anti-fungal agents fungal infections to a large extent are iatrogenic in nature. fungal infections...

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Anti-fungal agents Anti-fungal agents Fungal infections to a large Fungal infections to a large extent are iatrogenic in nature. extent are iatrogenic in nature. Fungal infections are associated Fungal infections are associated with the use of broad spectrum with the use of broad spectrum antibiotic, indwelling catheters, antibiotic, indwelling catheters, AIDS. AIDS. Poor penetration of the drug Poor penetration of the drug because fungus infects poorly because fungus infects poorly vascularized. vascularized.

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Anti-fungal agentsAnti-fungal agents

Fungal infections to a large extent Fungal infections to a large extent are iatrogenic in nature.are iatrogenic in nature.

Fungal infections are associated with Fungal infections are associated with the use of broad spectrum antibiotic, the use of broad spectrum antibiotic, indwelling catheters, AIDS.indwelling catheters, AIDS.

Poor penetration of the drug because Poor penetration of the drug because fungus infects poorly vascularized.fungus infects poorly vascularized.

Anti-fungal agentsAnti-fungal agents

Eukaryotic nature of fungus – Eukaryotic nature of fungus – resembling human cell makes it resembling human cell makes it difficult treat.difficult treat.

Fungus cell wall contains ergosterol Fungus cell wall contains ergosterol whereas mammalian cell contains whereas mammalian cell contains cholesterol.cholesterol.

 

Drugs for Subcutaneous / Systemic Fungal infections

Polyene antibiotics Amphotericin BEchinocandinsCaspofunginPyrimidine antimetabolitesFlucytosineAzoles Ketoconazole, Fluconazole, Itraconazole 

Drugs for Superficial Fungal infections

Systemic drugsTerbinafineGriseofulvin

Topical drugsNystatinAzoles (miconazole, econazole, butaconazole, clotrimazole)Terbinafine

Anti-fungal agentsAnti-fungal agents

Amphotericin B :Amphotericin B : It is obtained from It is obtained from streptomyces streptomyces

nodosus.nodosus. It has double bonds on one side – It has double bonds on one side –

lipid solublelipid soluble. It has OH on other - . It has OH on other - water solublewater soluble

They have amino and carboxyl They have amino and carboxyl group.group.

Anti-fungal agentsAnti-fungal agents

Amphotericin B : Amphotericin B :

Mechanism of action :Mechanism of action : It has affinity for ergosterol present It has affinity for ergosterol present

in the cell membrane and forms a in the cell membrane and forms a micropore thus disrupt the micropore thus disrupt the membrane function and cell death.membrane function and cell death.

Anti-fungal agentsAnti-fungal agents

Amphotericin B :Amphotericin B : It is active against wide range : It is active against wide range :

Aspergillosis, Candida albicans, Aspergillosis, Candida albicans, Cryptococcus neoformans, Cryptococcus neoformans, Coccidioides immitis, Histoplasma, Coccidioides immitis, Histoplasma, MucormycosisMucormycosis

It is active against It is active against Naegleria fowleri Naegleria fowleri and and LeishmaniasisLeishmaniasis

Anti-fungal agentsAnti-fungal agents

Amphotericin B : Amphotericin B : PharmacokineticsPharmacokinetics

It is not absorbed orallyIt is not absorbed orally Half life is ~ 15 daysHalf life is ~ 15 days Metabolized in liver and excreted in Metabolized in liver and excreted in

urine and bileurine and bile Relatively safe in pregnancy.Relatively safe in pregnancy.

