k45 - antiviral antifungi anthelmentic antiamoeba antimalaria (ft)
TRANSCRIPT
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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
Universitas Sumatera Utara
15 Se tember 2012 Pemicu 3 TROPMED
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Dept. Pharmacology & TherapeuticSchool of Medicine
Universitas Sumatera Utara
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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
Perlu tapi tidak diharuskan:
CD4
Fungsi hati (ALT/SGPT) bila ada gejala
CD4setiap 6 -12 bulan, bila tersedia, untukmemantau efikasi
d4T + 3TC +
EFV
Diharuskan: Tes kehamilan
Perlu tapi tidak diharuskan:
CD4
Pemantauan toksisitas tergantung gejala (tidak
rutin)
CD4setiap 6 -12 bulan, bila tersedia, untuk
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
800/100 High-fat Meal
400/400 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)
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
Perlu tapi tidak diharuskan:
CD4
Fungsi hati (ALT/SGPT) bila ada gejala
CD4setiap 6 -12 bulan, bila tersedia, untukmemantau efikasi
d4T + 3TC +
EFV
Diharuskan: Tes kehamilan
Perlu tapi tidak diharuskan:
CD4
Pemantauan toksisitas tergantung gejala (tidak
rutin)
CD4setiap 6 -12 bulan, bila tersedia, untuk
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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Dept. Pharmacology & Therapeutic
School of MedicineUniversitas Sumatera Utara
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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
Mekanisme kerja anthelmentic
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Mekanisme kerja anthelmentic
ObatMekanisme
Kerja
Efek
Spesifik
Niclosamide
Menghambat
produksi energi
Menghambat fosforilasi oksidatif
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.
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Dept. Pharmacology & Therapeutic
School of MedicineUniversitas Sumatera Utara
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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
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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
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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
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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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Adverse Effects and Cautions
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.
Adverse Effects and Cautions
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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Dept. Pharmacology & Therapeutic
School of MedicineUniversitas Sumatera Utara
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
Mekanisme kerja anthelmentic
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
Menghambat fosforilasi oksidatif
Mekanisme kerja anthelmentic
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
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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:
Adverse Effects and Cautions
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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