Antifungal drugs

Pharmacology of antifungal drugs

1. Antifungal agents

2. Yeasts Fungi may be classified as Moulds Yeasts: Blastomyces , candida , histoplasma , coccidioides , cryptococcus . Moulds: Aspergillus spp. Dermatophytes, mucor Superficial mycosis Clinically classified as: Deep (systemic) mycosis

3. Systemic fungal infections: Systemic candidiasis : RTI with progressive dimunition Cryptococcal meningitis, endocarditis Rhinocerebral mucormycosis Pulmonary aspergillosis Blastomycosis ( pneumonitis , with dissemination) Histoplasmosis (cough , fever, multiple pneumonic infiltrates) Coccidiodomycosis Pnemocystis carinii pneumonia

4. Azoles inhibit Polyenes (Disrupt membrane structure & function) Flucytosine inhibits DNA synthesis

5. Caspofungin inhibits cell wall synthesis

6. Classification based 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 .

7. Classification based on structure ANTIBIOTICS Polyene : Amphotericin , nystatin , hamycin Hetrocyclic benzofuran : griseofulvin ANTIMETABOLITE : Flucytosine AZOLES Imidazoles : Ketoconazole , clotrimazole , oxiconazole , miconazole , Triazoles: Fluconazole, itraconazole, voriconazole,

8. ALLYLAMINES Terbinafine, butenafine ECHINOCANDINS Caspofungin, anidulafungin, micafungin O THER TOPICAL AGENTS Tolnaftate , Undecyclinic acid, benzoic acid Classification based on structure

9. Polyene antibiotics Amphotericin B: Obtained from Streptomyces Nodosus Amphoteric in nature Lactone ring Lipophilic part Hydrophilic part

10. Mechanism of action

11. Mechanism of action Amphotericin B Binds ergosterol in fungal cell membrane Form pores in cell membrane Cell contents leak out Cell death

12. Antifungal spectrum Aspergillus Blastomyces dermatitidis Candida albicans Cryptococcus neoformans Coccidioides immitis Histoplasma capsulatum Mucor spp . Also active against Leshmania Broadest spectrum of action Fungicidal at high & static at low conc.

13. Mechanism of resistance Resistance: Replacement of ergosterol by other sterols in fungal plasma membrane. Resistance is not a problem clinically.

14. Pharmacokinetics Poorly absorbed orally Insoluble in water so colloidal suspension prepared with sodium deoxycholate (1:1 complex) 90% bound to plasma proteins Metabolized in liver slowly excreted in urine t ½ = 15 days

15. Administration & dose Systemic mycosis: IV Available as 50mg vial – suspended in 10 ml water and then diluted with 500 ml glucose 0.5mg/kg to 1 mg/kg Total dose- 3-4 gm over 2-3 months Intestinal Monoliasis : 50-100 mg QID Orally Vaginitis : topical Otomycosis : 3 % drops Intrathecal : 0.5 mg BD in fungal meningitis

16. Useful drug in nearly all life threatening mycotic infections Treatment of invasive aspergillosis Rapidly progressive Blastomyc osis & Coccidio mycosis Cryptococcus neoformans Mucor mycosis . Disseminated rapidly progressing Histoplasm osis Reserve drugs for resistant kala azar Topical uses: Uses

17. Adverse events: Acute reaction: Chills, fever, headache, pain all over, nausea, vomiting, dyspnoea lasting 2-5 hrs because of release of IL & TNF can be treated with hydrocortisone 0.6mg/kg Long term toxicity: Nephrotoxicity: Azotemia , Hypokalemia, acidosis, ↓ GFR anemia CNS toxicity : intrathecal administration, headache, vomiting, nerve palsies Hepatotoxicity rarely

18. Disadvantages of AMB Amphotericin B is toxic SIDE EFFECTS OF AMB Nephrotoxicity Acute infusion related reactions Hypopotassemia, anemia, hepatic dysfunction..

