FARMAKOLOGI OBAT

ANTI MALARIA
K E LOM P OK 2
R IN DA H – 2 1 7 04101 082

D OS E N P E M B IM B IN G :
A N D R I T IL AQZ A , M . FA R M , A P T.

KEPANITRAAN KLINIK MADYA

LABORATORIUM ILMU FARMASI
FAKULTAS KEDOKTERANUNIVERSITAS ISLAM MALANG
2019
DEFINISI
•Malaria adalah penyakit infeksi yang disebabkan oleh parasit
plasmodium yang hidup dan berkembang biak di dalam sel darah
manusia.
•Penyakit ini secara alami ditularkan melalui gigitan nyamuk
anopheles betina (vector).
ETIOLOGI
•Plasmodium falciparum
•Plasmodium vivax
•Plasmodium malariae
•Plasmodium ovale, penyebab malaria ovale
•Plasmodium knowlesi
 MANIFESTASI KLINIS
a. Periode dingin
• Mulai menggigil, kulit dingin dan kering, pucat sampai sianosis, pada anak bisa terjadi kejang.
• berlangsung 15–60 menit diikuti dengan meningkatnya temperatur.

b. Periode panas
• Muka penderita merah, kulit panas dan kering, nadi cepat dan demam 40° C atau lebih.
• Berlangsung 2 jam atau lebih, diikuti keadaan berkeringat.

c. Periode berkeringat
• Berkeringat mulai dari temporal dan seluruh tubuh, temperatur turun drastic, merasa capek dan
sering tertidur dengan nyenyak dan setelah bangun tidak ada keluhan kecuali badan lemah.
• berlangsung 2- 4 jam.
 MALARIA BERAT
Malaria berat : ditemukannya Plasmodium falciparum stadium aseksual dengan minimal satu dari manifestasi klinis
atau didapatkan temuan hasil laboratorium (WHO, 2015):
1. Perubahan kesadaran (GCS<11, Blantyre <3)
2. Kelemahan otot (tak bisa duduk/berjalan)
3. Kejang berulang-lebih dari dua episode dalam 24 jam
4. Distres pernafasan
5. Gagal sirkulasi atau syok: pengisian kapiler > 3 detik,
tekanan sistolik <80 mm Hg (pada anak: <70 mmHg)
6. Jaundice (bilirubin>3mg/dL dan kepadatan parasit
>100.000)
7. Hemoglobinuria
8. Perdarahan spontan abnormal
9. Edema paru (radiologi, saturasi Oksigen <92%
SIKLUS HIDUP
ALGORITME
KELOMPOK OBAT ANTIMALARIA
Gol. Kuinidin:
Kuinine, Kuinidin, Primakuin,
Klorokuin, Amodiakuin,
Meflokuine, Halofantrin
Gol. Antifolat:
Pirimetamin, Trimetropim,
Proguanil, Klorprokuanil
Gol. Antibakteri:
Sulfonamid, Tetrasiklin,
Spiramisin, Azitromisin,
Klindamisin, Rifampisin
Gol. Artemisin:
Artemisin, Artemer, Artesunat
UNCOMPLICATED MALARIA P.FALSIPARUM
CHLOROQUINE RESISTANCE OR UNKNOWN RESISTANCE

ATOVAQUONE- ARTEMETHER-
PROGUANIL LUMEFANTRINE

QUININE SULFATE +
DOXYCYCLINE or
TETRACYCLINE or MEFLOQUINE
CLINDAMYCYN
 REASON
ATOVAQUONE-PROGUANIL ARTEMETHER-LUMEFANTRINE
(AP) (AL)
• Kombinasi dari obat erythrocytic • Can be used in second and third
(atovaquone) dan schizontisida trimesters of pregnancy.
jaringan (proguanil).
• Can be used in first trimester of
• Can be used in second and third pregnancy if no other drug options
trimesters of pregnancy. are available.
• Can be used in first trimester of • Not recommended in infants
pregnancy if no other drug options weighing <5 kg.
are available. Not recommended in
infants weighing <5 kg.
• Atovaquone/proguanil menunjukkan
profil keamanan komparatif yang
baik
 REASON

