Antifungal AgentsAntifungal Agents

Prof. Suheil ZmeiliProf. Suheil ZmeiliFaculty of MedicineFaculty of Medicine

Department of Department of PharmacologyPharmacology

University of JordanUniversity of Jordan

Antifungal AgentsAntifungal Agents

Objectives:Objectives:- Know Available antifungal drugsKnow Available antifungal drugs- Know their MOAKnow their MOA- Know their Pharmacokinetic Know their Pharmacokinetic

propertiesproperties- Know theirKnow their clinical uses clinical uses- Know their major side effects Know their major side effects

and drug interactionsand drug interactions

Fungi consist of:Fungi consist of:

- - RigidRigid cell wall cell wall composed of chitin ( N composed of chitin ( N –acetylglucosamine ) (bacterial cell –acetylglucosamine ) (bacterial cell wall is composed of peptidoglycan)wall is composed of peptidoglycan)

- Plasma or cell membrane which - Plasma or cell membrane which contains contains ergosterolergosterol (human cell (human cell mebmrane is composed of mebmrane is composed of cholesterol) (selectivity to some cholesterol) (selectivity to some antifungal agents)antifungal agents)

- Fungi have - Fungi have nucleus and well defined nucleus and well defined nuclear membrane, and chromosomes nuclear membrane, and chromosomes

Fungi are eukaryotic organisms that live Fungi are eukaryotic organisms that live as saprobes or parasitesas saprobes or parasites

They are complex organisms in They are complex organisms in comparison to bacteria (prokaryotic comparison to bacteria (prokaryotic cells=have no nuclear membranes and cells=have no nuclear membranes and no mitochondria)no mitochondria)

Therefore antibacterial agents are not Therefore antibacterial agents are not effective in fungal infections and effective in fungal infections and antifungal agents are ineffective in antifungal agents are ineffective in bacterial infections bacterial infections

Fungal infections are termed Fungal infections are termed mycosesmycoses and can be divided into:and can be divided into:(1) Superficial infections: affecting (1) Superficial infections: affecting skin, nails, scalp or mucous skin, nails, scalp or mucous membranes membranes (2) Systemic infections: affecting (2) Systemic infections: affecting deeper tissues and organs. deeper tissues and organs.

Superficial fungal infections can be Superficial fungal infections can be classified into the dermatomycoses classified into the dermatomycoses and candidiasis (Candida is a and candidiasis (Candida is a commonly commonly normal flora of mouth, skin, intestines normal flora of mouth, skin, intestines and vagina)and vagina)

Dermatomycoses are infections of Dermatomycoses are infections of the skin, hair and nails, caused the skin, hair and nails, caused by dermatophytes. The commonest by dermatophytes. The commonest are due to are due to TineaTinea organisms organisms which are also known as ringwormswhich are also known as ringworms

In superficial candidiasis, the In superficial candidiasis, the fungus candida infects the fungus candida infects the mucous membranes of the mouth mucous membranes of the mouth (oral thrush), or the vagina (oral thrush), or the vagina (vaginal thrush) or the skin (vaginal thrush) or the skin

Systemic fungal infections include:Systemic fungal infections include:- Systemic candidiasisSystemic candidiasis- Cryptoccocal meningitis or Cryptoccocal meningitis or

endocarditisendocarditis- Pulmonary aspergillosisPulmonary aspergillosis- Blastomycosis Blastomycosis - HistoplasmosisHistoplasmosis- CoccidioidomycosisCoccidioidomycosis- Paracoccidioidomycosis…etcParacoccidioidomycosis…etc

Fungal infections whether, superficial Fungal infections whether, superficial or systemic, are common in patients or systemic, are common in patients with weak immune system e.g.:with weak immune system e.g.:

- Patients with AIDS Patients with AIDS - Debilitated patientsDebilitated patients- Patients underwent organ Patients underwent organ

transplantation and on transplantation and on immunosuppressantsimmunosuppressants

