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Management of Malaria

Treating Uncomplicated P. Falciparum Malaria


ACTs are the mainstay of recommended treatment for P. falciparum malaria. Artemisinin and
its derivatives must not be used as oral monotherapy, as this promotes the development of
artemisinin resistance. Moreover, fixed-dose formulations (combining 2 different active
ingredients co-formulated in 1 tablet) are strongly preferred and recommended over co-
blistered, co-packaged or loose tablet combinations, since they facilitate adherence to
treatment and reduce the potential use of the individual components of co-blistered medicines
as monotherapy.

1 Artesunate (4mg/kg
. BB/hari)
3 hari
Amodiaquin (10 mg/kg
Primakuin 1 hari
First Line BB/hari)
(0,75 (Hari
(ACT) 2 Dihydroartemisinin (2-4
mg/kg BB) pertama)
. mg/kg BB/hari)
3 hari
Piperakuin (16-32 mg/kg
BB/hari)
1 3x
Kina (10 mg/kg BB/kali)
. 1
Doksisiklin (dewasa: 7
2x
4mg/kg BB; usia 8-14: 2 hari
1 Primakuin 1 hari
Second mg/kg BB/kali)
(0,75 (Hari
Line
2 3x mg/kg BB) pertama)
Kina (10 mg/kg BB/kali)
1 7
Tetrasiklin (4-5 mg/kg
4x hari
BB/kali)
1

Keterangan:

First Line:
- ACT tidak dapat diberikan pada ibu hamil trimester 1
- Primakuin tidak dapat diberikan pada Ibu hamil, bayi usia <6 bulan, penderita defisiensi
G6DP, ibu menyusui (usia bayi<6 bulan)
Second Line :
- Diberikan jika pengobatan first line tidak efektif dimana ditemukan: gejala klinis tidak
memburuk tapi parasit aseksual tidak berkurang (persisten) atau timbul kembali
(rekrudensi)
- Doksisiklin dan Tetrasiklin tidak dapat diberikan pada ibu hamil dan anak usia<8tahun

Obat sebaiknya diberikan sesuai berat badan, karena jika tidak sesuai akan menimbulkan efek
samping yang lebih berat karena dosis tidak tepat (berlebih) seperti mual muntah sakit kepala

Apabila pemberian dosis tidak memungkinkan sesuai berat badan penderita, pemberian obat
dapat diberikan berdasarkan golongan umur (Tabel IV.1-4)
Sediaan dosis dalam tablet
Artesunat : 200 gr (setara dengan
150gr basa)
Amodiakuin : 50 gr
Primakuin : 25 gr (setara dengan 15gr
basa)

Doksisiklin
Sediaan dosis dalam tablet atau
kapsul
50 dan 100 mg
Tetrasiklin
Sediaan dosis dalam bentuk kapsul
250 dan 500 mg

Treating Uncomplicated P. vivax, P. ovale, and P. malariae and P.


knowlesi Malaria
P. vivax infections should be treated with chloroquine in areas where this medicine remains
effective. In areas where chloroquine-resistant P. vivax has been identified, infections should
be treated with an ACT.
In order to prevent relapses, primaquine should be added to the treatment; dose and
frequency of the administration should be guided by the patients glucose-6-phosphate
dehydrogenase (G6PD) enzyme activity. In people with G6DP deficiency, consider preventing
relapse by giving primaquine base at 0,75 mg/kg bw once a week for 8 weeks, with close
medical supervision for potensial primaquine-induced haemolyssis

Pengobatan untuk Malaria P. vivax dan P. ovale

1 Artesunate (4mg/kg
. BB/hari)
3 hari
Amodiaquin (10 mg/kg
Primakuin
First Line BB/hari)
(0,25 14 hari
(ACT) 2 Dihydroartemisinin (2-4
mg/kg BB)
. mg/kg BB/hari)
3 hari
Piperakuin (16-32 mg/kg
BB/hari)
Second 1 Kina (10 mg/kg BB/kali) 3x 7 Primakuin 14 hari
Line . 1 hari (0,25 mg/kg
BB)
Keterangan:

Second Line :
- Diberikan jika pengobatan first line tidak efektif dimana ditemukan: gejala klinis tidak
memburuk tapi parasit aseksual tidak berkurang (persisten) atau timbul kembali
(rekrudensi)
- Doksisiklin dan Tetrasiklin tidak dapat diberikan pada ibu hamil dan anak usia<8tahun

Pengobatan untuk Malaria P. malariae

Pengobatan cukup dengan ACT 1 kali per-hari selama 3 hari dengan dosis yang sama
seperti pengobatan untuk malaria yang lainnya

