Antifungals for GIT Infections - PDF

Antimicrobials for GIT infections 4. Antifungals Presented by Dr Brooke Storey-Lewis Discipline of Pharmacology Learning outcomes – Identify antifungal drugs used in the treatment of infections of the gastrointestinal tract – Describe the mechanism of action of azoles, amphotericin B & nys...

Antimicrobials for GIT infections 4. Antifungals Presented by Dr Brooke Storey-Lewis Discipline of Pharmacology Learning outcomes – Identify antifungal drugs used in the treatment of infections of the gastrointestinal tract – Describe the mechanism of action of azoles, amphotericin B & nystatin, and echinocandins – Describe pharmacokinetic considerations for the use of azoles, amphotericin B, and echinocandins – Describe adverse effects and contraindications for the use of azoles, amphotericin B, and echinocandins Introduction –Amphotericin B – Echinocandins – Anidulafungin – Caspofungin –Azoles – Micafungin –Fluconazole –Voriconazole –Miconazole (oral gel) –Clotrimazole (topical) AMH Online AMH Online Mechanism of action Pharmacokinetic considerations Amphotericin B Two formulations Amph B deoxycholate – only avail via SAS Liposomal (AmBisome) – improve tolerability/reduce tox Poor oral bioavailability IV admin, lozenge for oral candidiasis Protein bound (up to 99%) No dose adjustments for renal/hepatic impairment Adverse effects & contraindications Amphotericin B Use limited by adverse effects Infusion-related toxicity reactions: fever, chills, muscle spasm, vomiting, headache, hypotension; slow infusion rate + reduce dose test dose pre-treat with antihistamines, paracetamol, corticosteroids Renal toxicity: decreased perfusion (reversible); tubular injury (irreversible) Increase in serum creatinine Pharmacokinetic considerations Azoles Fluconazole has highest oral bioavailability Loading dose  maintenance dose Long t1/2 (e.g. flu, itra 30hrs) therefore long time to reach steady state concentration Adverse effects & contraindications Azoles Mild GI disturbance Liver enzyme abnormalities Prolong QT interval  arrythmia Visual abnormalities, photosensitivity (voriconazole) Fluconazole pregnancy cat D Drug interactions via CYPs (least chance with fluc) CYP3A4 inhibitors Pharmacokinetic considerations Echinocandins IV only Variable t1/2 Variable metabolism Poor CYP P450 substrates Protein bound up to 99% Reduce dose of caspofungin in mod hepatic failure though risk subtherapeutic conc No dose reduction for renal impairment Adverse effects & contraindications Echinocandins Well tolerated, safest of antifungals Similar AEs across all echinocandins Minor GI upset Liver enzyme abnormalities Infusion reaction, rare Resources Australian Medicines Handbook MIMS online UpToDate Brown et al (2019) Clinical Pharmacology Rang et al (2020) Rang & Dale’s Pharmacology Katzung (2015) Basic and Clinical Pharmacology