EXAM 3- KHAN - ANTIFUNGALS

2 major classes of fungal infections?

• superficial fungal infections

• invasive fungal infections

What are the antifungal drug classes?

• Inhibitors of fungal membrane stability

  • Polyenes

    • Amphotericin B

    • Nystatin

• Inhibitors of nucleic acid synthesis

  • Flucytosine

• Inhibitors of ergosterol synthesis

  • Azoles

  • Allylamines

• Inhibitors of fungal wall synthesis

  • Echinocandins

• Inhibitor of fungal mitosis

  • Griseofulvin

What are the structural features of Amphotericin B?

Is this drug soluble or insoluble in water

• has many double bonds—> INSOLUBLE IN WATER

• has large macrolide lactone ring (a cyclic ester)

What is the composition of conventional Amphotericin B?

Amphotericin B complexed with deoxycholate

What are the advantages of using liposomal preparation for Amphotericin B?

• LESS NEPHROTOXIC than conventional preparation

• less infusion related rxns

What’s the difference in cell walls between fungi and mammals?

• fungi—> uses ergosterol in membrane

  • fxn: structural support, ion transport, enzyme activity

• mammals—> use cholesterol in membrane, NO ERGO

MOA of inhibitors of fungal membrane stability like Amphotericin B and Nystatin?

• binds to ergosterol of fungal membrane

  • destroys integrity of membrane—> forms pores/channels

  • increase in permeability—> cell contents leak= cell death

Is Amphotericin B selective or non-selective towards fungal cells?

selective towards fungal cells, no ergo in mammal cells

Answer the following about the PK of Amphotericin B:

• absorption?

• distribution?

• excretion?

• A- poor oral, only IV route

• D- long t 1/2 , no CNS pen.

• E- kidneys, slow

Main ADRs with Amphotericin B?

• infusion related reactions (fever, shakes, chills, hypotension, tachypnea)

• nephrotoxicity

How do you manage infusion-related rxns associated with Amphotericin B?

• decrease rate of drug admin

• use of opioids, NSAIDs, or hydrocortisone to decrease rxns

Amphotericin B causes nephrotoxicity.

• what is the mechanism behind this?

• what electrolytes are altered?

• which agents should not be co-administered?

• mechanism: vasoconstriction of afferent arterioles, renal ischemia

• electrolytes: hypoKALEMIA, hypoMAGNESEMIA

• agents to avoid/caution: other nephrotoxic agents (NSAIDs, aminoglycosides), hypokalemic agents (loop diuretic)

What’s the oral bioavailability of nystatin?

poor—> topical product only

What antifungal has an allyl amine group? IDENTIFY IT!!!!!!

• Terfinabine

• 

MOA of terfinabine?

• inhibits ergosterol synthesis

  • inhibits squalene epoxidase

    • responsible for squalene to squalene epoxide

    • squalene accumulation= toxic to fungal cells

How is the selectivity of Terfinabine?

• selective towards fungal cell!!

  • only inhibits mammal squalene epoxidase at high conc

IDENTIFY SQUALENE EPOXIDE:

NOTE HOW THE SQUALENE EPOXIDE HAS AN -O- group

Answer the following about the PK of Terfinabine:

• Absorption?

• bound?

• excretion?

• A- PO or topical, well absorbed PO, bioavailability decreased due to 1st pass effect

• 99% protein bound—> accumulates in skin, nails, fat

• E- kidney

Terfinabine INHIBITS CYP____.

Terfinabine INHIBITS CYP2D6..

List the names of the azole antifungals:

• Fluconazole

• Itraconazole

• Posaconazole

• Voriconazole

• Isavuconazonium

• Clotrimazole

• Miconazole

• Ketoconazole

What is the ONLY azole antifungal that contains a THIAZOLE?

(note: TRIAZOLE AND THIAZOLE not the same thing)

Isavuconazonium

What azole antifungals contain an IMIDAZOLE?

• Ketoconazole

• Clotrimazole

• Miconazole

What azole antifungals contain an TRIAZOLE?

(note: TRIAZOLE AND THIAZOLE not the same thing)

• Fluconazole

• Itraconazole

• Posaconazole

• Voriconazole

Be able to IDENTIFY a Imidazole and triazole group!!!!

Tip: notice how a TRIazole has 3 nitrogens!!!!!!!!

What is the MOA of azole antifungals?

