K45 - Antiviral Antifungi Anthelmentic Antiamoeba Antimalaria (FT)

8/10/2019 K45 - Antiviral Antifungi Anthelmentic Antiamoeba Antimalaria (FT)

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Dept. Pharmacology & TherapeuticSchool of Medicine

Universitas Sumatera Utara


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Different living organisms

Eucaryotes Mono or polycellularCell nucleus; DNAMay have cell wall

Sexual and/or asexual

replication

Animals

PlantsFungi

Protocista (protozoea, algea)

Procaryotes BacterieaMonocellular, no nucleus

DNA single strandCell wall, asexual replication

Virus RNA or DNA + protein coating(not really a cell)

Use other organisms

ribosomes for protein

synthesis


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INFEKSI VIRUS

PELEKATAN VIRUS DAN DINDING SEL(DIHIDROLISA OLEH ENZIM VIRUS)

DNA/RNA MASUK KE DLM SEL SEDANG

CAPSID TIDAK VIRUS SEBAGAI PARASIT, MENGGUNAKAN

PROSES ASIMILASI SELVIRION BARU

( PERBANYAKAN VIRION SAMPAI PUNCAKGEJALA PENYAKIT)


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Antiviral Drugs

Amantadine and analogs

Neuraminidase Inhibitors

Nucleoside analogs - Antimetabolites

Other comp. that interfere with replication

Comp. that interfere with translation (protein synth)

Interferon / interferon inducers

Specific retroviral drugs Reverse transcriptase inhibitors Nucleosides (NRTIs) Non-nucleosides (NNRTIs)

Protease inhibitors


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Klasifikasi Antivirus berdasarkanMekanisme Kerjanya

Mekanisme Kerja Antivirus

Menghalangi penetrasi Globulins

Menghalangi uncoating Amantadine & Rimantadine

Menghambat sintesis protein awal Formivirsen

Menghambat sintesis asam nukleat 1. Analog purin & pirimidin (Acyclovir,

Valacyclovir, Famciclovir, Penciclovir,

Ganciclovir, Idoxurudine, Sorivudine,Trifluridine,

Cidofovir, Vidarabine, Ribavirine)2. Pyrophosphate anorganic (Foscarnet )

3. NRTI (Zidovudine, Lamivudine, Stavudine

Didanosine, Zalcitabine, Abacavir)

4. NNRTI (Nevirapine, Delavirdine, Efavirenz)

Menghambat sintesis protein akhir Inhibitor protease (Saquinavir, Ritonavir,Indinavir, Nelfinavir, Amprenavir)

Menghambat perakitan Rifampin

Menghambat rilis Inhibitor neuraminidase (Zanamivir, Oseltamivir)

Menghambat penetrasi, uncoating,

sintesis mRNA, translasi,

perakitan,rilis

Interferon


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RT

Provirus

Proteins

RNA

DNA

RNA

DNA

DNA

RT

RNA

RNA

DNA

DNA

DNA

Viral regulatory

proteins

Viral protease

Reversetranscriptase

Viralintegrase

Viral zinc-finger

nucleocapsid

proteins

Fusioninhibition


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Aznan Lelo

Dep. Farmakologi & Terapeutik,Fakultas Kedokteran


15 Se tember 2012 Pemicu 3 TROPMED


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Dept. Pharmacology & TherapeuticSchool of Medicine



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Antiretroviral Classes

NRTIs(Nucleoside OR Nucleotide ReverseTranscriptase Inhibitors, aka Nukes)

NNRTIs(Non-Nucleoside ReverseTranscriptase Inhibitors, aka Non-Nukes)

PIs(Protease Inhibitors)

Fusion Inhibitors Chemokine Receptor Antagonists Integrase Inhibitors


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Mechanism of Action of ARVs

NNRTI

NRTI

Protease

Inhibitor

Illustration by David Klemm

Fusion

Inhibitor

Chemokine

Receptor

Antagonist

IntegraseInhibitor


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NRTIs (Nucleoside OR NucleotideReverse Transcriptase Inhibitors)

Drug Std Dose Dosage forms Side Effects Elimination

Zidovudine(ZDV/AZT)

Retrovir

300mg bid* 300mg tab,100mg cap,

iv, oral soln

Fatigue, malaise, HAmyalgia, anemia, GI

Renal

Lamivudine

(3TC) Epivir

150mg bid* or

300mg qd

150, 300mg tab,

oral soln

Well tolerated Renal

Emtricitabine

(FTC) Emtriva

200mg qd* 200mg cap Well tolerated Renal

Didanosine

(ddI) Videx

400mg EC qd (

60kg)

250mg EC qd

(


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NRTI Class Toxicities

Lactic Acidosis Damage to mitochondria in cells Elevated lactate, low pH/bicarbonate, N/V,

shortness of breath, if untreated can lead todeath

Lactic acidosis can occur with any NRTIs

Hepatomegaly with Steatosis Build up of fat droplets

inside liver cells

Enlarged liver


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NNRTIs

Drug Std Dose Dosage forms Side Effects Elimination

Delavirdine

(DLV)

Rescriptor

400 mg tid 100mg tab,

200mg cap

Rash Potent CYP3A

inhibitor; 3A4

substrate

Nevirapine

(NVP)

Viramune

200 mg qd

x 14 d then

200 mg bid

200mg tabs,

Oral susp

Rash (SJ),

hepatotoxicity

CYP3A

inducer, auto

inducer; 3A4,

2B6 substrate

Efavirenz*

(EFV) Sustiva

600 mg qhs 50, 100,

200mg cap,

600mg tab

Vivid dreams,

drowsiness or

insomnia, rash(SJ),

hyperlipidemia

CYP3A, 2B6

inducer; 2B6,

3A4 substrate

*Pregnancy Class D


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Protease Inhibitors (PIs)Drug Std Dose Dosage forms Side Effects Metabolism

Atazanavir

(Reyataz) (1)

400qd or

300/ rtv 100qd

100, 150, 200mg

caps

Hyper-

bilirubinemia, PR

prolongation

3A substrate;

3A and UGT1A1

inhibitor

Fosamprenavir

(Lexiva) (1)

1400mg bid;

700/100 RTV mg

bid; 1400/200 RTV

mg qd

700mg tabs

(Agenerase-APV

liq available)

Rash,

GI intolerance,

caution with

sulfur allergy

3A4, Pgp

substrate;

3A4 inducer/

Inhibitor

Tipranavir

(Aptivus) (1,2)

500/200 RTV mg

bid

250mg caps Hepatotoxicity,

Increased

bleeding

caution with

sulfur allergy

3A4, Pgp

substrate;

3A4, inducer/

inhibitor??; Pgp

inducer

Darunavir

(Prezista) (1)

600/100 RTV mg

bid

300mg tabs Diarrhea, nausea,

nasopharyngitis

3A4 substrate;

3A4 inhibitors

Ritonavir

(Norvir) (1,2)

Used as a PK

booster 100-

200mg

100mg caps;

80mg/mL

Nausea,vomiting,

diarrhea, GI

upset

2D6, 3A4, Pgp

substrate; 3A4,

Pgp inhibitor

(1) Take with Food; (2) Must be refrigerated** All PIs except atazanavir can increase lipids and cause insulin resistance


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Dose adjustments to consider

Renally-eliminatedNRTIs (except Abacavir)

Adjust for CrCl


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ARV metabolism, induction, and inhibition

Drug Substrate Inhibits Induces

Efavirenz 2B6, 3A4 3A4 3A4, 2B6

Nevirapine 3A4, 2B6 3A4

Ritonavir 2D6, 3A4, Pgp 3A4, 2D6, Pgp 2D6 (at highdoses only)

Saquinavir 3A4, Pgp 3A4Nelfinavir 2C19 (M83A4) 3A4

Amprenavir 3A4, Pgp 3A4 (in vitro) 3A4 (in vivo)

Fosamprenavir 3A4, Pgp 3A4 (in vitro) 3A4 (in vivo)

Lopinavir/ritonavir 3A4, Pgp 3A4 2C9, 2C19, 1A2Atazanavir 3A4, Pgp 3A4, UGT, 1A2

Tipranavir 3A4, Pgp 3A4 Other enzymes

Darunavir 3A4, Pgp 3A4

Maraviroc 3A4, Pgp


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Cytochrome P450: Non-Antiretrovirals

CYP Substrate Inhibitor Inducer

3A4 Macrolides,cyclosporine,

CCB, statins, azoles, PDE5inhibitors, aprepitant,

midazolam, triazolam

Cimetidine,

Macrolides, FQs,SSRIs, CCB,

azoles, aprepitant

rifamycins,

phenytoin, CBZ,St. Johns wort,aprepitant, garlic

2D6 nortriptyline, amitriptyline,

tramadol, trazodone, opiates,

paroxetine, metoprolol,

propranolol, carvedilol

Haldol, SSRIs,

cimetidine,

amiodarone

rifamycins,

phenytoin, CBZ,

St. Johns wort

1A2 Amitriptyline, clozapine,

caffeine, clozapine, imipramine,

R-warfarin, theophylline,

proprnaolol

FQs, azoles,

macrolides,

rifamycins,

phenytoin, CBZ,

smoking, St.