QUININE SULFATE + DOXYCYCLINE or

TETRECYCLINE or CLINDAMYCYNE MEFLOQUINE

• Treatment with
• Beberapa antibakteri sebagai antiplasmodial, namun tindakannya mefloquine is not
lambat sehingga direkomendasikan hanya dalam kombinasi dengan recommended in
obat antimalaria lainnya.
• Not recommended in pregnancy or in children <8 years old. persons who have
• However, doxycycline or tetracycline may be used in combination acquired infections
with quinine (as recommended for non-pregnant adults) if other from Southeast Asia
treatment options are not available or are not being tolerated, and due to drug
the benefit is judged to outweigh the risks. resistance.
• Doxycycline & tetracycline: Penggunaannya dalam kehamilan
manusia dikaitkan dengan gangguan pertumbuhan tulang janin dan
dengan pewarnaan gigi ireversibel ketika diberikan pada trimester
ketiga dan pada masa bayi.
UNCOMPLICATED MALARIA P.FALSIPARUM
CHLOROQUINE SENSITIVE

CHLOROQUINE PHOSPHATE HYDROXYCHLOROQUINE

UNCOMPLICATED MALARIA P.MALARIAE &
P.KNOWLESI

CHLOROQUINE PHOSPHATE HYDROXYCHLOROQUINE

 REASON
CHLOROQUINE PHOSPHATE vs HYDROXYCHLOROQUINE

• Mengobati infeksi daerah yang sensitif terhadap klorokuin (Central America

west of Panama Canal; Haiti; the Dominican Republic; and most of the Middle
East)
• Lini pertama karena aktivitas skizontisidal yang cepat terhadap semua infeksi P.
malariae dan P. ovale dan terhadap infeksi chloroquinesensitive P. falciparum
dan P. vivax.
• Selain itu juga, gametositosidal terhadap P. vivax, P. malariae dan P. ovale
serta gametosit yang belum matang dari P. falciparum.
• Hydroxychloroquine jauh lebih tidak aktif daripada chloroquine terhadap
Plasmodium falciparum
• Efek samping jarang terjadi dan umumnya ringan pada chloroquine
UNCOMPLICATED MALARIA P.VIVAX & P.OVALE
FOR SUSPECTED CHLOROQUINE-RESISTANT P. VIVAX

CHLOROQUINE PHOSPHATE HYDROXYCHLOROQUINE +

+ PRIMAQUINE PHOSPHATE PRIMAQUINE PHOSPHATE or
or TAFENOQUINE TAFENOQUINE
 REASON

CHLOROQUINE PHOSPHATE vs HYDROXYCHLOROQUINE

• Mengobati infeksi pada daerah yang sensitif terhadap klorokuin (Central

America west of Panama Canal; the Dominican Republic; and most of the
Middle East)
• Lini pertama karena aktivitas skizontisidal yang cepat terhadap semua infeksi P.
malariae dan P. ovale dan terhadap infeksi chloroquinesensitive P. falciparum
dan P. vivax.
• Hydroxychloroquine jauh lebih tidak aktif daripada chloroquine terhadap
Plasmodium falciparum
• Efek samping jarang terjadi dan umumnya ringan pada chloroquine
• aman pada semua trimester kehamilan dan ibu menyusui
PRIMAQUINE & TAFENOQUINE
• Membunuh semua hypnozoite yang tidak aktif di hati, sehingga mencegah kambuhnya
infeksi P. vivax dan P. ovale.
• Menyebabkan anemia hemolitik pada orang yang kekurangan G6PD (pengujian G6PD
kuantitatif)
• Untuk orang dengan defisiensi G6PD batas, primaquine dapat diberikan 45 mg secara
oral satu kali per minggu selama 8 minggu
• Tidak boleh digunakan selama kehamilan. Pasien hamil dengan infeksi P. vivax dan P.
ovale harus dipertahankan dengan profilaksis klorokuin selama masa kehamilan mereka.
• Setelah melahirkan + tidak kekurangan G6PD -> primaquine atau tafenoquine.
• Primakuin : tidak diresepkan pada kehamilan karena risiko hemolisis intravaskular pada
ibu dan janin & digunakan selama menyusui jika bayi ditemukan memiliki kadar G6PD
normal.
• Tafenoquine : tidak dianjurkan pada wanita menyusui.
UNCOMPLICATED MALARIA P.VIVAX
(CHLOROQUINE-RESISTANT)
Quinine sulfate plus either Atovaquone-proguanil plus
Doxycycline or Tetracycline either Primaquine
plus either Primaquine phosphate or Tafenoquine
phosphate or Tafenoquine

