AntifungalsAntifungals

Dr Mesfin HunegnawDr Mesfin Hunegnaw

Consultant Dermatologist & Consultant Dermatologist & VenerologistVenerologist

AAU, Medical facultyAAU, Medical faculty

Dept. of DermtovenerologyDept. of Dermtovenerology

• Prior to 1990, only two oral antifungal agents had been Prior to 1990, only two oral antifungal agents had been released over three decades. released over three decades.

• The first and the only synthetic agent was Griseofulvin.The first and the only synthetic agent was Griseofulvin.• Subsequently other drugs, including amphotericin B Subsequently other drugs, including amphotericin B

and ketoconazole, were introduced. and ketoconazole, were introduced. • Prolonged treatment, poor oral bioavailability, and Prolonged treatment, poor oral bioavailability, and

potentially serious side effects discouraged physicians potentially serious side effects discouraged physicians from using these drugs.from using these drugs.

• As a result of recent advancements in antifungal As a result of recent advancements in antifungal chemotherapy, new drugs with a broad spectrum of chemotherapy, new drugs with a broad spectrum of activity, high efficacy, tolerability, and with rare and activity, high efficacy, tolerability, and with rare and mild side effects are now available.mild side effects are now available.

• Three new oral antifungal agents that have been Three new oral antifungal agents that have been released are the first oral allylamine, released are the first oral allylamine, terbinafine terbinafine (Lamisil), and the triazoles fluconazole (Diflucan) (Lamisil), and the triazoles fluconazole (Diflucan) and itraconazole (Sporanoxand itraconazole (Sporanox). ).

• Selection of therapy depends on the mechanism of Selection of therapy depends on the mechanism of action of each agent and an understanding of tissueaction of each agent and an understanding of tissuepharmacokinetics, spectrum of clinical activity, pharmacokinetics, spectrum of clinical activity, potential adverse reactions, significant drug potential adverse reactions, significant drug interactions, efficacy, and optimal dosage protocols.interactions, efficacy, and optimal dosage protocols.

Terbinafine:Terbinafine:• Terbinafine hydrochloride (Lamisil) is a synthetic Terbinafine hydrochloride (Lamisil) is a synthetic

antimycotic agent that belongs to a new family of antimycotic agent that belongs to a new family of compounds known as the compounds known as the allylaminesallylamines..

• All allylamine derivatives, including naftifine, possess a All allylamine derivatives, including naftifine, possess a tertiary allylamine, i.e., a nitrogen atom with a tertiary allylamine, i.e., a nitrogen atom with a neighboring double bond, a structural componentneighboring double bond, a structural componentcrucial for antifungal activity .crucial for antifungal activity .

• The drug has a broad spectrum and is primarily a The drug has a broad spectrum and is primarily a fungicidal agent. fungicidal agent.

• In vitro it is highly active against dermatophytes but In vitro it is highly active against dermatophytes but less active against molds, dimorphic fungi, and various less active against molds, dimorphic fungi, and various yeasts. yeasts.

• At clinical concentrations the drug is fungistatic only At clinical concentrations the drug is fungistatic only against against C.albicansC.albicans..

Mechanism of Action:Mechanism of Action: Terbinafine blocks the biosynthesis of Terbinafine blocks the biosynthesis of ergosterolergosterol, a , a

sterol essential to the integrity of fungal sterol essential to the integrity of fungal cell cell membranemembrane and overall cell growth. and overall cell growth.

It inhibits squalene epoxidaseIt inhibits squalene epoxidase, a complex, , a complex, microsomal, non–cytochrome P-450 enzyme catalyzing microsomal, non–cytochrome P-450 enzyme catalyzing the first step of the enzymatic pathway, the conversion the first step of the enzymatic pathway, the conversion of of squalene into squalene epoxide.squalene into squalene epoxide.

Consequently, it causes a concomitant abnormal Consequently, it causes a concomitant abnormal intracellular accumulation of squalene and intracellular accumulation of squalene and deficiency in ergostrol. deficiency in ergostrol.

Accumulation of squalene accounts for the drug's Accumulation of squalene accounts for the drug's fungicidal activity, i.e.cellular disruption and cell deathfungicidal activity, i.e.cellular disruption and cell death..

