Antifungal drugs (4) Flashcards
systemic fungal infections
– Systemic candidiasis: RTI – Cryptococcal meningitis, endocarditis – Rhinocerebral mucormycosis (rare) – Pulmonary aspergillosis – Blastomycosis (pneumonia) – Histoplasmosis (cough, fever, multiple pneumonic infiltrates) – Coccidiodomycosis
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: (Ciclopirox)
fungal cell wall synthesis inhibition
Echinocandins
Caspofungin
bind to fungal cell membrane ergosterol
Polyenes:
Amphotercin–B,
Nystatin.
Inhibition of ergosterol + lanosterol synthesis
Terbinafine, (Naftifine)
Inhibition of ergosterol synthesis
Azoles
imidazole:
(Ketoconazole)
Clotrimazole
(Miconazole)
Triazole:
(1st-gen’)
Fluconazole
Itraconazole
(2nd-gen’)
Voriconazole
Inhibition of nucleic acid synthesis
5–Flucytosine
Disruption of mitotic spindle and inhibition of fungal mitosis
(not on the list)
Griseofulvin
Miscellaneous
not on the list
Ciclopirox
Systemic antifungal drugs for systemic infections
Polyenes (macrolide antibiotics)
Amphotericin B, liposomal amphotericin B
- Differentiates between fungal and mammalian cell membranes so it can be used systemically (binds with higher affinity to the ergosterol type membranes)
- fungicid, binds to ergosterol and alters the permeability of the cell by forming pores in the cell membrane
Antimetabolites
5- fluorocitozine (flucytosine)
Azoles
(Imidazoles: clotrimazole!!!, (ketoconazole- used mainly locally))
Triazoles:
Ist. gen. fluconazole!!, itraconazole!!
IInd. gen. voriconazole!!, (posaconazole, isavuconazole)
Echinocandins – newest class of antifungal agents Caspofungin, (micafungin) (anidulafungin)
Amphotericin B, liposomal amphotericin B
Polyenes (macrolide antibiotics)
Amphotericin B, liposomal amphotericin B
- Differentiates between fungal and mammalian cell membranes so it can be used systemically (binds with higher affinity to the ergosterol type membranes)
- fungicid, binds to ergosterol and alters the permeability of the cell by forming pores in the cell membrane
- Amphoteric compounds with both polar and nonpolar structural components →
interact with ergosterol in fungal membranes to form ‘pores’, which disrupt membrane permeability - Fungicidal effect
- Resistant fungal strains appear to have low ergosterol content in their cell membranes
Antifungal spectrum - Broadest antifungal spectrum - Systemic fungal infections: Aspergillus, Blastomyces, Candida, Cryptococcus, Histoplasma, Mucor, Sporothrix - Aspergillus - Blastomyces dermatitidis - Candida sp. - Cryptococcus neoformans - Coccidioides immitis - Histoplasma capsulatum - Mucor spp. Also active against Leishmania, Acanthamoeba! No effect against dermatophytones! (broad spectrum of action)
Pharmacokinetics: - only parenterally, - good distribution, except CNS - liposomal form: better effect, less side effects - slow elimination through the kidney - IV - Oral (poor bioavailability) - Topical - Poor CNS penetration (intrathecal injection is required against Cryptococcal or Candida meningitis) - T1/2upto2w' - Clearance via hepatic metabolism and renal elimination
Clinical indications:
- useful drug in nearly all life threatening mycotic infections : mycosis of the organs, sepsis
- coccidio- or candida meningitis – intrathecally
- topically applied for ocular or bladder infections
- effective in leishmaniasis
Adverse effects:
- fever, chills, GI side effects (infusion related toxicity)
- cumulative toxicity
- nephrotoxicity (monitorization!)
- impaired liver functions
- bone marrow suppression etc.
Infusion-related: - Fever, chills - Muscle spasm - Injection-site phlebitis - Hypotension (due to histamine release)
Dose-dependent: - Nephrotoxicity (GFR ↓, RTA, K+ and Mg2+ wasting, EPO ↓) - CNS toxicity (seizures, neurologic damage) - Anemia
- liposomal amphotericin B
- less nephrotoxicity and bone marrow suppression
- higher doses can be used
Potential means of reducing toxicity and adverse effects:
Infusion-related:
- Anti-histamines
- NSAID’s
- Meperidine
- Corticosteroids
Dose-dependent:
- Liposomal formulation of amphotericin B
- Co-administration with flucytosine (allows dose reduction of amphotericin B while still maintaining potent antifungal activity)
- Volume expansion with IV saline
- K+ and Mg2+ supplementation
5- fluorocitozine (flucytosine)
Antimetabolites
5-FU is formed from it in the fungal cells, incorporates into RNA, inhibits protein synthesis
- Activated by fungal cytosine deaminase to 5-fluorouracil (5-FU), which after tri- phosphorylation is incorporated into fungal RNA
- 5-FU also forms 5-Fd-UMP, which inhibits thymidylate synthase → thymine ↓ (inhibits DNA synthesis)
Pharmacokinetics: - well absorbed orally - good distribution, enters CNS - Oral - Freely enters CNS - Renal elimination (dose reduction may be required in renal dysfunction) - short half life
Adverse effects:
- bone marrow- and hepatotoxicity
- GI, toxic enterocolitis (rare, at high serum level)
- Bone marrow suppression (reversible)
- Alopecia
- Liver dysfunction
Clinical indications: - synergic effect with Amphotericin B, they are given together
Advantages of combination:
– enhanced entry of flucytosine – reduced toxicity
– reduced duration of therapy
– decreased resistance (!)