Mefloquine plus either

Primaquine phosphate or
Tafenoquine

Quinine sulfate plus either
Doxycycline or Tetracycline
plus either Primaquine
phosphate or Tafenoquine
• Not recommended in
pregnancy or in children
<8 years old.
• However, doxycycline or
tetracycline may be used
in combination with
quinine (as recommended
for non-pregnant adults) if
other treatment options
are not available or are
not being tolerated, and
the benefit is judged to
outweigh the risks.
REASON
Atovaquone-proguanil plus Mefloquine plus either
either Primaquine Primaquine phosphate or
phosphate or Tafenoquine Tafenoquine
• Can be used in second • Cannot be used in areas
and third trimesters of with mefloquine resistance
pregnancy. • Cannot be used in patients
• Can be used in first with certain psychiatric
trimester of pregnancy if conditions
no other drug options are • Cannot be used in patients
available. Not with a seizure disorder
recommended in infants • Not recommended for
weighing <5 kg. persons with cardiac
conduction abnormalities
UNCOMPLICATED MALARIA FOR PREGNANT
WOMEN
CHLOROQUINE
PHOSPHASE OR ARTEMETHER-
HYDROXYCHLOROQ LUMEFANTRINE
UINE

QUININE SULFATE + MEFLOQUINE

CLINDAMYCYN
 Target siklus hidup malaria dan obat
antimalaria tahap plasmodium.

Ket:
Huruf kapital mengindikasikan target
tahap antimalaria obat-obatan dari
Plasmodium.
A: Tissue schizonticides;
B: Hypnozoiticides;
C: Blood schizonricides;
D: Gametocytocides;
E: Sporontocides.
 REASON
CHLOROQUINE PHOSPHASE
or HYDROXYCHLOROQUINE
• Chloroquine-resistant or
unknown resistance
• Some people are already
taking hydroxychloroquine
chronically for rheumatologic
conditions. In those instances,
they may not have to take an
additional medicine
• Can be used in all trimesters
of pregnancy
ARTEMETHER-LUMEFANTRINE
• Can be used in second and
third trimesters of pregnancy.
Can be used in first trimester
of pregnancy if no other drug
options are available. Not
recommended in infants
weighing <5 kg.
 REASON

QUININE SULFATE + MEFLOQUINE

CLINDAMYCYNE

• Not recommended in • Can be used during

pregnancy or in children <8 pregnancy
years old.) • Recommended for use
anytime during pregnancy in
chloroquine-resistant
PROFILAKSIS MALARIA UNTUK TRAVELER

ATOVAQUONE- CHLOROQUINE DOXYCYCLINE

PROGUANIL

MEFLOQUINE PRIMAQUINE TAFENOQUINE


Drug
Atovaquone/Proguanil (Malarone)
Adults: 1 adult tablet daily.
Children: 5-8 kg: ½ pediatric tablet
daily. 8-10 kg: ½ pediatric tablet
daily. 10-20 kg: 1 pediatric tablet
daily. 20-30 kg: 2 pediatric tablets
daily. 30-40 kg 3 pediatric tablets
daily. 40 kg and over: 1 adult
tablet daily. Begin 1-2 days before
travel, daily during travel, and for
7 days after leaving.
Reasons that might make you
consider using this drug
 Good for last-minute travelers
because the drug is started 1-2
days before traveling to an area
where malaria transmission occurs
 Some people prefer to take a
daily medicine11
Good choice for shorter trips
 