- Patients under anticancerous therapyPatients under anticancerous therapy

Antifungal Drugs ClassesAntifungal Drugs Classes

1. Polyenes (1. Polyenes (polyene macrolide polyene macrolide antibiotics)antibiotics)

Amphotericine B Amphotericine B

Nystatin Nystatin

NatamycinNatamycin

Polyenes Mechanism of action:Polyenes Mechanism of action:Bind to ergosterol in fungal plasma Bind to ergosterol in fungal plasma

membrane leading to formation of membrane leading to formation of pores and hence increased pores and hence increased permeability of the membrane. This permeability of the membrane. This allows leakage of intracellular ions and allows leakage of intracellular ions and enzymes especially loss of intracellular enzymes especially loss of intracellular k+ causing death to the fungusk+ causing death to the fungus

They bind selectively to ergosterol in They bind selectively to ergosterol in fungus but not in mammalian plasma fungus but not in mammalian plasma membranesmembranes

Mechanisms of resistance to Mechanisms of resistance to polyenes:polyenes:

- Decreased ergosterol content of Decreased ergosterol content of the fungal membranethe fungal membrane

- Impaired binding to ergosterolImpaired binding to ergosterol

2. Azoles:2. Azoles:

Azoles mechanism of action:Azoles mechanism of action:- Azoles are fungistatic Azoles are fungistatic - They inhibit cytochrome P450 demethylase They inhibit cytochrome P450 demethylase

enzyme which is important for formation enzyme which is important for formation of ergosterolof ergosterol

- This inhibition disrupts membrane This inhibition disrupts membrane structure and function and, thereby, structure and function and, thereby, inhibits fungal growthinhibits fungal growth

Mechanism of resistance to Azoles:Mechanism of resistance to Azoles:

Mutation in the gene encoding for Mutation in the gene encoding for demethylase demethylase

3. Allylamines: 3. Allylamines:

TerbinafineTerbinafine

Naftifine Naftifine

Butenafine Butenafine

Mechanism of action Allylamines:Mechanism of action Allylamines:

IInhibit fungal squalene epoxidase, nhibit fungal squalene epoxidase, thereby decreasing the synthesis of thereby decreasing the synthesis of ergosterol. This plus the accumulation ergosterol. This plus the accumulation of toxic amounts of squalene result in of toxic amounts of squalene result in the death of the fungal cell. the death of the fungal cell.

Significantly higher concentrations of Significantly higher concentrations of terbinafine are needed to inhibit human terbinafine are needed to inhibit human squalene epoxidase, an enzyme required squalene epoxidase, an enzyme required for the cholesterol synthetic pathwayfor the cholesterol synthetic pathway

Echinocandins:Echinocandins:

Caspofungin Caspofungin

MicafunginMicafungin

AnidulafunginAnidulafungin Mechanism of action:Mechanism of action:

Interfere with the synthesis of the Interfere with the synthesis of the fungal cell wall by inhibiting the fungal cell wall by inhibiting the synthesis of D-glucan, leading to synthesis of D-glucan, leading to lysis and fungal cell deathlysis and fungal cell death

Antifungals Antifungals that inhibit mitosis:that inhibit mitosis: GriseofulvinGriseofulvin

Mechanism of action:Mechanism of action:It inhibits fungal mitosis by inhibiting It inhibits fungal mitosis by inhibiting

mitotic spindle formationmitotic spindle formationThe drug binds to tubulin, interfering The drug binds to tubulin, interfering

with microtubule function, thus with microtubule function, thus inhibiting mitosisinhibiting mitosis

Drugs that inhibit DNA synthesis Drugs that inhibit DNA synthesis (antimetabolites):(antimetabolites):

Flucytosine (-5FC)Flucytosine (-5FC) Mechanism of action:Mechanism of action:It enters fungal cells by permease (an It enters fungal cells by permease (an

enzyme not found in mammalian cells) enzyme not found in mammalian cells) and is then converted by a series of and is then converted by a series of steps to 5-fluorodeoxyuridine 5'-steps to 5-fluorodeoxyuridine 5'-monophosphate. monophosphate.

