pharmacology & therapeutics dept . sh l fmdiischool of...

Antifungal Drugs

Dr. Yunita Sari Pane, MSi

Pharmacology & Therapeutics Dept .S h l f M di iSchool of Medicine

Universitas Sumatera Utara

The antifungal drugs presently available fall into several categories:

systemic drugs (oral or parenteral) for systemic infections,systemic infections,

l d f t i f ti doral drugs for mucocutaneous infections, and

topical drugs for mucocutaneous infections.

ANTIFUNGAL

I Systemic Antifungal Agents

ANTIFUNGAL

I. Systemic Antifungal Agents1. Griseofulvin2 O l A l D i ti2. Oral Azole Derivatives3. Terbinafine4. Hidroksistilbamidin5 Flucytosin5. Flucytosin6. Amphoterisin B

II. TOPICAL ANTIFUNGAL AGENTS1. Topical Azole Derivatives2. Ciclopirox Olamine3. Naftitine4. Terbinafine5 B t fi5. Butenafine6. Tolnaftate7 Nystatin7. Nystatin8. Natamisin9. Asam lemak9. Asam lemak10. Haloprogin

The treatment of superficial fungal infections caused by dermatophytic fungi may be accomplished

1. Topical antifungal agents

y p y g y p

p g g- clotrimazole- miconazole- econazole- ketoconazole- oxiconazole- sulconazole

ciclopirox olamine- ciclopirox olamine- naftitine- terbinafineterbinafine - and tolnaftate

2. Orally administered agents- griseofulvin- terbinafine

ketoconazole- ketoconazole- fluconazole - and itraconazole.and itraconazole.

3. Superficial infections caused by candida species may be treated with topical applications ofmay be treated with topical applications of- clotrimazole - miconazolemiconazole- econazole- ketoconazole- oxiconazole- ciclopiroxolamine

nystatin- nystatin

4 Chronic generalized mucocutaneous candidiasis is4. Chronic generalized mucocutaneous candidiasis is responsive to long-term therapy with oral ketoconazole.

Mechanism of action antifungal drugs

ANTIFUNGAL DRUGSGriseofulvin, Amfoterisin B, Nistatin, Flusitosin

Ketokonazol, Flukonazol,

NatamisinFlusitosin Flukonazol,

Itrakonazol, Mikonazol

Pharmacokinetic Antifungal DrugsNo Drugs Absorp

tionDistribution Meta

bolismExcretion

1 Amphoterisin - √ - Urine1. Amphoterisin B

√ Urine Billier

2. Fluconazole √ √ √ Urine

3. Fluciytosin √ CNS fluid √ Urine

4 Ketoconazole √ √ √ Urine4. Ketoconazole √ √ √ Urine Billier

5. Griseofulvin √ Tissue keratin

√ UrineFaecesFaeces

6. Nystatin - FungalSterol

- Faeces

7 Salicylic Acid7. Salicylic Acid - - - -

Pharmacodynamic Antifungal Drugs

No Drugs Indications Side effects Contraindications Exp.

1. Amphoterisin B -Kandidiasis-SinusitisM i i i k i

-Menggigil-Demam M h

-Muntah-DiareG f i h i

Obat pilihan untuk infeksi jamur sistemik yang berat-Meningitis kronis -Muntah

-Sakit Kepala-Hipotensi

-Gangguan fungsi hati yang berat

2. Fluconazole -Kandidiasis oral dan esophagus

-MuntahDiare

-Gangguan fungsi hatiKehamilan dan laktasidan esophagus

-Kandidiasissistemik-Meningitis

-Diare-Gangguan fungsi hati

-Kehamilan dan laktasi-Hipersensitivitas

3. Flucytosine -Kandidiasis-Meningitiskriptokokal

-Mual,Muntah-Rash-Depresi sum-sum tulang

-Gagal Ginjal-Kehamilan dan Laktasi

+ Amfoterisin B =Aktifitasnya

sum tulang

4. Ketoconazole -Blastomikosis-Histoplasmosis-Kandidiasis-Dermatomikosis

-Mual-Ginekomastia-Hepatitis Kolestatik

-Hipersensitivitas-Kehamilan dan Laktasi-Penyakit hepar akut

Ketokonazol merupakan obat pilihan untuk Blastomikosis

Pharmacodynamic con’t…

No Drugs Indications Side Effects Contraindication Explanation

5 Griseofulvin Infeksi Infections Kehamilan Obat pilihan untuk5. Griseofulvin Infeksi dermatofitosis berat pd kulit, rambut, kuku disebabkan

-Infections-SerumSickness-Leukopenia

Kehamilan Obat pilihan untuk infeksi dermatofitosis yang berat

Trycophyton rubrum.