Anti-fungal agentsAnti-fungal agents

Amphotericin B :Amphotericin B : It can be given intravenously and It can be given intravenously and

intrathecallyintrathecally New formulations have reduced New formulations have reduced

nephrotoxicity nephrotoxicity

ABCD – ABCD – aamphotericinmphotericin BB ccolloidal olloidal ddispersionispersion ABLC -- ABLC -- aamphotericin mphotericin BB llipid ipid ccomplexomplex

ABCDABCD – – aamphotericinmphotericin BB ccolloidal olloidal ddispersionispersion

is a lipid formulation of amphotericin B. is a lipid formulation of amphotericin B. the major goal of developing ABCD has the major goal of developing ABCD has

been to attain a compound with: been to attain a compound with: – lower toxicity lower toxicity

– at least similar efficacy compared to the at least similar efficacy compared to the parent compound, amphotericin B parent compound, amphotericin B deoxycholate.deoxycholate.

ABCD is composed of amphotericin B ABCD is composed of amphotericin B complexed with cholesteryl sulfate.complexed with cholesteryl sulfate.

ABLC -- ABLC -- aamphotericin mphotericin BB llipid ipid ccomplexomplex

ABLC is composed of amphotericin B ABLC is composed of amphotericin B complexed with dymyristoyl complexed with dymyristoyl phosphatidylcholine and dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol.. phosphatidylglycerol..

Anti-fungal agentsAnti-fungal agents

Amphotericin B : Adverse Amphotericin B : Adverse reactions :reactions :

A.A. INFUSION-RELATED TOXICITYINFUSION-RELATED TOXICITY Acute reactions (immediate reactions)– related Acute reactions (immediate reactions)– related to the infusion of the drug: Fever and chills, to the infusion of the drug: Fever and chills, muscle spasms, vomiting, headache, and muscle spasms, vomiting, headache, and hypotensionhypotension

B. CUMULATIVE TOXICITY Long term - Nephrotoxicity, anemia, CNS Long term - Nephrotoxicity, anemia, CNS toxicitytoxicity

Anti-fungal agentsAnti-fungal agents

AmphotericinAmphotericin is used in : is used in : AspergillosisAspergillosis CoccidioidomycosisCoccidioidomycosis CryptococcosisCryptococcosis CandidiasisCandidiasis HistoplasmosisHistoplasmosis MucormycosisMucormycosis

FlucytosineFlucytosine is a fluorinated is a fluorinated pyrimidinepyrimidine

Flucytosine is taken up by fungal cells via Flucytosine is taken up by fungal cells via the enzyme cytosine permease. the enzyme cytosine permease.

It is converted intracellularly first to 5-FU It is converted intracellularly first to 5-FU and then to 5-fluorodeoxyuridine and then to 5-fluorodeoxyuridine monophosphate (FdUMP) and monophosphate (FdUMP) and fluorouridine triphosphate (FUTP), which fluorouridine triphosphate (FUTP), which inhibit DNA and RNA synthesis, inhibit DNA and RNA synthesis, respectively.respectively.

Anti-fungal agentsAnti-fungal agents

Flucytosine : Flucytosine : Fungi staticFungi static blockade of fungal DNA synthesisblockade of fungal DNA synthesis Selectivity occurs because Selectivity occurs because

mammalian cells do not accumulate mammalian cells do not accumulate and do not deaminate flucytosineand do not deaminate flucytosine

Well absorbed orally and penetrates Well absorbed orally and penetrates into CSF.into CSF.

Anti-fungal agentsAnti-fungal agents

Flucytosine : Flucytosine : Antifungal spectrumAntifungal spectrum

Cryptococcus neoformans Cryptococcus neoformans Candida albicans Candida albicans ChromoblastomycosisChromoblastomycosis

Anti-fungal agentsAnti-fungal agents

Flucytosine :Flucytosine : Adverse effectsAdverse effects Reversible bone marrow depression Reversible bone marrow depression

( leukopenia, ( leukopenia, thrombocytopenia)thrombocytopenia)

Liver dysfunction Liver dysfunction Enterocolitis - rareEnterocolitis - rare

Anti-fungal agentsAnti-fungal agents

Flucytosine :Flucytosine : Therapeutic usesTherapeutic uses Candida infections Candida infections ( in combination with ( in combination with

amphotericin B)amphotericin B) Cryptococcal meningitis Cryptococcal meningitis ( in combination ( in combination

with amphotericin B)with amphotericin B)

