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16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
16. antifungal
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16. antifungal

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  • Sporotrichosis; chronic granulomatous infection usually of skin and lymph node marked by formation of abscesses, caused by fungal sporothrixPityrosporum : a genous of lipophilic yeast present in normal skin
  • Endocarditis: inflammation or infection of heart valvesmucormycosis: caused by mucoraceae. Afinity towards blood vessels cause thrombosis Blastomycosis: caused by inhalation of blastomyces. It produce inflammation lesion of skin
  • Antibiotic
  • Kalaazaar: infections caused by Leishmania an intracellular protozovan fever, splenic enlargement
  • Nephrotoxicity renal tubulaes acidosis,Anemia dec. erythropoietin production from damaged renal tubules.Azotemia inc. ureates levels in blood
  • At high doses it acts as fungicidal
  • ELEVATES SERUM TRANSAMINES
  • Azoles dec. ergosterol production , so no use of AMB
  • Hypotension due to odema formation
  • Transcript

    • 1. ANTIFUNGAL 1
    • 2.  Fungi are eukaryotes VIJAy  Fungal infections Mycoses  Less frequent than bacterial & Virus but common.  Anyone can succumb to fungal infection but more at risk in older people, diabetics, pregnant women and burn wound. 2
    • 3. FUNGI MAY BE CLASSIFIED AS YEAST OR MOULDS. Yeast like pathogenic  Histoplasmosis  Coccidioidomycosis Blastomycosis  Cryptococcosis  Candida  Mould group of pathogenic  Aspergillosis  Dermatophytes  Mucormicosis  Candida Spp. and Pneumocyst carinii are not pathogenic  pathogenic in immuno compromised patients OPPORTUNISTIC INFECTION. 3
    • 4. Oropharyngeal  Vaginal candidiasis  Sporotrichosis (Granulomatus of skin & Lymph abscess)  Pityrosporum orbiculare - hyperpigmetnation  4
    • 5.  Fungal infections classified as Superficial & Deep mycosis (Systemic)  Superficial affecting skin, hair, nails, mucous membranes.  Most common: Dermatophytoses Encouraged by hot (Hygiene)and humid environment  Dermatophytoses classified according to body site • Tinea barbae • Tenia capitis(Scalp) • Tinea corporis(Body) • Tinea manuum(Hand) • Tinea pedis(Foot) • Tinea unguium(Nails)  5
    • 6.  Systemic fungal infections: Affect deeper tissues and organs.  Systemic candidiasis (RTI)  Meningitis, endocarditis  Rhinocerebral mucormycosis (Thrombosis)  Pulmonary aspergillosis  Blastomycosis (lesion of skin)  Histoplasmosis (cough , fever, multiple pneumonic infiltrates)  Coccidioidomycosis  Pneumocystis carinii pneumonia 6
    • 7.  Fungal cell structure and function is essential for understanding the pharmacology of antifungal agents.  Four targets in fungal pathogens:  Fungal Cell Wall  Fungal Cell Membrane  DNA/RNA Synthesis  Inhibition of fungal mitosis 7
    • 8. Fungal Cell Wall contain β- 1,3-D-glucan  Depletion of glucan  Leads to death  Capsofungin 8
    • 9. Altering membrane permeability AMPHOTERICIN-B Leading to cell death. 9
    • 10. MEMBRANE SYNTHESIS  Ergosterol is the predominant sterol in many pathogenic fungi. Squalene Terbinafine squalene 2,3 epoxide Lanosterol Azoles 14-demethylase Ergosterol 10
    • 11.  Inhibits DNA synthesis by blocking the functions of a key enzyme in DNA replication- thymidylate synthetase.  Fungal cell mitosis by disrupting mitotic spindle formation-a critical step in cellular division. 11
    • 12. 12
    • 13. CLASSIFICATION BASED ON MECHANISM OF ACTION Inhibitor of cell wall synthesis:  Caspofungin Drugs altering membrane synthesis  Inhibition of ergosterol Drugs altering membrane permeability Trimidazoles  Fluconazle,  Itraconazole,  Voriconazole Imidazoles  Ketoconazole,  Miconazole,  Clotrimazole. Amphotericin-B,  Nystatin,  Hamycin  Inhibit nucleic acid Synthesis  5 Flucytosine Disruption of mitotic spindle  Griseofulvin  Inhibition of ergosterol+ lanosterol  Terbinafine 13
    • 14. Drugs altering membrane permeability  Amphotericin-B Nystatin Hamycin Amphotercin:  First drug introduced in 1950s  Obtained from Strepomyces nodosus  Systemic Antifungal drug  Polyene group- Multi lactone ring with conjugated double bond .  One end – Hydroxyl group (OH)–polar (Hydrophilc)  Other end – Hydrocarbon group-non polar (Lipophilic) 14
    • 15.  MOA: Lipophilc end Hydrophilc end Creates ion channel 15 Leading to cell death.