19. Lıpıd formulations of amphotericin B (ABLC; Abelcet ® ) (ABCD; Amphocil ® or Amphotec ® ) (L-AMB; Ambisome ® ) Amphotericin B Lipid Complex Amphotericin B Colloidal Dispersion Liposomal Amphotericin B

20. ABLC Ribbon-like particles Carrier lipids: DMPC, DMPG J Liposome Res 1993; 3: 451 A MB Lipid complex (ABLC): 35% AMB incorporated in ribbon like particles of dimyristoyl phospholipids

21. ABCD Disk-shaped particles Carrier lipid: Cholesteryl sulfate J Pharmaceutics 1991; 75: 45 AMB colloidal dispersion (ABCD): Disc shaped particles containing 50% each of AMB & cholesteryl ester in aqueos dispersion

22. The ‘LIPOSOME’.. Hospital Practice 1992; 30: 53 Liposomal AMB (Small unilamellar vesicles) : 10% AMB incorporated in SUV made up of lecithin Lipid formulations: 20-50 times more expensive than AmB-deoxycholate

23. Milder acute reaction Can be used in intolerance to conventional preparations Lower nephrotoxicity & anemia Deliver AMB to RES of liver speen so useful in leshmania & immunocompromised Can be used in higher doses Major advantages of lipid AMB formulations Liposomes in the therapy of infectious diseases and cancer 1989: 105 Release from macrophage Macrophage Release in blood compartment Endocytosis Liposome Lysosome Fusion Liposome degradation Endocytic vesicle

24. Nystatin Obtained from S.Noursei 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 Prevention of oral candidiasis Can be used in oral, cutaneous , conjunctival candidiasis Adverse events: Gastointestinal disturbances with oral tablets

25. Hamycin : S. Pimprina Hindustan antibiotics pimpri More water soluble, fraction absorbed orally but unreliable in systemic infections Topical use in thrush, cutaneous candidiasis , trichomonas & monilial vaginitis , otomycosis by aspergillus Natamycin : Similar to nystatin , broad spectrum Used topically 1%, 3% ointment Fusarium solani keratitis , trichomonas & monilial vaginitis

26. Griseofulvin One of early antibiotics from penicillium griseofulvum Fungistatic, systemic drug for superficial fungal infections Active against most dermatophytes Dermatophytes concentrate it actively hence selective toxicity Resistance: loss of concentrating ability

27. Mechanism of action: Griseofulvin interacts with polymerized microtubules and disrupts the mitotic spindles thus arresting fungal mitosis Pharmacokinetics: Oral administration, irregular absorption, increased by fatty food and microfine particles Gets conc in keratinized tissue Metabolized in liver, excreted in urine,t1/2=24 hrs

28. Adverse events: Headache most common GIT disturbances CNS symptoms: confusion, fatigue, vertigo Peripheral neuritis Rashes, photoallergy Transient leukopenia , albuminuria

29. Uses: Systemically only for dermatophytosis , ineffective topically Systemic azoles more effective and preferred Duration of treatment depends on site, thickness of keratin and turnover of keratin. Treatment must be continued till infected tissue is completely replaced by normal skin,hair , nail. Dose: 125-250 mg QID

30. Duration of treatment Body skin = 3 weeks Palm, soles = 4- 6 weeks Finger nails = 4- 6months Toe nails = 8 – 12 months Griseofulvin should be reserved for nail hair or larger body surface involvement Interactions: Warfarin , OCP Phenobarbitone , Disulfiram like reaction

31. 5 flucytosine Prodrug, pyrimidine analog, antimetabolite Converted to 5 FU Human cells cant convert it to 5FU Adverse events: Bone marrow toxicity , GIT , Alopecia, skin rashes, itching , rarely hepatitis Uses: in combination with AMB in cryptococcal meningitis Narrow spectrum of action

32. Advantages of combination: Entry of 5 FC Reduced toxicity Rapid culture conversion Reduced duration of therapy Decreased resistance

33. Differences between AMB & 5 FC AMB = Active drug, broad spectrum, antibiotic, fungicidal Not absorbed, high protein binding, no BBB, metabolized in liver, highly efficacious, IV,Intrathecal,topical

