Antifungals

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Antifungals

  1. 1. AntifungalsAntifungals Dr Mesfin HunegnawDr Mesfin Hunegnaw Consultant Dermatologist & VenerologistConsultant Dermatologist & Venerologist AAU, Medical facultyAAU, Medical faculty Dept. of DermtovenerologyDept. of Dermtovenerology
  2. 2. • Prior to 1990, only two oral antifungal agents had beenPrior 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 BSubsequently other drugs, including amphotericin B and ketoconazole, were introduced.and ketoconazole, were introduced. • Prolonged treatment, poor oral bioavailability, andProlonged treatment, poor oral bioavailability, and potentially serious side effects discouraged physicianspotentially serious side effects discouraged physicians from using these drugs.from using these drugs. • As a result of recent advancements in antifungalAs a result of recent advancements in antifungal chemotherapy, new drugs with a broad spectrum ofchemotherapy, new drugs with a broad spectrum of activity, high efficacy, tolerability, and with rare andactivity, high efficacy, tolerability, and with rare and mild side effects are now available.mild side effects are now available.
  3. 3. • Three new oral antifungal agents that have beenThree new oral antifungal agents that have been released are the first oral allylamine,released are the first oral allylamine, terbinafineterbinafine (Lamisil), and the triazoles fluconazole (Diflucan)(Lamisil), and the triazoles fluconazole (Diflucan) and itraconazole (Sporanoxand itraconazole (Sporanox).). • Selection of therapy depends on the mechanism ofSelection of therapy depends on the mechanism of action of each agent and an understanding of tissueaction of each agent and an understanding of tissue pharmacokinetics, spectrum of clinical activity,pharmacokinetics, spectrum of clinical activity, potential adverse reactions, significant drugpotential adverse reactions, significant drug interactions, efficacy, and optimal dosage protocols.interactions, efficacy, and optimal dosage protocols.
  4. 4. Terbinafine:Terbinafine: • Terbinafine hydrochloride (Lamisil) is a syntheticTerbinafine hydrochloride (Lamisil) is a synthetic antimycotic agent that belongs to a new family ofantimycotic agent that belongs to a new family of compounds known as thecompounds known as the allylaminesallylamines.. • All allylamine derivatives, including naftifine, possess aAll allylamine derivatives, including naftifine, possess a tertiary allylamine, i.e., a nitrogen atom with atertiary allylamine, i.e., a nitrogen atom with a neighboring double bond, a structural componentneighboring double bond, a structural component crucial for antifungal activity .crucial for antifungal activity .
  5. 5. • The drug has a broad spectrum and is primarily aThe drug has a broad spectrum and is primarily a fungicidal agent.fungicidal agent. • In vitro it is highly active against dermatophytes butIn vitro it is highly active against dermatophytes but less active against molds, dimorphic fungi, and variousless active against molds, dimorphic fungi, and various yeasts.yeasts. • At clinical concentrations the drug is fungistatic onlyAt clinical concentrations the drug is fungistatic only againstagainst C.albicansC.albicans..
  6. 6. Mechanism of Action:Mechanism of Action:  Terbinafine blocks the biosynthesis ofTerbinafine blocks the biosynthesis of ergosterolergosterol, a, a sterol essential to the integrity of fungalsterol essential to the integrity of fungal cellcell 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 catalyzingmicrosomal, non–cytochrome P-450 enzyme catalyzing the first step of the enzymatic pathway, the conversionthe first step of the enzymatic pathway, the conversion ofof squalene into squalene epoxide.squalene into squalene epoxide.  Consequently, it causes a concomitant abnormalConsequently, it causes a concomitant abnormal intracellular accumulation of squalene andintracellular accumulation of squalene and deficiency in ergostrol.deficiency in ergostrol.  Accumulation of squalene accounts for the drug'sAccumulation of squalene accounts for the drug's fungicidal activity, i.e.cellular disruption and cell deathfungicidal activity, i.e.cellular disruption and cell death..
  7. 7. • Terbinafine has little effect on human hepaticTerbinafine has little effect on human hepatic cytochrome P450 isozymes and therefore does notcytochrome 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 natureTerbinafine is highly lipophilic and keratophilic in nature and is widely distributed upon absorption throughoutand is widely distributed upon absorption throughout skin and adipose tissue via dermal-epidermal passiveskin and adipose tissue via dermal-epidermal passive diffusion and sebum transport.diffusion and sebum transport. • The concentration of terbinafine was found to beThe concentration of terbinafine was found to be highest in sebum and hair samples when compared tohighest in sebum and hair samples when compared to plasma samples.plasma samples.
  8. 8. AzolesAzoles Azoles inhibit the enzymeAzoles inhibit the enzyme lanosterol 14-alpha-demethylaselanosterol 14-alpha-demethylase, an, an enzyme that converts lanosterol to ergosterol, which is anenzyme 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 rendersMembrane damage results in permeability problems and renders the fungus unable to reproduce.the fungus unable to reproduce.
