Anti fungal agents

Anti-fungal Agents

1. ANTIFUNGAL AGENTS By: Mrs. Kalaivani Sathish M. Pharm Assistant Professor, PIMS - PANIPAT Dr Mrs Borkar 1

2. Fungi are eukaryotic, heterotrophic organisms that live as saprobes or parasites . Complex organisms in comparison to bacteria . Have nucleus and well defined nuclear membrane, and chromosomes. Have rigid cell wall composed of chitin (bacterial cell wall is composed of peptidoglycan ) Fungal cell membrane contains ergosterol , human cell mebmrane is composed of cholesterol Antibacterial agents are not effective against fungi. Fungal infections are also called as mycoses ANTIFUNGAL AGENTS Introduction 2 Dr Mrs Borkar

3. ANTIFUNGAL AGENTS Systemic fungal infections are a major cause of death in patients whose immune system is compromised cancer or its chemotherapy , organ transplantation HIV-1 infection. Superficial infections of the skin and other soft tissue structures. Antifungal agents target distinctive components of the fungal cell membrane others alter cell wall synthesis nucleic acid synthesis Introduction 3 Dr Mrs Borkar

4. 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 Infections : Affect internal organs as : lung ,heart , brain leading to pneumonia , endocarditis , meningitis. ANTIFUNGAL AGENTS Types of Fungal Infections 4 Dr Mrs Borkar

5. Disrupt fungal cell membrane Polyenes – amphotericin , Nystatin Azoles Imidazole – Ketoconazole , Miconazole , Clotrimazole Triazole – Fluconazole , Itraconazole Allylamines - Terbinafin Echinocandins - Capsofungin Inhibit mitosis - Gresiofulvin Inhibit DNA synthesis - Flucytosine Miscellaneous Tolnaftate Cyclopirox ANTIFUNGAL AGENTS Mechanism of action of Antifungal agents 5 Dr Mrs Borkar

6. Membrane function Amphotericin B Cell Wall Synthesis Capsofungin Nucleic acid synthesis Flucytosine Ergosterol synthesis Azoles Lanosterol synthesis Terbinafine 6 Dr Mrs Borkar

7. 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 ). ANTIFUNGAL AGENTS Amphotericin B 7 Dr Mrs Borkar

8. Broad range of pathogenic fungi Protozoa , Leishmania braziliensis and Naegleria fowleri No antibacterial activity Amphotericin A & B are antifungal antibiotics. Amphotericin A is not used clinically. ANTIFUNGAL AGENTS Amphotericin B 8 Dr Mrs Borkar

9. Mechanism of action of Amphotericin 9 Dr Mrs Borkar

10. 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 ANTIFUNGAL AGENTS Amphotericin - ADME 10 Dr Mrs Borkar

11. Amphotericin ADME 11 Dr Mrs Borkar

12. 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. Bladder irrigation in Candiduria . ANTIFUNGAL AGENTS Routes of Administration 12 Dr Mrs Borkar

13. Packaged in a lipid- associated delivery system which acts as a reservoir Large doses can be administered – 5 times Reduces binding to human cell membrane Clinically have more efficacy , less nephrotoxicity More expensive ANTIFUNGAL AGENTS Amphotericin – Liposomal Preparations 13 Dr Mrs Borkar

14. Liposomal preparations of Amphotericin 14 Dr Mrs Borkar

15. Usual dose is 0.5–0.6 mg/kg , administered in 5% glucose over 4 hours Candida esophagitis , Rapidly progressive mucormycosis or invasive aspergillosis . Coccidioides meningitis : Intrathecal infusion ; started with twice weekly schedule , increased to thrice weekly and continued on twice-weekly schedule. Treatment of cryptococcal meningitis, Severe or rapidly progressing histoplasmosis , blastomycosis , coccidioidomycosis , penicilliosis marneffei , invasive aspergillosis , extracutaneous sporotrichosis , fusariosis , alternariosis , and trichosporonosis . Given once weekly to prevent relapse in patients with AIDS who have been treated successfully for cryptococcosis or histoplasmosis . ANTIFUNGAL AGENTS Amphotericin B - Therapeutic Uses and Dosage 15 Dr Mrs Borkar