    • 16. PK:  Poor absorbed from GIT- effective against intestinal fungal infection  For systemic - IV slow infusion  Peak antifungal activity at pH 6.0-7.5.  High con- Fungicidal, low- fungi static  90% plasma protein binding  T1/2- 15days ( binds with sterol)  It is insoluble in water  colloidal suspension with sodium 16 desoxycholate(1:1)
    • 17. Antifungal spectrum & uses:  After advent of azoles groups, the use of AMB declined.  Still it is DOC for  Treatment of Invasive aspergillosis in immune compromised patients  Mucormycosis  Rapidly progressing histoplasmosis, blastomycosis, meningeal cocciodomycosis(intrathecal) Topical use:- 3% cream for oropharngeal candidiasis,  Reserve drug for resistant case of KALA AZAR. Leishmania . Splenic enlargement  17
    • 18. Dose: 0.5 mg/kg/day  Adverse events:   Acute reaction (infusion related events, chills, fever, headache, nausea, vomiting)  Long term toxicity: nephrotoxicity(>4g), anemia (D. Ery)  azotemia, hypokalemia  CNS toxicity : intrathecal administration-seizures, headache, vomiting, nerve palsies   Hepatotoxicity rarely DI:Flucytosine –synergetic action inc. permeability FC  Aminoglycoside inc. renal toxicity.  18
    • 19.  3 new formulations available  AMB Lipid complex (ABLC): 35% AMB incorporated in ribbon like particles of dimyristoyl phospholipids  AMB colloidal dispersion (ABCD): Disc shaped particles containing 50% each of AMB & cholesteryl ester in aqueos dispersion  Liposomal AMB (Small Unilamellar Vesicles) : 10% AMB incorporated in SUV made up of lecithin 19
    • 20.  Special features of these formulations:  Milder acute reaction  Dec. infusion associated side effects  Can be used in intolerance to conventional preparations  Lower nephrotoxicity & anemia  Deliver AMB to reticular endothlial cell of liver spleen so useful in leshmania & immuno compromised 20
    • 21.  Nystatin:  Similar to AMB in antifungal properties  high systemic toxicity so used locally only Poorly absorbed from mucus membrane  Available as ointment, cream, powder, tablet   Uses:5 lac U in intestinal moniliasis TDS  1 lac U in vaginitis (1mg=2000U)  Can be used in oral, cutaneous, conjunctival candidiasis  Adverse events: Gastrointestinal disturbances with oral tablets  21
    • 22.  Drugs altering membrane synthesis Azoles: 1970   Broad spectrum  Fungistatic / Fungicidal  Most commonly used   Synthetic anti fungals Classified as imidazoles & triazoles Imidazoles: Two nitrogen in structure Topical: Econazole, Miconazole, Clotrimazole  Systemic : ketoconazole   Newer : Butaconazole, Oxiconazole, Sulconazole 22
    • 23.  Triazoles : Three nitrogen in structure 1980    Fluconazole, itraconazole, voriconazole, Terconazole Topical for superficial infections Both these groups are  Structurally related compounds  Have same mechanism of action  Have similar antifungal spectrum 23
    • 24. Acetyl CoA Squalene Allylamine Drugs (Terbinafine) Squalene monooxygenase Squalene-2,3 oxide Lanosterol Azoles 14-α-demethylase (ergosterol)
