Pharm 2 - Antifungals

drraythe's version from 2015-11-23 11:51

Basics & Organizing

Question Answer
Fungi are what type of pathogens, usually?Usually opportunistic, so often seen in cases of ↓ immunity
What are dermatophytoses?Fungal infxn of the skin
What are the DIFFERENCES btwn fungi cells & animal cells? (3)(1) DNA - animal is diploid, fungi are haploid (1 set of chromosomes)
(2) CELL WALL - animal cells don't have 1, fungi cell walls are made of chitin, mannans, glucans
(3) CELL MEMBRANE - animal is mostly cholesterol, Fungi is mostly Ergosterol
Amphotericin, Echinocandins, Azoles, Griseofulvin, Flucytosine, Terbinafine/Naftifine/Amorolfine(Allylamines)... what do each of these work onAmphotercin - Membrane
Echinocandins - Cell wall
Azoles - Inhibit formation of Ergosterol out of Lanosterol
Griseofulvin - Microtubules
Flucytosine - DNA
Terbinafine/ Naftifine/ Amorolfine (Allylamines) - Squalene → Lanosterol (which then can't proceed to Ergosterol)
Intracellular → Pyrimidine Analogues/ Thymidylate Synthase inhibitors → which drug is here?Flucytosine
Intracellular → mitotic inhibitors → which drug is here?Griseofulvin
What are the naturally occuring antifungal ABx? (3 categories)(1) Griseofulvin
(2) Polyenes (Amphotericin B, Nystatin, Natamycin)
(3) Echinocandins (Echinocandin-B, Caspofungin, Anidulafungin)
What are the synthetic drugs? (2 categories)(1) Azoles (Imidazoles (Ketoconazole), Triazoles (Itraconazole), Benzimidazoles (Thiabendazole) )
(2) Pyrimidines (Flucytosine)
Polyenes MOA?Selectively binds to Ergosterol in fungal cell membrane - much less binding to cholesterol (so doesnt hurt host cell) (makes pores & cz electrolyte imbalances)
Azoles MOA?Selectively blocks Ergosterol synthesis by inhibiting demethylation of Lanosterol fungal CYP450 more sensitive than mammalian CYP450
Flucytosine MOA?Converted by fungal cytosine deaminase into 5-fluorouracil: Inhibits DNA synthesis - mammalian cells lack cytosine deaminase (the enzyme it inhibits has the cytosine in it like the drug name does)
Griseofulvin MOA?Binds to microtubules, disrupting mitotic spindles
Echinocandins MOA?Inhibit fungal β-glucan synthesis (cell wall inhibition)
Allylamines MOA?Inhibits squalene epoxidase to block Ergosterol synthesis (membrane) (AL comes before AZ in the alphabet, so AL works before AZ in the chain of making Ergosterol)
What are the systemic antifungals?Purely systemic: Flucytosine, Griseofulvin
Systemic & topical: Terbinafine, Ketoconazole, Fluconazole, Itraconazole, Voriconazole, Caspofungin, Amphotericin B (systemic & local)
What are the localized antifungals?Nystatin
Amphotericin B (systemic & local)
Key notes on antifungal drug resistance (3)(1) Reduced uptake
(2) Efflux-pump mediated drug export
(3) Reduced affinity for target enzymes
Which drugs are the gold standard for disseminated infxns?Polyenes