6. Nystatin -Skin Candidiasisselaput

-MuntahDiarrhae

Hypersensitivitas

(-) Superinfeksi√ pada wanita hamil,selaput

Lendir, GIT-Stomatitis

-Diarrhae sensitivitas √ pada wanita hamil

7. Salisilyc acid -Ptyriasis versicolor-Tinea Pedis

-Alergi Hipersensitivitas

Asam salisilat bekerja keratolitis, yaitu dapat melarutkan lapisanmelarutkan lapisan tanduk

Antifungal Clinical ApplicationsNo Disease TherapyNo. Disease Therapy1. Oral Candidiasis Oral : Fluconazole tablet 1 dd 50-100 mg during 1-2 week

2. Vaginal Candidiasis Ovula: Clotrimazole 200 mg during 3 days or single dose 500 mg Oral: Fluconazole tablet 150 mg single dose

3. Aspergilosis Parenteral: Amphotericin B IV 0,5-1,0 mg/kgbw daily

4. Criptoccosis Parenteral: Amphoterisin B IV 0,4-0,5 mg/kgbw

5. Blastomicocys Oral : Ketoconazole tablet 1 dd 400 mg during 6-12 month

6. Tinea Pedis Myconazole ointment 2% 1-2 dd during 3-5 weekUng.Whitfield (Benzoic Acid 5 %, Salisilyc acid 5% in lanolin-vaselin ana)

7. Tinea Unguium (Onicomycosis)

Terbinafine tablet 250 mg/days6 weeks for finger hand, 12 weeks for finger foot

8. Tinea capitis Griseofulvin 500mg/day [tidak lebih dari 10 mg/kgBB/hari]hingga sembuh [6-8 weeks].hingga sembuh [6 8 weeks].

9. Ptyriasis versicolor Salisilat acid 5-10% (used in ruam)Ketoconazole cream during 2-3 weeks

• As with all topical products, selection of s a op ca p oduc s, se ec o othe dosage form may be as important as proper drug selection. p p g

• Thin liquids may preferable for application• Thin liquids may preferable for application to hairy areas, creams for the hands and face and ointments may be preferable forface, and ointments may be preferable for the trunk and legs. Other dosage forms available include shampoos and spraysavailable include shampoos and sprays.

• Most topical antifungal drugs require fourMost topical antifungal drugs require four weeks of treatment. Infections in some areas particularly the spaces betweenareas, particularly the spaces between toes, may take up to six weeks for cure.

Precautions• Most topical antifungal agents are well tolerated.

The most common adverse effects are localized irritation caused by the vehicle or its components. This may include redness, itch,

d b i ti S di t ll iand a burning sensation. Some direct allergic reactions are possible.

• Topical antifungal drugs should only be applied• Topical antifungal drugs should only be applied in accordance with labeled uses. They are not intended or ophthalmic (eye) or otic (ear) useintended or ophthalmic (eye) or otic (ear) use. Application to mucous membranes should be limited to appropriate formulations.

• The antifungal drugs have not been l t d f f t i devaluated for safety in pregnancy and

lactation on topical application under the i k t t Alth hpregnancy risk category system. Although

systemic absorption is probably low, i ifi freview specific references.

Interactions• Could be reduced metabolism of severalCould be reduced metabolism of several

drugs

M d 28 J i 2009Medan, 28 Januari 2009

ANTILEPROSY DRUGS

dr Yunita Sari Pane MSidr. Yunita Sari Pane, MSi

Dept. Pharmacology & TherapeuticS h l f M di iSchool of Medicine

Universitas Sumatera Utara

Leprosy (Hansen's Disease)

Leprosy or Hansen's diseaseLeprosy, or Hansen s disease, is a chronic infectious diseasecaused by the bacteriumcaused by the bacteriumMycobacterium leprae.

Incubation : ~ 5 years

Mycobacterium leprae

Mycobacterium leprae, the causative agent of leprosy. As acid-fast bacteria, M. lepraeappear red when a Ziehl-Neelsen stain is used

Leprosy is primarily a granulomatousLeprosy is primarily a granulomatousdisease of the peripheral nerves and mucosa of the upper respiratory tract; skinmucosa of the upper respiratory tract; skin lesions are the primary external symptom. Left untreated leprosy can be progressiveLeft untreated, leprosy can be progressive, causing permanent damage to the skin, nerves limbs and eyesnerves, limbs, and eyes.

Cutaneous leprosyCutaneous leprosy lesions on a patient's thighthigh.

The clinical symptoms of leprosy vary but primarily affect the skin, nerves, and mucous p ymembranes.

Effective treatment for leprosy appeared in ythe late 1940s with the introduction of dapsone and its derivatives. However, leprosy ybacilli resistant to dapsone gradually evolvedand became widespread, and it was not until the introduction of multidrug therapy (MDT) in the early 1980s that the disease could be diagnosed and treated successfully within the community.

CLASSIFICATIONCLASSIFICATION

• Paucibacillary (tuberculoid leprosy)• Multibacillary Hansen's diseasey

(lepromatous leprosy)• or borderline leprosyor borderline leprosy

PAUCIBACILLARYPAUCIBACILLARY

Paucibacillary Hansen's disease isPaucibacillary Hansen s disease is characterized by one or more hypopigmented skin macules andhypopigmented skin macules and anaesthetic patches, i.e., damaged peripheral nerves that have been attackedperipheral nerves that have been attacked by the human host's immune cells.