16. Major acute reaction to intravenous is fever and chills, which typically end spontaneously in ~30 minutes and often abate with subsequent infusions. T achypnea and modest hypotension may occur, but true bronchospasm or anaphylaxis is rare. Hypotension and hypoxia in preexisting cardiac or lung disease Prophylactic use of IV glucocorticoids decreases reaction Transient azotemia occurs in 80% of patients Kidney function may be affected if other nephrotoxic agents like aminoglycoside are used concurrently. Administration of 1 L of NS IV prior to amphotericin B administration is recommended for adults who can tolerate the Na+ load . Azotemia occurs less frequently with lipid preparations of amphotericin , and saline loading is not needed. ANTIFUNGAL AGENTS Amphotericin B - Adverse effects 16 Dr Mrs Borkar

17. Hypochromic , normocytic anemia is usual and reverses slowly following cessation of therapy . It is due decreased production of erythropoietin and often responds to erythropoietin . Headache , nausea, vomiting, malaise, weight loss, and phlebitis at peripheral infusion sites are common. Arachnoiditis , manifested by fever and headache, can occur with intrathecal injection; it may be decreased by intrathecal administration of 10–15 mg of hydrocortisone. Local i njections of amphotericin B into a joint or peritoneal dialysate fluid commonly produce irritation and pain. ANTIFUNGAL AGENTS Amphotericin B - Adverse effects 17 Dr Mrs Borkar

18. Immediate reactions ( Infusion –related toxicity ). Fever, muscle spasm, vomiting ,headache, hypotension. Can be avoided by : Slowing the infusion Decreasing the daily dose Premedication with antipyretics, antihistamincs or corticosteroids. test dose . Slower Reactions: Most serious is renal toxicity (nearly in all patients ). Hypokalemia Hypomagnesaemia Impaired liver functions Anemia, Thrombocytopenia ANTIFUNGAL AGENTS Amphotericin B - Adverse effects 18 Dr Mrs Borkar

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20. 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 ANTIFUNGAL AGENTS Flucytosine 20 Dr Mrs Borkar

21. Absorbed rapidly and well from the GI tract, widely distributed Minimally bound to plasma proteins. Penetrates well into CSF . Mainly excreted unchanged through kidney Half life drug normally is 3–6 hours but may reach 200 hours in renal failure. Dose modification is necessary in renal dysfunction plasma concentrations should be measured periodically Flucytosine is cleared by hemodialysis and peritoneal dialysis ANTIFUNGAL AGENTS Flucytosine - ADME 21 Dr Mrs Borkar

22. Given orally at 100 mg/kg/day, in 4 divided doses and is used predominantly in combination with amphotericin B . Severe deep fungal infections as in meningitis Cryptococcal meningitis : begin with amphotericin B plus flucytosine and change to fluconazole after the patient has improved. There is the risk of amphotericin induecd azotemia and flucytocine dose has to be reduced in this situation otherwise the combination will cause bone marrow suppression or colitis ANTIFUNGAL AGENTS Flucytosine – Uses 22 Dr Mrs Borkar

23. 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 ANTIFUNGAL AGENTS Flucytosine – Adverse effects 23 Dr Mrs Borkar

24. Bacteria l origin. Isolated from Streptomyces noursei in 1950 by Elizabeth Lee Hazen and Rachel Fuller Brown,. Polyene macrolide ,similar in structure & mechanism to amphotericin B. Too toxic for systemic use. Used only topically - available as creams, ointment , suppositories & other preparations. Not significantly absorbed from skin, mucous membrane, GIT s o little significant toxicity. ANTIFUNGAL AGENTS Nystatin / Nysfungin 24 Dr Mrs Borkar

