20231_Pharmacology_3_Santi fungal.pdf

Chapter 33 Antifungal Drugs Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 145 Antifungal Drugs ➢Overview: • Infectious diseases caused by fungi – mycoses • Mycotic infections: Cutaneous mycoses (skin-extending into the epidermis) or subcutaneous o...

Chapter 33 Antifungal Drugs Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 145 Antifungal Drugs ➢Overview: • Infectious diseases caused by fungi – mycoses • Mycotic infections: Cutaneous mycoses (skin-extending into the epidermis) or subcutaneous or systemic infections • Fungi: Eukaryotic, rigid cell wall (chitin), cell membrane (ergosterol) // targets for chemotherapeutic agents • Medications are selective (antifungal drugs; antibiotics are ineffective) • Increased incidence of mycoses due to various reasons: e.g. cancer chemotherapy, HIV, organ transplantation. (Immune suppression) Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 146 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 147 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 148 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 149 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 150 Antifungal Drugs / Drugs for subcutaneous and systemic mycotic infections ➢Amphotericin B: • Amphoteric polyene macrolide • Naturally occurring – produced by Streptomyces nodosus • Drug of choice for several life-threatening mycoses • Water insoluble - colloidal suspension of amphotericin B and sodium deoxycholate or liposomes – parenterally (slow IV infusion) • Oral amphotericin B – local GI tract treatment Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 151 Antifungal Drugs / Drugs for subcutaneous and systemic mycotic infections ➢Amphotericin B: • MOA: • Fungicidal • Binds to ergosterol – forming pores – disrupt membrane function – leakage – cell death • Antifungal Spectrum: • Wide • Candida albicans, Histoplasma capsulatum, Cryptococcus neoformans, Coccidioides immitis, Blastomyces dermatitidis, and many strains of Aspergillus Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 152 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 153 Antifungal Drugs / Drugs for subcutaneous and systemic mycotic infections ➢Amphotericin B: • Resistance: • Ergosterol content and structure • PK: • Water insoluble - colloidal suspension of amphotericin B and sodium deoxycholate or liposomes – parenterally (slow IV infusion) • Extensively bound to plasma proteins • High distribution – but little of drug is found in CSF (intrathecal administration), vitreous humor, peritoneal fluid, synovial fluid • Excreted in the urine over a long period of time Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 154 Antifungal Drugs / Drugs for subcutaneous and systemic mycotic infections ➢Amphotericin B: • Adverse effects: • Fever, chills, kidney failure, hypotension, anemia, thrombophlebitis • Infusion-related toxicity: • Fever, chills, muscle spasm, headache, hypotension, vomiting • Subside with repeated administration / ameliorated by decreasing infusion rate or daily dose • Prevented with premedication: corticosteroid, antipyretic • Cumulative toxicity: • Renal damage (most significant toxicity) • Decreased glomerular filtration rate + decreased renal tubular function Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 155 Antifungal Drugs / Drugs for subcutaneous and systemic mycotic infections ➢Amphotericin B: • Adverse effects: • Cumulative toxicity: • Creatinine clearance decrease • K and Mg wasting • Renal tubular acidosis • Reversible, but residual damage at high doses (> 4g cumulative dose; prolonged) • Azotemia – might require dialysis / hydration might decrease its severity • Risk of nephrotoxicity minimized by normal saline infusion prior amphotericin B administration Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 156 Antifungal Drugs / Drugs for subcutaneous and systemic mycotic infections ➢Antimetabolite antifungals (Flucytosine) (5-FC): • Synthetic pyrimidine • Combined with other antifungal agents (Amphotericin B + 5-FC – synergistic effect + safer) • MOA: • Fungistatic • Selective toxicity; no effect on human cells (lack of enzymes) • Disrupting nucleic acid and protein synthesis Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 157 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 158 Antifungal Drugs / Drugs for subcutaneous and systemic mycotic infections ➢Antimetabolite antifungals (Flucytosine) (5-FC): • Antifungal spectrum: • Restricted (narrow) • Combined with amphotericin B (for treatment of systemic mycoses and for meningitis caused by C. neoformans and C. albicans) or itraconazole (a triazole, for the treatment of chromoblastomycosis) • Not used alone; high susceptibility of resistance • Resistance: • Altered metabolism of 5-FC Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 159 Antifungal Drugs / Drugs for subcutaneous and systemic mycotic infections ➢Antimetabolite antifungals (Flucytosine) (5-FC): • PK • Well-absorbed orally • Distributes throughout body water and penetrates into CSF • 5-FU detectable