This false nucleotide inhibits thymidylate This false nucleotide inhibits thymidylate synthase, thus depriving the fungus of synthase, thus depriving the fungus of thymidylic acid an essential DNA thymidylic acid an essential DNA componentcomponent

The mononucleotide is further The mononucleotide is further metabolized to a trinucleotide (5-metabolized to a trinucleotide (5-fluorodeoxyuridine 5'-triphosphate) fluorodeoxyuridine 5'-triphosphate) and is incorporated into fungal RNA, and is incorporated into fungal RNA, thus disrupting nucleic acid and thus disrupting nucleic acid and protein synthesis. Amphotericin B protein synthesis. Amphotericin B increases cell permeability, allowing increases cell permeability, allowing more flucytocin to penetrate the cell. more flucytocin to penetrate the cell. Thus, flucytosin and amphotericin B Thus, flucytosin and amphotericin B are synergisticare synergistic

Amphotericin BAmphotericin B

- It is macrolide antibiotic, poorly absorbed - It is macrolide antibiotic, poorly absorbed orally, useful for fungal infection of orally, useful for fungal infection of gastrointestinal tractgastrointestinal tract

- Drug of choice for most systemic - Drug of choice for most systemic infections, given as slow IV infusioninfections, given as slow IV infusion

- Locally used in corneal ulcers, arthritis - Locally used in corneal ulcers, arthritis and bladder irrigationand bladder irrigation

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

- Excreted slowly via kidneys, traces found - Excreted slowly via kidneys, traces found in urine for months after cessation of drugin urine for months after cessation of drug

- Half life 15 days- Half life 15 days

Side effects to amphotericine:Side effects to amphotericine:

- Most serious is - Most serious is renal toxicityrenal toxicity, , which occurs in 80% of patientswhich occurs in 80% of patients

- Hypokalaemia in 25% of patients- Hypokalaemia in 25% of patients

- Hypomagnesaemia - Hypomagnesaemia

- Anemia & Thrombocytopenia- Anemia & Thrombocytopenia

- Impaired hepatic function- Impaired hepatic function

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

- Anaphylactic shock- Anaphylactic shock

- To reduce the toxicity of - To reduce the toxicity of amphotericin B, several new amphotericin B, several new formulations have been developed in formulations have been developed in which amphotericin B is packaged in which amphotericin B is packaged in a lipid-associated delivery system a lipid-associated delivery system (Liposomal preparations)(Liposomal preparations)

Such delivery systemsSuch delivery systems have more have more efficacy , less nephrotoxicity but efficacy , less nephrotoxicity but very expensivevery expensive

NYSTATINNYSTATIN

- It is polyene macrolide, similar in - It is polyene macrolide, similar in structure to amphotericin B and structure to amphotericin B and with same MOAwith same MOA

- Too toxic for systemic use- Too toxic for systemic use

- Not absorbed from GIT, skin or - Not absorbed from GIT, skin or vagina, therefore administered vagina, therefore administered orally toorally to prevent or treat prevent or treat superficial candidiasis of mouth, superficial candidiasis of mouth, esophagus or intestinal tract esophagus or intestinal tract

- Oral suspension of 100,000 U/ml 4 - Oral suspension of 100,000 U/ml 4 times a day and tablets 500,000 U times a day and tablets 500,000 U of nystatin are used to decrease of nystatin are used to decrease GIT colonization with Candida GIT colonization with Candida

- For vaginal candidiasis in form of - For vaginal candidiasis in form of pessaries used for 2 weekspessaries used for 2 weeks

- In cutaneous infection available in - In cutaneous infection available in cream, ointment or powder forms cream, ointment or powder forms and applied 2-3 times a dayand applied 2-3 times a day

