Antifungal agents

very used for master of pharmacy education level

1. RECENT ADVANCE TREAT FUNGAL INFECTIONS SUBMITTED TO- SUBMITTED BY- Dr .SUDIPTA SAHA ANAND KUMAR M.PHARM (PHARMACOLOGY) FIRST YEAR DEPARTMENT OF PHARMACEUTICAL SCIENCES

2. ANTIFUNGAL AGENTS ANTIFUNGAL AGENTS-: Drugs used to treat infection caused by fungi or systemic and topical infections FUNGI-: Very large and diverse group of micro-organism Fungi are eukaryotic, heterotrophic organisms that live as saprobes or parasites Consist of Cell wall (chitin) homopolymer of N- acetylglucogamine Cell memb contains Ergosterol & Zymiosterol TYPES OF FUNGI -: (1) Yeasts (2) Mould (3)Dimorphic Single cell fungi,ovoid or spherical shape Multicellular characterized Have growth characteristic of both Reproduce by budding & devision By ong , broching filament Called -hyphae Form mycelium At body temp glow as yeast in host tissue Baking At ambient temp glow as mold in saprophytic,free living state Alcohalic beverages

3. FUNGAL INFECTIONS TYPES-: Superficial : Affect skin – mucous membrane Tinea versicolor Dermatophytes : affect keratin layer of skin, hair, nail. e.g.tinea pedis , ring worm infection Candidiasis : Yeast-like, oral thrush, vulvo -vaginitis , nail infections. Deep (Disseminated) Infections : Affect internal organs as : lung ,heart , brain leading to pneumonia , endocarditis , meningitis. FACTORS WHICH INCRESED RISK FUNGS GROWTH Use broad spectrum antibiotics which destroy normal flora which complete fungi Immunocompromized Immunosuppressant Anticancers Increased International travelling Pregnacy Diabetes Oral contraceptics

4. CLASSIFICATION ON MECHANISM OF ACTION Fungal cell wall synthesis inhibition: Caspofungin . Bind to fungal cell membrane ergosterol : Amphotercin –B, Nystatin . Inhibition of ergosterol + lanosterol synthesis: Terbinafine , Naftifine , Butenafine . Inhibition of ergosterol synthesis: Azoles Inhibition of nucleic acid synthesis: 5– Flucytosine . Disruption of mitotic spindle and inhibition of fungal mitosis: Griseofulvin . Miscellaneous: Ciclopirox , Tolnaftate , Haloprogin , Undecylenic acid, Topical azoles .

5. CLASSIFICATION ON CHEMICAL STRUCTURE ANTIBIOTICS Polyene : AmphotericinB ( S.nodosus ) N ystatin ( S.noursei ) H amycin ( S.pimprina ) E chinocandins : Caspofungin ( Glarea lozoyesis ) A nidulafungin ( Aspergillus nidulans ) M icafungin ( Coleophoma empedri ) Hetrocyclic benzofuran : G riseofulvin ( Penicillium griseofulvum ) ANTIMETABOLITE : Flucytosine

6. AZOLES Imidazoles : (Topical) -: Ketoconazole , Clotrimazole O xiconazole , Miconazole Triazoles : ( Syastemic ) -: Fluconazole , I traconazole , V oriconazole , Posaconazole ALLYLAMINES Terbinafine, B utenafine O THER TOPICAL AGENTS Tolnaftate , Undecyclinic acid, Benzoic acid, Quidinochlor Sod.thiosuphate , Ciclofirox olamine

7. AMPHOTERICIN -B Antifungal agent with the broadest spectrum of activity Produced by Streptomyces nodosus . Natural, Amphoteric polyene macrolide – Amphoteric = can react as an acid as well as a base polyene = many double bonds macrolide = containing a large lactone ring Heptaene macrolide - large lactone ring with multiple ketone and hydroxyl group) Drug of choice for the vast majority of life-threatening systemic fungal infections Interacts with ergosterols , forms pores that increase membrane permeability and allow leakage of intracellular ions & macromolecules from fungal cell ( cell death ). Carbohydrade moiety is D- mycosamine and trans is active form

8. AmB -ADME Poorly absorbed orally, useful for fungal infection of gastrointestinal tract. For systemic infections given as slow I/V infusion. Locally used in corneal ulcers, arthritis and candidial bladder irrigation Highly protein bound - > 90% Penetration through BBB is poor but increases in inflamed meninges. Excreted slowly via kidneys , traces found in urine for months after cessation of drugs. Half life 15 days

9. Routes of Administration For AmB Slow IV infusion for systemic fungal disease. Intrathecal for fungal CNS infections. Topical drops & direct subconjunctival injection for Mycotic corneal ulcers & keratitis. Local injection into the joints in fungal arthritis.

