ANTI FUNGAL DRUGSANTI FUNGAL DRUGS

By;By;Dr. Saeed AhmedDr. Saeed Ahmed

Medical pharmacologyMedical pharmacologyKing Saud UniversityKing Saud University

Fungi are eukaryotic, heterotrophic (not self Fungi are eukaryotic, heterotrophic (not self sustaining) organisms that live as saprobes or sustaining) organisms that live as saprobes or parasites.parasites.

They are complex organisms in comparison to They are complex organisms in comparison to bacteria .Thus antibacterial agents are not effective bacteria .Thus antibacterial agents are not effective against fungi.against fungi.

Fungal infections are also called as mycosesFungal infections are also called as mycoses

Difference between prokaryotes and eukaryotes

They have nucleus and well defined nuclear They have nucleus and well defined nuclear membrane, and chromosomes.membrane, and chromosomes.

they have rigid cell wall composed of chitin ( N –they have rigid cell wall composed of chitin ( N –acetylglucosamine )acetylglucosamine )

where as bacterial cell wall is composed of where as bacterial cell wall is composed of peptidoglycan peptidoglycan

fungal cell membrane contains ergosterol , human fungal cell membrane contains ergosterol , human cell mebmrane is composed of cholesterolcell mebmrane is composed of cholesterol

Fungal infection may beFungal infection may be

SUPERFECIALSUPERFECIAL DermatomycosesDermatomycoses affecting skin, hair or nails. affecting skin, hair or nails.

Epidermophyton (skin and nails)Epidermophyton (skin and nails) Trichophyton (skin,hair & nail)Trichophyton (skin,hair & nail) Microsporum (skin and hair) Microsporum (skin and hair)

b) b) CandidiasisCandidiasis (commonly normal flora of mouth, skin, (commonly normal flora of mouth, skin,

intestines and vagina) infection caused by genus candida affecting intestines and vagina) infection caused by genus candida affecting skin, mucous membrane of mouth or G.I.T or female genital tractskin, mucous membrane of mouth or G.I.T or female genital tract

SYSTEMICSYSTEMIC Candidiasis ,cryptococosis, Aspergillosis, Candidiasis ,cryptococosis, Aspergillosis, Blastomycosis, Histoplasmosis, Blastomycosis, Histoplasmosis, Coccidioidomycosis, Paracoccidioidomycosis etcCoccidioidomycosis, Paracoccidioidomycosis etc

Drug ClassificationDrug Classification A) Drugs that disrupt fungal cell membraneA) Drugs that disrupt fungal cell membrane i) i) PolyenesPolyenes

AmphotericinAmphotericin NystatinNystatin NatamycinNatamycin

ii) Azolesii) Azoles A) ImidazoleA) Imidazole

KetoconazoleKetoconazole ButaxonazoleButaxonazoleClotrimazoleClotrimazoleEconazole Econazole MiconazoleMiconazole

OxiconazoleOxiconazole SulconazoleSulconazole

B) TriazoleB) Triazole FluconazoleFluconazole ItraconazoleItraconazole TioconazoleTioconazole

iii) Allylaminesiii) Allylamines

TerbinafineTerbinafine Naftifine Naftifine

Butenafine Butenafine

vi) vi) Echinocandins caspofungin,

Diagram showing mechanism of action of different anti fungal durgs

Drug classification cot’dDrug classification cot’d

B)B) Drugs that inhibits mitosisDrugs that inhibits mitosis Griseofulvin Griseofulvin

C)C) Drugs that inhibits DNA synthesisDrugs that inhibits DNA synthesis flucytosine flucytosine

d)d) MiscellaneousMiscellaneousHaloprogiTolnaftateWhitefield's ointmentCiclopirox olamine

Superficial MycosisSuperficial Mycosis a) Dermatophyte infection a) Dermatophyte infection (ring worm,tinea).(ring worm,tinea).

Benzoic acidBenzoic acid ointement for mild infection. ointement for mild infection.

Topical imidazoleTopical imidazole (like miconazole,clotrimazole) is (like miconazole,clotrimazole) is preferred now a dayspreferred now a days

TioconazoleTioconazole for nail infection for nail infection

Griseofulvin Griseofulvin orally for extensive scalp or nail tinea orally for extensive scalp or nail tinea infection. infection.

b) Candida infectionb) Candida infection..

Cutaneous infectionCutaneous infection: by : by topical amphotericin,clotrimazole ,econazole, topical amphotericin,clotrimazole ,econazole, miconazole or nystatinmiconazole or nystatin

Candidiais of elementary tractCandidiais of elementary tract mucosamucosa amphotericin,fluconazole, ketoconazole, amphotericin,fluconazole, ketoconazole, miconazole or nystatin.miconazole or nystatin.

