Antifungals

Question 1

What drugs are used to treat dermatomycoses?

Answer 1

1. Tolnaftate (tinactin)
2. Cltrimazole (lotrimin)
3. Griseofulvin

Question 2

What is the mechanism of action of tolnaftate?

Answer 2

It inhibits fungal squalene epoxidase, resulting in decreased ergosterol biosynthesis in susceptible fungi

Question 3

What is ergosterol? Why is this a useful drug target?

Answer 3

main component of membranes in fungi

inhibition of its biosynthesis results in selective toxicity of the drug for the parasite

Question 4

What are some other squalene epoxidase inhbitiors used aside from tolnaftate?

Answer 4

Terbenafine
Naftifine
Butenafine

Question 5

What is the mechanism of action of clotrimazole?

Answer 5

Clotrimazole is a member of the azole class of antifungal agents. The azoles inhibit cytochrome P450, which catalyzes the 14α-demethylation of lanosterol during its conversion to ergosterol.

Question 6

What is actually occupied by CYP450s WRT azole action?

Answer 6

the iron that is involved in binding O2 and activating it for metabolic reaction

Question 7

What are other azole antifungles aside from clotrimazole?

Answer 7

miconazole

ketoconazole

Question 8

What is the mechanisms of action of griseofulvin?

Answer 8

It disrupts the mitotic spindle by binding to polymerized microtubules to inhibit mitosis

Question 9

What is griseofulvin used to treat?

Answer 9

It is used in the treatment of onychomycosis (fungal infection of nails). It is deposited in newly formed keratin, where it prevents fungal growth. However, the keratin in old tissue may still support fungal growth, so therapy may last up to a year

Question 10

What antifungals are used to treat systemic infections?

Answer 10

1. Amphotericin B (fungizone)
2. 5-Fluorocytosine (ancobon, flucytosin)
3. Ketoconazole (nizoral)
4. Fluconzaole (Diflucan)
5. Itraconazole
6. Echinocandins

Question 11

Comments about the structure and availability of amphotericin B

Answer 11

a. amphoteric - it has both an acidic and a basic group.
b. Structure contains a lipophilic polyene region (bottom) and a hydrophilic polyalcohol region.
c. Poor water solubility - not absorbed well from the GI tract - must be administered by slow IV infusion
d. Available as a bile salt complex called the deoxycholate complex or the cholesterol complex as a sterile lyophilized form, which is reconstituted with sterile water. It is also available as liposomal Amphotericin B suspension for injection.

Question 12

Amphotericin B

• major acute reaction
• use
• mechanism
• selectivity

Answer 12

e. Major acute reaction is fever and chills. Sometimes headache, nausea, vomiting, nephrotoxicity, and hypotension occur. The major limiting toxicities are nephrotoxicity and hypokalemia.
f. Broad spectrum antimycotic used in the treatment of deep mycoses including aspergillosis, blastomycosis, coccidioidomycosis, cryptococcosis, histoplasmosis, and mucormycosis.
g. The mechanism of action involves binding to ergosterol in the membranes of sensitive fungi. Pores open in the membrane, allowing leakage of ions and small organic molecules.
h. Selectivity. Amphotericin B binds 10 times more strongly to vesicles containing ergosterol than to those containing cholesterol. However, some binding to cholesterol still occurs, resulting in toxicity.

Question 13

Mechanism of 5-Fluorocytosine

Answer 13

Susceptible fungi convert 5-fluorocytosine to 5-fluorouracil, which is converted into 5-fluorodeoxyuridine monophosphate (5-fluoro-2’-deoxyuridylic acid).

5-Fluorodeoxyuridine monophosphate inhibits thymidylate synthase, thus inhibiting DNA biosynthesis.

Question 14

Review of the biosynthetic conversion of deoxyuridine monophosphate to deoxythymidine monophosphate

Answer 14

Initially, the enzyme carries out a Michael addition on uracil (1)

to generate an enolate 2

which then adds to the iminium ion present in methylenetetrahydrofolate (3)

The resulting intermediate then eliminates tetrahydrofolate (6) to form the uracil derivative 5.

The delivery of hydride from tetrahydrofolate (6) to the uracil intermediate 5 in another Michael addition then generates an enolate 7 which eliminates the enzyme to generate the product 8.

Question 15

In the presence of 5-fluorouracil the elimination of F+ is impossible because …

Answer 15

fluorine is the most electronegative element

Question 16

5-fluorouracil

• selectivity
• therapeutic use
• absorption, toxicity, etc

Answer 16

Selectivity. Human cells have little or no cytosine deaminase activity.

