Antifungal DrugsEvi Sovia

Pharmacology Departement

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, keratin-

containing 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 P-

450 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)-D-

glucan → 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 N-

acetylation 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 synthesis1. 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, paru-

paru, dan otot skelet dapat menginaktivasi senyawa ini

ImunoglobulinDigunakan sebagai antiviral,

terutama untuk pencegahan infeksi

Hepatitis B dan rabiesDiberikan secara SC, IM dan IVDistribusi ke seluruh tubuhWaktu paruh 20-30 hari

Indikasi pemberian antivirusantivirusantivirus Indikasi Indikasi AmantadinAmantadinRimantadinRimantadinAsiklovir, valasiklovir, famsiklovirAsiklovir, valasiklovir, famsiklovirGansiklovirGansiklovirFoscarnetFoscarnetRibavirinRibavirinZidovudinZidovudinDidanosinDidanosinZalsitabinZalsitabinLamivudinLamivudinStavudinStavudinNevirapinNevirapinSaquinavirSaquinavirIndinavirIndinavirRitonavirRitonavirIdoxuridinIdoxuridinFluorourasilFluorourasilInterferonInterferonimunoglobulinimunoglobulin

Profilaksis dan terapi Influenza AProfilaksis dan terapi Influenza AProfilaksis dan terapi Influenza AProfilaksis dan terapi Influenza AInfeksi herpes simpleks dan herpes zosterInfeksi herpes simpleks dan herpes zosterCMV retinitisCMV retinitisCMV retinitisCMV retinitisSevere respiratory syncytial virus pneumonia, lassa Severe respiratory syncytial virus pneumonia, lassa feverfeverinfeksi HIV, AIDSinfeksi HIV, AIDSinfeksi HIV, AIDSinfeksi HIV, AIDSinfeksi HIV, AIDSinfeksi HIV, AIDSinfeksi HIV, AIDSinfeksi HIV, AIDSinfeksi HIV, AIDSinfeksi HIV, AIDSinfeksi HIV, AIDSinfeksi HIV, AIDSinfeksi HIV, AIDSinfeksi HIV, AIDSinfeksi HIV, AIDSinfeksi HIV, AIDSinfeksi HIV, AIDSinfeksi HIV, AIDSInfeksi kornea herpes simpleksInfeksi kornea herpes simpleksCondyloma acuminatumCondyloma acuminatumCondyloma acuminatum, hepatitis B dan CCondyloma acuminatum, hepatitis B dan CProfilaksis untuk hepatitis A dan B, rabies, Profilaksis untuk hepatitis A dan B, rabies, measles, varicellameasles, varicella

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