Pharm: Systemic Antifungals Flashcards
One drug acts on fungi to inhibit the mitotic spindle in the nucleus. What is it?
Griseofulvin - different than the others, which mostly act on fungal membrane; this one acts to disrupt MTs
One drug acts on fungi as an anti-metabolite. What is it?
Flucytosine
If fungi rarely cause disease in hosts, why are anti-fungals becoming increasingly important in medicine?
with advances in treatments for other conditions, there are more patients who are immunocompromised and therefore falling victim fungal infections
Describe the MOA and indications of Amphotericin B.
amphipathic drug that binds to ergosterol, forms pores in the membrane, and causes loss of cell integrity; used to treat lots of things
Describe the MOA and indications of Caspofungin (echinocandins).
inhibits beta-glucan synthase thereby preventing synthesis of beta-1,3 glucan, an important cell wall component; used to treat aspergillus and candida infections - tolerated well if used alone
Please characterize Fluconazole.
good oral bioavailability, good CSF penetration; best tolerance - widest therapeutic index
Please characterize Itraconazole.
poor CSF penetration, new formulations overcome poor oral bioavailability
Describe the MOA and indications of Terbinafine.
prevents the conversion of squalene to squalene epoxide, an important step in the synthesis of ergosterol; used to treat athlete’s foot
Describe the MOA and indications of Nystatin.
amphipathic drug that binds to ergosterol, forms pores in the membrane, and causes loss of cell integrity; used topically to treat mucocutaneous, oropharyngeal, and vulvovaginal candidiasis
Antifungals fall into 2 classes of administration: ____ and ____.
- systemic - administered either orally or parenterally
2. topical - for mucocutaneous infections
What is the first line drug choice for Aspergillosis?
Voriconazole
What is the first line drug choice for Blastomycosis (mild)?
Itraconazole
What is the first line drug choice for Blastomycosis (severe)?
Amphotericin B IV then Itraconazole PO
What is the first line drug choice for Candidiasis?
Fluconazole
What is the first line drug choice for Coccidioidomycosis?
Fluconazole IV/PO or Itraconazole PO
What is the first line drug choice for Cryptococcus?
Amphotericin B IV plus Flucytosine PO, then Fluconazole PO
What is the first line drug choice for Histoplasmosis?
Amphotericin B IV plus Itraconazole PO
What is the first line drug choice for Mucormycosis?
Amphotericin B
What is the first line drug choice for Sporotrichosis?
Amphotericin B IV and/or Itraconazole PO
What all infections would Voriconazole be used for?
Aspergillosis
What all infections would Itraconazole be used for?
mild Blastomycosis, severe Blastomycosis, Coccidioidomycosis, Histoplasmosis, Sporotrichosis*
*would be in combination with another drug
What all infections would Fluconazole be used for?
Candidiasis, Coccidioidomycosis, Cryptococcus*
*would be in combination with another drug
What all infections would Flucytosine be used for?
Cryptococcus*
*would be in combination with another drug
What all infections would Amphotericin B be used for?
severe Blastomycosis, Cryptococcus, Histoplasmosis, Mucormycosis, Sporotrichosis
*would be in combination with another drug
What is the MOA of amphotericin B, and what is its effect on humans?
fungicidal that causes loss of cell integrity by binding to ergosterol and forming pores there; pores allow leakage–>cell death.
the damage to membranes also occurs in the kidneys, therefore there is high risk of renal toxicity
What is the MOA of azoles and terbinafine? (big picture)
blocks synthesis of ergosterol
What is the MOA of the echinocandins (such as caspofungin)?
prevents formation of glucans in the fungal cell wall by inhibiting Beta-glucan synthase from making beta-1,3-glucan
Flucytosine is an inhibitor of ____ ____ synthesis, and thus prevents ____ replication.
nucleic acid synthesis; cell replication
What are the steps of the ergosterol synthesis pathway, and where do each terbinafine and the azoles act?
Step 1. squalene to squalene epoxide Step 2. squalene epoxide to lanosterol Step 3. lanosterol to ergosterol Terbinafine inhibits Step 1. Azoles inhibit Step 3.
Accumulation of ____ as a result of terbinafine action is toxic to the fungal cell.
squalene
Which drug is comparable to amphotericin B (having the same MOA)? What are the downsides to this drug?
Nystatin; can ONLY be used topically because its toxicity is so great it precludes systemic administration
Agents whose names end in -fungin belong to which class?
Echinocandins
Agents whose names end in -azole are so-called due to what?
these agents have an azole ring structure; imidazoles have 2 nitrogens and triazoles have 3 nitrogens
Which drugs discussed are imidazoles and which are triazoles?
imidazoles: ketoconazole
triazoles: fluconazole
What interaction do azoles have with CYP450 enzymes?
they inhibit them in fungi, as well as humans - this interaction has an impact on drug-drug interactions
True or False: almost all anti-fungals in the azole class are capable of inhibiting CYP3A4.
True - and this is very important because it will not only change metabolism of concurrent medications but also of the azoles; this concern is unique to the azoles and to griseofulvin
____ and ____ are two azoles that are not good at treating CSF fungal infections because they don’t cross the BBB well. However, ____ and ____ do get into the CSF well.
