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Pharmacology > Antifungal Drugs > Flashcards

Antifungal Drugs Flashcards

1
Q

Drugs that alter cell membrane?

A

Drugs that alter cell membrane?
Polyenes
Azoles
Allylamines

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2
Q

Drugs that block nucleic acid synthesis

A

Flucytosine

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3
Q

Drugs that disrupt microtubule function

A

Griseofulvin

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4
Q

Drugs that disrupt the fungal cell wall

A

Echinocandins

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5
Q

SYSTEMIC DRUGS FOR SUBCUTANEOUS AND

SYSTEMIC MYCOSES

A
  • Amphotericin B
  • Flucytosine
  • Azoles
  • Echinocandins
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6
Q

Amphotericin B description and MOA? Antifungal activity?

A

• Polyene antibiotic.

MOA:
• Amphotericin B binds to ergosterol, forming
pores in the cell membrane.
• The pores allow leakage of intracellular ions and
macromolecules, leading to cell death.

Antifungal Activity:
• Antifungal agent with the broadest spectrum of
action.
• It has activity against the clinically significant
yeasts, the organisms causing endemic
mycoses, and the pathogenic molds.

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7
Q

AMPHOTERICIN B: PHARMACOKINETICS

A

• Amphotericin B is highly insoluble: formulated as
deoxycholate colloidal suspension.
• Poorly absorbed from the GI tract.
• Must be given IV.
• Penetration into the CSF is extremely low.
• Intrathecal therapy may be necessary for
meningeal disease.

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8
Q

Amphotericin B uses?

A

• Broad spectrum and fungicidal action: useful for
nearly all life-threatening fungal infections.
• Often used as initial induction regimen to
rapidly reduce fungal burden.
• Then patients continue therapy with an azole.
• Given by slow IV infusion.
• Amphotericin B is the preferred treatment for
deep fungal infections during pregnancy.

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9
Q

AMPHOTERICIN B: ADVERSE EFFECTS INFUSION-RELATED TOXICITY?

A

INFUSION-RELATED TOXICITY
• Nearly universal. Fever and chills, muscle
spasms, vomiting, headache and hypotension.
• Can be attenuated by slowing infusion rate or
decreasing daily dose.
• Pre-medication with antihistamines,
glucocorticoids, antipyretics or meperidine can
be helpful.

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10
Q

AMPHOTERICIN B: ADVERSE EFFECTS SLOWER TOXICITY Renal related?

A

• Amphotericin B also binds to cholesterol and forms
pores in mammalian cell membranes, leading to
renal toxicity.
• Renal impairment occurs in nearly all patients.
• Azotemia occurs in most patients.
• GFR may be decreased.
• Renal toxicity commonly presents with renal tubular
acidosis with severe magnesium and potassium
wasting.
• Renal damage can be attenuated with sodium
loading: it is common practice to administer saline
infusion with amphotericin B.

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11
Q

AMPHOTERICIN B: ADVERSE EFFECTS SLOWER TOXICITY other areas?

A

• Abnormalities of liver function tests occasionally
seen.
• Hypochromic normocytic anemia, due to reduced
erythropoietin production.
• Renal function should be monitored frequently
during amphotericin B therapy.
• It is also advisable to monitor liver function, serum electrolytes (particularly magnesium and
potassium), blood counts, and hemoglobin.
• Intrathecal administration can cause seizures and
serious neurological damage.

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12
Q

AMPHOTERICIN B: LIPID FORMULATIONS?

A

• The three FDA-approved lipid formulations of
amphotericin B are:
• Liposomal amphotericin B (L-AMB)
• Amphotericin B lipid complex (ABLC)
• Amphotericin B colloidal dispersion (ABCD)
• Nephrotoxicity is less common and less severe
with the lipid formulations.

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13
Q

FLUCYTOSINE description and MOA?

A

• Synthetic pyrimidine antimetabolite.
• Taken by fungal cells via the enzyme cytosine
permease.
• Converted intracellularly first to 5-fluorouracil (5-
FU) and then to 5-fluorodeoxyuridine
monophosphate (5-FdUMP) which inhibits
thymidylate synthetase, thus blocking synthesis of dTMP.
• Fluorouridine triphosphate (5-FUTP) is also
formed, which inhibits protein synthesis.
• Mammalian cells are unable to convert the
parent drug to its active metabolites.
• Combination of flucytosine and amphotericin
B is synergistic.

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14
Q

FLUCYTOSINE: SPECTRUM?

A

• Fungistatic
• Narrow spectrum.
• Not used as a single agent because of synergy
with other agents and to avoid development of
resistance.

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15
Q

FLUCYTOSINE: USES?

A

• Indicated only for serious infections caused by
susceptible strains of Candida and/or
Cryptococcus.
• Should be used in combination with
amphotericin B for the treatment of systemic
candidiasis and cryptococcosis in order to avoid resistance.