Chromoblastomycocis Chromoblastomycocis ( in combination ( in combination with Itraconazole )with Itraconazole )

Anti-fungal agentsAnti-fungal agents

Azoles :Azoles : mainly fungistatic in nature mainly fungistatic in nature Ketoconazole, Fluconazole, Ketoconazole, Fluconazole,

Itraconazole, VoriconazoleItraconazole, Voriconazole Clotrimazole, Econazole, MiconazoleClotrimazole, Econazole, Miconazole

Anti-fungal agentsAnti-fungal agents

Ketoconazole :Ketoconazole : First orally effective broad spectrum First orally effective broad spectrum

azole anti-fungal agent. azole anti-fungal agent.

Mechanism of action :Mechanism of action : It inhibits C -14 demethylase It inhibits C -14 demethylase

thus blocking the demethylation of thus blocking the demethylation of lanosterol to ergosterol – sterol of lanosterol to ergosterol – sterol of fungal membrane.fungal membrane.

Anti-fungal agentsAnti-fungal agents

Ketoconazole :Ketoconazole : Gastric acidity promotes absorption. Gastric acidity promotes absorption. Hepatic metabolism is extensive and Hepatic metabolism is extensive and

metabolites are excreted mainly in metabolites are excreted mainly in bile.bile.

CNS penetration is poor.CNS penetration is poor.

Anti-fungal agentsAnti-fungal agents

Ketoconazole : Ketoconazole : Replaced by Replaced by ItraconazoleItraconazole

Anti-fungal spectrumAnti-fungal spectrum Candidia, Coccidioides, Blastomyces, Candidia, Coccidioides, Blastomyces,

Histoplasma.Histoplasma. Active against dermatophytes alsoActive against dermatophytes also

Anti-fungal agentsAnti-fungal agents

Ketoconazole : adverse effects :Ketoconazole : adverse effects : Nausea and vomiting.Nausea and vomiting. Hepatitis.Hepatitis. Hair loss, gynaecomastia, loss of Hair loss, gynaecomastia, loss of

libido, Oligospermia -- decrease libido, Oligospermia -- decrease androgen production. androgen production.

Menstrual irregularities in women Menstrual irregularities in women due to decreased estradiol synthesis.due to decreased estradiol synthesis.

Anti-fungal agentsAnti-fungal agents

Ketoconazole : adverse effects :Ketoconazole : adverse effects : Disulfiram like reaction with alcohol.Disulfiram like reaction with alcohol. It inhibits gonadal and steroid It inhibits gonadal and steroid

synthesis.synthesis. It inhibits cyto P450 – dangerous It inhibits cyto P450 – dangerous

interaction with astemizole, interaction with astemizole, terfenadine and cisapride – resulting terfenadine and cisapride – resulting in ventricular fibrillation.in ventricular fibrillation.

Anti-fungal agentsAnti-fungal agents

Fluconazole : Fluconazole : Not active against Not active against dermatophytesdermatophytes

It has good activity against – It has good activity against – Cryptococcus, Coccodioides, Cryptococcus, Coccodioides, Candidiasis.Candidiasis.

Oral absorption is very good – not Oral absorption is very good – not dependent on gastric aciditydependent on gastric acidity

Fungicidal concentration in CNS, Fungicidal concentration in CNS, saliva and nails.saliva and nails.

Anti-fungal agentsAnti-fungal agents

Fluconazole : adverse effects Fluconazole : adverse effects Nausea, skin rashNausea, skin rash Hepatitis Hepatitis It does not inhibit androgen synthesisIt does not inhibit androgen synthesis Inhibit cyto P 450 metabolizing drugsInhibit cyto P 450 metabolizing drugs Not recommended for pregnant Not recommended for pregnant

women.women.

