FARMAKOLOGI OBAT-OBAT UNTUK TERAPI MIKOSIS SUPERFISIALIS, SUBKUTAN, DAN SISTEMIK

PENDAHULUAN Infeksi oleh jamur disebut mikosis Mikosis Superfisial adalah infeksi yang disebabkan

oleh jamur yang menyerang pada daerah superfisial, yaitu kulit, rambut, kuku.

Mikosis Subkutan adalah Infeksi oleh jamur yang mengenai kulit, mengenai lapisan bawah kulit meliputi otot dan jaringan konektif (jaringan subkutis).

Mikosis Sistemik adalah infeksi jamur yang mengenai organ internal dan jaringan sebelah dalam. Semua jamur bersifat dimorfik, artinya mempunyai daya adaptasi morfologik yang unik terhadap pertumbuhan dalam jaringan atau pertumbuhan pada suhu 37 ºC.

FUN FACTS….. Infeksi superfisial umumnya diterapi dengan preparat

lokal (dermatologi) Infeksi sistemik lebih sulit diobati, memerlukan terapi

jangka panjang, dan seringkali pengobatan menyebabkan efek samping yang berat.

Why are the fungal diseases harder to treat than bacterial infections?

Why are the fungal diseases harder to treat than bacterial infections?

The reason for this is that fungi, like people, are eukaryotes, making the two types of cells similar, at least more similar than to bacterial cells. There is enough similarity that when attempts are made to rid your body of a fungal infection, with chemicals, it is difficult to find a treatment that can remove the fungus without doing significant damage to your own cells.

ANTIFUNGAL DRUGS Klasifikasi obat antijamur: 1. Kelompok Polyene 2. Kelompok Azole 3. Kelompok Allilamin (Terbinafin) 4. Griseofulvin 5. Flusitosin

1. Polyene Amphotericin B Mechanism: Disrupt fungal cell membrane by binding to ergosterol , so alters the permeability of the cell membrane leading to leakage of intracellular ions & macromolecules (cell death). Amphotericin B has activity against Candida spp., Cryptococcus neoformans, Blastomyces dermatitidis, Histoplasma capsulatum, Sporothrix schenckii, Coccidioides immitis, Paracoccidioides braziliensis, Aspergillus spp., Penicillium marneffei, etc.

PHARMACOKINETICS Poorly absorbed orally For systemic infections given as slow

I.V.I. Highly bound to plasma protein . Poorly crossing BBB (Blood-Brain

Barrier). Metabolized in liver Excreted slowly in urine over a

period of several days. Half-life 15 days.

ADVERSE EFFECTS I. Immediate reactions ( Infusion –related

toxicity ). Fever, muscle spasm, vomiting ,headache,

hypotension. Can be avoided by : A. Slowing the infusion B. Decreasing the daily dose C. Premedication with antipyretics,

antihistamincs or corticosteroids. D. A test dose.

II- SLOWER TOXICITY Most serious is renal toxicity (nearly

in all patients ). Hypokalemia Hypomagnesaemia Impaired liver functions Thrombocytopenia Anemia

Several lipid formulations of amphotericin B – colloidal dispersion and liposomal amphotericin B, have been developed in an attempt to reduce the toxicity profile of this drug and to increase its efficacy. Formulating amphotericin with lipids alters drug distribution, with lower levels of drug in the kidneys, reducing the incidence of nephrotoxicity. While less toxic, the lipid formulations are significantly more expensive than conventional amphotericin B.

Polyene binds

Nystatin is a polyene antifungal drug with a ring structure and a mechanism of action similar to that of amphotericin B. Too toxic for systemic use, nystatin is limited to the topical treatment of superficial infections caused by C. albicans. Infections commonly treated by this drug include oral candidiasis (thrush), mild esophageal candidiasis, and vaginitis.

CLINICAL USES Prevent or treat superficial

candidiasis of mouth, esophagus, intestinal tract.

Vaginal candidiasis Can be used in combination with

antibacterial agents & corticosteroids.

2. Antifungal Azoles are synthetic drugs with broad-spectrum fungistatic activity. Azoles can be divided into two groups: the older imidazole agents (clotrimazole, ketoconazole, miconazole) in which the five-member azole nucleus contains two nitrogens and the newer triazole compounds (fluconazole, itraconazole), in which the azole nucleus contains three nitrogens.