    • 25.  Miconazole & clotrimazole: Topical use  Cream, gel, spray, lotion ,solution , pessary     Dermatophyte infections ( pedis, cruris, corporis, versicolor) Candida: oral pharyngeal, vaginal, cutaneous Adverse events:  Local irritation , itching or burning  Miconazole shows higher incidence of vaginal irritation & pelvic cramps  No systemic side effects 25
    • 26. Ketoconazole: First orally effective broad spectrum antifungal  Effective against  Dermatophytosis  Deep mycosis  Candidiasis   Pharmacokinetics:  Effective orally  Requires acidic environment for absorption  High protein binding  Readily distributed, not to BBB  Metabolized in liver, excreted in bile t1/2 = 8-10 hrs 26
    • 27.  Dose : 200 mg OD or BD  Adverse events:  Nausea , vomiting , anorexia  Headache , paresthesia, alopecia  Reduces steroid, testosterone & estrogen synthesis  Thus can cause gynaecomastia,  oligospermia, loss of libido & impotence in males.  Menstrual irregularities & amenorrhoea in females  Elevation of liver enzymes  Hypersensitivity reaction like skin rashes 27
    • 28.  Drug interactions: Inhibits CYP450 enzyme  H2 receptor blockers  ↑ Sr conc of cisapride, terfenadine, astemizole, quinidine  Phenytoin toxicity  Sulfonylureas: hypoglycemia  Cyclosporine: nephrotoxicity  Warfarin: bleeding  Rifampicin, phenytoin ↑ metabolism of ketoconazole  Should not combine with AMB 28
    • 29.  Use: Restricted use, most serious mycoses  Dermatophytosis: conc in stratum corneum  Monilial vaginitis : 5-7 days  Systemic mycosis: blastomycosis, histoplasmosis, Coccidioidomycosis  Less efficacious than AMB & produces slower response  Efficacy low in immunocompromized and meningitis  Lower toxicity than AMB higher than triazoles  So triazoles have replaced it in systemic mycosis  High dose used in cushings syndrome  Topical: T.pedis, cruris, corporis, versicolor 29
    • 30. RESISTANCE May develop by altered demethylase or by enhanced removal from the fungal cell.  30
    • 31. Fluconazole:  Newer water soluble triazole  Oral, IV as well as topical  Broad spectrum antifungal activity  Candida, cryptococcosis, coccidioidomycosis  Dermatophytosis  Blastomycosis  Histoplasmosis  Sporotrichosis 31
    • 32.  Pharmacokinetics:  94% oral bioavailability  Not affected by food or gastric pH  Primarily excreted unchanged in urine t1/2 = 25 -30 hrs  Poor protein binding (10-12%)  Widely distributed crosses BBB   T ½ -27-32hrs Adverse events:  GIT upset  Headache, alopecia, skin rashes, hepatic necrosis  Teratogenic effect  CYP450 Enzyme inhibiting property less  No anti androgenic & other endocrine effects 32
    • 33.  Drug Interactions:  Effects hepatic drug metabolism to lesser extent than Ketoconazole   H2 blockers & PPI do not effect its absorption Uses:  Candida:    150 mg oral dose  cure vaginal candidiasis with few relapse Oral candidiasis  2 weeks treatment required Tinea infections & cutaneous candidiasis:  150 mg weekly  4 weeks, tinea unguim  12 months 33
    • 34.  Disseminated candidiasis, cryptococcal, coccidiodal meningitis & other systemic fungal infections:  200-400 mg / day 4- 12 weeks or longer  3 days oral  Candida UTI (100-800mg OD)  Meningitis preferred drug  Eye drops for fungal keratitis 34
