Antifungal Drugs

Evi Sovia Pharmacology Departement

Sasaran belajar

Mengetahui klasifikasi obat-obat antijamur Mengatahui farmakokinetik dan farmakodinamik obat-obat antijamur Mengetahui efek samping obat-obat antijamur Mengetahui interaksi obat-obat antijamur

Antifungal drugs
Drugs for Cutaneus Mycoses Drugs For Subcutaneus And Sistemic Mycoses

Drugs for Cutaneus Mycoses

Butoconazole Clotrimazole Econazole Griseofulvin Miconazole Nystatin Terbinafine Terconazole

Tebinafine

D.o.c for dermatophytoses, especially onychomyccoses (fungal infections of nails) Better tolerated Requires shorter d.o.a of therapy More effective than either itaconazole or groseofulvin

MOA

inhibits fungal squalene epoxidase, thereby decreasing the synthesis of ergosterol. This plus the accumulation of toxic amounts of squalene result in the death of the fungal cell

Antifungal spectrum: fungicidal Antifungal activity is limited to dermatophytes and Candida albicans. Therapy is prolonged usually about 3 months but consederably shorter than that with griseofulvin

Pharmacokinetics

orally active bioavailability 40% due to first pass metabolism Absorption is not significantly enhanced by food Greater than 99% bound to plasma protein

Deposited in the nails, skin and fat Accumulates in breast milk, should not be given to nursing mothers T1/2 200-400 hours Extensively metabolized Excretion: urinary

Adverse effects

Gastrointestinal disturbance (diarrhea, dyspepsia, and nausea) Headache Rash Taste and visual disturbance Transient elevated in serum liver enzyme levels

Resolve upon drug discontinuation

Drugs interaction

Rifampin decreased blood levels of terbinafine Cimetidine increased blood levels of terbinafine

Griseofulvin

Has been largely replaced by terbinafine for the treatment of dermatophytic infection of the nails. Duration of treatment: 6-12 months

MOA

Accumulates in newly synthesized, keratincontaining tissue, causes disruption of the mitotis spindle and inhibition of fungal mitosis

Duration of therapy is dependent on the rate of replacement of healthy skin or nails. Ultrafine crystalline preparations are absorbed adequately from the GI tract Absorption is enhanced by high fat meals Induces hepatic cytochrome P450 activity Increases the rate metabolism of number of drugs, including anticoagulants

Exacerbate intermittent porphyria Patients should not drink alcoholic beverages during therapy because potentiates the intoxicating effect of alcohol

Nystatin

Polyene antibiotic Structure, MOA, resistance resemble those to amphotericin B Usage is restricted to topical treatment of candida infections because of its systemic toxicity Negligibly absorbed from the GI tract, and its never used parenterally

Administered as an oral agent (swish and swallow) for the treatment of oral candidiasis Excretion in the feses Adverse efect is rare because of the lack absorption, but nausea and vomitting occasionally occur

Miconazole and other topical agent

Miconazole, clotrimazole, butoconazole and terconazole Topically active drugs Rarely administered parenteral because of their severe toxicity MOA = ketoconazole Topical use is associated with contact dermatitis, vulvar irritation, and edema

Potent inhibitor of warfarin metabolism, resulted in bleeding in warfarin-treated patients even when miconazole is applied topically No significant difference in clinical outcomes is associated with any azole or nystatin in the treatment of vulvar candidiasis

Drugs For Subcutaneus And Sistemic Mycoses

Amphotericin B Caspofungin Fluconazole Flucytosine Itraconazole Ketoconazole Voriconazole

Amphotericin B

MOA

Bind to ergosterol in the plasma membranes of sensitive fungal cells they form pores disrupt membrane function electrolytes and small molecules leak from the cell cell death

Antifungal spectrum

Fungicidal and fungistatic depending on the organism and the concentration of the drug. Effective against C. albicans, H. capsulatum, C. neoformans, C. immitis, B. dermatitidis, and many strains of aspergillus

