Dept.

Pharmacology & Therapeutic

School of Medicine

Universitas Sumatera Utara

Different living organisms

Eucaryotes

Mono or polycellular
Cell nucleus; DNA
May have cell wall
Sexual and/or asexual
replication
Animals
Plants
Fungi
Protocista (protozoea, algea)

Procaryotes

Bacteriea
Monocellular, no nucleus
DNA single strand
Cell wall, asexual replication

Virus

RNA or DNA + protein coating

(not really a cell)
Use other organisms
ribosomes for protein
synthesis

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 SEL VIRION BARU
( PERBANYAKAN VIRION SAMPAI PUNCAK
GEJALA PENYAKIT )

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

Klasifikasi Antivirus berdasarkan

Mekanisme Kerja
Antivirus
Mekanisme Kerjanya
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

Viral zinc-finger
nucleocapsid
proteins
Fusion
inhibition

Viral protease

RNA

RNA
Proteins

Reverse
transcriptase

RT
RNA
RNA
DNA
RT

Viral regulatory
proteins

DNA
DNA

Provirus

Viral integrase

Aznan Lelo
Dep. Farmakologi & Terapeutik,

Fakultas Kedokteran
Universitas Sumatera Utara
15 September 2012, Pemicu 3 TROPMED

Dept. Pharmacology & Therapeutic

School of Medicine

Universitas Sumatera Utara

Antiretroviral Classes
NRTIs (Nucleoside OR Nucleotide Reverse
Transcriptase Inhibitors, aka Nukes)

NNRTIs (Non-Nucleoside Reverse

Transcriptase Inhibitors, aka Non-Nukes)

PIs (Protease Inhibitors)

Fusion Inhibitors
Chemokine Receptor Antagonists
Integrase Inhibitors

Mechanism of Action of ARVs

Integrase
Inhibitor

Fusion
Inhibitor &
Chemokine
Receptor
Antagonist

NNRTI
NRTI
Illustration by David Klemm

Protease
Inhibitor

NRTIs (Nucleoside OR Nucleotide

Reverse 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, HA
myalgia, 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
(<60kg)*

125,200,250,
400mg cap,
pwdr for soln

Pancreatitis,
peripheral
neuropathy,
LA/HS

Renal

Stavudine
(d4T) Zerit IR

40mg bid ( 60kg)

30mg bid (<60kg)

15,20,30,40 mg
cap,oral soln

Peripheral
neuropathy,
Pancreatitis, LA/HS,
Lipoatrophy,
facial wasting

Abacavir
(ABC) Ziagen

300mg bid,
600mg qd

300mg tabs, oral

soln

hypersensitivity

Tenofovir
(TDF) Viread

300mg qd*

300mg tabs

Few SEs,
renal toxicity

Renal

Hepatic by alcohol
dehydrogenase and
glucuronyl transferase
Renal

NRTI Class Toxicities

Lactic Acidosis
Damage to mitochondria in cells
Elevated lactate, low pH/bicarbonate, N/V,
shortness of breath, if untreated can lead to
death
Lactic acidosis can occur with any NRTIs

Hepatomegaly with Steatosis

Build up of fat droplets
inside liver cells
Enlarged liver

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

Protease Inhibitors (PIs)

Drug

Std Dose

Dosage forms

Side Effects

Metabolism

Atazanavir
(Reyataz) (1)

400qd or
300/ rtv 100qd

100, 150, 200mg

caps

Hyperbilirubinemia, 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, 3A4 substrate;

nasopharyngitis
3A4 inhibitors

Ritonavir
(Norvir) (1,2)

Used as a PK
booster 100200mg

100mg caps;
80mg/mL

Nausea,vomiting,
diarrhea, GI
upset

(1) Take with Food; (2) Must be refrigerated

** All PIs except atazanavir can increase lipids and cause insulin resistance

2D6, 3A4, Pgp

substrate; 3A4,
Pgp inhibitor

Dose adjustments to consider

Renally-eliminated
NRTIs (except Abacavir)
Adjust for CrCl <50 ml/min or
dialysis
Didanosine
Emtricitabine
Lamivudine
Stavudine
Tenofovir
Zidovudine

Reference: Drug product info and

DHHS guidelines (see tables)

Hepatic Metabolism
NNRTIs
PIs
Adjust for certain inducers,
substrates, or inhibitors of
P450 system

Adjust for insufficiency

Indinavir
Fosamprenavir
Atazanavir
Avoid
Amprenavir oral soln
Foasmprenavir (+/- ritonavir)
Tipranavir

ARV metabolism, induction, and inhibition

Drug

Substrate

Inhibits
3A4

Induces

Efavirenz

2B6, 3A4

3A4, 2B6

Nevirapine

3A4, 2B6

Ritonavir

2D6, 3A4, Pgp

3A4, 2D6, Pgp

Saquinavir

3A4, Pgp

3A4

Nelfinavir

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, 1A2

Atazanavir

3A4, Pgp

3A4, UGT, 1A2

Tipranavir

3A4, Pgp

3A4

Darunavir

3A4, Pgp

3A4

Maraviroc

3A4, Pgp

3A4
2D6 (at high
doses only)

Other enzymes

Cytochrome P450: Non-Antiretrovirals

CYP

Substrate

Inhibitor

Inducer

3A4

Macrolides,cyclosporine,
CCB, statins, azoles, PDE5
inhibitors, 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

Protease Inhibitors and Acid Suppression

Do Not combine Atazanavir and Proton
Pump Inhibitors
May Combine ATV and Famotidine but
dose adjustments are REQUIRED

May use Indinavir with PPIs but ONLY if

coadministered with RTV
May use Fosamprenavir with
Esomeprazole
Separate FPV from H2 blockers if used
concomitantly

PI Drug Interactions
All PIs are metabolized all or in part by the
CYP3A4 enzyme system
All PIs can inhibit CYP3A4 enzymes
Ritonavir most potent inhibitor
Saquinavir least potent inhibitor

Ritonavir can also induce CYP1A2

Important Drug Interactions

Do NOT use Simvastatin, Lovastatin, Antiarrthymics,
Midazolam, Triazolam, Ergot derivatives, Rifamin, St. Johns
Wort, 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 with

PIs and NNRTIs
Do NOT use Fluticasone or Alfuzosin with Ritonavir
Caution with Azoles, Clarithromycin, Oral Contraceptives,
Phenytoin, Carbamazepine, Phenobarbital, Methadone, PDE5
inhibitors, Atorvastatin, Beta blockers, when combined with PIs
Avoid Herbal Products with Known or Suspected Interactions
When combining Protease Inhibitors, Often Dose Adjustments
are Necessary

PI / NNRTI / Antidepressant
Drug Interactions
Antidepressant

Potential for
Interaction

Effects

Management

Amitriptyline

ritonavir,
lopinavir/r,
amprenavir,

Levels of
Start with lower dose
amitriptyline may be (50%) of amitriptyline,
increased
adjust dose when
addIng ritonavir.
Monitor for side effects

Fluoxetine

ritonavir,
lopinavir/r, all
other PIs,
efavirenz

Levels of both
fluoxetine and
ARVs may be
increased

Sertraline

ritonavir,
lopinavir/r, all
other Pis,
efavirenz

Levels of sertraline As above

may be increased.
ARV levels
not likely to change.

