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63 Cards in this Set
- Front
- Back
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What is the mechanism of Amphotericin B? |
Formation of a pore in the fungal membrane by binding to ergosterol
FUNGICIDAL |
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What is the mechanism of resistance to Amphotericin B?
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Rare
When it does happen, it's due to the alteration in membrane ergosterol |
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What is the absorption of Amphotericin B?
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None in the GI tract
Administered via IV |
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What is the distribution of Amphotericin B?
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Widely distributed
Sequestered into cell membranes (think logically here: sterols in human membranes. Side effects, long distribution) Poor CSF penetrance |
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What is the metabolism and half life of Amphotericin B?
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Terminal half life of 15 days
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What is the excretion of Amphotericin B?
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2-5% excreted unchanged in the urine after IV dose.
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What are the adverse effects of Amphotericin B? |
Fever within an hour
NEPHROTOXICITY
Anemia
1. Infusion related Fever, chills, muscle spasms, shock like fall in bp
2.dose limiting Decreased glomerular filtration rate, renal tubular acidosis, hypokalemia, hypomagnesimia, anema(decreased epo)
Lower toxicity with flu cytosine or as liposomal formulation
3.neurotoxicity Intrathecal injection causes seizures and neurological damage |
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What formulation of Amphotericin B decreases nephrotoxicity?
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Lipid formulation
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What is the mechanism of nephrotoxicity with Amphotericin B?
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Binding to the sterols inside kidney cell membranes, increasing perameability
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What are the clinical uses of Amphotericin B? |
Broad spectrum antifungal IV administration for severe fungal infections
Systemic infections by Aspergillus, Blastomyces, Candida albicans, cryptococcus, histoplasma, mucor |
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What other antifungal drug is Amphotericin B commonly administered with?
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Flucytosine
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What other antifungal drug is Flucytosine commonly administered with?
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Amphotericin B
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What enzyme is necessary for the activation of 5-Flucytosine? Where is it found?
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Cytosine deaminase
Inside fungi |
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What is the active form of 5-Flucytosine? What kind of drug is this normally?
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5-Fluorouracil
A chemotherapeutic |
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What is the mechanism of action of 5-Flucytosine?
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Inhibition of DNA synthesis through blocking of thymadylate synthase
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In what situations does resistance to 5-Flucytosine develop?
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When the drug is used alone.
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What are the mechanisms of resistance to 5-Flucytosine?
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Decreased uptake of the drug through alterations of membrane transporters
Decreased activation of the drug by cytosine deaminase |
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What is the bioavailability of 5-Flucytosine?
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Very available orally
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What is the distribution of 5-Flucytosine?
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Widely distributed
PENETRATES THE CSF WELL! |
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What are antifungal drugs that can penetrate the CSF?
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5-Flucytosine
Fluconizole |
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What is the metabolism and half life of 5-Flucytosine?
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Needs to be metabolized to 5-florouracil by cytosine deaminase for activity
T1/2 = 3-6 hr. |
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What is the excretion of 5-Flucytosine?
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80% excreted unchanged in urine
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What are the adverse effects of 5-Flucytosine? |
Reversible Bone marrow toxicity Elevation of hepatic enzymes GI irritation
Alopecia
All of these are more prevalent in AIDS patients |
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What is the mechanism of bone marrow toxicity by 5-Flucytosine?
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Conversion of 5-Flucytosine to 5-Fluorouracil by GI flora
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What is the typical clinical use of 5-Flucytosine + Amphotericin B?
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Severe Cryptococcus infections
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What is the mechanism of action by Azole antifungals.
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Inhibition of lanosterol 14-alpha-demethylase
Can't convert lanosterol to ergosterol FungiSTATIC |
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Are the Azoles highly selective for fungal enzymes?
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No...not too terribly selective.
IC50 is only 10X greater in humans. |
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What are the mechanisms of resistance to the Azole antifungals?
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Decreased accumulation of azole due to increased efflux by ATP binding cassette proteins
Decreased affinity of lanosterol-14alpha-demethylase for the azole Overepxression of lanosterol-14alpha-demhtylase |
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What are the four Azole antifungals?
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Fluconazole
Itraconazole Voriconazole Posaconazole |
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What is the Azole antifungal that penetrates the CSF?
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Fluconazole
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What is the Azole antifungal that is metabolized in a short period of time?
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Voriconazole
6 hrs. |
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What are the two Azole antifungals that are excreted in the bile?
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Itraconazole
Posaconazole |
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What is the Azole antifungal that is excreted renally and penetrates the CSF?
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Fluconazole
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What is the absorption of Azole antifungals?
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Orally bioavailable
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What are the adverse effects of Azole antifungals? |
GI disturbances Hepatotoxicity (sometimes) Teratogenic to fetuses: DON'T USE IN PREGNANCY!
Vomiting, diarrhea, rash
Ketoconazole CYP450 inhibition Gynecomastia, menstrual irregularities, infertility
Voriconazole Visual disturbence Pregnancy risk
Posaconzazole Inhibitor of CYP 3A4 Increased level of cyclosporine and tacrolimus |
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What is the Azole antifungal that causes visual disturbances?
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Voriconazole
See funny colored lights |
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What liver enzyme does the Azole antifungals effect? What is the effect?