Question Answer
*Polyene ABx → which drugs in this category & the specific MOA?Amphotericin B
Polyenes are able to form pores in the cell membrane which leads to gross disturbances in electrolyte balance
*What is the order of type of cells, for most to least affinity, of polyenes?Fungi > Protozoa > Mammalian cells > Bacteria (fungi pizza → my belly)
*Spectrum of polyenes?Broad
*What are polyenes the gold standard for?Disseminated infxns
*Amphotericin B can enhance what other drug?Enhances the antifungal effect of Flucytosine (BB has the flu)
*What can you say about Amphotericin B & oral administration?Poorly absorbed oral admin. This could be good if Txing upper GI infxns - poor absorption so stays in GI & fights fungi (Bad oral absorption)
*What can you say about Amphotericin B & IV administration?*SLOW* IV INFUSION! Or it can be complexed w/ liposomes or other lipid containing preparations (slow renal excretion, slow IV infusion...Bound Amphotercin B slow)
*What is the protein binding of Amphotericin B like?HIGHLY protein bound (B for BOUND....& Bow-chika-bow-wow LOL)
*What is the tissue penetration of Amphotericin? Exceptions?Usually there is POOR tissue penetration bc of the high protein binding, EXCEPT if the tissue is inflamed, the barrier is compromised & the protein bound drug can get in
*What is the excretion of Amphotericin B like?VERY SLOW RENAL EXCRETION (>2mo) (hence, renal toxicity. I guess it only got a Amphotercin B slow)
*What are the unwanted effects of Amphotericin B? (3)(1) RENAL TOX (reversible)
(2) Hypokalemia (reverse w/ potassium chloride supplement)
(3) Irritant to endothelium (vomiting, chills, fever)
(AMP energy makes me pee like I have renal toxicity, & then I pee out all the potassium from my endothelium)
*How can you make it so there is less unwanted effects of Amphotericin B?Liposome - Lipid complexed preparations show less SFx
*WHERE are Nystatin & Natamycin not absorbed?Skin & mucous membranes (so...can put inside of vagina & it wont go systemically, will just stay in there & kill the yeast)
*What are Nystatin & Natamycin used to Tx?ONLY localized superficial infxns
*SFx of Nystatin & Natamycin?Vomiting & diarrhea (Nystatin goes in the vag & its SFx are
What kind of fungi are Nystatin & Natamycin good against?Dermatophytoses
Key notes of polyenes (5) (systemic, or local? Broad or narrow? MOA? SFx?)(1) Amphotericin B: Systemic & local
(2) Natamycin & Nystatin: Local
(3) Broad spectrum fungicidal drugs
(4) Binding to Ergosterol: Changes in membrane permeability
(5) Nephrotoxicity


Question Answer
*Natural or synth? Static or cidal?Synth, static (so only stop growth & then rely on immune system to take care of the rest)
*Are Azoles narrow or broad spectrum?Broad spectrum
*What is the specific MOA of azoles?Inhibition of the fungal CYP450-3A enzyme (Lanosterol 14α-demethylase) → inhibition of formation of Ergosterol out of Lanosterol
*Imidazoles → Admin? Spectrum? MOA?TOPICAL use
BROAD spectrum
Inhibit CYP450 enzymes
What are the 4 drugs of the Imidazole group of Azoles?Ketoconazole
Clotrimazole (topical)
(ME! KC!)
*Which group does Ketoconazole belong in? Properties of the drug? Any specific requirements?Group: Imidazoles
Properities: Highly lipophilic, highly protein bound
Requirements: Needs LOW GI pH to be absorbed
(I see keto, I think ketoACIDosis, so I think need acidic PH to be absorbed. Think that this requirement is bc it's so lipophilic & protein bound)
*What group does Clotrimazole belong in? Properties of the drug? Metabolism?Group: Imidazoles
Properities: Slightly water soluble (topical)
Metabolism: Undergoes 1st pass effect
(The clot has been passed)
*What group do Miconazole/Enilconazole belong in? Notable things about these?Imidazoles
Have ether group, which gives low topical absorption
(ETHER EN MY nose, not skin)
*What are the SFx of the Imidazoles? (5)(Ketoconazole, Clotrimazole, Miconazole, Enilconazole)
GIT upsets
↓ appetite
Inhibit CYP450
Inhibit PgP = P-glycoprotein....inhibit outward xport of PGP substrates
(IM got a tummy ache → well, GIT upset & a toxic liver would ↓ your appetite & liver issues affect CYP450...& CYP → PgP/xport of PGP unhappy)
Why are most Imidazoles topically used?They are highly lipophilic! So they will stay on the lipid layers of the skin
Azoles → Triazoles. Admin? Spectrum?Topical & systemic use. BROAD spectrum. (TRI it all!)
What are the 4 drugs in Triazoles?Fluconazole
(TriP FIV)
*Fluconazole is in which group? Properties? Excretion?In Triazoles (more) water soluble, minimally protein bound, LARGE Vd, penetrates barriers, renal excretion (the flu goes all over your body - so it gets everywhere)
*Itraconazole is in which group? Properties? Excretion?In Triazoles. Highly lipophilic, active metabolite!!! Biliary excretion (IT loves livers, so it is HIGHLY ACTIVE to get to bile needs to be fatty)
*Voriconazole/Posaconazole are in which group? Properties? Metabolism?Triazoles
Poor water solubility
Hepatic metabolism
*What are the SFx of the Triazoles?Teratogenic
Hepatotoxic (Itraconazole)
Inhibits CYP450-3A (Itraconazole) (in mammalian cells)
(tri, terato, & ITRAS go through the liver & have active metabolites, so the other 2 make sense)
What are the mechanisms of resistance against Azoles? (4)(1) Fail to accumulate (↑ out or ↓ in)
(2) Altered 14-demethylase (the CYP450 enzyme which converts Lanosterol → Ergosterol)
(3) Diminished affinity for the CYP450 (changes in interaction of drug w target enzyme)
(4) Changes in other enzymes in the Ergosterol path (compensating or circumventing the toxic consequences of changes in ergoesterol composition)