As above

ARV Interactions with Recreational Drugs

Effect

Comments

Alcohol

Abacavir AUC 41%

Clinical significance
unknown

Amphetamines

RTV may amphetamine

levels

Potential amphetamine
toxicity

Barbiturates

Potential levels of PIs and

NNRTIs

Potential virologic
failure/resistance

Benzo-diazepines

Midazolam and triazolam

levels with PIs and delavirdine
(levels of alprazolam and
clonazepam may )

Potential benzodiazepine
toxicity

-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

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
23

Continued impact of HAART on AIDS deaths

in some Western European countries, 1998-2002
1400

Italy

Number of AIDS deaths

1200

Spain
Germany

1000

United Kingdom

800
600
400
200
0

1998

1999

2000

2001

2002

Year
Source: HIV/AIDS surveillance in Europe (2002). End-of-year report. Data compiled by the European
Centre for the
Epidemiological Monitoring of AIDS

24

Obat-obat kombinasi
Kombinasi

Nama Paten

ABC + 3TC

Epzicom (US)
Take with or
Kivexa (Europe) without food
Trivizir
Take with or
without food
Combivir
Take with or
without food
Truvada
Take with or
without food

ABA + AZT +
3TC
AZT + 3TC

TDF + FTC

Keterangan

Pilihan Kombinasi Obat LINI PERTAMA

Zidovudine
2 x 300 mg
atau

Nevirapine

Lamivudine
2 x 150 mg

2x 200mg
atau

Stavudine

Efavirenz

2 x 40 mg

1 x 600 mg
Zidovudine + Lamivudine + Nevirapine
DepKes RI 2004

Pilihan Kombinasi Obat LINI KEDUA

Nelfinavir
2 x 1250 mg

Abicavir
2 x 300 mg
atau

atau Lopinavir/ritonafir
2x 400mg/100mg

Didanosine
2 x 250 mg

atau
Saquinavir/ritonavir
2 x 1000mg/100mg

Tenofovir
1 x 300 mg

DepKes RI 2004

Pemantauan laboratorium dasar untuk rejimen ARV lini-I

di Layanan Kesehatan Dasar, dan Menengah
Rejimen

Penilaian laboratorium
dasar (pra-terapi)

AZT + 3TC
+ NVP

Diharuskan: Hb
Perlu tapi tidak diharuskan: DL,
CD4

AZT + 3TC
+ EFV

Diharuskan: Tes kehamilan, Hb Hb, Lekosit bila ada gejala

CD4 setiap 6 -12 bulan, bila tersedia, untuk
Perlu tapi tidak diharuskan:
memantau efikasi
CD4, DL

D4T + 3TC + Perlu tapi tidak diharuskan:

NVP
CD4

d4T + 3TC +
EFV

Diharuskan: Tes kehamilan

Perlu tapi tidak diharuskan:
CD4

Penilaian laboratorium selama terapi

Hb, Lekosit, fungsi hati (ALT/SGPT)
CD4 setiap 6 -12 bulan, bila tersedia, untuk
memantau efikasi

Fungsi hati (ALT/SGPT) bila ada gejala

CD4 setiap 6 -12 bulan, bila tersedia, untuk
memantau efikasi
Pemantauan toksisitas tergantung gejala (tidak
rutin)
CD4 setiap 6 -12 bulan, bila tersedia, untuk
memantau efikasi

Dual Protease Inhibitor Combinations

Exploits the enzyme inhibition properties of
PIs, specifically RTV
Lessens pill burden
Theoretical ability to suppress resistant HIV
strains by enhancement of PI plasma levels

Basic Pharmacology Principles

Cmax

Cmin
IC90
Area of Potential HIV Replication

IC50

Dosing Interval
Time
Dose

Dose

Indinavir/Ritonavir
Pharmacokinetics
10,000

IDV/RTV q12h:
800/200 High-fat Meal

Indinavir
Plasma
Concentration 1,000
(nM)

800/100 High-fat Meal

400/400 High-fat Meal
IDV q8h:
800 mg Fasted

100

4
6
8
Time Postdose (hours)

10

12

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

Drug Interactions
Antiretroviral drugs in combination with
other drugs: conventional dose
modification situation
Example: Indinavir and rifabutin

Drug Interactions- Typical

IDV 800 mg q8hr + RIF 150 mg qd vs. IDV
800 mg q8hr
IDV AUC 32%
IDV Cmax 20%
IDV Cmin 40%

Recommendation:
Increase IDV dose to 1000 mg q8hr when
administered with RIF.

Drug Interactions
RIF 150 mg qd + IDV 800 mg q8hr vs. RIF
300 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 administered with IDV.

Binding

Reverse transcription

Fusion

Integration
Transcription
Splicing

Nuclear localization

Uncoating

Lysosome

RNA export
Genomic RNA

Endocytosi
s

Modification
mRNA

Assembly

Maturation

Budding

Translation

35

Dept. Pharmacology & Therapeutic

School of Medicine

Universitas Sumatera Utara

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.

ANTIFUNGAL
I. Systemic Antifungal Agents
1. Griseofulvin
2. Oral Azole Derivatives
3. Terbinafine
4. Hidroksistilbamidin
5. Flucytosin
6. Amphoterisin B

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

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

 2. Orally administered agents

- griseofulvin
- terbinafine
- ketoconazole
- fluconazole
- and itraconazole.

 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 is

responsive to long-term therapy with oral
ketoconazole.

Mechanism of action antifungal drugs

ANTIFUNGAL DRUGS
Griseofulvin,
Amfoterisin
B, Nistatin,
Natamisin

Flusitosin

Ketokonazol,
Flukonazol,
Itrakonazol,
Mikonazol

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
Faeces

6.

Nystatin

Fungal
Sterol

Faeces

7.

Salicylic Acid

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

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 sumsum 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

Obat pilihan untuk

infeksi jamur sistemik
yang berat

Pharmacodynamic 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

No.

Disease

Therapy

1.

Oral Candidiasis

2.

Vaginal Candidiasis

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

6.

Tinea Pedis

7.

Tinea Unguium
(Onicomycosis)

8.

Tinea capitis

9.

Ptyriasis versicolor

Oral : Fluconazole tablet 1 dd 50-100 mg during 1-2 week

Ovula: Clotrimazole 200 mg during 3 days or single dose 500 mg

Oral: Fluconazole tablet 150 mg single dose

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

Myconazole ointment 2% 1-2 dd during 3-5 week
Ung.Whitfield (Benzoic Acid 5 %, Salisilyc acid 5% in lanolinvaselin ana)
Terbinafine tablet 250 mg/days
6 weeks for finger hand, 12 weeks for finger foot
Griseofulvin 500mg/day [tidak lebih dari 10 mg/kgBB/hari]
hingga sembuh [6-8 weeks].