34. Azoles: Synthetic antifungals Broad spectrum Fungistatic or fungicidal depending on conc of drug Most commonly used Classified as imidazoles & triazoles Imidazoles : Two nitrogen in structure Topical: econazole , miconazole , clotrimazole Systemic : ketoconazole Newer : butaconazole , oxiconazole , sulconazole

35. Triazoles : Three nitrogen in structure Fluconazole, itraconazole, voriconazole Terconazole: Topical for superficial infections Both these groups are Structurally related compounds Have same mechanism of action Have similar antifungal spectrum

36. Ergosterol 14 α demethylase Ѳ Azoles squalene 2,3 epoxide Ѳ Lanosterol Squalene Terbinafine Mechanism of action:

37. Miconazole & clotrimazole Topical use: Miconazole 2 % and clotrimazole 1 % applied BD for 2 weeks in pityriasis versicolor , 4 weeks in cruris , capitis and corporis Uses: Dermatophyte infections Candida: oral pharyngeal, vaginal, cutaneous Adverse events: Local irritation , itching or burning Miconazole shows higher incidence of vaginal irritation & pelvic cramps

38. Ketoconazole First orally effective broad spectrum antifungal Effective against Dermatophytosis , Deep mycosis , Candidiasis

39. Pharmacokinetics Effective orally acidic environment favours absorption High protein binding Readily distributed, not to BBB Metabolized in liver, excreted in bile t1/2 = 8- 10 hrs Dose : 200 mg OD or BD

40. Adverse events Nausea , vomiting , anorexia Headache , paresthesia, alopecia ↓ steroid, testosterone & estrogen synthesis Gynaecomastia , oligospermia , loss of libido & impotence in males Menstrual irregularities & amenorrhoea in females Elevation of liver enzymes Hypersensitivity reaction - skin rashes, itching

41. Drug Interactions

42. Uses Dermatophytosis : conc in stratum corneum Monilial vaginitis : 5-7 days Systemic mycosis: blastomycosis , histoplasmosis , coccidiodomycosis Less efficacy than AMB & slower response ↓ Efficacy in immunocompromized and meningitis Lower toxicity than AMB higher than triazoles High dose used in cushings syndrome Topical: T.pedis , cruris , corporis , versicolor

43. Fluconazole Newer water soluble triazole Oral, IV as well as topical Broad spectrum antifungal activity Candida, cryptococcosis , coccidiodomycosis Dermatophytosis Blastomycosis Histoplasmosis Sporotrichosis Not effective against aspergillosis & mucormycosis

44. Pharmacokinetics 94% oral bioavailability Not affected by food or gastric pH Primarily excreted unchanged in urine t1/2 = 25 -30 hrs Poor protein binding Widely distributed crosses BBB

45. Adverse events GIT upset Headache, alopecia, skin rashes, hepatic necrosis Teratogenic effect CYP450 Enzyme inhibiting property less Interactions : Effects hepatic drug metabolism to lesser extent than Ketoconazole H2 blockers & PPI do not effect its absorption No anti androgenic & other endocrine effects

46. Uses Candida: 150 mg oral dose can cure vaginal candidiasis with few relapse Oral candidiasis - 2 weeks treatment required Tinea infections & cutaneous candidiasis : 150 mg weekly for 4 weeks, tinea unguim : 12 months systemic fungal infections: Disseminated candidiasis , cryptococcal , coccidiodal meningitis 200-400 mg / day 4- 12 weeks or longer Meningitis: preferred drug Eye drops for fungal keratitis

47. Itraconazole Broadest spectrum of activity also against aspergillus Fungistatic but effective in immunocompromised Does not inhibit steroid hormone synthesis and no serious hepatoxicity

48. 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

49. Uses DOC for paracoccidomycosis & chromoblastomycosis DOC for histoplasmosis & blastomycosis Esophageal, oropharyngeal vaginal candidiasis Not superior to fluconazole : 200 mg OD X 3 days Dermatophytosis : less effective than fluconazole 100- 200 mg OD X 15 days Onychomycosis : 200 mg / day for 3 months Intermittent pulse regime 200 BD once a week / month for 3 months equally effective Aspergillosis : 200 mg OD/ BD with meals for 3 months or more

