L37- Antifungals Flashcards
(1) is the main target for anti-fungal agents
fungi have cell walls made out of (2)
1- ergosterol
2- chitin
-fungi resistant to anti-bacterials, bacteria resistant to anti-fungals
describe the classic classification of fungal infections
Opportunistic, immuno-compromised hosts:
- cancer chemotherapy
- following organ transplant
- HIV infection
Primary, immuno-competent hosts
describe the classification of fungal infections based on site of infections
Superficial mycoses: skin, mucous membranes, hair, nails
Subcutaneous mycoses: dermis, subcutaneous tissue, adjacent bone
Systemic mycoses: affects internal organs
______ are the main superficial mycoses
- dermatophytoses
- superficial form of candidiasis
(1) are the common causes of systemic mycoses and (2) is the biggest issue with these types of infections
1- (rarely occurs, worse than sepsis) candidiasis, cryptococcosis, aspergillosis
2- difficult to treat –> life-threatening
list the anti-fungals by MOA
1) alter cell permeability: Polyenes, Azoles, Allylamines
2) block nucleic acid synthesis: Anti-metabolites
3) disrupts microtubule function: Griseofulvin
4) disrupts fungal cell wall: Echinocandins
list the systemic drugs (for subcutaneous and system mycoses)
- amphotericin B (polyene)
- flucytosine (anti-metabolite)
- azoles
- echinocandins
describe the MOA of amphotericin B
(polyene)
- binds to ergosterol on fungal cell membrane
- forms pore in the cell membrane
- pores allow leakage of intracellular ions / macromolecules => cell death
Amphotericin B:
- fungi-(static/cidal)
- (broad/narrow) spectrum
- (3) is the main clinical use in general because of (4)
1- fungicidal
2- broad spectrum
3- life-threatening mycoses – including pregnancy
4- very toxic
Amphotericin B, describe routes of administration
IV mainly, poor oral F as its highly insoluble (deoxycholate colloidal suspension)
Intrathecal administration in meningeal disease (only way to reach CSF)
______ is used to treat severe mycoses in pregnant patients
amphotericin B
(1) is the nearly universal side-effect from amphotericin B where (2) and (3) measures can be taken to minimize (1)
1- Infusion-related toxicity: fever/chills, muscle spasms, vomiting, HA, hypotension
2- slow infusion rate OR dec daily dose
3- pretreat with antihistamines, glucocorticoids, antipyretics, or analgesics
Besides infusion related toxicity, (1) is the main mechanism of the other common side effect of amphotericin B. (2) are the three major signs of toxicity from (1) and (3) can be given to slow (1) process. (4) is the other major result of toxicity from (1).
1- amphotericin B binds cholesterol –> forming pores –> renal toxicity
2- azotemia (high N in blood), slight dec GFR, renal tubular acidosis = severe K+/Mg++ wasting
3- Na loading (saline infusion with amphotericin B)
4- hypochromic normocytic anemia via dec EPO
Amphotericin B:
-(1) should be monitored closely during therapy (include all)
-(2) is a direct toxicity from intrathecal administration
1- renal function, LFTs, serum electrolytes (K, Mg), CBC, Hb
2- seizures or other serious neurological damage
Describe the improved formulation of amphotericin B and its advantages
Lipid formulations – adds lipid carrier:
- L-AMB, liposomal amphotericin B
- ABLC, amphotericin B lipid complex
- ABCD, amphotericin B colloidal dispersion
- improves distribution across BBB
- improves efficacy as fungi activate medication via lipases
- decreases AEs: less severe nephrotoxicity
(1) is the main anti-metabolite for treating systemic mycoses, it is a synthetic (purine/pyrimidine).
1- flucytosine
2- pyrimidine
Flucytosine in taken into fungal cells via (1). Then it is first converted into (2) in order to block (3). It is also converted in (4) in order to inhibit (5).