  9. 9. FluconazoleFluconazole  Fluconazole (Diflucan) is a bistriazole antifungalFluconazole (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 inIt 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 exceptionIt is effective against many yeasts (with the exception ofof C. kruseiC. krusei) & dermatophytes.) & dermatophytes.  The maximum plasma concentration is achieved withinThe 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-Exhibits a long half-life of 25 to 30 h, and a steady- state level is reached after 7 days of once-dailystate level is reached after 7 days of once-daily administrations.administrations.
  10. 10. • 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 thewith about 90 % of the drug circulating free in the plasma.plasma. • The drug is resistant to hepatic metabolism, henceThe drug is resistant to hepatic metabolism, hence ∼∼8080 % 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 and penetrates widely into body tissues and fluids.penetrates widely into body tissues and fluids.
  11. 11. • The ability to diffuse substantially into the CSFThe ability to diffuse substantially into the CSF distinguishes this compound from many otherdistinguishes 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 tosputum, skin, and blister fluids have been reported to be comparable with or to exceed simultaneous plasmabe comparable with or to exceed simultaneous plasma concentrations.concentrations.
  12. 12. S/E:S/E: • Fluconazole has been reported to be a potent teratogenFluconazole has been reported to be a potent teratogen that produces a characteristic pattern of congenitalthat produces a characteristic pattern of congenital malformations, including craniofacial, skeletal, andmalformations, including craniofacial, skeletal, and cardiac anomalies, following treatment in the firstcardiac anomalies, following treatment in the first trimester.trimester. • However, a lack of a teratogenic effect has beenHowever, a lack of a teratogenic effect has been observed after fluconazole therapy during the secondobserved after fluconazole therapy during the second trimester.trimester. • GI upset,GI upset,
  13. 13. • Alopecia, reversible upon dosage reduction orAlopecia, reversible upon dosage reduction or discontinuation of treatment with fluconazole, isdiscontinuation of treatment with fluconazole, is reported to be common in patients receivingreported to be common in patients receiving 400 mg of fluconazole for prolonged periods;400 mg of fluconazole for prolonged periods; • However, the condition has been observed in patientsHowever, 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 anaphylacticFluconazole has been reported to cause an anaphylactic reaction which presented as pruritus, and paraesthesiareaction which presented as pruritus, and paraesthesia with edema of the feet.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 orsensitization through an imidazole (ketoconazole or metronidazole).metronidazole).
  14. 14. Drug interactions:Drug interactions: • Fluconazole at doses of 200, 300, or 400 mg appearsFluconazole 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 significantlyContinuous therapy with fluconazole significantly elevates plasma levels of phenytoin, warfarin,elevates plasma levels of phenytoin, warfarin, tolbutamide, nortriptyline, midazolam, triazolam, andtolbutamide, nortriptyline, midazolam, triazolam, and FK506 (tacrolimus).FK506 (tacrolimus). • NB:See other azoles: Ketoconazole…NB:See other azoles: Ketoconazole…
  15. 15. Itraconazole (Sporanox)Itraconazole (Sporanox)  Fungistatic.Fungistatic.  Synthetic triazole antifungal agent that slows fungalSynthetic triazole antifungal agent that slows fungal cell growth by inhibiting cytochrome P450–dependentcell growth by inhibiting cytochrome P450–dependent synthesis of ergosterol, a vital component of fungalsynthesis of ergosterol, a vital component of fungal cell membranes.cell membranes.  100-200 mg; po; bid.100-200 mg; po; bid.
  16. 16. GRISEOFULVINGRISEOFULVIN  Griseofulvin is an antibiotic with a narrow spectrum ofGriseofulvin 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, isThe 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 corneumAlthough the drug is detected in the stratum corneum of the skin 4 to 8 h following oral administration, it isof the skin 4 to 8 h following oral administration, it is not present at this site 48 to 72 h after discontinuationnot present at this site 48 to 72 h after discontinuation of therapy.of therapy.
  17. 17.  Griseofulvin is mainly metabolized by the liver.Griseofulvin is mainly metabolized by the liver. • Griseofulvin was found to be effective againstGriseofulvin 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 ofAlthough griseofulvin is indicated for the treatment of fingernail and toenail onychomycosis, therapy isfingernail 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 ofrequiring approximately 6 months for the treatment of fingernails and 12 months for toenails.fingernails and 12 months for toenails.
  18. 18. • The most common side effects are related to theThe most common side effects are related to the gastrointestinal tract and CNS.gastrointestinal tract and CNS. • Between 20 and 50 % of patients on griseofulvinBetween 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 lupusThe 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.

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