10. Therapeutic Uses - AmB Aspergillosis Candidiasis, invasive Candidiasis, mucosal Cryptococcosis Coccidioidomycosis Blastomycosis Histoplasmosis Mucormycosis Penicilliosis Phaeohyphomycosis Sporotrichosis Cryptococcosis (in combination therapy) Second-line : Candidiasis

11. RECENT ADVANCE AmB FEATURE ABLC ABCD AmBisome Lipid components DMPC,DMPG Cholesteryl sulfate Phosphatidyl choline,Cholesterol,Distearoyl phosphatidy glycerol Structure Ribbon of lipid with AmB attached Discoid structure with AmBattached Unilamellar liposomes with AmB inside Toxicity 8-10 time less toxic 8-10 time less toxic 70-80 time less toxic Safety profile Preservation of renal function Preservation of renal function <5% preservation Efficacy response in humans 69% overall 78%candidiasis 60%aspergillosis 59% overall 83%candidiasis 67% candidiasis 86%aspergillosis Trade name Abelcet Amphocil AmBisome DMPC-: Dimyristoyl phosphatidyl choline DMPG-: Dimyristoyl phosphatidyl glcerol

12. Liposomal preparations of AmphotericinB

13. SIDE EFFECTS

14. NYSTATIN (MYCOSTATIN) Bacteria l origin. Isolated from Streptomyces noursei Polyene macrolide ,similar in structure & mechanism to amphotericin B. Too toxic for systemic use. Used only topically - available as creams, ointment , suppositories & other preparations. Topicallyactive against Candida albicans on skin, GIT ,vaginal

15. FLUCYTOSINE Synthetic, water soluble, fluorinated pyrimidine analog Often used in combination with amphotericin B and Itraconazole Spectrum of antigungal activity is considerably less than that of amphotericin B. Amphotericin B increases cell permeability , allowing more 5-FC to penetrate the cell, they are synergistic Fungistatic Has useful activity against Candida and Cryptococcus. Acts by inhibiting synthesis of fungal DNA

16. FLUCYTOSINE MOA

17. Flucytosine – Adverse effects Hematologic : Leukopenia, thrombocytopenia, bone marrow depression Allergic: Rash, nausea, vomiting, diarrhea, and enterocolitis Hepatic : Elevation in hepatic transaminases but this reverses when therapy is stopped. Toxicity is more frequent in patients with AIDS or azotemia. Alopecia

18. WHAT IS AZOLE Bivalent chemical group composed of five-membered organic rings Broad spectrum of activity - Antibacterial, antiprotozoal, anthelminthic and antifungal . Group of synthetic fungistatic agents Classification: according to the number of nitrogen atoms attached to the ring Imidazoles (2 nitrogen atoms): Ketoconazole, Miconazole , Econazole , Clotrimazole , Bifonazole Triazoles (3 nitrogen atoms): Itraconazole , Fluconazol , Vorionazole → systemic treatment

19. AZOLES MOA Inhibit the fungal cytochrome P450 enzyme Responsible for converting lanosterol to ergosterol ( the main sterol in fungal cell membrane ).

20. Azoles - antifungal activity Cryptococci, Blastomyces , Histoplasma capsulatum , Coccidioides , Paracoccidioides brasiliensis , and dermatophytes . Aspergillus spp., Scedosporium , apiospermum ( Pseudallescheria boydii ), Fusarium , and Sporothrix schenckii are intermediate in susceptibility. C. krusei and the agents of mucormycosis are resistant.

21. Imidazole – Ketoconazole- ADME Well absorbed orally as acidic environment favors its dissolution. Bioavailability is impaired with food. Cola drinks improve its absorption in patients with achlorhydria . Metabolized extensively in liver and inactive products appear in the feces. Moderate hepatic dysfunction has no effect on drug concentration. 84 % is bound to plasma proteins. Half life increases with dose It does not enter CSF.

22. Imidazole – Ketoconazole – Adverse Effects Inhibits adrenal and gonadal steroids which leads to menstrual irregularities, loss of libido, impotency and gynaecomastia in males. Efficacy is poor in immunosuppressed patients and in meningitis. Hepatotoxic - rare but may prove fatal. Dose dependant nausea, anorexia ,vomiting Hair loss Fluid retention and hypertension. Not used in Pregnancy, lactation ,hepatic dysfunction

23. Decrease in the ergosterol in the fungal membrane By K etoconazle reduces the fungicidal action of AmphotericinB

24. Ketoconazole is not useful for fungal infections of UT as level of parent drug in urine is very low

25. Azole Antifungals- Triazoles Damage the fungal cell membrane by inhibiting enzyme desmethylase They are selective Penetrate to CNS Resistant to degradation Cause less endocrine disturbance. Fluconazole, itraconazole , voriconazole

26. Itraconazole It is a synthetic triazole , new drug Lacks endocrine side effects of ketoconazole. Broad spectrum activity Metabolized in liver to active metabolite Highly lipid soluble ,well distributed to bone, sputum, adipose tissues. Can not cross BBB