Flucytosine, Griseofulvin, Echinocandins, Allylamine

Question Answer
*What is the specific MOA of Flucytosine?Flucytosine is converted via a fungal enzyme (no animal analogue = selective tox) to an ANTI-metabolite of 5-fluorouracil (5-FU.) 5-FU interferes w/ Thymidylate Synthetase & thus DNA synthesis
*Spectrum of Flucytosine?Narrow (inhibiting fungal Thymidylate Synthetase & DNA synthesis → selective toxicity bc not all fungi have this enzyme)
*Super important thing you should know about Flucytosine?RAPID EMERGENCE OF RESISTANCE - DO NOT USE ALONE!!! (the flu likes company...)
SFx of Flucytosine?Infrequent unwanted SFx
*Spectrum of Griseofulvin?Small spectrum (small grizzle is the only acceptable kind)
*What is Griseofulvin effective against?Trichophyton
(TEM would die if she ate grizzle)
*MOA of Griseofulvin?Interferes w/ mitosis by binding to fungal microtubules
*Indications of Griseofulvin?Dermatophytosis!! Involved w/ any of the fungi w/in its small spectrum (Trichophyton, Epidermophyton, Microsporum)
*Pharmacokinetics of Griseofulvin (properties, solubility, absorption, distributes where?)Oral absorption varies w/ preparation & particle size. Distributes to the SKIN! (thus, good w/ dermatophytes) (i will only eat grizzle depending on its size. I'm looking at you, sausage)
*SFx of Griseofulvin?INDUCES CYP450. cz important drug interactions. Also embryotoxic & teratogenic (grizzle getting lodged in your liver enzymes is bad for little fetuses)
MOA of Echinocandins?Inhibition of 1,3-Β-glucan synthesis → disruption of fungal cell wall. The disruption of the wall mannoproteins which leads to exposure of antigen & greater immune system response
Pharmacokinetics of Echinocandins. (Admin? Good against what? Not good against what? Pertinence to vetmed?)POOR oral bioavail. IV admin q24hrs. Effective against invasive forms of fungal infxns (aspergillosis, candidiasis). NOT YET USED in vetmed (no efficacy against the yeast form of fungi) (the little echino will kill invaders in its nesting area)
*Allylamine → what is the drug in this category?Terbinafine (ally loves wear turbans)
* Terbinafine. What is the MOA of Terbinafine?Non-competitive inhibition of squalene epoxidase (which makes squalene → Lanosterol. remember that Lanosterol then → Ergosterol, which is inhibited by azoles)
*Allylamine → Terbinafine. Pharmacokinetics? (Properities, absorbed well where, goes where, metabolism & excretion? SFx?)Lipophilic (so big Vd). Rapidly absorbed from GIT, rapid diffusion to dermis & epidermis, limited SFx!! (Ally loved fat turbans, shed eat them till her skin was covered in them!)