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Pharm - Drugs > Fungal Drugs > Flashcards

Fungal Drugs Flashcards

1
Q

Amphotericin B MOA:

A

Forms pores in fungal membranes (which contain ergosterol) but not in mammalian (cholesterol- containing) membranes

  • bind to ergosterol, and alters the permeability of the cell by forming amphotericin B-associated pores in the cell membrane.
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2
Q

Amphoterin targets:

A

Localized and systemic candidemia

Cryptococcus Histoplasma Blastomyces Coccidioides Aspergillus

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3
Q

Amphoterin B Effects:

A

Loss of intracellular contents through pores is fungicidal broad spectrum of action

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4
Q

Amphoterin PK:

A

Oral but not absorbed
IV for systemic use
intrathecal for fungal meningitis
topical for ocular and bladder infections duration, days

Toxicity: Infusion reactions
renal impairment
Interactions: Additive with other renal toxic drugs

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5
Q

What family of fungal drugs is amphoterin B in?

A

POLYENE MACROLIDE

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6
Q

Flucytosine MOA:

A

Interferes with DNA and RNA synthesis selectively in fungi

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7
Q

Flucytosine Effects:

A

Synergistic with amphotericin systemic toxicity in host due to DNA and RNA effects

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8
Q

Flucytosine targets:

A

Cryptococcus and chromoblastomycosis infections

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9
Q

Flucytosine PK

A

Oral duration, hours renal excretion Toxicity: Myelosuppression

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10
Q

What family of fungal drugs is flucytosine in?

A

PYRIMIDINE ANALOG

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11
Q

Ketoconazole MOA?

A

Blocks fungal P450 enzymes and interferes with ergosterol synthesis

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12
Q

Ketoconazole Effects:

A

Poorly selective interferes with mammalian P450 function

less selective for fungal P450 than are the newer azoles. has fallen out of clinical use in the USA , but was the 1st one introduced in clinical practice.

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13
Q

Ketoconazole Targets:

A

Broad spectrum but toxicity restricts use to topical therapy

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14
Q

Ketoconazole PK:

A

Oral, topical Toxicity and interactions: Interferes with steroid hormone synthesis and phase I drug metabolism

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15
Q

What drug family is ketoconazole in?

A

Azoles

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16
Q

Itraconazole MOA?

A

Same as for ketoconazole, (Blocks fungal P450 enzymes and interferes with ergosterol synthesis)

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17
Q

Itraconazole Effects?

A

Much more selective than ketoconazole

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18
Q

Itraconazole Targets?

A

Broad spectrum: Candida, Cryptococcus, blastomycosis, coccidioidomycosis, histoplasmosis

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19
Q

Itraconazole PK:

A

Oral and IV duration, 1–2 d poor entry into central nervous system (CNS) Toxicity and interactions: Low toxicity

  • rug absorption is increased by food and by low gastric pH. Like other lipid-soluble azoles, it interacts with hepatic microsomal enzymes, though to a lesser degree than ketoconazole.

-

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20
Q

What drug family is itraconazole in?

A

Azole

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21
Q

Caspofungin MOA?

A

Blocks -glucan synthase

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22
Q

Caspofungin Effects?

A

Prevents synthesis of fungal cell wall

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23
Q

Caspofungin Targets:

A

Fungicidal Candida sp also used in aspergillosis

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24
Q

Capsofungin PK:

A

IV only duration, 11–15 h Toxicity: Minor gastrointestinal effects, flushing Interactions: Increases cyclosporine levels (avoid combination)

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25
Q

What drug family is Capsofungin in?

A

ECHINOCANDINS

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26
Q

Terbinafine MOA?

A

Inhibits epoxidation of squalene in fungi increased levels are toxic to them

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27
Q

Terbinafine Effects?

A

Reduces ergosterol prevents synthesis of fungal cell membrane

28
Q

Terbinafine Targets:

A

Mucocutaneous fungal infections

29
Q

Terbinafine PK:

A

Oral duration, days Toxicity: Gastrointestinal upset, headache, hepato- toxicity Interactions: None reported

30
Q

What drug family is terbinafine in?

A

ALLYLAMINE

31
Q

What are some extra info for amphotericin B?

