Presentation on theme: "Anti-fungal agents Fungal infections to a large extent are iatrogenic in nature. Fungal infections are associated with the use of broad spectrum antibiotic,"— Presentation transcript:
1 Anti-fungal agentsFungal infections to a large extent are iatrogenic in nature.Fungal infections are associated with the use of broad spectrum antibiotic, indwelling catheters, AIDS.Poor penetration of the drug because fungus infects poorly vascularized.
2 Anti-fungal agentsEukaryotic nature of fungus – resembling human cell makes it difficult treat.Fungus cell wall contains ergosterol whereas mammalian cell contains cholesterol.
9 Anti-fungal agents Amphotericin B : It is active against wide range : Aspergillosis, Candida albicans, Cryptococcus neoformans, Coccidioides immitis, Histoplasma, MucormycosisIt is active against Naegleria fowleri and Leishmaniasis
10 Anti-fungal agents Amphotericin B : Pharmacokinetics It is not absorbed orallyHalf life is ~ 15 daysMetabolized in liver and excreted in urine and bileRelatively safe in pregnancy.
11 Anti-fungal agents Amphotericin B : It can be given intravenously and intrathecallyNew formulations have reduced nephrotoxicityABCD – amphotericin B colloidal dispersionABLC -- amphotericin B lipid complex
12 ABCD – amphotericin B colloidal dispersion is a lipid formulation of amphotericin B.the major goal of developing ABCD has been to attain a compound with:lower toxicityat least similar efficacy compared to the parent compound, amphotericin B deoxycholate.ABCD is composed of amphotericin B complexed with cholesteryl sulfate.
13 ABLC -- amphotericin B lipid complex ABLC is composed of amphotericin B complexed with dymyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol..
14 Anti-fungal agents Amphotericin B : Adverse reactions : INFUSION-RELATED TOXICITY Acute reactions (immediate reactions)– related to the infusion of the drug: Fever and chills, muscle spasms, vomiting, headache, and hypotensionCUMULATIVE TOXICITY Long term - Nephrotoxicity, anemia, CNS toxicity
15 Anti-fungal agents Amphotericin is used in : Aspergillosis CoccidioidomycosisCryptococcosisCandidiasisHistoplasmosisMucormycosis
16 Flucytosine is a fluorinated pyrimidine Flucytosine is taken up by fungal cells via the enzyme cytosine permease.It is converted intracellularly first to 5-FU and then to 5-fluorodeoxyuridine monophosphate (FdUMP) and fluorouridine triphosphate (FUTP), which inhibit DNA and RNA synthesis, respectively.
18 Anti-fungal agents Flucytosine : Fungi static blockade of fungal DNA synthesisSelectivity occurs because mammalian cells do not accumulate and do not deaminate flucytosineWell absorbed orally and penetrates into CSF.
21 Anti-fungal agents Flucytosine : Therapeutic uses Candida infections ( in combination with amphotericin B)Cryptococcal meningitis ( in combination with amphotericin B)Chromoblastomycocis ( in combination with Itraconazole )
23 Anti-fungal agents Ketoconazole : First orally effective broad spectrum azole anti-fungal agent.Mechanism of action :It inhibits C -14 demethylase thus blocking the demethylation of lanosterol to ergosterol – sterol of fungal membrane.
25 Anti-fungal agents Ketoconazole : Gastric acidity promotes absorption. Hepatic metabolism is extensive and metabolites are excreted mainly in bile.CNS penetration is poor.
26 Anti-fungal agents Ketoconazole : Replaced by Itraconazole Anti-fungal spectrumCandidia, Coccidioides, Blastomyces, Histoplasma.Active against dermatophytes also
27 Anti-fungal agents Ketoconazole : adverse effects : Nausea and vomiting.Hepatitis.Hair loss, gynaecomastia, loss of libido, Oligospermia -- decrease androgen production.Menstrual irregularities in women due to decreased estradiol synthesis.