Anti-fungal agentsAnti-fungal agents

Fluconazole : Uses :Fluconazole : Uses : Candidiasis Disseminated. Candidiasis Disseminated. Cryptococcal meningitis.Cryptococcal meningitis. Coccidioidomycosis.Coccidioidomycosis.

Anti-fungal agentsAnti-fungal agents

Itraconazole :Itraconazole : Broad spectrum than fluconazole – Broad spectrum than fluconazole –

includes Aspergillus, Blastomyces, includes Aspergillus, Blastomyces, Histoplamosis, Histoplamosis, Tinea,Tinea, Sporotrichosis. Sporotrichosis.

Inhibits cyto P450 like ketoconazoleInhibits cyto P450 like ketoconazole CNS penetration is poorCNS penetration is poor Impotence is commonImpotence is common

Anti-fungal agentsAnti-fungal agents

Voriconazole :Voriconazole :

Broad spectrum includes aspergillosis.Broad spectrum includes aspergillosis.

Orally well absorbedOrally well absorbed

Good tissue distribution including – Good tissue distribution including – CNSCNS

Visual disturbance is the limitation.Visual disturbance is the limitation.

Anti-fungal agentsAnti-fungal agents

Clotrimazole :Clotrimazole : Effective for topical treatment of Effective for topical treatment of

tinea infectionstinea infections oral, vaginal and cutaneous oral, vaginal and cutaneous

candidiasis candidiasis respond to itrespond to it

Miconazole :Miconazole :

effective for tinea, pityriasis effective for tinea, pityriasis Versicolor, candidiasisVersicolor, candidiasis

Anti-fungal agentsAnti-fungal agents

Griseofulvin :Griseofulvin : It is obtained from It is obtained from penicillium penicillium

griseofulvumgriseofulvum It is active againstIt is active against DermatophytesDermatophytes

– – Epidermatophyton, Trichophyton Epidermatophyton, Trichophyton and Microsporumand Microsporum

Anti-fungal agentsAnti-fungal agents

Griseofulvin : Mechanism of action Griseofulvin : Mechanism of action It gets deposited in the keratin It gets deposited in the keratin

forming cells of the skin, hair and forming cells of the skin, hair and nails – especially concentrated and nails – especially concentrated and retained in the tinea infected cells – retained in the tinea infected cells – disruption of mitotic spindles - thus disruption of mitotic spindles - thus interferes with mitosis.interferes with mitosis.

Newly formed keratin is not invaded Newly formed keratin is not invaded by the fungusby the fungus

Anti-fungal agentsAnti-fungal agents

Griseofulvin : Griseofulvin : Pharmacokinetics :Pharmacokinetics :

Absorption from the GIT is Absorption from the GIT is irregular – better with irregular – better with ultramicrofine granulesultramicrofine granules

Better absorption with high fat Better absorption with high fat mealsmeals

It is an inducer of liver enzymesIt is an inducer of liver enzymes

Anti-fungal agentsAnti-fungal agents

Griseofulvin :Griseofulvin : It is used only for the It is used only for the

DermatophytesDermatophytes Body skin -------- 3 weeks Body skin -------- 3 weeks

Palm and Soles -------- 4 – Palm and Soles -------- 4 – 6 weeks Finger nails -------- 6 weeks Finger nails -------- 4 – 6 months Toe nails 4 – 6 months Toe nails -------- 8 – 12 months-------- 8 – 12 months

Anti-fungal agentsAnti-fungal agents

Griseofulvin :Griseofulvin : Headache is the common complaintHeadache is the common complaint Peripheral neuritis and LeucopeniaPeripheral neuritis and Leucopenia Potentiates the intoxicating effects Potentiates the intoxicating effects

of alcohol.of alcohol.

