- a crucial component of the fungal cell membrane

Anti-Fungal Drugs Flashcards by Jean-Luc Banks

Fluconazole
Itraconazole
Posaconazole
Voriconazole 
Amphotericin B used to treat

Blastomyces
Histoplasma
Coccidioides

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Sulfamethoxazole/Trimethoprim used to treat

Pneumocystis jirovecii

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what is ergosterol

a crucial component of the fungal cell membrane

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Azole antifungals MOA

which one

inhibition of enzymes involved in ergosterol synthesis

- lanosterol demethylase

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Azole antifungals selectivities

highly selective for the fungal enzymes

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Azole antifungal toxicities

Prolonged QT
drug interactions
hormonal effects

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are Azole antifungals safe to use during pregnancy

potential teratogen

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which azole antifungals cause prolonged QT

fluconazole, posaconazole

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drug interactions with azole antifungals

inhibit CYP enzymes

- slow metabolism of drugs and elevate their plasma concentration

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what is an important cytochrome that azole antifungals inhibit?

CYP3A4

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what azole drug causes hormonal effects

which effects?

ketoconazole

- gynecomastia, decreased libido, impotence

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MOA of polyenes

ergosterol binding agents

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amphotericin B structures

hydrophobic and hydrophilic face

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MOA of amphotericin B

selective for

binds ergosterol and forms pores in fungal cell membrane

- selective for ergosterol only

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which part of amphotericin B associates with ergosterol

hydrophobic face

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resistance mechanism to amphotericin B

reduced concentration of ergosterol in the membrane

- modification of ergosterol to a form with reduced amphotericin B binding

how is amphotericin B administered

why?

- poor GI tract absorption

what is one condition in which we may orally administer amphotericin B?

luminal GI tract infections

amphotericin B distribution

aqueous insolubility requires formulation with lipids

immediate toxicities of amphotericin B

how frequently do these symptoms occur?

fever
chills
muscle spasms
occur in nearly 100% of patients

when do immediate amphotericin toxicities abate

30-45 minutes

cumulative toxicities of amphotericin B

nephrotoxicity/acute tubular damage
leads to loss of Na+/K+/Mg2+
Azotemia

amphotericin B cumulative toxicities, effect is _____

dose dependent

what is the safest anti fungal drug used during pregnancy

amphotericin B

Importance of pneumocystis jirovecii in pharmacology

- naturally resistant to almost all anti-fungals

how is pneumocystis jirovecii resistant to azoles

- uses cholesterol from host, not ergosterol | - contains natural resistance mutations

how is pneumocystis jirovecii resistant to polyenes (amphotericin B)

- lacks ergosterol so amphotericin can't bind to it

sulfonamides MOA

- inhibit pteroate synthase in folic acid biosynthesis pathway

trimethoprim MOA

- inhibit DHFR in folic acid biosynthesis pathway

how pneumocystis jirovecii can become resistant to SMX/TMP

- mutations in target enzymes (pteroate synthase and DHFR) confer resistance - overproduction of PABA may overwhelm drug

what is PABA

- early compound in folic acid biosynthesis pathway

sulfamethoxazole toxicities

- fever - rash - photosensitivity - urticaria - nausea/vomiting - Steven's Johnson syndrome

steven's Johnson syndrome a side effect of

- all sulfonamide drugs

trimethoprim side effects

- folate deficiency effects - megaloblastic anemia - leukopenia - granulocytopenia

SMX category in pregnancy

- B

TMP category in pregnancy

- C

When is Amphotericin B used for fungal pneumonia

First-line for severe systemic infections and/or Immunocompromised patients

When are Azoles used for fungal pneumonia

Less severe infections, in immunocompetent patients, for prophylaxis or for maintenance following initial amph B

risky during pregnancy

Azoles and SMZ/TMP