• Terbinafine has little effect on human hepatic Terbinafine has little effect on human hepatic cytochrome P450 isozymes and therefore does not cytochrome P450 isozymes and therefore does not interfere with synthesis of steroid hormones, interfere with synthesis of steroid hormones, prostaglandins, and drug metabolism. prostaglandins, and drug metabolism.

• Terbinafine is highly lipophilic and keratophilic in nature Terbinafine is highly lipophilic and keratophilic in nature and is widely distributed upon absorption throughout and is widely distributed upon absorption throughout skin and adipose tissue via dermal-epidermal passive skin and adipose tissue via dermal-epidermal passive diffusion and sebum transport. diffusion and sebum transport.

• The concentration of terbinafine was found to be The concentration of terbinafine was found to be highest in sebum and hair samples when compared to highest in sebum and hair samples when compared to plasma samples.plasma samples.

AzolesAzoles

Azoles inhibit the enzyme Azoles inhibit the enzyme lanosterol 14-alpha-demethylaselanosterol 14-alpha-demethylase, an , an enzyme that converts lanosterol to ergosterol, which is an enzyme that converts lanosterol to ergosterol, which is an important component of the fungal cell wall. important component of the fungal cell wall.

Membrane damage results in permeability problems and renders Membrane damage results in permeability problems and renders the fungus unable to reproduce. the fungus unable to reproduce.

FluconazoleFluconazole Fluconazole (Diflucan) is a bistriazole antifungal Fluconazole (Diflucan) is a bistriazole antifungal

derivative with a low molecular weight. derivative with a low molecular weight. It is a white crystalline solid that is water soluble in It is a white crystalline solid that is water soluble in

both basic and neutral conditions. both basic and neutral conditions. It is effective against many yeasts (with the exception It is effective against many yeasts (with the exception

of of C. kruseiC. krusei) & dermatophytes. ) & dermatophytes. The maximum plasma concentration is achieved within The maximum plasma concentration is achieved within

approximately 2 h of administration. approximately 2 h of administration. • Exhibits a long half-life of 25 to 30 h, and a steady-state Exhibits a long half-life of 25 to 30 h, and a steady-state

level is reached after 7 days of once-daily level is reached after 7 days of once-daily administrations.administrations.

• Fluconazole is only weakly bound to plasma proteins, Fluconazole is only weakly bound to plasma proteins, with about 90 % of the drug circulating free in the with about 90 % of the drug circulating free in the plasma. plasma.

• The drug is resistant to hepatic metabolism, hence The drug is resistant to hepatic metabolism, hence 80 80 % of fluconazole is excreted unchanged in urine, with 2 % of fluconazole is excreted unchanged in urine, with 2 % in feces & about 11 % as metabolites in urine.% in feces & about 11 % as metabolites in urine.

• Fluconazole is almost minimally lipophilic andFluconazole is almost minimally lipophilic andpenetrates widely into body tissues and fluids. penetrates widely into body tissues and fluids.

• The ability to diffuse substantially into the CSF The ability to diffuse substantially into the CSF distinguishes this compound from many other distinguishes this compound from many other antimycotic agents.antimycotic agents.

• The levels of fluconazole in CSF, saliva, vaginal tissue, The levels of fluconazole in CSF, saliva, vaginal tissue, sputum, skin, and blister fluids have been reported to sputum, skin, and blister fluids have been reported to be comparable with or to exceed simultaneous plasma be comparable with or to exceed simultaneous plasma concentrations.concentrations.

S/E:S/E:• Fluconazole has been reported to be a potent teratogen Fluconazole has been reported to be a potent teratogen

that produces a characteristic pattern of congenital that produces a characteristic pattern of congenital malformations, including craniofacial, skeletal, and malformations, including craniofacial, skeletal, and cardiac anomalies, following treatment in the first cardiac anomalies, following treatment in the first trimester.trimester.

• However, a lack of a teratogenic effect has been However, a lack of a teratogenic effect has been observed after fluconazole therapy during the second observed after fluconazole therapy during the second trimester.trimester.

• GI upset,GI upset,

• Alopecia, reversible upon dosage reduction or Alopecia, reversible upon dosage reduction or discontinuation of treatment with fluconazole, is discontinuation of treatment with fluconazole, is reported to be common in patients receivingreported to be common in patients receiving400 mg of fluconazole for prolonged periods; 400 mg of fluconazole for prolonged periods;

• However, the condition has been observed in patients However, the condition has been observed in patients receiving a dose as low as 100 mg.receiving a dose as low as 100 mg.