27. Itraconazole - ADME Food increases its absorption Metabolized in liver extensively It is highly lipid soluble and well distributed to bone, sputum and adipose tissue. Highly bound to plasma protein Half life is 30-40 hours Does not penetrate CSF adequately The capsule is better absorbed with food, but the oral solution is better absorbed in the fasting state

28. Itraconazole - Therapeutic Uses Dermatophytose Onychomycosis - For deep mycoses Histoplasmosis : It easily penetrate CSF and is a drug of choice in cryptococcal meningitis and coccido mycosis Cryptococcosis : meningitis

29. Itraconazole – Adverse Effects Interact with many drugs Interactions can cause serious toxicity Fatal cardiac arrhythmias. Congestive heart failure in patients with impaired ventricular function. Hepatic failure and death. If symptoms of hepatotoxicity occur, the drug should be discontinued and liver function assessed. Anaphylaxis and severe rash have rarely occurred . GI distress Chemical phlebitis

30. Griseofulvin Fungistatic in vitro for various species of dermatophytes . Inhibits fungal mitosis Entirely local action, no systemic absorption Obtain from Penicillium griseofulvum Deposited in keratin precursor cells and persists in keratin to provide prolonged resistance to fungi. The new growth of hair or nails is the first to become free of disease. As the fungus-containing keratin is shed, it is replaced by normal tissue . Sweat and transepidermal fluid loss play important roles in drug transfer to the stratum corneum . Only a very small fraction of the drug is present in body fluids and tissues.

31. Griseofulvin - Uses Mycotic infections of the hair ( tinea capitis ) Tinea of the hands and beard “Athlete’s foot” or epidermophytosis involving the skin and nails Not effective in treatment of subcutaneous or deep mycoses

32. Griseofulvin – adverse effects Headache, GI symptoms (e.g., nausea, vomiting, diarrhea, heartburn, flatulence), and rash. More serious reactions include hepatotoxicity, serum sickness reaction, angioedema, and hematologic effects (e.g., leukopenia, neutropenia, punctate basophilia , and monocytosis ). Blood should be checked weekly during treatment. Estrogen-like effects have been observed in children.

33. RECENT ADVANCE ANTIFUNGAL DRUGS DRUGS TARGETED DISEASE PRE-CLINICAL STAGES Aminocandin First line therapy against invasive fungal infections Novamycin Bloodstream and deep tissue infections caused by Candida and other clinically relevant yeasts and moulds PHASE -I CLINICAL TRIAL IN COMPLETED Recombinant Protein Vaccine(NDV-3) Recurrent Vulvovaginal Candidiasis Virosome Formulated Anti- CandidaVaccine (PEV7) Administered by the vaginal (PEV7C) or intramuscular (PEV7B) route to healthy adult volunteers. Being developed for recurrent Vulvovaginal Candida infection

34. DRUGS TARGETED DISEASE PHASE – II CLINICAL TRIAL COMPLETED VT-1161 Acute vulvovaginal candidiasis Luliconazole Distal subungual onychomycosis MOB015 Distal subungual onychomycosis Albaconazole Distal subungual Onychomycosis Novexatin Topical brush-on treatment for onychomycosis PHASE- III CLINICAL TRIAL COMPLETED Isavuconazole Primary treatment of patients with invasive aspergillosis Treatment of Candidemia and other invasive Candida infections Glucocorticoid Allergic bronchopulmonary Aspergillosis

35. ECHINOCANDIDINS Caspofungin is a semisynthetic lipopeptide . It inhibits the synthesis of beta -(1, 3)D- glucan , a cell wall component of filamentous fungi. Caspofungin is approved for the treatment of invasive aspergillosis and candida SIDE EFFECTS Phlebitis Hypokalemia Rash Vomiting Joint pain

36. BUTENAFINE AND TERBINAFINE Its Allylamine compound A cts as a non-competitive inhibitor of squalene epoxidase an early atep enzyme in ergosterol biosynthesis by fungi Accumulation of squalene within fungal cells to be responsible for fungicidal Butenafine is only topically used

37. POSACONAZOLE Inhibit the fungal cytochrome P450 enzyme Responsible for converting lanosterol to ergosterol ( the main sterol in fungal cell membrane More potent broad spectrum antifungal activity SIDE EFFECTS Nausea Vomiting Abdominal pain Loose motion Headach Dizziness Drowsiness

38. Topical Antifungal Agents Topical azole derivatives Nystatin & Amphotericin Terbinafine Tolnaftate Naftifine Griseofulvin Haloprogin Undecylenic acid (DESENEX) Benzoic acid and Salicylic acid Natamycin ( S.natalensis )

39. REFERANCE Tripathi KD Essential of Medical pharmacology seventh edition publishe by jaypee brothers Goodman & Gilman’s The pharmacological Basis of Therapeutics 12 edition

40. THANK YOU