because you only have to take
the medicine for 7 days after
traveling rather than 4 weeks
 Very well tolerated medicine –
side effects uncommon
 Pediatric tablets are available
and may be more convenient
Reasons that might make you
avoid using this drug
 Cannot be used by women who
are pregnant or breastfeeding a
child less than 5 kg
 Cannot be taken by people with
severe renal impairment
Tends to be more expensive than
some of the other options
(especially for trips of long
duration)
 Some people (including children)
would rather not take a medicine
every day
 Reasons that might make you
Drug
consider using this drug
CHLOROQUINE
 Some people would rather take
medicine weekly
Chloroquine
 Good choice for long trips
Adults: 300 mg base (500 mg
because it is taken only weekly
salt), once/week.
 Some people are11 already taking
Children: 5 mg/kg base (8.3
hydroxychloroquine chronically
mg/kg salt) (maximum is adult
for rheumatologic conditions. In
dose), once/week. Begin 1-2
those instances, they may not
weeks before travel, once/week
have to take an additional
during travel, and for 4 weeks
medicine
after leaving.
 Can be used in all trimesters of
pregnancy
Reasons that might make you
avoid using this drug
 Cannot be used in areas with
chloroquine or mefloquine
resistance
May exacerbate psoriasis

 Some people would rather not
take a weekly medication
 For trips of short duration, some
people would rather not take
medication for 4 weeks after
travel
 Not a good choice for last-
minute travelers because drug
needs to be started 1-2 weeks
prior to travel
 Drug
Doxycycline
Adults: 100 mg daily.
Children: ≥8 years old: 2.2 mg/kg
(maximum is adult dose) daily.
Begin 1-2 days before travel, daily
during travel, and for 4 weeks
after leaving.
Reasons that might make you
consider using this drug
 Some people prefer to take a
daily medicine
 Good for last-minute travelers
because the drug is started 1-2
days before traveling to an area
where malaria transmission
occurs
 Tends to be the least expensive
antimalarial
 Some people are already taking
doxycycline chronically for
prevention of acne. In those
instances, they do not have to
take an additional medicine
 Doxycycline also can prevent
some additional infections (e.g.,
Rickettsiae and leptospirosis) and
so it may be preferred by
people planning to do lots of
hiking, camping, and wading and
swimming in fresh water
Reasons that might make you
avoid using this drug
 Cannot be used by pregnant
women and children <8 years
old
 Some people would rather not
take a medicine every day
 For trips of short duration, some
people would rather not take
medication for 4 weeks after
travel
 Women prone to getting vaginal
yeast infections when taking
antibiotics may prefer taking a
different medicine
 Persons planning on considerable
sun exposure may want to avoid
the increased risk of sun
sensitivity
 Some people are concerned
about the potential of getting an
upset stomach from doxycycline
 Drug
Mefloquine
Adults: 228 mg base (250 mg
salt), weekly.Children: ≤9 kg: 4.6
mg/kg base (5 mg/kg salt),
weekly. 10-19 kg: ¼ tablet
weekly. 20-30 kg: ½ tablet
weekly. 31-45 kg: ¾ tablet
weekly. >45 kg: 1 tablet weekly.
Begin 1-2 weeks before travel,
weekly during travel, and for 4
weeks after leaving.
Reasons that might make you Reasons that might make you avoid
consider using this drug using this drug
 Cannot be used in areas with
mefloquine resistance
 Cannot be used in patients with
certain psychiatric conditions
 Cannot be used in patients with a
 Some people would rather seizure disorder
take medicine weekly
 Not recommended for persons with
 Good choice for long trips cardiac conduction abnormalities
because it is taken
11
only  Not a good choice for last-minute
weekly travelers because drug needs to be
 Can be used during started at least 2 weeks prior to
pregnancy travel
 Some people would rather not take
a weekly medication
 For trips of short duration, some
people would rather not take
medication for 4 weeks after travel
 Drug Reasons that might make you
consider using this drug
 It is one of the most effective
medicines for preventing P.
vivax and so it is a good
Primaquine choice for travel to places
Adults: 30 mg with > 90% P. vivax
base, daily
Children: 0.5  Good choice for shorter trips
mg/kg base up to because you only have to
adult dose daily take the medicine for 7 days
after traveling rather than 4
weeks
Begin 1-2 days  Good for last-minute
prior to travel, travelers because the drug is
daily during started 1-2 days before
travel, and for 7 traveling to an area where
days after leaving malaria transmission occurs
 Some people prefer to take
a daily medicine
Reasons that might make you avoid using this drug
 Cannot be used in patients with glucose-6-
phosphatase dehydrogenase (G6PD) deficiency
 Cannot be used in patients who have not been tested
for G6PD deficiency
 There are costs and delays associated with getting a
G6PD test done; however, it only has to be done
once. Once a normal G6PD level is verified and
documented, the test does not have to be repeated
the next time primaquine is considered
 Cannot be used by pregnant women
 Cannot be used by women who are breastfeeding
unless the infant has also been tested for G6PD
deficiency
 Some people (including children) would rather not
take a medicine every day
 Some people are concerned about the potential of
getting an upset stomach from primaquine
 Drug Reasons that might make
you consider using this drug
 One of the most effective
drugs for prevention of P.
vivaxmalaria, but also
prevents P. falciparum
Tafenoquine
(ArakodaTM)  Good choice for shorter
Adults only: 200 mg trips because you only
per dose. have to take the medicine
once, 1 week after 11
Begin daily for 3 days traveling rather than 4
prior to travel, weekly weeks
during travel, and for 1
week after leaving.  Good for last-minute
travelers because the drug
is started 3 days before
traveling to an area where
malaria transmission occurs
Reasons that might make you avoid using this
drug
 Cannot be used in patients with glucose-6-
phosphatase dehydrogenase (G6PD) deficiency
 Cannot be used in patients who have not been
tested for G6PD deficiency
There are costs and delays associated with