28 Anti-fungal agents Ketoconazole : adverse effects : Disulfiram like reaction with alcohol.It inhibits gonadal and steroid synthesis.It inhibits cyto P450 – dangerous interaction with astemizole, terfenadine and cisapride – resulting in ventricular fibrillation.
29 Anti-fungal agents Fluconazole : Not active against dermatophytes It has good activity against – Cryptococcus, Coccodioides, Candidiasis.Oral absorption is very good – not dependent on gastric acidityFungicidal concentration in CNS, saliva and nails.
30 Anti-fungal agents Fluconazole : adverse effects Nausea, skin rash HepatitisIt does not inhibit androgen synthesisInhibit cyto P 450 metabolizing drugsNot recommended for pregnant women.
32 Anti-fungal agents Itraconazole : Broad spectrum than fluconazole – includes Aspergillus, Blastomyces, Histoplamosis, Tinea, Sporotrichosis.Inhibits cyto P450 like ketoconazoleCNS penetration is poorImpotence is common
33 Anti-fungal agents Voriconazole : Broad spectrum includes aspergillosis.Orally well absorbedGood tissue distribution including – CNSVisual disturbance is the limitation.
34 Anti-fungal agents Clotrimazole : Effective for topical treatment of tinea infectionsoral, vaginal and cutaneous candidiasis respond to itMiconazole :effective for tinea, pityriasis Versicolor, candidiasis
35 Anti-fungal agents Griseofulvin : It is obtained from penicillium griseofulvumIt is active against Dermatophytes – Epidermatophyton, Trichophyton and Microsporum
36 Anti-fungal agents Griseofulvin : Mechanism of action It gets deposited in the keratin forming cells of the skin, hair and nails – especially concentrated and retained in the tinea infected cells – disruption of mitotic spindles - thus interferes with mitosis.Newly formed keratin is not invaded by the fungus
37 Anti-fungal agents Griseofulvin : Pharmacokinetics : Absorption from the GIT is irregular – better with ultramicrofine granulesBetter absorption with high fat mealsIt is an inducer of liver enzymes
38 Anti-fungal agents Griseofulvin : It is used only for the DermatophytesBody skin weeks Palm and Soles – 6 weeks Finger nails – 6 months Toe nails – 12 months
39 Anti-fungal agents Griseofulvin : Headache is the common complaint Peripheral neuritis and LeucopeniaPotentiates the intoxicating effects of alcohol.
40 Anti-fungal agents Terbinafine : Fungicidal Active against dermatophytes and candidiasisShort course of therapy and relapse is poorIt acts as a non competitive inhibitor of squalene epoxidase – in the ergosterol synthesis
45 Anti-fungal agents NYSTATIN : It is very toxic when given systemically and used only for local anti-fungal effectIt is not absorbed orallyUsed only for oral candidiasis - locally
46 Anti-fungal agents Caspofungin : It is the first approved of EchinocandinsIt interferes with the synthesis of fungal cell wall by inhibiting the synthesis of beta ( 1,3 ) D – glucan, leading to cell lysis.Specific for aspergillus and Candida.Excreted by urine and fecesAvailable for intravenous use only.
47 Anti-fungal agents Other topical anti-fungal agents : Tolnaftate : effective drug for dermatophytes and tinea versicolorCiclopirox : used for tinea infections, pityriasis versicolor and candidiasisBenzoic acid : anti-fungal agents and anti-bacterial property .Salicylic acid : acts as keratolytic action
48 Histoplasma capsulatum FungiDiseases Drug(s) of choiceCandida speciesMucocutaneous thrushMiconazole Nystatin (topical)FluconazoleDeep infectionAmphotericin B ±flucytosineCoccidioides immitisRapid progressingAmphotericin BMeningitisHistoplasma capsulatumPulmonaryItraconazole
49 Blastomyces dermatitidis Itraconazole Paracoccidioide brasiliensisCutaneous and disseminatedAspergillus fumigatusInvasiveAmphotericin BCryptococcus neoformansInitialAmphotericin B + FlucytosineMaintenanceFluconazole