Antifungals.Dr shah fahad hussain hmc pico

Antifungal drugs

1. Antifungals 24 th Oct. 2011

2. Classification

3. Mechanism Overview

4. Amphotericin B Mechanism Binds to Ergosterol ~ Change in membrane permeability Resistance Low affinity/binding for ergo Low conc. of ergo Spectrum Candida , Cryptococcus, Histoplasma , Blastomyces , Coccidioides , Aspergillus , mucor , Sporothrix .

5. Pharmacokinetics & ADR Pharmacokinetics Poor GI abs (For GI mycoses) i.v ./ intrathecal (slow) ~ high ppb metabolized ~ slow urinary excretion + liposomes Adverse Effects Infusion related reactions fever, chills, muscle spasms, vomiting, headache, and hypotension Others Renal ~ Reversible (decreased renal perfusion ) Irreversible (renal tubular injury) Abnormal LFT Anemia Seizures, Arachnoiditis

6. Flucytosine Mechanism C ytosine permease ~ converted to 5-FU ~ FdUMP ( thymidylate synthase ) & FUTP ~ Inhibit DNA & RNA syn Spectrum Yeasts like Cryptococcus, Candida (+Amp) Chromoblasto (+ Itra ) Resistance ↓ ed enzymes or ↑ cyto syn (mono)

7. Pharmacokinetics & ADR Pharmacokinetics Good oral abs. Low PPB ~ Good dist. Inc. CSF ~ metabolized Urinary exc. (Amp) Adverse Effects Bone marrow toxicity (anemia, leukopenia , and thrombocytopenia) Hepatic dys ( abn LFT) Enterocolitis

8. Azoles Mechanism Inhibit C-14 demethylase ( Lano →Ergo ) CYP also inhibited Resistance Active efflux, target alteration/overproduction

9. Ketoconazole Pharmacokinetics Oral (Stomach, low pH) ~ high ppb ~ limited dist Hep meta ~ biliary exc. Spectrum Histoplasma , Blastomyces , Candida, and Coccidioides Adverse Effects Hypersensitivity GI Endocrine ( gynecomastia , decreased libido, impotence, and menstrual irregularities) Hepatitis Teratogenic Interactions Cyclosporine, phenytoin , tolbutamide , and warfarin Rifampin With Amph

10. Itraconazole Pharmacokinetics Oral/iv. Like keto . Poor dist. Abs. ↑ ed by low pH & food Hydroxy itra ~ urinary exc. does not affect mammalian steroid synthesis Spectrum B lastomycosis , sporotrichosis , paracoccidioidomycosis , and histoplasmosis Aspergillus Dermatophytoses and onychomycosis (DOC) ADR & Interactions GI, rash, hypokalemia , hypertension, edema, and headache Inhibits meta of drugs

11. Fluconazole Pharmacokinetics (Oral/iv) Good oral bioavailability ~ high water solubility & CSF dist. Abs. not dependent on low pH. Low ppb. Poor metabolism. Renal excretion. Spectrum Crypto (Post/Pre), Candida (systemic/ muco ), coccidioidomycosis ADR No endocrine. Nausea, vomiting, and rashes. Hepatitis CYP inhibition

12. Voriconazole Pharmacokinetics (Oral/iv) Good abs ~ Good dist inc. CSF. Hepatic meta Spectrum Aspergillosis Scedosporium apiospermum and Fusarium species ADR Visual (Prompt) Photosensitivity dermatitis (Chronic oral) rash and elevated hepatic enzymes Interaction (Inhibitor)

13. Posaconazole Pharmacokinetics (Oral) Good oral abs (with fatty meal) Spectrum Candida, Aspergillus , Zygo , Mucor ADR GI, headaches, abnormal LFT hemolytic uremic syndrome, purpura , pulmonary embolus (with cyclo / tacrolimus ) CYP inhibitor

14. Echinocandins Caspofungin , micafungin ,  and anidulafungin   Mechanism Inhibit β (1–3)- glucan Spectrum Candida and Aspergillus Pharmacokinetics Only iv Caspo has PPB ~ meta ~ exc by both fecal/urinary route

15. Adverse Effects ADR GI Histamine release Caspo shouldn’t be given in combination with cyclosporin ~ abnormal LFT’s.

16. Griseofulvin rption with fatty food. DepoInsoluble fungistatic Good absosited in skin ~ binds to keratin ~ mitotic spindle and inhibition of fungal mitosis. Used systemically for tineas . For skin ~ 2-6 weeks therapy. For nails ~ months Adverse effects inc. allergic syndrome much like serum sickness, hepatitis, and drug interactions with warfarin and phenobarbital .

17. Terbinafine Fungicidal, effective orally, keratophilic Interferes with ergo syn. by inhibiting the enzyme squalene epoxidase ~ squalene acc. Only effective orally ~ 1 st pass ~ meta by CYP (Rif/ Cim ) ~ urinary exc. Dermatophytosis esp. onychomycosis . GI, headache, rash, taste/visual dist, abn . LFT’s

18. Topical Antifungals Nystatin Polyene macrolide . Only for candida Azoles ( Clo / Mico ) Candida Ketoconazole topical/shampoo for seborrheic dermatitis and pityriasis versicolor Allylamine Terbinafine and naftifine topical creams for tinea ( cruris , corporis ) ADR Limited to local irritation, dermatitis, edema.