Salisilat acid 5-10% (used in ruam)

Ketoconazole cream during 2-3 weeks

 As with all topical products, selection of the

dosage form may be as important as proper
drug selection.
Thin liquids may preferable for application to
hairy 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.

 Most topical antifungal drugs require four

weeks of treatment. Infections in some areas,
particularly the spaces between toes, may
take up to six weeks for cure.

Precautions
Most topical antifungal agents are well tolerated. The
most common adverse effects are localized irritation
caused by the vehicle or its components. This may
include redness, itch, and a burning sensation. Some
direct allergic reactions are possible.
Topical antifungal drugs should only be applied in
accordance with labeled uses. They are not intended
or ophthalmic (eye) or otic (ear) use. Application to
mucous membranes should be limited to appropriate
formulations.

 The antifungal drugs have not been evaluated

for safety in pregnancy and lactation on
topical application under the pregnancy risk
category system. Although systemic
absorption is probably low, review specific
references.
Interactions
Could be reduced metabolism of several drugs

Rejimen ARV

AZT : zidovudin
3TC : lamivudin
NVP : navirapin
d4T : Stavudine
EFV : Efavirens

Rejimen ARV

AZT + 3TC + NVP

d4T + 3TC + NVP
AZT + 3TC + EFV
d4T + 3TC + EFV

Pemantauan laboratorium dasar untuk rejimen ARV lini-I

di Layanan Kesehatan Dasar, dan Menengah
Rejimen

Penilaian laboratorium
dasar (pra-terapi)

AZT + 3TC
+ NVP

Diharuskan: Hb
Perlu tapi tidak diharuskan: DL,
CD4

AZT + 3TC
+ EFV

Diharuskan: Tes kehamilan, Hb Hb, Lekosit bila ada gejala

CD4 setiap 6 -12 bulan, bila tersedia, untuk
Perlu tapi tidak diharuskan:
memantau efikasi
CD4, DL

D4T + 3TC + Perlu tapi tidak diharuskan:

NVP
CD4

d4T + 3TC +
EFV

Diharuskan: Tes kehamilan

Perlu tapi tidak diharuskan:
CD4

Penilaian laboratorium selama terapi

Hb, Lekosit, fungsi hati (ALT/SGPT)
CD4 setiap 6 -12 bulan, bila tersedia, untuk
memantau efikasi

Fungsi hati (ALT/SGPT) bila ada gejala

CD4 setiap 6 -12 bulan, bila tersedia, untuk
memantau efikasi
Pemantauan toksisitas tergantung gejala (tidak
rutin)
CD4 setiap 6 -12 bulan, bila tersedia, untuk
memantau efikasi

30
25
Monotherapy
No therapy

20

Dual therapy
15
10
Triple therapy
5
0
0

10

11

12

13

14

15

Dept. Pharmacology & Therapeutic

School of Medicine

Universitas Sumatera Utara

Mechanisms for treatment-I

Attack a unique enzyme found in parasite
Folate synthesis blocked by sulfonamide
(Folate- dihydrofolate reductase - FH2
dihydrofolate reductase FH4
Deoxythymidylic acid Methionine.
Allopurinol riboside is phosohorylated and
is added to 5-O position in purines and is
non functional, all protozoa especially
Leishmainaia.

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 causing
rapid lysis.

Mechanism III
Common biochemical functions found in
host / parasite but have different
pharmacological properties
Ivermectin affects synaptic transmission by
increasing 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

Antiprotozoal drugs
Chemotherapy of Amebiasis
Chloroquine, Dehydroemetine, Diloxanide furoate,
Emetine, Metronidazole, Paramomycin.
.

Chemotherapy of Malaria
Chloroquine, Mefloquine, Primaquine, Pyrimethamine,
quinine/ quinidine.

Chemotherapy of Tyrpanosomiasis
Melarsoprol, Nifurtimox, Pentamidine, Suramin.

Antiprotozoal drugs (contd)

Chemotherapy of Leishmaniasis
Sodium stibogluconate

Chemotherapy of Toxoplasmosis
Pyrimethamine.

Chemotherapy of Giardiasis
Quinacrine

Drugs used in leishmaniasis and

trypanosomiasis
Leishmaniasis may occur as a skin infection or as an infection
of 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 given
i.v and pentamidine i.m.

Anthelminthic Drugs
An anthelminthic drug may act by causing narcosis or paralysis
of 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 these
parasites 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

Ascaris lumbricoides
(roundworm)

Albendazole/
Piperazine
Pyrantel pamoate/
Mebendazole

Trichuris trichiura
(whipworm)

Mebendazole/
Albendazole

Necator americanus
(hookworm);
Ancylostoma duodenale
(hookworm)

Pyrantel pamoate/
Mebendazole/
Albendazole

Strongyloides stercoralis
(threadworm)

Ivermectin

Thiabendazole,
Albendazole

Enterobius vermicularis
(pinworm)

Mebendazole/
Pyrantel pamoate

Albendazole

Trichinella spiralis
(trichinosis)

Mebendazole

Albendazole

(+kortikosteroid untuk
infeksi berat)

(+kortikosteroid untuk
infeksi berat)

Trichostrongylus species

Oxantel/
Pyrantel pamoate

Pyrantel pamoate/ Albendazole

Mebendazole

1st choice

2nd choice

Cutaneous larva migrans

(creeping eruption)

Albendazole/
Ivermectin

Thiabendazole
(topikal)

Visceral larva migrans

Albendazole

Mebendazole

Thiabendazole

Albendazole/
Mebendazole

Angiostrongylus cantonensis

Wuchereria bancrofti (filariasis);

Brugia malayi (filariasis); tropical
eosinophilia;
Loa loa (loiasis)

Diethylcarbamazi Ivermectin
ne

Onchocerca volvulus
(onchocerciasis)

Ivermectin

Suramin

Dracunculus medinensis (guinea Metronidazole

worm)

Thiabendazole/
Mebendazole

Capillaria philippinensis
(intestinal capillariasis)

Mebendazole/
Thiabendazole

Albendazole

Trematoda (flukes)

1st choice

2nd choice

Schistosoma haematobium
(bilharziasis)

Praziquantel

Metrifonate

Schistosoma mansoni

Praziquantel

Oxamniquine

Schistosoma japonicum

Praziquantel

Clonorchis sinensis
(liver fluke);
opisthorchis species

Praziquantel

Albendazole

Paragonimus westermani
(lung fluke)

Praziquantel

Bithionol

Fasciola hepatica
(sheep liver fluke)

Bithionol/
Triclabendazole

Fasciolopsis buski
(large intestinal fluke)

Praziquantel/
Niclosamide

Heterophyes heterophyes
Metagonimus yokogawai
(small intestinal flukes)

Praziquantel/
Niclosamide

Cestoda (cacing pita)

