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
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
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, 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
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
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
Resistance
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
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
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
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
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