NatamycinNatamycin

- It is a macrolide polyene antifungal - It is a macrolide polyene antifungal used to treat fungal keratitis, an used to treat fungal keratitis, an infection of the eye. It is especially infection of the eye. It is especially effective against effective against AspergillusAspergillus and and FusariumFusarium corneal infections corneal infections

- Also effective in - Also effective in CandidaCandida, , CephalosporiumCephalosporium and and PenicilliumPenicillium

- Not absorbed when given orally- Not absorbed when given orally

- Available in cream and ophthalmic - Available in cream and ophthalmic eye drops eye drops

FLUCYTOSINEFLUCYTOSINE

- Has useful activity against Candida and - Has useful activity against Candida and CryptococcusCryptococcus

- It is synthetic pyrimidine antimetabolite - It is synthetic pyrimidine antimetabolite that is often used in combination with that is often used in combination with amphotericin Bamphotericin B

- It is - It is fungistatic, fungistatic, effective in combination effective in combination with itraconazole for treating with itraconazole for treating chromoblastomycosis and with chromoblastomycosis and with amphotericin B for treating cryptococosisamphotericin B for treating cryptococosis

- Highly effective in cryptococcal meningitis - Highly effective in cryptococcal meningitis in AIDS patientsin AIDS patients

- Flucytocin is absorbed rapidly and well - Flucytocin is absorbed rapidly and well from GITfrom GIT

- Widely distributed in body and penetrates - Widely distributed in body and penetrates well into CSFwell into CSF

Side effects to flucytocin:Side effects to flucytocin:

- Reversible neutropenia, thrombocytopenia - Reversible neutropenia, thrombocytopenia and occasional bone marrow depressionand occasional bone marrow depression

- Nausea ,vomiting ,diarrhea, severe - Nausea ,vomiting ,diarrhea, severe enterocolitisenterocolitis

- Reversible hepatic enzyme elevation in 5% - Reversible hepatic enzyme elevation in 5% of patients of patients

KetoconazoleKetoconazole

- The first orally active narrow - The first orally active narrow specrum azole available for the specrum azole available for the treatment of systemic mycosestreatment of systemic mycoses

- Well absorbed orally as acidic - Well absorbed orally as acidic environment favors its dissolutionenvironment favors its dissolution

- Only administered orally- Only administered orally- Bioavailability is decreased with H-- Bioavailability is decreased with H-

2 blocking drugs, proton pump 2 blocking drugs, proton pump inhibitors and antacids and is inhibitors and antacids and is impaired with foodimpaired with food

- Ketokonazole is 84 % bound to - Ketokonazole is 84 % bound to plasma proteinsplasma proteins

- It does not enter CSF- It does not enter CSF- Metabolized extensively in liver - Metabolized extensively in liver

by cytochrome P450 (CYP3A4) and by cytochrome P450 (CYP3A4) and the inactive metabolites are the inactive metabolites are excreted in bileexcreted in bile

- Induction of microsomal enzymes - Induction of microsomal enzymes by other drugs like rifampicin by other drugs like rifampicin reduces its blood concentrationreduces its blood concentration

- Ketoconazole is active against many - Ketoconazole is active against many fungi, including Histoplasma, fungi, including Histoplasma, Blastomyces, Candida, and Blastomyces, Candida, and Coccidioides, but not aspergillus Coccidioides, but not aspergillus speciesspecies

- Ketoconazole is available in oral tablet, - Ketoconazole is available in oral tablet, aerosol , cream and shampoo dosage aerosol , cream and shampoo dosage formsforms

- The shampoo and aerosols foams - The shampoo and aerosols foams containing ketoconazole are highly containing ketoconazole are highly effective in treating seborrheic effective in treating seborrheic dermatitisdermatitis

