ID: Echinocandins, griseofulvin, Polyenes, Pyrimidine, Antifungals, Lamisil
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Echinocandins is a class of antifungals that targets:
fungal cell walls
how do antifungal drugs not affect human cell walls?
Humans don’t have a cell wall, can target the fungi while minimizing likelihood of toxicities to patient being treated
- Caspofungin (Cancidas)
- Micafungin (Mycamine)
- Fungal cells have both an outer cell wall and a cell membrane.
- Cell wall is thought to provide structural rigidity.
- Chitin & beta-1,3-glucan are responsible for the cell wall’s rigidity.
- Beta-1,3-glucan is synthesized via beta-1,3-glucan synthase
- Echincandins inhibit beta-1,3-glucan synthase so the cell wall is not as strong.
- This leads to cell lysis.
indications for echinocandins:
- Severe invasive fungal infections:
- Candida (fungicidal)·
- Aspergillus (fungistatic)
Micafungin (Mycamine) SE:
- common: diarrhea, N/V, fever, hypokalemia, HA, thrombocytopenia
- serious: anaphylaxis, hemolytic anemia, hepatotoxicity, renal impairment, sepsis
what is Griseofulvin?
an antifungal used for dermatophytes
MC fungal species:
when do you use it?
- Tinea: dermatophyte infections (Trichophyton, Microsporum & Epidermophyton) of the skin & hair
- when to use? When topicals don’t work
- Griseofulvin is deposited into keratin precursor cells (increases keratin resistance to fungal infection)
- Disrupts mitotic spindle
- Then it is taken up by fungal cells & binds to fungal proteins, including tubulin
- Tubulin is needed to separate dividing chromosomes
- Thus, griseofulvin inhibits cell division in fungi
- Griseofulvin is a hepatic enzyme inducer; thus it reduces the half-life of other drugs metabolized by CYP3A4.
- Lots of interactions!!!
- Half-life is 24 hours
- GI upset
- Hepatic failure
- Caution if hypersensitive to penicillin
- Cholesterol, found in human cell membranes and ergosterol, found in fungal cell membranes, are examples of sterols.
- Polyenes bind sterols. They bind ergosterol with higher affinity than cholesterol.
- Polyenes bind to ergosterol and create channels in the fungal membrane.
- Ions leak out of the channels, killing the cell
- Binding of polyenes to cholesterol is responsible for the toxicities.
- The polyenes become integrated into the fungal membrane and pores are formed
how can resistance develop?
indication for Ampho B?
Serious invasive or systemic fungal infections
- Amphotericin B is frequently the only effective treatment available for potentially life-threatening fungal disease.
- In each case, its possible life-saving benefit must be balanced against its dangerous side effects.
what are Amphotericin formulations?
- formulations are not bioequivalent!
- Amphotericin B salts
- Liposomal amphotericin: this formulation incorporates the drug into small lipid vesicles
- Amphotericin B lipid complex (ABLC) : a non-liposomal formulation that complexes with two phospholipids
- Amphotericin has a long half-life (15 days)
- It accumulates in and is slowly released from tissues
- Infusion reactions*
- Electrolyte abnormalities
- Noninvasive candidal infections, including· oropharyngeal thrush·
- vaginal candidiasis·
- intertriginous candidal infections
clinical applications of nystatin:
The yeast Candida Albicans can cause thrush
symptoms of thrush:
- Curd-like patches inside the mouth·
- Oral thrush is common in babies, young kids, immunocompromised and the elderly
kinetics of nystatin:
- Too toxic for parenteral administration
- Poor oral absorption
- Used topically and as an oral rinse (swish and swallow)
Pyrimidine antifungal drugs:
Pyrimidine antifungals MOA:
- Flucytosine interferes with DNA & RNA replication
- Flucytosine is transported in to susceptible fungi by an enzyme called, cytosine permease, only present in fungi.
- Flucytosine is converted to 5-fluorouracil (5-FU) which is then converted to (5-FDUMP).
- 5-FDUMP is an irreversible inhibitor of thymidine synthetase needed for DNA replication.
- How does it block protein synthesis? Acts like an analog§ Blocks RNA and DNA synthesis
indications for the pyrimidine antifungals:
- Severe fungal infections ·
- Nausea or vomiting may be reduced or avoided if the capsules are given a few at a time over a fifteen minute period.
- Flucytosine should be used in combination with amphotericin B due to the emergence of resistance to flucytosine
pyrimidine antifungals kinetics:
- Given orally; well absorbed
- Renal elimination; thus dosage adjustments required in renal impairment
pyrimidine antifungals BBW:
- Cardiac arrest
- Respiratory arrest
- GI bleed
- Renal failure
- Bone marrow suppression
- Toxic epidermal necrolysis
- Common; chest pain, dyspnea, rash, N&V, abdominal pain, diarrhea
- Terbinafine (Lamisil)
- Topical formulation (Lamisil AT)
- Remember, ergosterol is a component of the fungal cell membrane
- Terbinafene blocks the production of lanosterol via inhibition of sqaulene epoxidase.
- Results in a decrease in ergosterol production
- Fungal infection of the nails
- Tinea capitus
- Tinea pedis, tinea corporis & tinea cruris· (usually topical)
- Metabolized by the liver
- Lipid soluble; distributes into nails, skin & fat
- Long half-life
- Avoid use is CrCl <50
- Avoid use in hepatic impairment
- Liver failure
- Stevens Johnson syndrome
- SLE exacerbation
- Psoriasis exacerbation
- Also; headache, fever, upper respiratory infection, cough, rash, dyspepsia
Lamisil treatment duration for-
- Fingernails: 6 weeks
- Toenails: 12 weeks
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