Vaginal candidiasisVaginal candidiasis:: Clotrimazole,econazole,ketoconazole, miconazoleClotrimazole,econazole,ketoconazole, miconazole or or nystatinnystatin

Systemic MycosisSystemic Mycosis POLYENE ANTIBIOTICSPOLYENE ANTIBIOTICS They act by:They act by:

Binding to sterol in cell membrane.Binding to sterol in cell membrane.

Deformity in plasma membrane occursDeformity in plasma membrane occurs

Interferes with permeability and with transport functionsInterferes with permeability and with transport functions

This allows leakage of intracellular ions and enzymes especially loss of This allows leakage of intracellular ions and enzymes especially loss of

intracellular k+, causing cell death.intracellular k+, causing cell death.

They bind selectively to ergosterol in fungus but not in mammalian cell They bind selectively to ergosterol in fungus but not in mammalian cell wall.wall.

AMPHOTERICIN.AMPHOTERICIN. It is macrolide antibiotic A large lactone ring with multiple ketone and hydroxyl It is macrolide antibiotic A large lactone ring with multiple ketone and hydroxyl

group)group)

Poorly absorbed orally, useful for fungal infection of Poorly absorbed orally, useful for fungal infection of gastrointestinal tract.gastrointestinal tract.

Locally used in corneal ulcers, arthritis and candidial bladder irrigationLocally used in corneal ulcers, arthritis and candidial bladder irrigation

For systemic infections given as slow I/V infusion.For systemic infections given as slow I/V infusion.

Highly protein boundHighly protein bound

Penetration through BBB is poor but increases in inflamed meninges.Penetration through BBB is poor but increases in inflamed meninges.

Excreted slowly via kidneys, traces found in urine for months after cessation of Excreted slowly via kidneys, traces found in urine for months after cessation of drugs.drugs.

Half life 15 daysHalf life 15 days

Mechanism of action of Amphotericin

Remains in the body for weeks after stopping the Remains in the body for weeks after stopping the drug. drug.

Drug of choice for most systemic infections.Drug of choice for most systemic infections.

Course of treatment lasts 6-12 weeks.Course of treatment lasts 6-12 weeks.

Dose .5-1 mg\kg\dayDose .5-1 mg\kg\day

Adverse reactionsAdverse reactions Most serious is Most serious is renal toxicityrenal toxicity, which occurs in 80% of patients, which occurs in 80% of patients There may occur decrease in glomerular filtration, and renal There may occur decrease in glomerular filtration, and renal

function, drop in creatinine clearance,and loss of potassium and function, drop in creatinine clearance,and loss of potassium and magnesium, nephrotoxcity may be potenciated by sodium depletion. magnesium, nephrotoxcity may be potenciated by sodium depletion.

Hypokalaemia in 25% of patients, requiring potassium Hypokalaemia in 25% of patients, requiring potassium supplementation.supplementation.

Hypomagnesaemia Hypomagnesaemia AnemiaAnemia Impaired hepatic functionImpaired hepatic function ThrombocytopeniaThrombocytopenia

Anaphylactic shockAnaphylactic shock

Anorexia, nausea, vomiting, abdominal, joint and Anorexia, nausea, vomiting, abdominal, joint and muscle pain, loss of weight, and fever.muscle pain, loss of weight, and fever.

Aspirin, antihistamines (H1) antiemetics may help in Aspirin, antihistamines (H1) antiemetics may help in alleviating the symptoms.alleviating the symptoms.

Febrile reactions can be mitigated by hydrocortisone Febrile reactions can be mitigated by hydrocortisone 25-50 mg before each infusion.25-50 mg before each infusion.

Liposomal preparations of amphotericin B.Liposomal preparations of amphotericin B.

To reduce the toxicity of amphotericin B ,several new To reduce the toxicity of amphotericin B ,several new formulations have been developed in which formulations have been developed in which amphotericin B is packaged in a lipid-associated delivery amphotericin B is packaged in a lipid-associated delivery system, to assume that they will less bind to mammalian system, to assume that they will less bind to mammalian cell. Lipid vehicle act as a reservoir, reducing binding to cell. Lipid vehicle act as a reservoir, reducing binding to human cell. In this way it permits a larger doses, even human cell. In this way it permits a larger doses, even five times more than colloidal preparation, they have five times more than colloidal preparation, they have better clearance .better clearance .

