Anti-Fungal Drugs Flashcards
Fluconazole Itraconazole Posaconazole Voriconazole Amphotericin B used to treat
- Blastomyces
- Histoplasma
- Coccidioides
Sulfamethoxazole/Trimethoprim used to treat
- Pneumocystis jirovecii
what is ergosterol
- a crucial component of the fungal cell membrane
Azole antifungals MOA
which one
- inhibition of enzymes involved in ergosterol synthesis
- lanosterol demethylase
Azole antifungals selectivities
- highly selective for the fungal enzymes
Azole antifungal toxicities
- Prolonged QT
- drug interactions
- hormonal effects
are Azole antifungals safe to use during pregnancy
- potential teratogen
which azole antifungals cause prolonged QT
- fluconazole, posaconazole
drug interactions with azole antifungals
- inhibit CYP enzymes
- slow metabolism of drugs and elevate their plasma concentration
what is an important cytochrome that azole antifungals inhibit?
- CYP3A4
what azole drug causes hormonal effects
which effects?
- ketoconazole
- gynecomastia, decreased libido, impotence
MOA of polyenes
- ergosterol binding agents
amphotericin B structures
- hydrophobic and hydrophilic face
MOA of amphotericin B
selective for
- binds ergosterol and forms pores in fungal cell membrane
- selective for ergosterol only
which part of amphotericin B associates with ergosterol
- hydrophobic face
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?
- IV
- 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