1- cytosine permease
2/3- 5-FU –> 5-FdUMP –> inhibits Thymidylate synthetase –> blocks dTMP synthesis
4/5- 5-FUTP –> inhibits protein synthesis
Flucytosine:
- fungi-(static/cidal)
- (narrow/broad) spetrum
- works best when used with (3), specifically for (4) disease
- used in combination because (5)
1- fungistatic 2- narrow spectrum 3- amphotericin B 4- systemic candidiasis or cryptococcosis 5- to avoid resistance
list the AEs for Flucytosine
- -> metabolized into 5-FU => bone marrow toxicity:
- pancytopenia: anemia, leukopenia, thrombocytopenia
list all the azoles
Imidazoles: *ketoconazole, miconazole, clotrimazole
Triazoles: itraconazole, flucanazole, vorionazole, posaconizole
describe the MOA of Azoles
- inhibition of cytochrome P450 enzyme 14-α-sterol demethylase leading to inhibition of lanosterol —> ergosterol
- reduction in overall ergosterol synthesis
- membrane function is disrupted and permeability is increased => cell death
describe the AEs of Azoles in general
- relatively non-toxic
- minor GI upset is most common AE
describe the additional effects Ketoconazole has in addition to its main MOA (hint- 3)
1) dec plasma testosterone:
- Men: gynecomastia, dec libido, dec potency
- Women: menstrual irregularities
2) high doses inhibits adrenal steroid synthesis and dec plasma cortisol (addison’s)
3) strong CYP3A4 inhibitor –> inc toxicity of drugs (warfarin, cyclosporin)
Ketoconazole:
- (1) describe absorption and distribution
- (2) is the main clinical use
1:
- best absorbed at low gastric pH –> therefore use of antacids, H2 blockers, PPIs => dec absorption
- poor CSF penetration
2: topically for superficial mycoses due to narrow spectrum and high toxicity
Fluconazole:
- (1) route of administration, include F
- (2) describe distribution
- (3) are the main AEs
1- IV, oral (high oral F)
2- good CSF penetration
3: drug interactions
- moderate CYP3A4 inhibitor
- strong CYP2C9 inhibitor
describe the many clinical uses for fluconazole
1) Candidiasis (esophageal, oropharyngeal, vulvovaginal, urinary) and Candidemia
2) coccidiodiomycosis
3) maintenance therapy for cryptococcal meningitis (after amphotericin B, flucytosine
4) alternative to amphotericin B in non-severe cryptococcal meningitis
5) initial and secondary prophylaxis for cryptococcal meningitis
fluconazole is notably ineffective against ______
Aspergillus and other filamentous fungi
Itraconazole:
- (1) describe absorption and what effects it
- (2) describe distribution
- metabolized by (3) and strong inhibitor of (3) and may lead to (4) if co-administered with (5)
1- poor F: reduced by antacids, H2 blockers, PPIs
2- poor CSF penetration
3- CYP3A4
4- fatal arrhythmias
5- cisapride, quinidine
Itraconazole:
- preferred drug for mycoses due to (1)
- effective against (2) superficial mycoses
- effective against (3), but has been replaced by (4) which is more effective
1- Dimorphic Fungi: blastomyces, Sporothrix, Histoplasma
2- onychomycosis, dematophytoses
3- Aspergillus
4- voriconazole
Voriconazole:
- similar spectrum to (1) azole
- DOC for (2)
1- itraconazole
2- invasive aspergillosis
describe the AEs for voriconazole
-transient visual disturbances, 30% Pts
Drug interactions:
-metabolized and inhibits CYP2C19, CYP2C9, CYP3A4
Posaconazole:
- similar spectrum to (1) azole with additional (2) activity
- 2nd line / alternative to (3) drug for (4) mycoses
- AE –> inhibits (5)
1- itraconazole
2- Zygomycetes (like Mucor)
3- amphotericin B
4- mucoid mycoses
5- inhibits CYP3A4
(1) is the main echinocandins. It functions by inhibiting (2) synthesis, resulting in (3). It is administered in (4) fashion.
