drugs Flashcards by skug LU

Limitations of antifungal drugs:

○ Significant side effects.
○ Narrow antifungal spectrum.
○ Poor tissue penetration.
○ Resistance development.

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Bind to ergosterol in fungal membranes.

● Polyenes

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Pyrimidine analog interfering with DNA/RNA
synthesis.

Flucytosine

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Inhibit ergosterol synthesis.

Azoles and Allylamines:

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● : Block β-glucan synthesis in the fungal cell wall.

Echinocandins

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● : Disrupts microtubule assembly.

Griseofulvin

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Investigational Drugs:

○ Nikkomycin and pradimicin (cell wall inhibitors).
○ Sordarin (elongation factor 2 inhibitor).

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Resistance Mechanisms

● Efflux pumps expel antifungal drugs.
● Overexpression of drug targets (e.g., ergosterol).
● Amino acid substitutions in target proteins reduce drug binding.

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resistant to
fluconazole.

Candida glabrata and Candida krusei

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○ Multidrug-resistant

Candida auris.

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amphotericin b mechanism

Mechanism of Action:
○ Binds to ergosterol in fungal cell membranes.
○ Alters membrane fluidity and forms pores, leading to ion
leakage and cell death.
○ Weak binding to cholesterol in mammalian cells
contributes to toxicity.
○ Lipid formulations reduce toxicity and allow higher doses.

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Broad spectrum: Effective against coccidioidomycosis,
blastomycosis,
histoplasmosis,
cryptococcosis,
aspergillosis, mucormycosis, candidiasis, etc.

amphotericin nb

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○ Often used with flucytosine for cryptococcosis.

amphotericin b

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○ Ineffective against some fungi (e.g., P. boydii, A. terreus).

amphotericin b

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given intravenously as micelles with sodium deoxycholate dissolved in dextrose solution

amphotericin b

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side effect of amphotericin b

Acute reactions: Fever, chills, dyspnea, hypotension
(alleviated with hydrocortisone or acetaminophen).

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Chronic side effects:
■ Nephrotoxicity: Azotemia, hypokalemia, renal
tubular acidosis.
■ Anemia, headache, nausea, vomiting.
■ Permanent glomerular/tubular damage possible.

amphotericin b

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significantly reduce toxicity. in amphotericin b

ipid formulations (Abelcet, Amphotec, AmBisome)

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A fluorinated derivative of cytosine.

Flucytosine

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Oral antifungal used primarily with
amphotericin B.

Flucytosine

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Effective against cryptococcosis, candidiasis, and
dematiaceous fungal infections.

Flucytosine

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Penetrates all tissues, including cerebrospinal
fluid.

Flucytosine

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produces spores in membranes through which ions and small molecules are kist

amphotericin b

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mechainism of flucytosine

○ Transport into Cells: Actively transported into fungal cells by a permease.
○ Conversion in Fungi:
■ Converted to 5-fluorouracil by fungal enzyme
cytosine deaminase.
■ Incorporated into 5-fluorodeoxyuridylic acid
monophosphate, disrupting thymidylate synthetase and inhibiting DNA synthesis

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○ Selective Action: Mammalian cells lack cytosine deaminase, protecting them from toxic effects

flucytosine

dna and protein synthesis inhibitor

flucytosine

effective against chromoblastomycosisand dermatiaceous fungal infections

flucytosine

Particularly beneficial in cryptococcal meningitis.

flucytosine

Main Toxicity Source of fluorocytosine :

Conversion to fluorouracil, a highly toxic compound.

Major Side Effects: ■ Bone marrow suppression. ■ Hair loss. ■ Abnormal liver function. ■ Colitis due to conversion to fluorouracil by enteric bacteria.

flucytosine

structure of azole

Structure: ■ Azoles ■ Imidazoles ■ Triazoles

have two nonadjacent nitrogen atoms

Imidazoles (e.g., ketoconazole)

have three nitrogen atoms.

Triazoles (e.g., fluconazole, voriconazole, itraconazole)

Oral administration makes them less toxic than amphotericin B for less severe mycoses.

azole

Oral administration makes them less toxic than amphotericin B for less severe mycoses.

azole

Miconazole and clotrimazole are used for topical applications.

○ Topical Imidazoles:

■ Treat systemic and localized fungal infections.

azole

Inhibit ergosterol synthesis by blocking cytochrome P450-dependent 14α-demethylation of lanosterol (precursor to ergosterol in fungi)

azole

interferes with activity of thymidylate synthase and dna synthesis

fluctocytosine

are 100–1000 times more sensitive to azoles than mammalian systems

Fungal cytochrome P450s

for treating Nonmeningeal forms of blastomycosis, coccidioidomycosis, paracoccidioidomycosis, histoplasmosis.

ketoconzaole

■ Best central nervous system (CNS) penetration.