Clinically they have more efficacy , less nephrotoxicity.Clinically they have more efficacy , less nephrotoxicity.

But these are very expansive.But these are very expansive.

Liposomal preparations of Amphotericin

Comparison between two types of Amphotericin

NYSTATINNYSTATIN

It is polyene macrolide,similar in structure to It is polyene macrolide,similar in structure to amphotericin and with same mechanism of amphotericin and with same mechanism of actionaction

Too toxic for systemic useToo toxic for systemic use

Not absorbed from GIT, skin or vagina, Not absorbed from GIT, skin or vagina, therefore administered orally totherefore administered orally to

Prevent or treat superficial candidiasis of mouth, Prevent or treat superficial candidiasis of mouth, esophagus or intestinal tract, oral suspension of esophagus or intestinal tract, oral suspension of 100,000 U/ml 4 times a day and tablets 500,000 U are 100,000 U/ml 4 times a day and tablets 500,000 U are used to decrease GIT colonization with Candida used to decrease GIT colonization with Candida

For vaginal candidiasis in form of pessaries used for For vaginal candidiasis in form of pessaries used for 2 weeks2 weeks

In Cutaneous infection available in cream, ointment In Cutaneous infection available in cream, ointment or powder form and applied 2-3 times a dayor powder form and applied 2-3 times a day

Can be used in combination with antibacterial agents Can be used in combination with antibacterial agents and corticosteroidsand corticosteroids

AZOLESAZOLES a bivalent chemical group composed of two nitrogen atoms.a bivalent chemical group composed of two nitrogen atoms. They are antibacterial, antiprotozoal, anthelminthic and They are antibacterial, antiprotozoal, anthelminthic and

antifungalantifungal..

These are group of synthetic These are group of synthetic fungistatic fungistatic agents agents

They have They have broad spectrumbroad spectrum of activity of activity Inhibit the fungal cytochrome P450 3AInhibit the fungal cytochrome P450 3A enzyme , lanosine enzyme , lanosine

1414-desmethylase ,which is responsible for converting -desmethylase ,which is responsible for converting lanosterol to ergosterol, the main sterol in the fungal cell lanosterol to ergosterol, the main sterol in the fungal cell membrane, this alters fluidity of the membrane, thus membrane, this alters fluidity of the membrane, thus inhibiting the growth of fungi.inhibiting the growth of fungi.

Imidazoles.Imidazoles. Ketoconazole, Ketoconazole, miconazole, miconazole, clotrimazole, clotrimazole, isoconazole ,isoconazole , TioconazoleTioconazole

They They interfere with fungal oxidative enzymes to cause lethal interfere with fungal oxidative enzymes to cause lethal accumulation of hydrogen peroxide; they reduceaccumulation of hydrogen peroxide; they reduce the formation the formation of ergosterol by inhibition of fungal cytochrome P450 enzyme, of ergosterol by inhibition of fungal cytochrome P450 enzyme, which become permeable to cellular constituents.which become permeable to cellular constituents.

They lack selectivity,and also inhibits human gonadal and They lack selectivity,and also inhibits human gonadal and steroid synthesis leading to decreased testosterone and cortisol steroid synthesis leading to decreased testosterone and cortisol production. It also inhibits cytochrome P450 –dependant production. It also inhibits cytochrome P450 –dependant hepatic drug –metabolizing enzyme.hepatic drug –metabolizing enzyme.

b).Triazoles.b).Triazoles.

Fluconazole,Fluconazole, itraconazole,itraconazole, voriconazolevoriconazole

They damage the fungal cell membrane by inhibiting enzyme They damage the fungal cell membrane by inhibiting enzyme desmethylase desmethylase

They are selective They are selective

Penetrate to CNSPenetrate to CNS

Resistant to degradationResistant to degradation

Cause less endocrine disturbance.Cause less endocrine disturbance.

KETOCONAZOLE:KETOCONAZOLE: First azole that could be given orally to treat systemic fungal infections.First azole that could be given orally to treat systemic fungal infections.

Well absorbed orally as acidic environment favors its dissolution.Well absorbed orally as acidic environment favors its dissolution. Only administered orallyOnly administered orally

Bioavailability is decreased with H-2 blocking drugs, proton pump Bioavailability is decreased with H-2 blocking drugs, proton pump inhibitors and antacids and is impaired with food.inhibitors and antacids and is impaired with food.

cola drinks improve its absorption in patients with achlorhydria.cola drinks improve its absorption in patients with achlorhydria.