25. Prevent or treat superficial candidiasis of mouth, esophagus, intestinal tract . Oral suspension of 100,000 U/ml 4 times a day and tablets 500,000 U are used to decrease GIT colonization with Candida Vaginal candidiasis - pessaries used for 2 weeks Can be used in combination with antibacterial agents & corticosteroids In Cutaneous infection available in cream, ointment or powder form and applied 2-3 times a day ANTIFUNGAL AGENTS Nystatin / Nysfungin – Clinical uses 25 Dr Mrs Borkar

26. 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 ANTIFUNGAL AGENTS Azole Antifungals 26 Dr Mrs Borkar

27. 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 . ANTIFUNGAL AGENTS Azole - antifungal activity 27 Dr Mrs Borkar

28. Inhibit the fungal cytochrome P450 enzyme Responsible for converting lanosterol to ergosterol ( the main sterol in fungal cell membrane ). ANTIFUNGAL AGENTS Azole Antifungals - Mechanism of Action 28 Dr Mrs Borkar

29. Contain 2 Nitrogen atoms attached to the ring Reduc e the formation of ergosterol in the cell membrae which become permeable to cellular constituents. They lack selectivity , and also inhibits human gonadal and steroid synthesis leading to decreased testosterone and cortisol production Ketoconazole , miconazole , clotrimazole , isoconazole , Tioconazole ANTIFUNGAL AGENTS Azole Antifungals - Imidazoles 29 Dr Mrs Borkar

30. Mechanism of action Ketoconazole 30 Dr Mrs Borkar

31. 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. ANTIFUNGAL AGENTS Imidazole – Ketoconazole - ADME 31 Dr Mrs Borkar

32. 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 ANTIFUNGAL AGENTS Imidazole – Ketoconazole – Adverse Effects 32 Dr Mrs Borkar

33. Decrease in the ergosterol in the fungal membrane By ketoconazle reduces the fungicidal action of amphotericin 33 Dr Mrs Borkar

34. Used topically or systematic (oral route only ) to treat Oral & vaginal candidiasis . Dermatophytosis . Systemic mycoses & mucocutaneous candidiasis . ANTIFUNGAL AGENTS Imidazole – Ketoconazole – Clinical uses 34 Dr Mrs Borkar

35. Ketoconazole is not useful for fungal infections of UT as level of parent drug in urine is very low 35 Dr Mrs Borkar

36. Bioavailability is low by taking orally. Used topically. Absorption less than 0.5 % from intact skin, 3-10 % from vagina Activity in vagina remains for 3 days. Stigma , erythema , edema, vesication , pruritus , urticaria mild vaginal burning sensation may occour . Cure dermatophytes , cutaneous candidiasis and vulvovaginal candidiasis ANTIFUNGAL AGENTS Imidazole – Clotrimazole 36 Dr Mrs Borkar

37. 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 ANTIFUNGAL AGENTS Azole Antifungals - Triazoles 37 Dr Mrs Borkar

38. It is a synthetic triazole , new drug Lacks endocrine side effects of ketoconazole . Broad spectrum activity Administered orally as well as I/V. Food increases its absorption Metabolized in liver to active metabolite Highly lipid soluble ,well distributed to bone, sputum, adipose tissues. Can not cross BBB ANTIFUNGAL AGENTS Azole antifungals – Itraconazole 38 Dr Mrs Borkar

39. 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 ANTIFUNGAL AGENTS Itraconazole - ADME 39 Dr Mrs Borkar

40. ANTIFUNGAL AGENTS Azole antifungals – Itraconazole - Therapeutic Uses Available as a capsule and solutions for oral or intravenous administration Oral solution is 60% more bioavailable than the capsules IV only in serious infections. Dose – Cap 200 to 400 mg/day doses exceeding 200 mg/day are given in 2 divided doses Loading dose: 200 mg 3 times daily can be given for the first 3 days The only agent with significant activity against aspergillus species It can safely be administered prophylactically in patients receiving bone marrow transplants 40 Dr Mrs Borkar