MULTIBACILLARYMULTIBACILLARY

Multibacillary Hansen's disease isMultibacillary Hansen s disease is associated with symmetric skin lesions, nodules plaques thickened dermis andnodules, plaques, thickened dermis, and frequent involvement of the nasal mucosa resulting in nasal congestion and epistaxisresulting in nasal congestion and epistaxis(nose bleeds) but typically detectable nerve damage is latenerve damage is late.

BORDERLINEBORDERLINEBorderline leprosy (also termed multibacillary), of intermediate severity, is the most common form. Skin lesions resemble tuberculoid leprosy but are more numerous and irregular; largebut are more numerous and irregular; large patches may affect a whole limb, and peripheral nerve involvement with weakness and loss ofnerve involvement with weakness and loss of sensation is common. This type is unstable and may become more like lepromatous leprosy or y p p ymay undergo a reversal reaction, becoming more like the tuberculoid form.

Tabel MIC ANTILEPROSY DRUGS

Obat MIC Dosis Rasio serum Lamanya konsentrasi Aktivitas

Ug/ml mg puncak MIC serum lampaui MIC (hari) bakterisidal

Rifampicin 0.3 600 30 1 +++DDS 0 003 100 500 10 +DDS 0.003 100 500 10 +Acedapson 0.003 225 15 200 -Etionamid 0.05 375 60 1 ++Protionamid 0.05 375 460 1 ++Clofazimin - 50/100 - - +

TREATMENT of LEPROSY

Multidrug therapy (MDT) and combining allMultidrug therapy (MDT) and combining all three drugs was first recommended by a WHO Expert Committee in 1981 TheseWHO Expert Committee in 1981. These three anti-leprosy drugs are still used in the standard MDT regimens None of themthe standard MDT regimens. None of them are used alone because of the risk of developing resistancedeveloping resistance.

THERAPYTHERAPY:

DAPSONRIFAMPICINRIFAMPICINCLOFAZIMIN

DAPSONDAPSON

Mechanism Of Action:Mechanism Of Action: Competitive antagonist of para-aminobenzoic

acid (PABA) and prevents normal bacterialacid (PABA) and prevents normal bacterial utilization of PABA for the synthesis of folic acidacid

RIFAMPICINRIFAMPICIN

Mechanism Of Action:Mechanism Of Action: Rifampicin inhibits DNA-dependent RNA

polymerase in bacterial cells by binding itspolymerase in bacterial cells by binding its beta-subunit, thus preventing transcription to RNA and subsequent translation toto RNA and subsequent translation to proteins.

CLOFAZIMINECLOFAZIMINE

Mechanism Of Action:Mechanism Of Action: Belongs to the class of drugs known as riminophenazines. Appears to preferentially bind to mycobacterial DNA leading to disruption of the cell cycle and eventually kills the bacterium. It l bi d t b t i l t iIt may also bind to bacterial potassium transporters, thereby inhibiting their function. Lysophospholipids have been found to mediateLysophospholipids have been found to mediate the activity of this drug. Evidence also suggests that it inhibits the Na/K ATPase.

The WHO Study Group's report on the Chemotherapy of Leprosy in 1993Chemotherapy of Leprosy in 1993 recommended two types of standard MDT regimen be adaptedregimen be adapted.

The first was a 24-month treatment for multibacillary (MB or lepromatous) cases using rifampicin, clofazimine, and dapsone.

The second was a six-month treatment for paucibacillary (PB or tuberculoid) cases usingpaucibacillary (PB or tuberculoid) cases, using rifampicin and dapsone.

Until the development of dapsone, rifampin, U e de e op e o dapso e, a p ,and clofazimine in the 1940s, there was no effective cure for leprosy. However, dapsone p y , pis only weakly bactericidal against M. lepraeand it was considered necessary for patients y pto take the drug indefinitely. Moreover, when dapsone was used alone, the M. lepraep , ppopulation quickly evolved antibiotic resistance; by the 1960s, the world's only ; y , yknown anti-leprosy drug became virtually useless.

WHO (1998) ( )

• MB (12-18 month)( )• PB with 2-5 lesion (6-9 month)• PB only 1 lesion :

Rifampicin 600 mg + Ofloxacin 400 mg + Minosiklin 100 mgsingle dose

Or• MB resistance to Rifampicin and DDS ‘CLOFAZIMIN’:• MB resistance to Rifampicin and DDS CLOFAZIMIN :

Clofazimin 50 mg + Ofloxacin 400 mg + Minosiklin 100 mgduring 18 month (everyday).during 18 month (everyday).

In Patient reject Clofazimin, we can use:j ,• Rifampicin 600 mg + Ofloxacin 400 mg + Minosiklin 100 mg

single dose/month (24 month)

Medan 28 Januari 2009Medan, 28 Januari 2009