Johns wort

2C19 Omeprazole, phenytoin SSRIs, azoles,fluvastatin,

omeprazole,

topiramate

rifamycins, CBZ,phenytoin

2C9 S-warfarin, sulfonylureas,

phenytoin, carvedilol

Amiodarone,

SSRIs, azoles,amiodarone

Phenytoin, CBZ,

rifammycins,aprepitant


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Protease Inhibitors and Acid Suppression

Do Not combine Atazanavir and ProtonPump Inhibitors May Combine ATV and Famotidine but

dose adjustments are REQUIRED

May use Indinavir with PPIs but ONLY ifcoadministered with RTV

May use Fosamprenavir withEsomeprazole Separate FPV from H2 blockers if used

concomitantly


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PI Drug Interactions

All PIs are metabolized all or in part by theCYP3A4 enzyme system

All PIs can inhibit CYP3A4 enzymes Ritonavir most potent inhibitor

Saquinavir least potent inhibitor

Ritonavir can also induce CYP1A2


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Important Drug Interactions

Do NOT use Simvastatin, Lovastatin, Antiarrthymics,Midazolam, Triazolam, Ergot derivatives, Rifamin, St. JohnsWort, or Garlic with most PIs or DLV

Do NOT combine Rifampin with PIs LPV/RTV may be dose increased and combined with Rifampin Conflicting data with EFV and NVP

Use other P450 inducers with CAUTION when combining withPIs and NNRTIs

Do NOT use Fluticasone or Alfuzosin with Ritonavir Caution with Azoles, Clarithromycin, Oral Contraceptives,

Phenytoin, Carbamazepine, Phenobarbital, Methadone, PDE5inhibitors, Atorvastatin, Beta blockers, when combined with PIs

Avoid Herbal Products with Known or Suspected Interactions When combining Protease Inhibitors, Often Dose Adjustments

are Necessary


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PI / NNRTI / Antidepressant

Drug Interactions

Anti-

depressant

Potential for

Interaction

Effects Management

Amitriptyline ritonavir,

lopinavir/r,

amprenavir,

Levels of

amitriptyline may be

increased

Start with lower dose

(50%) of amitriptyline,

adjust dose whenaddIng ritonavir.

Monitor for side effects

Fluoxetine ritonavir,

lopinavir/r, all

other PIs,

efavirenz

Levels of both

fluoxetine and

ARVs may be

increased

As above

Sertraline ritonavir,

lopinavir/r, all

other Pis,

efavirenz

Levels of sertraline

may be increased.

ARV levels

not likely to change.

As above


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ARV Interactions with Recreational Drugs

Effect Comments

Alcohol Abacavir AUC 41% Clinical significance

unknownAmphetamines RTV may amphetamine

levels

Potential amphetamine

toxicity

Barbiturates Potential levels of PIs and

NNRTIs

Potential virologic

failure/resistance

Benzo-diazepines Midazolam and triazolamlevels with PIs and delavirdine

(levels of alprazolam and

clonazepam may )

Potential benzodiazepinetoxicity

-hydroxybutyrate

(GHB)

Potential GHB levels Potential GHB toxicity

Heroin Potential enhanced heroin

effect

Clinical significance

unknown

Marijuana Minimal effect on IDV and NFV Interaction with ARVs

unlikely

3,4-MDMA(Ecstasy) Potential

ecstasy levels Potential ecstasy toxicity


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Antiretroviral therapy

Three classes of antiretroviral drugs:

nucleotide reverse transcriptase inhibitors (NRTIs)

non-nucleotide reverse transcriptase inhibitors (NNRTIs)

Protease inhibitors (PIs)

Life-long triple therapy

HAART: highly active antiretroviral therapy

Antiretrovirals are on WHO essential drugs list


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0

200

400

600

800

1000

1200

1400

1998 1999 2000 2001 2002

Year

NumberofAID

Sdeaths

Italy

Spain

Germany

United Kingdom

Continued impact of HAART on AIDS deathsin some Western European countries, 1998-2002

Source: HIV/AIDS surveillance in Europe (2002). End-of-year report. Data compiled by the EuropeanCentre for theEpidemiological Monitoring of AIDS


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Obat-obat kombinasi

Kombinasi Nama Paten Keterangan

ABC + 3TC Epzicom (US)

Kivexa (Europe)

Take with or

without foodABA + AZT +3TC

Trivizir Take with orwithout food

AZT + 3TC Combivir Take with orwithout food

TDF + FTC Truvada Take with orwithout food


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Pilihan Kombinasi Obat LINI PERTAMA

Zidovudine

2 x 300 mg

atau

Stavudine

2 x 40 mg

Lamivudine

2 x 150 mg

Nevirapine

2x 200mg

atau

Efavirenz

1 x 600 mg

+ +

DepKes RI 2004

Zidovudine + Lamivudine + Nevirapine


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Pilihan Kombinasi Obat LINI KEDUA

Abicavir

2 x 300 mg

atau

Tenofovir

1 x 300 mg

Didanosine2 x 250 mg

Nelfinavir

2 x 1250 mg

atau Lopinavir/ritonafir

2x 400mg/100mg

atau

Saquinavir/ritonavir

2 x 1000mg/100mg

DepKes RI 2004


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Pemantauan laboratorium dasar untuk rejimen ARV lini-I

di Layanan Kesehatan Dasar, dan Menengah

RejimenPenilaian laboratorium

dasar (pra-terapi)Penilaian laboratorium selama terapi

AZT + 3TC

+ NVP

Diharuskan: Hb

Perlu tapi tidak diharuskan: DL,

CD4

Hb, Lekosit, fungsi hati(ALT/SGPT)

CD4setiap 6 -12 bulan, bila tersedia, untuk

memantau efikasi

AZT + 3TC

+ EFV

Diharuskan: Tes kehamilan, Hb

Perlu tapi tidak diharuskan:

CD4, DL

Hb, Lekositbila ada gejala

CD4 setiap 6 -12 bulan, bila tersedia, untuk

memantau efikasi

D4T + 3TC +

NVP


CD4

Fungsi hati (ALT/SGPT) bila ada gejala

CD4setiap 6 -12 bulan, bila tersedia, untukmemantau efikasi

d4T + 3TC +

EFV

Diharuskan: Tes kehamilan


CD4

Pemantauan toksisitas tergantung gejala (tidak

rutin)


memantau efikasi


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Dual Protease Inhibitor Combinations

Exploits the enzyme inhibition properties ofPIs, specifically RTV

Lessens pill burden

Theoretical ability to suppress resistant HIVstrains by enhancement of PI plasma levels


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Basic Pharmacology Principles

IC90

IC50

Cmin

Cmax

Time

Dosing Interval

Area of Potential HIV Replication

Dose Dose


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Time Postdose (hours)

0 2 4 6 8 10 12

100

1,000

10,000IDV/RTV q12h:

800/200 High-fat Meal



IDV q8h:

800 mg Fasted

Indinavir

Plasma

Concentration

(nM)

6th Conference on Retroviruses and Opportunistic Infections; 1999. Abstract 362.

Indinavir/Ritonavir

Pharmacokinetics


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Drug Interactions

Antiretroviral drugs in combination withother drugs: conventional dose

modification situation

Example: Indinavir and rifabutin


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Drug Interactions- Typical

IDV 800 mg q8hr + RIF 150 mg qd vs. IDV800 mg q8hr

IDV AUC 32%

IDV Cmax 20%

IDV Cmin 40%

Recommendation: Inc rease IDV dose to 1000 mg q8hr when

adm in istered w ith RIF.


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Drug Interactions

RIF 150 mg qd + IDV 800 mg q8hr vs. RIF300 mg qd

RIF AUC 54%

RIF Cmax 29%

25-desacetyl-RIF AUC 300%

25-desacetyl-RIF Cmax 143%

Recommendation: Reduce RIF dose to one-half the standard

dose when adm inis tered w ith IDV.


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Binding

FusionReverse transcription

Nuclear localization

Uncoating

Integration

Transcription

Splicing

RNA export

Genomic RNA

mRNA

Translation

ModificationBudding

AssemblyMaturation

Endocytosi

s

Lysosome


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Dept. Pharmacology & Therapeutic

School of MedicineUniversitas Sumatera Utara


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The antifungal drugs presently

available fall into several

categories:

systemic drugs (oral or parenteral) for

systemic infections,oral drugs for mucocutaneous infections,

and

topical drugs for mucocutaneous

infections.