After oral administration of 200,400 and 800 mg, plasma conc. reaches to After oral administration of 200,400 and 800 mg, plasma conc. reaches to 4.8 and 20 ug/ml. 4.8 and 20 ug/ml.

Half life increases with dose and it is 7-8 hrs with 800 mgHalf life increases with dose and it is 7-8 hrs with 800 mg

Mechanism of action of ketoconazole

Decrease in the ergosterol in the funagal membraneBy ketoconazle reduces

the fungicidal action of amphotericin

Metabolized extensively in liver and inactive products appear Metabolized extensively in liver and inactive products appear in the feces.in the feces.

84 % is bound to plasma proteins.84 % is bound to plasma proteins.

It does not enter CSF.It does not enter CSF.

Moderate hepatic dysfunction has no effect on drug Moderate hepatic dysfunction has no effect on drug concentration. concentration.

Induction of microsomal enzymes by other drugs reduces the Induction of microsomal enzymes by other drugs reduces the concentration.concentration.

It inhibits adrenal and gonadal steroids. which leads It inhibits adrenal and gonadal steroids. which leads to menstrual irregularities, loss of libido,to menstrual irregularities, loss of libido,

impotency and gynaecomastia in males.impotency and gynaecomastia in males.

Its efficacy is poor in immunosuppressed patients and Its efficacy is poor in immunosuppressed patients and in meningitis.in meningitis.

Oral dose 400 mg daily.Oral dose 400 mg daily.

It is not useful for fungal infections of UT as level of parent drug in urine is very low

Side effectsSide effects:: Dose dependant nausea, anorexia ,vomitingDose dependant nausea, anorexia ,vomiting

Liver toxicity is rare but may prove fatal.Liver toxicity is rare but may prove fatal.

Hair lossHair loss

As it inhibits steroid biosynthesis, several As it inhibits steroid biosynthesis, several endocrinological abnormalities may be evident as endocrinological abnormalities may be evident as menstrual abnormalities, gynecomastia, decreased menstrual abnormalities, gynecomastia, decreased libido and impotency.libido and impotency.

Fluid retention and hypertension.Fluid retention and hypertension.

Drug interactionsDrug interactions

cyclosporin,phenytoin ,Hcyclosporin,phenytoin ,H11 blockers inhibit its blockers inhibit its metabolism and hence increase toxicity.metabolism and hence increase toxicity.

Warfarin ,Rifampin increase its metabolism Warfarin ,Rifampin increase its metabolism and hence decrease concentration.and hence decrease concentration.

HH22 blockers ,antacids decrease its absorption. blockers ,antacids decrease its absorption. Contraindicated in pregnancyContraindicated in pregnancy

ITRACONAZOLEITRACONAZOLE It is a synthetic triazoleIt is a synthetic triazole

it is new drugit is new drug

It lacks endocrine side effects of ketoconazole.It lacks endocrine side effects of ketoconazole.

It has It has broad spectrumbroad spectrum activirty activirty

Administered orally as well as I/V. Administered orally as well as I/V.

Food increases its absorptionFood increases its absorption

Metabolized in liver extensively by cytochrome CYP3A4 Metabolized in liver extensively by cytochrome CYP3A4

It is highly lipid soluble, it is well distributed to bone ,sputum It is highly lipid soluble, it is well distributed to bone ,sputum and adipose tissue. and adipose tissue.

Highly bound to plasma proteinHighly bound to plasma protein

Do not penetrate CSFDo not penetrate CSF adequately ,therefore its concentration adequately ,therefore its concentration is less to treat meningeal fungal infectionis less to treat meningeal fungal infection

Half life is 30-40 hoursHalf life is 30-40 hours

Steady state reaches in 4Steady state reaches in 4 days, so loading doses are days, so loading doses are recommended in deep mycosis.recommended in deep mycosis.

Dose 100 mg twice daily with food, initially 300 mg thrice Dose 100 mg twice daily with food, initially 300 mg thrice daily as a loading dose.daily as a loading dose.

Intravenously reserved only in serious infections.200 mg twice Intravenously reserved only in serious infections.200 mg twice daily in infusion for one hour for two days followed by 200 daily in infusion for one hour for two days followed by 200 mg daily for 12 days.mg daily for 12 days.

Side effects: nausea, vomiting, hypertriglyceridemia, Side effects: nausea, vomiting, hypertriglyceridemia, Hypokalaemia, increased aminotransferase, hepatotoxicty rash Hypokalaemia, increased aminotransferase, hepatotoxicty rash leads to drug discontinuation.leads to drug discontinuation.