    • 35. Itraconazole:    Broadest spectrum of activity also against aspergillus Fungistatic Pharmacokinetics:  50-60% bioavailability, absorption is variable, enhanced by food & gastric acidity  High protein binding 99 %  Well distributed accumulates in vaginal mucosa, skin, nails but CNS penetration is poor  Metabolized in liver CYP3A4 excreted in feces t1/2= 30- 64hr 35
    • 36.  Adverse events:   Dizziness, pruritis , headache, hypokalemia, hypotension  Increase plasma transaminase   GI Intolerance Rarely Hepatotoxicity Drug interactions:  Oral absorption decreased by antacids, H2 blockers  Rifampicin, phenytoin induce metabolism  Potentiates effect of hypnotic drugs  Inhibits CYP3A4 drug interaction profile similar to ketoconazole 36
    • 37.  Uses:  DOC for paracoccidomycosis & chromoblastomycosis  DOC for histoplasmosis & blastomycosis in AIDS patients  Esophageal, oropharyngeal vaginal candidiasis   Dermatophytosis: less effective than fluconazole   Not superior to fluconazole : 200 mg OD X 3 days 100- 200 mg OD X 15 days Onychomycosis : 200 mg / day for 3 months  Intermittent pulse regime 200 BD once weekly for 3 months equally effective  Aspergillosis: 200 mg OD/ BD with meals for 3 months or more 37
    • 38. Voriconazole:   High oral bioavailability, low protein binding  Good CSF penetration  Metabolized by CYP2C19  Doesn’t require gastric acidity for absorption   II generation triazole T1/2-6 hrs Uses:  DOC for invasive aspergillosis  Most useful for esophageal candidiasis  First line for moulds like fusarium  Useful in resistant candidal infections 38
    • 39. Dose : 200 mg BD  Adverse events:   Transient visual changes like blurred vision , altered color perception & photophobia  Rashes in 5 -6 %  Elevated hepatic enzymes  Prolongation of QT 39
    • 40. Cell wall synthesis inhibitor: Capsofungin  Introduced in 2000s.  Echinocandins  MOA: Inhibits- β-(1,3)-D-glucan  T½-9-11hrs.  P.B- albumin 97%  Excreted through urine(41%) and feces (35%)  Dose: IV infusion (intial 70mg slowly then 50mg/day) 40 »Contd.,
    • 41.  Active against wide variety of fungi.  Effective treatment for Aspergillus infection and Candidiasis (Esophageal, intra abdominal peritontis).  ADR: Sensation of warmth, flushing, rashes.  DI:- Cyclosporine hepatotoxicity. 41
    • 42. 5 Flucytosine   Prodrug, pyrimidine analogue, anti metabolite Mechanism of action Converted to 5 FU by FUNGAL CYTOSINE DEAMINASE  5FU  5FUTP RNA DEFECTIVE  5FU 5dUMP Inhibit Thymidylate synthesis  , Human cells cant convert it to 5FU  Adverse events:   Bone marrow toxicity , GIT , Alopecia, skin rashes, itching , rarely hepatitis
    • 43. 5-flucytosine permease 5-flucytosine (outside) (inside) Cytosine deaminase 5-fluorouracil 5dUMP (inhibits thymidylate synthase) RNA Phosphoribosyl transferase 5-FUMP
    • 44.  Uses: in combination with AMB in cryptococcal meningitis  ,  Advantages of combination: Entry of 5 FC  Reduced toxicity  Rapid culture conversion  Reduced duration of therapy & resistance 
