Fungal Chemotherapy Flashcards
What is selective toxicity?
your selectivey targeting particular pathways, enzymes, proteins, cell walls that are specific to the pathogen and not found in normal cells so that only the bad stuff is harmed
What is the cell size of a prokaryotic bacteria?
Eukaryotic fungi?
1-5 U to the third power
20-50 u to the third power
What is the ribsome type found in prokaryotes (bacteria)?
Eukaryotes (fungi)?
70S
80S
What is found in the cell wall of bacteria?
Fungi?
peptidoglycan
chitin
What is found in the membrane of bacteria?
fungi?
no sterols
ergosterols
What kind of pathogens are these: candida albicans cryptococcus neoformans pneumocystic jiroveci (carinii) aspergillus
opportunistic pathogens-> systemic infections
What kind of pathogens are these: mucor blastomyces dermatitidis paracoccidiodes brasiliensis histoplasma capsulatum
systemic infections
What are these:
epidermopyton
trichophyton
microsporum
superficial infections-dermatophytes
What are the drugs used for systemic infections?
polyene antibiotics
imidazole and triazole drugs
flucytosine
pentamidine
What are the drugs used for superficial infections?
polyenes
Azoles
Griseofulvin
naftifine
How does amphotericin B work?
disrupts the membrane
How should amphotericin B be given?
IV (mainly), topical, parenteral
NOT ORALLY
How should candicidin be given?
topically
How nystatin be given?
topically, orally for GI tract only
How should natamycin be given?
topically
What drug WILL be on the exam?
amphotericin B (KNOW THIS)
What kind of molecule is a polyene antibiotic?
large, lipophilic, water insoluble molecule
How do polyene antibiotics work?
they dissolve into cell membrane of fungi, bind to ergosterol in the membrane and increase the permeability to ions and metabolites
What is the selectivity of polyenes?
polyenes are toxic to fungi, protozoa and some algae. Selectivity is poor because human cell membranes also contain sterols (cholesterol). These drugs can be toxic :(
What do polyenes bind to?
sterols (selectivity is poor)
What are the polyene antibiotics?
Amphotericin B
Nystatin
Natamycin
Candicidin
What do you use amphotericin B for?
systemic fungal infections
What do you use nystatin?
topical treatment of skin, oral and intestinal Candida infections
What is used as a 5% opthalmic suspension?
natamycin
What do you use candicidin for?
topica treatment of vaginal candidiasis
What are the adverse reactions of polyene antibiotics?
FEVER, GI distress, cardiotoxicity, hemolytic anemia, leukopenia, hepatotoxicity, NEPHROTOXICITY
What are the adverse effects following IV infusion of amphotericin B?
Fever Chills Hypotension Vomiting Dyspnea Thrombophlebitis at injection site Renal toxicity is invariable, but treatment can be continued to a creatinine concentration of 200mmol/liter
How can you attenuate the adverse effects of IV amphotericin B infusion?
with a slow infusion rate or by premedication with anti-histamines, antipyretics, meperidine or glucocorticoids
What 2 drugs are usually applied topically?
nystatin and candicidin
When can amphotericin B be given orally? When do you give it via IV?
for intestinal candida infection
for systemic infections
How do you eliminate polyene antibiotics? Does renal insufficiency affect half life significantly?
via kidney
no because the drug binds avidly to plasma membranes and slowly elutes into the blood stream. Elimination is very slow
(blank) is the drug of choice in most systemic fungal infections including systemic candidiasis. These infections are rare but quite dangerous. It can also be used in ointments for topical infections.
Amphotericin B
(blank) is often applied topically, but is also available as an oral preparation for oral and intestinal Candida infections.
Nystatin
(blank) is used topically to treat vaginal candidiasis
candicidin
What drugs are not very selective and are quite toxic?
polyene ntibiotics
(blank) is usually the dose-limiting toxicity of polyene antiobiotics
Nephrotoxicity
What are the two major groups of antifungal azole drugs?
imidazole
triazole
What are the 3 kinds of imidazole antifungal?
miconazole
clotrimazole
ketoconazole
What is the first orally active azole antifungal drug?
ketoconazole
How does ketoconazole work?
Increases permeability of fungal cell membranes by inhibiting ergosterol synthesis.