Taenia saginata
(beef tapeworm)
Taenia solium
(pork tapeworm)
Diphyllobothrium latum
(fish tapeworm)
Cysticercosis
(pork tapeworm larval stage)
Hymenolepis nana
(dwarf tapeworm)
Echinococcus granulosus
(hydatid disease);
Echinococcus
multilocularis

1st choice
Praziquantel/
Niclosamide
Praziquantel/
Niclosamide
Praziquantel/
Niclosamide
Albendazole

2nd choice
Mebendazole

Praziquantel

Niclosamide

Albendazole

Praziquantel

Mekanisme kerja anthelmentic

Obat

Mekanisme
Kerja

Efek
Spesifik

Piperazine

Memparalisis
otot cacing

Memblokir myoneural junction;

agonis gated chloride channels
hiperpolarisasi paralisis 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

Memparalisis
otot cacing

Menginaktivasi asetilkolinesterase &

mempotensiasi efek-efek kolinergik
inhibitori

Memparalisis
otot cacing

Meningkatkan permeabilitas membran

terhadap Ca2+ memaparkan proteinprotein membran diserang antibodi

Menghambat
produksi energi

Menghambat fosforilasi oksidatif

Metrifonate
(Trichlorfon)

Praziquantel
Bithionol

Mekanisme kerja anthelmentic

Obat

Mekanisme
Kerja

Efek
Spesifik

Menghambat
produksi energi

Menghambat fosforilasi oksidatif

anaerobik dalam mitokondria cacing
sintesa ATP

Menghambat
produksi energi

Berikatan dengan tubulin & menghambat

polimerisasi

Menghambat
produksi energi &
fungsi protein

Menghambat fumarat reduktase &

sintesa ATP; berikatan dengan tubulin

Menghambat
produksi energi

Menghambat enzim-enzim otot yang

berkait dengan glikolisis & konsumsi
oksigen

Oxamniquine

Mengesterifikasi &
mengikat DNA

Menghambat sintesa asam nukleat &

protein

Diethylcarbamazine

Mempermudah
fagositosis &
eliminasi

Meningkatkan kesensitifan mikrofilaria,

memerangkap mikrofilaria dalam sistem
retikuloendotelial

Niclosamide
Mebendazole
Thiabendazole

Suramin

Farmakoterapi
Obat-obat pilihan adalah
benzidimazole (BZA):

albendazole (dosis tunggal 400

mg, 200 mg: anak-anak 12-24 bulan) /

mebendazole (100 mg 2x/hari

untuk 3 hari (dewasa & anak >2 tahun) /

levamisole (dosis tunggal 2,5

mg/kg) /

pyrantel pamoate (dosis tunggal

11 mg/kg, tetapi 1 g)
(WHO 2002)

Migrasi larva A. lumbricoides

bisa menyebabkan

pneumonia hemoragik.

Dept. Pharmacology & Therapeutic

School of Medicine

Universitas Sumatera Utara

Drugs used in amoebiasis

Amoebiases is due to infection with Entamoeba
histolytica, which causes dysentery associated with
invasion of the intestinal wall and, rarely, of the liver. The
organism may be present in motile, invasive form, or as
a cyst.
Metronidazole: given orally,is active against the invasive
form 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 invasive
form.
Chloroquine: used for hepatic amoebiasis.

Classification of anti-amoeba
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
Anti-amoeba
Chloroquine

Indication

MoA

ADR

Amebic liver
abscess

Metronidazole Intestinal &

Disruption of
extra-intestnal DNA synthesis
& nucleic acid
synthesis

Metallic taste,
nausea,
vomiting,
diarrhea,
abdominal
cramps

Iodoquinol

Intestinal

Directly kills the

protozoa

N/V, diarrhea,
anorexia,
agranulocytosis

Paramomycin

Intestinal

Inhibiting protein N/V, diarrhea,

synthesis
stomach
cramps,
ototoxic, tinnitus

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. et al.

Metronidazole
Prototype drug introduced in 1959
Bactericidal against
Giardia lamblia, anaerobic bacteria,
Bacteroides fragilis, Fusobacterium,
Clostridium perfringes, Helicobacter
pylori, Anaerobic Streptococci

Metronidazole (MoA)
Not clearly understood
Enters micro-organism by diffusion
Nitro group reduced DNA damaged
Cytotoxicity
High selective anaerobic action
interference with electron transportation from
NADPH or other reduced substrates
Also inhibits cell mediated immunity
Induce mutagenesis
Cause radio-sensitization

Metronidazole
A nitroimidazole. The nitro group of metronidazole is
chemically 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 (<20%)
Through blood brain barrier
Metabolizing in liver.
Excreted mainly in the urine.

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

Metronidazole
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
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 drug not 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
Diloxanide furoate is a dichoroacetamide derivative.
Effective luminal amebicide but is not active against
tissue 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, abdominal
cramps, rashes, abortion.

Notice !

Treatment with tissue

amoebicide SHOULD always be
followed by Luminal
amoebicide to eradicate
source of infection

Anti-trichomoniasis Drugs
Metronidazole
Acetarsol

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 with
parasites which have no exo-erythrocytic stage.e.g quinine,
chloroquine
Drugs used for chemoprophylaxis, i.e to prevent malarial
attacks when in a malarious area, act on merozoites emerging
from liver cells. e.g quinine, chloroquine
Drugs used for radical cure are active against parasites in the
liver e.g primaquine.
Drugs act on gametocytes and prevent transmission by the
mosquito e.g primaquine.

Anti malarial drugs

Chloroquine: Drug of choice for both chemoprophylaxis
and 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.

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.

Classification of anti-malaria

Classified by their selective actions on

different phases of the parasite life cycle:
1. Tissue schizonticides: eliminate developing or
dormant liver forms.
2. Blood schizonticides: act on erythrocytic
parasites.
3. Gametocides: kill sexual stages and prevent
transmission to mosquitoes.

No one available agent can reliably effect a

radical cures.

Control symptoms

Chloroquine
A synthetic 4-aminoquinoline formulated as the
phosphate 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 Effects
1. Antimalarial action:
Schizonticide gametocyte
Not active against liver stage
highly effective blood schizonticide.
Moderately effective against gametocytes of P vivax, P ovale,
and P malariae but not against those of P falciparum
not active against liver stage parasites.
Mechanism:
plasmodium aggregates chloroquine.
chloroquine incorporated into DNA chain of plasmodium inhibit
proliferation.
chloroquine prevents the polymerization of the hemoglobin breakdown
product, 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 falciparum and 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

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 adverse
effects.
Rare reactions include hemolysis in G6PDdeficient persons, impaired hearing, confusion,
psychosis, seizures, hypotension, ECG changes.
teratogenesis

Control symptoms

Quinine
Quinine and quinidine remain first-line
therapies for falciparum malaria
especially severe disease.
Quinine is an alkaloid derived from the bark of
the 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.