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ANTIFUNGAL

I. Systemic Antifungal Agents

1. Griseofulvin

2. Oral Azole Derivatives

3. Terbinafine

4. Hidroksistilbamidin

5. Flucytosin6. Amphoterisin B


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III. TOPICAL ANTIFUNGAL AGENTS

1. Topical Azole Derivatives

2. Ciclopirox Olamine

3. Naftitine

4. Terbinafine

5. Butenafine

6. Tolnaftate

7. Nystatin

8. Natamisin

9. Asam lemak

10. Haloprogin


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The treatment of superficial fungal infections caused

by dermatophytic fungi may be accomplished

1. Topical antifungal agents

- clotrimazole

- miconazole

- econazole

- ketoconazole

- oxiconazole

- sulconazole

- ciclopirox olamine

- naftitine

- terbinafine

- and tolnaftate


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2. Orally administered agents

- griseofulvin

- terbinafine

- ketoconazole

- fluconazole- and itraconazole.


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3. Superficial infections caused by candida species may

be treated with topical applications of- clotrimazole- miconazole- econazole

- ketoconazole- oxiconazole- ciclopiroxolamine- nystatin

4. Chronic generalized mucocutaneous candidiasis isresponsive to long-term therapy with oralketoconazole.


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Mechanism of action antifungal drugs

ANTIFUNGAL DRUGS


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ANTIFUNGAL DRUGS

Griseofulvin,

Amfoterisin

B, Nistatin,

NatamisinFlusitosin Ketokonazol,Flukonazol,

Itrakonazol,

Mikonazol


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Pharmacokinetic Antifungal Drugs

No Drugs Absorp

tion

Distribution Meta

bolism

Excretion

1. Amphoterisin

B

- - Urine

Billier

2. Fluconazole Urine

3. Fluciytosin CNS fluid Urine

4. Ketoconazole Urine

Billier

5. Griseofulvin Tissue

keratin

Urine

Faeces6. Nystatin - Fungal

Sterol

- Faeces

7. Salicylic Acid - - - -

Ph d i A tif l D


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Pharmacodynamic Antifungal Drugs

No Drugs Indications Side effects Contraindications Exp.

1. Amphoterisin B -Sinusitis

-Meningitis kronis

-Kandidiasis

-Menggigil

-Demam

-Muntah

-Sakit Kepala

-Hipotensi

-Muntah

-Diare

-Gangguan fungsi hati

Obat pilihan untuk

infeksi jamur sistemik

yang berat

2. Fluconazole -Kandidiasis oral

dan esophagus

-Kandidiasis

sistemik

-Meningitis

-Muntah

-Diare

-Gangguan

fungsi hati

-Gangguan fungsi hati

-Kehamilan dan laktasi

-Hipersensitivitas

3. Flucytosine -Kandidiasis

-Meningitis

kriptokokal

-Mual,Muntah

-Rash

-Depresi sum-

sum tulang

-Gagal Ginjal

-Kehamilan dan Laktasi

+ Amfoterisin B =

Aktifitasnya

4. Ketoconazole -Blastomikosis

-Histo

plasmosis

-Kandidiasis

-Dermato

mikosis

-Mual

-Ginekomastia

-Hepatitis

Kolestatik

-Hipersensitivitas

-Kehamilan dan Laktasi

-Penyakit hepar akut

Ketokonazol merupakan

obat pilihan untuk

Blastomikosis


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harmacodynamic cont

No Drugs Indications Side Effects Contraindication Explanation

5. Griseofulvin Infeksi

dermatofitosis

berat pd kulit,

rambut, kuku

disebabkan

Trycophyton

rubrum.

-Infections

-Serum

Sickness

-Leukopenia

Kehamilan Obat pilihan untuk

infeksi

dermatofitosis yang

berat

6. Nystatin -Skin Candidiasis

,selaput

Lendir, GIT

-Stomatitis

-Muntah

-Diarrhae

Hyper

sensitivitas

(-) Superinfeksi

pada wanita hamil

7. Salisilyc acid -Ptyriasis

versicolor

-Tinea Pedis

-Alergi Hiper

sensitivitas

Asam salisilat

bekerja keratolitis,

yaitu dapat

melarutkan lapisan

tanduk

Antifungal Clinical Applications


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Antifungal Clinical Applications

No. Disease Therapy

1. 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 week

Ung.Whitfield (Benzoic Acid 5 %, Salisilyc acid 5% in lanolin-

vaselin ana)

7. Tinea Unguium

(Onicomycosis)

Terbinafine tablet 250 mg/days

6 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].

9. Ptyriasis versicolor Salisilat acid 5-10% (used in ruam)

Ketoconazole cream during 2-3 weeks


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As with all topical products, selection of thedosage form may be as important as proper

drug selection.

Thin liquids may preferable for application tohairy areas, creams for the hands and face,

and ointments may be preferable for the trunk

and legs. Other dosage forms available include

shampoos and sprays.


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Most topical antifungal drugs require fourweeks of treatment. Infections in some areas,

particularly the spaces between toes, may

take up to six weeks for cure.


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Precautions

Most topical antifungal agents are well tolerated. The

most common adverse effects are localized irritationcaused by the vehicle or its components. This may

include redness, itch, and a burning sensation. Some

direct allergic reactions are possible.

Topical antifungal drugs should only be applied inaccordance with labeled uses. They are not intended

or ophthalmic (eye) or otic (ear) use. Application to

mucous membranes should be limited to appropriateformulations.


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The antifungal drugs have not been evaluatedfor safety in pregnancy and lactation on

topical application under the pregnancy riskcategory system. Although systemic

absorption is probably low, review specific

references.

Interactions

Could be reduced metabolism of several drugs


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Rejimen ARV

AZT : zidovudin

3TC : lamivudin

NVP : navirapin

d4T : Stavudine

EFV : Efavirens


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Rejimen ARV

AZT + 3TC + NVP

d4T + 3TC + NVP

AZT + 3TC + EFV

d4T + 3TC + EFV


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Pemantauan laboratorium dasar untuk rejimen ARV lini-I

di Layanan Kesehatan Dasar, dan Menengah

RejimenPenilaian laboratorium

dasar (pra-terapi)Penilaian laboratorium selama terapi

AZT + 3TC

+ NVP

Diharuskan: Hb

Perlu tapi tidak diharuskan: DL,

CD4

Hb, Lekosit, fungsi hati(ALT/SGPT)


memantau efikasi

AZT + 3TC

+ EFV

Diharuskan: Tes kehamilan, Hb


CD4, DL

Hb, Lekositbila ada gejala

CD4 setiap 6 -12 bulan, bila tersedia, untuk

memantau efikasi

D4T + 3TC +

NVP


CD4

Fungsi hati (ALT/SGPT) bila ada gejala

CD4setiap 6 -12 bulan, bila tersedia, untukmemantau efikasi

d4T + 3TC +

EFV

Diharuskan: Tes kehamilan


CD4

Pemantauan toksisitas tergantung gejala (tidak

rutin)


memantau efikasi


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0

5

10

15

20

25

30

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Triple therapy

No therapyMonotherapy

Dual therapy


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Mechanisms for treatment-I

Attack a unique enzyme found in parasite

Folate synthesis blocked by sulfonamide(Folate- dihydrofolate reductase - FH2dihydrofolate reductase FH4Deoxythymidylic acid Methionine.

Allopurinol riboside is phosohorylated andis added to 5-O position in purines and isnon functional, all protozoa especially

Leishmainaia.


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Mechanism II

Drug affect enzyme system found in both

host / parasite but is indispensable for

parasite.

Trypansomebrucic lack krebs cycle Salicyl hyroxamic acid (SHAM) forces

parasite into anaerobic condition,

glycolysis is blocked by glycerol causingrapid lysis.


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Mechanism III

Common biochemical functions found in

host / parasite but have different

pharmacological properties

Ivermectin affects synaptic transmission byincreasing inhibitory transmitter (GABA) increase

inhibition causes flaccid paralysis.

does not cross mammalian blood / brain barrier. Drug can act as a GABA agonist causing

increased muscular contaction e.g Levamisol


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Antiprotozoal drugs

Chemotherapy of AmebiasisChloroquine, Dehydroemetine, Diloxanide furoate,Emetine, Metronidazole, Paramomycin.

. Chemotherapy of MalariaChloroquine, Mefloquine, Primaquine, Pyrimethamine,quinine/ quinidine.

. Chemotherapy of Tyrpanosomiasis

Melarsoprol, Nifurtimox, Pentamidine, Suramin.


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Antiprotozoal drugs (contd)

Chemotherapy of Leishmaniasis Sodium stibogluconate

Chemotherapy of Toxoplasmosis Pyrimethamine.