Resistance

Infrequent Associated with decreased ergosterol content of the fungal membrane

Pharmacokinetics

ROA: iv infusion Insoluble in water sodium deoxycholate Extensively bound to plasma proteins Distributed throughout the body Excretion: urine

Adverse effects

Low therapeutic index Total daily dose should not exceed 1.5 mg/kg

Fever and chills Renal impairment Hypotension Anemia Neurologic effects thrombophlebitis

Flucytosine (5-FC)

MOA: 5-FC 5-FdUMP inhibits thymidylate synthase depriving essential DNA component

Antifungal spectrrum

Effective in combination with itraconazole chromoblastomycosis With amphotericin B candidiasis or cryptococcosis

Resistance

Decreased levels of any of the enzymes in the conversion of 5-FC to 5-FU

Pharmacokinetics

Well absorbed by the oral route Distributed throughout the body Excretion: urine The dose must be adjusted in patients with compromised renal function

Adverse effects

Neutropenia Thrombocytopenia Occasional bone marrow depresion Reversible hepatic dysfunction GI disturbances : nausea, vomitting, and diarrhea, enterocolitis

Ketoconazole

MOA: inhibits C-14 -demethylase (cyt P450 enzyme) blocking the demethylation of lanosterol to ergosterol (the principal sterol of fungal membranes)

Antifungal spectrum

Active against histoplasma, blastomyces, candida, and coccidioides but not aspergillus sp Itraconazole: broader spectrum, greater potency and fewer adverse effects

Resistance

Mutation in tne C-14 -demethylase gene decreased azole binding

Pharmacokinetics

Only administered orally Requires gastric acid for dissolution and is absorbed through the gastric mucosa antacids, AH2, PPI impair absorption Administering acidifying agent improve absorption Extensively bound to plasma proteins Does not enter the CSF Metabolism : liver Excretion : primarily through the bile

Adverse effects

Allergies GI disturbances: nausea, anorexia, vomiting Gynecomastia, decreased libido, impotence and menstrual irregularities Increased of serum transminase

Drugs interactions and contraindication

Inhibiting cyt P450 potentiate the toxicities of drugs such as cyclosporine, phenitoin, tolbutamide, and warfarin Rifampin shorter the DOA of ketoconazole Teratogenic CI: pregnancy

Fluconazole

Lack of the endocrine side effect Excellent penetrability into the CSF DOC for C. neoformans, candidemia and coccidioidomycosis Administered orally or iv Absorption is excellent, not dependent on gastric acidity

Binding to plasma proteins is minimal Poorly metabolized Excreted via the kidney

Itraconazole

Broad antifungal spectrum Lack of endocrine side effects Effective in AIDS associated histoplasmosis Well absorbed orally, requires acid for dissolution Extensively bound to plasma proteins Distributed well throughout most tissue

Extensively metabolized by the liver but does not inhibit androgen synthesis CI: pregnancy Inhibits the metabolism of many drugs (anticoagulans, statins, quinidine)

Caspofungin

Echinocandins class of antifungal drugs Interfere with the synthesis of (1,3)-Dglucan lysis and cell death Spectrum: limited to aspergillus and candida sp Not active by the oral route Highly bound to serum proteins

T1/2 : 9-11 hr Slowly metabolized by hydrolysis and Nacetylation Elimination: urine and fecal route Adverse effects: fever, rash, nausea, and phlebitis Second line antifungal for those who have failed or cannot tolerate amphotericin B or itraconazole Very expensive

ANTI VIRUS

Inhibitors of viral DNA and RNA synthesis

1. Asiklovir (analog guanosin sintesis) Antiherpesvirus Obat lain: famsiklovir, valasiklovir Harus mengalami fosforilasi (monofosfat trifosfat) oleh thymidine kinase untuk menjadi aktif