 Pharmacological Effects
Highly effective blood schizonticide against the
four species of human malaria paresites.
Gametocidal against P vivax and P ovale but not P
falciparum.
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
Clinical Uses: mainly for chloroquine-resistant
falciparum malaria, especially for cerebral
malaria.
Parenteral treatment of severe falciparum malaria
Oral treatment of falciparum malaria
Malarial chemoprophylaxis
Babesiosis

Adverse Effects and Cautions

1. Cinchonism: tinnitus, headache, nausea,
dizziness, flushing, visual disturbances
2. Cardiovascular effects: severe hypotension and
arrhythmia can follow too-rapid intravenous
infusion.
3. Idiosyncrasy: hemolysis with G6PD deficiency.
4. Others: hypoglycemia through stimulation of
insulin release, stimulate uterine contractions

Control symptoms

Mefloquine
A synthetic 4-quinoline methanol that is chemically
related to quinine.
Pharmacokinetics
Only be given orally because severe local irritation occurs
with parenteral use.
Well absorbed.
Highly protein-bound, extensively distributed in tissues,
and eliminated slowly. t1/2 is 20 days.

Pharmacological Effects:

Strong blood schizonticidal activity against P falciparum

and P vivax, but not active against hepatic stages or
gametocytes.

 Clinical Uses
Chemoprophylaxis:
Treatment: mainly for chloroquine-resistant
falciparum malaria.

Adverse Effects and Cautions

Nausea, vomiting, diarrhea, abdominal pain
dose-dependent
Neuropsychiatric toxicities: dizziness, headache,
behavioral disturbances, psychosis, seizures.

Control
symptoms

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:

Control symptoms

Artemether and Artesunate

Dihydroartemisinin

Control relapse
and transmission

Primaquine

Synthetic 8-aminoquinoline.
Pharmacological Effects
Against hepatic stages of malaria parasites.
The only available agent active against the
dormant hypnozoite stages of P vivax and P ovale.
Also gametocidal against the four human malaria
species.

 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 against
falciparum 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 P
falciparum gametocytes noninfective to mosquitoes. This
therapy is of no clinical benefit to the patient but will
disrupt transmission
Pneumocystis carinii infection: clindamycin+primaquine
mild to moderate pneumocystosis

Primaquine
Adverse Effects and Cautions
Nausea, epigastric pain, abdominal cramps,
headache.
Hemolysis or methemoglobinemia, especially
in persons with G6PD deficiency or other
hereditary metabolic defects.

Etiological factor
prophylaxis

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 erythrocytic
stage.
No action against gametocytes, but can inhibit
development of plasmodium in mosquito.
Inhibit plasmodial dihydrofolate reductase inhibiting
breeding of plasmodium.

Pyrimethamine
Adverse Effects and Cautions
Gastrointestinal symptoms, skin rashes.
Interfering folic acid metabolism in human
megalocyte anemia, granulocytopenia.
Acute intoxication
Teratogenesis

Etiological factor
prophylaxis

Sulfonamides and Sulfone

Competing dihydropteroatesye synthase with
PABA 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

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: therapeutic
effect, resistance

Antimalarial Drugs
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 additive
killing power

Antimalarials:
Mechanism of Action
4-Aminoquinoline derivatives:
chloroquine and hydroxychloroquine
Bind to parasite nucleoproteins and interfere with
protein synthesis; also alter pH within the parasite

Interfere with parasites ability to metabolize and use

erythrocyte hemoglobin
Effective only during the erythrocytic phase

Antimalarials:
Mechanism of Action
4-Aminoquinoline derivatives:
quinine and Mefloquine (Lariam)
Alter pH within the parasite
Interfere with parasites ability to metabolize
and use erythrocyte hemoglobin
Effective only during the erythrocytic phase

Antimalarials:
Mechanism of Action
Diaminopyrimidines
(pyrimethamine & trimethoprim)
Inhibit protein synthesis essential for growth and
survival
Only effective during the erythrocytic phase
These drugs may be used with sulfadoxine or
dapsone or synergistic effects

Antimalarials:
Mechanism of Action
Primaquine
Only exoerythrocytic drug (works in both phases)
Binds and alters parasitic DNA

Sulfonamides, tetracyclines, clindamycin

Used in combination with antimalarials to
increase protozoacidal effects

Antimalarials
Drug Effects
Kill parasitic organisms
Chloroquine and hydroxychloroquine also have
antiinflammatory effects
Indications
Kills Plasmodium organisms, the parasites that cause malaria
The drugs have varying effectiveness on the different malaria
organisms
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
Adverse Effects
Many adverse effects for the various drugs
Primarily gastrointestinal: nausea, vomiting,
diarrhea, anorexia, and abdominal pain

Dirgahayu negeriku
Dirgahayu FK USU

KEBANGGAAN INDONESIA UNTUK DUNIA

Mebendazole
A synthetic benzimidazole that has a wide spectrum
of anthelmintic activity and a low incidence of
adverse effects.
Pharmacokinetics
Oral absorption 10, Absorption increases with fatty
meal
First pass elimination is high.
Protein-binding 90
Excreted mostly in the urine, a portion of absored
drug and its derivatives are excreted in the bile. It is
converted to inactive metabolites rapidly in liver.
It has half life of 2-6 hours

 Pharmacologic Effects
Inhibits microtubule synthesis in nematodes, thus
irreversibly impairing glucose uptake. Intestinal parasites
are 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

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 may
cause convulsion in this group.
enzyme inducers and inhibitors affect plasma
level of the drug.
hepatic parenchymal disease

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
Mechanism of action:
It inhibits microtubule synthesis in
nematodes(intestinal round worms) that irreversibly
impairs glucose uptake, intestinal parasites are
immobilized and die slowly.
It is larvicidal in hydatid, cysticercosis, ascariasis and
hook worm infection.
Also ovicidal in ascariasis, ancyclostomiasis
(hookworm), tricurasis
121

Pharmacokinetics (Albendazole)
it is adminstered orally , and absorbed
erratically (unpredictable) , absorption
can be increased with fatty meal
It is metabolized in the liver rapidly to
active 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
122

 Clinical Uses
Administered on an empty stomach when used
against intraluminal parasites but with a fatty
meal when used against tissue parasites.
1. Ascariasis, Trichuriasis, and Hookworm and
Pinworm infections.
2. Strongyloidiasis
3. Hydatid Disease
4. Neurocysticercosis
5. Other infections: cutaneous larva migrans,
gnathostomiasis

Albendazole cond
Adverse effects:
In short term: use no significant adverse effects.
In long term use : as used in hydatid cyst and
cysticercosis, abdominal distress, headache ,fever ,
fatigue, alopecia , increased liver enzymes ,
pancytopenia. Blood counts and LFT should be
followed.
Not given during pregnancy and in hypersensitive
people.

124

Piperazine
Only recommended for the treatment of ascariasis.
No longer recommended for treatment of pinworm
infection, because a 7-day course of treatment is
required.
Not useful in hookworm infection, trichuriasis, or
strongyloidiasis.
Causes flaccid paralysis of ascaris by blocking
acetylcholine at the myoneural junction.
Neurotoxic adverse effects.