Blocks synthesis of ergosterol by inhibitin 14 alpha demethylase, a cytochrome p450 enzyme system
Is ketoconazole orally effective? What is its half life?
yes
12 hr
Is ketoconazole more toxic and more effective than amphotericin?
no it is LESS TOXIC
LESS effective
What is the clincal use of Ketoconozole?
alternative to amphotericin B for treating systemic and mucocutaneous fungal infections
What are some adverse reactions of ketoconazole?
nausea
GI disress
pruritis
Potentially fatal Hepatic toxicity and gynecomastia
When should you stop use of ketoconazole?
if hepatitis occurs
Ketoconazole also inhibits human (blank) synthesis by inhibiting cytochrom p450 enzymse. This is why you can get gynecomastia in males, and menstrual irregularities in females and decreased plasma cortisol levels.
steroid
Because ketoconazole decreases cortisol evels, ketoconazole has been used to treat (blank)
cushings disease
High dose ketoconazole should be avoided in patients with what disease?
TB
histoplasmosis
paracoccidiodomycosis
AIDS
How does miconazole work?
messes up cell membranes of fungi by inhibiting ergosterol synthesis by inhibiting 14 alpha demethylase, a cytochrome p450 enzyme system
How should you give miconazole?
topicaly, NOT GIVEN ORALLY
Will you find miconazole in your CSF or urine?
no
What is the clincal use of miconazole?
used mostly as topicl treatment of dermatophyte infections and treatment of vaginal candidiasis
What are the adverse reactions of miconazole?
skin irriation
via IV admin can cause thrombophlebitis, rash nausea, anorexia
What is clotrimazole used for?
to treat a variety of cutaneous and vaginal infections
What are some adverse effects of clotrimazole?
local irritation and rash, GI distress may occur if drug is swallowed during topical oral admin for oropharyngeal candidiasis
How should you give econoazole?
topical administration
Why would you rather use itraconazole than ketoconazole?
because it has fewer adverse effects than ketoconazole and a wider spectrum of action.
How is Itraconazole administered?
systemically
What do you use itraconazole for?
drug of choice for several systemic mycoses.
What are the triazole antifungal drugs and why are they more awesome than the Imidazole antifungals?
Itraconazole and Fluconazole
because they are metabolized more slowly and have less effect on human sterol synthesis and fewer side effects.
**NOTE: traiazoles have replaced ketoconazole for treatment of systemic mycoses*
How is Fluconazole administered?
systemically
What do you use fluconazole for?
cryptococcal meningitis in HIV positive pt.
Caninda in immune competent nt.
What is the most frequently prescribed antifungal drug?
Why?
fluconazole
because it has the least effect on host cytochrome P450 enzymes and best therapeutic index of all azole compounds
What is a newer antifungal drug belongin to the Echinocandin family and is used for systemic candiasis and as a LAST RESORT for aspergillosis refractory to amphotericin?
caspofungin
What is the mechanism of action of caspofungin?
inhibits syntehsis of beta 1-3 glucan which disrupts fungal cell wall structure and reduces viability
What is variconazole?
a recently introduced dug that is more specific for fungal p450
What are naftifine and terbinafines?
broad spectrum, fungicidals
What are the MOAs of naftifine and terbinafines?
inhibit squalene epoxidase and causes buildup of intracellular squalene which decreases ergosterol synthesis
How is naftifine administered?
topically
How is terbinafine administered?
orally active
What do you use naftifine and teribafine for?
dermatophytes (tinea cruris and tinea corporis) Candida
What is an adverse effect of natifine and terbinafine?
local irritation
What is the enzyme naftifine and terbinafine block?
squalene epoxidase
What is the enzyme that fluconazole, ketoconzole, itraconazoe, and variconzole block?
cytochrome p450 dependent 14alpha-demethylase
What is the mechanism of action of fluctyosine?
prodrug-> turned into 5 flurouracil by fungal cytosine deaminase which release toxic metabolites into host cell that block RNA and DNA synthesis through reduction in thymidylate synthetase
What is the spectrium of flucytosine?
narrow
When does resistance to flucytosine occur?
when the drug is used alone
What is the prodrug form of flucytosine?
