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CMOD Week 3 > Antifungal Drugs > Flashcards

Antifungal Drugs Flashcards

1
Q

What is the first line drug for Aspergillosis? Alternative?

A

Voriconazole IV

Lipid Amphotericin B

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2
Q

What is the first line drug for(mild)?

Alternative?

A

Itraconazole PO

Fluconazole

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3
Q

What is the first line drug for Blastomycosis (severe)?

A

Amphotericin B IV then Itraconazole PO

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4
Q

What is the first line drug for Candidiasis?

Alternative?

A

Fluconazole PO

Azole, or Amphotericin B or fungin agent

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5
Q

What is the first line drug for Coccidioidomycosis?

Alternative?

A

Fluconazole IV/PO or Itraconazole PO

Amphotericin B

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6
Q

What is the first line drug for Cryptococcus?

Alternative?

A

Amphotericin B IV + Flucytosine PO, then Fluconazole PO

Amphotericin B, Fluconazole, Fluctosine comb.

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7
Q

What is the first line drug for Histoplasmosis?

Alternative?

A

Amphotericin B IV+ Itraconazole PO

Fluconazole

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8
Q

What is the first line drug for Mucormycosis?

Alternative?

A

Amphotericin B

Poscaconazole

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9
Q

What is the first line drug for Sporotrichosis?

Alternative?

A

Amphotericin B IV +/or Itraconazole PO

Itraconazole PO

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10
Q

How does Amphotericin B (and nystatin) work?

A

a fungicidal agent that causes loss of cell membrane integrity by binding to ergosterol and punching holes through the membrane.

amphotericin B is an amphipathic molecule capable of associating both with a lipid and an aqueous environment.

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11
Q

How do the -azole drugs and Terbinafine work?

A

Allylamines, such as Naftifine and Terbinafine, inhibit the formation of squalene epoxide from squalene, an intermediate in ergosterol synthesis (a major fungal sterol component of the cell membrane). NOTE: an accumulation of squalene is itself toxic

-Azole drugs block the synthesis of ergosterol from lanosterol, by inhibiting 14-a-sterol demethylase (a CYP450) (these drugs are STATIC not fungicidal.. meaning that treatment regimens must be longer than fungicidal drugs like Ampho B because it won’t kill the fungus quickly)

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12
Q

How does Flucytosine work?

A

a nucleic acid synthesis inhibitor that prevents cell replication

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13
Q

How does Caspofungin (family of drugs called echinocandins) work?

A

inhibitor of beta-1-3 glucan production via gluten synthetase which is an important structural component of the cell wall.

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14
Q

How does Griseofulvin work?

A

works through the inhibition of the mitotic spindle in the cell nucleus.

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15
Q

What is the major side effect of Amphotericin B?

A

Binding to human membrane sterols does occur, causing renal toxicity in up to 80% of patients

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16
Q

How is Amphotericin B administered?

A

IV. BAD CSF absorption if taken orally

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17
Q

What are some alternatives to Amphotericin B? Downsides?

A

these have lipid packaging

Fungizone, AmBisone, Amphotec, Abelcet

These reduce renal toxicity but are expensive and not usually given unless specifically contraindicated

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18
Q

Other side effects of Amphotericin B?

A

Immediate: Infusion-related reactions (pre-medication hydrocortisone can decrease risk of this)
-Arrthymias (and possible cardiac arrest), fever, chills, muscle spasms, vomiting, etc.

Delayed: Renal toxicity
Anemia, Seizures, abnornal liver function tests

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19
Q

Why is anemia a side effect of Amphotericin B?
Why are arrhythmia a side effect of this drug?
Drug-Drug interactions?

A

the kidney is a major source of erythropoietin that serves to maintain red blood cell population. Thus, the anemia often accompanying amphotericin B is the result of drug-induced damage and loss of erythropoietin production by the kidney.

In common with the majority of antifungal agents, there are also reports of abnormal liver function tests in patients receiving this drug. These abnormalities will resolve on cessation of drug treatment.

Kidney disfunction causes a loss of K+. Potassium is critical to the function of the heart and so you can get arrhythmia and potentially cardiac arrest as a result of drugs that impair renal function.

Drug-Drug interactions: Cyclosporine and Gentamicin (these both cause renal damage), and diuretics

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20
Q

So are there any comparable drugs to amphotericin B?

A

Yes, Nystatin.

This drug has a comparable amphipathic structure and works in an identical manner. The major difference is that nystatin can only be used topically; drug toxicity precludes systemic administration.

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21
Q

Nystatin is primarily used for what?

A

treatment of candidiasis.

22
Q

Echocandins (Caspofungin and Micofungin) have utility in treating?

A

Aspergillus and Candida infections. With the exception of infusion related reactions, these agents are well tolerated.

23
Q

From a chemical standpoint, AZOLE antifungals can be subdivided into the ___, which contained 2 nitrogens, and the ___ which contained 3.

A

imidazoles (Of the drugs discussed, only ketoconazole belongs to the imidazole group.)

triazoles

24
Q

Specifically, what mechanism do AZOLE drugs inhibit?

A

they associate with 14-alpha demethylase, a CP450, and inactivate its normal job of transforming lanosterol to ergosterol. Could be bad if the drugs interact with host CP450.

25
Q

Name brand AZOLEs?

A 
Ketoconazole (the only imidazole)
Fluconazole
Itraconazole
Posaconazole
Voriconazole
26
Q

Which AZOLEs can inhibit host CYP3A4?