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16
Q

FLUCYTOSINE: ADVERSE EFFECTS?

A

• Result from metabolism (possibly by intestinal
flora) to 5-fluorouracil.
• Bone marrow toxicity is the most common.

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17
Q

Description of Azole?

List 3 imidazoles?

A
  • Relatively nontoxic oral drugs.
  • Important role in systemic therapy.
  • Classified as imidazoles or triazoles.

Imidazoles
• Ketoconazole
• Miconazole
• Clotrimazole

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18
Q

List 4 Triazoles?

A
  • Itraconazole
  • Fluconazole
  • Voriconazole
  • Posaconazole
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19
Q

Azoles MOA?

A

• The fungal cytochrome P450 enzyme 14-α-sterol demethylase catalyzes the conversion of lanosterol to ergosterol.
• Azoles inhibit the enzyme, thus reducing ergosterol synthesis.
• This disrupts membrane function and increases
permeability.
• Specificity of azole drugs results from their
greater affinity for fungal than for human P450
enzymes.
• Triazoles are more specific than imidazoles.

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20
Q

Azoles AE?

A
  • Relatively nontoxic.

* Most common adverse reaction: minor GI upset.

21
Q

Ketoconazole description and moa?

A

• Inhibits mammalian cytochrome P450 enzymes.
• Can decrease plasma testosterone levels and
cause gynecomastia, decreased libido and loss
of potency in men and menstrual irregularities in
women.
• High doses may inhibit adrenal steroid synthesis
and decrease plasma cortisol concentrations.

22
Q

Ketoconazole PK?

A

• Strong inhibitor of CYP3A4. It can potentiate the
toxicities of several drugs such as warfarin and
cyclosporine.
• Best absorbed at low gastric pH: antacids, H2
blockers or proton pump inhibitors interfere with
absorption of ketoconazole.
• Poor penetration in the CSF.

23
Q

Ketoconazole uses?

A

• Due to its narrow spectrum and adverse effects
ketoconazole is rarely used for systemic
mycoses.
• Still used for superficial mycoses

24
Q

Fluconazole PK?

A
  • Good CSF penetration.
  • High oral bioavailability.
  • Available in oral and IV formulations.
  • Moderate inhibitor of CYP3A4.
  • Strong inhibitor of CYP2C9: can increase plasma levels of phenytoin, zidovudine and warfarin.
25
Q

Fluconazole uses?

A

• DOC in esophageal, oropharyngeal,
vulvovaginal or urinary candidiasis.
• DOC for candidemia.
• DOC for coccidioidomycosis.
• DOC for consolidation and maintenance therapy of cryptococcal meningitis after
induction with amphotericin B.
• Alternative to amphotericin B for non-severe
criptococcal meningitis.
• DOC for initial and secondary prophylaxis
against cryptoccocal meningitis.
• Ineffective against Aspergillus or other
filamentous fungi.

26
Q

Itraconazole PK?

A

• Metabolized primarily by CYP3A4.
• Strong inhibitor of CYP3A4. May cause potentially fatal arrhythmias when given
concurrently with cisapride or quinidine.
• Poor bioavailability.
• Penetrates poorly in CSF.
• Absorption reduced by antacids, H2 blockers
and proton pump inhibitors.

27
Q

Itraconazole uses?

A

• Preferred azole for mycoses due to the
dimorphic fungi Blastomyces, Sporothrix and
Histoplasma.
• Effective against Aspergillus, but has been
replaced by voriconazole for this indication.
• Used for dermatophytoses and onychomycosis.

28
Q

Voriconazole spectrum, DOC, pk, drug interaction and AE?

A

• Spectrum similar to itraconazole.
• DOC for invasive aspergillosis.
• Transient visual disturbances occur in up to 30% of patients.
• Voriconazole is metabolized by and inhibits
CYP2C19, CYP2C9 and CYP3A4.
• The significant number of drug interactions due
to its metabolism through the various hepatic
enzymes may limit its use.

29
Q

Posaconazole pk and spectrum?

A

• Spectrum similar to itraconazole, but it has
activity against Zygomycetes such as Mucor.
• Inhibits CYP3A4.

30
Q

ECHINOCANDINS: CASPOFUNGIN description, spectrum, pk, moa?

A

• Large cyclic peptides linked to a long-chain
fatty acid.
• Active against candida and aspergillus but
not Cryptococcus neoformans.
• Only available IV.
• Inhibit synthesis of beta(1-3)-D-glucans in the
fungal cell wall.
• This results in disruption of the fungal cell wall
and cell death.

31
Q

DRUGS FOR SUPERFICIAL MYCOSES

A
  • SYSTEMIC DRUGS

* TOPICAL DRUGS

32
Q

SYSTEMIC DRUGS FOR SUPERFICIAL MYCOSES?