FLUCONAZOLEFLUCONAZOLE It is fluorinated bistriazole.It is fluorinated bistriazole.

Completely absorbed from GITCompletely absorbed from GIT

Excellent bioavailability by oral route.Excellent bioavailability by oral route.

Concentration in plasma is same by oral or I/v route.Concentration in plasma is same by oral or I/v route.

Bioavailability not altered by food or gastric acidityBioavailability not altered by food or gastric acidity

It has least effect on hepatic microsomal enzymes.It has least effect on hepatic microsomal enzymes.

Drug interactions are less common.Drug interactions are less common.

Peak plasma concentration 4-8ug/ml with Peak plasma concentration 4-8ug/ml with

It easily penetrate CSFIt easily penetrate CSF and is a drug of choice in cryptococcal meningitis and is a drug of choice in cryptococcal meningitis and coccido mycosis.and coccido mycosis.

It can safely be administered prophylactically in patients receiving bone It can safely be administered prophylactically in patients receiving bone marrow transplants.marrow transplants.

Resistance not a problem except in patients with HIVResistance not a problem except in patients with HIV

100mg repetitive dose.100mg repetitive dose.

Renal excretion 90%Renal excretion 90%

t1/2 25-30 hours.t1/2 25-30 hours.

Diffuse in all body fluids including CSF concentration 50-90 %.Diffuse in all body fluids including CSF concentration 50-90 %.

UsesUses

Candidiasis: 200 mg on 1st day then 100 mg daily for 2 weeks.Candidiasis: 200 mg on 1st day then 100 mg daily for 2 weeks.

Cryptococcosis: 400 mg daily for 8 weeks in meningitis.Cryptococcosis: 400 mg daily for 8 weeks in meningitis.

In AIDS 200 mg for life.In AIDS 200 mg for life.

Coccidial meningitis it is drug of choiceCoccidial meningitis it is drug of choice

It has also activity against histoplasmosis, blastomycosis, It has also activity against histoplasmosis, blastomycosis, spirotrichosis ,and ring worm but itraconazole is better in same spirotrichosis ,and ring worm but itraconazole is better in same dosedose

Not effective in aspergillosis.Not effective in aspergillosis.

Unwanted effectsUnwanted effects::

nausea, vomiting, headache, skin rash, abdominal nausea, vomiting, headache, skin rash, abdominal pain, diarrhea, reversible alopecia pain, diarrhea, reversible alopecia

No endocrine adverse effects.No endocrine adverse effects.

Hepatic failure may lead to death Hepatic failure may lead to death

It is highly teratogenicIt is highly teratogenic

VoriconazoleVoriconazole A new drugA new drug

available in i.v and oral fromulations.available in i.v and oral fromulations.

recommended dosage is 400 mg/ dayrecommended dosage is 400 mg/ day

high biological availability when given orallyhigh biological availability when given orally

hepatic metabolism predominant.hepatic metabolism predominant.

mammalian inhibition of P450 less.mammalian inhibition of P450 less.

reversible visual disturbancesreversible visual disturbances

it is similar to itraconazole but more potent.it is similar to itraconazole but more potent.

FLUCYTOSINEFLUCYTOSINE Has useful activity against Candida and Cryptococcus.Has useful activity against Candida and Cryptococcus.

it is synthetic pyrimidine antimetabolite that is often used in it is synthetic pyrimidine antimetabolite that is often used in combination with amphotericin Bcombination with amphotericin B

it is it is fungistatic,fungistatic,effective in combination with itraconazole for treating effective in combination with itraconazole for treating chromoblastomycosis and with amphotericin for treating chromoblastomycosis and with amphotericin for treating

cryptococosis.cryptococosis.

Mechanism of actionMechanism of action It is converted to antimetabolite 5-florouracil in a fungal but not It is converted to antimetabolite 5-florouracil in a fungal but not human cell. This 5-FU inhibits thymidylate synthetase enzyme and human cell. This 5-FU inhibits thymidylate synthetase enzyme and thus DNA synthesis. Resistant mutants may occur, should never be thus DNA synthesis. Resistant mutants may occur, should never be used alone.used alone.

Mechanism of action of Flucytosine

Fdump(fluorodeoxyuridne monophosphate

Ph/kineticsPh/kinetics

Absorbed rapidly and well from GITAbsorbed rapidly and well from GIT

Widely distributed in body and penetrates well into CSF.Widely distributed in body and penetrates well into CSF.

Minimally bound to plasma proteinMinimally bound to plasma protein

Peak plasma con. reaches 70-80 ug /ml in 1-2 hours.Peak plasma con. reaches 70-80 ug /ml in 1-2 hours.

