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Antifungal Drugs

Evi 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
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, paru-
paru, 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 Indikasi
Amantadin
Rimantadin
Asiklovir, valasiklovir, famsiklovir
Gansiklovir
Foscarnet
Ribavirin
Zidovudin
Didanosin
Zalsitabin
Lamivudin
Stavudin
Nevirapin
Saquinavir
Indinavir
Ritonavir
Idoxuridin
Fluorourasil
Interferon
imunoglobulin
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
terimakasih