41. Dermatophytoses and onychomycosis . Onychomycosis - 200 mg daily after food for 3 months For deep mycoses , loading dose of 200 mg three times daily for 3 days. Thereafter, two 100-mg capsules are given twice daily with food. Histoplasmosis : AIDS-associated histoplasmosis maintainance therapy - 200 mg once daily It easily penetrate CSF and is a drug of choice in cryptococcal meningitis and coccido mycosis Cryptococcosis : 400 mg daily for 8 weeks in meningitis, In AIDS 200 mg for life. ANTIFUNGAL AGENTS Azole antifungals – Itraconazole - Therapeutic Uses 41 Dr Mrs Borkar

42. Itraconazole solution - for oropharyngeal and esophageal candidiasis . Taken fasting in a dose of 100 mg once daily and swished vigorously in the mouth before swallowing to optimize topical effect. 100 mg of the solution twice a day for 2–4 weeks. Candidiasis : 200 mg on 1st day then 100 mg daily for 2 weeks. Not effective in aspergillosis . Used orally in dermatophytosis & vulvo -vaginal candidiasis . ANTIFUNGAL AGENTS Azole antifungals – Itraconazole - Therapeutic Uses 42 Dr Mrs Borkar

43. 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. ANTIFUNGAL AGENTS Itraconazole – Adverse Effects 43 Dr Mrs Borkar

44. Relative to capsules, the oral solution of itraconazole more frequently causes diarrhea, abdominal cramps, anorexia, and nausea. Intravenous itraconazole has all the adverse effects of capsules but generally is well tolerated. Chemical phlebitis : dedicated catheter port is required, Infusion durations >1 hour are recommended. Intravenous formulation is contraindicated in patients with a creatinine clearance <30 mL /min. ANTIFUNGAL AGENTS Itraconazole – Adverse Effects 44 Dr Mrs Borkar

45. The adverse effects are related to dose and duration of use In the absence of interacting drugs, itraconazole capsules are well tolerated at 200 mg daily. GI distress occurs with use of 300 mg/day or more In patients receiving 50–400 mg/day, nausea and vomiting, hypertriglyceridemia , hypokalemia , elevated serum aminotransferases , and rash occurred in few patients Doses of 300 mg twice daily have led to adrenal insufficiency, lower limb edema, hypertension, and rhabdomyolysis Doses above 400 mg/day are not recommended for long-term use ANTIFUNGAL AGENTS Itraconazole – Adverse Effects 45 Dr Mrs Borkar

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47. It is fluorinated bistriazole . The widest therapeutic index of the azoles. Excellent bioavailability by oral route. Bioavailability not altered by food or gastric acidity Not hepatotoxic It can safely be administered prophylactically in patients receiving bone marrow transplants. Maximum excretion by kidney Half life is 25-30 hours. ANTIFUNGAL AGENTS Fluconazole - ADME 47 Dr Mrs Borkar

48. Fluconazole is almost completely absorbed from the GI tract irrespective of food or gastric acidity. Concentration in plasma is same by oral or I/v route. Only 10% of drug in circulation is protein bound. Readily diffuses into body fluids, including breast milk, sputum, saliva, and CSF. ANTIFUNGAL AGENTS Fluconazole - ADME 48 Dr Mrs Borkar

49. Tablets for oral administration Powde r for oral suspension Intravenous solutions containing 2 mg/ mL . Dosage is 50–800 mg once daily for oral or intravenous administration. Children are treated with 3–6 mg/kg once daily ANTIFUNGAL AGENTS Fluconazole - Dosage 49 Dr Mrs Borkar

50. Candidiasis - 200 mg on the first day and then 100 mg daily for at least 2 weeks, in oropharyngeal candidiasis . single dose of 150 mg is effective in uncomplicated vaginal candidiasis . 400 mg daily in deep candidiasis in allogeneic bone marrow transplant recipients Systemic fungal infections 400-800 mg q24h > 800 mg q24h in unstable patient Maintenance for cryptococcal meningitis - 400 mg/day, for the initial 8 weeks in the treatment in AIDS after the patient has been stabilized with intravenous amphotericin B. ANTIFUNGAL AGENTS Fluconazole - Uses 50 Dr Mrs Borkar