A

Lipid formulations: Lower toxicity, higher doses can be used

32
Q

What are some extra info for azole drugs?

A

Fluconazole, voriconazole, posaconazole: Fluconazole has excellent CNS penetration, used in fungal meningitis

33
Q

What are some extra info for ECHINOCANDINS

A

Micafungin, anidulafungin: Micafungin increases levels of nifedipine, cyclosporine, sirolimus; anidulafungin is relatively free of this interaction

34
Q

What is one down side of amphotericin B?

A

it’s toxic properties

35
Q

What is an advantage of azole?

A
  • nontoxic, given orally or parenterally
36
Q

What route of administration is for echinocandins?

A

ONLY parenterally

37
Q

What are the 3 types of antifungal drugs?

A

systemic drugs (oral or parenteral) for systemic infections, oral systemic drugs for mucocutaneous infections, and topical drugs for mucocutaneous infections.

38
Q

What are the chemical properties of amphotericin B?

A
  • nearly insoluble in water
  • must be prepared in suspension
  • poorly absorbed in the GI
39
Q

Based on the chemical properties of Amphotericin B, when would you want to prescribe amphotericin B orally?

A

Oral amphotericin B is thus effective only on fungi within the lumen of the tract and cannot be used for treatment of systemic disease

40
Q

If amphotericin B is given IV, what are some PK?

A
  • 90% bound to albumin
  • mostly metabolized, but slowly excreted in urine over several days
  • half life: 15 days
  • mostly distributed to tissue
  • hepatic & renal impairment and dialysis have little effect on drug conc., thus no dose adjustment is needed
41
Q

Amphotericin Resistance

A

Resistance to amphotericin B occurs if ergosterol binding is impaired, either by decreasing the membrane concentration of ergosterol or by modifying the sterol target molecule to reduce its affinity for the drug.

42
Q

Azoles are good for

A

chronic therapy and prevention of relapse

43
Q

What are the adverse effects of amphotericin?

A
  • immediate reaction: related to infusion

- slower reaction:

44
Q

Infusion-related reactions are

A

fever, chills, muscle spasms, vomiting, headache, and hypotension.

  • They can be ameliorated by slowing the infusion rate or decreasing the daily dose
45
Q

What are the cumulative toxicity of amphotericin?

A

Renal damage is the most significant toxic reaction.

  • Renal impairment occurs in nearly all patients treated with clinically significant doses of amphotericin
46
Q

What is the chemistry and PK of flucytosine?

A

Flucytosine is a water-soluble pyrimidine analog related to the chemotherapeutic agent 5-fluorouracil (5-FU)

  • currently available in North America only in an oral formulation.
  • The dosage is 100–150 mg/kg/d in patients with normal renal function. It is well absorbed (> 90%), with serum concentrations peaking 1–2 hours after an oral dose.
  • poorly protein-bound; penetrates into all body fluid compartments, including the cerebrospinal fluid.
  • eliminated by glomerular filtration with a half-life of 3–4 hours and is removed by hemodialysis. Levels rise rapidly with renal impairment and can lead to toxicity. Toxicity is more likely to occur in AIDS patients and those with renal insufficiency. Peak serum concentrations should be measured periodically in patients with renal insufficiency and maintained between 50 and 100 mcg/mL.
47
Q

Flucytosine MOA

A

is taken up by fungal cells via the enzyme cytosine permease. It is converted intracellularly first to 5-FU and then to 5-fluorodeoxyuridine monophosphate (FdUMP) and fluorouridine triphosphate (FUTP), which inhibit DNA and RNA synthesis, respectively (Figure 48–1). Human cells are unable to convert the parent drug to its active metabolites, resulting in selective toxicity

48
Q

How is resistance mediated for the drug flucytosine?

A

altered metabolism of flucytosine

49
Q

what are the clinical use of flucytosine?

A

restricted to C neoformans, some Candida sp, and the dematiaceous molds that cause chromoblastomycosis.

50
Q

Is flucytosine normally used alone?

A

No. It is best when used in combination with another drug for its synergic effects.
Clinical use at present is confined to combination therapy, either with amphotericin B for cryptococcal meningitis or with itraconazole for chromoblastomycosis

51
Q

What is the adverse effects of flucytosine?

