Oral Antifungal Agents

ORAL ANTIFUNGAL ORAL ANTIFUNGAL AGENTSAGENTS

AKSA AKBARAKSA AKBAR

KURNIAWATI HATARYKURNIAWATI HATARY

SARI IFDIANA JALALSARI IFDIANA JALAL

INTRODUCTIONINTRODUCTION

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

ANTIFUNGAL AGENTSANTIFUNGAL AGENTS

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

ORAL ANTIFUNGAL AGENTSORAL ANTIFUNGAL AGENTS

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

AGENTSAGENTS

• GriseofulvinGriseofulvin• Azoles (ketoconazole, fluconazole, Azoles (ketoconazole, fluconazole,

itraconazole)itraconazole)• Amphotericin BAmphotericin B• TerbinafineTerbinafine• FlucytosineFlucytosine

GRISEOFULVINGRISEOFULVIN

MECHANISM OF ACTION :MECHANISM OF ACTION :

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

Pict. 1 Structure of GriseofulvinPict. 1 Structure of Griseofulvin

THERAPEUTIC USESTHERAPEUTIC USES

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

SIDE EFFECTSSIDE EFFECTS

Usually mild side effect caused by Usually mild side effect caused by Griseofulvin such as :Griseofulvin such as :

- headacheheadache

- nauseanausea

- hypersensitivity reactions like urticaria- hypersensitivity reactions like urticaria

- skin eruption.- skin eruption.

DOSAGEDOSAGE

Children : 5-15 mg/kg a dayChildren : 5-15 mg/kg a day

Adult : 500 mg – 1 g a dayAdult : 500 mg – 1 g a day

AZOLEAZOLE

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

KETOCONAZOLEKETOCONAZOLE

Pict. 2 Structure of Ketoconazole


Ketoconazole effective for :Ketoconazole effective for :- DermatofitosisDermatofitosis- Candidiasis vaginalisCandidiasis vaginalis- HistoplasmosisHistoplasmosis- BlastomycosisBlastomycosis- Ptyriasis versicolor Ptyriasis versicolor


- Nausea- Nausea

- Anaphylactic- Anaphylactic

- Gynecomastia- Gynecomastia

- Endocrine changes- Endocrine changes

DOSAGEDOSAGE

Adult : starting dose with 200 mg a day (1 Adult : starting dose with 200 mg a day (1 tablet), increased by 400 mg a day if tablet), increased by 400 mg a day if starting dose not responded.starting dose not responded.

Children : 3,3 – 6,6 mg/kg a dayChildren : 3,3 – 6,6 mg/kg a day

Therapy for 4-6 weeksTherapy for 4-6 weeks

FLUCONAZOLEFLUCONAZOLE

Pict. 3 Structure of Fluconazole


Flukonazole effective for :Flukonazole effective for :

- Dermatofitosis- Dermatofitosis

- Candidiasis (oropharyng, oesophagus, - Candidiasis (oropharyng, oesophagus, vagina, systemic)vagina, systemic)

- Cryptococcal meningitis- Cryptococcal meningitis


- Itching- Itching

- Edema- Edema

- Respiratory problem- Respiratory problem

- Hypotension- Hypotension

- Diarrhea- Diarrhea

- Stomachache- Stomachache

DOSAGEDOSAGE

Preparation are in tablets 50 mg, 100 mg, Preparation are in tablets 50 mg, 100 mg, 150 mg and 200 mg.150 mg and 200 mg.

Therapeutic doses are 50- 400 mg a day.Therapeutic doses are 50- 400 mg a day.

Candidiasis : 200 mg first day, 100 mg a Candidiasis : 200 mg first day, 100 mg a day for next 2 weeks. Single dose 150 mg day for next 2 weeks. Single dose 150 mg for for candidiasis vaginalis. candidiasis vaginalis. Children age Children age above 6 years old : 3-6 mg/kg a day.above 6 years old : 3-6 mg/kg a day.

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

ITRACONAZOLEITRACONAZOLE

Pict. 4 Structure of ItraconazolePict. 4 Structure of Itraconazole


Itraconazole effective for :Itraconazole effective for :

- Blastomikosis- Blastomikosis

- Histoplasmosis- Histoplasmosis

- Aspergilosis- Aspergilosis

- Candidiasis- Candidiasis

- Onikomikosis- Onikomikosis


─ VomitingVomiting─ NauseaNausea─ Rash Rash ─ HypokalemiaHypokalemia─ OedemaOedema─ HeadacheHeadache

DOSAGEDOSAGE

Therapeutic dose are 2-5 mg/kg a day, Therapeutic dose are 2-5 mg/kg a day, maximum dosage are 100-400 mg a day maximum dosage are 100-400 mg a day orally. Better use after meal to increase orally. Better use after meal to increase absorption. absorption.

Onikomikosis : 200 mg a day for 12 weeksOnikomikosis : 200 mg a day for 12 weeks

Aspergillosis : 200-400 mg a day at least Aspergillosis : 200-400 mg a day at least for 3 weeks.for 3 weeks.

AMPHOTERICIN BAMPHOTERICIN B

A macrocyclic polyene antibiotic derived A macrocyclic polyene antibiotic derived from from Streptomyces nodosusStreptomyces nodosus..

