antifungal agents Flashcards
Classification based on mechanism of
action
- Fungal cell wall synthesis inhibition: Echinocandins
- Bind to fungal cell membrane ergosterol: Amphotercin–B,
Nystatin. - Inhibition of ergosterol + lanosterol synthesis: Terbinafine,
Naftifine - Inhibition of ergosterol synthesis: Azoles
- Inhibition of nucleic acid synthesis: 5–Flucytosine.
- Disruption of mitotic spindle and inhibition of fungal mitosis:
Griseofulvin. - Miscellaneous: Ciclopiro
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
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:
- Binds ergosterol in fungal cell membrane
- Form pores in cell membrane
- Cell contents leak out
- 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
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
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)
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
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
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
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
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
other local antifungal drugs:
- Amorolphin: fungicid, nail polish
- Ciclopirox: broad spectrum antifungal drug, with antibacterial and antiinflammatory effect
onychomycosis, dermatomycosis
cream, nail polish, solution - Azoles: clotrimazole, bifonazole, econazole, flutrimazole, ketoconazole, omoconazole
