Cao - Antifungals Flashcards by Evanna Dyer

a substance intended for use as a component of a medicine but not a device or a component, part, or accessory of a device

drugs

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Science that deals with the origin, nature, chemistry, effects, and uses of drugs including pharmacognosy, PK, PD, pharmacotherapeutics, and toxicology

pharmacology

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It is concerned with the development, identification, and interpretation of the mode of action of biologically active compounds at the molecular level

medicinal chemistry

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It is concerned with the study, identification and synthesis of the metabolic products of these drugs and related compounds

medicinal chemistry

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What are the two fungal categories?

superficial mycoses and deep seated mycoses

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What is superficial mycoses?

dermatophytoses (skin or mucous membrane)
- contagious skin infections that are limited to the epidermis regions

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What is deep-seated mycoses?

systemic mycoses (systemic fungal infections)
– lung or central nervous system

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3 reasons for fungal infection

overuse of abx
immune compromised
translocation

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How are superficial mycoses caused?

relatively homogenous group of fungi, dermatophytoses, specialized saprophytic molds that unusually digest keratin of the skin

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Where does systemic mycoses occur?

they invade the skin, lungs and lymphatic tissue

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Name the systemic mycosis

histoplasmosis
blastomycosis
sporotrichosis
coccidiomycosis

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systemic mycosis causative agents

free-living saprophytes

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fx of fungal cell wall

Critical for cell viability and pathogenicity

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Fungal cell wall is a critical site for…

exchange and filtration of ions and proteins, as well, as metabolism and catabolism of complex nutrients

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T/F
mammalian cells have a cell wall so are not an ideal target for anti-fungal therapy

false - mammalian cells lack a cell way and it also represents an ideal and specific target for anti-fungal therapy

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human cell membrane contains cholesterol and fungal cell membrane contains …

ergosterol

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Do lipid bilayers form a stable or unstable structure?

it forms an unstable structure that cannot retain its shape and functions.

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What lies within the lipid bilayer and what do they do?

Sterols lie within the lipid bilayer and act as stiffening agents

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What are the predominant sterol in many pathogenic fungi?

ergosterol

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What is a problem for designing drugs?

to be selective for the toxic fungal cell but not effect the host

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What does the disruption of the fungi’s protein/carbohydrate matrix result in?

It results in structurally defective cell wall thus rendering the fungal cell sensitive to osmotic lysis

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Drugs that target on the synthesis of ergosterol will lead to…

death of fungi

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Allylamines

Naftifine and Terbinafine

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Benzylamine

Butenafine

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Imidazoles

Miconazole, Clotrimazole, Ketoconazole

Triazoles

Fluconazole, Itraconazole, Posaconazole, Voriconazole, Isavuconazole

Polyenes

Nystatin, natamycin (Pimaricin), Amphotericin B

Echinocandins

Caspofungin, Anidulafungin, Micafungin

Other anti-fungals

Griseofulvin, Flucytosine. Tolnaftate

MOA for Allylamine and Benzylamine

Inhibition of ergosterol biosynthesis at the level of squalene epoxidase

MOA for Azoles and Triazoles

Inhibition of CYP450-dependent enzymes (particularly C14a-demethylase) involved in the biosynthesis of ergosterol

Polyene MOA

Interaction with sterols in the cell membrane to form channels through which small molecules leak from inside the fungal cell leading to death.

Echinocandin MOA

Act as [ ]-dependent noncompetitive inhibitors of beta-1,3 glucan synthase

what is an essential component of the cell wall of susceptible filamentous fungi that's absent in mammalian cells

beta-1,3 glucan synthase

Where did Polyenes get their name from?

alternating conjugated double bonds that constitute a part of their macrolide ring structure

Which species are polyenes a product of?

Streptomycin species

What did Elizabeth Hazel and Rachel Brown propose/prove?

bacterial and fungi seem to keep each other in check and bacterial should be useful in identifying anti-fungal agents

Which class of anti-fungals are the only fungicidal agent?

Polyenes

What is the toxicity most likely due to for fungicides?

polyenes bind to cholesterol, although they have a 500X affinity for ergosterol over cholesterol

First broad-spectrum anti-fungal agent

Nystatin

Nystatin dosage forms

topical Cream, oral suspension, pill

Nystatin is absorbed ______________ and is used for the treatment of fungal ____________. It's also widely used as a "natural" anti-fungal ______ ___________.

systemically; keratitis; food additive

Amphotericin B dosage forms

injectable, pil

Why is Amphotericin B use limited?

due to its toxicity in the liver and kidneys - should never be given with other nephrotoxic drugs

Which formulation of Amphotericin B limits the toxic liability?

formulation with liposomes

Liposomal amphotericin B

AmBisome

Amphotericin B lipid complex

ABLC, Abelcet

Amphotericin B colloidal dispersion

ABCD, Amphotec (AmBisome)

MOA for Polyenes

1. bind to ergosterol in the cell membrane 2. results in membrane formation of pores --> eventually leading to cell death

Polyenes attach with higher affinity to...

ergosterol

higher [ ] of amphotericin B binds to...

cholesterol in mammalian cell membranes leading to various organ toxicities

Most common adverse effects of amphotericin B

Nephrotoxicity (MOST COMMON) Hypokalemia, Hypomagnesemia, bones marrow suppression

