ORAL ANTIFUNGAL AGENTS

AKSA AKBAR KURNIAWATI HATARY SARI IFDIANA JALAL

INTRODUCTION

Fungal diseases (mycoses) are chronic infection diseases caused by fungus. Divided into superficial fungal infections and systemic fungal infections.

ANTIFUNGAL AGENTS Anti fungal agents are drugs that selectively eliminate pathogen fungus from host with minimal toxicity to the host. Divided into 2 major groups : topical agents and systemic agents.

ORAL ANTIFUNGAL AGENTS Oral antifungal agents are systemic agents used as treatment for superficial, subcutaneous and systemic mycoses.

AGENTS

Griseofulvin Azoles (ketoconazole, fluconazole, itraconazole) Amphotericin B Terbinafine Flucytosine

GRISEOFULVIN MECHANISM OF ACTION : Inhibits nuklease acid and chitin synthesis. Griseofulvin is fungistatic that attached to the new keratin that will resistant to fungus invasion and also inhibits mitosis of fungus.

Pict. 1 Structure of Griseofulvin

THERAPEUTIC USES Griseofulvin used as treatment for dermatophytosis and other tinea infection that not responded to other antifungal treatments.

SIDE EFFECTS Usually mild side effect caused by Griseofulvin such as : - headache - nausea - hypersensitivity reactions like urticaria - skin eruption.

DOSAGE
Children : 5-15 mg/kg a day Adult : 500 mg 1 g a day

AZOLE A broad spectrum antifungal agent that disturb ergosterol biosynthesis, main sterol to keep fungus membrane cell integrity, by inhibit essential enzyme (14-demethylase lanosterol P-450 cytochrome enzyme) in fungus membrane cell ergosterol synthesis.

KETOCONAZOLE

Pict. 2 Structure of Ketoconazole

THERAPEUTIC USES Ketoconazole effective for : - Dermatofitosis - Candidiasis vaginalis - Histoplasmosis - Blastomycosis - Ptyriasis versicolor

SIDE EFFECTS - Nausea - Anaphylactic - Gynecomastia - Endocrine changes

DOSAGE Adult : starting dose with 200 mg a day (1 tablet), increased by 400 mg a day if starting dose not responded. Children : 3,3 6,6 mg/kg a day Therapy for 4-6 weeks

FLUCONAZOLE

Pict. 3 Structure of Fluconazole

THERAPEUTIC USES Flukonazole effective for : - Dermatofitosis - Candidiasis (oropharyng, oesophagus, vagina, systemic) - Cryptococcal meningitis

SIDE EFFECTS - Itching - Edema - Respiratory problem - Hypotension - Diarrhea - Stomachache

DOSAGE

Preparation are in tablets 50 mg, 100 mg, 150 mg and 200 mg. Therapeutic doses are 50- 400 mg a day. Candidiasis : 200 mg first day, 100 mg a day for next 2 weeks. Single dose 150 mg for candidiasis vaginalis. Children age above 6 years old : 3-6 mg/kg a day.

For AIDS patient with cryptococcal meningitis : intial dose as 400 mg a day for 8 weeks, continued with 200 mg a day for a life time.

ITRACONAZOLE

Pict. 4 Structure of Itraconazole

THERAPEUTIC USES Itraconazole effective for : - Blastomikosis - Histoplasmosis - Aspergilosis - Candidiasis - Onikomikosis

SIDE EFFECTS
Vomiting Nausea Rash

Hypokalemia
Oedema

Headache

DOSAGE Therapeutic dose are 2-5 mg/kg a day, maximum dosage are 100-400 mg a day orally. Better use after meal to increase absorption. Onikomikosis : 200 mg a day for 12 weeks Aspergillosis : 200-400 mg a day at least for 3 weeks.

AMPHOTERICIN B
A macrocyclic polyene antibiotic derived from Streptomyces nodosus.

Pict. 5 Structure of Amphotericin B

MECHANISM OF ACTION Molecules of amphotericin B bind ergosterol in fungus membrane cells cause disturbance of fungus membrane cells and electrolytes that makes cells leakage and death.

THERAPEUTIC USES Amphotericin B effective for : Life threatening fungus infection and not cured with azoles preparate Fungus such as : Candida spp, Aspergillus spp, Cryptococcus neoformans, Histoplasma capsulatum, Mukormikosis, Fusarium spp,

Trichosporon beigelii, Sporotrikosis diseminata, Coccidiodes immitis.

SIDE EFFECTS
Fever,

rigidity Anorexia, vomiting, nausea Headache Anaphylactic (1% user) Hypokalemia

DOSAGE
Candidiasis : (adult) 100-200 mg x 4 a day (Child) 100 mg x 4 a day Other infection : adult : 0,3-1,0 mg/kg a day. For deep fungal infection, therapy is used for 6-10 weeks.

TERBINAFINE

Pict. 6 Structure of Terbinafine

MECHANISM OF ACTION Inhibition of squalene epoxidase (enzyme of fungus membrane synthesis) that cause ergosterol deficiency and squalene accumulation. Squalene accumulationtoxic to membranemembrane destabilisation (activity of fungisidal)

Ergosterol deficiencyinhibits growth of fungus cells (activity of fungistatic)

THERAPEUTIC USES Broad spectrum and actively sensitive to dermatofit. Fungistatic to candida. Effective for fungal nail infection caused by dermatophytes.

SIDE EFFECTS
Dyspepsia Nausea Headache

Skin

reaction Eruption exanthem (Usually as well tolerated drugs)

DOSAGE - Preparation is in tablet 125 mg. - 250 mg a day is well responded for dermatophytosis and onychomycosis in 14 days. - Therapy for onychomycosis : 250 mg a day for 6 weeks in finger nail infection and 12 weeks in toe nail.

For Tinea kapitis therapy based on body weight : 12-18 kg : 62,5 mg (0,5 tablet) 18-25 kg : 125 mg (1 tablet) above 25 kg : 250 mg (2 tablet) a day in 6 weeks.

FLUCYTOSINE

Pict 7. Structure of Flucytosine

MECHANISM OF ACTION Fungistatic : metabolised into fluorouracyl which enter fungus RNA and inhibits protein synthesis and fluorodeoxiuridinmonophosphate which inhibits fungus DNA synthesis.

THERAPEUTIC USES Candidiasis Cryptococcal disease Severe deep mycoses Chromoblastomycosis subcutan

SIDE EFFECTS Bone marrow depression and lead to development of leucopenia and trombositopenia Rash Vomiting Nausea Severe enterokolitis

DOSAGE 37,5 mg/kg a day or maximum dose150 mg/kg a day divided in 4 doses (6 hours duration).

SPECIAL CONDITION Allergy (Awareness of past experience to drug reaction) Pregnancy (Awareness to baby) Breast-milk feeding (oral antifungal are transferred through breast-milk) Liver disease (systemic antifungal agents are metabolised in liver), renal disease

CONCLUSION Oral antifungal agents are usually for wide lesion infection and non-responded topical antifungal agent treatment. Special medical condition need attention on oral antifungal agents usage.

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