Anti-fungal & anti-protozoal drugs Flashcards
What are infections by fungi called?
Mycoses
Fungi are ____ with rigid cell walls composed largely of ___ rather than peptidoglycan
eukaryotes
chitin
What do fungal cell membranes contain?
Ergosterol (not cholesterol)
Name 2 polyenes antifungal
- Amphotericin B
2. Nystatin
Name the 2 categories of azole antifungals
- Triazole (fluconazole, itraconazole, voriconazole
2. Imidazole (clotrimazole, miconazole)
What are the systemic & subcutaneous antifungal drugs used?
- Amphotericin B
- 5-Flucytosine
- Echocandin (caspofungin, micafungin, anidulafungin)
- Triazoles (fluconazole, itraconazole, voriconazole)
What are the cutaneous antifungal drugs used?
- Imidazole (clotrimazole, miconazole)
- Nyastatin
- Terbinafine
What is the antiprotozoal agent used?
Metronidazole
What is the mechanism of action polyene antifungals?
bind to ergosterol in the plasma membranes of sensitive fungal cells to forms pores (channels). These pores disrupt membrane function, allowing electrolytes and other small molecules to leak from the cell, resulting in cell death.
How is amphotericin B commonly administered?
IV (poor oral bioavailability)
What advantage does the liposomal formulation of amphotericin B has over the conventional deoxycholate formulation?
- Liposomal formulation has reduced renal toxicity
2. better CSF penetration
What’s the consideration when using liposomal formulation of amphotericin B?
Cost
Name 2 clinical indications for amphotericin B
Broad spectrum
- Candidiasis
- Aspergillosis
- Cryptococcal meningitis (used with 5-flucytosine)
State 2 adverse effects associated with amphotericin B deoxycholate formulation
- Fever and chills (Infusion related toxicity)– “shake & bake syndrome”
- Nephrotoxicity
- Bone marrow suppression (like linezolid), ototoxicity
Name an anti-fungal, which is relatively safe for use in pregnancy despite systemic exposure.
Amphotericin B
What is the mechanism of action for 5-Flucytosine?
*5-flucytosine is converted,
by *cytosine deaminase,
to its metabolically active form *5-fluorouracil (5-FU), which inhibits *protein synthesis and inhibits *thymidylate synthase hence inhibiting DNA synthesis.
How is 5-Flucytosine commonly administered?
Oral (good oral bioavailability)
IV is available too
State at least 2 adverse effects associated with the use of 5 flucytosine
- Bone marrow suppression
- Hepatotoxicity
- GI related effects
State one clinical indication for 5-flucytosine
- Cryptococcal meningitis
(usually in combination with amphotericin B,
rarely used as single agent due to resistance + SYNERGISTIC increased penetrance due to pores)
Both amphotericin b & 5-flucytosine use should be adjusted in which group of patients?
Renal impairment
AmphB (low levels in urine for long time)
Name 3 echinocandins
- Caspofungin
- Micafungin
- Anidulafungin
State the mechanism of action of the echinocandins
Echinocandins inhibit the activity of the glucan synthase complex, resulting in loss of the structural integrity of the cell wall.
How are echinocandins commonly administered?
Intravenously (poor oral bioavailability)
Name 2 fungal species against which Echinocandins have potent activity
- Candida (first line)
2. Aspergillus (second line: 1st line voriconazole then amphotericin b)
What is the mechanism of action of azoles?
inhibit C-14 α-demethylase (CYP450 enzyme),
thereby blocking the demethylation of lanosterol to ergosterol.
This inhibition of ergosterol biosynthesis disrupts membrane structure and function and inhibits fungal cell growth.
Do the triazoles have good oral bioavailability?
Yes
Use of triazole
systemic *tx or *prophylaxis
for cutaneous/systemic fungal infections
State 3 adverse effects common to the triazoles
- QT prolongation
- Hepatotoxicity
- GI side effects
Name a triazole which is associated with the adverse effect of cardiotoxicity
Itraconazole
Name a triazole which is associated with the adverse effect of neurotoxicity (visual disturbances/hallucinations)
Voriconazole
What’s the first line tx for invasive aspergillosis?
