antifungal agents Flashcards Preview

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Flashcards in antifungal agents Deck (11):
1

Classification based on mechanism of
action

1. Fungal cell wall synthesis inhibition: Echinocandins
2. Bind to fungal cell membrane ergosterol: Amphotercin–B,
Nystatin.
3. Inhibition of ergosterol + lanosterol synthesis: Terbinafine,
Naftifine
4. Inhibition of ergosterol synthesis: Azoles
5. Inhibition of nucleic acid synthesis: 5–Flucytosine.
6. Disruption of mitotic spindle and inhibition of fungal mitosis:
Griseofulvin.
7. Miscellaneous: Ciclopiro

2

Classification based on structure

Classification based on structure
• ANTIBIOTICS
Polyene: Amphotericin, nystatin
Heterocyclic benzofuran: griseofulvin

• ANTIMETABOLITE : Flucytosine

• AZOLES
Imidazoles: ketoconazole, clotrimazole, oxiconazole,
miconazole,
Triazoles: fluconazole, itraconazole, voriconazole,
posaconazole

• ALLYLAMINES
– Terbinafine, naftitine
• ECHINOCANDINS
– Caspofungin, anidulafungin, micafungin

3

Systemic antifungal drugs for systemic infections
Which group does Amphotericin B and liposomal amphotericin B belong to?
Mechanism: 4 steps.
Spetrcum?

Kinetics:
ADmin?
CNS?
Half life?
Eliminiation?
ADverse effect?
1- has 3 side effects.
2- has 3 side effects.

Polyenes (macrolide antibiotics)
Amphotericin B, liposomal amphotericin B

Mechanism:
1. Binds ergosterol in fungal cell membrane
2. Form pores in cell membrane
3. Cell contents leak out
4. Cell death

Antifungal spectrum
- Aspergillus
- Blastomyces dermatitidis
- Candida sp. - Cryptococcus neoformans
- Coccidioides immitis
- Histoplasma capsulatum
- Mucor spp.
Also active against Leishmania, Acanthamoeba!
No effect against dermatophytones!
Highest spectrum!


- useful drug in nearly all life threatening mycotic
infections : mycosis of the organs, sepsis
- coccidio- or candida meningitis - intrathecal
administration
- topically applied for ocular or bladder infections
- effective in leishmaniasis

Pharmacokinetics:
- only parenterally
- good distribution, exception CNS
- long elimination half life

- liposomal form: better effect, less side effects
- slow elimination through the kidney
- no dose adjustment is necessary at
hepatic or kidney impairment,

Adverse effects:
1. fever, chills, GI side effects (infusion related
toxicity)
2. cumulative toxicity
- nephrotoxicity (monitorization!)
- impaired liver functions
- bone marrow suppression etc.

** liposomal amphotericin B
- less nephrotoxicity and bone marrow suppression
- higher doses can be used

4

5- fluorocitozine (flucytosine)
What is it used for?
Mechanism?
advantages of synergism
kinetics:
admin
good dist?
half life
elimination?
adverse effects- 3
indications- 2

Systemic antifungal drugs for systemic infections
Antimetabolite

Mechanism of action: 5-FU is formed from it in the
fungal cells (it is a prodrug), incorporates into RNA, inhibits protein (it synergizes with amphotericin B for better delivery to the cell as a permease for the drug to pass the membrane).
synthesis.

Advantages of combination: – enhanced entry of 5
fluorocitozine
– reduced toxicity
– reduced duration of therapy
– decreased resistance (!).

Pharmacokinetics:
- well absorbed orally
- good distribution, enters CNS
- short half life
- eliminated by the urine, dose adjustment at
impaired kidney functions

Adverse effects: - bone marrow- and hepatotoxicity
- GI, toxic enterocolitis (rare, at high serum level)

Clinical indications: - synergic effect with Amphotericin B, they are given together
- effective mainly against Cryptococcus neoformans and Candida species

5

Systemic antifungal drugs for systemic infections
Azoles
Which imidazoles do you use?
which triazoles do you use?
Mechanism of action?
Kinetics- 3 specific things you should remember.
Adverse effects: 3
indications... wtf?

(Imidazoles: clotrimazole, ketoconazole-not used systemically)
Triazoles: Ist. gen. fluconazole, itraconazole
IInd. gen. voriconazole, posaconazole

Mechanism of action: - inhibit the ergosterol synthesis by binding to the cytochrome P-450 enzyme (14 α demethylase) system.
- high selectivity, greater affinity for the fungal
enzyme system

Pharmacokinetics:
- Well absorbed orally
- itraconazole – poorly enters CNS, eliminated mainly through the GI tract
- fluconazole and voriconazole – enter CNS, excreted mainly by the urine,
- itraconazole and fluconazole – accumulate in the nails and skin.

