6. Anti-fungal and Anti-protozoal Agents Flashcards
Classification of anti-fungal drugs
- Drugs for subcutaneous and systemic mycotic infection
2. Drugs for cutaneous mycotic infections
Types of drugs for subcutaneous and systemic mycotic infection
- Amphotericin B
- Antimetabolite antifungals: Flucytosine
- Echinocandins: Caspofungin
- Azole antifungals: Triazoles
Types of drugs for cutaneous mycotic infection
- Nystatin
- Squalene epoxidase inhibitors: Terbinafine
- Azole antifungals: Imidazoles
MOA of amphotericin B
Binds to ergosterol in the plasma membrane of sensitive fungal cells → forms pores (channels) → disrupts membrane functions → allowing electrolytes (particularly potassium) and small molecules to leak from the cell → cell death
→ fungicidal or fungistatic depending on the organism and the conc. of the drug
Indications for amphotericin B
- Candida albicans (candidiasis)
- Histoplasmosis
- Crpytococcus neoformans
- Aspergillus (Aspergillosis)
Adverse effects of amphotericin B
- Fever and chills
- Nephrotoxicity
- Hypotension
- Thrombophlebitis
- Bone marrow suppression
- Ototoxicity
MOA of 5-Flucytosine
5-Flucytosine enters the fungal cells through cytosine specific permeases and is then converted, by cytosine deaminase, to its metabolically active form 5-Fluorouracil (5-FU)
- Conversion of 5-FU into 5-fluorouridine triphosphate (FUTP). FUTP is incorporated into fungal RNA in place of uridylic acid; and inhibits protein synthesis
- Metabolism of 5-FU into 5-fluorodeoxyuridine monophosphate (FdUMP), a potent inhibitor of thymidylate synthase, which is a key enzyme of DNA synthesis
→ fungistatic
Indications for 5-Flucytosine
effective in combination with amphotericin B for treating candidiasis and cryptococcosis (meningitis and pulmonary infections)
Resistance to 5-Flucytosine
Decreased levels of any of the enzymes in the conversion of 5-FC to its metabolites and/or development of an increased synthesis of cytosine during therapy → not used as a single antimycotic drug, used in combination with amphotericin B which allows more 5-FC to penetrate the cell thus leading to synergistic anti-fungal effects and minimises resistance
Adverse effects of 5-Flucytosine
- GI effects
- Bone marrow suppression
- Hepatotoxicity
Types of Echinocandins
- caspofungin
- micafungin
- anidulafungin
MOA of Echinocandins
Inhibit the activity of the glucan synthase complex → loss of structural integrity of the cell wall
Indications for Echinocandins
- First-line option for invasive candidiasis, including candidemia
- Second-line option for aspergillosis (for those who have failed or cannot tolerate amphotericin B or an azole)
Adverse effects of Echinocandins
- GIT related symptoms
- Fever
- Chills
- Rashes
- Skin flushing
- Thrombocytopenia
Types of triazoles
- Fluconazole
- Itraconazole
- Voriconazole
MOA of triazoles
Inhibit C-14 alpha-demethylase (CYP450 enzyme) → blocking the demethylation of lanosterol to ergosterol → inhibition of ergosterol biosynthesis disrupts membrane structure and function → inhibits fungal cell growth
→ fungistatic
Indications for fluconazole
- Treatment of candidemia, and most forms of mucocutaneous candidiasis
- Cryptococcal meningitis
- Histoplasmosis
- Blastomycosis
- Single-dose oral treatment for vulvovaginal candidiasis
- Most types of fungal meningitis
Indications for itraconazole
- Broad antifungal spectrum compared to fluconazole
- Treatment of blastomycosis and aspergillosis in patients intolerant to amphotericin B
- Onychomycosis in non-immunocompromised patients
- Oral solution for esophageal and oropharyngeal candidiasis
Indications for voriconazole
- Broad-spectrum antifungal
- Treatment of choice for invasive aspergillosis
- Candida infections
Adverse effects of triazoles
- Nausea, vomiting, headache, and skin rashes
- Hepatotoxicity
- QT prolongation
- Cardiotoxicity → Itraconzaole
- Neurotoxicity → Voriconazole
Resistance to triazoles
- Mutations in the C-14 alpha-demethylase gene → decreased azole binding
- Development of efflux pumps that pump the azole out of the cell
Drug interactions with triazoles
- Inhibit CYP450 3A4 isoenzyme to varying degree
- Also interfere with CYP2C9 and CYP2C19
- Enhance activity of drugs metabolised by CYP450 including warfarin, cyclosporine, oral hypoglycemic agents
Contraindications to triazoles
Teratogenic → avoid in pregnancy
Types of cutaneous anti fungal
Imidazoles
- Clotrimazole
- Miconazole
Indications for imidazoles
- Epidermophyton
- Microsporum
- Trichophyton
- Candida → oropharyngeal and vulvovaginal candidiasis
- Malassezia
Adverse effects of imidazoles
Topical:
- Contact dermatitis
- Valvular irritation
- Edema
Oral:
- GI disturbances
- Elevated liver enzymes
Indications for nystatin
Broad spectrum anti-fungal agent → used to treat oral or GI fungal infections and vulvovaginal candidiasis
Commonly used for the treatment of cutaneous and oral candida infections
Adverse effects of nystatin
Rare after oral administration
Topical and vaginal forms may cause skin infections
MOA of terbinafine
- Inhibiting squalene epoxidase → blocking its conversion to lanosterol and biosynthesis of ergosterol, an essential component of the fungal cell membrane
- Accumulation of toxic amounts of squalene → increased membrane permeability and death of the fungal cell
Indications for terbinafine
Trichophyton → causes tinea
Oral → dermatophyte onychomycoses and tinea capitis
Topical → tinea pedis, tinea corporis, tinea cruris
Adverse effects of terbinafine
- GI disturbances
- Headaches
- Rash
- Hepatic failure
- Exacerbation of autoimmune diseases (SLE)
Drug interactions with terbinafine
- Increase serum concentration with CYP450 inhibitors (azoles)
- Inhibits CYP450 2D6 isoenzymes which is involved in the metabolism of beta-blockers, MAO inhibitors
MOA of metronidazole
- Amoebas possess electron transport protein that participate in metabolic electron removal reactions
- Metronidazole → nitroimidazole
- Nitro group of metronidazole is able to serve as an electron acceptor → forming reduced cytotoxic free radicals that result in protein and DNA damage → resulting in death of E. histolytica trophozoites
Indications for metronidazole
- Amebic infections → Protozoa including Entamoeba histolytica, Trichomonas vaginalis, Giardia lamblia
- Anaerobes → Bacteriodes spp. and Clostridium difficile
- H. Pylori
- Surgical prophylaxis
Adverse effects of metronidazole
- GI: nausea, vomiting, epigastric distress, abdominal cramps
- Unpleasant, metallic taste
- Oral candidiasis
- CNS and PNS effects: convulsive seizures, optic and peripheral neuropathy (rare). Discontinuation of drug. Avoid alcohol
Drug interactions with metronidazole
Potentiate the effects of warfarin
Contraindications with metronidazole
First trimester pregnancy
