antifungals Flashcards
immunocompetent fungal infections
Blastomycosis, Chromoblastomycosis, Coccidioidomycosis, Histoplasmosis, Paracoccidioidomycosis and Sporotrichosis.
infection in immunocompromised
(eg. leukemic, neutropenic, debilitated patients- burns, surgery, etc.):
Aspergillosis, Candidiasis, Cryptococcosis, Mucormycosis, Pseudallescheriasis. These are termed opportunistic pathogens.
fungal infections in AIDs pts
Candidiasis
Crypto
Histoplasmosis, Coccidiodomycosis
Antifungal Therapy for subcutaneous and systemic mycosis.
Amphotericin B [AmphotecR, AmbisomeR, AbelcetR]
- Ketoconazole [Nizoral®]
- Miconazole [MonistatR]
- Fluconazole [DiflucanR]
- Itraconazole [SporanoxR]
Empiric Antifungal Therapy
for ??
Common element ??
antifungals of choice??
consider prophylaxis for what fungal infections?
neutropenic pts who do NOT respond to broad spectrum antibacterial tx (4-7 days), seriously ill patients (e.g. cancer, diabetes).
- impairment of normal phagocyte response to fungal infection
- use broad-spectrum: AmpB, miconazole
-candidiasis, Aspergillosis: use Nystantin, ampB, and -azoles
Drugs used for Superficial Fungal Infections: Dermatophytic infections:
- mild-moderate: Miconazole [MonistatR], Tolnaftate [TinactinR]
- moderately severe: the “azoles”, Terbinafine
- severe: Griseofulvin
- Tinea Versicolor: “azoles” esp. ketoconazole
for all drugs don’t need to know specific use except
know MOA, SEs
Capsofugin KNOW USE (later card)
Moderately severe Tinea infections (* oral administration)??
- cutaneous: ampB, azoles, nystatin, terbinafine
- vulvovag: azoles, nystatin
- oropharyngeal: azoles, nystatin
targets of certain antifungals (Figure 1)
- ampB, nystatin (Polyenes): alter membrane function
- Echinocandins: alter cell wall synthesis
- Allyamines/thiocarbamates/azoles: inhibit ergosterol synthesis
- Griseofulvin: inhibit nuclear division
remember ergosterol synthesis (Figure 2)
squalene–>lanosterol via squalene monooxygenase (inhibited by terbinafine and tolnaftate: squalene accumulates)
lanosterol–>ergosterol (via C-14 demethylase: cytP450 enzyme, inhibited by azoles-lanosterol accumulates))
amphotericin B
- insoluble in water: challenge, used parenterally, fungistatic,
- Binds to sterols (ergosterol) in fungal cell membrane
- pores or channels are formed in the cell membrane, permeability increases–>lose cell contents
ampB: selective or not??
not very, sterol selectivity also accounts for drugs toxicity, Mammalian cells, e. g. kidney cells and erythrocytes contain sterols (cholesterol)–>ampB alters cell perm
ampB SEs
- Frequent infusion-related reactions: fever, chills, ha, hypotension, tachy, muscle/ joint pain, N/V
- Nephrotoxicity*
- Anemia: Hypochromic and normocytic* reversible anemia is usual. Decreased production of erythropoietin is the probable mechanism.
ampB nephrotoxicity
Azotemia (nitrogen retention) (80% of pts). Toxicity is transient and increases by concurrent therapy with other nephrotoxic agents (aminoglycosides, cyclosporine). Damage to renal tubules occurs, but permanent functional deficits are uncommon. Renal function should be monitored frequently.
ampB uses: not going to test us on specifically
systemic (IV, intrathecal) and superficial infections (topical)
Imidazoles and Triazoles
Systemic triazoles: more slowly metabolized (longer half-life) and less effect on human sterol synthesis than imidazoles.
Imidazoles and Triazoles MOA
inhibition of sterol 14-α-demethylase, (cytP450-dependent) an enzyme that demethylates lanosterol, a precursor of ergosterol
-accumulation of 14-α-methylsterols, impairing membrane-bound enzymes systems, permeability of fungal cell membrane and thus inhibiting fungal growth
(binds weakly to mammalian enzyme; so less toxicity, better selectivity)
imidazoles
Miconazole [MonistatR, MicatinR]
Ketoconazole [Nizoral®]
Triazoles
Itraconazole [SporanoxR]
Fluconazole [DiflucanR]
Ketoconazole [Nizoral®]
imidazole
fungistatic at lower concentrations and fungicidal at higher concentration
shuts down steroid synthesis
-7-8 hr half-life
Ketoconazole [Nizoral®] SEs
Endocrinologic abnormalities: Due to inhibition of steroid biosynthesis (females: 10% menstrual abnormalities; in males: gynecomastia and decreased libido and potency)
GI
Hypersensitivity
inhibits P450-dependent enzymes
Miconazole [MonistatR, MicatinR]
imidazole
12 hr half-life, metabolized by liver
low toxicity
Fluconazole [DiflucanR]
triazole
25-30 hr half-life! can use 1 pill/day
interacts w. cytP450
low toxicity
Itraconazole [SporanoxR]
30 hour half-life (1x/day) Incr. conc. of drugs metab cyt P-450: i.e. cyclosporine, digoxin, phenytoin
-Low toxicity
Griseofulvin [Grifulvin VR] MOA (KNOW)
(used for superficial infections)
- *Disrupts cell’s mitotic spindle structure, thus arresting the metaphase of cell division
- deposited in keratin precursor cells; takes time, requires wks-mos, concentrates in skin, hair, nails, liver, fat, skel. muscles
- Ultramicrosize
Griseofulvin [Grifulvin VR] SEs
minor
CNS, GI, hypersensitivity
-assess renal, liver, hematopoietic function before therapy
Nystatin
CANNOT USE PARENTALLY: too toxic (vs. ampB), few SEs if used correctly
- similar MOA as ampB*: Binds to sterols in the fungal cell membrane
- oral candidiasis
Tolnaftate [Tinactin®] MOA
- interferes with sterol biosynthesis by inhibiting the enzyme squalene monooxygenase (squalene 2,3-epoxidase) which results in decreased synthesis of ergosterol and accumulation of squalene, which results in changes in membrane properties
- low toxicity, used for topically for superficial infections (Dermatophytoses)
Terbinafine hydrochloride [LamisilR cream] MOA
interfere with ergosterol biosynthesis by inhibiting the enzyme squalene monooxygenase (squalene 2,3-epoxidase) which results in decreased amounts of ergosterols and accumulation of squalene, which results in changes in membrane properties.
-low toxicity, -used for topically for superficial infections (Dermatophytoses)
Caspofungin [Cancidas®]
(echinocandins class) inhibits the SYNTHASE of β (1,3) –D-glucan, an essential polysaccharide component of the cell wall of filamentous fungi
- not present in mammalian cell
- low adverse effects
Caspofungin [Cancidas®] uses (KNOW)***
FDA-approved for treatment of ??
invasive aspergillosis and esophageal candidiasis in patients who are refractory or intolerant to other antifungals (eg. amphotericin B or itraconazole)
case: coccidiodal infection, treated w. fluconazole
will have case like this on test, will ask about MOA or SEs
