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Antifungal drugs
Antifungal drugs
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Antifungal drugs-Synthetic agents



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Antifungal drugs-Synthetic agents

  1. 1. Antifungal Drugs II Synthetic agents Dr. S. Parasuraman
  2. 2. Anti-fungal agents • Azoles – lmidazoles • topical: Clotrimazole, Econazole, Miconazole, Oxiconazole • systemic: Ketoconazole – Triazoles (systemic): Fluconazole, Itraconazole, Voriconazole, Posaconazole • Allylamine: Terbinafine • Other topical agents: Tolnaftate, Undecylenic acid, Benzoic acid, Quiniodochlor, Ciclopirox olamine, Butenafine, Sod. thiosulfate.
  3. 3. Imidazoles and triazoles • Mechanism of action: – Imidazoles and triazoles on fungi is inhibition of 14-α-sterol demethylase and impair the biosynthesis of ergosterol in cytoplasmic membrane and accumulates the 14-αmethylsterols. These methylsterols may disrupt the close packing of acyl chains of phospholipids, impairing the functions/ inhibit the growth of the fungi. – Some azoles (e.g., clotrimazole) directly increase permeability of the fungal cytoplasmic membrane- topical use. • Resistance: – Azole resistance (clinical failure) observed in HIV infection and oropharyngeal or esophageal candidiasis. The primary mechanism of resistance in C. albicans is accumulation of mutations in ERG11, the gene coding for the 14-a-sterol demethylase. Increased production of 14-a-sterol demethylase is another potential cause of resistance.
  4. 4. Clotrimazole • It is effective in the topical treatment of tinea infections like ringworm. • Absorption of clotrimazole is less than 0.5% after application to the intact skin; from the vagina, it is 3% to 10%. • The small amount absorbed is metabolized in the liver and excreted in bile. • ADR: clotrimazole on the skin may cause stinging, erythema, edema, vesication, desquamation, pruritus, and urticaria. When it is applied to the vagina, about 1.6% of recipients complain of a mild burning sensation, and rarely of lower abdominal cramps, a slight increase in urinary frequency, or skin rash. No systemic toxicity is seen after topical use. • Dose: 1% lotion, cream, powder; 100 mg vaginal tab.
  5. 5. Econazole It is similar to clotrimazole. Effective in dermatophytosis, otomycosis and oral thrush. Dose: 1% oint, 150 mg vaginal tab Miconazole highly efficacious (>90% cure rate) drug for tinea, pityriasis versicolor, otomycosis, cutaneous and vulvovaginal candidiasis. ADR: Irritation after cutaneous application is infrequent. No systemic adverse effects are seen. Dose: 2% gel, 2% powder and solution; 2% vaginal gel
  6. 6. Ketoconazole (KTZ) • First orally effective broad-spectrum antifungal drug, useful in both dermatophytosis and deep mycosis. • It has been replaced by itraconazole for the treatment of all mycoses • Ketoconazole sometimes is used to inhibit excessive production of glucocorticoids in patients with Cushing's syndrome • PK-PD: Elimination of KTZ is dose dependent: t1/2 varies from 11/2 to 6 hours. Penetration in CSF is poor: not effective in fungal meningitis. However, therapeutic concentrations are attained in the skin and vaginal fluid. • ADR: Ketoconazole is much less toxic than AMB, most common side effects are nausea and vomiting. Gynaecomastia, loss of hair and libido, and oligozoospermia may be the manifestations.
  7. 7. Ketoconazole (KTZ) • Interaction: H2 blockers, proton pump inhibitor and antacids decrease the oral absorption of KTZ. Ketoconazole inhibits cytochrome P450, especially CYP3A4, and raises the blood levels of several drugs including phenytoin, digoxin, diazepam, cyclosporine, warfarin, etc.. • Use: – Effective in dermatophytosis, monilial vaginitis, Systemic mycosis – KTZ is occasionally used in dermal leishmaniasis and kala azar – High-dose KTZ has been used in Cushing's syndrome to decrease corticosteroid production.
  8. 8. Fluconazole • It is a water-soluble triazole having a wider range of activity than KTZ. It has good cerebrospinal fluid penetration. • PK: Fluconazole is 94% absorbed; oral bioavailability is not affected by food or gastric pH. It is primarily excreted unchanged in urine with a t1/2 of 25-30 hr. Fungicidal concentrations are achieved in nails, vagina and saliva; penetration into brain and CSF is good. Dose reduction is needed in renal impairment. • ADR: Mostly nausea, vomiting, abdominal pain, rash and headache. Elevation of hepatic transaminase has been noted • in AIDS patients. • Use: vaginal candidiasis, oropharyngeal candidiasis, disseminated candidiasis, cryptococcal/ coccidioidal meningitis; eye drop is useful in fungal keratitis. • Dose: 150- 200 mg weekly for 1-12 months; 0.3% eye drops.