80% dose is excreted unchanged in urine.80% dose is excreted unchanged in urine.

t t 1/2 1/2 3-6 hours in renal failures it may be 200 hours 3-6 hours in renal failures it may be 200 hours

UsesUses

dose 100-150 mg /kg per day divided into 4 doses.dose 100-150 mg /kg per day divided into 4 doses.

Generally use in combination with amphotericinGenerally use in combination with amphotericin

For cryptococcal meningitis in AIDS patientsFor cryptococcal meningitis in AIDS patients

Unwanted effectsUnwanted effects::

reversible neutropenia, thrombocytopenia and reversible neutropenia, thrombocytopenia and occasional bone marrow depression.occasional bone marrow depression.

Nausea ,vomiting ,diarrhea, severe enterocolitisNausea ,vomiting ,diarrhea, severe enterocolitis

Hepatic enzyme elevation in 5% patients is Hepatic enzyme elevation in 5% patients is reversible.reversible.

CaspofunginCaspofungin

It is echinocandin class of antifungal drugsIt is echinocandin class of antifungal drugs it interferes with the synthesis of fungal cell it interferes with the synthesis of fungal cell

wall by inhibiting synthesis of D-glycan.wall by inhibiting synthesis of D-glycan. especially useful for aspergillus and especially useful for aspergillus and

candida.candida. not active orallynot active orally Higly bound to serum proteinsHigly bound to serum proteins Has half life of 9-11 hoursHas half life of 9-11 hours

slowly metabolized by hydrolysis slowly metabolized by hydrolysis and N-acetylation.and N-acetylation.

eliminated equally by urinary and eliminated equally by urinary and fecal route.fecal route.

Adverse effects include Adverse effects include nausea ,vomiting, flushing nausea ,vomiting, flushing

very expensivevery expensive

Anti fungal drugs used for Anti fungal drugs used for topical fungal infectionstopical fungal infections

Topical anti fungal preparationsTopical anti fungal preparations

1.1. Topical azole derivativesTopical azole derivatives

2.2. Ciclopirox olamineCiclopirox olamine

3.3. NaftifineNaftifine

4.4. TerbinafineTerbinafine

5.5. Butenafine Butenafine

6.6. tolnaftatetolnaftate

7.7. Nystatin and AmphotericinNystatin and Amphotericin

Oral anti fungal agents used Oral anti fungal agents used for topical infectionsfor topical infections

1. 1. GriseofulvinGriseofulvin

2.2. oral azolesoral azoles

3.3. TerbinafineTerbinafine

TOPICAL ANTIFUNGAL AGENTSTOPICAL ANTIFUNGAL AGENTS

In superficial fungal infections those drugs are In superficial fungal infections those drugs are preferred which get confined to stratum preferred which get confined to stratum corneum, squamous mucosa, or cornea.corneum, squamous mucosa, or cornea.

Such disease includes dermatophytosis (ring Such disease includes dermatophytosis (ring worm), candidiasis tinea and fungal keratitis.worm), candidiasis tinea and fungal keratitis.

Topical administration of antifungal agents is usually Topical administration of antifungal agents is usually not successful in mycoses of the nails and hair and has not successful in mycoses of the nails and hair and has no place in the treatment of subcutaneous mycoses.no place in the treatment of subcutaneous mycoses.

The efficacy of topical agents in the superficial mycoses The efficacy of topical agents in the superficial mycoses depends not only on the type of lesion and the depends not only on the type of lesion and the mechanism of the drug action but also on the viscosity, mechanism of the drug action but also on the viscosity, hydrophobicity and acidity of the formulation.hydrophobicity and acidity of the formulation.

The preferred formulation for cutaneous application The preferred formulation for cutaneous application usually is a cream or solution.usually is a cream or solution.

IMIDAZOLE AND TRIAZOLES FOR TOPICAL IMIDAZOLE AND TRIAZOLES FOR TOPICAL infectionsinfections

These are synthetic and used both topically and These are synthetic and used both topically and systemicallysystemically

Selection depends on cost and availabilitySelection depends on cost and availability

Should be applied twice a day for 2-3 weeks.Should be applied twice a day for 2-3 weeks.

Vaginal creams, suppositories and tablets for vaginal Vaginal creams, suppositories and tablets for vaginal candidiasis used once a day preferably at bed time.candidiasis used once a day preferably at bed time.