• Fluconazole has been reported to cause an Fluconazole has been reported to cause an anaphylactic reaction which presented as pruritus, and anaphylactic reaction which presented as pruritus, and paraesthesia with edema of the feet. paraesthesia with edema of the feet.

• An allergic reaction was attributed to possible cross-An allergic reaction was attributed to possible cross-sensitization through an imidazole (ketoconazole or sensitization through an imidazole (ketoconazole or metronidazole).metronidazole).

Drug interactions:Drug interactions:• Fluconazole at doses of 200, 300, or 400 mg appears Fluconazole at doses of 200, 300, or 400 mg appears

not to affect the level of endogenous testosterone.not to affect the level of endogenous testosterone.• Continuous therapy with fluconazole significantly Continuous therapy with fluconazole significantly

elevates plasma levels of phenytoin, warfarin, elevates plasma levels of phenytoin, warfarin, tolbutamide, nortriptyline, midazolam, triazolam, and tolbutamide, nortriptyline, midazolam, triazolam, and FK506 (tacrolimus).FK506 (tacrolimus).

• NB:See other azoles: Ketoconazole…NB:See other azoles: Ketoconazole…

Itraconazole (Sporanox) Itraconazole (Sporanox) Fungistatic. Fungistatic. Synthetic triazole antifungal agent that slows fungal Synthetic triazole antifungal agent that slows fungal

cell growth by inhibiting cytochrome P450–dependent cell growth by inhibiting cytochrome P450–dependent synthesis of ergosterol, a vital component of fungal synthesis of ergosterol, a vital component of fungal cell membranes.cell membranes.

100-200 mg; po; bid. 100-200 mg; po; bid.

GRISEOFULVINGRISEOFULVIN Griseofulvin is an antibiotic with a narrow spectrum of Griseofulvin is an antibiotic with a narrow spectrum of

antimycotic activity produced by the penicillin species.antimycotic activity produced by the penicillin species. It disrupts microtubule mitotic spindle formation, It disrupts microtubule mitotic spindle formation,

thereby causing mitotic arrest at the metaphase stage.thereby causing mitotic arrest at the metaphase stage. The absorption, which is primarily in the duodenum, is The absorption, which is primarily in the duodenum, is

enhanced concurrent intake of a fatty meal.enhanced concurrent intake of a fatty meal. Griseofulvin demonstrates a weak affinity to keratin. Griseofulvin demonstrates a weak affinity to keratin. Although the drug is detected in the stratum corneum Although the drug is detected in the stratum corneum

of the skin 4 to 8 h following oral administration, it is of the skin 4 to 8 h following oral administration, it is not present at this site 48 to 72 h after discontinuation not present at this site 48 to 72 h after discontinuation of therapy. of therapy.

Griseofulvin is mainly metabolized by the liver.Griseofulvin is mainly metabolized by the liver.• Griseofulvin was found to be effective against Griseofulvin was found to be effective against

dermatophytes but not against yeast and bacteria. dermatophytes but not against yeast and bacteria. • Although griseofulvin is indicated for the treatment of Although griseofulvin is indicated for the treatment of

fingernail and toenail onychomycosis, therapy is fingernail and toenail onychomycosis, therapy is prolonged with low cure and high relapse rates, prolonged with low cure and high relapse rates, requiring approximately 6 months for the treatment of requiring approximately 6 months for the treatment of fingernails and 12 months for toenails.fingernails and 12 months for toenails.

• The most common side effects are related to the The most common side effects are related to the gastrointestinal tract and CNS.gastrointestinal tract and CNS.

• Between 20 and 50 % of patients on griseofulvin Between 20 and 50 % of patients on griseofulvin experience severe headaches. experience severe headaches.

• Visual and psychic impairment are reported as well. Visual and psychic impairment are reported as well. • As a result of impaired porphyrin metabolism,As a result of impaired porphyrin metabolism,

griseofulvin is associated with photoallergic rxns.griseofulvin is associated with photoallergic rxns. • The drug has been reported to precipitate lupus The drug has been reported to precipitate lupus

erythematosus and severe skin reactions;erythematosus and severe skin reactions;• It is teratogenic and carcinogenic in animal models.It is teratogenic and carcinogenic in animal models.