Pict. 5 Structure of Amphotericin B

MECHANISM OF ACTIONMECHANISM OF ACTION

Molecules of amphotericin B bind Molecules of amphotericin B bind ergosterol in fungus membrane cells ergosterol in fungus membrane cells cause disturbance of fungus membrane cause disturbance of fungus membrane cells and electrolytes that makes cell’s cells and electrolytes that makes cell’s leakage and death.leakage and death.


Amphotericin B effective for :Amphotericin B effective for :─ Life threatening fungus infection and not Life threatening fungus infection and not

cured with azoles preparatecured with azoles preparate─ Fungus such as : Fungus such as : Candida spp, Candida spp,

Aspergillus spp, Cryptococcus Aspergillus spp, Cryptococcus neoformans, Histoplasma capsulatum, neoformans, Histoplasma capsulatum, Mukormikosis, Fusarium spp, Mukormikosis, Fusarium spp,

Trichosporon beigelii, Sporotrikosis Trichosporon beigelii, Sporotrikosis diseminata, Coccidiodes immitis.diseminata, Coccidiodes immitis.


─ Fever, rigidityFever, rigidity─ Anorexia, vomiting, nauseaAnorexia, vomiting, nausea─ Headache Headache ─ Anaphylactic (1% user)Anaphylactic (1% user)─ Hypokalemia Hypokalemia

DOSAGEDOSAGE

Candidiasis : (adult) 100-200 mg x 4 a dayCandidiasis : (adult) 100-200 mg x 4 a day

(Child) 100 mg x 4 a day(Child) 100 mg x 4 a day

Other infection : adult : 0,3-1,0 mg/kg a Other infection : adult : 0,3-1,0 mg/kg a day.day.

For deep fungal infection, therapy is used For deep fungal infection, therapy is used for 6-10 weeks.for 6-10 weeks.

TERBINAFINETERBINAFINE

Pict. 6 Structure of Terbinafine


Inhibition of Inhibition of squalene epoxidase squalene epoxidase (enzyme (enzyme of fungus membrane synthesis) that cause of fungus membrane synthesis) that cause ergosterol deficiency and squalene ergosterol deficiency and squalene accumulation. accumulation.

Squalene accumulationSqualene accumulation→toxic to →toxic to membrane→membrane destabilisation membrane→membrane destabilisation (activity of fungisidal)(activity of fungisidal)

Ergosterol deficiencyErgosterol deficiency→inhibits growth of →inhibits growth of fungus cells (activity of fungistatic)fungus cells (activity of fungistatic)


Broad spectrum and actively sensitive to Broad spectrum and actively sensitive to dermatofit. dermatofit.

Fungistatic to candida. Fungistatic to candida.

Effective for fungal nail infection caused Effective for fungal nail infection caused by dermatophytes.by dermatophytes.


─ DyspepsiaDyspepsia─ NauseaNausea─ HeadacheHeadache─ Skin reactionSkin reaction─ Eruption exanthemEruption exanthem

((Usually as well tolerated drugsUsually as well tolerated drugs))

DOSAGEDOSAGE

- Preparation is in tablet 125 mg. - Preparation is in tablet 125 mg. - 250 mg a day is well responded for - 250 mg a day is well responded for

dermatophytosis and onychomycosis dermatophytosis and onychomycosis in 14 days.in 14 days.- Therapy for onychomycosis : - Therapy for onychomycosis : 250 mg a day for 6 weeks in finger nail 250 mg a day for 6 weeks in finger nail

infection and 12 weeks in toe nail.infection and 12 weeks in toe nail.

For Tinea kapitis therapy based on body For Tinea kapitis therapy based on body weight : weight :

12-18 kg : 62,5 mg (0,5 tablet)12-18 kg : 62,5 mg (0,5 tablet)

18-25 kg : 125 mg (1 tablet)18-25 kg : 125 mg (1 tablet)

above 25 kg : 250 mg (2 tablet)above 25 kg : 250 mg (2 tablet)

a day in 6 weeks.a day in 6 weeks.

FLUCYTOSINEFLUCYTOSINE

Pict 7. Structure of Flucytosine


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


CandidiasisCandidiasis

Cryptococcal diseaseCryptococcal disease

Severe deep mycosesSevere deep mycoses

Chromoblastomycosis subcutanChromoblastomycosis subcutan


Bone marrow depression and lead to Bone marrow depression and lead to development of leucopenia and development of leucopenia and trombositopeniatrombositopenia

RashRash

VomitingVomiting

NauseaNausea

Severe enterokolitisSevere enterokolitis

DOSAGEDOSAGE

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

SPECIAL CONDITIONSPECIAL CONDITION

Allergy (Awareness of past experience to Allergy (Awareness of past experience to drug reaction)drug reaction)

Pregnancy (Awareness to baby)Pregnancy (Awareness to baby)

Breast-milk feeding (oral antifungal are Breast-milk feeding (oral antifungal are transferred through breast-milk)transferred through breast-milk)

Liver disease (systemic antifungal agents Liver disease (systemic antifungal agents are metabolised in liver), renal diseaseare metabolised in liver), renal disease

CONCLUSIONCONCLUSION

Oral antifungal agents are usually for wide Oral antifungal agents are usually for wide lesion infection and non-responded lesion infection and non-responded topical antifungal agent treatment.topical antifungal agent treatment.

Special medical condition need attention Special medical condition need attention on oral antifungal agents usage.on oral antifungal agents usage.

THANK YOUTHANK YOU

Oral Antifungal Agents

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