CLOTRIMAZOLECLOTRIMAZOLE

Absorption less than 0.5 % from intact skin, 3-10 % Absorption less than 0.5 % from intact skin, 3-10 % from vagina and activity in vagina remains for 3 from vagina and activity in vagina remains for 3 days.days.

Oral dose of 200 mg per day give rise to 0.2-Oral dose of 200 mg per day give rise to 0.2-0.35ug/ml concentration.0.35ug/ml concentration.

Stigma, erythema, edema, vesication, pruritus, Stigma, erythema, edema, vesication, pruritus, urticaria mild vaginal burning sensation may urticaria mild vaginal burning sensation may occour.occour.

Cure dermatophytes.it is effective in 60-Cure dermatophytes.it is effective in 60-100%.cutaneous candidiasis is80-100% and 100%.cutaneous candidiasis is80-100% and vulvovaginal candidiasis is 80%. vulvovaginal candidiasis is 80%.

ItraconazoleItraconazole

Itraconazole is effective for treatment of Itraconazole is effective for treatment of onychomycosis in a dose of 200 mg daily onychomycosis in a dose of 200 mg daily after food for 3monthsafter food for 3months

Should not be given in patients with Should not be given in patients with ventricular dysfunctionventricular dysfunction

Routine evaluation of hepatic function is Routine evaluation of hepatic function is recommended.recommended.

should not be used concurrently with should not be used concurrently with midazolam, triazolam and HMG-CoA.midazolam, triazolam and HMG-CoA.

TOLNAFTATETOLNAFTATE Effective in most cutaneous mycosis.Effective in most cutaneous mycosis.

It is ineffective against Candida.It is ineffective against Candida.

In tinea pedis cure rate is around 80%.In tinea pedis cure rate is around 80%.

Available in 1% con.as cream,gel,powder and topical Available in 1% con.as cream,gel,powder and topical solution.solution.

Applied locally twice a day.Applied locally twice a day.

NAFTIFINENAFTIFINE

It is broad spectrum, fungicidal.It is broad spectrum, fungicidal.

Available as 1% cream or gel Available as 1% cream or gel

Effective for tropical treatment of tinea cruris.Effective for tropical treatment of tinea cruris.

TERBINAFINETERBINAFINE It is synthetic allylamineIt is synthetic allylamine it is a drug of choice for treating dermatophytesit is a drug of choice for treating dermatophytes

it is better tolerated , requires shorter duration of therapyit is better tolerated , requires shorter duration of therapy

it inhibits fungal sequalene epoxidase ,decreases synthesis of it inhibits fungal sequalene epoxidase ,decreases synthesis of ergosterol ergosterol

Also accumulation of toxic amounts of squalene causes cell Also accumulation of toxic amounts of squalene causes cell death.death.

it is fungicidal but activity is limited to C.albicans and it is fungicidal but activity is limited to C.albicans and dermatophytes.dermatophytes.

quite effective for the treatment of onychomycosisquite effective for the treatment of onychomycosis250 mg daily for 6weeks for finger nail infection and for 12 250 mg daily for 6weeks for finger nail infection and for 12 weeks in toe nail infectionweeks in toe nail infection

Well absorbed orally ,bioavailability decreases due to first Well absorbed orally ,bioavailability decreases due to first pass metabolism in liver.pass metabolism in liver.

Protein binding more than 99% in plasma.Protein binding more than 99% in plasma.

Drug accumulates in skin,nails and fat.Drug accumulates in skin,nails and fat.

severely hepatotoxic , liver failure even death.severely hepatotoxic , liver failure even death.

Mechanism of action of terbinafine

Initial half life 12 hrs but extends to 200-400 hrs ,which Initial half life 12 hrs but extends to 200-400 hrs ,which reflects it slow release from the tissuesreflects it slow release from the tissues

Can be found in plasma for 4- 8 weeks after prolong therapy.Can be found in plasma for 4- 8 weeks after prolong therapy. Clearance is reduced in moderate and hepatic impairment.Clearance is reduced in moderate and hepatic impairment.

Not recommended in azotemia or hepatic failure.Not recommended in azotemia or hepatic failure.

Dose 250 mg for 3 months/for local infection applied twice Dose 250 mg for 3 months/for local infection applied twice dailydaily.. unwanted effects include GIT disturbance ,Taste and visual unwanted effects include GIT disturbance ,Taste and visual

disturbance ,transient rise in serum liver enzymes.disturbance ,transient rise in serum liver enzymes. Rifampicin decreases it serum and cimetidine increasesRifampicin decreases it serum and cimetidine increases

GRISEOFULVINGRISEOFULVIN it has largely been replaced by terbinafine for treatment of it has largely been replaced by terbinafine for treatment of

dermatophytic infections of the nails.dermatophytic infections of the nails. very insoluble in watervery insoluble in water It is useful for dermatophytesIt is useful for dermatophytes

It is fangistatic for species of dermatophytes. it has narrow It is fangistatic for species of dermatophytes. it has narrow spectrum.spectrum.

