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Antifungals NURSING.pptx
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- 2. Cell membrane synthesis •Acetyl Co A • HMG Co A • Mevalonate • Squalene Squalene epoxidase • Lanosterol 14 α sterol demethylase • Ergosterol
- 3. Timeline of antifungals •1949 1st antifungal Nystatin discovered • 1958 1st use of amphotericin B • 1963 5-flucytosine discovered • 1967 1st antifungal use of an azole • 1972 Discovery of echinocandins • 1990 Fluconazole FDA approved • 2002 Caspofungin FDA approved • 2006 Posaconazole approved
- 4. Classification I. Drugs thatdisrupt fungal cell membrane: i) Inhibitors of fungal membrane stability – a. Polyene antibiotics – amphotericin B, nystatin, hamycin, natamycin b. D-reductase/ D-isomerase inhibitors – amorolfine
- 5. ii) Inhibitors ofergosterol synthesis pathway a. 14 α sterol demethylase inhibitors – Azoles - imidazoles: ketoconazole, miconazole, econazole, clotrimazole, tioconazole, sulconazole, oxiconazole, fenticonazole, luliconazole, butoconazole, sertaconazole - triazoles: fluconazole, itraconazole, terconazole, posaconazole, voriconazole, ravuconazole b. Squalene epoxidase inhibitors - terbinafine, naftifine, butenafine, tolnaftate
- 6. II. Drugs thatdisrupt fungal cell wall: echinocandins – caspofungin, micafungin, anidulafungin III. Drugs that inhibit DNA synthase: flucytosine IV. Drugs that inhibit mitosis: griseofulvin V. Miscellaneous: ciclopirox olamine, sodium thiosulphate
- 7. A. Polyene antibiotics 1.Amphotericin B - Produced from Streptomyces nodosus - Broadest spectrum of antifungal activity: Candida spp., Cryptococcus neoformans, Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis, Aspergillus fumigatus, Sporothrix schenckii, Paracoccidioides braziliensis, Penicillium marnefei, Rhizopus, Rhizomucor, Cunninghamella - Candida lusitaniae, Pseudallescheria boydii, Scadosporium, dermatophytes resistant - Effective against protozoa Leishmania spp.
- 8. • Mechanism ofaction - Binds to ergosterol and alters the permeability of the cell; forms pores which leak ions and macromolecules leading to cell death - Destabilises fungal cell membrane by generating toxic free radicals
- 9. Pharmacokinetics - Poorly absorbed– oral AMB used for luminal infections - For systemic use - complexed with sodium deoxycholate (ABCD for iv) or as liposomes - Highly ppb - t ½ 15 days - CSF penetration poor - Crosses placenta - Excreted slowly via kidneys
- 10. Adverse effects • Immediate(cytokine storm): due to release of TNF α /IL-1; fever, chills, muscle spasms, headache, vomiting, hypotension, thrombophlebitis - Decrease rate or pre treat with NSAIDs/ hydrocortisone • Delayed: renal damage (80%), hypokalemia, anaemia, thrombocytopenia
- 11. Indications • DOC forlife-threatening mycotic infections – aspergillosis, coccidioidomycosis, blastomycosis, mucormycosis, histoplasmosis, sporotrichosis • With flucytosine in cryptococcal meningitis Dose • 50-100 mg qid • 0.3 mg/kg iv • 3-6 mg/kg/day liposomal
- 12. 2. Nystatin • Namedafter New York Health State Laboratory • Produced from Streptomyces noursei or albidus • Similar to AMB • Too toxic for parenteral use • Use topically for superficial candidiasis of mouth, oesophagus, skin, vagina