- Ketocoazole inhibits adrenal and - Ketocoazole inhibits adrenal and gonadal steroidogenesis (cortisol, gonadal steroidogenesis (cortisol, progesterone, estrogens, and progesterone, estrogens, and testosterone). This leads to menstrual testosterone). This leads to menstrual irregularities, loss of libido,irregularities, loss of libido,

impotency and gynaecomastia in malesimpotency and gynaecomastia in males

- Ketoconazole could be used in the - Ketoconazole could be used in the management of Cushing’s syndrome management of Cushing’s syndrome and Ca of prostateand Ca of prostate

Ketoconazole side effects:Ketoconazole side effects:- - Dose dependant nausea, anorexia ,vomitingDose dependant nausea, anorexia ,vomiting- Liver toxicity (main toxicity) is rare but - Liver toxicity (main toxicity) is rare but

may prove fatalmay prove fatal- Hair loss- Hair loss- As it inhibits steroid biosynthesis, several - As it inhibits steroid biosynthesis, several

endocrinological abnormalities may be endocrinological abnormalities may be evident as menstrual abnormalities, evident as menstrual abnormalities, gynecomastia, decreased libido and gynecomastia, decreased libido and impotencyimpotency

- Fluid retention and hypertension- Fluid retention and hypertension- Ketokonazole is contraindicated in - Ketokonazole is contraindicated in

pregnancypregnancy

Ketoconazole drug-drug interactions:Ketoconazole drug-drug interactions:- Ketokonazole inhibit cytochrome P450 - Ketokonazole inhibit cytochrome P450

system, so it can potentiate the toxicities of system, so it can potentiate the toxicities of drugs such as cyclosporine, phenytoin, drugs such as cyclosporine, phenytoin, tolbutamide, and warfarin, among others…tolbutamide, and warfarin, among others…

- Cyclosporin and phenytoin inhibit its - Cyclosporin and phenytoin inhibit its metabolism and hence increase metabolism and hence increase ketokonazole toxicityketokonazole toxicity

- Warfarin and rifampin increase its - Warfarin and rifampin increase its metabolism and hence decrease metabolism and hence decrease concentration (shorten its DOA)concentration (shorten its DOA)

- H- H22 blockers, antacids, proton pump inhibitors blockers, antacids, proton pump inhibitors and sucralfate decrease its absorptionand sucralfate decrease its absorption

Ketokonazole decreases ergosterol in the funagal membrane thus, it reduces the fungicidal action of amphotericin B

TriazolesTriazoles

- The triazoles (- The triazoles (Fluconazole, Fluconazole, Itraconazole, Voriconazole) Itraconazole, Voriconazole) are are newer antifungal agents, and are newer antifungal agents, and are less toxic and more effectiveless toxic and more effective

- They damage the fungal cell membrane - They damage the fungal cell membrane by inhibiting enzyme demethylase by inhibiting enzyme demethylase

- They are selective - They are selective - Penetrate to CNS- Penetrate to CNS- Resistant to degradation- Resistant to degradation- Cause less endocrine disturbances- Cause less endocrine disturbances

FluconazoleFluconazole- Completely absorbed from GIT- Completely absorbed from GIT- Excellent bioavailability by oral - Excellent bioavailability by oral

route including CSFroute including CSF- Concentration in plasma is same - Concentration in plasma is same

by oral or IV routeby oral or IV route- Bioavailability not altered by - Bioavailability not altered by

food or gastric acidityfood or gastric acidity- It has least effect on hepatic - It has least effect on hepatic

microsomal enzymesmicrosomal enzymes- Drug interactions are less - Drug interactions are less

commoncommon

- Fluconazole easily penetrates CSF - Fluconazole easily penetrates CSF and is a and is a drug of choice in drug of choice in cryptococcal meningitis and coccido cryptococcal meningitis and coccido mycosismycosis

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

- Resistance not a problem except in - Resistance not a problem except in patients with HIVpatients with HIV

