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Pharmacology Semester II > EXAM III Antifungals > Flashcards

EXAM III Antifungals Flashcards

1
Q

Fungus Types

A

Kingdom, Eukaryotic, Heterotrophs, Acrophyllus

Yeasts, Molds

Present widely

Approx 300 of pathogenic fungi

  • Candida spp.*
  • Cryptococcus spp.*
  • Aspergillus spp.*
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2
Q

Fungal infections

A

Increasing number of immunocompromised PTs

Transplants

HIV/AIDS

Autoimmune conditions requiring immunosuppression

Cystic fibrosis

Corticosteroid/antibiotic use

Chemo

Can occur in immunocompetent PT as well

Route of transmission

Respiratory

Traumatic implantation

Direct contact

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3
Q

Fungal cell

A
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4
Q

Fungus Structure

A
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5
Q

Antifungal Agents

A

Allylamines - Topical agents

Polyenes

Azoles

Echinocandins

Misc - Flucytosine

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6
Q

Allylamines

A

Topical agents

Indication: Tinea cosporis, tinea pedis, tinea cruris, onychomycosis (terbinafine)

MOA: Inhibition of squalene epoxidase -> reducing fungal cell membrane ergosterol synthesis

Agents:

  • Terbinafine (Lamisil) - Also PO*
  • Butenafine*
  • Naftifine*
  • Amorolfine*
  • * The Fines!*
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7
Q

Terbinafine

A

Renally eliminated

Half-life: 36 Hrs

Terminal Half-Life 200-400 Hrs -> prolonged elimination from skin and adipose

Dose:

  • Fingernails - 250mg PO QD x6 W*
  • Toenails - 250 mg QD x12 W*
  • Tinea - 250 mg PO QD x2 W*

Monitoring

SCr, LFTs (at baseline & throughout treatment), CBC if > 6 weeks tx in immunodeficient PTs

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8
Q

Azoles

A

Imidazoles and triazoles

MOA: Inhibition of 14 alpha-demethylase which converts lanosterol to ergosterol = disruption in cell membrane synthesis; block steroid synthesis in humans

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9
Q

Azoles: Imidazoles

A

Clotrimazole

Ketoconazole

Miconazole

Econazole

Mebendazole

Oxiconazole

Sertaconazole

Thiabendazole

Imidazoles CloK ME MOST

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10
Q

Azoles: Imidazoles Indications

A

Mostly Topical agents

Indications:

  • Tinea* cotporis
  • Tinea pedis*
  • Tinea* cruris
  • Oropharyngeal candidiasis*
  • Vulvovaginal candidiasis*
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11
Q

Ketoconazole

A

Effective against Candida spp., blastomycosis, histoplasmosis (high failure rates)

Excreted in feces

Half-Life: 8 Hrs

CYP450 3A4 substrate -> CYP inhibition = drug interactions

Needs Acidic gastric pH for absorption - think drug interactions w/ H2RA, PPIs, Antacids

Note poor distribution into CSF and eye

Dose:

  • 200-4– mg PO QD*
  • Contraindicated in PTs w/ hepatic impairment*
  • Available in many forms*
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12
Q

Azoles: Triazoles

A

Itraconazole

Fluconazole

Isavuconazole

Voriconazole

Posaconazole

Triazoles IF I VP

Think for systemic invasive fungal infections

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13
Q

Azoles: Triazoles Details

A

MOS: Inhibition of CYP450 and sterol C-14alpha-demethylation

  • THink drug interaction*
  • All azoles inhibit CYP3A4 (Itra&posa > fluc, vori, & isavuconazole)*

Primary Fungistatic

Newer Azoles = less hormonal inhibition, broader spectrum, less toxic, better tissue distribution

Spectrum of activity:

  • Fluconazole &itraonazole: Candida, Aspergillus, Fusarium, Scedosporium, and other molds*
  • Posaconazole and Isavuconazole also cover mucormycosis*
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14
Q

Triazoles - Spectrum of Activity

A
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15
Q

Fluconazole

A

Indication

  • Candidiasis: invasive (oroesophageal/urogenital/vulvovaginal); prophylaxis in BMT recipients/TXT PTs*
  • Cryptococcus: consolidation phase*

80% excreted unchanged in urine; high urine levels

Half-Life: 30Hrs; prolonged in renal impairment (98-125 Hrs)

CNS penetration

Minor inhibition of CYP 3A4/moderate inhibition of CYP 2C9

Dose:

  • Depends on indication*
  • 100-800mg QD*
  • Needs renal adjust*
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16
Q

Itraconazole

A

Indication:

  • Candidiasis: oropharyngeal and esophageal*
  • Maybe a step-down therapy in Aspergillosis (not first line)*

99% protein bound

35% renally eliminated

Half-Life 34-42 Hrs

Dose:

