Antifungals Flashcards
1
Q
ANTIFUNGAL DRUGS CLASSIFIED BY MOA
A
- Drugs that alter cell membrane permeability: Polyenes, Azoles, Allylamines
- Drugs that block nucleic acid synthesis: Flucytosine
- Drugs that disrupt microtubule function: Griseofulvin
- Drugs that disrupt the fungal cell wall: Echinocandins
2
Q
SYSTEMIC DRUGS FOR SUBCUTANEOUS AND SYSTEMIC MYCOSES
A
- Amphotericin B
- Flucytosine
- Azoles
- Echinocandins
3
Q
AMPHOTERICIN B
A
- Polyene antibiotic.
- 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.
- Often used as initial induction regimen to rapidly reduce fungal burden.
- Then patients continue therapy with an azole.
**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.
**Indications: **Cryptococcus
PK
- Amphotericin B is highly insoluble: formulated as deoxycholate colloidal suspension.
- Poorly absorbed from the GI tract.
- Must be given IV (slow infusion).
- Penetration into the CSF is extremely low.
- Intrathecal therapy may be necessary for meningeal disease.
- Amphotericin B is the preferred treatment for deep fungal infections during pregnancy.
4
Q
AMPHOTERICIN B: ADVERSE EFFECTS
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 for 2 wk
- Pre-medication with antihistamines, glucocorticoids, antipyretics or meperidine can be helpful.
SLOWER TOXICITY
- Amphotericin B also binds to cholesterol and forms pores in mammalian cell membranes, leading to renal toxicity.
- Renal impairment occurs in nearly all patients.
- Renal damage can be attenuated with sodium loading: it is common practice to administer saline infusion with amphotericin B.
- Hypochromic normocytic anemia, due to reduced EPO production.
- advisable to monitor liver function, serum electrolytes (particularly magnesium and potassium), blood counts, and hemoglobin.
- Intrathecal administration can cause seizures and serious neurological damage.
Pregnancy
- Induction should be performed with Amphotericin B (pregnancy category B) with or without flucytosine.
5
Q
AMPHOTERICIN B: LIPID FORMULATIONS
A
- 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.
6
Q
FLUCYTOSINE including Adverse
A
Synthetic pyrimidine antimetabolite.
Taken by fungal cells via the enzyme cytosine permease.
Converted first to 5- FU and then to 5-fluorodeoxyuridine monophosphate (5-FdUMP) which inhibits thymidylate synthetase, thus blocking synthesis of dTMP -> suicide inhibitor
MOA:
- 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.
Uses
- 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.
Adverse:
- Bone marrow toxicity is the most common.
- Flucytosine is a category C drug for pregnancy, and therefore, its use must be considered in relationship to benefit versus risk. Fluconazole (pregnancy category C)
7
Q
AZOLES including adverse
A
- Relatively nontoxic oral drugs.
- Important role in systemic therapy.
- Classified as imidazoles or triazoles.
Imidazoles
- Ketoconazole
- Miconazole
- Clotrimazole
Triazoles
- Itraconazole
- Fluconazole
- Voriconazole
- Posaconazole
MOA
- Azoles inhibit the 14-alpha-demethylase converting of lanosterol to ergosterol
- 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.
Adverse
- Relatively nontoxic.
- Most common adverse reaction: minor GI upset.
8
Q
Ketoconazole
A
- Strong inhibitor of 3A4
- 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.
- Best absorbed at low gastric pH:antacids,H2 blockers or proton pump inhibitors interfere with absorption of ketoconazole.
- Poor penetration in the CSF.
Uses
- Due to its narrow spectrum and adverse effects ketoconazole is rarely used for systemic mycoses.
- Still used for superficial mycoses.
9
Q
FLUCONAZOLE
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.
Uses
- 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.
**PK: **
- highly water soluble so highly absorable (CSF: serum conc ratio > 0.7)
- renal excretion
10
Q
ITRACONAZOLE
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.
Uses
- 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.
11
Q
VORICONAZOLE
A
- Spectrum similar to itraconazole.
- DOC for invasive aspergillosis.
- Transient visual disturbances occur inupto30% 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.
12
Q
POSACONAZOLE
A
- Spectrum similar to itraconazole, but it has activity against Zygomycetes such as Mucor.
- Inhibits CYP3A4.
13
Q
ECHINOCANDINS: CASPOFUNGIN
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.
14
Q
SYSTEMIC DRUGS FOR SUPERFICIAL MYCOSES
A
- Griseofulvin
- Terbinafine
- Ketoconazole
- Fluconazole
- Itraconazole
15
Q
GRISEOFULVIN including adverse
A
- Only use: treatment of dermatophytosis.
- Absorption improved when given with fatty foods.
**MOA: **Disrupts mitotic spindle and inhibits mitosis.
**Uses: **Severe dermatophytoses of the skin,hair,and nails.
Adverse: Induces P450 enzymes: increases metabolism of a number of drugs, including warfarin.
22
Q
Opportunistic infections may appear in HIV-infected Pt according to CD4+ count
A
The risk for specific opportunistic infections varies with the degree of immunosuppression.
- Asymptomatic patients with moderate immunosuppression (CD4+ counts 200–500) may become infected with herpes viruses and Candida and/or develop pneumonias, enteric infections, and meningitis with common pathogens.
- A CD4+ count < 200 increases the risk for opportunistic pathogens (e.g., PCP), opportunistic tumors, wasting, and neurologic complications.
- With a CD4+ count of 50 to 100, invasive candidiasis, cerebral toxoplasmosis, cryptococcosis, and various protozoal infections are observed.
- When the CD4+ count falls below 50, the patient is in an advanced immunosuppressed state, which is associated with non-Hodgkin lymphoma (NHL), CMV, and disseminated Mycobacterium avium complex.
