Antifungals Flashcards
Amphotericin B
Large molecules with hydroxylated portion that is hydrophilic and a portion containing 4-7 double bond which is lipophilic, Effective but toxic
Amphotericin B Spectrum of Action
Drug of choice for life-threatening fungal infection, Choice for empiric therapy of suspected fungal infection in neutropenic patients, Available as ointment or non absorbable oral forms for non-systemic candida infections
Amphotericin B Mechanism of Action
Binds to sterols (Ergosterol) in cell membranes, Forms pores or channels that alter fungal cell membrane permeability and cause leakage of essential cell components leading to death; Fungicidal or Fungistatic depending on conc. of ergosterol in membrane
Amphotericin B Pharmacokinetics
Poorly absorbed from GI tract so not given orally, Insoluble in water so prepared as colloidal dispersion with sodium deoxycholate, SUV, ABCD to, Excreted in urine
Amphotericin B Drug Interactions
Synergistic with Flucytosine, Antagonistic with Imidazoles - Inhibit synthesis of sterol
Amphotericin B Adverse Effects
Rapid infusion produces cardiotoxicity, Amph B causes release of TNF-alpha and IL-1 from host immune cells leading to chills, fever, rigors, hypotension, headache; Nephrotoxic, vasoconstrict renal artery, leading to renal ischemia, Anemia due to inhibition of erythropoietin production rather than suppressing bone marrow
Amphotericin B Resistance
Decreased amount of, or complete lack of ergosterol in cell membranes, Elevated levels of ergosterol precursor in membranes
Nystatin
Effective but systemic toxicity, Polyene macrolide anti fungal agent
Nystatin Uses
Polyene anti fungal used topically/enterally (not absorbed from gut), Systemic toxicity, Choice for candidial infection of oral cavity (Oral monoliasis, thrush, denture stomatitis), Topical and oral forms of nystatin are not absorbed on ingestion and consequently are not associate with drug-drug interactions, HIV/AIDS with low CD4 count - Patients undergoing chemotherapy and patient whom azole anti-fungals contraindicated.
Prescription
Oral suspension for oral candidiasis - 100,000units/mL - - 480mL (1pint) bottle - Swish then swallow 2tsp qid for 14days; Cream - 100,000units/g, 30g tube, Apply 4-5times/day for 2 weeks
Flucytosine Chemistry
Antifungal Agent; Fluorinated pyrimidine related to Fluorouracil blocks synthesis of RNA
Flucytosine Spectrum of Action
Active VS Candia, Toralopsis and Cryptococcus, Fungistatic VS Aspergillus fumigatus (chromomycosis), Combined with amphotericin B for cryptococcal meningitis in AIDS patients
Azoles Chemistry
Antifungal Agent;
Imidazoles - 2N in Azole ring - Clotrimazole (Oral candidiasis in form of troche), Miconazole, Ketoconazole (Nizoral - mucocutaneous candidiasis)
Triazoles - 3N in Azole ring - Fluconazole (Systemic candidiasis), Itraconazole, Voriconazole, Efinaconazole (Jublia)
Azoles Mechanism of Action
Antifungal Agent; Inhibit synthesis of ergosterol by inhibiting sterol 14-alpha-demethylase, a cytochrome P450 dependent enzyme system that converts lanosterol to ergosterol
Azoles Spectrum of Action
Broad spectrum including Dermatophytes (Microsporum, Trichophyton, Epidermophyton), Yeasts (Cryptococcus Neoformans, Candida, Torulopsis Glabrata), Dimorphic Fungi (Coccidioides Immitis, Histoplasma Capsulatum, Blastomyces Dermatidis, Paracoccidioides)
Ketoconazole Uses
Useful for vulvovaginitis, Oral and esophageal candidiasis, Mucocutaneous candidiasis, Available as cream and lotions for common skin fungi, Ketoconazole used to inhibit androgen production in cases of advanced prostate cancer, Inhibit corticosteroid synthesis in cases of advanced adrenal cancer
Ketoconazole Drug Interactions
Inhibit hepatic P450 enzymes causing drug interactions, Inhibit P450 enzymes 17,20 lyase (desmolase) and side-chain cleavage enzyme in adrenal glands and gonads thereby decrease steroid hormone biosynthesis, High dose Ketoconazole inhibit androgen synthesis to cause gynecomastia and impotence - Menstrual irregularity due to decrease steroid biosynthesis
Ketoconazole Pharmacokinetics
Available in both oral and topical forms, Ketoconazole is well absorbed from GI tract - need acidic environment for dissolution, Little penetration into CSF in absence of disease, Ketoconazole is extensively bound to plasma proteins (Albumin), Unbound drug distributes to most tissue, Ketoconazole is extensively metabolized in liver by O-dealkylation and aromatic hydroxylation to inactive metabolites, Inhibit CYP3A4, 2C9, 2C19, UGTA1, UGT2B7, P-glycoprotein
Ketoconazole Adverse Effects
Ketoconazole causes GI ulceration with nausea, dizziness, pruritus, headache, Hepatotoxicity and increase in liver enzymes in plasma - Fatal hepatic necrosis may occur (Hepatic failure), N, V, D abdominal pain, Reversible alopecia w/prolonged oral therapy, Rare cases of Stevens Johnson syndrome, Inhibit androgen production, Inhibit corticosteroid synthesis