in patients due to metabolism by intestinal bacteria • Excretion (parent drug + metabolites) in the urine via glomerular filtration • Adverse effects: • Due to formation of 5-FU by intestinal bacteria • Bone marrow toxicity with anemia, leukopenia, and thrombocytopenia • Nausea, vomiting, diarrhea, severe enterocolitis, reversible hepatic dysfunction with elevation of serum transaminases Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 160 Antifungal Drugs / Drugs for subcutaneous and systemic mycotic infections ➢Azole antifungals (imidazoles + triazoles): • Similar MOA and spectra of activity • Differ in PK properties and therapeutic use • Imidazoles: applied topically for cutaneous infections • Triazoles: administered systemically for the treatment or prophylaxis of cutaneous and systemic mycoses • Triazoles: e.g. fluconazole, itraconazole, posaconazole, voriconazole, isavuconazole Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 161 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 162 Antifungal Drugs / Drugs for subcutaneous and systemic mycotic infections ➢Azole antifungals (imidazoles + triazoles): • MOA: • Fungistatic • Reduce ergosterol synthesis • Inhibit 14 α-demethylase – blocking demethylation of lanosterol to ergosterol – disrupts fungal membrane function and structure – inhibit fungal cell growth • Resistance: • Mutations in the 14 α-demethylase gene • Efflux pumps Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 163 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 164 Antifungal Drugs / Drugs for subcutaneous and systemic mycotic infections ➢Azole antifungals (imidazoles + triazoles): • Drug interactions: • All azoles inhibit the hepatic CYP450 3A4 isoenzyme to varying degrees • Concomitant medications that are substrate for the above enzymes – result in high concentrations and toxicity – drug-drug interactions • Several azoles, such as itraconazole and voriconazole, are metabolized by CYP450 3A4 and other CYP450 isoenzymes – drug-drug interactions with CYP450 inhibitors (ritonavir) and inducers (rifampin, phenytoin) will occur • Imidazoles exhibit a lesser degree of selectivity than the triazoles, accounting for their higher incidence of drug interactions and adverse effects Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 165 Antifungal Drugs / Drugs for subcutaneous and systemic mycotic infections ➢Azole antifungals (imidazoles + triazoles): • Contraindications: • Azoles are teratogenic – avoided in pregnancy (unless benefit > risk to fetus) • Fluconazole: • 1st triazole • Least active of all triazoles • Spectrum: yeast and some dimorphic fungi • No role in the treatment of aspergillosis or zygomycosis • Activity against: Cryptococcus neoformans, Candia albicans, Candida parapsilosis Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 166 Antifungal Drugs / Drugs for subcutaneous and systemic mycotic infections ➢Azole antifungals (imidazoles + triazoles): • Fluconazole: • Prophylactic – against invasive fungal infections in recipients of bone marrow transplants • Drug of choice for Cryptococcus neoformans after induction therapy with amphotericin B and flucytosine • Used for candidemia and coccidiomycosis • Active against mucocutaneous candidiasis – vulvovaginal candidiasis • Oral (high distribution) / IV • Excreted in the urine • Adverse effects: nausea, vomiting, headache, skin rashes Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 167 Antifungal Drugs / Drugs for subcutaneous and systemic mycotic infections ➢Azole antifungals (imidazoles + triazoles): • Itraconazole: • Broader spectrum than fluconazole • Drug of choice for the treatment of blastomycosis, sporotrichosis, paracoccidioidomycosis, and histoplasmosis • Capsule, tablets: taken with food + acidic beverage • Solution: on empty stomach • High distribution in the body • Metabolized in liver – drug + inactive metabolites excreted in urine and feces • Adverse effects: nausea, vomiting, rash, hypokalemia, HTN, edema, headache // has negative inotropic effect = avoided in patients with HF Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 168 Antifungal Drugs / Drugs for subcutaneous and systemic mycotic infections ➢Azole antifungals (imidazoles + triazoles): • Voriconazole: • Broad-spectrum of activity • Oral / IV • Drug of choice for invasive aspergillosis • Used for invasive candidiasis and infections caused by Scedosporium and Fusarium species • Drug-drug interactions; metabolized and inhibits various CYP450 isoenzymes • High doses – visual and auditory hallucinations, hepatotoxicity Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 169 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 170 Antifungal Drugs / Drugs for subcutaneous and systemic mycotic infections ➢Echinocandins (caspofungin, micafungin, anidulafungin): • Newest class of antifungal agents • Fungicidal / act on cell wall • Large cyclic peptides linked to a long-chain fatty acid – IV • Caspofungin and anidulafungin require loading dose • Potent activity against Aspergillus and most Candida species, including