Chemotherapy of Giardiasis Quinacrine

Drugs used in leishmaniasis and


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Drugs used in leishmaniasis and

trypanosomiasis

Leishmaniasis may occur as a skin infection or as an infectionof the viscera. Metronidazole is used for the former, and

sodium stibogluconate given parenterally for the latter.

Trypanosome species cause sleeping sickness in Africa and

chagas diseasein south america .Drugs used are suramin giveni.v and pentamidine i.m.


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Anthelminthic Drugs

An anthelminthic drug may act by causing narcosis or paralysisof the worm, or by damaging the cuticle,leading to partial

digestion or to rejection by immune mechanisms.

Anthelminthic drugs may also interfere with the metabolism

of the worm, and since the metabolic requirements of theseparasites vary greatly from one species to another , this may

be the reason why drugs that are highly effective against one

type of worm are ineffective against others.

Nematoda (roundworms) 1st choice 2nd choice


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Nematoda (roundworms) 1 choice 2 choice

Asc aris lumbr ico ides

(roundworm)

Albendazole/

Pyrantel pamoate/

Mebendazole

Piperazine

Trichu r is tr ichiura

(whipworm)

Mebendazole/

Albendazole

Oxantel/

Pyrantel pamoate

Necator americanus

(hookworm);

Anc ylostom a duod enale(hookworm)

Pyrantel pamoate/

Mebendazole/

Albendazole

Strongy loides stercoral is

(threadworm)

Ivermectin Thiabendazole,

Albendazole

Enterobius verm icular is

(pinworm)

Mebendazole/

Pyrantel pamoate

Albendazole

Trichinel la sp iral is

(trichinosis)

Mebendazole(+kortikosteroid untuk

infeksi berat)

Albendazole(+kortikosteroid untuk

infeksi berat)

Tr ichostrong ylus speciesPyrantel pamoate/

Mebendazole

Albendazole


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1stchoice 2ndchoice

Cutaneous larva migrans

(creeping eruption)

Albendazole/

Ivermectin

Thiabendazole

(topikal)

Visceral larva migrans Albendazole Mebendazole

Ang iostrongy lus cantonensisThiabendazole Albendazole/

Mebendazole

Wucherer ia bancroft i (filariasis);

Bru gia malayi (filariasis); tropicaleosinophilia;

Loa loa (loiasis)

Diethylcarbamazi

ne

Ivermectin

Onchocerca volvu lus

(onchocerciasis)

Ivermectin Suramin

Dracunc ulus m edinensis (guinea

worm)

Metronidazole Thiabendazole/

Mebendazole

Capi l lar ia ph i l ippinensis

(intestinal capillariasis)

Albendazole Mebendazole/

Thiabendazole

Trematoda (flukes) 1stchoice 2ndchoice


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( )

Schistosom a haematobium

(bilharziasis)

Praziquantel Metrifonate

Schis tosoma manson i Praziquantel OxamniquineSchistosom a japon icum Praziquantel

Clonorchis s inensis

(liver fluke);

opisthorchis species

Praziquantel Albendazole

Paragon imus westermani

(lung fluke)

Praziquantel Bithionol

Fasc iola hepatica

(sheep liver fluke)

Bithionol/

Triclabendazole

Fascio lop sis buski

(large intestinal fluke)

Praziquantel/

Niclosamide

Heterophyes heterophyes

Metagon imu s yokogawai

(small intestinal flukes)

Praziquantel/

Niclosamide

C t d ( i it ) 1st h i 2nd h i


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Cestoda (cacing pita) 1stchoice 2ndchoice

Taenia sagin ata

(beef tapeworm)

Praziquantel/

Niclosamide

Mebendazole

Taenia sol ium

(pork tapeworm)

Praziquantel/

Niclosamide

Diphyl lobothr ium latum

(fish tapeworm)

Praziquantel/

Niclosamide

Cysticercosis

(pork tapeworm larval stage)

Albendazole Praziquantel

Hymenolepis nana

(dwarf tapeworm)

Praziquantel Niclosamide

Echinococcu s granulosu s

(hydatid disease);

Echinococcus

mult i locular is

Albendazole

Mekanisme kerja anthelmentic


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j

ObatMekanisme

Kerja

Efek

Spesifik

PiperazineMemparalisisotot cacing

Memblokir myoneural junction;agonis gated chloride channels

hiperpolarisasiparalisis flasid

Ivermectin

Memparalisis

otot cacing

Memblokir transmisi sinyal-sinyal saraf

dengan berinteraksi dengan glutamate

gated chloride channels

Pyrantel

Memparalisis

otot cacing

Agonis reseptor asetilkolin nikotinik &

menghambat kolinesterase

depolarisasi & paralisis spastik

Metrifonate

(Trichlorfon)

Memparalisis

otot cacing

Menginaktivasi asetilkolinesterase &

mempotensiasi efek-efek kolinergik

inhibitori

Praziquantel

Memparalisis

otot cacing

Meningkatkan permeabilitas membran

terhadap Ca2+memaparkan protein-

protein membrandiserang antibodi

Bithionol

Menghambat

produksi energi

Menghambat fosforilasi oksidatif



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ObatMekanisme

Kerja

Efek

Spesifik

Niclosamide

Menghambat

produksi energi


anaerobik dalam mitokondria cacing

sintesa ATP

MebendazoleMenghambat

produksi energi

Berikatan dengan tubulin & menghambat

polimerisasi

ThiabendazoleMenghambatproduksi energi &

fungsi protein

Menghambat fumarat reduktase &sintesa ATP; berikatan dengan tubulin

Suramin

Menghambat

produksi energi

Menghambat enzim-enzim otot yang

berkait dengan glikolisis & konsumsi

oksigen

OxamniquineMengesterifikasi &

mengikat DNA

Menghambat sintesa asam nukleat &

protein

Diethyl-

carbamazine

Mempermudah

fagositosis &

eliminasi

Meningkatkan kesensitifan mikrofilaria,

memerangkap mikrofilaria dalam sistem

retikuloendotelial

Farmakoterapi


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Farmakoterapi

Obat-obat pilihan adalahbenzidimazole(BZA):

albendazole(dosis tunggal 400mg, 200 mg: anak-anak 12-24 bulan) /

mebendazole(100 mg 2x/hariuntuk 3 hari (dewasa & anak >2 tahun) /

levamisole (dosis tunggal 2,5mg/kg) /

pyrantel pamoate (dosis tunggal11 mg/kg, tetapi 1 g)

(WHO 2002)

Migrasi larva A. lumbr ico ides

bisa menyebabkan

pneumonia hemoragik.
http://www.who.int/water_sanitation_health/index.html


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73/210


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Drugs used in amoebiasis

Amoebiasesis due to infection with Entamoebahistolytica, which causes dysentery associated withinvasion of the intestinal wall and, rarely, of the liver. Theorganism may be present in motile, invasive form, or asa cyst.

Metronidazole: given orally,is active against the invasiveform in gut and liver but not the cyst.Unwanted effects,which are rare, include GI upsets and CNS symptoms.

Diloxanide: given orally with no serious unwanted

effects, active while unabsorbed against the non invasiveform.

Chloroquine: used for hepatic amoebiasis.


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Classification of anti-amoeba

Tissue Amoebiasis*Both intestinal & extra intestinal

Nitroimidazoles Metronidazole, Tinidazole, Secnidazole, Ornidazole

Alkaloids Emetine, Hydroemetine

* Extra intestinal amoebiasis only

ChloroquineLuminal amoebiasis Amide (Diloxanide furoate) 8-Hydroxy quinolones (Quinidochlor) Antibiotics (Tetracycline)


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Anti-AmoebaAnti-amoeba Indication MoA ADR

Chloroquine Amebic liverabscess

Metronidazole Intestinal &extra-intestnal

Disruption of

DNA synthesis

& nucleic acidsynthesis

Metallic taste,

nausea,

vomiting,diarrhea,

abdominal

cramps

Iodoquinol Intestinal Directly kills the

protozoa

N/V, diarrhea,

anorexia,agranulocytosis

Paramomycin Intestinal Inhibiting proteinsynthesis

N/V, diarrhea,

stomach

cramps,

ototoxic, tinnitus


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5-nitroimidazoles

Metronidazole, tinidazole, ornidazole,nimorazole.

Active on anaerobic bacteria and protozoa.

Entamoeba(not invariably the cysts) ,Trichomonas, Giardia, Blastocystis, ...

Disulfiram-like effects, mutagenic in bacteria.Pearson R.D. 2005. Chapter 41, In Mandell G.L. etal.


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Metronidazole

Prototype drug introduced in 1959

Bactericidal against

Giardia lamblia, anaerobic bacteria,

Bacteroides fragilis, Fusobacterium,

Clostridium perfringes, Helicobacter

pylori, Anaerobic Streptococci

d l ( )


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Metronidazole (MoA)

Not clearly understood Enters micro-organism by diffusion Nitro group reducedDNA damaged

Cytotoxicity High selective anaerobic actioninterference with electron transportation fromNADPH or other reduced substrates

Also inhibits cell mediated immunity Induce mutagenesis Cause radio-sensitization

id l


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Metronidazole

A nitroimidazole. The nitro group of metronidazole ischemically reduced in anaerobic bacteria and

sensitive protozoans. Reactive reduction products

appear to be responsible for antimicrobial activity.

