Exam 5 lecture 4 Flashcards
How do most antifungal drugs act
They inhibit ergosterol biosynthesis in fungi
how does amphoterecin B act?
- disrupts fungal cell membranes by binding ergosterol in fungal cell membrane
Why are B glucans so well tolerated
B glucan synthase is not something we see in human cells (selective toxicity)
How do Polyenes act
Form pores in fungal cell membrane
How do azoles act? Terbinafine
Azole- Disrupt formation of ergosterol by inhibiting lanosterol conversion to ergosterol
Terbinafine- stops squalene turning to lanosterol
How do flucytosines act
Inhibit formation of purines (Thymidine csynthesis)
Recognize structure of Amphoterecin
Based on structure of amphoterecin B, WHat can we assume
does not absorb very well from the gut. Needs to be IV.
What is the use of the mycosamine in amphoterecin B
Binding to cholesterol (leads to toxicity in humans)
Toxicity seen with amphoterecin B
Nephrotoxic
What are the two natural products used in antifungal therapy
Amphoterecin and nystatin
What partr of amphoterecin causes complement pore formation
OH on bottom lipophilic group
MOA of amphoterecin B? Reason for specificity
Amphoterecin B binds to ergosterol- predominant sterol in fungal cell membranes, causes pores to form in outer membrane
Reason for specificity- mammalian cell membranes contain cholesterol
ROA of amphoterecin Badverse effects of amphoterecin B
TOxicity is low enough to allow use, but renal damage occurs in all patients.
What are the reversible and irreversible component during amphoterecin B renal damage
Reversible- reduced renal perfusion
Irreversible- renal tubular injury (occurs after prolonged administration) (>4g)
Therapeutic applications of amphoterecin B
- drug of choice for life threatening fungal infections.
- Broad spectrum antimycotic
What is superficial fungal infections treated by
Nystatin (similar to amphoterecin B)
Which formulations of amphoterecin reduce nephrotoxicity? why?
Lipid formulations reduce nephrotoxicity
Act as reservoir of amphoterecin (lipids have intermediate affinity for amphoterecin- higher than cholesterol but lower than ergosterol
Ambisome also reduce infusion toxicity
know structures
What enzyme does Terbinafine target
Squalene Epoxidase
What converts Lanosterol to ergosterol?
CYP 450 14 a reductase
Terbinafine structure
Terbinafine MOA
Disrupts ergosterol synthesis by inhibiting squalene epoxidase (squalene build up is toxic to fungal cell)
What is the death of a fungal cell attributed to for terbinafine
Death results from accumulation of squalene, not loss of ergosterol
selectivity and toxicity rofile compared to other drugs of terbinafine
2500 fold selectivity for fungal enzyme compared to mammalian enzyme. More effective and less toxic than griseofulvin
Main uses of terbinafine? ROA?
Oral and topical administration.
Used for ringworm, pityriasis, versicolor, and fungal nail infection
What drugs are chemically similar to terbinafine and have the same MOA
Naftifine (lotrimin) and butenafine (lotrimin ultra)
What antifungal drug has a structure different from terbinafine but also inhibits squalene epoxidase
Tolnaftate
What is the largest class of antimycotics
azoles (>20 drugs)
Key features, MOA and fungicidal/static of azoles)
Key feature- 5 membered aromatic ring (nitrogen essential to bind to Fe)
MOA- inhibition of 14-a demethylase
Fungistatic
describe MOA of azoles (Know what it looks like structrually)
Lanosterol ring turned to intermediate and eventually to ergosterol ring
Azoles can bind to iron 3 in P450, form strong bond and prevent lanosterol from turning into intermediate that is necessary for ergosterol
They inhibit conversion of lanosterol to ergosterol
Compare selectivity of azoles to terbinafine
azoles have better selectivity, but not as good as terbinafine
How are azoles metbolized? Are metabolites active
Metabolized extensively by liver cytochrome P450.
Metabolites are inactive
know structures of ketoconazole, itraconazole, flucanozole, voriconazole, isavuconazole, osteconazole
What is unique about structure of ketoconazole
Diocolane ring on asymetrial carbon (two oxyens in ring)
Itranonazole structure describe?
Triazole (three nitrogen) instead of imidazole
What does the triazole of itraconazole lead to
improved specificity for fungal P450 enzyme
Substantial moditfications seen in flucanozole from ketoconazole
Triazole in place of imidazole
F in place of Cl on benzene ring
Hydroxyl and 2nd triazole on asymmetric carbon
Dioxolane ring eliminated
explain the voriconazole struture
Based on flucanozole but they changed
-2nd triazole replaced with fluoropyrimidine ring.
Added methyl group (improved binding to fungal 14 a demethylase and invcreased spectrum)
Which azole has broadest SOA
Posaconazole
Explain structure of isavucanozole?
Is a prodrug that is similar to voriconazole. Has triple bond nitrogen.
compare voriconazole and isavucanozole
Isvucanozole has Reduced nephrotoxicity compared to voriconazole
Very long half life of isavucanozole
describe the prodrug process of isavucanozole (What is pro drug called? WHat is it cleaved by?
Prodrug is isavuconazonium
cleaved by plasma esterases
What is oteseconazole used for? Selectivity?