Voriconazole
Name one class of anti-fungals, which is significantly associated with CYP450 enzymes related drug-drug interactions?
Azoles
(Other non anti-fungal agents include macrolides, HIV protease inhibitors, rifampicin, which all have either significant CYP450 inhibitory or inducing activity)
Antibiotics like fluoroquinolones and tetracyclines does have some DDI too)
Which azole should not be taken with antacids?
Itraconazole (low pH improves absorption)
Indications for fluconazole
- Cryptococcal meningitis (but first line: amphotericin b + 5-flucytosine)
- good CSF penetrance- most fungal meningitis
Indications for itraconazole
Broad spectrum compared to fluconazole
- Onychomycosis (non-imm compromised)
- Oral solution- esopha & oropharyngeal candidiasis
Dosage forms of itraconazole
Oral capsules- taken full meal increased absorption w acidic pH
Oral solution - empty stomach
How are the imidazoles commonly administered?
Topical (minimally absorbed)
Adverse effect of topical imidazole use
- Contact dermatitis
- Vulvular irritation
- Edema
Name 2 anti-fungal drugs that can be used in the management of vuvlovaginal candidiasis and describe how it is administered
- clotrimazole (cream)
- fluconazole (single dose oral)
- miconazole (vaginal suppository)
- nystatin (vaginal suppository)
Indications for topical clotrimazole
- dermatophyte infections
- vulvovaginal candidiasis
- oral thrush (dm/hiv/dentures)
Is nystatin administered parenterally?
No, oral suspension/tablets, cream, pessary
State a clinical indication for nystatin, and how it is administered.
- oropharyngeal candidiasis (oral agent; swish and swallow or swish and spit)
- vulvovaginal candidiasis (vaginal suppository)
What is terbinafine’s mechanism of action?
inhibits squalene epoxidase, thereby blocking its conversion to lanosterol and biosynthesis of ergosterol, an essential component of the fungal cell membrane.
How is terbinafine administered for the management of tinea capitis?
Oral against trichophyton causing tinea
(Topical application cannot be used for the management of tinea capitis)
Which of the following option(s) is/are least suited for a fungal meningeal infections? A. Amphotericin B B. 5-Flucytosine C. Echinocandins D. Fluconazole E Itraconazole F.Voriconazole
Echinocandins and Itraconazole have poor CSF penetration.
What are some of the anti-fungal agents used in the treatment or onychomycosis?
Itraconazole - oral
Terbinafine - oral
In pregnancy, what route of administration is preferred for terbinafine?
Vaginal (little ab as topical)
What’s the drug used as an anti-protozoal agent?
Metronidazole
Where are protozoal infections common?
Underdeveloped tropical/subtropical countries
Can most anti-protozoal agents be used during pregnancy?
No
What cell type is protozoal?
unicellular eukaryotes
What is amebiasis caused by?
Entamoeba histolytica
Chemotherapy for amebiasis -routes of administration
- Luminal- in int. lumen
- Systemic- intestinal wall & liver
- Mixed
MOA of metronidazole
nitro group of metronidazole electron acceptor forms reduced cytotoxic free radicals protein & DNA damage death of Entamoeba histolytica trophozoites
more so for anaerobic org
Indications for metronidazole
- Amebic infections- E. histolytica, trichomonas vaginalis, Giardia lamblia
- Anaerobes- Bacteroides spp, clostridium difficile
- H pylori
Does metronidazole penetrate CSF?
Yes very well
Which patients should metronidazole be dose adjusted for?
Hepatic (metabolism) & renal (elimination) impairements pt
Name at least 2 side effects for metronidazole
- Metallic taste
2. Oral moniliasis (yeast infection in mouth)
If pregnant pt has amebic infection, would you give metronidazole?
No unless clearly needed