- 13. 3. Hamycin • Indiandiscovery- Thirumalachar, Menon, Bhate from Streptomyces pimprina at Hindustan Antibiotics, Pimpri, Pune • Similar to nystatin • Used topically for superficial candidiasis of mouth, skin, vagina
- 14. B. Azoles Mechanism ofaction • Inhibit ergosterol synthesis by selective inhibition of 14 α sterol demethylase • Primarily fungistatic • Imidazoles more toxic systemically; used topically except ketoconazole • Triazoles less toxic, used systemically
- 15. • Acetyl CoA • HMG Co A • Mevalonate • Squalene Squalene epoxidase • Lanosterol 14 α sterol demethylase X azoles • Ergosterol
- 16. Systemic azoles 1. Ketoconazole Spectrumof activity • Broad spectrum- C albicans, H capsulatum, B dermatitidis, C immitis, Malassezia furfur, dermatophytes Pharmacokinetics • Well absorbed orally – salt formation in acidic pH • Food increases, antacids decrease absorption • t ½ 7-10 hrs, highly ppb • CSF concentration low, secreted in breast milk • Hepatic elimination; biliary excretion
- 17. Adverse effects • N,V, giddiness, photophobia common • Decreases human gonadal steroid synthesis – decreases testosterone causing decrease in libido, oligozoospermia, impotence, menstrual irregularities, gynaecomastia • Hepatotoxicity rare 1-2% • Teratogenic in animals- CI in pregnancy and lactation
- 18. Drug interactions • Antacids,H2 blockers, PPI, sucralfate decrease absorption • Inhibits metabolism of oral anticoagulants, phenytoin, cyclosporine • Can cause disulfiram-like reaction with alcohol
- 19. Indications • Coccidioidomycosis, blastomycosis,histoplasmosis, candidiasis – 200 mg bd after meals • Seborrheic dermatitis – 2% shampoo twice weekly for 2-4 weeks • Pityriasis versicolor – 2% ointment od for 5 days • Dermatophytosis
- 20. 2. Fluconazole Spectrum ofactivity • Broad spectrum- Candida, H capsulatum, Cryptococcus, C immitis Pharmacokinetics • Almost 100% bioavailability, not affected by food or pH • Good CSF penetration • t ½ 30 hrs • 80% excreted unchanged in urine, 10% unchanged in faeces
- 21. Adverse effects • WidestTI of azoles • N, headache, abdominal pain in 10% • Reversible alopecia • Rash, hepatic necrosis, SJ Syndrome, neutropenia rare; esp in HIV pts
- 22. Drug interactions • Inhibitsmetabolism of oral anticoagulants, phenytoin, amitriptyline (mild) • Effect of fluconazole decreased by carbamazepine, INH Indications • DOC for coccidioidal meningitis, histoplasmosis • Azole of choice for cryptococcal meningitis • Systemic candidiasis (150 mg weekly for 4 weeks), vulvovaginal candidiasis (150 mg SD)
- 23. 3. Itraconazole Spectrum ofactivity • Candida, Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis, Aspergillus fumigatus, Sporothrix schenckii, Pseudallescheria boydii, Malassezia furfur, dermatophytes, agents of chromoblastomycosis
- 24. Pharmacokinetics • Absorption increasedby food, low pH • Highly ppb • Active hydroxy itraconazole has 50% activity • t ½ 24-42 hrs • Poor entry in CSF, urine
- 25. Adverse effects • N,V, hypertriglyceridaemia, hypokalemia, pedal oedema • Rarely CHF, arrhythmias, peripheral neuropathy Drug interactions • H2 blockers, antacids, PPI decrease absorption • Interacts with many drugs and decreases the metabolism of H1 antagonists, warfarin, cyclosporin, tacrolimus, digoxin, lovastatin, methylprednisolone, glibenclamide , phenytoin, saquinavir and nortriptyline.