Therapeutic use. Used in combination with amphotericin B to treat systemic Candida infections and Cryptococcus neoformans meningitis.

Its spectrum of activity is limited to susceptible strains of Candida, Cryptococcus, Torulopsis glabrata (now called Candida glabrata), Cladosporium, and Aspergillus.

Well absorbed through the GI tract, has a low incidence of toxicity, and can penetrate into the cerebrospinal fluid (CSF).

Question 17

5-fluorouracil

• Resistance
• toxicity
• how can N&V be avoided

Answer 17

Resistance. Marked resistance can develop during therapy. Consequently, 5- fluorocytosine is used in combination with amphotericin B to kill resistant strains when they emerge. In addition, amphotericin B increases permeability of fungal cells to enhance the uptake of 5-fluorocytosine.

Toxicity. May depress bone marrow function, leading to leukopenia and thrombocytopenia.

Eliminated by the kidneys - administered with extreme caution to patients with impaired renal function and renal function
should be monitored during therapy

Other untoward effects include nausea, vomiting, diarrhea, rash, and enterocolitis.

Nausea and vomiting may be reduced or avoided if the capsules are administered a few at a time over a 15 min period.

Question 18

Comment on the use of ketoconazole in comparison to the use of amphoteracin B

What is it used for?

Answer 18

It is tolerated better than amphotericin B, but is also less effective

It is effective in treatment of blastomycosis, histoplasmosis, coccidioidomycosis, and paracoccidioidomycosis.

Question 19

General commends on Fluconazole

• structure
• bioavailability
• selectivity

Answer 19

1. Triazole (3 nitrogens in the five-membered ring), as opposed to an imidazole (2 nitrogens).
2. High bioavailability and penetrates well into the CSF. Thus fluconazole is useful in the treatment of meningitis caused by susceptible fungi.
3. Fluconazole has increased selectivity for fungal vs. human cytochrome P450. This diminishes the incidence of adverse effects and drug interactions.

Question 20

General commends on Fluconazole

• therapeutic use
• toxicity

Answer 20

4. Therapeutic use. Administered by IV infusion to treat cryptococcal meningitis in AIDS patients. Fluconazole (200 mg daily) is the first drug of choice for prevention of relapse of cryptococcal meningitis in AIDS patients whose infection has been controlled by amphotericin B. It is administered as a single oral dose (150 mg) for treatment of vaginal candidiasis.
5. Toxicity. Rare cases of hepatotoxicity, including fatalities, have been reported. Patients with abnormal liver function tests should be monitored for symptoms of hepatotoxicity.

Question 21

General comments on Itroconazole

• what does the drug consist of
• structure
• where is it bound
• useful for CNS?
• therapeutic use

Answer 21

1. Itraconazole is a 1:1:1:1 racemic mixture of four diastereomers.
2. Like fluconazole, itraconazole is a triazole.
3. Itraconazole is more than 90% bound to serum proteins and is extensively bound in tissues.
4. No detectable drug appears in the CSF. It is therefore not useful in treatment of infections in the CNS.
5. Therapeutic use.
   Nonmeningeal histoplasmosis.
   It is also used in treatment of AIDS patients with disseminated histoplasmosis whose disease has stabilized during amphotericin B therapy.

Question 22

General comments on Itroconazole

-untoward effects

Answer 22

Well tolerated at 200 mg/day, but GI distress occasionally prevents use of 400 mg/day.

Other side effects include nausea and vomiting (10%), hypokalemia (9%), and rash (2%).

Can cause heart failure rarely and should not be administered to patients with symptoms of congestive heart failure. It should be discontinued if symptoms of heart failure appear.

Rare cases of severe hepatotoxicity have occurred, including liver failure and death. Treatment should be discontinued if symptoms of liver disease appear.

Coadministration of itraconazole with drugs that are metabolized by cytochrome P450 can lead to interactions. Coadministration is contraindicated with cisapride, pimozide, quinidine, and dofetilide.

Question 23

Echinocandins

• mechanism of action
• selectivity
• spectrum
• admin
• adverse reactions

Answer 23

The echinocandins inhibit 1,3-β-glucan synthesis in the fungal cell walls by noncompetitive inhibition of 1,3-β-glucan synthase.

Selective toxicity for the fungus and not the host is that mammalian cells lack 1,3-β-glucan synthase.

The echinocandins are broad spectrum antifungal
agents that have no cross-resistance with other antifungals and are synergistic with voriconazole and amphotericin B.

Administration is IV.

Adverse reactions include hepatotoxicity and sensitivity/allergic reactions.