Thymidine kinase pada virus herpes simplek 1 dan 2 lebih sensitif terhadap asiklovir daripada thymidine kinase sel inang asiklovir terakumulasi di dalam sel yang terinfeksi Perubahan pada thymidine kinase resistensi Foscarnet M.K: menghambat DNA polimerase

Farmakokinetik

Asiklovir dapat diberikan secara topikal, oral dan IV Valasiklovir dan famsiklovir: hanya oral Bioavailabilitas asiklovir 15-30%, valasiklovir 2x lipat Makanan tidak mempengaruhi absorpsi Ikatan dengan protein 10-30% Distribusi baik

Absorpsi perkutan rendah dan hanya terjadi pada lesi luas Valasiklovir dimetabolisme menjadi asiklovir di hepar Valasiklovir diabsorpsi lebih baik konsentrasi serum lebih tinggi (3-5x dari asiklovir) Famsiklovir dimetabolisme menjadi pensiklovir (metabolit aktif) Waktu paruh asiklovir 3,3-3,8 jam Dieksresi di urin

2. Gansiklovir asiklovir, tetapi toksik Diberikan secara oral atau IV Waktu paruh 3-4 jam >90% dieksresi dalam urin penyesuaian dosis pd gangguan fungsi ginjal

3. Foscarnet MK: menghambat DNA polimerase, RNA polimerase, dan reverse transkriptase Efektif untuk herpesvirus, virus influenza, dan HIV Bioavabilitas 20% Hanya diberikan secara IV Berikatan dengan kalsium dideposit dalam tulang 80-90% dieksresi di ginjal

4. Ribavirin (analog purin sintesis) Fosforilasi oleh adenosin kinase sel inang Bioavailabilitas 45% Konsentrasi plasma setelah pemberian IV 10x lebih besar daripada oral Diberikan secara inhalasi pada pengobatan infeksi virus berat Eliminasi terutama di hati, 30% di urin

Interferon Merupakan glikoprotein alami yang dihasilkan oleh limfosit, makrofag, fibroblast, dan sel lain Interferon ,, dan MK: menghambat sintesis protein virus, menghambat penyusunan, dan menstimulasi respon imun Dapat melindungi sel yang tidak terinfeksi Digunakan untuk mengobati hepatitis dan papilloma Karena merupakan glikoprotein, farmakokinetiknya sukar dinilai Diberikan secara IM atau SC Efektif bila disuntikan langsung ke kondiloma Distribusi ke seluruh tubuh Eliminasi kompleks, melalui hati, ginjal, jantung, paruparu, dan otot skelet dapat menginaktivasi senyawa ini

Imunoglobulin Digunakan sebagai antiviral, terutama untuk pencegahan infeksi Hepatitis B dan rabies Diberikan secara SC, IM dan IV Distribusi ke seluruh tubuh Waktu paruh 20-30 hari

Indikasi pemberian antivirus

antivirus Amantadin Rimantadin Asiklovir, valasiklovir, famsiklovir Gansiklovir Foscarnet Ribavirin Zidovudin Didanosin Zalsitabin Lamivudin Stavudin Nevirapin Saquinavir Indinavir Ritonavir Idoxuridin Fluorourasil Interferon imunoglobulin Indikasi Profilaksis dan terapi Influenza A Profilaksis dan terapi Influenza A Infeksi herpes simpleks dan herpes zoster CMV retinitis CMV retinitis Severe respiratory syncytial virus pneumonia, lassa fever infeksi HIV, AIDS infeksi HIV, AIDS infeksi HIV, AIDS infeksi HIV, AIDS infeksi HIV, AIDS infeksi HIV, AIDS infeksi HIV, AIDS infeksi HIV, AIDS infeksi HIV, AIDS Infeksi kornea herpes simpleks Condyloma acuminatum Condyloma acuminatum, hepatitis B dan C Profilaksis untuk hepatitis A dan B, rabies, measles, varicella

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