Adverse effects: - relatively non toxic
- mainly GI - liver enzyme elevation
- rarely hepatitis
(- ketoconazole – gynaecomastia, oligospermia,
impotence (inhibits testosterone synthesis))

Clinical indications:
all fungi except aspergillus
- broad spectrum, Candida sp., Cryptococcus, blastomycosis,
coccidioidomycosis, histoplasmosis, dermatophytons
- itraconazole and voriconazole – effective in Aspergillus infections too
- itraconazole, fluconazole – in dermato- and onychomycosis
- fluconazole – Cryptococcus meningitis
- fluconazole, voriconazole – often used at ICU for the treatment of sepsis,
ex. Candida sepsis
- posaconazole – the newest, indicated in invasive aspergillosis. Significant
effect in mucormycosis.
- (ketoconazole is used only locally)

6

Echinocandins – newest class of antifungal agents
What are the 3 names?
Mechanism?
Effective against?
Given?
Adverse effects- 4
Indications-

Systemic antifungal drugs for systemic infections:
Caspofungin, micafungin, anidulafungin


Mechanism of action:
- inhibit beta- glucan synthesis → disruption of fungal cell wall
- effective: Candida sp, Aspergillus niger
- only i.v.

Adverse effects: - well tolerated
- fever, GI, flush
- liver enzyme elevation
- micafungin increased the risk of liver tumors, and
supresses bone marrow,

Indications: - Candida and Aspergillus infections
- sepsis
- multiresistant infections

7

Terbinafine
Belongs to which family and what is it used for?
Mechanism?
Kinetics- 2
Adverse- 3+ accumulation.
Indication: 3

Systemic antifungal drugs for mucocutaneous infections
belongs to ALLYLAMINES

Mechanism of action:
- inhibits the fungal enzyme squalene epoxidase → squalenes accumulate → toxic effect and lack of ergosterol ( Inhibition of ergosterol + lanosterol synthesis)
- fungicid, broad spectrum

Pharmacokinetics:
- Good oral absorbtion
- accumulates in skin, nails, hair

Adverse effects:
- GI
- skin reactions (rarely Stevens-Johnson syndrome)
- liver enzyme elevation

Indications: - local and systemic treatment of onycho- and dermatomycosis (dermatophytons)
- some Candida infections

8

Griseofulvin
Mechanism
effective against?
Kinetics- 2
Adverse- 3
indication:
interaction:

Systemic antifungal drugs for mucocutaneous infections
Antibiotics: Heterocyclic benzofuran: griseofulvin

Mechanism of action:
- not clear, inhibits mitosis

- effective against: fungistatic, effective mainly against
dermatophytons

Pharmacokinetics:
- well absorbed orally
- accumulates in nails, hair and skin

Adverse effects:
- GI
- liver enzymes elevation, hepatotoxicity
(toxic reaction)

Indications: - microsporia capitis of the scalp
Interactions: - enzyme inducer

9

Local antifungal drugs
Nystatin
Mechanism of action
Kinetics: 2x
Adverse effect: 4
indications: 3

Nystatin (polyene macrolide antibiotic)

Mechanism of action:
- it is a compound similar to Amphotericin B

Pharmacokinetics:
- not absorbed orally, local effect in the GI tract
- poor absorbtion from the skin and mucosal membranes

Adverse effects:
- nausea, vomit, diarrhoeia
- exanthema

Indications:
- candidiasis of oral cavity and of oesophagus
- infections of the gastrointestinal tract
- superficial infections of skin and mucosas

10

Other local antifungal drugs
From allilamines.. 2 drugs.

Other local antifungal drugs
1. Allilamines:
A. Terbinafine, fungicid cream, spray, gel.
B. Naftitin, fungicid cream and solution



Ciclopirox: broad spectrum antifungal drug, with antibacterial and
antiinflammatory effect
onychomycosis, dermatomycosis
cream, nail polish, solution
Azoles: clotrimazole, bifonazole, econazole, flutrimazole,
ketoconazole, omoconazole

11

other local antifungal drugs:

1. Amorolphin: fungicid, nail polish

2. Ciclopirox: broad spectrum antifungal drug, with antibacterial and antiinflammatory effect
onychomycosis, dermatomycosis
cream, nail polish, solution

3. Azoles: clotrimazole, bifonazole, econazole, flutrimazole, ketoconazole, omoconazole