Piperazine cond
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 after
one 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
126

Levamizole
A synthetic imidazothiazole derivative and the
L isomer of D,L-tetramisole.
Highly effective in eradicating ascaris and
trichostrongylus and moderately effective
against both species of hookworm.
Inhibiting succinic dehydrogenase energy
flaccid paralysis
Immunomodulating effect.

PYRANTEL PAMOATE
A tetrahydropyrimidine derivative.
A broad-spectrum anthelmintic, but it is not
effective against tricuriasis (whip worms), and
trichostrongylus orientalis infections. Oxantel
pamoate 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 blocking agent
that causes release of acetylcholine and
inhibition of cholinestrase leads to spastic
128
paralysis of worms.

Pyrental pamoate cond

Adverse Effects .
Infrequent mild transient GI disturbance
drowsiness , headache ,insomnia.
Rash ,fever
Contraindciations
Should not be used in liver diseases.
Pregnancy
and child under 2 years of age
129

Pyrvinium Embonate

A dye.
Not absorb orally.
treatment of pinworm
Selectively interfering energy metabolism
enzymatic system
Inhibiting glucose-transporting enzymatic
system
Red feces

Niclosamide
A salicylamide derivative
Treatment of most tapeworm infection.
Pharmacologic Effects
Scoleces and segments of cestodes but not
ova are rapidly killed on contact with
nicolsamide due to the drugs inhibition of
oxidative phosphorylation or to its ATPasestimulating property.
With the death of the parasite, digestion of
scoleces and segments begins.

 Clinical Uses
Given in the morning on an empty stomach.
The tablets must be chewed thoroughly and are
then 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
Effective in the treatment of schistosome
infections of all species and most other
trematode and cestode infections, including
cysticercosis.
A first choice in the treatment cestodiasis.

Benzimidazoles

Albendazole, mebendazole, thiabendazole

Inhibit glucose absorption
Poorly absorbed (PO).
Active against nematodes (drugs of choice).
Leder K. & Weller P. 2003. In ASM Manual of CM.

Write the pharmacological action and side

effects of the following drugs

Chloroquine
Metronidazole
Melarsoprol
Primaquine
Mebendazole
Praziquantel
Niclosamide
Pyrantel pamoate
Thiabendazole

Books & sites

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

Dept. Pharmacology & Therapeutic

School of Medicine

Universitas Sumatera Utara

Nematoda (roundworms)

1st choice

2nd choice

Ascaris lumbricoides
(roundworm)

Albendazole/
Piperazine
Pyrantel pamoate/
Mebendazole

Trichuris trichiura
(whipworm)

Mebendazole/
Albendazole

Necator americanus
(hookworm);
Ancylostoma duodenale
(hookworm)

Pyrantel pamoate/
Mebendazole/
Albendazole

Strongyloides stercoralis
(threadworm)

Ivermectin

Thiabendazole,
Albendazole

Enterobius vermicularis
(pinworm)

Mebendazole/
Pyrantel pamoate

Albendazole

Trichinella spiralis
(trichinosis)

Mebendazole

Albendazole

(+kortikosteroid untuk
infeksi berat)

(+kortikosteroid untuk
infeksi berat)

Trichostrongylus species

Oxantel/
Pyrantel pamoate

Pyrantel pamoate/ Albendazole

Mebendazole

1st choice

2nd choice

Cutaneous larva migrans

(creeping eruption)

Albendazole/
Ivermectin

Thiabendazole
(topikal)

Visceral larva migrans

Albendazole

Mebendazole

Thiabendazole

Albendazole/
Mebendazole

Angiostrongylus cantonensis

Wuchereria bancrofti (filariasis);

Brugia malayi (filariasis); tropical
eosinophilia;
Loa loa (loiasis)

Diethylcarbamazi Ivermectin
ne

Onchocerca volvulus
(onchocerciasis)

Ivermectin

Suramin

Dracunculus medinensis (guinea Metronidazole

worm)

Thiabendazole/
Mebendazole

Capillaria philippinensis
(intestinal capillariasis)

Mebendazole/
Thiabendazole

Albendazole

Trematoda (flukes)

1st choice

2nd choice

Schistosoma haematobium
(bilharziasis)

Praziquantel

Metrifonate

Schistosoma mansoni

Praziquantel

Oxamniquine

Schistosoma japonicum

Praziquantel

Clonorchis sinensis
(liver fluke);
opisthorchis species

Praziquantel

Albendazole

Paragonimus westermani
(lung fluke)

Praziquantel

Bithionol

Fasciola hepatica
(sheep liver fluke)

Bithionol/
Triclabendazole

Fasciolopsis buski
(large intestinal fluke)

Praziquantel/
Niclosamide

Heterophyes heterophyes
Metagonimus yokogawai
(small intestinal flukes)

Praziquantel/
Niclosamide

Cestoda (cacing pita)

Taenia saginata
(beef tapeworm)
Taenia solium
(pork tapeworm)
Diphyllobothrium latum
(fish tapeworm)
Cysticercosis
(pork tapeworm larval stage)
Hymenolepis nana
(dwarf tapeworm)
Echinococcus granulosus
(hydatid disease);
Echinococcus
multilocularis

1st choice
Praziquantel/
Niclosamide
Praziquantel/
Niclosamide
Praziquantel/
Niclosamide
Albendazole

2nd choice
Mebendazole

Praziquantel

Niclosamide

Albendazole

Praziquantel

Mekanisme kerja anthelmentic

Obat

Mekanisme
Kerja

Efek
Spesifik

Piperazine

Memparalisis
otot cacing

Memblokir myoneural junction;

agonis gated chloride channels
hiperpolarisasi paralisis 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

Memparalisis
otot cacing

Menginaktivasi asetilkolinesterase &

mempotensiasi efek-efek kolinergik
inhibitori

Memparalisis
otot cacing

Meningkatkan permeabilitas membran

terhadap Ca2+ memaparkan proteinprotein membran diserang antibodi

Menghambat
produksi energi

Menghambat fosforilasi oksidatif

Metrifonate
(Trichlorfon)

Praziquantel
Bithionol

Mekanisme kerja anthelmentic

Obat

Mekanisme
Kerja

Efek
Spesifik

Menghambat
produksi energi

Menghambat fosforilasi oksidatif

anaerobik dalam mitokondria cacing
sintesa ATP

Menghambat
produksi energi

Berikatan dengan tubulin & menghambat

polimerisasi

Menghambat
produksi energi &
fungsi protein

Menghambat fumarat reduktase &

sintesa ATP; berikatan dengan tubulin

Menghambat
produksi energi

Menghambat enzim-enzim otot yang

berkait dengan glikolisis & konsumsi
oksigen

Oxamniquine

Mengesterifikasi &
mengikat DNA

Menghambat sintesa asam nukleat &

protein

Diethylcarbamazine

Mempermudah
fagositosis &
eliminasi

Meningkatkan kesensitifan mikrofilaria,

memerangkap mikrofilaria dalam sistem
retikuloendotelial

Niclosamide
Mebendazole
Thiabendazole

Suramin

Farmakoterapi
Obat-obat pilihan adalah
benzidimazole (BZA):

albendazole (dosis tunggal 400

mg, 200 mg: anak-anak 12-24 bulan) /

mebendazole (100 mg 2x/hari

untuk 3 hari (dewasa & anak >2 tahun) /

levamisole (dosis tunggal 2,5

mg/kg) /

pyrantel pamoate (dosis tunggal

11 mg/kg, tetapi 1 g)
(WHO 2002)

Migrasi larva A. lumbricoides

bisa menyebabkan

pneumonia hemoragik.