- 26. Indications • Dermatophytosis, onychomycosis,oropharyngeal / cutaneous / vaginal candidiasis, coccidioidomycosis, histoplasmosis, aspergillosis, pseudallescheriasis, pityriasis versicolor • Azole of choice in blastomycosis, sporotrichosis, chromoblastomycosis (with flucytosine) Dose • For superficial mycosis: 100 mg daily for 15 days • For deep mycosis: 600-800 mg daily for 3 days ; 200-400 mg daily for 6-12 months
- 27. 4. Voriconazole • Spectrumsimilar to itraconazole • Fatty food decreases bioavailability • CSF entry good • t½ 6-24 hrs • ADRs include visual disturbances (colour changes imm after dose), hepatotoxicity, rash; photosensitivity, dermatitis (on chronic use) • Azole of choice in invasive aspergillosis • Indicated in candidiasis (inc C krusei), histoplasmosis, blastomycosis, fusariosis, pseudallescheriasis and infection by Scadosporium apiospermum • Dose: 400 mg daily on empty stomach
- 28. 5. Posaconazole • Broadestspectrum among azoles; activity against zygomycetes and mucoralis sp • High fatty meals increase absorption • Rapid tissue distribution • t½ 20-65 hrs • ADRs include GIT disturbances, abnormal LFTs, headache • Indicated in invasive aspergillosis, zygomycosis, mucormycosis • Used for prophylaxis during induction chemo for leukaemia or bone marrow transplant pts • Dose: 400 mg bd/ 200 mg qid
- 29. Topical azoles • Causedirect damage to fungal cytoplasmic membrane • <1% absorbed systemically , 4% absorbed through damaged skin • Rarely cause itching, burning • Indicated in cutaneous candidiasis, vaginal candidiasis, fungal keratitis, dermatophytosis, seborrheic dermatitis and pityriasis versicolor • Not useful in onychomycosis, tinea capitis, sporotrichosis and chromomycosis
- 30. Squalene epoxidase inhibitors 1.Terbinafine • Mainly effective against Trichophyton rubrum /mentagrophytes, Candida • Gets concentrated in cornea, nail plates and hair • Inhibits squalene epoxidase thus causing accumulation of toxic squalene • 50-70% bioavailability • t ½ 300 hrs • CI in pregnancy and lactation • ADRs include GIT disturbances, taste disturbances, hepatitis, rash, dizziness, pancytopenia • DOC in dermatophytosis; used in onychomycosis, sporotrichosis • Dose: 250 mg od for 2-4 weeks; 3 months (finger nails), 6 months (toe nails); 1% cream
- 31. • Acetyl CoA • HMG Co A • Mevalonate • Squalene Squalene epoxidase X terbinafine • Lanosterol 14 α sterol demethylase • Ergosterol
- 32. 2. Naftifine Similar toterbinafine, but only topical for dermatophytosis 3. Butenafine Topical like naftifine , also effective against M furfur
- 33. Griseofulvin • Narrow spectrumfungistatic antibiotic from Penicillium griseofulvum • Interacts with microtubules and interferes with mitosis of dermatophytes • t ½ 24 hrs • ADRs include GIT upsets, rash, fever; headache (15 %), exacerbated by alcohol • Indicated in superficial dermatophytosis- 125-250 mg qid
- 34. Flucytosine • Useful activityagainst C neoformans and agents of chromoblastomycosis • Never used alone – resistance • ADRs include anaemia, leucopenia, thrombocytopenia, toxic enterocolitis, N,V,D • Indications: - Cryptococcosis (with AMB) - Chromoblastomycosis (with itraconazole)
- 35. Echinocandins • Inhibit β-(1,3)-D-glucansynthase, preventing formation of β-glucan, a main component of cell wall • Effective against Candida, aspergillus (static), histoplasma • ADRs include N, V, fever, venous thrombophlebitis, flushing • Indicated in invasive refractory aspergillosis, candida oesophagitis, candidemia
- 36. • Cyclopirox olamine-tinea infections, pityriasis versicolor, vaginal candidiasis, onychomycosis (8% laquer) • Sodium thiosulphate- only against M furfur
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