  9. 9. Itraconazole • • • • It has a broader spectrum of activity than KTZ or fluconazole. It is fungistatic, but effective in immunocompromised patients. Its structurally closely related to the imidazole (ketoconazole). Steroid hormone synthesis inhibition is absent in itraconazole, and serious hepatotoxicity is rare. • PK: Accumulates in vaginal mucosa, skin and nails, but penetration into CSF is poor. T1/2 varies from 30-64 hours. Itraconazole is metabolized in the liver and it is substrate for and a potent inhibitor of CYP3A4.
  10. 10. ltraconazole • ADR: Dizziness, pruritus, headache and hypokalaemia. Itraconazole is not carcinogenic but is teratogenic in rats, and is contraindicated for the treatment of onychomycosis during pregnancy or for women contemplating pregnancy (category C). • Serious hepatotoxicity has rarely led to hepatic failure and death. • Use: Vaginal candidiasis, dermatophytosis, onychomycosis • Dose: 100, 200-400 mg cap
  11. 11. Voriconazole • Voriconazole is the second generation triazole used for systemic fungal infections. • Pk: The recommended dosage is 400 mg/d. The drug is well absorbed orally, and metabolism is predominantly in liver. • ADR: Observed toxicities include rash and QTc prolongation, elevated hepatic enzymes. Visual disturbances are common, occurring in up to 30% of patients receiving voriconazole, and include blurring and changes in color vision or brightness. These visual changes usually occur immediately after a dose of voriconazole and resolve within 30 minutes.
  12. 12. TERBINAFINE • Terbinafine is a synthetic allylamine that is available in an oral formulation and is used at a dosage of 250 mg/d. • It is used in the treatment of dermatophytoses, especially onychomycosis . • PK: – Approximately 75% of oral terbinafine is absorbed, but only 5% or less from unbroken skin. First pass metabolism further reduces oral bioavailability. – lt is lipophilic, widely distributed in the body, strongly plasma protein bound and concentrated in sebum, stratum corneum and nail plates. – It is inactivated by metabolism and excreted in urine (80%) and faeces (20%); elimination t1/2 of 11-16 hr is prolonged to 10 days after repeated dosing.
  13. 13. TERBINAFINE • MOA: Terbinafine inhibits the fungal enzyme squalene epoxidase. This leads to the accumulation of the sterol squalene, which is toxic to the organism. • ADR: – Adverse effects are rare, consisting primarily of gastrointestinal upset and headache. – Topical terbinafine can cause erythema, itching, dryness, irritation, urticaria and rashes. • Dose: One tablet given daily for 12 weeks achieves a cure rate of up to 90% for onychomycosis and is more effective than griseofulvin or itraconazole.
  14. 14. Antimetabolite – Flucytosine (5-FC) • It is a pyrimidine antimetabolite (inactive as such) • After fungal uptake, it is converted into 5-fluorouracil and then to 5-fluorodeoxyuridylic acid which is an inhibitor of thymidylate synthesis. • 5-FC is narrow spectrum fungistatic. • ADR: Toxicity of 5-FC is lower than that of AMB. Dose dependent bone marrow depression. Liver dysfunction is mild and reversible. • Therapy with 5-FC is generally limited to first 2 weeks of AMB regimen to avoid its bone marrow toxicity.
  15. 15. OTHER TOPICAL ANTIFUNGALS Drug Use Dose Tolnaftate drug for tinea cruris and tinea corporis for 1-3 weeks 1% lotion/ cream Ciclopirox olamine newer drug effective in tinea infections, pityriasis versicolor and dermal candidiasis; used for onychomycosis, vaginal candidiasis 1% cream, 1% topical solution, 1% vaginal cream Undecylenic acid It is fungistatic. Used for tinea pedis, nappy rash and tinea cruris Benzoic acid It has antifungal and antibacterial property. It is fungistatic-weaker than tolnaftate. On hyperkeratotic lesions, it is used in combination with salicylic acid Butenafine Efficacy in tinea cruris/ corporis/pedis is similar to that of topical terbinafine 1% cream; apply locally once/ twice daily. Quiniodochlor Weak antifungal and antibacterial activity. It has been used for dermatophytosis, mycosis barbae, seborrhoeic dermatitis, infected eczema, furunculosis and pityriasis versicolor 3% / 4% / 8% cream Sodium thiosulfate weak fungistatic, active against Malassezia furfur Karpin Lotion 20%.
  16. 16. Thank you
  17. 17. Back
  18. 18. esophageal candidiasis oropharyngeal candidiasis Back
  19. 19. stinging desquamation vesication pruritus erythema Back urticaria
  20. 20. Visceral leishmaniasis (VL)/ kala-azar/ black fever/ Dumdum fever caused by protozoan parasites of the Leishmania genus. This disease is the second-largest parasitic killer in the world (after malaria), responsible for an estimated 500,000 infections each year worldwid Back
  21. 21. Back
  22. 22. onychomycosis Back