Kesimpulan & Saran

Secara umumnya, obat anthelmintika terbagi atas beberapa
macam tergantung pada mekanisme kerjanya, yaitu
vermifuge (menghambat produksi energi), flaccid paralyzing
agents (memblokir respon cacing terhadap asetilkolinmenyebabkan paralisis flasid), spastic paralyzing agents
(menginhibisi kolinesterase), dan systemic anthelmintic
agents (mengurangi produksi ATP).
Infeksi cacing dari spesies yang berbeda memerlukan obat
dan terapi yang berbeda. Drug of choice haruslah diberikan
sekiranya tidak ada kontraindikasi.
Infeksi ascariasis merupakan suatu masalah kesehatan yang
penting di banyak negara sedang berkembang.
Pengobatannya tidak sulit dan kadar penyembuhannya
sangat tinggi kalau tidak terjadi reinfeksi.

Classification of anti-amoeba
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
Anti-amoeba
Chloroquine

Indication

MoA

ADR

Amebic liver
abscess

Metronidazole Intestinal &

Disruption of
extra-intestnal DNA synthesis
& nucleic acid
synthesis

Metallic taste,
nausea,
vomiting,
diarrhea,
abdominal
cramps

Iodoquinol

Intestinal

Directly kills the

protozoa

N/V, diarrhea,
anorexia,
agranulocytosis

Paramomycin

Intestinal

Inhibiting protein N/V, diarrhea,

synthesis
stomach
cramps,
ototoxic, tinnitus

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. et al.

Metronidazole
Prototype drug introduced in 1959
Bactericidal against
Giardia lamblia, anaerobic bacteria,
Bacteroides fragilis, Fusobacterium,
Clostridium perfringes, Helicobacter
pylori, Anaerobic Streptococci

Metronidazole (MoA)
Not clearly understood
Enters micro-organism by diffusion
Nitro group reduced DNA damaged
Cytotoxicity
High selective anaerobic action
interference with electron transportation from
NADPH or other reduced substrates
Also inhibits cell mediated immunity
Induce mutagenesis
Cause radio-sensitization

Metronidazole
A nitroimidazole. The nitro group of metronidazole is
chemically 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 (<20%)
Through blood brain barrier
Metabolizing in liver.
Excreted mainly in the urine.

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

Metronidazole
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
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 drug not 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
Diloxanide furoate is a dichoroacetamide derivative.
Effective luminal amebicide but is not active against
tissue 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, abdominal
cramps, rashes, abortion.

Notice !

Treatment with tissue

amoebicide SHOULD always be
followed by Luminal
amoebicide to eradicate
source of infection

Anti-trichomoniasis Drugs
Metronidazole
Acetarsol

Classification of anti-malaria

Classified by their selective actions on

different phases of the parasite life cycle:
1. Tissue schizonticides: eliminate developing or
dormant liver forms.
2. Blood schizonticides: act on erythrocytic
parasites.
3. Gametocides: kill sexual stages and prevent
transmission to mosquitoes.

No one available agent can reliably effect a

radical cures.

Control symptoms

Chloroquine
A synthetic 4-aminoquinoline formulated as the
phosphate 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 Effects
1. Antimalarial action:
Schizonticide gametocyte
Not active against liver stage
highly effective blood schizonticide.
Moderately effective against gametocytes of P vivax, P ovale,
and P malariae but not against those of P falciparum
not active against liver stage parasites.
Mechanism:
plasmodium aggregates chloroquine.
chloroquine incorporated into DNA chain of plasmodium inhibit
proliferation.
chloroquine prevents the polymerization of the hemoglobin breakdown
product, 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 falciparum and 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

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 adverse
effects.
Rare reactions include hemolysis in G6PDdeficient persons, impaired hearing, confusion,
psychosis, seizures, hypotension, ECG changes.
teratogenesis

Control symptoms

Quinine
Quinine and quinidine remain first-line
therapies for falciparum malaria
especially severe disease.
Quinine is an alkaloid derived from the bark of
the 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.

 Pharmacological Effects
Highly effective blood schizonticide against the
four species of human malaria paresites.
Gametocidal against P vivax and P ovale but not P
falciparum.
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
Clinical Uses: mainly for chloroquine-resistant
falciparum malaria, especially for cerebral
malaria.
Parenteral treatment of severe falciparum malaria
Oral treatment of falciparum malaria
Malarial chemoprophylaxis
Babesiosis

Adverse Effects and Cautions

1. Cinchonism: tinnitus, headache, nausea,
dizziness, flushing, visual disturbances
2. Cardiovascular effects: severe hypotension and
arrhythmia can follow too-rapid intravenous
infusion.
3. Idiosyncrasy: hemolysis with G6PD deficiency.
4. Others: hypoglycemia through stimulation of
insulin release, stimulate uterine contractions

Control symptoms

Mefloquine
A synthetic 4-quinoline methanol that is chemically
related to quinine.
Pharmacokinetics
Only be given orally because severe local irritation occurs
with parenteral use.
Well absorbed.
Highly protein-bound, extensively distributed in tissues,
and eliminated slowly. t1/2 is 20 days.

Pharmacological Effects:

Strong blood schizonticidal activity against P falciparum

and P vivax, but not active against hepatic stages or
gametocytes.

 Clinical Uses
Chemoprophylaxis:
Treatment: mainly for chloroquine-resistant
falciparum malaria.

Adverse Effects and Cautions

Nausea, vomiting, diarrhea, abdominal pain
dose-dependent
Neuropsychiatric toxicities: dizziness, headache,
behavioral disturbances, psychosis, seizures.

Control
symptoms

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:

Control symptoms

Artemether and Artesunate

Dihydroartemisinin

Control relapse
and transmission

Primaquine

Synthetic 8-aminoquinoline.
Pharmacological Effects
Against hepatic stages of malaria parasites.
The only available agent active against the
dormant hypnozoite stages of P vivax and P ovale.
Also gametocidal against the four human malaria
species.

 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 against
falciparum 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 P
falciparum gametocytes noninfective to mosquitoes. This
therapy is of no clinical benefit to the patient but will
disrupt transmission
Pneumocystis carinii infection: clindamycin+primaquine
mild to moderate pneumocystosis

Primaquine
Adverse Effects and Cautions
Nausea, epigastric pain, abdominal cramps,
headache.
Hemolysis or methemoglobinemia, especially
in persons with G6PD deficiency or other
hereditary metabolic defects.