A

all 5 of these drugs are capable of inhibiting CYP3A4, the major metabolic pathway for prescription medications. Thus, these drugs can inhibit concurrent medications and can also experience a change in their own metabolism where they too are processed through the same metabolic route.

27
Q

Which AZOLEs would be bad for fighting fungal infections in the CSF? Why?

A

ketoconazole or itraconazole have very poor ability to penetrate into cerebrospinal fluid and would have no utility in treating infections there. This capacity may be related to these drugs being substrates for P-gp located in the blood- brain barrier.

By contrast, both fluconazole and voriconazole have utility in reaching the CSF and good oral bioavailability

28
Q

With the exception of ____, each of the other agents is eliminated primarily through ____ processes.

A

fluconazole (renal-urine)

hepatic

29
Q

All orally administered azaleas produce symptoms of GI discomfort, such as pain, constipation, diarrhea, weight loss, etc. BUT the highest incidence occurs with the use of which AZOLEs?

A

itraconazole (has both poor oral bioavailability, and poor penetration into the CSF) and posaconazole

Fluconazole is the best tolerated and has the widest therapeutic index (most used)

30
Q

Which AZOLEs should be avoided during pregnancy?

A

Fluconazole and Voriconazole

There are also reports that some of these drugs are associated with a pro-arrythmogenic event, that is to say, they cause cardiac arrhythmias or facilitate arrhythmias in the presence of concurrent cardio active drugs.

31
Q

What are some major side effects of Ketoconazole?

A

sever liver injuries and adrenal gland insufficiency (only AZOLE to cause this)

ketoconazole use is being discouraged because of hepatic toxicity and CYP drug interactions

32
Q

Why does adrenal insufficiency arise with Ketoconazole use?

A

Ketoconazole is unique in its ability, at doses higher than those required for antifungal activity, to inhibit the synthesis of adrenal steroids, leading to a reduction in aldosterone, cortisol, and testosterone. This ability is sometimes employed clinically, for example, in the treatment of hormone-sensitive prostate cancer; not so much these days with the advent of newer more specific agents.

33
Q

a

A

a

34
Q

Fluconazole and Voriconazole both have good bioavailability, both can reach the CSF, and both have similar side effects. So why is Fluconazole more used?

A

Fluconazole appears to have the best profile, because voriconazole possesses the highest problem for cytochrome mediated drug-drug interactions and this drug is also associated with photosensitive dermatitis, temporary visual disturbances, and several neurologic symptoms, including most commonly, hallucinations.

35
Q

Voriconazole has seen drug-drug interactions with what drugs?

A

CNIs (both)

36
Q

What is Posaconazole best used for?

A

Mucormycosis infections

37
Q

What are clotrimazole and miconazole?

A

are topical agents used in the treatment of candidiasis infection. By virtue of their application, systemic events with these drugs are rare.

Adverse effects are rare, available OTC

38
Q

How does Flucytosine work?

A

This drug has a narrow therapeutic window by virtue of its mechanism of action. On entry into the fungal cell through a process facilitated by cytosine permease, the pharmaceutical product is rapidly converted into 5 fluorouracil

5-FU becomes incorporated into intermediary metabolism where it causes an interruption in RNA and DNA synthesis. Whereas mammalian cells do not conduct the 1st conversion step to 5-FU, intestinal microflora do! As a result, the patient may experience the typical side effects of cell-cycle inhibition that are manifest in normally dividing cell populations. Thus, the hematologic toxicities are entirely predictable, based upon mechanism of action. In common with many of the other antifungals, use of this drug may temporarily elevate hepatic enzyme levels.

has renal elimination, good oral absorption, extensive distribution, anemia, leukopenia, thromobcytopenia

39
Q

Which antifungals have an adverse effect on the liver?

A

All AZOLEs, Amphotericin B, 5-FC, Echinocandins

40
Q

Which antifungals have an adverse effect of renal toxicity ?

A

Ampho B

41
Q

Which antifungals have an adverse effect on the CNS?

A

Voriconazole

42
Q

Which antifungals have an adverse effect of infusion reactions?

A

Ampho B and Echinocandins

43
Q

Which antifungals have an adverse effect of bone marrow suppression?

A

5-FC, Ampho B

44
Q

Which antifungals have an adverse effect on the GI?

A

Itraconazole, Posaconazole, 5-FC

45
Q

What is a mechanism of resistance against Amphotericin B and Nystatin?

A

sterol modification

46
Q

What are some mechanisms of resistance against AZOLEs?

A

efflux, demethylase alteration, bypass

47
Q

What is a mechanism of resistance against Terbinafine?

A

Efflux

48
Q

What is Griseofulvin?

A

an older drug whose use is declining in deference to terbinafine. This is one of the few drugs that works in the fungal cell nucleus, rather than upon membrane structure and function. It is a mitotic spindle inhibitor (microtubules); the drug, in consequence, is a cell-cycle inhibitor. The most significant aspect of this drug is its potential for drug-drug interactions including but not limited to: warfarin, oral contraceptives, cyclosporine

49
Q

Griseofulvin is mainly used to treat what?

A

Used systemically in the treatment of severe fungal skin infections, onchomycoses and tinea

50
Q

What is Terbinafine?

A

inhibits ergosterol synthesis at the level of squalene epoxide (squalene accumulates which is toxic)

No effects upon CYP activity

This drug is well tolerated, with the exception of transient lympho- and neutropenia, which possibility requires routine CBC testing.

CMOD Week 3 (10 decks)

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