Zheng - Antifungal Drugs

Question 1

Mycoses

Answer 1

Fungi that cause disease in humans

Question 2

Amphotericin B

Answer 2

A membrane disrupting agent

• has a amphipathic ring structure.
• the non-polar side binds tightly it the ergosterol in the cell membrane of the fungus –> the polar side forms pores for ions to leak out of cells
• broad anti-fungal spectrum
• used for life-threatening systemic infections

Question 3

Mycosamine sugar unit of amphotericin B

Answer 3

Link between amphotericin and ergosterol that lets it form ion channel pores.

Question 4

Administration and pharmacokinetics of amphotericin B

Answer 4

Insoluble in water
excreted slowly in the urine
Drug levels are insensitive to renal or hepatic dysfunction
- they sometimes package the drug in a liposomal preparation which enables higher doses with reduced nephrotoxicity.

Question 5

Adverse effects of amphotericin B

Answer 5

Infusion related toxicity - fever, chills, vomiting, headache, hypotension

Slower toxicity - renal damage is most common problem

Question 6

Flucytosine

Answer 6

Taken up by fungal cytosine permease.
Converted to 5-fluorouracil (5-FU) by cytosine deaminase
5-FU is converted to 5-FUTP that inhibits RNA synthesis
5-FU is converted to 5-FdUMP that inhibits DNA synthesis

Question 7

Selectivity of Flucytosine

Answer 7

Mammalian cells poorly convert 5-FC –> 5-FU

Question 8

Pharmacokinetics of Flucytosine

Answer 8

Removed from the kidney in 3-6 hours
Drug can rise to toxic levels with renal impairment
Synergy with amphotericin B and itraconazole

Question 9

What is Flucytosine used for?

Answer 9

Limited spectrum - Candida and cryptococcus

Question 10

Anti-fungal Azoles

Answer 10

There are imidazole rings

• they inhibit ergosterol biosynthesis at the point of Lanosterol demethylation via the enzyme ERG11
• this causes buildup of toxic methylsterols that inhibit membrane enzymes.
• broad spectrum

Question 11

Drug interactions of Azoles

Answer 11

Affects many drugs metabolism through P450.

it also binds less efficiently to mammalian p450s than fungal, which AIDS in specificity

Question 12

Ketoconazole

Answer 12

The first oral Azole but has since been replaced

Question 13

Miconazole and clotrimazole

Answer 13

Used topically only

Question 14

Itraconazole

Answer 14

Most potent Azole
Wider spectrum - but can’t get through CSF
Fewer side effects
Improved with cyclodextrin formulations
Metabolism in liver through CYP3A4 isoenzyme
Long half-life

Question 15

Drug interaction for itraconazole

Answer 15

H2 and proton pump blockers that decrease gastric acidity

Drugs metabolized by P450 enzymes

Question 16

Flucoconazole

Answer 16

Widely distributed including CSF.
Least affects on hepatic Microsomal enzymes, which leads to fewer drug interactions.
Long half life
No problem with gastric acidity so it is orally absorbed

Question 17

Voronazole, Posaconazole

Answer 17

Newest triazoles
Improved bioavailability
Broadest spectrum

Question 18

Echinocandins

Answer 18

Water soluble

• caspofungin, micafungin, anidulafungin
• they disrupt the integrity of the fungal cell wall by inhibiting beta(1,3)-glucan synthase

Question 19

Terbinafine

Answer 19

Drug for mucocutaneous infections

• inhibits squalene Epoxidase (ERG1), which leads to toxic accumulation of sterol squalene and inhibits ergosterol biosynthesis
• drugs usually accumulate in the skin, nail and fat to prevent nail beds and skin infections
• synergistic with triazole compounds
• the topical form targets dermatophyte-cause Tinea

Question 20

Nystatin

Answer 20

Topical drug that is an amphotericin derivative.

• it is an ergosterol binder and pore former
• usually used for candidal infections

Question 21

Clotrimazole and miconazole

Answer 21

Oral and vulvovaginal candidiasis as well as dermatophyte infections