5-fluorocytosine
What is the fungal enzyme that converts the prodrug flucytosine into the antimetabolite? and what is the antimetabolite?
cytosine deaminase
5-fluorouracil
5-fluorouracil inhibits (blank)
RNA and DNA synthesis
How should flucytosine be used?
in combo w/ amphotericin B to treat systemic Cryptococcus and candida infections
What are the adverse reactions to flucytosine?
bone marrow depression leading to leukopenia, thombocytopenia, GI distress, reversible hepatotoxicity. (toxicity may be a result of metabolism of flucytosine by GI flora to 5-fluorouracil)
How does Griseofulvin work?
drug is actively transported into sensitive cells where it binds tubulin WHICH prevents proper separation of chromosomes during mitosis and interferes with transport functions of microtubules.
How come griseofulvin has good selective toxicity?
because the drug has lack of active transport into mammalian cells
With griseofulvin, about (blank) percent of an oral dose of micronized drug is absorbed. How can you increase absorption?
50%
if taken with a fatty meal
What is the only way to administer griseofulvin?
ORALLY
Griseofulvin has a unique pattern of distribution. The drug binds to (blank) and reaches high concentrations in the the skin and hair
keratin
Griseofulvin is metabolized to glucuronide by the (Blank) and excreted via the (blnk)
liver
kidney
What is the clinical use of griseofulvin?
effective against common dermatophytes; trichophyton, epidermophyton, microsporum. These fungi cause Tinea (ringworm)
What are the adverse reactions of griseofulvin?
- relatively safe drug, incidience of side effect is low
- temporary headache is common in intial few days of therapy
- nervous system-mental confusion, fatigue, visual impairment
- GI distress
How does pentamidine work?
binds to kinetoplast DNA and inhibits mitochondrial DNA synthesis. Blocks polyamine biosynthesis, blocks topoisomerase II.
What is the clinical use of pentamidine?
- pneumocystis jiroveci (carinii) infection in patients allergic to trimethoprimsulfamethoxazole.
- aeroslize for prophylaxis against pneumocystic pneumonia in AIDS patients
- also effective against African trypanosomiasis and leishmaniasis
What are naftifine and terbinafine (lamasil) classified as?
broad spectrum, fungicidal drugs classified as allylmines.
What do allylamines inhibit?
squalene epoxidase which cause buildup of intracellular squalene concentrations and decreases ergosterol synthesis
What are allyamines effective against?
dermatophyts and candida.
Indications include tinea cruris, tinea corporis, and onychomyosis.
Is terbinafine fungicidal?
yes
Is the onset of action for allylamines faster or slower than imidazoles?
faster
What drugs are used for sytemic infections?
polyene antibiotics
imidazole and triazole drugs
flucytosine
pentamidine
What drugs are used for superficial infections?
polyenes
azoles
griseofulvin
naftifine
(blank) is a fatty acid that is effective against Epidermophyton, the cause of tinea pedis (athlete’s foot). The mechanism of antifungal action is not known.
undecylenic acid
(blank) is a synthetic topical drug that is effective against superficial infections by dermatophytes. The mechanism of antifungal action is unknown
tolnaftate
A 28-year-old woman presents to the office complaining of 2-days of itchy vaginal discharge. One week ago you saw and treated her for a urinary tract infection (UTI) with sulfamethox-azole and trimethoprim (SMX-TMP). She completed her medi-cation as ordered and developed the vaginal discharge shortly thereafter. She denies abdominal pain, and her dysuria has resolved. She is not currently taking any medications. On examination, she appears to be comfortable and has normal vital signs. Her general physical examination is normal. A pelvic examination reveals a thick, curd-like, white discharge in her vagina that is adherent to the vaginal sidewalls. There is no cervical discharge or cervical motion tenderness, and bimanual examination of the uterus and adnexa is normal.
What is the most likely cause of these symptoms?
How would you treat this infection?
candida albicans
Flucanozole or Candicidin
A debilitated cancer patient has bone marrow that is just beginning to recover from previous chemotherapy. He is still receiving three antibiotics to treat a presumed (but never proven) bacterial infection. An alert first year resident notices several new small pustules: a properly stained specimen of the pus reveals a yeast infection. At the same time, a blood culture grows out Candida albicans. Just before going off duty, the resident orders a new drug to treat the fungemia. The patient receives the first dose I.V., and immediately develops shortness of breath, hives, hypotension, fever and shaking. You are called to see the patient.
What is a likely cause of the new symptoms?
What alternate drugs might work?
What new adverse reactions might occur?
AmB
Azoles or flucytosine BUT the best one would be you wouldnt want to use flucytosine because it can have a bone marrow depression as a side effect!
Probably want to do flucanozole (less bad effects than ketoconazole)
