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30 Cards in this Set
- Front
- Back
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Blood and Lymph-Antifungals Drugs by Boy Bridges
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Blood and Lymph-Antifungals Drugs by Boy Bridges
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the most important for severe infections is?
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Amphotericin B
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The mainstays of treatment are the
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azoles.
itraconazole fluconazole |
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MoA of Polyenes:
Amphotericin B Nystatin |
Selectively bind ergosterol in fungal cell membrane, altering membrane fluidity and producing pores and osmotic cell death
Much less binding to cholesterol |
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MoA of Azoles:
Ketoconazole Fluconazole Itraconazole Voriconazole |
Selectively block ergosterol synthesis by inhibiting demethylation of lanosterol (14a-sterol demethylase)
Fungal P450 enzyme much more sensitive than mammalian counterpart |
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MoA 5-Flucytosine
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Converted by fungal cytosine deaminase into 5-fluorouracil; inhibits DNA synthesis
Mammalian cells lack cytosine deaminase |
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MoA Griseofulvin
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Inhibit fungal growth by binding to microtubules, disrupting mitotic spindles
Mammalian microtubules less sensitive |
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MoA Allylamines
(Terbinafine) |
Selectively blocks ergosterol synthesis by inhibiting squalene epoxidase (not found in animals)
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MoA Echinocandins
(Caspofungin) |
Inhibit fungal Beta glucan synthesis, disrupting cell wall integrity
Mammalian cells have no cell walls |
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Nystatin. how do you take it? good oral absorption?
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Nystatin
oral or topical use only Too toxic for systemic use very poor oral absorption not absorbed from the GI tract, skin or vagina it will stay in the gut for antifungal effects and is eliminated in feces |
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Amphotericin B
reserved for what again? |
Broad spectrum
-DOC for many severe, invasive fungal infections -reserved for severe, life-threatening infections -Often given initially … then followed with a less toxic systemic oral drug like fluconazole or itraconazole punch a hole. lose osmotic integrity. -binds sterols- preferentially ergosterol; greater affinity over cholesterol -makes membranes leaky -disrupts osmotic integrity -can be fungistatic or fungicidal; dependent on membrane ergosterol content |
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Amphotericin B adverse effects
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NEPHROTOXICITY
Most common and serious adverse effect -Up to 80% of patients may have some degree of renal toxicity Slow developing and cumulative toxicity;Watch for it Monitor renal function -Acute tubular necrosis -Electrolyte abnormalities --Monitor potassium, chloride & magnesium Avoid use of other nephrotoxic drugs (e.g., aminoglycosides and cyclosporine) Anticipate this immediate effect … CYTOKINE STORM |
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Amp B pharmacokinetics
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Pharmacokinetics
IV route only for systemic infection Oral dosing -preparations no longer available in US Poor CNS penetration -intrathecal administration required for meningitis |
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Amp B Lipid Formulations
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Fungizone:
good bc less nephrotox |
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Antimetabolites:
Flucytosine what dont you ever do |
converted into 5-fluorouricil
NEVER used alone!! Resistance develops rapidly if used alone Used in combination with Amp B (especially if CNS involvement) Narrow spectrum Used mostly to treat… -*Systemic candidiasis -*Cryptococcal meningitis Good oral absorption Excellent CNS penetration |
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Flucytosine
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bone marrow depression (just like 5fluorouricil)
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Antimitotics:
Griseofulvin used for what? |
inhibits mitosis.
Systemic treatment of dermatophytosis (skin, hair scalp, nail infections) most effective against tinea infection of the scalp and glabrous (nonhairy) skin **tinea infections -Terbinafine is the DOC -azoles are alternatives Deposits in keratin producing cells (keratophilic) Keratin becomes resistant to fungi -As new hair or nails grow … they are fungal free Takes months to clear nail infections -fingernails (6+ mo.), toenails (8-18 mo.) |
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what don't you use griseofulvin for?
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Not used for systemic fungal infections
Not effective topically for dermatophytic infections …. -Given orally to be effective Enters cells by an active process -Interacts with polymerized microtubules -Disrupts mitotic spindle; Fungistatic Serious adverse effects are pretty rare -**Hepatotoxicity can occasionally occur -Patients with compromised liver function, or are allergic, or suffer acute intermittent porphyria should avoid griseofulvin -teratogenic -disulfiram like reaction with ethanol -potent p450 inducer |
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Allylamines:
Terbinafine drug of choice for what? |
blocks the conversion of squalene into lanosterol (step before conversion into ergosterol) which is part of the cell membrane
Fungicidal Drug of choice for treating …Dermatophytoses -superficial skin infections e.g., athletes foot and jock itch Onychomycosis (nail infections) -oral administration -high cure rate (76%) -prolonged therapy required GO-TO FOR SKIN AND NAIL INFECTIONS!! |
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Terbinafine MoA
why is it the go-to? |
Mechanism of action
-Inhibits squalene metabolism inhibits squalene epoxidase (fungal enzyme) -leads to an accumulation of squalene in fungal cells -**squalene is toxic to fungal cells leading to fungicidal effect Adverse effects are rare but …. -Severe hepatotoxicity (hepatic failure) and neutropenia are concerns -Less risk of hepatotoxicity compared to griseofulvin -Avoid use in patients with liver disease *better tolerated, shorter therapy, more effective than griseofulvin --also better than azoles for shorter duration and effectiveness. |
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Azoles:
Ketoconazole Fluconazole Itraconazole Voriconazole |
prevent ergosterol formation. no membrane integrity. dead cell. don't use in combo with amb b because that binds to the ergosterol (that wouldn't exist)
Inhibits fungal cytochrome P450 -decrease ergosterol synthesis -decrease sterol in fungal membranes --leads to damaged, leaky membranes cannot use in combination with Amp B |
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azole side effect (at high doses)...
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May see hormonal deficiency side effects
decrease testosterone and cortisol production |
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Ketoconazole used for...
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the model. broad spectrum, low efficacy
**tinea corporis and capitis (ringworm) -topical formations Prostate cancer (dec testosterone production) Adrenal cancer (dec corticosteroid synthesis) Cushing’s syndrome (dec glucocorticoid production) Not used for systemic fungal infections Narrow therapeutic index, drug interactions and toxicity |
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Pharmacokinetics of ketoconazole...what do you need in order for the drug to dissolve?
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Food and acidic stomach fluid required to dissolve drug and for absorption
-Cola / soft drinks inc. absorption up to 65% -**Antacids, H2 blockers and proton pump inhibitors interfere with absorption |
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keto adverse effects
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Adverse effects
P450 inhibition can interfere with adrenal and gonadal steroid synthesis -Persistent adrenal insufficiency -Gynecomastia -Impotence -decreased libido -Menstrual abnormalities Hepatoxicity (1% to 2% of pts) Monitor liver enzymes *potent p450 inhibitor |
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Fluconazole
the least effect of all azoles on... |
on p450
-**less provlems with drug interactions -**little or no endocrine effects good csf penetration -**useful in CNS infections eliminated by **kidneys (keto is liver) |
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Voriconazole
common disturbances... DOC for what? |
**Visual disturbances are common
-blurring and changes in color vision -do not drive at night for outpatient rx DOC for invasive aspergillosis |
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Echinocandins:
Caspofungin MoA salvage therapy for what? |
MOA: Impairs cell wall production
**inhibits beta-(1,3)-D-glucan synthesis (cell wall component) Invasive aspergillosis **salvage therapy when Amp B or voriconazole has failed (or drug intolerance) |
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any kind of tinea you use
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terbinafine.
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candidiasis, use...
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topical azole.
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