Used for high risk of fungal or yeast infection (reoccurring)
Selective inhibition of the fungal enzyme CYP51 (a 14 a demethylase) (low number of adverse events), but worry about drug drug interactions
In general describe azole antifungal drug interactions? What drug to look out for
In general azole antifungals are metabolizede and inhibit liver cyp450 enzymes
Rifampin is a potent inducer
describe the drug interactions of ketoconazole
Potent inhibitor of CYP3A4
Drug ia
- Rifampin reduces ketoconazole levels
- INcreases bioavailability of cyclosporin
What is itraconazole metabolized by? What is flucanozole excreted bu
Itraconazole extensively metabolized by CYP34 in liver
Flucanozole- 80% excreted by kidney unchanged
voriconazole metabolized by
CYP2C19> CYP3A4> CYP2C9
Name echinocandin drugs? ROA
Casofungin, micafungin, anidulafungin
All administered IV
MOA of echinocandins
Inhibit synthesis of B 1-3 glucan synthase, which is a cell wall component
what is the source of echinocandins selectivity?
Mammalian cells lack B 1-3 glycan synthase, which is its target
Are echinocandins fungicidal or fungistatic? Spectrum of activity? What drugs is it synergistic with? Cross resistance with other antifungals?
Fungicidal
synergistic with voriconazole and amphoterecin B
No cross resistance with other antifungals
clinical use of caspofungin
disseminated and mucocutaneous candida.
Salvage therapy in patients with aspergilosis who fail to respond to amphoterecin B
clinical use of micafungin
-Mucocutaneous candida
-Candida prophylaxis in bone marrow transplant patients
Andilafungin clinical use
-Esophageal candidiasis
- invasive candidiasis
- Have longest half life and no known drug interactions
Which echinocandins are associated with fewer adverse events
Micafungin and anidulafungin
metabolism of echinocandins
Not metabolized by liver CYPs
Degraded in blood and in tissue (not stable in plasma)
What is special about rezafungin? MOA and ROA?
Much longer half life than other echinocandins, allow for once weekly dosing
Still IV
Same MOA (inhibit B glucan synthase enzyme)
structure of caspofungin, micafungin, anidulafungin and rezafungin memorize
Ibrexafungerp MOA and ROA
Oral drug, small molecule inhibitor of glucan synthase enzyme in fungi, depletes 1,3 B-D glucan
Is ibrexafungerp cidal or static?
Cidal
Memorize ibrexafungerp structure
What is ibrexafungerp mostly active against? What is it metabolized by?
Mostly active against candida and used for vulvovaginal candidiasis
Is metabolized by hydroxylation by CYP3A4 and then via glucronidation and sulfation
Method of selectivity of ibrexafungerp
Well tolerated due to selective activity against the glucan synthase enzyme
flucytosine mode of action? MOA?
Mode of action- Antimetabolite (pyrimidine analog)
MOA- Inhibits thymidylate synthase and interefres with protein synthesis
Why does flycytosine have such good specificity
Mammalian cells are unable to convert flucytosine to active metabolite
WHat does flucytosine synergize with
AMphoterecin B
Know the structure of flucytosine
Describe the full MOA of flucytosine (how does it get into cell, How is it activated, what are its intermediates
Flucytosine is let in to cytosol of fungal cell by cytosine permease
Cytosine deaminsase activates flucytosine
5- FU is turned to 5-FUMP by PRT
5- FUMP turns 5-FdUMP by ribonucleotide reductase
5-dUMP blocks fungal cell enzyme (active form)
How does 5-FdUMP (active form of flucytosine work
competitively Inhibits thymidylate synthase to inhibit formation of dTMP by mimicking dUMP
explain the SAR of flucytosine
In 5-FdUMP, there is a F in place of H found in dUMP. F is the most electronegative atom so it can not be eliminated.
Traps thymidylate synthase in inactive form
In in active form it cannot react with dUMP
ROA of flucytosine? How is it removed? what could lead to Toxicity? Does it penetrate CSF?
Available only orally
Penetrates well into CSF
Removed by kidney
Renal impairement can lead to toxicity
Adverse effects of flucytosine? What should we monitor
Intestinal flora can metabolite to 5-FU and anti cancer drug
Monitor levels when combined with amphoterecin B (they are kidney toxic)
When is flucytosine combined with amphoterecin B? Spectrum of activity of flucytosine
Cryptococcus neoformans- combined with amphoterecin B for cryptococcal meningitis
Candida spp, aspergillus, most filamentous fungi not susceptble
nearly always administered with amphoterecin B or flucanozole
griseofulvin ROA? MOA? indication? What is it inactive against? fungistatic/cidal?
Oral drug that disrupts fungal microtubules
Used for dermatophytes (skin hair and nails)
Inactive against yeast, mold and dimorphic fungi
know structure for tavaborole
Tavaborole MOA, indication and ROA
Inhibits leucyl transfer RNA synthase (LeuRS), (inhibits protein synthesis)
Boron essential for activity
Topical tx of onychomycosis
WHat is a side effects ALL azoles have primarily? WHich antifungals have secondary hepatic side effects (not main side effects)
Hepatic
Amphoterecin and 5-FU have secondary side effects
Which antifungals have renal toxicity as main side effects
amphoterecin (reversible until 4 g of delivery or more, where permanent damage happens
Which antifungal has CNS and photopsia as mian side effects
Voriconazole
Which antifungals have GI toxicity
Itraconazole, posaconazole and 5-FY
Which antifungals have cardiac toxicity
itraconazole
ALl azoles have QTc prolongation
Which antifungals have infusion rxns
Amphoterecin B and echinocandins
Which antifungals have bone marrow suppression
5-FU, amphoterecin B
When can we use antifungals during pregnancy? tx of choice for systemic infection
Topical tx is OK
Amphoterecin B is tx of choice for systemic infection
Which drugs to avoid in 1st trimester during pregnancy
Flucanozole, itraconazole, posaconazole and isavucanozole
It is okay to use single dose flucanozole for yeast infection
Which antifungals are contraindicated in pregnancy
Voriconazole, flucytosine and griseofulvin
