drugs comparable to Amphotericin B?

A
  • Nystatin; comparable amphipathic structure, and works in identical manner
  • Toxicity prevents systemic administration
  • Major difference: TOPICAL administration (esp. for candidiasis)
    1. Mucocutaneous, oropharyngeal (thrush), and vulvovaginal
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12
Q

What is the “solution” for Amphotericin B renal toxicity?

A
  • 3 drug products formulate the drug in a lipid milieu (AmBisome spheres, Amphotec discs, and Abelcet ribbons)
  • Some successing in reducing, but not eliminating, renal toxicity
  • Dramatically increased cost, so pts typically receive Amphotericin B unless contraindicated
13
Q

What is the source of the azole name? What are the two categories?

A
  • Azole ring substituent
  • Imidazoles: 2 nitrogens in the azole ring (of those discussed, only Ketoconazole)
  • Triazoles: 3 Ns
15
Q

Why are antifungal drugs increasingly important to the practice of medicine?

A

Large number of patients who through disease,or drug therapy, are immunocompromised, and are therefore less capable of withstanding endemic fungi

17
Q

Explain some of the differences in solubility, absoprtion, CSF penetration, excretion and side effects for the azoles.

A
  • Solubility: FLU and VORI highest
  • Absorption: FLU, VORI, and POSA high oral absorption
  • CSF penetration: poor for KETO and ITRA
  • All excreted through liver, except FLU (renal; urine)
  • Side effects: all orally admin azoles produce symptoms of GI discomfort (pain, constipation, diarrhea, N/V, etc.), but highest incidence with POSA and ITRA
18
Q

What is a mechanism of resistance to Caspofungin and Micafungin?

A

Altered synthetase

MOA: glucan synthesis (glucan synthetase)

20
Q

What are the common AE’s for Amphotericin B (in both its standard and lipid packaging forms)?

A
  • Immediate: infusion-related reactions (fever, chills, muscle spasms, vomiting, headache, hypotension)
    1. Premedicate: antipyretics, antihistamines, corticosteroids; test dose often to gauge patient response
  • Delayed: renal toxicity (may necessitate dialysis)
    1. Anemia (loss of erythropoietin production by kidney that maintains RBCs)
    2. Abnormal liver function tests (resolve on cessation of drug treatment)
    3. Seizures following intrathecal (inside sheath, i.e., arachnoid membrane) administration
    4. Sodium loading often used to reduce pre-renal toxicity (decreased renal perfusion)
21
Q

What is the MOA of Flucytosine?

A
  • 5-FC: pyrimidine analog with narrow therapeutic window
  • Enters fungal cell via cytosine permease enzyme, converted to 5-FU (NOT possible in human cells), and becomes incorporated into intermediary metabolism
    1. FdUMP and FUTP inhibit DNA and RNA synthesis, respectively
23
Q

What is a mechanism of resistance to Flucytosine?

A

Permease or modifying enzymes mutation

MOA: DNA synthesis, RNA transcription

24
Q

What is the MOA of terbinafine? What other class of antifungal drugs acts on this same pathway?

A
  • Blocks the conversion of squalene to squalene epoxide, causing an interruption in manufacturing of important cell membrane components, and leading to an accumulation of squalene (which is toxic)
  • The azoles act in the same pathway (preventing cell membrane synthesis at a later step)
25
Q

Briefly characterize each of the azoles.

A
  • KETO: systemic use now discouraged by FDA due to hepatic toxicity and CYP drug interactions
  • ITRA: poor penetration of CSF; new formulations overcome poor oral bioavailability
  • FLU: good oral bioavailability and CSF penetration; best tolerance - WIDEST THERAPEUTIC INDEX
  • POSA: orally admin, CYP-mediated drug-drug interactions; only azole w/activity against mucormycosis (an opportunistic infection of vascular occlusion)
  • VORI: good oral bioavailability, clinically relevant INH of CYP3A4 (drug-drug interaxns, esp. w/Cyclosporine and Tacrolimus)
    1. But, VORI associated with photosensitive dermatitis, elevated liver enzymes, temporary visual disturbances upon IV admin, and neurologic symptoms, like hallucinations
26
Q

Describe Grisefulvin (MOA, clinical utility, AE’s).

A
  • Limited clinical utility; systemic treatment of dermatophytosis (severe fungal skin infections, onchomycoses, and tinea
    1. Poor penetration topically, largely replaced by terbinafine
  • MOA: mitotic spindle inhibitor (cell-cycle inhibitor that works in cell nucleus)
  • CYP3A4 inducer, producing drug-drug interaxns with reduced clinical activity of: Warfarin, oral contraceptives, Cyclosporine, and others
27
Q

What are fungi and where are they found?

A

Eukaryotes found almost exclusively in soil, water, or on plants

28
Q

What are conidia? What about spores?

A

Conidia: asexual reproductive elements

Spores: sexual reproductive elements

29
Q

What two differences between animal and fungi cells are exploited for medical use?

A
  • Fungi have rigid cell wall with chitin that can be visualized with 10% KOH treatment of infected tissue
  • Instead of cholesterol, fungal membranes contain erosterol, a target for several anti-fungal drugs
30
Q

What are the two basic morphological forms of fungi?

A
  1. Yeasts: single cells
  2. Molds: multi-cellular
    a. Develop tube-like extensions called hyphae (septate or non-septate); intertwined mass called mycelium
  3. Dimorphic: grow in both forms (yeast at 37 C in culture, and mold in culture at room temp)
31
Q

What are the three types of problems caused by fungi?

A
  1. Allergies
  2. Mycotoxicoses (e.g., mushroom poisoning)
  3. Mycoses (true infections)
32
Q

Describe the 5 “working classifications” of fungi.

A
  1. Superficial mycoses: outermost layer of skin, often from poor hygiene
  2. Cutaneous: tineas (ring worm, athelete’s foot)
  3. Subcutaneous: often from wound to skin, and can involve lymphatics
  4. Systemic: mostly from inhalation of conidia or spores, and can cause mild to severe disease in healthy individuals (most virulent of the fungi)
    a. Can cause chronic infection resembling TB
  5. Opportunistic: found mostly in immunocompromised pts, severe infections that don’t respond to ABs
33
Q

How do fungi cross the initial barrier of human defenses to infect (3)?

A
  • Mechanical breaks
  • Inhalation of spores or conidia
  • Invasive hyphae formation
34
Q

What is Sabouraud’s medium?

A
  • Low pH, high glucose envo that inhibits bacterial growth
  • ABs incorporated to further limit bacterial growth
  • Necessary because fungi are slow-growing, and bacteria would overwhelm culture dish

Pharmacology (3 decks)

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