Etiological factor
prophylaxis

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 erythrocytic
stage.
No action against gametocytes, but can inhibit
development of plasmodium in mosquito.
Inhibit plasmodial dihydrofolate reductase inhibiting
breeding of plasmodium.

Pyrimethamine
Adverse Effects and Cautions
Gastrointestinal symptoms, skin rashes.
Interfering folic acid metabolism in human
megalocyte anemia, granulocytopenia.
Acute intoxication
Teratogenesis

Etiological factor
prophylaxis

Sulfonamides and Sulfone

Competing dihydropteroatesye synthase with
PABA 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

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: therapeutic
effect, resistance

Dirgahayu negeriku
Dirgahayu FK USU

KEBANGGAAN INDONESIA UNTUK DUNIA

Mebendazole
A synthetic benzimidazole that has a wide spectrum
of anthelmintic activity and a low incidence of
adverse effects.
Pharmacokinetics
Oral absorption 10, Absorption increases with fatty
meal
First pass elimination is high.
Protein-binding 90
Excreted mostly in the urine, a portion of absored
drug and its derivatives are excreted in the bile. It is
converted to inactive metabolites rapidly in liver.
It has half life of 2-6 hours

 Pharmacologic Effects
Inhibits microtubule synthesis in nematodes, thus
irreversibly impairing glucose uptake. Intestinal parasites
are 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

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 may
cause convulsion in this group.
enzyme inducers and inhibitors affect plasma
level of the drug.
hepatic parenchymal disease

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
Mechanism of action:
It inhibits microtubule synthesis in
nematodes(intestinal round worms) that irreversibly
impairs glucose uptake, intestinal parasites are
immobilized and die slowly.
It is larvicidal in hydatid, cysticercosis, ascariasis and
hook worm infection.
Also ovicidal in ascariasis, ancyclostomiasis
(hookworm), tricurasis
182

Pharmacokinetics (Albendazole)
it is adminstered orally , and absorbed
erratically (unpredictable) , absorption
can be increased with fatty meal
It is metabolized in the liver rapidly to
active 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
183

 Clinical Uses
Administered on an empty stomach when used
against intraluminal parasites but with a fatty
meal when used against tissue parasites.
1. Ascariasis, Trichuriasis, and Hookworm and
Pinworm infections.
2. Strongyloidiasis
3. Hydatid Disease
4. Neurocysticercosis
5. Other infections: cutaneous larva migrans,
gnathostomiasis

Albendazole cond
Adverse effects:
In short term: use no significant adverse effects.
In long term use : as used in hydatid cyst and
cysticercosis, abdominal distress, headache ,fever ,
fatigue, alopecia , increased liver enzymes ,
pancytopenia. Blood counts and LFT should be
followed.
Not given during pregnancy and in hypersensitive
people.

185

Piperazine
Only recommended for the treatment of ascariasis.
No longer recommended for treatment of pinworm
infection, because a 7-day course of treatment is
required.
Not useful in hookworm infection, trichuriasis, or
strongyloidiasis.
Causes flaccid paralysis of ascaris by blocking
acetylcholine at the myoneural junction.
Neurotoxic adverse effects.

Piperazine cond
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 after
one 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
187

Levamizole
A synthetic imidazothiazole derivative and the
L isomer of D,L-tetramisole.
Highly effective in eradicating ascaris and
trichostrongylus and moderately effective
against both species of hookworm.
Inhibiting succinic dehydrogenase energy
flaccid paralysis
Immunomodulating effect.

PYRANTEL PAMOATE
A tetrahydropyrimidine derivative.
A broad-spectrum anthelmintic, but it is not
effective against tricuriasis (whip worms), and
trichostrongylus orientalis infections. Oxantel
pamoate 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 blocking agent
that causes release of acetylcholine and
inhibition of cholinestrase leads to spastic
189
paralysis of worms.

Pyrental pamoate cond

Adverse Effects .
Infrequent mild transient GI disturbance
drowsiness , headache ,insomnia.
Rash ,fever
Contraindciations
Should not be used in liver diseases.
Pregnancy
and child under 2 years of age
190

Pyrvinium Embonate

A dye.
Not absorb orally.
treatment of pinworm
Selectively interfering energy metabolism
enzymatic system
Inhibiting glucose-transporting enzymatic
system
Red feces

Niclosamide
A salicylamide derivative
Treatment of most tapeworm infection.
Pharmacologic Effects
Scoleces and segments of cestodes but not
ova are rapidly killed on contact with
nicolsamide due to the drugs inhibition of
oxidative phosphorylation or to its ATPasestimulating property.
With the death of the parasite, digestion of
scoleces and segments begins.

 Clinical Uses
Given in the morning on an empty stomach.
The tablets must be chewed thoroughly and are
then 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
Effective in the treatment of schistosome
infections of all species and most other
trematode and cestode infections, including
cysticercosis.
A first choice in the treatment cestodiasis.

Antimalarial Drugs
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 additive
killing power

Antimalarials:
Mechanism of Action
4-Aminoquinoline derivatives:
chloroquine and hydroxychloroquine
Bind to parasite nucleoproteins and interfere with
protein synthesis; also alter pH within the parasite

Interfere with parasites ability to metabolize and use

erythrocyte hemoglobin
Effective only during the erythrocytic phase

Antimalarials:
Mechanism of Action
4-Aminoquinoline derivatives:
quinine and Mefloquine (Lariam)
Alter pH within the parasite
Interfere with parasites ability to metabolize
and use erythrocyte hemoglobin
Effective only during the erythrocytic phase

Antimalarials:
Mechanism of Action
Diaminopyrimidines
(pyrimethamine & trimethoprim)
Inhibit protein synthesis essential for growth and
survival
Only effective during the erythrocytic phase
These drugs may be used with sulfadoxine or
dapsone or synergistic effects

Antimalarials:
Mechanism of Action
Primaquine
Only exoerythrocytic drug (works in both phases)
Binds and alters parasitic DNA

Sulfonamides, tetracyclines, clindamycin

Used in combination with antimalarials to
increase protozoacidal effects

Antimalarials
Drug Effects
Kill parasitic organisms
Chloroquine and hydroxychloroquine also have
antiinflammatory effects
Indications
Kills Plasmodium organisms, the parasites that cause malaria
The drugs have varying effectiveness on the different malaria
organisms
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
Adverse Effects
Many adverse effects for the various drugs
Primarily gastrointestinal: nausea, vomiting,
diarrhea, anorexia, and abdominal pain

Benzimidazoles

Albendazole, mebendazole, thiabendazole

Inhibit glucose absorption
Poorly absorbed (PO).
Active against nematodes (drugs of choice).
Leder K. & Weller P. 2003. In ASM Manual of CM.

Dept. Pharmacology & Therapeutic

School of Medicine

Universitas Sumatera Utara