(be able to identify which methyl group is normally removed)

• Inhibits 14-a-demethylase CYP enzyme

  • Inhibits demethylation of Lanosterol to Ergosterol

    • Ergosterol analog formed lacks proper properties—> membrane leakage= cell death

HOW do azoles inhibit the 14-a-demethylase enzyme?

N on azole antifungals forms a bond to the heme iron prevent 14-a-demthylase from normal action

What are the adverse effects of ketoconazole?

• fatal hepatotoxicity

• inhibits steroid biosynthesis

• drug interactions

What are the resistance mechanism to azoles?

• Mutations in gene coding for 14-a-demethylase

• Increase azole efflux

• Increased production of 14-a-demethylase

Answer the following about the PK of Fluconazole:

• absorption?

• tissue penetration?

• excretion?

(idk how imp)

• complete absorption from GIT

• CSF penetration good

• renal excretion

Describe each of the followings interactions with CYP enzymes:

• Fluconazole

• Voriconazole

• Itraconazole

• Posaconazole

• Fluconazole- inhibits CYP3A4 (weak), CYP2C9 (STRONG)

• Voriconazole- inhibits CYP3A4, 2C9, 2C19

• Itraconazole- METABOLIZED by CYP3A4—> less d/i

• Posaconazole- inhibits CYP3A4

What ADR is seen in Fluconazole, Voriconazole, Itraconazole, and Posaconazole?

QT prolongation (tip: these are all triazoles)

ADRs of Fluconazole:

• GI, HA, dizzy

• increased LFTs

• QT PROLONGATION

ADRs of Voriconazole:

• increased LFTs, SCr

• QT prolongation

• hallucinations

• visual disturbances

ADRs of Itraconazole:

• QT prolongation

• Congestive HF

  • C/I in pts. with ventricular dysfunction or CHF

ADRs of Posaconazole:

• increased LFTs

• QT prolongation

How is POSACONAZOLE METABOLIZED?

UDP-glucuronidation (tip: UDP = Posaconazole)

How is Isavuconazium activated?

ester prodrug—> converted to isavuconazole by esterase

What drugs are Echinocandins?

• Caspofungin (Cancidas)

• Anidulafungin (Eraxis)

• Micafungin (Mycamine)

MOA of Echinocandins:

• Inhibits fungal cell wall synthesis

  • By inhibiting synthesis of beta(1-3) glucan

    • Component of cell wall (glucose homopolymers)

ADRs of Echinocandins:

• Histamine mediated effects (rash, pruritic, facial swelling)

• Increased LFTs

• Electrolyte disturbances

Describe the PK of Echinocandins:

• binding?

• metabolism?

• excretion

• CNS penetration

• CYPs?

(idk how imp)

• protein binding 97%

• metabolism—> peptide bond hydrolysis, N-acetylation

• excretion—> biliary

• minimal CNS penetration

• not a CYP inducer/ any interactions with P-gp

ROA of Echinocandins?

IV

Describe the structure of Echinocandins:

cyclic peptide linked to a side chain

Describe the structure of Griseofulvin:

• what functional groups?

• benzofuran

• 

MOA of Griseofulvin:

• mitotic inhibitor

  • binds to tubulin and microtubule-associated protein

    • disrupts assembly of mitotic spindle

What other effect is see by Griseofulvin besides its MOA?

• Accumulates in keratin precursor cells

  • Prolonged association= new growth of skin, hair, nails

Answer the following about Griseofulvin:

• absorption?

• ADRs?

(idk how important)

• PO, absorption increased with fatty meal

• ADRs: HA, GI

What antifungal (that Khan talked about) is C/I in pregnancy?

Griseofulvin

Be able to Identify 5-flucytosine and 5-FU:

What is the function of cytosine permease?

cytosine permease—> cytosine transporter, takes up Flucytosine into fungal cell

What is the function of cytosine deaminase?

cytosine deaminase—> enzyme, inside fungal cells converts Flucytosine to 5-FU via deamination

What is the function of 5-fDUMP?

Inhibits thymidylate synthase= inhibits DNA synthesis

How does 5-FU acquire resistance?

• Loss of cytosine permease for cytosine transport

• Decreased activity of cytosine deamine

ADRs and BBW of Fluocytosine:

• ADRs:

  • BMS (leukopenia, thrombocytopenia)

  • increased SCr and liver enzymes

• BBW:

  • extreme caution in pts. with renal dysfunction

  • monitor hematologic, renal, and hepatic status