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CYP3A4, a hepatic P450 enzyme. Inhibition
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What enzyme metabolizes the Azole antifungals?
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CYP3A4
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What is an example of a drug that can decrease the plasma levels of Azole antifungals? How?
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Rifampin
The induction of P450s. |
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What are the clinical uses of Azole antifungals?
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Broad spectrum activity
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What is a unique uses of Fluconazole?
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Coccidioidal meningitis
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What is safer for patients, Voriconazole or Amphotericin B?
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Voriconazole.
Less fever, less nephrotoxicity. |
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What is an example of a echinocandin?
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Caspofungin
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Caspofungin is a member of what antifungal drug class?
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Echinocandins
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What is the mechanism of action of the echinocandins? |
Inhibition of the synthesis of Beta-1,2 glucan
Fungicidal |
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What is the absorption of Caspofungin?
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Not orally absorbed
IV administration |
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What is the distribution of Caspofungin?
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Well distributed
DOESN'T PENETRATE THE CSF! |
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What is the metabolism and half life of Caspofungin? ??? |
Extensive metabolism Normal 9-11 hs
Long terminal half life: 40-50 hr. |
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What are the adverse effects of Caspofungin? |
Flushing ( histamine release) Fever, rash Infusion-related phlebitis Headache with cyclosporine- Elevation of liver transaminases GI distress
Micafungin Histamine release Increased cyclosporine |
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What are the clinical uses of Caspofungin? |
Candida infections, especially candida galbrata, which is resistant to the azole antifungals.
Mucormycosis
Micofungin Mucocutanous candidiasis Prophylaxis in bone marrow transplant
Anidulafungin Esophageal and invasive candidiasis
Invasive aspergillosis? |
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Amphotericin toxicity |
Amphotericin Toxicities AMPHTERICIN B
A nemia M uscle spasms P hlebitis H eadaches/ H ypotension/ H ypokalemia T hrombocytopenia E mesis/ E ncephalopathy R espiratory stridor I ncreased temperature (fever) C hills I mmediate hypersensitivity (anaphylaxis) N ephrotoxicity B ronchospasm |
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Inhibiton by ketoconazole Chloradiazepoxide Cisapride Cyclosporine Didanosine Fluoxetine Loratadine Lovastatin Methadone Nifedipine Phenytoin Quinidine Tacrolimus Theophylline Verapamil Warfarin Zidovudine Zolpidem |
Chloradiazepoxide Cisapride Cyclosporine Didanosine Fluoxetine Loratadine Lovastatin Methadone Nifedipine Phenytoin Quinidine Tacrolismus Theophylline Verapamil Warfarin Zidovudine Zl |
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Other inhibitors of CYP 450 |
Chloramphenicol Cimetidine Clarithromycin Disulfiram Erythromycin Ethanol Ethinyl estradiol Fluconazole Furanocoumarins (grapefruit juice) Isoniazid Itraconazole MAO inhibitors Phenylbutazone Secobarbital |
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Itraconazole |
Dermatomycosis Histoplasmosis, blastomycosis, coccidioidomycosis, sporotrichosis
Hepatitis, GI upset, rash, headache, dizziness, hypokalemia, hypertension, edema, QT prolongation
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:) |
:) |
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Flucytosine |
Flucytosine
Candidiasis (systemic)
Cryptococcosis
12.5–37.5 mg/kg po qid
Pancytopenia due to bone marrow toxicity, neuropathy, nausea, vomiting, hepatic and renal injury, colitis
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Flucytosine |
Candidiasis (systemic) Cryptococcosis
Pancytopenia due to bone marrow toxicity, neuropathy, nausea, vomiting, hepatic and renal injury, colitis
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Fluconazole |
Fluconazole 3 Cs
C andidiasis C occidiomycosis C ryptocococcal meningitis
Mucosal and systemic candidiasis Cryptococcal meningitis Coccidioidal meningitis
GI upset, hepatitis, QT prolongation
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Micafungin |
Candidiasis, including candidemia
Increases blood levels of cyclosporine and sirolimus
Echinocandins and cyclosporine elevate liver transaminases
Histamine release
Phlebitis, hepatitis, rash, headache, nausea
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Posaconazole |
?Prophylaxis for invasive aspergillosis and candidiasis
Hepatitis, GI upset, rash, QT prolongation
Oral candidiasis refractory to itraconazole |
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Voriconazole |
Voriconazole
Invasive aspergillosis
Fusariosis
Scedosporiosis
6 mg/kg IV for 2 loading doses, then 200 mg po q 12 h
or
3 to 6 mg/kg IV q 12 h
GI upset, transient visual disturbances, peripheral edema, rash, hepatitis, QT prolongation
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Voriconazole |
Invasive aspergillosis
Fusariosis
Scedosporiosis
GI upset, transient visual disturbances, peripheral edema, rash, hepatitis, QT prolongation
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Disulfiram like reaction |
Disulfiram-like reaction inducing drugs PM PMT
P rocarbazine M etronidazole Cefo (P erazone, M andole, T etan)
No FO’TE’s for A-MAN OPERAting a METRO or PROCAR or he’ll SULF-er a GRISzly TOLL Cephalosprorins: ceFOTEtan, cefAMANdole, cefOPERAzone METROnidazole PROCARbazine 1st gen SULFonylureas: TOLbutamide, chlorpropramide GRISeofulvin |