51. Nausea and vomiting at doses >200 mg/day Headache , skin rash, abdominal pain, and diarrhea Reversible alopecia may occur with prolonged therapy Rare deaths due to hepatic failure or Stevens-Johnson syndrome have occurred. Highly teratogenic : Associated with skeletal and cardiac deformities in infants born to women taking high doses during pregnancy and should be avoided during pregnancy ANTIFUNGAL AGENTS Fluconazole – Adverse effects 51 Dr Mrs Borkar

52. Fungistatic in vitro for various species of dermatophytes . Inhibits fungal mitosis 52 Dr Mrs Borkar ANTIFUNGAL AGENTS Griseofulvin

53. Entirely local action, no systemic absorption Micronized and ultramicronized powders are used to facilitate dissolution Half life in plasma of ~1 day. 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. Griseofulvin is detectable in the stratum corneum within 4–8 hours of oral administration. 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. 53 Dr Mrs Borkar ANTIFUNGAL AGENTS Griseofulvin - ADME

54. 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 54 Dr Mrs Borkar ANTIFUNGAL AGENTS Griseofulvin - Uses

55. 5–15 mg/kg for children 0.5–1 g for adults in 4 divided doses Severe infections: 1.5–2 g daily for short periods Best results are obtained Treatment must be continued until infected tissue is replaced by normal hair, skin, or nails , which requires 1 month for scalp and hair ringworm, 6–9 months for fingernails, and at least a year for toenails . 55 Dr Mrs Borkar ANTIFUNGAL AGENTS Griseofulvin - Dosage

56. 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 . 56 Dr Mrs Borkar ANTIFUNGAL AGENTS Griseofulvin – adverse effects

57. Topical treatment is useful in superficial fungal infections confined to the stratum corneum , squamous mucosa, or cornea, including dermatophytosis (ringworm), candidiasis , tinea versicolor , piedra , tinea nigra , and fungal keratitis. Unsuccessful for mycoses of the nails ( onychomycosis ) and hair ( tinea capitis ) No place in subcutaneous mycoses, such as sporotrichosis and chromoblastomycosis . Efficacy of topical agents depends not only on the type of lesion and the mechanism of drug action, but also on the viscosity, hydrophobicity, and acidity of the formulation. 57 Dr Mrs Borkar ANTIFUNGAL AGENTS Topical Antifungal Agents

58. Regardless of formulation, penetration of topical drugs into hyperkeratotic lesions often is poor . Removal of thick, infected keratin may be a useful adjunct to therapy. Preferred formulations are Creams Solutions Powders , whether applied by shake containers or aerosols , largely are used for the feet and moist lesions of the groin and other intertriginous areas 58 Dr Mrs Borkar ANTIFUNGAL AGENTS Topical Antifungal Agents

59. Topical azole derivatives Nystatin & Amphotericin Terbinafine Tolnaftate Naftifine Griseofulvin 59 Dr Mrs Borkar ANTIFUNGAL AGENTS Topical Antifungal Agents

60. Used in superficial fungal infections: Dermatophytosis ( ring worm) Candidiasis Fungal keratitis . Not effective in mycoses of the nails & hair or subcutaneous mycoses. Preferred formulation for cutaneous application is cream or solution. 60 Dr Mrs Borkar ANTIFUNGAL AGENTS Topical Antifungal Agents

61. Indications for topical use include tinea corporis tinea pedis tinea cruris tinea versicolor cutaneous candidiasis . Agents for topical use should be selected based on cost and availability. They are applied twice daily for 3–6 weeks. Preparations for cutaneous use are effective for 61 Dr Mrs Borkar ANTIFUNGAL AGENTS Topical Antifungal Agents - Azoles