Pharmacokinetics Oral metronidazole is readily absorbed and permeates all

tissues by simple diffusion.

Protein binding is low (


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Metronidazole

Mechanism of Action

Mechanism of action

Disruption of DNA synthesis as well as nucleic acid synthesis

Bactericidal, amebicidal, trichomonacidal

Used for treatment of trichomoniasis, amebiasis,giardiasis,and antibiotic-associated pseudomembranous

colitis

Also has anthelmintic activity

Adverse Effects:

Metallic taste, nausea, vomiting, diarrhea,abdominal cramps, many others

M id l


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Metronidazole

Contraindications Neurological diseases, blood dyscrasias, First trimester, Chronic alcoholism

Drug Interactions Disulfiram reaction Enzyme inducers - Rifampicin -therapeutic effect

Cimetidine - metronidazole metabolism - reducedose Metronidazole renal elimination of Lithium

Emetine


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Emetine Alkaloid from Cephaelis ipecacuanha

Potent directly acting amoebicide (trophozoites) Does not kill cysts

Cumulative toxicity high Seldom used

- Because of major toxicity concerns they have been

almost completely replaced by metronidazole.Reserve drugnot responding/intolerant to

metronidazole

Luminal amoebicide follows emetine to eradicate cysts

Administered subcutaneously (preferred) or i.m. (butnever i.v.) because oral preparations are absorbed

erratically

Dihydroemetine=effective but less toxic

Preferred over emetine

Dil id


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Diloxanide

Diloxanide furoate is a dichoroacetamide derivative. Effective luminal amebicide but is not active against

tissue trophozoites.

The unabsorbed diloxanide in the gut is the activeantiamebic substance.

Effective for asymptomatic luminal infections. It is used with a tissue amebicide, usually

metronidazole. Adverse Effects: flatulence, nausea, abdominalcramps, rashes, abortion.

N ti !


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Notice !

Treatment with tissueamoebicide SHOULD always be

followed by Luminalamoebicide to eradicate

source of infection

A ti t i h i i D


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Anti-trichomoniasis Drugs

Metronidazole Acetarsol

A h t ti l i l th


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Approaches to antimalarial therapy

Drugs used to treat the acute attack of malaria (clinical cure)act on the parasites in the blood; they can cure infections withparasites which have no exo-erythrocytic stage.e.g quinine,chloroquine

Drugs used for chemoprophylaxis, i.e to prevent malarialattacks when in a malarious area, act on merozoites emergingfrom liver cells. e.g quinine, chloroquine

Drugs used for radical cure are active against parasites in theliver e.g primaquine.

Drugs act on gametocytes and prevent transmission by themosquito e.g primaquine.

A ti l i l d


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Anti malarial drugs

Chloroquine: Drug of choice for both chemoprophylaxisand treating the acute attack . It is given orally; it is

concentrated in the parasite. Unwanted effects include GI

tract upsets, dizziness, urticaria; given i.v. it can cause

dysrhythmias.

Quinine: Drugsfor treating the acute attack are quinine,given orally; it can be given i/v in emergency. Unwanted

effects include GI tract upsets, tinnitus, blurred vision and

with large doses,dysrhythmias and CNS disturbances.

A ti l i l d


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Anti malarial drugs

Primaquine: It is effective against the liver hypnozoites, and is also active

against gametocytes. Given orally . Unwanted effects are

mainly GI tract upsets and, with large doses,

methaemoglobinaemia. Haemolysis is produced in individuals

with genetic deficiency of erythrocyte glucose 6 phosphate

dehydrogenase.

Cl ifi ti f ti l i


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Classification of anti-malaria

Classified by their selective actions ondifferent phases of the parasite life cycle:

1. Tissue schizonticides: eliminate developing ordormant liver forms.

2. Blood schizonticides: act on erythrocyticparasites.

3. Gametocides: kill sexual stages and prevent

transmission to mosquitoes. No one available agent can reliably effect a

radical cures.

Chl iControl symptoms


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Chloroquine

A synthetic 4-aminoquinoline formulated as thephosphate salt for oral use.

Pharmacokinetics Rapidly and almost completely absorbed from the

gastrointestinal tract. Very large apparent volume of distribution of 100-1000

L/kg.

Necessitate the use of a loading dose to rapidly achieve

effective serum concentrations. Slowly released from tissues and metabolized. Principally excreted in the urine.

Pharmacological Effects1. Antimalarial action: Schizonticide gametocyte


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1. Antimalarial action:

highly effective blood schizonticide.

Moderately effective against gametocytesof P vivax, P ovale,

and P malariaebut not against those of Pfalciparumnot active against liver stageparasites. Mechanism:

plasmodium aggregates chloroquine.

chloroquine incorporated into DNAchain of plasmodium inhibit

proliferation.chloroquine prevents the polymerization ofthe hemoglobin breakdownproduct, heme, into hemozoin and thus eliciting parasite toxicity due to the

buildup of free heme.

pH plasmodium protease activity

Resistance: very common among strains of P falciparumand uncommonbut increasing for P vivax. The mechanism of resisitance to chloroquine is

resistant strains excretes drug more rapidly.

1. Killing Amibic trophozoites : chloroquine reaches high liver

concentrations.

2. Immunosuppression action:

Schizonticide gametocyte

Not active against liver stage


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Adverse Effects and Cautions Usually very well tolerated, even with prolonged

use.

Pruritus is common. Nausea, vomiting, abdominal pain, headache,

anorexia, malaise, blurring of vision, and urticariaare uncommon.

Dosing after meals may reduce some adverseeffects.

Rare reactions include hemolysis in G6PD-deficient persons, impaired hearing, confusion,psychosis, seizures, hypotension, ECG changes.

teratogenesis

QuinineControl symptoms


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Quinine

Quinine and quinidine remain first-linetherapies for falciparum malariaespecially severe disease.

Quinine is an alkaloid derived from the bark ofthe cinchona tree, a traditional remedy for

intermittent fevers from South America.

Quinine is the levorotatory stereoisomer of

quinidine. Rapidly absorbed after oral administration. Metabolized in the liver and excreted in the

urine.


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Pharmacological Effects

Highly effective blood schizonticide against thefour species of human malaria paresites.

Gametocidal against P vivaxand P ovalebut not Pfalciparum.

Not active against liver stage parasites.

Depressing cardiac contractility and conduction,lengthening refractory period, exciting uterine

smooth muscle, depressing central nervoussystem, little antipyretic-analgesic effect.

Quinine


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Clinical Uses: mainly for chloroquine-resistantfalciparum malaria, especially for cerebral

malaria.

Parenteral treatment of severe falciparum malaria Oral treatment of falciparum malaria

Malarial chemoprophylaxis

Babesiosis

Quinine


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Adverse Effects and Cautions1. Cinchonism: tinnitus, headache, nausea,

dizziness, flushing, visual disturbances

2. Cardiovascular effects: severe hypotension and

arrhythmia can follow too-rapid intravenousinfusion.

3. Idiosyncrasy: hemolysis with G6PD deficiency.

4. Others: hypoglycemia through stimulation ofinsulin release, stimulate uterine contractions

MefloquineControl symptoms


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Mefloquine

A synthetic 4-quinoline methanol that is chemicallyrelated to quinine. Pharmacokinetics

Only be given orally because severe local irritation occurswith parenteral use.

Well absorbed. Highly protein-bound, extensively distributed in tissues,

and eliminated slowly. t1/2is 20 days.

Pharmacological Effects:

Strong blood schizonticidal activity against P falciparumand P vivax, but not active against hepatic stages orgametocytes.


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Clinical Uses

Chemoprophylaxis: Treatment: mainly for chloroquine-resistant

falciparum malaria.

Adverse Effects and Cautions Nausea, vomiting, diarrhea, abdominal paindose-dependent

Neuropsychiatric toxicities: dizziness, headache,behavioral disturbances, psychosis, seizures.

ArtemisininControl

symptoms


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Artemisinin

Extracted from yellow flower mugwort. Kill trophozoites of erythrocytes.

quick and effective. maybe kill earlier period

trophozoites. Through blood-brain barrie, treatment for

cerebral malaria.

recurrence rate is high.

Resistence.

Interaction with others antimalarial drugs:

symptoms

Control symptoms


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Artemether and Artesunate Dihydroartemisinin

PrimaquineControl relapse

and transmission


102/210

Primaquine

Synthetic 8-aminoquinoline. Pharmacological Effects

Against hepatic stages of malaria parasites.

