Antifungal Drugs

Front 1

What type of drug is Amphotericin B?

Back 1

It is a Polyene Antifungal agent.

Front 2

How does Amphotericin B function?

Back 2

It binds directly to ergosterol in the fungal cell membrane and forms a pore through which molecules and ions can leak.

Front 3

Is Amphotericin B fungicidal or fungistatic?

Back 3

Fungicidal

Front 4

What is special about the properties of Amphotericin B?

Back 4

It has amphiteric properties.

Front 5

What causes resistance to Amphotericin B?

Back 5

Resistance is rare but it is caused by a decrease or alteration to the ergosterol in the fungal membrane.

Front 6

What are the pharmacokinetics of Amphotericin B?

Back 6

Amphotericin B's pharmacokinetics are not great:

It CANNOT be given orally and can only be given through IV.
It distributes widely throughout the body and is sequestered in cell membranes because it is able to bind to the sterol in our plasma membranes. It does not penetrate well into the CSF.
It has a VERY VERY long half life (15 days)
It is released VERY slowly from the body through the urine.

Front 7

What are the adverse effects of Amphotericin B?

Back 7

It can bind to human cells and prevents these cells from functioning.
It can cause fever. In 80% of patients it causes nephrotoxicity (the drugs bind to the renal tubules). Patients with kidney disease are more susceptible to this side-effect.
It can cause anemia.

Front 8

What was done to try and reduce the nephrotoxic effects of Amphotericin B?

Back 8

Lipid formulations were formed with Amphotericin B. this decreases the nephrotoxicity of the drug (although it is still pretty toxic) but does not decrease its efficacy.

Front 9

What is Amphotericin B used for clinically?

Back 9

It is a broad spectrum antifungal agent that can work against infections with Histoplasma, Blastomyces, Coccidioides, Cryptococcus and Candida.

It is administered IV for many systemic infections.

A combination of Amphotericin B and Flucytosine is used to treat Cryptococcal infections due to their synergistic interactions.

Front 10

What is nystatin?

Back 10

Nystatin is a Polyene antifungal drug that is available OTC as a cream. It is not given IV because it is VERY VERY toxic.

Front 11

What is special about Flucytosine?

Back 11

It is the ONLY antifungal drug that requires activation. It requires the fungal enzyme cytosine deaminase to activate it before it is able to work. There is NO equivalent enzyme to cytosine deaminase in human cells making this drug selective for fungi. It is activated into Fluorouracil (also used for chemotherapy).

Front 12

How does Flucytosine act?

Back 12

It is activated by Fungal Cytosine Deaminase into a form that can inhibit thymidylate synthesis and thus inhibit DNA synthesis by the fungus.

Front 13

What is the resistance fungi have to Flucytosine?

Back 13

Resistance is acquired RAPIDLY when Flucytosine is used alone so it is always used with another drug. The resistance is due to a decreased uptake of the drug and a decreased activation of the drug by the fungus.

Front 14

What are the pharmacokinetics of Flucytosine?

Back 14

It can be given orally and widely distributes throughout the body. It gets into the CSF and has a moderate half-life. It is excreted in the urine.

Front 15

What are the adverse effects of Flucytosine?

Back 15

It causes bone marrow toxicity (SERIOUS).
It can elevate hepatic enzymes (reversible if therapy is stopped)
It causes GI irritation

Toxicity is more frequent with AIDs patients.

Front 16

What is Flucytosine used for clinically?

Back 16

It is given alongside Amphotericin B to treat severe infections of Cryptococcus. Amphotericin B and Flucytosine are synergistic. This combination of drugs if fungicidal.

Front 17

What is Flucytosine's action on its own (fungicidal or fungistatic)?

Back 17

It is fungistatic if given on its own.

Front 18

How do Azole Antifungals work?

Back 18

They are competitive inhibitors of Lanosterol 14-alpha-demethylase. this is the enzyme that converts lanosterol to ergosterol in fungi.