- effective mainly against Cryptococcus neoformans and Candida species
- Narrow spectrum
- In combination with amphotericin B or triazole; used to treat Cryptococcal meningitis and invasive candidiasis
systemic antifungal drug for systemic infections
- Resistance emerges rapidly if used alone; involves decreased activity of the fungal permease
Azoles
Systemic antifungal drugs for systemic infections
Azoles
(Imidazoles: clotrimazole!!!, ketoconazole- used mainly locally)
Triazoles:
1st. gen. fluconazole!!, itraconazole!!
2nd. gen. voriconazole!!, (posaconazole, isavuconazole)
Mechanism of action:
- Interfere with the synthesis of ergosterol → inhibiting 14-α-demethylase, a fungal P450 enzyme, which converts lanosterol to ergosterol
- Fungicidal effect
- Resistance develops with long-term use via decreased intracellular accumulation, and altered sensitivity of target enzymes
- inhibit the ergosterol synthesis by binding to the cytochrome P-450 enzyme 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
- Oral, parenteral, topical
- Only fluconazole can cross the
BBB and penetrate into the CSF
- Hepatic metabolism (ketoconazole, itraconazole, voriconazole)
- Renal elimination (fluconazole)
- Inhibitors of CYP450 enzymes
Adverse effects: - relatively non toxic - mainly GI
- liver enzyme elevation
- rarely hepatitis
(- ketoconazole – gynaecomastia, oligospermia, impotence (inhibits testosterone synthesis))
- GI symptoms, skin rash
- Hepatotoxicity (rare)
- Decreased synthesis of steroid hormones (mainly cortisol and testosterone): libido ↓, gynecomastia, menstrual irregularity (most potent effect with ketoconazole)
- Visual disturbances (voriconazole)
Clinical indications:
- 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, 1st choice in mucocutan Candidiosis (gastrointestinal tract, genitorurinary), less effective against Aspergillus
- fluconazole, voriconazole – often used at ICU for the treatment of sepsis, ex. Candida sepsis
(- posaconazole, isavuconazole- indicated in invasive aspergillosis. Significant effect in mucormycosis.)
- (ketoconazole is used mainly locally)
Spectrum: Ketoconazole: - Mucocutaneous candidiasis (topical) - Dermatophytosis (topical) - Cushing's disease (cortisol synthesis ↓) *Systemic use in limited as it causes more adverse effects than any other available agents
Clotrimazole (Miconazole):
- Topical formulations treat dermatophytes, superficial candidiasis, vaginal candidiasis
- Available as over-the-counter drug
Fluconazole: - Esophageal, oropharyngeal, vaginal, and invasive candidiasis - Coccidioides infections - Cryptococcus meningitis (treatment and prophylaxis)
Itraconazole:
- Dimorphic fungi, Blastomyces and Sporothrix infections
- 2nd-line agent for Aspergillus, Coccidioides, Cryptococcus, Histoplasma
Voriconazole:
- Aspergillus infections
- Invasive candida infections (including
sepsis)
name some of these exampeles!!
Echinocandins
Caspofungin!!!, (micafungin, anidulafungin)
Caspofungin!!!, (micafungin, anidulafungin)
Echinocandins– newest class of antifungal agents
Systemic antifungal drugs for systemic infections
Mechanism of action:
- inhibit beta- glucan synthesis → disruption of fungal cell wall
- Inhibit the synthesis of β(1-3)-glucan, a critical component of fungal cell wall
Indications:
- Candida and Aspergillus infections
- sepsis
- multiresistant infections
- effective: Candida sp, Aspergillus niger
- Candida infections failed to respond to amphotericin B (disseminated and mucocutaneous infections)
- Mucor infection
- Aspergillus infection
- only i.v.
- Hepatic metabolism
- T1/2 9-12 h’
Adverse effects: - well tolerated - fever, GI, flush - liver enzyme elevation - micafungin increased the risk of liver tumors, and supresses bone marrow - GI distress - Fever, headaches, flushing, skin rash - Monitor liver enzymes (rarely hepatotoxic)