those resistant to azoles • MOA: • Inhibiting the synthesis of β(1,3)-D-glucan (cell wall component forming chitin) – lysis – cell death Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 171 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 172 Antifungal Drugs / Drugs for subcutaneous and systemic mycotic infections ➢Echinocandins (caspofungin, micafungin, anidulafungin): • Adverse effects: • Fever, rash, nausea, phlebitis at infusion site • Should be administered via a slow IV infusion – prevent histamine-like reaction (flushing) if infused rapidly • Caspofungin: • 1st line option for patients with invasive candidiasis, including candidemia • 2nd line option for invasive aspergillosis in patients who have failed or cannot tolerate amphotericin B or an azole • Metabolized via CYP450 enzymes – drug-drug interactions Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 173 Antifungal Drugs / Drugs for subcutaneous and systemic mycotic infections ➢Echinocandins (caspofungin, micafungin, anidulafungin): • Micafungin and anidulafungin: • 1st line option for the treatment of invasive candidiasis, including candidemia • Not substrates for CYP450 enzymes – NO drug-drug interactions Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 174 Antifungal Drugs / Drugs for cutaneous mycotic infections ➢Overview: • Mold-like fungi cause cutaneous infections = dermatophytes / tinea • Infections = dermatophytosis / e.g. tinea pedis, tinea corporis (ringworm), tinea capitis, tinea cruris, tinea versicolor, onychomycoses • Majority of dermatophytosis caused by: • Trichophyton, Microsporum, and Epidermophyton fungi Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 175 Antifungal Drugs / Drugs for cutaneous mycotic infections ➢Squalene epoxidase inhibitors: • E.g. terbinafine, naftifine, butenafine • Inhibiting squalene epoxidase – block synthesis of ergosterol • Accumulation of squalene – increased membrane permeability – cell death Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 176 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 177 Antifungal Drugs / Drugs for cutaneous mycotic infections ➢Squalene epoxidase inhibitors: • Terbinafine: • Fungicidal • Orally – drug of choice – onychomycosis • Better tolerated, short duration of therapy, more effective compared to itraconazole or griseofulvin • Therapy is prolonged – 3 months (shorter than griseofulvin) • Tinea capitis – require oral formulation • Topically (1% cream, gel or solution) – 1 week treatment – tinea pedis, tinea corporis, tinea cruris, tinea versicolor Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 178 Antifungal Drugs / Drugs for cutaneous mycotic infections ➢Squalene epoxidase inhibitors: • Terbinafine: • PK: • Oral/topical administration • 40% bioavailable – first-pass metabolism • Highly protein-bound and deposited in skin, nails and adipose tissue // keratophilic • Prolonged half-life – 200 to 400 hrs • Oral terbinafine - metabolized in liver and excreted in the urine – avoided in patients with moderate to severe renal impairment or hepatic dysfunction • Inhibitor of CYP450 2D6 isoenzyme – drug-drug interaction Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 179 Antifungal Drugs / Drugs for cutaneous mycotic infections ➢Squalene epoxidase inhibitors: • Terbinafine: • Adverse effects: • Diarrhea, dyspepsia, nausea, headache, rash • Taste and visual disturbances reported • Elevations in serum hepatic transaminases Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 180 Antifungal Drugs / Drugs for cutaneous mycotic infections ➢Griseofulvin: • Fungistatic / keratophilic • Causes disruption of mitotic spindle – inhibition of fungal mitosis • Deposited in newly forming skin where it binds to keratin • Used to be used for onychomycosis (6-12 months of treatment) • Still used for dermatophytosis of the scalp and hair – taken with high-fat meals • Induces hepatic CYP450 – drug-drug interactions • Contraindicated in pregnancy and patients with porphyria. Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 181 Antifungal Drugs / Drugs for cutaneous mycotic infections ➢Nystatin: • Resembles amphotericin B • Treatment of cutaneous and oral Candida infections • Not absorbed from GI tract / systemic toxicity if given parenterally • Oral agent – “swish and swallow” or “swish and spit” – oropharyngeal candidiasis (thrush) • Intravaginally – vulvovaginal candidiasis • Topically – cutaneous candidiasis Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 182 Antifungal Drugs / Drugs for cutaneous mycotic infections ➢Imidazoles: • E.g.: butoconazole, clotrimazole, econazole, ketoconazole, miconazole, oxiconazole, sertaconazole, sulconazole, terconazole, and tioconazole • Uses: tinea corporis, tinea cruris, tinea pedis, and oropharyngeal and vulvovaginal candidiasis • Oral ketoconazole has historically been used for the treatment of systemic fungal infections but is rarely used today due to the risk for severe liver injury, adrenal insufficiency, and adverse drug interactions. Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 183