1- caspofungin
2- β(1-3)-D-glucans
3- disruption of cell wall –> cell death
4- IV
Caspofungin:
- active against (1) fungi
- although not active against (2)
1- candida, aspergillus
2- cryptococcus neoformans
list the systemic drugs used to treat superficial mycoses
- griseofulvin
- allylamines / terbinafine
-ketoconazole, fluconazole, itraconazole
Griseofulvin:
- (1) MOA, simply
- absorption of food improves with (2)
- (3) is the main AE
1- disrupts mitotic spindle –> inhibit mitosis
2- fatty foods
3- drug interactions: inhibits CYP450 enzymes
Griseofulvin:
1) is its only clinical use, although it has largely been replaced by (2
1- dermatophytoses of skin, hair, nails
2- itraconazole (azole), terbinafine (allylamine)
(1) is the main allylamine, and is administered in (2) fashion. It functions to inhibit (3) in order to raise (4) levels (include effect) and decrease (5) levels (include effect).
1- terbinafine
2- oral, topical
3- squalene epoxidase (squalene –> squalene 2,3 oxide)
4- squalene => toxicity
5- ergosterol => loss of cell membrane integrity
Terbinafine is effective against…..
dermatophytes: tinea cruris, tinea corporis
onychomycosis
Terbinafine AEs:
- (1) common Sxs
- (2) metabolism effects
1- GI upset, rash, HA, taste disturbances
2- elevates serum liver transaminases — inhibits CYP2D6
______ are the common topical polyenes
nystatin
amphotericin B
topical amphotericin B is used for ______
cutaneous candidiasis
describe the MOA of Nystatin
(polyene macrolide)
- binds to ergosterol on fungal cell membrane
- forms pore in the cell membrane
- pores allow leakage of intracellular ions / macromolecules => cell death
Nystatin:
- not administered in (1) fashion because of (2), so typically administered in (3) fashion (include advantage)
- only used to treat (4)
1- IV
2- extremely nephrotoxicity
3- cutaneous, vaginal, oral preparations => not absorbed via GIT, skin, vagina, so little toxicity
4- candidiasis (thrush, esophageal, vulvovaginal, etc)
______ are the most commonly used topical azoles, found OTC
- miconazole
- clotrimazole
list the topical antifungals used to treat superficial mycoses
- nystatin
- amphotericin B
- miconazole, clotrimazole, ketoconazole
- terbinafine
______ is primary therapy for esophageal candidiasis
______ is primary therapy for oropharyngeal candidiasis
1- IV, oral fluconazole
2:
mild: topical clotrimazole or nystatin
moderate to severe: oral fluconazole
AIDS pts: oral fluconazole
______ is primary therapy for urinary candidiasis
IV, oral fluconazole
______ is primary therapy for cutaneous candidiasis
topical amphotericin B
topical azole
topical nystatin
______ is primary therapy for vulvovaginal candidiasis
______ is primary therapy for recurrent vulvovaginal candidiasis
1:
- topical azoles
- oral fluconazole
2: oral fluconazole
______ is primary therapy for candidemia
IV fluconazole IV echinocandin (caspofungin)
______ is primary therapy for cryptococcosis
amphotericin B + oral flucytosine —> followed by fluconazole maintenance
______ is primary therapy for invasive aspergillosis
IV voriconazole —> followed by oral voriconazole (+ amphotericin B)
______ is primary therapy for mucormycosis + second line treatment
1) amphotericin B
2) posaconazole
______ is primary therapy for fusariosis
amphotericin B
______ is primary therapy for onychomycosis
oral terbinafine
oral itraconazole
oral fluconazole
PCP:
- (1) is the unique fungal feature
- (2) Sxs
- (3) primary therapy
- (4) alternatives
- (5) adjunct in moderate to severe cases
(pneumocystis jirovecii pneumonia)
1- cholesterol over ergosterol
2- fever, dyspnea, dry cough
3- co-trimoxazole (trimethoprim + sulfamoxazole – folate synthesis inhibitors)
4- clindamycin + primaquine // dapsone + trimethoprim // atovaquone // pentamindine
5- prednisone
