Antifungal drugs


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Pharmacology of antifungal drugs

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  • Name polyene is derived from highly double bonded structure
  • amphotericin B combines avidly with lipids (ergosterol) along the double bond-rich side of its structure and associates with water molecules along the hydroxyl-rich side. This amphipathic characteristic facilitates pore formation by multiple amphotericin molecules, with the lipophilic portions around the outside of the pore and the hydrophilic regions lining the inside. The pore allows the leakage of intracellular ions and macromolecules, eventually leading to cell death. Some binding to human membrane sterols does occur, probably accounting for the drug's prominent toxicity.
  • Dermatophytes are inhibited in vitro but conc of AMB attained inskin are low and ineffective
  • Bile salt –doc60% metabolized in liver, excretion occurs slowly in both urine and bile
  • Started at 0.3 mg/kg – 0.7 mg/kg , 1 mg test dose injected over 20 min to see acute reaction
  • Owing to its broad spectrum of activity and fungicidal action, amphotericin B remains a useful agent for nearly all life-threatening mycotic infections, although newer less toxic agents have largely replaced amphotericin B for most conditions. It is often used as the initial induction regimen in order to rapidly reduce fungal burden and is then replaced by one of the newer azole drugs (described below) for chronic therapy or prevention of relapse. Such induction therapy is especially important for immunosuppressed patients and those with severe fungal pneumonia, severe cryptococcal meningitis, or disseminated infections with one of the endemic mycoses such as histoplasmosis or coccidioidomycosis. Once a clinical response has been elicited, these patients then often continue maintenance therapy with an azole; therapy may be lifelong in patients at high risk for disease relapse. For treatment of systemic fungal disease, amphotericin B is given by slow intravenous infusion at a dosage of 0.5–1 mg/kg/d. It is usually continued to a defined total dose (eg, 1–2 g), rather than a defined time span, as used with other antimicrobial drugs.
  • ameliorated by slowing the infusion rate or decreasing the daily dose. Premedication with antipyretics, antihistamines, meperidine, or corticosteroids can be helpful. When starting therapy, many clinicians administer a test dose of 1 mg intravenously to gauge the severity of the reaction. This can serve as a guide to an initial dosing regimen and premedication strategy.
  • Used in superficialcandidiasis,
  • Torula, chromoblastomyces, candida some strains
  • Available as Cream, gel, spray, lotion, pessary ,. ( pedis, cruris, corporis, versicolor)
  • Most toxic among azoles so not used so much triazolespreferedAcidic environment favours absorption so orange juice increases absorption and proton pump inhibitors decrease absorption. But saturation of metabolism occurs shortly which prolongs the its half life and permits once daily dosing , since small amount of drug appears in urine it is not suitable for
  • Not used in fungal meningitis
  • Much less toxic than AMB but more side effects than fluconazole, itraconazoleNausea etc can be minimized by taking with food
  • Proton pump inhibitors : decrease absorption Rifampicin, phenytoin increase metabolism With sulfonylureas can cause hypoglycemia Nephrotoxicity can occur with cyclosporine H2 receptor blockers ↑ Srconc of cisapride, terfenadine, astemizole, quinidinePhenytoin toxicity Sulfonylureas: hypoglycemiaCyclosporine: nephrotoxicityWarfarin: bleeding Rifampicin, phenytoin ↑ metabolism of ketoconazoleShould not combine with AMB
  • 200 mg OD Also tried in dermal leshmaniasis
  • Oral candidiasis : fluconazole 200 mg on first day then 100 mg daily for atleast 2 weeksCryptococcosis: 400 mg daily 8 weeks after stabilization with amb , after 8 weeks dose is reduced to 200 mg for life aids related only Coccodiodal meningitis: drug of choice Fluconazole has activity against histoplasma, blasto, sporotrich , ring worm but efficacy less Nor against aspergillusAll azoles not against mucormycosis. Children doses = 3-6 mg/kg
  • Capsule form of drug better absorbed in fed state , invasive aspergillosis outside the CNSIN treating deep mycosis two 100 mg capsules given twice daily with food , divided doses increase the AUC WHY PULSE THERAPY: retention of active drug in nail keratin . Daily therapy prefered for recurring infection. Terbinbafine 250 mg OD better in onychomycosis than itraconazole
  • effective against candida & aspergillosis
  • Not effective in hyperkeratinized lesions like tineapedis , tineacapitis , tineaunginum as poor penetration , symptomatic relief occurs early with tolnaftate but if discontinued before fungal bearing tissue is shed relapses occur
  • Active against malasesseziafurfur
  • Antifungal drugs