50. Adverse events GI Intolerance Dizziness, pruritis , headache , hypokalemia Increase plasma transaminase Rarely hepatotoxicity Drug interactions: Oral absorption ↓ by antacids, H2 blockers Rifampicin , phenytoin induce metabolism Inhibits CYP3A4 drug interaction profile similar to ketoconazole

51. Triazoles Itraconazole Varied absorption. Metabolized by cyt P450 less endocrine effects but occur at high doses Less penetration in CSF Many drug interactions (due to inhibition of CYT P450/ 3A4) Fluconazole Completely absorbed and better tolerated, Renal excretion Less endocrine effects Penetrates well into CSF Drug Interactions

52. Voriconazole II generation triazole High oral bioavailability, low protein binding Good CSF penetration Metabolized by CYP2C19 Doesn’t require gastric acidity for absorption T1/2= 6 hrs Uses: DOC for invasive aspergillosis Most useful for esophageal candidiasis First line for moulds like fusarium Useful in resistant candida infections

53. Dose and Adverse effects 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

54. Terbinafine Orally & topically effective drug against candida & dermatophytes Fungicidal : shorter courses of therapy required & low relapse rates Mechanism of action: Pharmacokinetics: Well absorbed orally 75% Highly keratophilic & lipophilic High protein bound , poor BBB permeability t1/2- 15 days Negligible effect on CYP450

55. Adverse events and uses 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

56. Caspofungin acetate Semisynthetic antifungal MOA: Inhibits B (1,3) D glucan an essential component of fungal cell wall Uses: Treatment of invasive aspergillosis & candidiasis (esophageal, intraperitoneal ) Dose: IV 70 mg slowly then 50 mg daily infusion Adverse events: Flushing rashes , nausea, vomiting, phlebitis

57. Topical agents used in dermatophytosis Tolnaftate : Tinea, cruris , corporis , 1- 3 weeks treatment Not effective in hyperkeratinized lesions Salicylic acid aids its effect by keratolysis Ciclopirox olamine : Tinea infections, pitryasis versicolor ,dermal candidiasis , vaginal candidiasis Penetrates superficial layers Acts by inhibiting membrane uptake of precursors of macromolecules needed for fungal growth

58. Undecyclenic acid: 5% ( Tineafax ) Generally combined with zinc (20%) Requires prolonged treatment has high relapse rate Weaker antifungal action used in tinea cruris and nappy rash Sodium thiosulfate : ( Karpin lotion) Reducing agent known as hypo Effective in pitryasis versicolor only 20 % solution for 3-4 weeks Topical agents used in dermatophytosis

59. Benzoic acid: Used in combination with salicylic acid Whitfields ointment: ( benzoic acid 6% + salicyclic acid 3 %) Salicyclic acid due to its keratolytic action helps to remove infected tissue & promotes penetration of benzoic acid in fungal infected lesion Adverse events: irritation & burning sensation (Ring cutter ointment) Topical agents used in dermatophytosis

60. Quinidiochlor ; Luminal amoebicide Weak antifungal & antibacterial External application : dermatophytosis , mycosis barbae , pitryasis versicolor Selenium sulfide: T versicolor Potassium iodide: Dermatophytic infection Topical agents used in dermatophytosis

61. Systemic administration Topical Griseofulvin Ketoconazole Ketoconazole Miconazole Fluconazole Clotrimazole Itraconazole Terbinafine Terbinafine Nystatin

62. Spectrum of action AMB 5FC KTZ FLU ITR Asp ergillus -- -- -- 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 Fusarium

63. Nystatin: Candidiasis only Griseofulvin: Dermatophytosis only Terbinafine : Dermatophytosis & candidiasis Caspofungin: Aspergillosis & candidiasis Spectrum of action

64. 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 Important characteristics