A

result from metabolism (possibly by intestinal flora) to the toxic antineoplastic compound fluorouracil. Bone marrow toxicity with anemia, leukopenia, and thrombocytopenia are the most common adverse effects, with derangement of liver enzymes occurring less frequently

52
Q

What is the MOA of azole?

A

inhibition of fungal cytochrome P450 enzymes.

  • The selective toxicity of azole drugs results from their greater affinity for fungal than for human cytochrome P450 enzymes. Imidazoles exhibit a lesser degree of selectivity than the triazoles, accounting for their higher incidence of drug interactions and adverse effects.
53
Q

What are the clinical use of azole?

A
  • The spectrum of action of azole medications is broad
54
Q

What are some adverse effects of azole?

A

All azole drugs are prone to drug interactions because they affect the mammalian cytochrome P450 system of enzymes to some extent.

55
Q

What is one of the drug interaction in ITRACONAZOLE?

A
  • important drug interaction is reduced bioavailability of itraconazole when taken with rifamycins (rifampin, rifabutin, rifapentine).
  • Drug absorption is increased by food and by low gastric pH
56
Q

What is FLUCONAZOLE MOA and its PK?

A
  • high degree of water solubility
  • good cerebrospinal fluid penetration.
  • Unlike ketoconazole and itraconazole, its oral bioavailability is high.
  • Drug interactions are also less common because fluconazole has the least effect of all the azoles on hepatic microsomal enzymes.
  • Because of fewer hepatic enzyme interactions and better gastrointestinal tolerance, fluconazole has the widest therapeutic index of the azoles, permitting more aggressive dosing in a variety of fungal infections.
  • The drug is available in oral and intravenous formulations and is used at a dosage of 100–800 mg/d
57
Q

the azole of choice in the treatment and secondary prophylaxis of cryptococcal meningitis is

A

FLUCONAZOLE

58
Q

What is the chemical and PK properties of Echinocandins?

A

Echinocandins are available only in intravenous formulations.

  • mostly water soluble
59
Q

What is the MOA of Echinocandins?

A

Echinocandins act at the level of the fungal cell wall by inhibiting the synthesis of (1–3)-glucan, leading to disruption of cell wall.

60
Q

What are some ORAL SYSTEMIC ANTIFUNGAL DRUGS FOR MUCOCUTANEOUS INFECTIONS?

A

Griseofulvin

- Terbinafine

61
Q

What is Griseofulvin MOA and PK?

A

Griseofulvin’s mechanism of action at the cellular level is unclear, but it is deposited in newly forming skin where it binds to keratin, protecting the skin from new infection

  • very insoluble fungalstatic, admin with fatty food
62
Q

What is Terbinafine MOA?

A

Like griseofulvin, terbinafine is a keratophilic medication, but unlike griseofulvin, it is fungicidal. Like the azole drugs, it interferes with ergosterol biosynthesis, but rather than interacting with the P450 system, terbinafine inhibits the fungal enzyme squalene epoxidase (Figure 48–1). This leads to the accumulation of the sterol squalene, which is toxic to the organism.

  • oral
63
Q

What are some topical antifungal treatments?

A

Nystatin

  • Topical Azoles: clotrimazole and miconazole
  • Topical Allylamines: Terbinafine and naftifine; effective for treatment of tinea cruris and tinea corporis
64
Q

Nystatin:

A

Nystatin is a polyene macrolide much like amphotericin B.

  • It is too toxic for parenteral administration and is only used topically.
  • Nystatin is currently available in creams, ointments, suppositories, and other forms for application to skin and mucous membranes.
  • It is not absorbed to a significant degree from skin, mucous membranes, or the gastrointestinal tract.
  • As a result, nystatin has little toxicity, although oral use is often limited by the unpleasant taste.
65
Q

Topical Azole:

A

available over-the-counter and are often used for vulvovaginal candidiasis.

ral clotrimazole troches are available for treatment of oral thrush and are a pleasant-tasting alternative to nystatin

  • dermatophytic infections, including tinea corporis, tinea pedis, and tinea cruris

Pharm - Drugs (9 decks)

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