They INTERFERE with ergosterol synthesis.

Front 19

What are the properties of azoles (fungicidal or fungistatic)?

Back 19

Azoles are fungistatic

Front 20

What is the selectivity of azole antifungals?

Back 20

These drugs are have more inhibitory action of the fungal methylase enzyme than the human methylase enzyme giving them their selectivity.

Front 21

What forms of resistance are there to Azole antifungals?

Back 21

Fungi can cause a decreased accumulation of azole due to increased efflux (this is mediated by the overexpression of ATP-Binding Cassette proteins which includes many different efflux transporters).

Decreased affinity of the target enzyme for azole.

Overexpression of the target enzyme (lanosterol-14alpha-demethylase) (it cannot all be bound up by the drug)

A variety of methods are used by bacteria to resist azole drugs.

There is cross-resistance between azole drugs.

Front 22

Does resistance to azoles confer resistance to Amphotericin B?

Back 22

NO

Front 23

Which azole have bacteria developed the greatest resistance against?

Back 23

Fluconazole

Front 24

What are the 4 types of Azole drugs?

Back 24

Fluconazole

Itraconazole

Voriconazole

Posaconazole

Front 25

What are the pharmacokinetics of each of the 4 Azole drugs?

Back 25

Fluconazole- best at penetrating the CSF, little metabolism, long half-life, excreted renally

Itraconazole- doesn't get into CSF, excreted via bile, some metabolism, moderate half-life

Voriconazole- little bit gets into CSF, extensive metabolism, shortest half-life, excreted by liver

Posaconazole- some gets into CSF, glucuronidated, longest half-life, excreted via bile

ALL the drugs can be given orally. They ALL interact with P450 enzymes.

Front 26

What are the common adverse effects to azoles?

Back 26

GI disturbances

Hepatotoxicity- they all interact with P450 enzymes

NONE OF THEM CAN BE USED DURING PREGNANCY- they cause fetal abnormalities

Voriconazole can cause visual disturbances which occur within the 1st hour the drug is given and then goes away.

Front 27

What are some of the drug-drug interactions of Azoles?

Back 27

They all interact with P450 enzymes.
Azoles are metabolized by and can inhibit P450 enzymes.
The plasma levels of azoles can be reduced by drugs that induce P450 enzymes such as rifampin.
Azoles can raise the plasma concentrations of drugs by inhibiting P450 enzymes leading to drug toxicities of drugs such as Warfarin.

Front 28

What are the clinical uses for azoles?

Back 28

They have broad spectrum activity.

Voriconazole is key for invasive aspergillosis. It is a safer drug with less side effects compared to Amphotericin B, it can be given orally and it is more effective.

They can be used to treat a variety of fungal infections.

Front 29

What are the 3 Echinocandins?

Back 29

Caspofungin

Micafungin

Anidulafungin

Front 30

How do the Echinocandins work?

Back 30

They inhibit the synthesis of the beta-D-glucan in the fungal cell wall.

Front 31

How is resistance against echinocandins generated?

Back 31

Resistance is generated by altering the beta-D-glucan enzyme.

Front 32

What are the pharmacokinetics of caspofungin?

Back 32

It CANNOT be given orally and is only given via IV.
It has extensive tissue distribution but does not penetrate the CSF.
It is extensively metabolized and has a long terminal half-life (can be given 1 X day).
It is excreted through the bile and kidneys.

Front 33

What are the adverse effects of Caspofungin?

Back 33

Flushing (it must be infused over more than 1 hour; same effect as vancomycin)
Fever
Infusion-related phlebitis (vein inflammation)
Headache
Elevation of liver enzymes

Front 34

What are the clinical uses of Caspofungin?

Back 34

Candida infections- bactericidal; it is a safer drug, much less toxic and has as much effectiveness as Amphotericin B in treating invasive Candidiasis.

Invasive aspergillosis- bacteristatic