The only available agent active against thedormant hypnozoite stages of P vivaxand P ovale.

Also gametocidal against the four human malaria

species.


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Clinical Uses Therapy (Radical Cure) of Acute Vivax and Ovale Malaria:

chloroquine + primaquine Terminal Prophylaxis of Vivax and Ovale Malaria: prevent a

relapse

Chemoprophylaxis of Malaria: protection againstfalciparum and vivax malaria. But potential toxicities of

long-term use limited its routinely administration. Gametocidal Action: A single dose of primaquine (45 mg

base) can be used as a control measure to render Pfalciparum gametocytes noninfective to mosquitoes. Thistherapy is of no clinical benefit to the patient but will

disrupt transmission Pneumocystis cariniiinfection: clindamycin+primaquine mild to moderate pneumocystosis

Primaquine


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Adverse Effects and Cautions Nausea, epigastric pain, abdominal cramps,

headache.

Hemolysis or methemoglobinemia, especiallyin persons with G6PD deficiency or other

hereditary metabolic defects.

Primaquine

PyrimethamineEtiological factor

prophylaxis


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Pyrimethamine

Pharmacokinetics Slowly but adequately absorbed from the gastrointestinal

tract.

Slowly eliminated and excreted from urine.

Pharmacological Effects Kill schizonts of primary exoerythrocytic stage.

Act slowly against premature schizonts of erythrocyticstage.

No action against gametocytes, but can inhibitdevelopment of plasmodium in mosquito.

Inhibit plasmodial dihydrofolate reductase inhibitingbreeding of plasmodium.

p p y

Pyrimethamine


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Adverse Effects and Cautions Gastrointestinal symptoms, skin rashes.

Interfering folic acid metabolism in human

megalocyte anemia, granulocytopenia. Acute intoxication

Teratogenesis

Pyrimethamine

Etiological factor

prophylaxis


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Sulfonamides and Sulfone

Competing dihydropteroatesye synthase withPABA inhibiting to form dihydrofolic acid inhibiting production of purines and synthesis

of nucleic acids. Only inhibiting plasmodial of exoerythrocytic

stage

Not used as single agents for the treatment.Combination with other agents.

Rational Use of Antimalarial Drugs


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Rational Use of Antimalarial Drugs

1. Choice of Antimalarial Drugs: Control symptoms: chloroquine Cerebral malaria: chloroquine phosphate, quinine bimuriate,

artemisinin injection Chloroquine-resistant falciparum malaria: quinine, mefloquine,

artemisinin Dormant hypnozoite stages : pyrimethamine + primaquine Prophylaxis: pyrimethamine, chloroquine

2. Combination therapy: chloroquine + primaquine: symptom stages

pyrimethamine + primaquine: dormant hypnozoite stages

Combination of drugs with different mechanisms: therapeuticeffect, resistance

Antimalarial Drugs


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g

Attack the parasite during the asexual phase,when it is vulnerable

Erythrocytic phase drugs: chloroquine,

hydroxychloroquine, quinine, mefloquine Primaquine: kills parasite in both phases

May be used together for synergistic or additivekilling power

Antimalarials:

M h i f A ti


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Mechanism of Action

4-Aminoquinoline derivatives:chloroquine and hydroxychloroquine

Bind to parasite nucleoproteins and interfere withprotein synthesis; also alter pH within the parasite

Interfere with parasites ability to metabolize and useerythrocyte hemoglobin

Effective only during the erythrocytic phase

Antimalarials:

M h i f A ti


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Mechanism of Action

4-Aminoquinoline derivatives:quinine and Mefloquine (Lariam)

Alter pH within the parasite

Interfere with parasites ability to metabolizeand use erythrocyte hemoglobin

Effective only during the erythrocytic phase

Antimalarials:

M h i f A ti


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Mechanism of Action

Diaminopyrimidines

(pyrimethamine & trimethoprim)

Inhibit protein synthesis essential for growth andsurvival

Only effective during the erythrocytic phase

These drugs may be used with sulfadoxine ordapsone or synergistic effects

Antimalarials:

Mechanism of Action


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Mechanism of Action

Primaquine Only exoerythrocytic drug (works in both phases)

Binds and alters parasitic DNA

Sulfonamides, tetracyclines, clindamycin

Used in combination with antimalarials toincrease protozoacidal effects

AntimalarialsDrug Effects


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Drug Effects

Kill parasitic organismsChloroquine and hydroxychloroquine also have

antiinflammatory effects

Indications

Kills Plasmodiumorganisms, the parasites that cause malaria

The drugs have varying effectiveness on the different malariaorganisms

Some drugs are used for prophylaxis against malaria

2 weeks prior and 8 weeks after return

Chloroquine is also used for rheumatoid arthritis and systemic

lupus erythematosus

Antimalarials


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Adverse Effects

Many adverse effects for the various drugs

Primarily gastrointestinal: nausea, vomiting,diarrhea, anorexia, and abdominal pain

Dirgahayu negeriku


116/210

Dirgahayu negeriku

Dirgahayu FK USU

KEBANGGAAN INDONESIA UNTUK DUNIA

Mebendazole


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Mebendazole

A synthetic benzimidazole that has a wide spectrumof anthelmintic activity and a low incidence ofadverse effects.

Pharmacokinetics

Oral absorption10, Absorption increases with fattymeal

First pass elimination is high. Protein-binding90

Excreted mostly in the urine, a portion of absoreddrug and its derivatives are excreted in the bile. It isconverted to inactive metabolites rapidly in liver.

It has half life of 2-6 hours


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Pharmacologic Effects

Inhibits microtubule synthesis in nematodes, thusirreversibly impairing glucose uptake. Intestinal parasitesare immobilized or die slowly.

Kills hookworm, ascaris, and trichuris eggs.

Clinical Uses Pinworm infection Ascaris lumbricoides, Trichuris trichiura, Hookworm, and

Trichostrongylus

Other infections: intestinal capillariasis, trichinosis,taeniasis, strongyloidiasis, dracontiasis, et al.

Adverse Effects and Cautions


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Low-dose: nearly free adverse effects.

Diarrhea, abdominal pain is infrequent. High-dose: pruritus, rash, eosinophilia,

reversible neutropenia, musculoskeletal pain,

fever, transient liver function abnormalities,alopecia, glomerulonephritis, agranulocytosis

used with caution under 2ys of age maycause convulsion in this group.

enzyme inducers and inhibitors affect plasmalevel of the drug.

hepatic parenchymal disease

Albendazole


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Albendazole

A benzimidazole carbamate A broad-spectrum oral anthelmintic for

treatment of hydatid disease and cysticercosis,

pinworm infection, ascariasis, trichuriasis,strongyloidiasis, and infections with both

hookworm species.

Effect better than Mebendazole.

Albendazole con;d


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121

;

Mechanism of action:

It inhibits microtubule synthesis innematodes(intestinal round worms) that irreversiblyimpairs glucose uptake, intestinal parasites are

immobilized and die slowly.

It is larvicidal in hydatid, cysticercosis, ascariasis andhook worm infection.

Also ovicidal in ascariasis, ancyclostomiasis(hookworm), tricurasis

Pharmacokinetics (Albendazole)


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122

it is adminstered orally , and absorbederratically (unpredictable) , absorptioncan beincreased with fatty meal

It ismetabolized in the liverrapidly toactive metabolite albendazole sulphoxide

It has a plasma half life of 8-12 hours Sulphoxide is mostly protein bound ,

distributes well to tissues and enters bile,CSF, hydated cyst

Metabolites are excreted in urine


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Clinical Uses

Administered on an empty stomach when usedagainst intraluminal parasites but with a fattymeal when used against tissue parasites.

1. Ascariasis, Trichuriasis, and Hookworm and

Pinworm infections.2. Strongyloidiasis

3. Hydatid Disease

4. Neurocysticercosis5. Other infections: cutaneous larva migrans,

gnathostomiasis

Albendazole cond


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124

Adverse effects: In short term:use no significant adverse effects.

In long term use: as used in hydatid cyst andcysticercosis, abdominal distress, headache ,fever ,

fatigue, alopecia , increased liver enzymes ,

pancytopenia. Blood counts and LFT should be

followed.

Not given during pregnancy and in hypersensitivepeople.


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Piperazine cond


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126

p

pharmacokinetics :

it is readily absorbed orally and excreted unchanged in

urine.

75 mg /kg/day for 2 days once daily

treatment is continued for 3-4 days or repeated afterone week in case of heavy infections.

Adverse effects:

GI disturbance, Neurotoxicity ,allergic reactions serum

sickness like syndrome

Contraindications

Epilepsy, Impaired liver or kidney functions, pregnancy,

Malnutrition

Levamizole


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A synthetic imidazothiazole derivative and theL isomer of D,L-tetramisole.