Allylamine organic compound formula

C3H5NH2

Naftifine is the first..

anti-fungal allylamine , against tinea

Which anti fungal is stronger against tinea and onychomycosis (oral)

Terbinafine

Butenafine is active against

Candida albicans in tolnaftate resistant cases

Naftifine is a potential _____________ inhibitor and inhibits __________ ____________. Also represent the first member of the __________ class of antifungals

serotonin reuptake; squalene epoxidase; allylamine

who am I? active in vitro against a number of different fungal species, cleared very slowly so only used for topical indications, and a plasma half life of 60hrs

Naftifine (Naftin)

WHO AM I? readily absorbed in the GI tract w/ 40% oral availability; high level of metabolism by multiple CYP isoforms and high protein binding; plasma t1/2 of 36h; accumulates in the nails with a t1/2 of 300hrs; active against a broad spectrum of fungal strains

Terbinafine (Lamisil)

WHO AM I? similar activity profile as Naftifine; currently only used for topical indications; active against a number of different external infections.

Butenafine

WHO AM I? a thiocarbamate that can be made very inexpensively; active for athlete's foot, ring worm, and jock itch indications by inhibiting squalene epoxidase; not active against Candida and other fungal infection; only used topically

Tolnaftate (Tinactin)

WHO AM I? onychomycosis treatment that disrupts other enzymes; only used topically but can be combined with systemic Terbinafine to improve efficacy of both

Amorolfine (Loceryl/Curanail)

Imidazole antifungals are typically used for what?

external fungal infections

Triazole antifungals are more commonly used for...

systemic infections

WHO AM I? First Azole discovered; not well-absorbed; available as cream, aerosolized spray and solution for fungal ear infection

Clotrimazole (Lotrimin)

WHO AM I? 2nd member of the azole class of antifungals; exert their activity against 14a-sterol demethylase (CYP450); the most widely used OTC anti-fungal primarily for superficial mycoses; also can be used for neonatal thrush; racemic compound

Miconazole (Desenex/Monistat)

WHO AM I? generally used for exterior (non-systemic) indications; differs from Miconazole only by chlorine substitution pattern

Isoconazole (Travogen)

WHO AM I? Chlorine substitution analog widely available in the US and around the world; exists only as a cream

Econazole (Spectazole)

WHO AM I? first azole to be used to treat systemic Candida infections. Has poor PK (moderate absorption, high protein binding; relatively short t1/2)

Ketoconazole (Nizoral)

WHO AM I? Better PK than Ketoconazole; readily metabolized by CYP 3A4; highly protein bound that protects it from rapid metabolism and clearance

Itraconazole

WHO AM I? one of the most active triazole anti fungal agents for systemic fungal infections

Posaconazole

WHO AM I? Contains 2 triazole units and does not contain a chiral center making it less expensive and less likely to have an undesired SE by a "spectator" isomer; broad-spectrum antifungal; not highly metabolized; inhibit CYP 2C9 and 3A4; DO NOT MIX WITH CHOLESTEROL DRUGS

Fluconazole (Diflucan/Forcan)

WHO AM I? broad-spectrum triazole is available as a tablet and an IV formulation

Voriconazole (Vorzu/Vfend)

Voriconazole Adverse effects and DI's

hepatotoxicity, visual disturbances (common), hallucinations, and dermatologic rxns. Prolong QT interval numerous DI notably with certain immunosuppressants used after organ transplantation.

WHO AM I? Acts through the inhibition of 14a-sterol demethylase (same target as azaleas). Shows limited antibacterial activity suggesting more than 1 MOA

Abafungin (Abasol)

triazoles that are available for systemic use

fluconazole, itraconazole, Voriconazole, posaconazole, isavuconazole

imidazole available for systemic use

Ketoconazole

What class am I? anti fungal drugs that inhibit the synthesis of gluten in the cell wall via noncompetitive inhibition of the enzyme 1,3-B glucan synthase; called penicillin f antifungals

Echinocandins

which Echinocandin blocks B-1,3-glucan synthase (an enzyme necessary for cell wall formation)

Caspofungin Micafungin Anidulafungin

Echinocandins are potently ___________ against most clinically important Candida sp but are considered ___________ against Aspergillus

fungicidal; fungistatic

Echinocandins adverse effects

hepatitis and rash

WHO AM I? Not viable as an oral drug and must be administered intravenously. t1/2 10h - single daily injection is suitable

Caspofungin

WHO AM I? Metabolized by CYP3A4 on the hydrophobic tail, leading to decreased toxicity. no DDI problems which makes it useful for treatment of severely immunocompromised patients

Micafungin

WHO AM I? only metabolism through hydrolysis (no CYP) and no DDI. excellent therapeutic index

Anidulafungin

t1/2 of 9h and metabollzied by beconjugation rather than any CYP itxns

Griseofulvin

Nucleic acid analog, water soluble and well-absorbing after oral administration

Flucytosine

Flucytosine AEs

bone marrow suppression (thrombocytopenia & leukopenia), hepatotoxicity, and enterocolitis

Known to have anti fungal activity for 40yrs but MOA is still unknown. Typically used in combination with an azalea or allylamine anti-fungal agent

Ciclopirox