Fluconazole

Maintenance therapy for cryptococcal and coccidioidal meningitis.

fluconazole

Treats oropharyngeal candidiasis in AIDS patients and candidemia in immunocompetent patients.

fluconzaole

■ Effective for chromomycosis, onychomycosis.

itraconazole

Broad spectrum for molds and yeasts

Voriconazole

(aspergillosis, fusariosis, pseudallescheriasis).

vorizonazole

■ Newest triazole with wide spectrum.

Posaconazole

: Most toxic, causing reversible effects like gynecomastia, decreased libido, impotence, menstrual irregularities, adrenal insufficiency.

Ketoconazole

At recommended doses, do not impair mammalian steroidogenesis.

○ Other Azoles (e.g., fluconazole, itraconazole):

s may cause asymptomatic liver function test elevations or rare cases of hepatitis.

azole

Causes reversible visual impairment in ~30% of patients.

voriconazole

Azoles interact with P450 enzymes, leading to altered levels of drugs such as:

■ Increased azole levels with isoniazid, phenytoin, rifampin. ■ Higher serum levels of cyclosporine, phenytoin, oral hypoglycemics, anticoagulants, digoxin, etc

ECHINOCANDINSINS MECHANISM OF ACTION

Mechanism of Action: ○ Inhibit 1,3-β-glucan synthase, disrupting cell wall synthesis and integrity. ○ Reduces the synthesis of β-glucan, a critical cell wall polysaccharide.

■ First approved echinocandin.

Capsofungin

Effective against invasive aspergillosis and systemic candidiasis (various Candida species).

CASPOFUNGIN

■ Often used for refractory aspergillosis.

CASPOFUNGIN

■ Similar mechanism and spectrum as caspofungin.

○ Micafungin and Anidulafungin:

Esophageal candidiasis.

Micafungin and anidulafungin

Better pharmacokinetics and in vivo stability compared to caspofungin.

Micafungin and Anidulafungin:

Effective for mucosal/systemic candidiasis, refractory aspergillosis, and in combination therapies.

Micafungin and Anidulafungin

Griseofulvin

Mechanism of Action: - Binds to microtubules, disrupting the mitotic spindle, inhibiting fungal growth. - Effective only on actively growing hyphae.

accumulates in keratinized tissues (e.g., skin, hair, nails).

Griseofulvin

Poor systemic absorption.

Griseofulvin

Treats dermatophyte infections of the skin, hair, and nails.

Griseofulvin

Side Effects: Common: Headache (usually resolves without discontinuation). Less Common: ■ Gastrointestinal disturbances. ■ Drowsiness. ■ Hepatotoxicity.

Griseofulvin

Terbinifine mechanism of action

Mechanism of Action: ○ Inhibits squalene epoxidase, blocking ergosterol synthesis. ○ Accumulation of squalene is toxic to fungal cells.

Oral treatment for dermatophyte infections.

Terbinafine

Effective for onychomycosis (nail infections) and other dermatophytoses.

Terbanifine

Can be given intermittently (pulse treatment) for tinea unguium.

Terbanifine

Terbanifine Side effect

Side Effects: ○ Uncommon: ■ Gastrointestinal distress. ■ Headaches. ■ Skin reactions. ■ Loss of taste

A polyene antibiotic, structurally related to amphotericin B.

Nystatin

Mechanism: Binds to ergosterol, disrupting fungal cell membranes.

Nystatin

Local candidal infections:

Nystatin

Local candidal infections occurs in

■ Mouth (e.g., oral thrush). ■ Vagina.

■ Suppresses esophageal candidiasis and gastrointestinal candida overgrowt

Nystatin

No systemic absorption occurs.

Nystatin

Toxicity: Too toxic for parenteral (systemic) administration.

Nystatin

A variety of antifungal azoles are available for topical use due to systemic toxicity.

Clotrimazole, Miconazole, and Other Azoles

What are the widely used azole

Clotrimazole, Miconazole

Azoles used only in special or certain situations

Econazole, Butoconazole, Tioconazole, Terconazole (specialized uses)

(athlete's foot).

Tinea pedis

(ringworm).

Tinea corporis

(fungal skin discoloration).

Tinea versicolor

Cutaneous candidiasis Vulvovaginal candidiasis - Treated with suppositories or creams.

Clotrimazole, Miconazole, and Other Azoles ● Description: ○ A variety of antifungal azoles are ava

■ Oral and esophageal thrush:

Clotrimazole troches.

Nail infections

Luliconazole

■ Dermatophyte infections. ■ Tinea versicolor.

Tolnaftate and Naftifine:

Treated with creams, powders, and sprays.

Volvovaginal candidiasis

Indications: ■ Tinea pedis. ■ Tinea cruris.

Undecylenic acid

Well-tolerated but less effective compared to azoles, naftifine, and tolnaftate.

Undecylenic Acid:

Commonly used for dermatophyte infections.

Haloprogin and Ciclopirox:

is also used for onychomycosis (nail fungus) in topical formulations.

Ciclopirox

drugs Flashcards

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