Highly effective in eradicating ascaris and

trichostrongylus and moderately effectiveagainst both species of hookworm.

Inhibiting succinic dehydrogenase energy flaccid paralysis

Immunomodulating effect.

PYRANTEL PAMOATE


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128

A tetrahydropyrimidine derivative.

A broad-spectrum anthelmintic, but it is noteffective against tricuriasis (whip worms), andtrichostrongylus orientalis infections. Oxantelpamoate is more effective

Pharmacokinetics: It is poorly absorbed orally , Half of the drug is excreted unchanged in the

feces.

Mechanism of action: It is a depolrazing neuromuscular blockingagent

that causes release of acetylcholine andinhibition of cholinestrase leads to spastic

paralysis of worms

Pyrental pamoate cond


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129

y p

Adverse Effects . Infrequent mild transient GI disturbance drowsiness , headache ,insomnia.

Rash ,feverContraindciations

Should not be used in liver diseases.

Pregnancy and child under 2 years of age

Pyrvinium Embonate


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y

A dye. Not absorb orally.

treatment of pinworm

Selectively interfering energy metabolismenzymatic system

Inhibiting glucose-transporting enzymaticsystem

Red feces

Niclosamide


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A salicylamide derivative Treatment of most tapeworm infection. Pharmacologic Effects

Scoleces and segments of cestodes but notova are rapidly killed on contact withnicolsamide due to the drugs inhibition ofoxidative phosphorylation or to its ATPase-

stimulating property. With the death of the parasite, digestion of

scoleces and segments begins.


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Clinical Uses Given in the morning on an empty stomach.

The tablets must be chewed thoroughlyand arethen swallowed with water.

Niclosamide can be used as an alternative drug for

the treatment of intestinal fluke infections.


Infrequent, mild and transitory. Nausea, vomiting, diarrhea, and abdominal

discomfort.

Praziquantel


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q

Effective in the treatment of schistosomeinfections of all species and most other

trematode and cestode infections, including

cysticercosis. A first choice in the treatment cestodiasis.

Benzimidazoles


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Albendazole, mebendazole, thiabendazole Inhibit glucose absorption Poorly absorbed (PO).

Active against nematodes (drugs of choice).

Leder K. & Weller P. 2003. InASM Manual of CM.

Write the pharmacological action and side

effects of the following drugs


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effects of the following drugs

Chloroquine Metronidazole

Melarsoprol

Primaquine

Mebendazole Praziquantel

Niclosamide

Pyrantel pamoate

Thiabendazole

Books & sites


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Basic and clinical Pharmacology by B.G. Katzung Pharmacological basis of therapeutics by Goodman and

gillman

Pharmacology by Rang and Dale

www.pharmacology2000.com www. medicalstudents.com
http://www.pharmacology2000.com/http://www.pharmacology2000.com/http://www.pharmacology2000.com/http://www.pharmacology2000.com/


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Nematoda (roundworms) 1stchoice 2ndchoice

Asc aris lumbr ico idesAlbendazole/

P t l t /

Piperazine


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(roundworm)Pyrantel pamoate/

Mebendazole

Trichu r is tr ichiura

(whipworm)Mebendazole/

AlbendazoleOxantel/Pyrantel pamoate

Necator americanus

(hookworm);

Anc ylostom a duod enale

(hookworm)

Pyrantel pamoate/

Mebendazole/

Albendazole

Strongy loides stercoral is

(threadworm)

Ivermectin Thiabendazole,

Albendazole

Enterobius verm icular is

(pinworm)

Mebendazole/

Pyrantel pamoate

Albendazole

Trichinel la sp iral is

(trichinosis)

Mebendazole(+kortikosteroid untuk

infeksi berat)

Albendazole(+kortikosteroid untuk

infeksi berat)

Tr ichostrong ylus speciesPyrantel pamoate/

Mebendazole

Albendazole

1stchoice 2ndchoice


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Cutaneous larva migrans

(creeping eruption)

Albendazole/

Ivermectin

Thiabendazole

(topikal)

Visceral larva migrans Albendazole Mebendazole

Ang iostrongy lus cantonensisThiabendazole Albendazole/

Mebendazole

Wucherer ia bancroft i (filariasis);

Bru gia malayi (filariasis); tropicaleosinophilia;

Loa loa (loiasis)

Diethylcarbamazi

ne

Ivermectin

Onchocerca volvu lus

(onchocerciasis)

Ivermectin Suramin

Dracunc ulus m edinensis (guineaworm)

Metronidazole Thiabendazole/Mebendazole

Capi l lar ia ph i l ippinensis

(intestinal capillariasis)

Albendazole Mebendazole/

Thiabendazole

Trematoda (flukes) 1stchoice 2ndchoiceSchistosom a haematobium

(bilharziasis)

Praziquantel Metrifonate


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(bilharziasis)

Schis tosoma manson i Praziquantel Oxamniquine

Schistosom a japon icum Praziquantel

Clonorchis s inensis

(liver fluke);

opisthorchis species

Praziquantel Albendazole

Paragon imus westermani

(lung fluke)Praziquantel Bithionol

Fasc iola hepatica

(sheep liver fluke)

Bithionol/

Triclabendazole

Fascio lop sis buski(large intestinal fluke)

Praziquantel/Niclosamide

Heterophyes heterophyes

Metagon imu s yokogawai

(small intestinal flukes)

Praziquantel/

Niclosamide

Cestoda (cacing pita) 1stchoice 2ndchoice

Taenia sagin ata Praziquantel/ Mebendazole


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Taenia sagin ata

(beef tapeworm)

Praziquantel/

Niclosamide

Mebendazole

Taenia sol ium(pork tapeworm)

Praziquantel/Niclosamide

Diphyl lobothr ium latum

(fish tapeworm)

Praziquantel/

Niclosamide

Cysticercosis(pork tapeworm larval stage)

Albendazole Praziquantel

Hymenolepis nana

(dwarf tapeworm)

Praziquantel Niclosamide

Echinococcu s granulosu s

(hydatid disease);

Echinococcus

mult i locular is

Albendazole


ObatMekanisme Efek


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ObatKerja Spesifik

Piperazine

Memparalisis

otot cacing

Memblokir myoneural junction;

agonis gated chloride channels

hiperpolarisasiparalisis flasid

Ivermectin

Memparalisis

otot cacing

Memblokir transmisi sinyal-sinyal saraf

dengan berinteraksi dengan glutamate

gated chloride channels

PyrantelMemparalisisotot cacing

Agonis reseptor asetilkolin nikotinik &menghambat kolinesterase

depolarisasi & paralisis spastik

Metrifonate

(Trichlorfon)

Memparalisis

otot cacing

Menginaktivasi asetilkolinesterase &

mempotensiasi efek-efek kolinergik

inhibitori

Praziquantel

Memparalisis

otot cacing

Meningkatkan permeabilitas membran

terhadap Ca2+memaparkan protein-

protein membrandiserang antibodi

BithionolMenghambat

produksi energi



Mekanisme Efek


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ObatMekanisme

Kerja

Efek

Spesifik

NiclosamideMenghambatproduksi energi

Menghambat fosforilasi oksidatifanaerobik dalam mitokondria cacing

sintesa ATP

MebendazoleMenghambat

produksi energi

Berikatan dengan tubulin & menghambat

polimerisasi

Thiabendazole Menghambatproduksi energi &

fungsi protein

Menghambat fumarat reduktase &sintesa ATP; berikatan dengan tubulin

Suramin

Menghambat

produksi energi

Menghambat enzim-enzim otot yang

berkait dengan glikolisis & konsumsi

oksigen

OxamniquineMengesterifikasi &

mengikat DNA

Menghambat sintesa asam nukleat &

protein

Diethyl-

carbamazine

Mempermudah

fagositosis &

eliminasi

Meningkatkan kesensitifan mikrofilaria,

memerangkap mikrofilaria dalam sistem

retikuloendotelial

Farmakoterapi


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Obat-obat pilihan adalahbenzidimazole(BZA):

albendazole(dosis tunggal 400mg, 200 mg: anak-anak 12-24 bulan) /

mebendazole(100 mg 2x/hariuntuk 3 hari (dewasa & anak >2 tahun) /

levamisole (dosis tunggal 2,5mg/kg) /

pyrantel pamoate (dosis tunggal11 mg/kg, tetapi 1 g)

(WHO 2002)

Migrasi larva A. lumbr ico ides

bisa menyebabkan

pneumonia hemoragik.

Kesimpulan & Saran
http://www.who.int/water_sanitation_health/index.html


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Secara umumnya, obat anthelmintika terbagi atas beberapamacam tergantung pada mekanisme kerjanya, yaituvermifuge (menghambat produksi energi),flaccid paralyzingagents(memblokir respon cacing terhadap asetilkolin-menyebabkan paralisis flasid), spastic paralyzing agents(menginhibisi kolinesterase), dan systemic anthelminticagents(mengurangi produksi ATP).