Anti-fungal agentsAnti-fungal agents

Terbinafine : FungicidalTerbinafine : Fungicidal Active against Active against dermatophytesdermatophytes and and

candidiasiscandidiasis Short course of therapy and relapse Short course of therapy and relapse

is pooris poor It acts as a non competitive inhibitor It acts as a non competitive inhibitor

of squalene epoxidase – in the of squalene epoxidase – in the ergosterol synthesisergosterol synthesis

Anti-fungal agentsAnti-fungal agents

Terbinafine : FungicidalTerbinafine : Fungicidal Oral absorption – 40 %.Oral absorption – 40 %. It is lipophilic, concentrated in skin It is lipophilic, concentrated in skin

and nail.and nail.

Anti-fungal agentsAnti-fungal agents

Terbinafine : adverse effects :Terbinafine : adverse effects : Taste and visual disturbancesTaste and visual disturbances Hepatic dysfunction, hematological Hepatic dysfunction, hematological

disorderdisorder No inhibition of cyto P450No inhibition of cyto P450

Anti-fungal agentsAnti-fungal agents

Terbinafine : Uses :Terbinafine : Uses :

Topical and Oral Topical and Oral Tinea - Onchomycosis - nailsTinea - Onchomycosis - nails Pityriasis VersicolorPityriasis Versicolor CandidiasisCandidiasis

Anti-fungal agentsAnti-fungal agents

NYSTATIN : NYSTATIN : It is very toxic when given It is very toxic when given

systemically and used only for systemically and used only for local local anti-fungalanti-fungal effect effect

It is not absorbed orallyIt is not absorbed orally Used only for oral candidiasis - Used only for oral candidiasis -

locallylocally

Anti-fungal agentsAnti-fungal agents

Caspofungin :Caspofungin : It is the first approved of EchinocandinsIt is the first approved of Echinocandins It interferes with the synthesis of fungal It interferes with the synthesis of fungal

cell wall by inhibiting the synthesis of cell wall by inhibiting the synthesis of beta ( 1,3 ) D – glucan, leading to cell beta ( 1,3 ) D – glucan, leading to cell lysis.lysis.

Specific for aspergillus and CandidaSpecific for aspergillus and Candida.. Excreted by urine and fecesExcreted by urine and feces Available for intravenous use only.Available for intravenous use only.

Anti-fungal agentsAnti-fungal agentsOther topical anti-fungal agents :Other topical anti-fungal agents : Tolnaftate :Tolnaftate : effective drug for effective drug for

dermatophytes and tinea versicolordermatophytes and tinea versicolor Ciclopirox :Ciclopirox : used for tinea used for tinea

infections, pityriasis versicolor and infections, pityriasis versicolor and candidiasiscandidiasis

Benzoic acid :Benzoic acid : anti-fungal agents anti-fungal agents and anti-bacterial property . and anti-bacterial property .

Salicylic acid :Salicylic acid : acts as keratolytic acts as keratolytic actionaction

 

Fungi  

Diseases Drug(s) of choice

 

Candida species 

 

Mucocutaneous thrush

 

Miconazole Nystatin (topical)Fluconazole

 

Deep infectionAmphotericin B ±flucytosineFluconazole

 

Coccidioides immitis

 

Rapid progressing 

Amphotericin B

 

MeningitisFluconazole

 

Histoplasma capsulatum

 

Pulmonary Itraconazole

 

Rapid progressing 

Amphotericin B

Blastomyces dermatitidis

Itraconazole

Paracoccidioide brasiliensis

Cutaneous and disseminated

Itraconazole

 

Aspergillus fumigatus

 

Invasive Amphotericin B Itraconazole

 

Cryptococcus neoformans

 

InitialAmphotericin B + Flucytosine

 

MaintenanceFluconazole

 

Sporothrix schenckii

 

Cutaneous 

Itraconazole

 

Extracutaneous  

Itraconazole

 

Mucormycosis 

All 

Amphotericin B

 

EpidermophytonTrichophytonMicrosporum

 

Dermatophytoses

 

Terbinafine GriseofulvinItraconazole

 

Malassezia furfur 

Tinea versicolor 

Miconazole(topical)