A
  • Griseofulvin
  • Terbinafine
  • Ketoconazole
  • Fluconazole
  • Itraconazole
33
Q

Griseofulvin overview, moa

A

• Only use: treatment of dermatophytosis.
• Absorption improved when given with fatty
foods.

MECHANISM OF ACTION
• Disrupts mitotic spindle and inhibits mitosis.

34
Q

GRISEOFULVIN: USES

A

• Severe dermatophytoses of the skin, hair, and
nails.
• Largely replaced by newer antifungal drugs like
itraconazole and terbinafine.
• Induces P450 enzymes: increases metabolism
of a number of drugs, including warfarin.

35
Q

TERBINAFINE description, moa, uses?

A 
• Allylamine.
• Available in oral formulation.
• Inhibition of squalene
epoxidase prevents
synthesis of ergosterol.
• It also causes
accumulation of toxic
levels of squalene in the
fungal cell.
• Effective in onychomycosis.
36
Q

TERBINAFINE: ADVERSE EFFECTS?

A
  • GI upsets, rash, headache, taste disturbances.
  • Elevations in serum liver transaminases.
  • Inhibits CYP2D6.
37
Q

Which azoles are used for treatment of dermatophytosis?

A

• Ketoconazole, fluconazole and itraconazole are commonly used orally in
the treatment of dermatophytoses.

38
Q

TOPICAL DRUGS FOR SUPERFICIAL MYCOSES?

A
  • Nystatin
  • Amphotericin B
  • Clotrimazole
  • Miconazole
  • Ketoconazole
  • Terbinafine
39
Q

Nystatin overview and moa

A
  • Polyene macrolide.
  • Structurally similar to amphotericin B.
  • Same mechanism of action.(binding to ergosterol)
40
Q

Nystatin pk and AE?

A
  • Too toxic for IV administration.
  • Used only for candidiasis.
  • Supplied in preparations for cutaneous, vaginal, or oral administration.
  • Not absorbed from the GI tract, skin, or vagina.
  • As a result it has little significant toxicity.
41
Q

Topical amphotericin B used for?

A

cutaneous candidiasis.

42
Q

Which two topical azoles used for superficial mycoses?

A

• The two azoles most commonly used
topically are clotrimazole and miconazole.
• Both available over-the-counter

43
Q

Terbinafine uses?

A
  • Available as topical creams.

* Effective for tinea cruris and tinea corporis.

44
Q

Primary therapy for each Infection?

Esophageal candidiasis

Urinary candidiasis

Oropharyngeal
candidiasis

Vulvovaginal candidiasis

Recurrent vulvovaginal
candidiasis

Candidemia

Cutaneous candidiasis

A

Infection Primary Therapy
Esophageal candidiasis- IV or Oral Fluconazole

Urinary candidiasis IV or Oral Fluconazole

Oropharyngeal
candidiasis
Mild: Topical Clotrimazole or Nystatin.
Moderate to severe: Oral Fluconazole

AIDS patient: Oral Fluconazole

Vulvovaginal candidiasis Topical Azoles or Oral Fluconazole

Recurrent vulvovaginal
candidiasis
Oral Fluconazole
Candidemia IV Fluconazole or an IV Echinocandin
Cutaneous candidiasis Topical Amphotericin B or Topical
Azole or Topical Nystatin

45
Q

Description of pneumocystis jirovecii pneumonia?

A

• Pneumocystis jirovecii is the cause of Pneumocystis pneumonia (PCP).
• The organism is a fungus but it does not
respond to antifungals.
• P carinii is now recognized to be the cause of
animal infections.

46
Q

PCP clinically presents as?

A

• PCP is a common cause of pneumonia in
immunosuppressed patients.
• It is the most common opportunistic infection in
HIV-infected patients.
• Symptoms include fever, dyspnea, and cough.

47
Q

Therapy for PCP? Alternative therapies?

A 
THERAPY
• DOC: co-trimoxazole.
• Co-trimoxazole is also DOC for prevention of P
jiroveci infection in immunocompromised
individuals. 
• Alternative therapies are:
• Clindamycin + primaquine
• Dapsone + trimethoprim
• Atovaquone
• Pentamidine
• Patients with moderate-to-severe disease should
also be given prednisone.
48
Q

Treatment for infection

Cryptococcosis

Invasive aspergillosis

Mucormycosis

Fusariosis

Onychomycosis

A

Cryptococcosis Amphotericin B + Oral FlucytosineThen Oral Fluconazole

Invasive aspergillosis IV and then Oral Voriconazole

Mucormycosis Amphotericin B

Fusariosis Amphotericin B

Onychomycosis Oral Terbinafine or Oral Itraconazole
or Oral Fluconazole

Pharmacology (49 decks)

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