Lecture 19 Antifungal Drugs PDF

PHAR2210 Foundations of Pharmacology Lecture 19 Antifungal drugs Dr Ricky Chen Chapter 54, Rang & Dale's Pharmacology (Tenth Edition, 2023)  Learning outcomes After completing this lecture, you should be able to list factors that contribute to the increased...

PHAR2210 Foundations of Pharmacology Lecture 19 Antifungal drugs Dr Ricky Chen Chapter 54, Rang & Dale's Pharmacology (Tenth Edition, 2023)  Learning outcomes After completing this lecture, you should be able to list factors that contribute to the increased prevalence of fungal infections describe the classification of mycoses and the relevant site of infection describe the pharmacokinetics, mechanism of action, and adverse effects of each of the four antifungal drug classes and provide an example for each drug class Core concepts of pharmacology pharmacodynamics pharmacokinetics Drug-target Drug target Steady-state Drug absorption Drug bioavailability interaction concentration Mechanism of Structure-activity Drug distribution Volume of distribution drug action relationship Zero- and first- order kinetics Drug metabolism Drug clearance Affinity Drug selectivity Drug elimination Drug elimination half-life Potency Efficacy DRUG Dose/concentration- Drug tolerance response relationship Therapeutic index Adverse drug reaction Individual variation Adapted from Guilding et al. (2023) Defining and Drug interaction in drug response unpacking the core concepts of pharmacology: A global initiative. British Journal of Pharmacology, 1-18. Patient outcomes https://doi.org/10.1111/bph.16222  Fungi fungi are eukaryotic cells​; ~100,000 species classified, estimates between 1.5 and 5.1 millions​ present in the environment or may coexist with humans as commensals​ a limited number of species are pathogenic in humans Yeasts grow as unicellular form Moulds grow as multicellular filaments (hyphae) → branch to form a network (mycelium)​ Dimorphic fungi assume either filamentous or yeast-like morphology depending on the environment​ Sudbery (2011)  Two sides of fungi consumption (e.g., mushrooms) Good manufacturing (e.g., Baker’s yeast in beer making; antibiotic production) damages to animals, crops or food fungal diseases in humans - cost > $7.2 billion in 2017 in the USA (Benedict et al., 2019) Bad o Candida infections and Aspergillus infections o dermatophyte infections responsible for over half of outpatient visits Most fungal infections are opportunistic infections rarely cause disease in healthy individuals nonpathogenic fungi become pathogenic in immunocompromised patients Increasing prevalence of fungal infections widespread use of broad-spectrum antibiotics - eliminate nonpathogenic bacterial competitors use of immunosuppressant AIDS cancer chemotherapy diabetes Fungal infections (mycoses) Classification Site of infection​ outermost epidermal layer of superficial skin (i.e., stratum corneum) or outer surface of hair shafts​ epidermal layer of skin, hair cutaneous shafts, and nails​ dermal and underlying layers of subcutaneous skin​ modified from Kabashima et al. (2019) serious infections of internal organs​ - gain access via the respiratory tract, the GI systemic tract, or blood vessels​ primary vs. opportunistic pathogens  Antifungal (antimycotic) drugs Challenges biological similarities between humans and fungi as eukaryotes can be toxic to host (oral antifungal drugs must be strictly monitored) distinctive sterols: ergosterol in fungal cell membranes vs. cholesterol in human cells Timeline of systemic antifungal drugs (Lewis, 2011)  Antifungal (antimycotic) drug classes route of administration (oral/topical/intravenous) - drug absorption from the GI tract? dosing strategies - ↑ drug efficacy and ↓ risk of toxicity spectrum of action (yeasts/moulds/dimorphic) site of infection renal/hepatic clearance drug-drug interaction inhibit cell wall synthesis o echinocandins* (semisynthetic) alter cell membrane integrity or permeability o polyenes* (natural occurring) o allylamines* (synthetic) o azoles* (synthetic) Volmer et al. (2010) Fungal cell wall cell wall structure of selected fungal cells Erwig and Gow (2016)  Echinocandins -fungin (e.g., caspofungin) o synthetic modification of echinocandin B (a hexapeptide + lipid side chain) bind to β-1,3-glucan synthase → inhibit β-1,3-glucan synthesis​ echinocandin B poor oral absorption - i.v. administration concentration-dependent activity - Cmax:MIC fungicidal for Candida species - treat invasive candidiasis fungistatic for Aspergillus species nausea, vomiting and diarrhoea infusion-related reactions Brown et al. (2011)  Polyenes natural products - broad-spectrum antifungal macrolides interaction with ergosterol is key to antifungal activity o ergosterol in fungi - regulation of cellular process; membrane stability and fluidity o form pores - leakage of intracellular contents, e.g., K+ ions o interactions at the surface of cell membranes Carolus et al. (2020) Polyenes Amphotericin B* broad spectrum - most fungi and yeasts poor oral absorption o treat infection of the upper GI tract amphotericin B o systemic infection - slow i.v. infusion minimal hepatic metabolism o mainly faecal elimination infusion-related - inflammatory response nephrotoxicity - interactions with cell membranes liposomal formulations - ↓ toxicity Gray et al. (2012) Inhibition of ergosterol biosynthesis squalene squalene monooxygenase allylamines* 2,3-oxidosqualene lanosterol cell membrane stability and fluidity 14-demethylase azoles* 4,4-dimethyl-Δ8,14,24-trienol 4,4-dimethyl-Δ8,24-dienol X ergosterol  Allylamines synthetic fungicidal antifungal drugs squalene squalene monooxygenase allylamines* 2,3-oxidosqualene terbinafine terbinafine* treatment for onychomycosis (fungal infection of the nail bed, matrix, or plate) o major cause of infection - dermatophytes (e.g., Trichophyton rubrum) o highly lipophilic and keratinophilic - dermatophytes require keratin for growth oral or topical administration - rapid absorption and is taken up by skin and nails CYP2D6 inhibitor - potential drug-drug interaction GI disturbance rash muscle pain  Azoles broad-spectrum synthetic fungistatic drugs lanosterol 14-demethylase azoles* 4,4-dimethyl-Δ8,14,24-trienol imidazoles Lewis (2011) e.g., ketoconazole - first azole administered orally to treat systemic infections triazoles e.g., itraconazole* itraconazole  Azoles itraconazole* can be administered orally but absorption is variable extensive hepatic metabolism GI disturbance hepatotoxicity cardiotoxicity - QT interval prolongation a CYP3A4 inhibitor - drug-drug interaction midazolam CYP3A4 1-hydroxymidazolam midazolam following itraconazole pretreatment (▲) midazolam 4 days after itraconazole pretreatment (∆) midazolam alone (○) Backman et al. (1998) Antifungal drug-related toxicities Lewis (2011)