    1. 1. Antifungal agents
    2. 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. 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. 4. Polyenes (Disrupt membrane structure & function)Azoles inhibit Flucytosine inhibits DNA synthesis
    5. 5. Caspofungin inhibitscell wall synthesis
    6. 6. Classification based on mechanism of action1. Fungal cell wall synthesis inhibition: Caspofungin.2. Bind to fungal cell membrane ergosterol: Amphotercin–B, Nystatin.3. Inhibition of ergosterol + lanosterol synthesis: Terbinafine, Naftifine, Butenafine.4. Inhibition of ergosterol synthesis: Azoles5. Inhibition of nucleic acid synthesis: 5–Flucytosine.6. Disruption of mitotic spindle and inhibition of fungal mitosis: Griseofulvin.7. Miscellaneous: • Ciclopirox, Tolnaftate, Haloprogin, Undecylenic acid, Topical azoles.
    7. 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. 8. Classification based on structure• ALLYLAMINES – Terbinafine, butenafine• ECHINOCANDINS – Caspofungin, anidulafungin, micafungin• OTHER TOPICAL AGENTS – Tolnaftate, Undecyclinic acid, benzoic acid
    9. 9. Polyene antibiotics• Amphotericin B: – Obtained from Streptomyces Nodosus – Amphoteric in nature Hydrophilic part Lactone ring Lipophilic part
    10. 10. Mechanism of action
    11. 11. Mechanism of action Amphotericin BBinds ergosterol in fungal cell membrane Form pores in cell membrane Cell contents leak out Cell death
    12. 12. Antifungal spectrum- Aspergillus- Blastomyces dermatitidis Broadest spectrum- Candida albicans of action- Cryptococcus neoformans- Coccidioides immitis Fungicidal at high & static at low conc.- Histoplasma capsulatum- Mucor spp.Also active against Leshmania
    13. 13. Mechanism of resistance• Resistance: – Replacement of ergosterol by other sterols in fungal plasma membrane. – Resistance is not a problem clinically.
    14. 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. 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. 16. Uses• Useful drug in nearly all life threatening mycotic infections• Treatment of invasive aspergillosis• Rapidly progressive Blastomycosis & Coccidiomycosis• Cryptococcus neoformans• Mucormycosis.• Disseminated rapidly progressing Histoplasmosis• Reserve drugs for resistant kala azar• Topical uses:
    17. 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. 18. Disadvantages of AMBSIDE AmphotericinAMB toxic EFFECTS OF B isNephrotoxicityAcute infusion related reactionsHypopotassemia, anemia, hepatic dysfunction..
    19. 19. Lıpıd formulations of amphotericin B Amphotericin B Lipid Complex(ABLC; Abelcet®) Amphotericin B Colloidal Dispersion(ABCD; Amphocil® or Amphotec®)Liposomal Amphotericin B(L-AMB; Ambisome®)
    20. 20. ABLC AMB Lipid complex (ABLC):35% AMB incorporated inribbon like particles ofdimyristoyl phospholipids Ribbon-like particles Carrier lipids: DMPC, DMPG J Liposome Res 1993; 3: 451
    21. 21. ABCDAMB colloidaldispersion (ABCD):Disc shapedparticlescontaining 50%each of AMB &cholesteryl ester in Disk-shapedaqueos dispersion particles Carrier lipid: Cholesteryl sulfate J Pharmaceutics 1991; 75: 45
    22. 22. The ‘LIPOSOME’..•Liposomal AMB (Smallunilamellar vesicles) :10% AMBincorporated inSUV made up oflecithin Lipid formulations: 20-50 times more expensive than AmB-deoxycholate Hospital Practice 1992; 30: 53
    23. 23. Major advantages of lipid AMB formulations Macrophage Milder acute reaction Liposome Lysosome Can be used in intolerance Fusion to conventional preparations Liposome degradation Lower nephrotoxicity & Endocytosis anemia Deliver AMB to RES of liver Endocytic vesicle speen so useful in leshmania Release in blood Release from & immunocompromised compartment macrophage Can be used in higher doses Liposomes in the therapy of infectious diseases and cancer 1989: 105
    24. 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. 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. 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. 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. 28. • Adverse events: – Headache most common – GIT disturbances – CNS symptoms: confusion, fatigue, vertigo – Peripheral neuritis – Rashes, photoallergy – Transient leukopenia, albuminuria
    29. 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. 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. 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. 32. Advantages of combination:–Entry of 5 FC–Reduced toxicity–Rapid culture conversion–Reduced duration of therapy–Decreased resistance
    33. 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. 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. 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. 36. Mechanism of action: Terbinafine Squalene Ѳ squalene 2,3 epoxide Lanosterol Ѳ Azoles 14 α demethylaseErgosterol
    37. 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. 38. Ketoconazole– First orally effective broad spectrum antifungal– Effective against • Dermatophytosis, Deep mycosis , Candidiasis
    39. 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. 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. 41. Drug Interactions
    42. 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. 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. 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. 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. 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. 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. 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. 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. 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. 51. Triazoles Itraconazole Fluconazole- Varied absorption. - Completely absorbed and Metabolized by cyt P450 better tolerated, Renal excretion- less endocrine effects but - Less endocrine effects occur at high doses - Penetrates well into CSF- Less penetration in CSF- Many drug interactions - Drug Interactions (due to inhibition of CYT P450/ 3A4)
    52. 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. 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. 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. 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. 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. 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. 58. Topical agents used in dermatophytosis• 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
    59. 59. Topical agents used in dermatophytosis• 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)
    60. 60. Topical agents used in dermatophytosis• Quinidiochlor; – Luminal amoebicide – Weak antifungal & antibacterial – External application : dermatophytosis , mycosis barbae, pitryasis versicolor• Selenium sulfide: T versicolor• Potassium iodide: Dermatophytic infection
    61. 61. Systemic TopicaladministrationGriseofulvin KetoconazoleKetoconazole MiconazoleFluconazole ClotrimazoleItraconazole TerbinafineTerbinafine Nystatin
    62. 62. Spectrum of actionAMB 5FC KTZ FLU ITRAspergillus -- -- -- YBlastomycosis -- Y Y Ycryptococcus Y -- Y YCoccidiodo -- Y Y Ycandida Y Y Y YHistoplasma -- Y Y Y mucor -- -- -- --Sporotrichosis -- -- Y Y chromoblast dermatophyte Fusarium
    63. 63. Spectrum of action• Nystatin: Candidiasis only• Griseofulvin: Dermatophytosis only• Terbinafine : Dermatophytosis & candidiasis• Caspofungin: Aspergillosis & candidiasis
    64. 64. 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