Isolated from Pencillium griseofulvumIsolated from Pencillium griseofulvum

It interacts with microtubules and interferes with mitosis.It interacts with microtubules and interferes with mitosis.

PharmacokineticsPharmacokinetics

Peak plasma concentration of 1ug/ml in about 4 hoursPeak plasma concentration of 1ug/ml in about 4 hours

Absorption increases with fatty mealAbsorption increases with fatty meal It is ineffective topically.It is ineffective topically. Barbiturates decreases the absorption from GIT.Barbiturates decreases the absorption from GIT. Extensivly metabolized in liver.Extensivly metabolized in liver. Induce CYP450.Induce CYP450. t 1/2 1day.t 1/2 1day. Drug is deposited in keratin and nail and hair are 1st to Drug is deposited in keratin and nail and hair are 1st to

get rid of disease.get rid of disease.

UsesUses Mycotic diseases of skin, hair (particularly for Mycotic diseases of skin, hair (particularly for

scalp) , nail.scalp) , nail.

It is also highly effective in athlete's footIt is also highly effective in athlete's foot

DoseDose

5-15 mg /kg for children and 0.5 -1 gram for adults.5-15 mg /kg for children and 0.5 -1 gram for adults.

Treatment required is 1 month for scalp and hair Treatment required is 1 month for scalp and hair ringworm, 6-9 months for finger nails, and at least 1 year ringworm, 6-9 months for finger nails, and at least 1 year for toe nailsfor toe nails. .

Not effective in subcutaneous or deep mycoses.Not effective in subcutaneous or deep mycoses.

Unwanted effects.Unwanted effects.

HeadacheHeadache

Peripheral neuritis , lethargy , mental Peripheral neuritis , lethargy , mental confusion, impairment in performance of confusion, impairment in performance of routine task, fatigue, vertigo ,syncope, blurred routine task, fatigue, vertigo ,syncope, blurred vision.vision.

Comparison of Azoles fungistatic drugsComparison of Azoles fungistatic drugs

KetoconazoleKetoconazoleFluconazoleFluconazoleItraconazoleItraconazole

spectumspectumnarrownarrowexpandedexpandedexpandedexpanded

Route of administrationRoute of administrationOral Oral Oral, i.vOral, i.voraloral

T T 1/21/26-96-9303030-4030-40

Csf penetrationCsf penetrationnonoyesyesnono

Renal excretionRenal excretionnonoyesyesnono

Interaction with other Interaction with other drugsdrugs

frequentfrequentOccasional Occasional occasionaloccasional

Inhibition of Inhibition of mammalian sterol mammalian sterol synthesissynthesis

Dose dependent Dose dependent inhibitory effectinhibitory effect

no inhibitionno inhibitionNO inhibitionNO inhibition

Uses of antifungal drugsUses of antifungal drugsDiseaseDiseaseDrug usedDrug used

Systemic infectionsSystemic infections systemic candidiasissystemic candidiasis

Cryptococcosis( meningitis) Cryptococcosis( meningitis)

systemic aspergillosissystemic aspergillosis

BlastomycosisBlastomycosis

HistoplasmosisHistoplasmosis

CoccidiomycosisCoccidiomycosis

ParacoccidiomycosisParacoccidiomycosis

MucormycosisMucormycosis Disseminated sportrichosisDisseminated sportrichosis

Amphotericin, flucytocin, , fluconazole.Amphotericin, flucytocin, , fluconazole.

Amphotericin, flucytocin , fluconazole, Amphotericin, flucytocin , fluconazole,

itraconazole itraconazole itraconazole Amphotericin, itraconazole Amphotericin,

itraconazole Amphotericin,itraconazole Amphotericin,

Amphotericin, itraconazole ,fluconazole.Amphotericin, itraconazole ,fluconazole.

fluconazole. itraconazole ,Amphotericin,fluconazole. itraconazole ,Amphotericin,

fluconazole. itraconazole ,Amphotericin,fluconazole. itraconazole ,Amphotericin,

Amphotericin, flucytocin ,Amphotericin,Amphotericin, flucytocin ,Amphotericin, Amphotericin, flucytocinAmphotericin, flucytocin