• All azoles exert antifungal activity by inhibiting cytochrome P450 enzymes responsible for the demethylation of lanosterol to ergosterol – (ergosterol Is the main sterol of cell membrane). • Reduced fungal membrane ergosterol concen- trations result in damaged, leaky cell membranes. Note: Cytochrome P450 (CYP450) enzymes are essential for the production of cholesterol, steroids, prostacyclins, and thromboxane A2. They also are necessary for the detoxification of foreign chemicals and the metabolism of drugs. • The triazoles tend to have fewer side effects, better absorption, better drug distribution in body tissues, and fewer drug interactions.

Ketoconazole can be absorbed orally, but it requires an acidic gastric environment. It remains useful in the treatment of cutaneous and mucous membrane dermatophyte and yeast infections, but it has been replaced by the newer triazoles in the treatment of most serious Candida infections and disseminated mycoses. Ketoconazole is usually effective in the treatment of thrush, but fluconazole is superior to ketoconazole for refractory thrush. Widespread dermatophyte infections on skin surfaces can be treated easily with oral ketoconazole. Thrush

KETOCONAZOLE Bioavailability is decreased with

antacids, H2 blockers, proton pump inhibitors & food .

Half-life increases with the dose , it is (7-8 hrs).

Inactivated in liver & excreted in bile (feces ) & urine.

Does not cross BBB.

CLINICAL USES Used topically or systematic (oral route only ) to treat : Oral & vaginal candidiasis. Dermatophytosis. Systemic mycoses & mucocutaneous

candidiasis.

ADVERSE EFFECTS Nausea, vomiting Hepatotoxic Inhibits human P 450 enzymes Inhibits adrenal & gonadal steroids

leading to : Menstrual irregularities Loss of libido Impotence

CONTRAINDICATIONS & DRUG INTERACTIONS

Contraindicated in : Pregnancy, lactation ,hepatic

dysfunction Interact with enzyme inhibitors ,

enzyme inducers. H2 blockers & antacids decrease its

absorption

CONTRAINDICATIONS & DRUG INTERACTIONS

Contraindicated in : Prgnancy, lactation ,hepatic

dysfunction Interact with enzyme inhibitors ,

enzyme inducers. H2 blockers & antacids decrease its

absorption

Clotrimazole is a broad-spectrum fungistatic imidazole drug used in the topical treatment of oral, skin, and vaginal infections with C. albicans. It is also employed in the treatment of infections with cutaneous dermatophytes. Topical use results in therapeutic drug concentrations in the epidermis and mucous membranes; less than 10% of the drug is systemically absorbed.

FLUCONAZOLE Water soluble Completely absorbed from GIT Excellent bioavailability after oral

administration Bioavailability is not affected by food

or gastric PH Conc. in plasma is same by oral or IV

route Has the least effect on hepatic

microsomal enzymes

Fluconazole does not require an acidic environment, as does ketoconazole, for GI absorption. • About 80 to 90% of an orally administered dose is absorbed. • The t1/2 of the drug is 27 to 37 h, permitting once-

daily dosing in patients with normal renal function. • Only 11% of the circulating drug is bound to plasma

proteins. • The drug penetrates widely into most body tissues. • About 80% of the drug is excreted unchanged in the urine. • Dosage reductions are required in the presence of renal insufficiency.

• A single 150 mg dose has been shown to be an effective treatment for vaginal candidiasis.

• A 3-day course of oral fluconazole is an effective

treatment for Candida urinary tract infection. • Fluconazole may be an alternative to amphotericin

B in the initial treatment of mild cryptococcal meningitis and coccidioidal meningitis.

FLUCONAZOLE (CONT.) Drug interactions are less common Penetrates well BBB so, it is the drug

of choice of cryptococcal meningitis Safely given in patients receiving

bone marrow transplants (reducing fungal infections)

Excreted mainly through kidney Half-life 25-30 hours Resistance is not a problem

CLINICAL USES Candidiasis ( is effective in all forms

of mucocutaneous candidiasis) Cryptococcus meningitis Histoplasmosis, blastomycosis, , ring

worm. Not effective in aspergillosis

SIDE EFFECTS Nausea, vomiting, headache, skin

rash , diarrhea, abdominal pain , reversible alopecia.