getting a G6PD test done; however, it only has to
be done once. Once a normal G6PD level is
verified and documented, the test does not have
to be repeated the next time tafenoquine is
considered
 Cannot be used by children
 Cannot be used by pregnant women
 Cannot be used by women who are
breastfeeding
 Not recommended in those with psychotic
disorders
ATOVAQUONE-PROGUANIL
• ES: headache, batuk, abdominal pain, nausea, vomiting, dan diare.
• Farmakokinetik:
• A : atovaquone sulit diabsorpsi oleh GI tract (bioavailabilitas 23% jika diberikan saat makan),
sedangkan proguanil mudah diabsorpsi oleh GI tract
• D : atovaquone 99% terikat protein plasma, sedangkan proguanil 75%
• M : biotransformasi melalui CYP2C19 menjadi antifolat metabolite cycloguanil
• E : 40-60% proguanil dieksresi melalui ginjal
• Farmakodinamik:
• Atovaquone: menghambat sistem transportasi, mengakibatkan collapsesnya membran mitokondria plasmodial
• Proguanil: aktif terhadap semua tahap siklus hidup parasit malaria. Proguanil dikonversi menjadi metabolit
triazin aktif (cycloguanil) yang bekerja dengan menghambat reduktase dihydrofolate.
ARTEMETHER-LUMEFANTRINE
• ES: nausea, dizziness, headache.
•Farmakokinetik:
• A: atremether (lipofilik) diabsorpsi di GI tract, mencapai puncak konsentrasi plasma setelah 2 jam.
Lumefantrine (lipofilik) lebih mudah diabsorpsi ketika bersamaan dengan makanan/susu.
• D: artemether 95% terikat protein plasma, sedangkan Lumefantrine 99,7%
• M: atremether dikonversi oleh CYP3A4 menjadi dihydroartemisinin dan lumefantrine menjadi desbutyl-
lumefantrine
• E: artemether dieliminasi setelah 7 jam pemberian, sedangkan lumefantrine 3 hari

•Farmakodinamik:
• Artemether: spesifisitas stadium luas terhadap parasit tahap darah, dari tahap cincin hingga schizont
awal. Itu juga mengurangi gametosit carriage, membatasi penularan malaria dari infeksi yang diobati.
• Lumefantrine: mencegah detoksifikasi heme dalam vakuola makanan parasit, sehingga menyebabkan
akumulasi kompleks heme yang beracun
QUININE
• ES: tinnitus, headache, nausea, dizziness, disforia, gg.pengihatan.
• Farmakokinetik:
• A: cepat diabsorpsi setelah pemberian oral dan parenteral
• D: didistribusikan secara luas ke seluruh tubuh dan di cairan cerebrospinal, breast milk, plasenta
• M: di hepar, biotransformasi oleh enzim CYP3A4
• E: 20% diekskresi melalui ginjal dan sebagian kecil di bile dan saliva.