- Renal excretion- Renal excretion

Clinical uses to Fluconazole:Clinical uses to Fluconazole:- Candidiasis- Candidiasis- Cryptococcosis - Cryptococcosis - In AIDS - In AIDS - Coccidial meningitis it is drug of - Coccidial meningitis it is drug of

choicechoice- It has also activity against - It has also activity against

histoplasmosis, blastomycosis, histoplasmosis, blastomycosis, spirotrichosis and ring worm but spirotrichosis and ring worm but itraconazole is better in the same doseitraconazole is better in the same dose

- Not effective in aspergillosis- Not effective in aspergillosis

Side effects to Fluconazole:Side effects to Fluconazole:

- Nausea, vomiting, headache, skin - Nausea, vomiting, headache, skin rash, abdominal pain, diarrhea, rash, abdominal pain, diarrhea, reversible alopecia 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 teratogenic- It is highly teratogenic

ItraconazoleItraconazole

- A new synthetic triazole- A new synthetic triazole- It lacks endocrine side effects of - It lacks endocrine side effects of

ketoconazoleketoconazole- It has broad spectrum activirty- It has broad spectrum activirty- Administered orally as well as IV - Administered orally as well as IV - Food increases its absorption- Food increases its absorption

- - Itraconazole isItraconazole is extensively extensively metabolized in liver by cytochrome metabolized in liver by cytochrome P450 (CYP3A4) P450 (CYP3A4)

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

- Highly bound to plasma protein- Highly bound to plasma protein

- Does not penetrate CSF adequately , - Does not penetrate CSF adequately , therefore its concentration is less to therefore its concentration is less to treat meningeal fungal infectiontreat meningeal fungal infection

- - ItraconazoleItraconazole steady state reaches in steady state reaches in 4 days, so loading doses are 4 days, so loading doses are recommended in deep mycosisrecommended in deep mycosis

- Intravenously reserved only in - Intravenously reserved only in serious infectionsserious infections

Side effects to Side effects to ItraconazoleItraconazole:: Nausea, vomiting, Nausea, vomiting,

hypertriglyceridemia, hypokalaemia, hypertriglyceridemia, hypokalaemia, increased aminotransferase, increased aminotransferase, hepatotoxicty and rash (leads to hepatotoxicty and rash (leads to drug discontinuation)drug discontinuation)

VoriconazoleVoriconazole

- - A new drug available in oral and A new drug available in oral and IV dosage formsIV dosage forms

- It is similar to Itraconazole but - It is similar to Itraconazole but more potentmore potent

- High biological availability when - High biological availability when given orallygiven orally

- Hepatic metabolism predominant- Hepatic metabolism predominant

- Inhibition of P450 less- Inhibition of P450 less

- Reversible visual disturbances- Reversible visual disturbances

PosaconazolePosaconazole

- Is a new oral, broad-spectrum antifungal - Is a new oral, broad-spectrum antifungal agent similar to Itraconazoleagent similar to Itraconazole

- It was approved to prevent Candida and - It was approved to prevent Candida and Aspergillus infections in severely Aspergillus infections in severely immunocompromised patients and for immunocompromised patients and for the treatment of oropharyngeal the treatment of oropharyngeal candidiasis candidiasis

- Due to its spectrum of activity, - Due to its spectrum of activity, posaconazole could possibly be used in posaconazole could possibly be used in the treatment of fungal infections the treatment of fungal infections caused by Mucor species and other caused by Mucor species and other zygomyceteszygomycetes

- Given orally and well tolerated - Given orally and well tolerated

- Like Ketokonazole, Posaconazole can - Like Ketokonazole, Posaconazole can cause an elevation of liver function cause an elevation of liver function tests and it inhibits cytochrome P450 tests and it inhibits cytochrome P450 systemsystem

Side effects to Posaconazole:Side effects to Posaconazole:

The most common side effects The most common side effects observed were gastrointestinal observed were gastrointestinal symptoms (nausea, vomiting, symptoms (nausea, vomiting, diarrhea, and abdominal pain) and diarrhea, and abdominal pain) and headachesheadaches