Hepatic failure may lead to death Highly teratogenic ( as other azoles) Inhibit P450 cytochrom

Itraconazole is lipophilic and water insoluble and requires a low gastric pH for absorption. Oral bioavailability is variable (20 to 60%). It is highly protein bound (99%) and is metabolized in the liver and excreted into the bile. Itraconazole is most useful in the long-term suppressive treatment of disseminated histoplasmosis in AIDS and in the oral treatment of nonmeningeal blastomycosis. It is the drug of choice for all forms of sporotrichosis except meningitis. Itraconazole has replaced ketoconazole as the drug of choice in the treatment of paracoccidioidomycosis and chromomycosis.

ITRACONAZOLE (CONT.) Side effects : Nausea, vomiting, hypokalemia,

hypertension, edema, inhibits the metabolism of many drugs as oral anticoagulants.

3. Allylamines – reversible noncompetitive inhibitors of the fungal enzyme squalene monooxygenase, which converts squalene to lanosterol. With a decrease in lanosterol production, ergosterol production is also diminished, affecting fungal cell membrane synthesis and function. These agents exhibit fungicidal activity against dermatophytes and fungistatic activity against yeasts. Terbinafine is available for topical and systemic use (oral tablet) in the treatment of dermatophyte skin and nail infections.

TERBINAFINE

Drug of choice for treating dermatophytes (onychomycoses).

Better tolerated, needs shorter duration of therapy.

Fungicidal ,its activity is limited to candida albicans & dermatophytes.

6 weeks for finger nail infection & 12 weeks for toe nail infections .

Well absorbed orally , bioavailability decreases due to first pass metabolism in liver.

Highly protein binding Accumulates in skin , nails, fat. Severely hepatotoxic, liver failure

even death. Accumulate in breast milk , should

not be given to nursing mother. GIT upset (diarrhea, dyspepsia,

nausea ) Taste & visual disturbance.

4. Griseofulvin is an oral fungistatic agent used in the long-term treatment of dermatophyte infections caused by Epidermophyton, Microsporum, and Trichophyton spp. Produced by Penicillium griseofulvin, it inhibits fungal growth by binding to the microtubules responsible for mitotic spindle formation – disrupts mitosis. The drug binds to keratin precursor cells and newly synthesized keratin in the stratum corneum of the skin, hair, and nails, stopping the progression of dermatophyte infection. In the treatment of ringworm of the beard, scalp, and other skin surfaces, 4 to 6 weeks of therapy is often required.

GRISEOFULVIN(CONT.) Highly effective in athlete,s foot. Ineffective topically. Not effective in subcutaneous or deep

mycosis. Adverse effects ; Peripheral neuritis, mental confusion,

fatigue, vertigo,GIT upset,enzyme inducer, blurred vision.

Increases alcohol intoxication.

5. FLUCYTOSINE Synthetic pyrimidine antimetabolite

(cytotoxic drug ) often given in combination with amphotericin B & itraconazole.

Systemic fungistatic

MECHANISM OF ACTION Converted within the fungal cell to 5-

fluorouracil (Not in human cell), that inhibits thymidylate synthetase enzyme that inhibits DNA synthesis.

Amphotericin B increases cell permeability , allowing more 5-FC to penetrate the cell, thus, they are synergistic.

PHRMACOKINETICS Rapidly & well absorbed orally Widely distributed including CSF. Mainly excreted unchanged through

kidney Half-life 3-6 hours

CLINICAL USES Severe deep fungal infections as in

meningitis Generally given with amphotericin B For cryptococcal meningitis in AIDS

patients

ADVERSE EFFECTS Nausea, vomiting , diarrhea, severe

enterocolitis Reversible neutropenia,

thrombocytopenia, bone marrow depression

Alopecia Elevation in hepatic enzymes (some adverse effects related to 5-Fu

formed by intestinal organisms from5-FC)

I. Antifungals damaging permeability of the cell membrane

•Imidazoles: Clotrimazole,Ketoconazole, Miconazole •Triazoles: Fluconazole, Itraconazole, Voriconazole •Allylamines: Terbinafine •Polyene : Amphotericin B, Nystatin

II. Antifungals inhibiting chitin synthesis in the cell wall • Griseofulvin

III. Antifungals inhibiting synthesis of nucleic acids •Flucytosine

Source: Lewis RE. Current concepts in antifungal pharmacology. In Mayo Clinic Proceedings 2011 Aug 31 (Vol. 86, No. 8, pp. 805-817). Elsevier.

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