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Flashcards in antifungals Deck (32):
1

immunocompetent fungal infections

Blastomycosis, Chromoblastomycosis, Coccidioidomycosis, Histoplasmosis, Paracoccidioidomycosis and Sporotrichosis.

2

infection in immunocompromised
(eg. leukemic, neutropenic, debilitated patients- burns, surgery, etc.):

Aspergillosis, Candidiasis, Cryptococcosis, Mucormycosis, Pseudallescheriasis. These are termed opportunistic pathogens.

3

fungal infections in AIDs pts

Candidiasis
Crypto
Histoplasmosis, Coccidiodomycosis

4

Antifungal Therapy for subcutaneous and systemic mycosis.

Amphotericin B [AmphotecR, AmbisomeR, AbelcetR]
-Ketoconazole [Nizoral®]
-Miconazole [MonistatR]
-Fluconazole [DiflucanR]
-Itraconazole [SporanoxR]

5

Empiric Antifungal Therapy
for ??
Common element ??
antifungals of choice??

consider prophylaxis for what fungal infections?

neutropenic pts who do NOT respond to broad spectrum antibacterial tx (4-7 days), seriously ill patients (e.g. cancer, diabetes).
-impairment of normal phagocyte response to fungal infection
-use broad-spectrum: AmpB, miconazole

-candidiasis, Aspergillosis: use Nystantin, ampB, and -azoles

6

Drugs used for Superficial Fungal Infections: Dermatophytic infections:

-mild-moderate: Miconazole [MonistatR], Tolnaftate [TinactinR]
-moderately severe: the "azoles", Terbinafine
-severe: Griseofulvin
-Tinea Versicolor: "azoles" esp. ketoconazole

7

for all drugs don't need to know specific use except
(know MOA, SEs)

*Capsofugin* KNOW USE (later card)

8

Moderately severe Tinea infections (* oral administration)??

-cutaneous: ampB, azoles, nystatin, terbinafine
-vulvovag: azoles, nystatin
-oropharyngeal: azoles, nystatin

9

targets of certain antifungals (Figure 1)

-ampB, nystatin (Polyenes): alter membrane function
-Echinocandins: alter cell wall synthesis
-Allyamines/thiocarbamates/azoles: inhibit ergosterol synthesis
-Griseofulvin: inhibit nuclear division

10

remember ergosterol synthesis (Figure 2)

squalene-->lanosterol via squalene monooxygenase (inhibited by terbinafine and tolnaftate: squalene accumulates)

lanosterol-->ergosterol (via C-14 demethylase: cytP450 enzyme, inhibited by azoles-lanosterol accumulates))

11

amphotericin B

-insoluble in water: challenge, used *parenterally*, fungistatic,
-Binds to sterols (ergosterol) in fungal cell membrane
-pores or channels are formed in the *cell membrane*, permeability increases-->lose cell contents

12

ampB: selective or not??

not very, sterol selectivity also accounts for drugs toxicity, Mammalian cells, e. g. *kidney cells and erythrocytes* contain sterols (cholesterol)-->ampB alters cell perm

13

ampB SEs

-Frequent infusion-related reactions: fever, chills, ha, hypotension, tachy, muscle/ joint pain, N/V
*Nephrotoxicity*
*Anemia: Hypochromic and normocytic* reversible anemia is usual. *Decreased production of erythropoietin* is the probable mechanism.

14

ampB nephrotoxicity

Azotemia (nitrogen retention) (80% of pts). Toxicity is transient and increases by concurrent therapy with other nephrotoxic agents (aminoglycosides, cyclosporine). Damage to renal tubules occurs, but permanent functional deficits are uncommon. Renal function should be monitored frequently.

15

ampB uses: not going to test us on specifically

systemic (IV, intrathecal) and superficial infections (topical)

16

Imidazoles and Triazoles

Systemic triazoles: more slowly metabolized (longer half-life) and less effect on human sterol synthesis than imidazoles.

17

Imidazoles and Triazoles MOA

inhibition of sterol 14-α-demethylase, (cytP450-dependent) an enzyme that demethylates lanosterol, a precursor of ergosterol
-accumulation of 14-α-methylsterols, impairing membrane-bound enzymes systems, permeability of fungal cell membrane and thus inhibiting fungal growth
(binds weakly to mammalian enzyme; so less toxicity, better selectivity)

18

imidazoles

Miconazole [MonistatR, MicatinR]
Ketoconazole [Nizoral®]

19

Triazoles

Itraconazole [SporanoxR]
Fluconazole [DiflucanR]

20

Ketoconazole [Nizoral®]

imidazole
fungistatic at lower concentrations and fungicidal at higher concentration
*shuts down steroid synthesis*
-7-8 hr half-life

21

Ketoconazole [Nizoral®] SEs

*Endocrinologic abnormalities: Due to inhibition of steroid biosynthesis (females: 10% menstrual abnormalities; in males: gynecomastia and decreased libido and potency)*

GI
Hypersensitivity
inhibits P450-dependent enzymes

22

Miconazole [MonistatR, MicatinR]

imidazole
12 hr half-life, metabolized by liver
low toxicity

23

Fluconazole [DiflucanR]

triazole
25-30 hr half-life! can use 1 pill/day
interacts w. cytP450
low toxicity

24

Itraconazole [SporanoxR]

30 hour half-life (1x/day) Incr. conc. of drugs metab cyt P-450: i.e. cyclosporine, digoxin, phenytoin
-Low toxicity

25

Griseofulvin [Grifulvin VR] MOA (KNOW)

(used for superficial infections)
-*Disrupts cell’s mitotic spindle structure, thus arresting the metaphase of *cell division*
-*deposited in keratin precursor cells; takes time, requires wks-mos*, concentrates in skin, hair, nails, liver, fat, skel. muscles
-Ultramicrosize

26

Griseofulvin [Grifulvin VR] SEs

minor
CNS, GI, hypersensitivity
-assess renal, liver, hematopoietic function before therapy

27

Nystatin

CANNOT USE PARENTALLY: too toxic (vs. ampB), few SEs if used correctly
*similar MOA as ampB*: Binds to sterols in the fungal cell membrane
-oral candidiasis

28

Tolnaftate [Tinactin®] MOA

-interferes with sterol biosynthesis by *inhibiting the enzyme squalene monooxygenase* (squalene 2,3-epoxidase) which results in decreased synthesis of ergosterol and accumulation of squalene, which results in changes in membrane properties
-low toxicity, used for topically for superficial infections (Dermatophytoses)

29

Terbinafine hydrochloride [LamisilR cream] MOA

interfere with ergosterol biosynthesis by inhibiting the enzyme *squalene monooxygenase* (squalene 2,3-epoxidase) which results in decreased amounts of ergosterols and accumulation of squalene, which results in changes in membrane properties.
-low toxicity, -used for topically for superficial infections (Dermatophytoses)

30

Caspofungin [Cancidas®]

(echinocandins class) inhibits the SYNTHASE of β (1,3) –D-glucan, an essential polysaccharide component of the cell wall of filamentous fungi
-not present in mammalian cell
-low adverse effects

31

Caspofungin [Cancidas®] uses (KNOW)***
FDA-approved for treatment of ??

*invasive aspergillosis and esophageal candidiasis in patients who are refractory or intolerant to other antifungals (eg. amphotericin B or itraconazole)*

32

case: coccidiodal infection, treated w. fluconazole

will have case like this on test, will ask about MOA or SEs