Infeksi cacing dari spesies yang berbeda memerlukan obatdan terapi yang berbeda. Drug of choiceharuslah diberikansekiranya tidak ada kontraindikasi.

Infeksi ascariasis merupakan suatu masalah kesehatan yangpenting di banyak negara sedang berkembang.Pengobatannya tidak sulit dan kadar penyembuhannyasangat tinggi kalau tidak terjadi reinfeksi.

Classification of anti-amoeba


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Tissue Amoebiasis*Both intestinal & extra intestinal

Nitroimidazoles Metronidazole, Tinidazole, Secnidazole, Ornidazole

Alkaloids Emetine, Hydroemetine

* Extra intestinal amoebiasis only

Chloroquine

Luminal amoebiasis Amide (Diloxanide furoate) 8-Hydroxy quinolones (Quinidochlor) Antibiotics (Tetracycline)

Anti-Amoeba


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Anti-amoeba Indication MoA ADR

Chloroquine Amebic liverabscess

Metronidazole Intestinal &extra-intestnal

Disruption of

DNA synthesis

& nucleic acid

synthesis

Metallic taste,

nausea,

vomiting,

diarrhea,abdominal

cramps

Iodoquinol Intestinal Directly kills theprotozoa

N/V, diarrhea,

anorexia,

agranulocytosis

Paramomycin Intestinal Inhibiting proteinsynthesis

N/V, diarrhea,

stomach

cramps,

ototoxic, tinnitus

5-nitroimidazoles


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Metronidazole, tinidazole, ornidazole,nimorazole.

Active on anaerobic bacteria and protozoa.

Entamoeba(not invariably the cysts) ,Trichomonas, Giardia, Blastocystis, ...

Disulfiram-like effects, mutagenic in bacteria.Pearson R.D. 2005. Chapter 41, In Mandell G.L. etal.

Metronidazole


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Prototype drug introduced in 1959 Bactericidal against

Giardia lamblia, anaerobic bacteria,

Bacteroides fragilis, Fusobacterium,

Clostridium perfringes, Helicobacter

pylori, Anaerobic Streptococci

Metronidazole (MoA)


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Not clearly understood Enters micro-organism by diffusion Nitro group reducedDNA damaged

Cytotoxicity

High selective anaerobic actioninterference with electron transportation fromNADPH or other reduced substrates

Also inhibits cell mediated immunity Induce mutagenesis Cause radio-sensitization

Metronidazole


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A nitroimidazole. The nitro group of metronidazole ischemically reduced in anaerobic bacteria and

sensitive protozoans. Reactive reduction products

appear to be responsible for antimicrobial activity.

Pharmacokinetics Oral metronidazole is readily absorbed and permeates all

tissues by simple diffusion.

Protein binding is low (


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Mechanism of action

Disruption of DNA synthesis as well as nucleic acid synthesis

Bactericidal, amebicidal, trichomonacidal

Used for treatment of trichomoniasis, amebiasis,giardiasis,and antibiotic-associated pseudomembranouscolitis

Also has anthelmintic activity

Adverse Effects:

Metallic taste, nausea, vomiting, diarrhea,abdominal cramps, many others

Metronidazole


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Contraindications Neurological diseases, blood dyscrasias, First trimester, Chronic alcoholism

Drug Interactions Disulfiram reaction Enzyme inducers - Rifampicin -therapeutic effect Cimetidine - metronidazole metabolism - reduce

dose

Metronidazole renal elimination of Lithium

Emetine Alkaloid from Cephaelis ipecacuanha


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Alkaloid from Cephaelis ipecacuanha

Potent directly acting amoebicide (trophozoites)

Does not kill cysts Cumulative toxicity high Seldom used

- Because of major toxicity concerns they have been

almost completely replaced by metronidazole.

Reserve drugnot responding/intolerant to

metronidazole

Luminal amoebicide follows emetine to eradicate cysts

Administered subcutaneously (preferred) or i.m. (but

never i.v.) because oral preparations are absorbed

erratically

Dihydroemetine=effective but less toxic

Preferred over emetine

Diloxanide


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Diloxanide furoate is a dichoroacetamide derivative. Effective luminal amebicide but is not active againsttissue trophozoites.

The unabsorbed diloxanide in the gut is the active

antiamebic substance. Effective for asymptomatic luminal infections. It is used with a tissue amebicide, usually

metronidazole.

Adverse Effects: flatulence, nausea, abdominalcramps, rashes, abortion.

Notice !


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Treatment with tissueamoebicide SHOULD always be

followed by Luminalamoebicide to eradicate

source of infection

Anti-trichomoniasis Drugs


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Metronidazole Acetarsol

Classification of anti-malaria


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Classified by their selective actions ondifferent phases of the parasite life cycle:1. Tissue schizonticides: eliminate developing or

dormant liver forms.

2. Blood schizonticides: act on erythrocyticparasites.

3. Gametocides: kill sexual stages and preventtransmission to mosquitoes.

No one available agent can reliably effect aradical cures.

ChloroquineControl symptoms


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A synthetic 4-aminoquinoline formulated as thephosphate salt for oral use. Pharmacokinetics

Rapidly and almost completely absorbed from the

gastrointestinal tract. Very large apparent volume of distribution of 100-1000

L/kg.

Necessitate the use of a loading dose to rapidly achieveeffective serum concentrations.

Slowly released from tissues and metabolized. Principally excreted in the urine.

Pharmacological Effects1. Antimalarial action:

highly effective blood schizonticide.

M d t l ff ti i t t t f P i P l

Schizonticide gametocyte

Not active against liver stage


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Moderately effective against gametocytesof P vivax, P ovale,

and P malariaebut not against those of Pfalciparumnot active against liver stageparasites. Mechanism:

plasmodium aggregates chloroquine.

chloroquine incorporated into DNAchain of plasmodium inhibit

proliferation.chloroquine prevents the polymerization ofthe hemoglobin breakdownproduct, heme, into hemozoin and thus eliciting parasite toxicity due to the

buildup of free heme.

pH plasmodium protease activity Resistance: very common among strains of P falciparumand uncommon

but increasing for P vivax. The mechanism of resisitance to chloroquine is

resistant strains excretes drug more rapidly.

1. Killing Amibic trophozoites : chloroquine reaches high liver

concentrations.

2 Immunosuppression action:



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Usually very well tolerated, even with prolonged

use. Pruritus is common. Nausea, vomiting, abdominal pain, headache,

anorexia, malaise, blurring of vision, and urticaria

are uncommon.

Dosing after meals may reduce some adverseeffects.

Rare reactions include hemolysis in G6PD-deficient persons, impaired hearing, confusion,

psychosis, seizures, hypotension, ECG changes.

teratogenesis

QuinineControl symptoms


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Quinine and quinidine remain first-linetherapies for falciparum malariaespecially severe disease.

Quinine is an alkaloid derived from the bark of

the cinchona tree, a traditional remedy forintermittent fevers from South America.

Quinine is the levorotatory stereoisomer of

quinidine. Rapidly absorbed after oral administration. Metabolized in the liver and excreted in the

urine.

Pharmacological Effects


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Highly effective blood schizonticide against thefour species of human malaria paresites.

Gametocidal against P vivaxand P ovalebut not Pfalciparum.

Not active against liver stage parasites. Depressing cardiac contractility and conduction,

lengthening refractory period, exciting uterine

smooth muscle, depressing central nervous

system, little antipyretic-analgesic effect.

Quinine


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Clinical Uses: mainly for chloroquine-resistantfalciparum malaria, especially for cerebral

malaria.

Parenteral treatment of severe falciparum malaria Oral treatment of falciparum malaria

Malarial chemoprophylaxis

Babesiosis

Ad Eff t d C ti


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Adverse Effects and Cautions1. Cinchonism: tinnitus, headache, nausea,

dizziness, flushing, visual disturbances

2. Cardiovascular effects: severe hypotension and

arrhythmia can follow too-rapid intravenousinfusion.

3. Idiosyncrasy: hemolysis with G6PD deficiency.

4. Others: hypoglycemia through stimulation of

insulin release, stimulate uterine contractions

MefloquineControl symptoms


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A synthetic 4-quinoline methanol that is chemicallyrelated to quinine. Pharmacokinetics

Only be given orally because severe local irritation occurswith parenteral use.

Well absorbed. Highly protein-bound, extensively distributed in tissues,

and eliminated slowly. t1/2is 20 days.

Pharmacological Effects:

Strong blood schizonticidal activity against P falciparumand P vivax, but not active against hepatic stages orgametocy

K45 - Antiviral Antifungi Anthelmentic Antiamoeba Antimalaria (FT)

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Transcript of K45 - Antiviral Antifungi Anthelmentic Antiamoeba Antimalaria (FT)