  • Available in capsules or solution -> cannot be interchanged*
  • Capsules need to be given w/ meal*
  • Solution* should be given on an empty stomach and is preferred formulation
  • 200-600mg QD*
  • Requires Renal elimination*
17
Q

Voriconazole

A

Indication

  • Resistant Candida infections*
  • Aspergillosis*
  • Other mold infections*

2% renal elimination

Half-Life is dose-dependent, non-linear kinetics

95% bioavailability, but :

  • Can be unpredictable*
  • Reduced w/high fat meal*

Large Vd with good CNS penetration

Substrate and inhibitor of CYP3A4/2C9/2C19 -> Drug interactions

18
Q

Voriconazole Dosing

A

Dose:

IV: load 6mg/kg Q12H x2 then 4mg/kg Q12H

PO:

  • Weight-Dependent*
  • >40kg: 200-300mg Q12H*
  • <40mg 100-150mg Q12H*
  • Admin 1 Hr before or after meal*

Monitoring

target Cmin 1-5.5mg/L, for severe infections >2mg/mL

Level > 5mg/L=CNS toxicity

SCr, electrolytes, LFTs, ophthalmic exam if therapy > 4 weeks

Side effects

N/V/D. liver dysfunction

Visual abnormalities

HA

hepatotoxicity

19
Q

Posaconazole

A

Indication:

  • Resistant Candida infections*
  • Aspergillosis*
  • Mucorales and other mold infections*

<1% eliminated in urine

Half-Life: 26-35 Hrs

Extensive distribution and penetration into tissues/ potentially therapeutic CSF levels

Potent inhibitor of CYP3A4

Inhibitor and substrate of P-glycoprotein

DEC absorption w/ PPis, H2RA

Oral bioavailability >90% w/high fat meal

20
Q

Posaconazole Dosing

A

Dose:

  • Indication dependent*
  • Tablet: QD delayed release*
  • Suspension: 300-400mg PO TID -QID*
  • IV: 300mg Q12H x1 day then QD*
  • Caution w/ oral admin-> slow onset*

No renal adjustment

Monitoring

SCr, electrolytes, LFTs

Side Effects: GI, HA, rare hepatotoxicity, QTc prolongation, hemolytic uremic syndrome

21
Q

Isavuconazole

A

Indication:

  • Invasive Aspergillosis*
  • Mucormycosis*

Admin as pro-drug; Isavuconazonium

Cleared primarily via Fecal excretion

Half-Life: 130 Hrs

Substrate of CYP3A4

Contraindicated with potent 3A4 inhibitors and inducers

22
Q

Isavuconazole Dosing

A

Dose:

  • Loading dose: 372mg IV/PO Q8H x2 days then QD*
  • 372mg=200mg of isavuconazole*
  • No dose adjust in hepatic/renal impairments*

Contraindicated in familial short QT syndrome

DDIs: Inhibits CYP3A4, P-glycoprotein, and OCT-2

Side Effects: GI, hypokalemia, elevated LFTs, HA

Monitor: LFTs

23
Q

Polyenes

A

MOA: Bind w/ sterols in the fungal cell membrane (principally ergosterol), leads to the cell contents leak out ultimately cell death.

Agents:

  • Nystatin*
  • Amphotericin B*
24
Q

Nystatin

A

Indication

Candida spp only

Minimal Systemic absorption -> almost entirely excreted in feces unchanged

Too toxic for systemic admin

Dose:

  • Oropharyngeal candidiasis: 4-6 ml PO QID; retain in mouth as long as possible*
  • Intestinal candidiasis: 5-10ml PO TID*
  • Also admin topically*
25
Q

Amphotericin B

A
26
Q

Amphotericin B Dosing

A

Exact routes for elimination and metabolism

>90% protein bound

Terminal Half-Life:>15 days

Dose:

  • AmB-d: 0.3-1.5 mg/g/day*
  • L-AmB: 3-5mg/kg/day*
  • No dose adjust*
27
Q

Amphotericin AmB-d

A

Nephrotoxic

ARF in 50% of PTS

Infusion-related reaction

  • Pre-medicate w/ APAP or IBU, diphenhydramine +/- steroids*
  • Rigors: meperidine*

Side Effects:

  • Thrombophlebitis, cardiac arrhythmias, rash*
  • Dose-dependent decrease in GFR (vasoconstrictive effect on renal arterioles)*
  • Decrease erythropoietin production*
  • Electrolyte derangement*

Monitor:SCr, BUN, electrolytes, CBC, LFTs

28
Q

Amphotericin B L-AmB

A

L-AMB

  • Less toxicities vs AmB-d*
  • Less nephrotoxic*
  • Reduced frequency and severity of infusion-related reactions*

Higher Cmax and larger AUC

Higher tissue concentrations vs other AmB formulations

Hepatotoxicity: INC alk, phos, and conjugated bili

29
Q
A

Pharmacology Semester II (21 decks)

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