Pengobatan untuk Malaria P. vivax dan P. ovale yang relaps


Regimen sama dengan pengobatan malaria sebelumnya, namun pemberian dosis
primakuin ditingkatkan menjadi 0,5 mg/kg BB selama 14 hari. Untuk penderita
defisiensi G6DP pemberian primakuin secara mingguan

Pengobatan untuk Malaria mix (P. falciparum dan P. vivax)


Pengobatan dengan ACT selama 3 hari serta pemberian primakuin pada hari 1 dengan
dosis 0,75 mg/kgBB dilanjutkan pada hari 2-14 dengan dosis 0,25 mg/kgBB

Treating Severe Malaria


PP Antimalarial Drugs
Drugs that eliminate developing or dormant liver forms are called tissue schizonticides;
those that act on erythrocytic parasites are blood schizonticides;
and those that kill sexualstages and prevent transmission to mosquitoes are gametocides.
No single available agent can reliably effect a radical cure, ie, eliminate both hepatic and erythrocytic stages.

CHLOROQUINE
Chloroquine has been the drug of choice for both treatment and chemoprophylaxis of malaria since the 1940s, but its
usefulness against P falciparum has been seriously compromised by drug resistance.

Chemistry & Pharmacokinetics


Chloroquine is a synthetic 4-aminoquinoline formulated as the phosphate salt for oral use. It is rapidly and almost
completely absorbed from the gastrointestinal tract, reaches maximum plasma concentrations in about 3 hours, and is
rapidly distributed to the tissues.. Chloroquine is principally excreted in the urine
with an initial half-life of 35 days.

Antimalarial Action & Resistance


When not limited by resistance, chloroquine is a highly effective blood schizonticide, moderately effective against
gametocytes of P vivax, P ovale, and P malariae but not against those of P falciparum. And not active against liver
stage parasites forms of P vivax and P ovale (for that reason primaquine must be added for the radical cure of these
species).

Chloroquine probably acts by concentrating in parasite food vacuoles, preventing the biocrystallization of the
hemoglobin breakdown product, heme, into hemozoin, and thus eliciting parasite toxicity due to the buildup of free
heme. It rapidly terminates fever (in 2448 hours) and clears parasitemia (in 4872 hours) caused by sensitive
parasites.

Adverse Effects
Chloroquine is usually very well tolerated, even with prolonged use. Dosing after meals may reduce some adverse
effects. Rare reactions include hemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient persons, impaired
hearing, confusion, psychosis, seizures, agranulocytosis, exfoliative dermatitis, alopecia, bleaching of hair,
hypotension.

Contraindications & Cautions


Chloroquine is contraindicated in patients with psoriasis or porphyria. It should generally not be used in those with
retinal or visual field abnormalities or myopathy. It should be used with caution in patients with a history of liver
disease or neurologic or hematologic disorders. The antidiarrheal agent kaolin and calcium-and magnesium-containing
antacids interfere with the
absorption of chloroquine and should not be co-administered with the drug. Chloroquine is considered safe in
pregnancy and for young children.

OTHER QUINOLINES

Amodiaquine
Shares mechanisms of action and resistance with that drug. Amodiaquine has been widely used to treat malaria because
of its low cost, limited toxicity, and, in some areas, effectiveness against chloroquine-resistant strains of P falciparum
thus it may be used as a replacement for chloroquine in areas with high rates of resistance but limited resources.
The World Health Organization (WHO) lists amodiaquine plus artesunate as a recommended therapy for falciparum
malaria in areas with resistance to older drugs. This combination is now available as a single tablet (ASAQ, Arsucam,
Coarsucam)

Chemoprophylaxis with amodiaquine is best avoided because of its apparent increased toxicity with
long-term use.

Piperaquine
is a bisquinoline that has been combined with
dihydroartemisinin in co-formulated tablets (Artekin,
Duocotecxin) that have shown excellent efficacy and safety for the treatment of falciparum malaria, without apparent
drug resistance. Piperaquine has a longer half-life ( 28 days) than amodiaquine ( 14 days), mefloquine ( 14 days),
or lumefantrine ( 4 days), leading to a longer period of post-treatment prophylaxis with dihydroartemisinin-
piperaquine than with the
other leading artemisinin-based combinations; this feature should be particularly advantageous in high transmission
areas.

ARTEMISININ & ITS DERIVATIVES


Artemisinin (qinghaosu) is a sesquiterpene lactone endoperoxide, the active component of an herbal medicine that has
been used as an antipyretic in China for over 2000 years. Artemisinin is insoluble and can only be used orally. Analogs
have been synthesized to increase solubility and improve antimalarial
efficacy. The most important of these analogs are artesunate (water-soluble; useful for oral, intravenous,
intramuscular, and rectal administration), artemether (lipid-soluble; useful for oral, intramuscular, and rectal
administration), and dihydroartemisinin (water-soluble; useful for oral administration).