Ketoconazole and itraconazole; fluconazole and voriconazole
In general, azoles–except for ____ – are eliminated through hepatic mechanisms.
fluconazole - eliminated in urine
All orally administered azoles produce symptoms of ____ disturbance, but the highest incidence occurs with use of ____ and ____.
GI; itraconazole and posaconazole (because they are the least soluble, poorly absorbed, and leave particulate in the GI tract which causes irritation)
Can fluconazole and voriconazole be administered in pregnancy?
No
Ketoconazole is notorious for what side effects, which have led to FDA limiting its use?
- hepatic damage - sometimes irreversible
- cardiac arrhythmogenic events
- adrenal insufficiency - unique to ketoconazole
How does adrenal insufficiency arise from use of ketoconazole?
ketoconazole is unique in high doses to inhibit synthesis of adrenal steroids, leading to reduction of Cortisol, Aldosterone, and Testosterone
Voriconazole is associated with what side effects?
drug-drug interactions; photosensitive dermatitis, elevated liver enzymes, temporary visual disturbances upon IV administration, neurologic symptoms, including hallucinations (think - this is one that crosses BBB, but isn’t widely used for CSF infections because of the side effects; also not taken during pregnancy)
Please characterize Posaconazole.
claim to fame is that it’s the only azole that can treat mucormycosis; but it is involved in CYP mediated drug-drug interactions
Azoles ____ and ____ are the most common topical agents and are used against candidiasis infections.
clotrimazole and miconazole (side effects are rare and clortrimazole troches taste good making them better than nystatin for treating oral thrush)
Does flucytosine have a wide or narrow therapeutic window?
narrow, because it’s a pyrimidine analog and interrupts RNA and DNA synthesis in both the fungal infection AND normally dividing host cell populations (such as GI and RBCs)
Griseofulvin is an inducer of ____ producing drug-drug interactions, and has largely been replaced by ____.
CYP3A4; Terbinafine
True or false: Terbinafine has no effect upon CYP activity and is generally well-tolerated.
True
Terbinafine is generally well-tolerated except for the risk of transient ____ and ____, which is monitored with routine CBCs.
lymphopenia and neutropenia
Most antifungals are fungicidal by inhibiting ____ ____ ____; except for ____ and ____.
cell wall integrity; flucytosine (nucleic acid synthesis inhibitor) and griseofulvin (mitotic spindle inhibitor)
Among the anti-fungals which class has the broadest spectrum of activity?
Azoles
Some ____ are pro-arrhythmogenic.
azoles
The best tolerated azole is ____.
Fluconazole
Amphotericin B has poor ____ and is quite ____-toxic.
solubility; nephro-toxic
Griseofulvin is used in the systemic treatment of ____.
dermatophytosis
For a patient given amphotericin: what is the molecular action and where is it occurring?
(clicker question)
pore formation in the cell membrane (not cell wall)
For a patient given a drug that inhibits fungal P450: which drug was most likely given? (class question)
an azole
For a patient given terbinafine: which enzyme was most likely inhibited? (class question)
the one that normally convertes squalene to squalene spoxide: squalene epoxidase
Which of the effects of terbinafine on fungal cells is more effective in killing the fungus: the destruction of the cell wall by inhibiting ergosterol synthesis, or the toxicity of accumulated squalene? (class question)
the toxicity of accumulated squalene
Are amphotericin B and the azoles are considered fungicidal or fungistatic? (class question)
- amphotericin B = static at low concentrations but cidal at higher/clinical concentrations
- azoles = fungistatic, therefore relapse rate can be high if drug treatment is incomplete
What type of drug-drug interactions would you be MOST concerned about in a patient receiving amphotericin B? (class question)
other drugs that also produce renal toxicity, because amphotericin B has high nephrotoxicity; side effect of amphotericin is hypokalemia therefore wouldn’t want to combine it with diuretics (also cause loss of potassium); this is part of the pro-arrhythmic predisposition caused by anti-fungals
An AIDS patient diagnosed with cryptococcal meningitis was given an IV dose of hydrocortisone, followed by IV infusion of amphotericin B. Hydrocortisone was given for what drug-related adverse effect? (class question)
infusion reaction
First side effect to think about with amphotericin B is \_\_\_\_ and the second is an \_\_\_\_. (class question)
nephrotoxicity; infusion-related reaction
Woman diagnosed with cryptococcal pneumonia was treated with liposomal amphotericin B. Why use liposomal preparation over the regular colloid suspension of amphotericin B? (class question)
because of the decreased systemic toxicity of the liposomal preparation of amphotericin B (later generation formulation intended to decrease toxicity; not incredibly successful and more expensive)
How are amphotericin B products administered? (class question)
IV (not orally)
Voriconazole interacts with which CYP the most, and is therefore the most impacted by the high rate of variability/polymorphisms in this enzyme? (class question)
CYP2C19
Which azole is affected by the most P450 enzymes? (class question)
Voriconazole
What is a TDM? (class question)
“therapeutic drug monitoring” - monitoring of serum levels of drug during a treatment course to ensure sufficient absorption due to the high variability of bioavailability among patients
What host factors predispose towards a fungal infection? (class question)
immunocompromised; patients living in hospitals; chemotherapy
What are the resistance mechanisms to antifungals? (class question)
- target modification
- efflux
- alternative pathways