CaspofunginCaspofungin

- It is echinocandin class of - It is echinocandin class of antifungal drugs that interfere with antifungal drugs that interfere with the synthesis of fungal cell wall by the synthesis of fungal cell wall by inhibiting synthesis of D-glycan (by inhibiting synthesis of D-glycan (by inhibiting D-glycan synthase)inhibiting D-glycan synthase)

- Especially useful for aspergillus - Especially useful for aspergillus and candidaand candida

- not active orally given IV- not active orally given IV

- Highly bound to serum proteins- Highly bound to serum proteins

- Slowly metabolized by hydrolysis - Slowly metabolized by hydrolysis and N-acetylationand N-acetylation

- Eliminated equally by urinary - Eliminated equally by urinary and fecal routeand fecal route

- Adverse effects include nausea , - Adverse effects include nausea , vomiting, flushing and liver vomiting, flushing and liver dysfunctiondysfunction

- Very expensive- Very expensive

Antifugal Drugs for Antifugal Drugs for Cutaneous Mycotic Cutaneous Mycotic

InfectionsInfections Topical antifungal preparationsTopical antifungal preparations- Topical azole derivatives- Topical azole derivatives- Nystatin and Amphotericin B- Nystatin and Amphotericin B- Tolnaftate- Tolnaftate- Terbinafine- Terbinafine……etcetc Oral anti fungal agents used for Oral anti fungal agents used for

topical infectionstopical infections- Oral azoles- Oral azoles- Griseofulvin- Griseofulvin- Terbinafine- Terbinafine

Topical AzolesTopical Azoles

- Miconazole, Clotrimazole, - Miconazole, Clotrimazole, Butoconazole and Terconazole Butoconazole and Terconazole are topically active drugs that are topically active drugs that are only rarely administered are only rarely administered parenterally because of their parenterally because of their severe toxicity severe toxicity

- Their mechanism of action and - Their mechanism of action and antifungal spectrum are the antifungal spectrum are the same as those of ketoconazolesame as those of ketoconazole

- Topical use of azoles is associated with - Topical use of azoles is associated with contact dermatitis, vulvar irritation, contact dermatitis, vulvar irritation, and edema. Miconazole is a potent and edema. Miconazole is a potent inhibitor of warfarin metabolism and inhibitor of warfarin metabolism and has produced bleeding in warfarin-has produced bleeding in warfarin-treated patients even when it is treated patients even when it is applied topically. No significant applied topically. No significant difference in clinical outcomes is difference in clinical outcomes is associated with any azole or nystatin associated with any azole or nystatin in the treatment of vulvar candidiasisin the treatment of vulvar candidiasis

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%- Exact mechanism of action is not - Exact mechanism of action is not

entirely known, it is believed to inhibit entirely known, it is believed to inhibit the squalene epoxidase, an important the squalene epoxidase, an important enzyme in the biosynthetic pathway of enzyme in the biosynthetic pathway of ergosterol ergosterol

- Available in as cream, gel, powder and - Available in as cream, gel, powder and topical solutiontopical solution

GriseofulvinGriseofulvin

- It has largely been replaced by - It has largely been replaced by terbinafine for treatment of terbinafine for treatment of dermatophytic infections of the dermatophytic infections of the nails because of toxicitynails because of toxicity

- Very insoluble in water- Very insoluble in water- It is useful for dermatophytes- It is useful for dermatophytes- It is fangistatic for species of - It is fangistatic for species of

dermatophytes. it has narrow dermatophytes. it has narrow spectrum.spectrum.

