1
Q
Antifungal drugs?
9
A
- Clot.RimaZol (ريما)
- Fluconazol
- Itraconazol
- Voriconazol
- Caspofungin (فنجان)
- Flucytosin
- Terbinafine
- Nystatin
- Amphotericin B
2
Q
what about Amphotericin B?
A
Amphotericin B is a polyene Abx related to nystatin
3
Q
Amphotericin B PharmacoKinetix?
A
- dministered I.V. in 3 forms poorly (absorbed from G.I.T):
1. nonlipid colloidal suspension
2. lipid complex
3. liposomal formulation - distribution: all tissues (except CNS)
- Elimination: slow hepatic metabolism
( a bit in urine) - 1/2 life: ± weeks
-
4
Q
Amphotericin MOA?
A
- fungicidal
- affect the permeability and transport
properties of fungal membranes - bind to Ergosterol (cell membranes)
–> artificial pores - Resistance: uncommon, occurs if membrane ergosterol level or structure decrease
5
Q
Amphotericin B Clinical uses?
A
- treatment of systemic mycoses
- used for initial induction regimens before Azole
- widest Antifungal spectrum
- drug of choice, or codrug of choice, for most systemic infections caused by (Aspergillus, C.Albicans, Cryptococcus)
- given by slow I.V.
6
Q
Amphotericin Toxicity?
A
infusion related
doe limiting
Neurotoxicity
7
Q
Amphotericin B I.V. Infusion related toxicity?
A
- fever
- chills
- muscle spasms
- vomiting
- shock-like fall in blood pressure
- effects can be attenuated by: slow infusion rate and premedication with antihistamines, antipyretics, glucocorticoids*
8
Q
Amphotericin B dose limiting toxicity?
A
- decreases the glomerular filtration rate + renal tubular acidosis (with magnesium and potassium wasting)
- Anemia: decrease of erythropoietin formation
- Liposomal formulations have reduced nephrotoxic effects
9
Q
Amphotericin B Neurotoxicity toxicity?
A
Intrathecal administration –> seizures and neurologic damage
10
Q
what about Flucytosine?
A
pyrimidine antimetabolite related to the anticancer 5-FU
11
Q
Flucytosin PharmacoKinetix?
A
- Bioavailability: effective orally
- distribution: most body (also CNS)
- Elemination: intact in the urine
(dose must be reduced in patients with renal impairment)
12
Q
Flucytosine MOA?
A
- membrane permease –> accumulate the drug in fungal cells –> cytosine deaminase –> 5-FU –> inhibits thymidylate synthase
- Resistance can occur rapidly if flucytosine is used alone
- When 5-FC is given with amphotericin B/ itraconazole –> emergence of resistance is decreased and synergistic antifungal effects may occur
13
Q
Flucytosine clinical uses?
A
- antifungal spectrum of 5-FC is narrow
- limited to the treatment in combination with amphotericin B / itraconazole
- used against:
1. Cryptococcus neoformans
2. molds (for chromoblastomycosis)
14
Q
Flucytosine Toxicity?
A
- Prolonged high plasma LvLs:
1. reversible bone marrow depression
2. alopecia
3. liver dysfunction.
15
Q
Azole Antifungal agents?
FIV(5)
A
- Fluconazol
- Itraconazol
- Voriconazol
16
Q
Azoles MOA
A
- inhibit ergosterol synthesis –> interfere with membrane permeability
- resistance: with increasing use of azoles (long-term prophylaxis in immunocompromised and neutropenics)
17
Q
Azoles PharmacoKinetix?
A
- Bioavailability: orally absorbed
- distribution: most body tissues
- metabolism and elimination:
- -> Liver for Itra and Vori
- -> kidney for Fluco (unchanged)
18
Q
Fluconazole clinical uses?
A
- Esophageal and Oropharyngeal candidiasis and most infections by Coccidioides
- A single oral dose usually eradicates vaginal candidiasis
- treatment and secondary prophylaxis against cryptococcal meningitis
- alternative drug (with amphotericin B) in active Cryptococcus neoformans
19
Q
Itraconazole clinical uses?
A
- systemic infections caused by Blastomyces and Sporothrix
- subcutaneous chromoblastomycosis
- alternative agent against Aspergillus, Coccidioides, Cryptococcus
- Esophageal candidiasis
- used in dermatophytoses (especially onychomycosis)
20
Q
Voriconazole clinical uses?
A
- wider spectrum than itraconazole
- against invasive aspergillosis
- alternative drug in candidemia
- in AIDS patients: candidal esophagitis and stomatitis
21
Q
Azoles Toxicity?
A
- vomiting
- diarrhea
- rash
- hepatotoxicity (preexisting liver dysfunction)|
- Voriconazole causes immediate but transient visual disturbances including blurring of vision of unknown cause in more than 30% of patients
22
Q
Echinocandins example?
A
Caspofungin
23
Q
what about Caspofungin ?
A
echinocandin
24
Q
Caspofungin pharmacoKinetix?
A
- Bioavailability: I.V.
- distribution: widely to the tissues
- elimination: hepatic metabolism
- 1/2 life: 9–12h
25
Caspofungin MOA?
- fungicidal
| - inhibits the synthesis of beta-Glucan (cell walls)
26
Caspofungin Clinical uses?
- used for disseminated and mucocutaneous Candida infections
- mucormycosis
* used after fail to respond to amphotericin B*
27
caspofungin Toxicity?
- well tolerated
- Infusion-related:
1. headache
2. G.I.T distress
3. fever
4. rash
5. flushing (histamine release)
*Combined use of echinocandins with cyclosporine may elevate liver transaminases*
28
Terbinafine MOA?
- fungicidal
| - inhibit squalene epoxidase --> accumulation of toxic levels of squalene--> interfere with ergosterol synthesis
29
Terbinafine Clinical uses?
- oral / topical
- accumulates in keratin
- effective in onychomycosis
30
Terbinafine Toxicity?
- G.I.T. upsets
- rash
- headache
- taste disturbances
31
Topical Antifungal?
Nystatin
32
what about Nystatin?
- polyene antibiotic
| - used topically for superficial infections caused by C.albicans and dermatophytes
33
Nystatin MOA?
disrupts fungal membranes by binding to ergosterol
34
Nystatin MOA?
disrupts fungal membranes by binding to ergosterol
35
Nystatin clinical uses?
- topically: suppresses local Candida infections
| - orally: eradicates GI fungi (if impaired defense)
35
Nystatin clinical uses?
- topically: suppresses local Candida infections
| - orally: eradicates GI fungi (if impaired defense)
mrts
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