Therapeutics ID Nieto Flashcard

Cholesterol Vs Ergosterol

  • 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

Polyenes

Amphotericin B

Nystatin

Natamycin

Polyenes: MOA

  • 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

Which is more active?  Nystatin or Amphotericin B

Amphotericin B because it has more double bonds

The greater number of double bonds = more active

Which is more toxic?  Nystatin or Amphotericin B

  • 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

Polyenes ADME

A: poor

D: Slow IV administration for deep fungal infections

M: unknown

E: unknown

Polyenes: Adverse Effects

  • 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

 

 

Azoles: MOA

  • 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

Metabolism of Azoles

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

 

Ketoconazole: Absorption and Metabolism

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

Itraconazole: Absorption and Metabolism

A: pH dependent

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

Fluconazole: ADM

A: equally bioavailable orally or IV

D: crosses BBB

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

 

Allylamines: Drug Names

  • Naftidine
  • Terbinafine
  • Butenafine
  • Tolnaftate

Will Allylamines affect human cells?

Yes

They are less selective than the Azoles

Naftidine: Administration and Metabolism

  • Topically adminstered
  • First-pass metabolism

Allylamines: MOA

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

Terbinadine: Adminstration and Metabolism

  • 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

1 and 4
Morpholines: MOA
Inhibits Δ8, Δ7-isomerase and Δ14-reductase
How are Echinocandins metabolized?

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)

Echinocandins: Drug Names

  • Caspofungin
  • Anidulafungin
  • Micafungin

Echinocandins: MOA
Glucan Synthesis Inhibitors
Echinocandins: Administration and Metabolism

IV

No metabolism (degradation) –> no drug interactions

Flucytosine: MOA

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

 

Griseofulvin: MOA

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

Haloprogin: MOA

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

Undecylenic Acid: MOA

  • Fungistatic
  • Nonspecific interactions with components of the cell wall

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