It interacts with microtubules and It interacts with microtubules and interferes with mitosisinterferes with mitosis

- Griseofulvin absorption increases with - Griseofulvin absorption increases with fatty mealfatty meal

- Barbiturates decrease the absorption from - Barbiturates decrease the absorption from GIT GIT

- It is ineffective topically it has to be given - It is ineffective topically it has to be given orally for Rx of hair and nail orally for Rx of hair and nail dermatophyte infectionsdermatophyte infections

- The drug has to deposit first in keratin of - The drug has to deposit first in keratin of growing skin, nail and hair to get rid of growing skin, nail and hair to get rid of diseasedisease

- Extensively metabolized in liver and - Extensively metabolized in liver and induces CYP450induces CYP450

Clinical uses of Griseofulven:Clinical uses of Griseofulven:- Mycotic diseases of skin, hair - Mycotic diseases of skin, hair

(particularly for scalp) and nail(particularly for scalp) and nail- It is also highly effective in athlete’s - It is also highly effective in athlete’s

footfoot- Treatment required is 1 month for - Treatment required is 1 month for

scalp and hair ringworm, 6-9 months scalp and hair ringworm, 6-9 months for finger nails, and at least 1 year for for finger nails, and at least 1 year for toe nailstoe nails. .

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

Griseofulvin side effects:Griseofulvin side effects:

- Headache- Headache

- Peripheral neuritis , lethargy , - Peripheral neuritis , lethargy , mental confusion, impairment in mental confusion, impairment in performance of routine task performance of routine task

- Fatigue, vertigo ,syncope, blurred - Fatigue, vertigo ,syncope, blurred visionvision

TerbinafineTerbinafine

- It is synthetic allylamine- It is synthetic allylamine- It is a drug of choice for treating - It is a drug of choice for treating

dermatophytesdermatophytes- As compared to Griseofulvin it is - As compared to Griseofulvin it is

better tolerated and requires shorter better tolerated and requires shorter duration of therapyduration of therapy

- It inhibits fungal sequalene epoxidase - It inhibits fungal sequalene epoxidase decreasing synthesis of ergosterol decreasing synthesis of ergosterol

- It is fungicidal but activity is limited - It is fungicidal but activity is limited to Candida albicans and to Candida albicans and dermatophytesdermatophytes

- Effective for the treatment of - Effective for the treatment of onychomycosis onychomycosis (fungal infections of nails).(fungal infections of nails). 250 mg daily for 6weeks for finger nail 250 mg daily for 6weeks for finger nail infection and for 12 weeks in toe nail infection and for 12 weeks in toe nail infectioninfection

- Well absorbed orally, bioavailability - Well absorbed orally, bioavailability decreases due to first pass metabolism in decreases due to first pass metabolism in liverliver

- Protein binding more than 99% in plasma.- Protein binding more than 99% in plasma.- The drug accumulates in skin, nails and fat- The drug accumulates in skin, nails and fat- Severely hepatotoxic (liver failure may lead - Severely hepatotoxic (liver failure may lead

to death)to death)

- Initial half life of Terbinafine is 12 hrs but - Initial half life of Terbinafine is 12 hrs but terminal half life extends to 200-400 hrs terminal half life extends to 200-400 hrs which reflects its slow release from the which reflects its slow release from the tissuestissues

- Can be found in plasma for 4- 8 weeks - Can be found in plasma for 4- 8 weeks after prolong therapyafter prolong therapy

- Terbinafine accumulates in breast milk - Terbinafine accumulates in breast milk and, therefore, should not be given to and, therefore, should not be given to nursing mothersnursing mothers

- Metabolites excreted in urine and its - Metabolites excreted in urine and its clearance is reduced in moderate and clearance is reduced in moderate and hepatic impairmenthepatic impairment

- Not recommended in azotemia or hepatic - Not recommended in azotemia or hepatic failurefailure

Side effects to Terbinafine:Side effects to Terbinafine:

- GIT disturbance - GIT disturbance

- Taste and visual disturbance - Taste and visual disturbance

- Transient rise in serum liver - Transient rise in serum liver enzymesenzymes

** Rifampicin decreases and ** Rifampicin decreases and cimetidine increases its blood cimetidine increases its blood concentrationsconcentrations