• Farmakodinamik:
• menghambat detoksifikasi heme dalam vakuola makanan parasit
• membunuh parasit cincin besar dan trofozoit
DOXYCYCLINE
• ES: nausea, vomiting, diare, iritasi mukosa, mulut kering, stomatitis, disfagia, ulserasi
esofagial, discolour teeth, enterocolitis, urtikaria.
• Farmakokinetik:
• A: cepat diabsorbsi setelah pemberin oral (lipofilik)
• D: ke cairan tubuh dan jaringan termasuk bone marrow, ASI, liver, lien, plasenta. 90% terikat protein
plasma.
• E: GI tract & renal

• Farmakodinamik: menghambat sintesis protein melalui gangguan fungsi normal

apicoplast pada parasit malaria
PRIMAQUINE
• ES: abdominal pain, nausea, vomiting, haemolisis pasien dg defisiensi G6PD, red or black
urine, anemia.
• Farmakokinetik:
• A: cepat diabsorbsi oleh GI tract, puncak konsentrasi 1-4 jam. Bioavailability 96%
• D: didistribusi le tubuh, 75% terikat protein plasma
• M: via CYP2C19, CYP2D6, CYP3A4 di hepar
• E: dieksresi melalui biliary tract dan bisa ditemukan di feses 24 jam pemberian, selain itu juga dieksresikan
melalui urin.

• Farmakodinamik:
• highly active pada exoerythrocityc form (hypnozoites) dan sexual stages pada parasite malaria (gametosit)
• Weak activity asexual blood stage P. vivax
• Memiliki efek pada oocyst dan sporozoite (gametocyte carriage)
MEFLOQUINE
• ES: kejang, anxietas, dizziness, paranoid, depresi, halusinasi, muntah.
• Farmakokinetik:
• Farmakodinamik:
• menghambat detoksifikasi heme dalam vakuola makanan parasit
• menghambat endositosis sitosol parasit
• kira-kira sama dengan spesifisitas aksi seperti quinine, terutama membunuh parasit cincin besar dan
trofozoit
BERDASARKAN
STRUKTUR KIMIA
 BERDASARKAN CARA KERJA OBAT PADA SIKLUS HIDUP
PLASMODIUM
Siklus hidup Nama Obat Mekanisme kerja
Skizontosida Proguanil, pirimetamin • Membasmi parasit praeritrosit sehingga mencegah masuknya parasite ke
jaringan primer dalam eritrosit
• Dapat digunakan sebagai profilaksis kausal
Skizontosida Primakuin • Membasmi parasit daur eksoeritrosit atau stadium jaringan P.vivax dan
jaringan sekunder P.ovale
• digunakan untuk pengobatan radikal sebagai obat anti relaps
Gametositosida Primakuin (gametositosida untuk 4 • Mengeliminasi semua stadium seksual termasuk gametosit P.falciparum, juga
spesies) mempengaruhi stadium perkembangan parasit malaria dalam nyamuk
Kina, klorokuin, amodiakuin Anopheles.
(gametositosida untuk P.vivax, P.ovale, • Beberapa obat gametositosida bersifat sporontosida.
P.malariae
Sporontosida Primakuin dan proguanil • Mencegah/menghambat gametosit dalam darah untuk membentuk ookista
dan sporozoit dalam nyamuk Anopheles
• Mencegah transmisi penyakit malaria (anti sporogonik)
Skizontosida Ampuh: kina, amodiakuin, halofantrine, • Membasmi parasite stadium eritrosit, yang berhubungan dgn penyakit akut
darah gol. Artemisin disertai gejala klinis
Efek terbatas: proguanil dan pirimetamin • Mengeliminasi stadium seksual di eritrosit P.vivax, P.ovale, dan P.malariae
MEKANISME KERJA OBAT
TERIMA KASIH