Ketoconazole Drug Interactions
Bioavailability decreased by antacids or drugs that inhibit acid production, Antacids and vitamin supplements chelate ketoconazole and impair absorption, GI absorption depend on acid conversion to salt in stomach so does not work if patient take bicarbonate, antacid, H2 blockers, proton pump inhibitors, achlorhydria
Ketoconazole (Nizoral) Dosing
Normal dose - 200/400mg q24h, No dose alter ate needed with kidney disease, 50% reduction with liver disease
Fluconazole
Diflucan;
Drug of choice to treat systemic candidiasis, cryptococcal meningitis, coccidioidal meningitis, not effective VS aspergillosis
Fluconazole Pharmacokinetics
Most widely used anti fungal drug, Available as both oral and IV, Almost bioavailable and absorption is not affected by gastric pH, Diffuses freely into CSF, sputum, urine and saliva, excreted mainly by kidney
Fluconazole Mechanism of Resistance
Candida most readily develop resistance, Mutation of fungal P450, Overexpression of multi drug efflux transporter proteins
Fluconazole Adverse Effect and Drug Interaction
Fluconazole increase levels of amitriptyline, cyclosporine, phenytoin and warfarin; Levels of Fluconazole can be decreased by carbamazepine, isoniazid, phenobarbital
Fluconazole (Diflucan) Prescription
Refractory oral or systemic candidiasis - 100mg/capsule, 15 capsules, Day 1 -2 - Day 2-14 - 1 daily
Esophageal candidiasis - 100mg/capsule, Variable disp, Take 1 capsule qd (400mg qd max) for 14-21days
Voriconazole
Vfend
Active VS Opportunistic fungi, Candida and environmental molds (outbreak in 2012), Well absorbed orally, hepatic metabolism, inhibit CYP3A4 (Interact with statins, cyclosporin), Adverse effects - Rash, Visual disturbances, Photosensitivity
Posaconazole
Noxafil
New triazole with broadest spectrum of action, Prophylaxis of fungal infections chemotherapy for leukemia and bone marrow transplant
Clotrimazole
Lotrimin, Mycelex
Topical agent used to treat superficial infections of stratum corneum, squamous mucosa and cornea, Used for oral candidiasis; Adverse effects - Itching, burning, sensitization
Clotrimazole Pharmacokinetics
Available as cream and troche, Oral absorption of drug is erratic, metabolized in liver, do not take with alcohol, Contraindicated in presence of liver disease, Avoid using benzodiazepine with clotrimazole because clotrimazole can cause significant elevation of Benzodiazepine levels by inhibiting CYP450 enzyme
Clotrimazole Prescription
Rx - Clotrimazole (Mycelex) cream - Dispense 15g tube, Rub into affected area 2-3times daily for 2 weeks
Rx - Clotrimazole (Mycelex) troches - 10mg troche, Dispense 70 troches - 14day supply; Dissolve 1 troche in the mouth 5times daily and swallow saliva - There should be no eating or drinking for 30min after use. Do not swallow
Griseofulvin Chemistry
Fulvicin
Isolated from molds of genus penicillin, Insoluble in water
Griseofulvin Mechanism of Action
Fungicidal to growing organisms, Inhibits fungal mitosis by binding to tubulin and blocks its polymerization to microtubules
Griseofulvin Spectrum of Action
Use limited to infections of skin, hair, nails by Dermatophytes (Microsporum, Epidermophyton, Trichophyton)
Griseofulvin Pharmacokinetics
Insoluble in water, so greater absorption from GI tract by decrease particle size of drug or take with fatty meal, Only effective in treating skin infections when taken orally; Deposits in keratin precursor cells and persists after differentiation making keratin resistant to fungal invasion, Metabolized by liver and excreted in urine and feces
Griseofulvin Adverse Effects
Headache, Lapses of memory, Impairment of judgement, Do not use for pilot and bus drivers, GI distress, Skin rashes, Paresthesia, Super infection with Candida, Hepatotoxicity and occasional photosensitivity, Teratogenic
Echinocandins
Caspofungin (Cancidas), Micafungin (Mycamine), Anidulafungin (Eraxiz) - Inhibit cell wall synthesis by inhibiting beta-1-3-glucan synthetase (not mammals), Resistance due to increased chitin in fungal cell wall, Fungicidal, Effective VS Azole resistant C. albicans, Micafungin can increase levels of nifedipine, cyclosporin and sirolimus
Undecylenic Acid
Desenex - Fatty acid used to treat tinea pedis, Produces transient burning sensation
Tolnaftate
Tinactin
Wider spectrum than undecylenic acid, Effective VS Trichnophyton but not Candida
Haloprogin
Mycanden
Similar activity to Tofnaftate but active VS Candida - Used to treat Tinea pedis
Ciclopirox Olamine
Loprox
Used for candidiasis and dermatophyte infections, Penetrates hair follicles, sebaceous glands and epidermis to systemic circulation
Allylamines
Naftifine, Terbinafine (Lamisil), Butenafine, Inhibit fungal ergosterol synthesis by inhibition of squalene-2,3-epoxidase, Used to treat dermatophytoses and superficial forms of candidiasis (1 tab daily for 12wks)
