• Cholesterol has one double bond in its B ring --> Ergosterol has a conjugated double bond in its B ring
• Cholesterol has no double bond on the alkyl chain at the C-17 position --> Ergosterol has a double on the alkyl chain at the C-17 position
• Cholesterol in mammalian cell membranes --> Ergosterol in fungal cell membranes

Amphotericin B

Nystatin

Natamycin

• Polyenes get inside cell membrane --> interact with ergosterol --> form pores that disrupt permeability of the cell --> interferes with biochemical processes (Glycolysis and Respiration)
• Has some affinity for mammalian cells (dose dependent)
• Activates our immune system -- causes the release of cytokines by circulating monocytes and induces phagocytosis

Amphotericin B because it has more double bonds

The greater number of double bonds = more active

• Nystatin
• The more double bonds, the less toxic
• Nystatin has one less double bond than Amphotericin B so it is more toxic -- this explains why Nystatin cannot be used for systemic infections but Amphotericin B can
• However, Amphotericin B is only used IV when benefits outweigh risks -- it is still a pretty toxic drug

A: poor

D: Slow IV administration for deep fungal infections

M: unknown

E: unknown

• N/V/D (PO)
• Occasional irritation (topical)
• Fever, shaking chills, hypotension
• Severe kidney toxicity (IV)
• Occasionally dyspnea, delirium
• Normochromic, normocytic anemia (inhibition of the erythropoietin production)
• Leukopenia, abdominal pain, anaphylaxis (rare)

Which is the most toxic?

1. Nystatin
2. AmphotericinB
3. Natamycin

Natamycin

Most toxic and therefore least active

• Inhibits 14 alpha-demethylase
• Selective for fungal 14 alpha demethylase
• Binds to heme portion of the enzyme and stops catalytic activity -- the rest of the molecule gives the drug its selectivity for the fungal enzyme

• Extensively and rapidly degraded (1st pass metabolism)
• Primary metabolic route via CYP450 enzymes - CYP3A4

A: at pH of stomach, they will be ionized and not absorbed -- at pH of intestines, they will be neutral

M: potent inhibitor of CYP3A4 (drug interactions), extensively metabolized

A: pH dependent

M: extensively metabolized by CYP3A4 (also an inhibitor), interferes with metabolism of some benzodiazepines

A: equally bioavailable orally or IV

D: crosses BBB

M: inhibition of CYP2C9 (doubles AUC of warfarin), decreases metabolism of phenytoin

• Naftidine
• Terbinafine
• Butenafine
• Tolnaftate

Yes

They are less selective than the Azoles

• Topically adminstered
• First-pass metabolism

• Squalene Epoxide Inhibitors
• Results in build up of squalene which is toxic to cells

• Topical and Tablet
• Extensively metabolized by several CYP450 enzymes
• Strong inhibitor of CYP2D6

Which of the following are the least toxic?

1. Butenafine
2. Terbinafine
3. Naftidine
4. Tolnaftate

THEY AREN'T!

• Anindulafungin degrades over time
• Micafungin undergoes desulfation (sulfate transferase) and you end up with an OH (altogether 2) on the aromatic ring --> it becomes a substrate for Catechol-O-Methyl Transferase (COMT)

• Caspofungin
• Anidulafungin
• Micafungin

IV

No metabolism (degradation) --> no drug interactions

• A Prodrug
• Converted to 5-FU by fungal cytosine deaminase
• Thymidylate Synthase Inhibitor (protein synthesis inhibitor)

• Binds to protein tubulin which interferes with the function of the mitotic spindle to inhibit cell division
• Interferes with DNA replication

• Non-specific metabolic disruption
• Interferes with DNA biosynthesis and cell respiration

• Fungistatic
• Nonspecific interactions with components of the cell wall