    • 45. SYSTEMIC ALLY FOR TOPICAL INFECTIONS  Terbinafine: Orally & topically effective drug against candida & dermatophytes  Fungicidal : shorter courses of therapy required & low relapse rates  Mechanism of action:  Inhibition of Lanosterol + Ergosterol production  Pharmacokinetics:       Well absorbed orally 75% Highly keratophilic & lipophilic High protein bound , poor BBB permeability Metabolized in liver excreted in urine & feces t1/2- 15 days Negligible effect on CYP450
    • 46. Adverse events:  Nausea , vomiting , Diarrhoea  Taste disturbances  Rarely hepatic dysfunction  Topical: erythema , itching , dryness , urticaria, rashes Uses:  Dermatophytosis: topically/ orally 2- 6 weeks  Onychomycosis: first line drug 3- 12 months  Candidiasis: less effective 2- 4 weeks therapy may be used as alternative 250 mg OD
    • 47. Griseofulvin :  Systemic administration for topical infections  Fatty meal inc. BV  T1/2- 24hrs   Obtained from Pencillium griseofulvum   Fungistatic Drug binds to keratin in stratum corneum of the skin Mechanism of action:- Interact with polymerised microtubles causing disruptions of mitotic spindle and arrest mitosis metaphase 47
    • 48.  Uses:-  Dematophytosis caused by Microsporum  Trichophyton, Epidermatophyton  Duration of therapy depend open the body area  TINEA CORPORIS – 2-4 WEEKS    TINEA CAPITIS -4-6WEEKS TINEA PEDIS – 4-8 WEEKS Dose- 500-1000mg/day/in 2doses 48
    • 49. OTHER DRUGS  Ciclopirox olamine - may block amino acid transport - penetrates well - useful for Candida and dermatophytes  Haloprogin - useful for dermatophytes and Candida, may cause burning  Tolnaftate - useful for dermatophytes - inhibits synthesis of macromolecules  Undecylenic  KI acid - dermatophytes - taken orally for cutaneous sporotrichosis may cause a rash and irritation of salivary and lacrimal glands
    • 50. Disease 1st choice drugs 2nd choice drugs Candiasis oral/vaginal/cutaneous disseminated FLU/NYS/CLO AMB/VOR ITR FLU Cryptococcosis AMB+/- 5-FC FLU Histoplasmosis ITR/AMB FLU Coccidioidomycosis AMB/FLU ITR/KTZ Blastomycosis ITR/AMB KTZ/FLU Sporotrichosis AMB ITR Paracoccidioidomycosis ITR AMB Aspergillosis AMB/VORI ITR Mucormycosis AMB - Chromomycosis ITR VIJAY KTZ/5-FC 50
    • 51. Topical Ketoconazole Miconazole Clotrimazole Terbinafine Nystatin VIJAy Systemic administration Griseofulvin Ketoconazole Fluconazole Itraconazole Terbinafine 51
    • 52. SPECTRUM OF ACTION AMB 5FC KTZ FLU ITR Aspergillus -- -- -- Y Blastomycosis -- Y Y Y cryptococcus Y -- Y Y Coccidiodo -- Y Y Y candida Y Y Y Y Histoplasma -- Y Y Y Mucor -- -- -- -- Sporotrichosis -- -- Y Y chromoblast dermatophyte 52 Fusarium
    • 53. TOPICAL AZOLES  Clotrimazole  Terconazole  Miconazole  Sulconazole  Econazole  Tioconazole  Oxiconazole  Butoconazole  Sertaconazole
    • 54.  Nystatin: Candidiasis only  Griseofulvin: Dermatophytosis only  Terbinafine : Dermatophytosis & candidiasis  Caspofungin: Aspergillosis & candidiasis 54
    • 55. Some important characteristics:  Broad spectrum: AMB, KTZ, FLU, ITR  Resistance: 5 FC  Nephrotoxic/ Anemia: AMB  LEUCOPENIA: 5 FC  GIT upset: All  Over all toxicity: highest for AMB lowest for fluconazole, itraconazole 55
    • 56.  Grisofulvin K M C VIJAy For SYSTEMIC F I T Nystatin For Topical 56
    • 57. TH VIJAy 57

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