Chemistry & Pharmacokinetics


Artemisinin and its analogs are rapidly absorbed, with peak plasma levels occurring in 12 hours and half-lives of 13
hours after oral administration. Artemisinin, artesunate, and artemether are rapidly metabolized to the active metabolite
dihydroartemisinin.

Antimalarial Action & Resistance


Artemisinin and its analogs are very rapidly acting blood schizonticides. against all human malaria parasites.
Artemisinins have no effect on hepatic stages. The antimalarial activity of artemisinins may result from the production
of free radicals that follows the iron-catalyzed cleavage of the artemisinin endoperoxide bridge in the parasite food
vacuole or from inhibition of a parasite calcium ATPase.

The WHO recommends five artemisinin-based combinations for the treatment of uncomplicated falciparum malaria
Adverse Effects & Cautions
Artemisinins are generally very well tolerated. The most commonly reported adverse effects are nausea, vomiting,
diarrhea, and dizziness, and these may often be due to underlying malaria rather than the medications. Rare serious
toxicities include neutropenia, anemia, hemolysis, elevated liver enzymes, and allergic reactions.
Artemisinins have been embryotoxic in animal studies, but rates of congenital abnormalities, stillbirths, and abortions
were not elevated, compared with those of controls, in women who received artemisinins during pregnancy. Based on
this information and the significant risk of malaria during pregnancy, the WHO recommends artemisininbased
combination therapies for the treatment of uncomplicated falciparum malaria during the second and third trimesters of
pregnancy, intravenous artesunate or quinine for the treatment of severe malaria during the first trimester, and
intravenous artesunate for treatment of severe malaria during the second and third trimesters.

QUININE & QUINIDINE (KINA)


Quinine and quinidine remain important therapies for falciparum malariaespecially severe diseasealthough
toxicity may complicate therapy. Resistance to quinine is uncommon but may be increasing.

Chemistry & Pharmacokinetics


Quinine is derived from the bark of the cinchona tree, a traditional remedy for intermittent fevers from South America.
The alkaloid quinine was purified from the bark in 1820, and it has been used in the treatment and prevention of
malaria since that time. Quinine is primarily metabolized in the liver and excreted in the urine.

Antimalarial Action & Resistance


Quinine is a rapid-acting, highly effective blood schizonticide against the four species of human malaria parasites. The
drug is gametocidal against P vivax and P ovale but not P falciparum. It is not active against liver stage parasites. The
mechanism of action of quinine is unknown.

Contraindications & Cautions


Quinine (or quinidine) should be discontinued if signs of severe cinchonism, hemolysis, or hypersensitivity occur. It
should be avoided if possible in patients with underlying visual or auditory problems. It must be used with great
caution in those with underlying cardiac abnormalities. Absorption may be blocked by aluminumcontaining antacids.
Dosage must be reduced in renal insufficiency.

PRIMAQUINE
Primaquine is the drug of choice for the eradication of dormant liver forms of P vivax and P ovale and can also be used
for chemoprophylaxis against all malarial species.

Chemistry & Pharmacokinetics


Primaquine phosphate is a synthetic 8-aminoquinoline.
The drug is well absorbed orally, reaching peak plasma levels in 12 hours. The plasma half-life is 38 hours.
Primaquine is widely distributed to the tissues, rapidly metabolized and excreted in the urine. Its three major
metabolites appear to have less antimalarial activity but more potential for inducing hemolysis than the parent
compound.

Antimalarial Action & Resistance


Primaquine is active against hepatic stages of all human malaria parasites. It is the only available agent active
against the dormant hypnozoite stages of P vivax and P ovale. Primaquine is also gametocidal against the four
human malaria species. Primaquine acts against erythrocytic stage parasites, but this activity is too weak to play an
important role. The mechanism of antimalarial action is unknown.

Adverse Effects
Primaquine in recommended doses is generally well tolerated. It infrequently causes nausea, epigastric pain, abdominal
cramps, and headache, and these symptoms are more common with higher dosages and when the drug is taken on an
empty stomach.
Standard doses of primaquine may cause hemolysis or methemoglobinemia (manifested by cyanosis), especially in
persons with G6PD deficiency or other
hereditary metabolic defects.

Contraindications & Cautions


Primaquine should be avoided in patients with a history of granulocytopenia or methemoglobinemia, in those receiving
potentially myelosuppressive drugs (eg, quinidine). It is never given parenterally because it may induce marked
hypotension. Patients should be tested for G6PD deficiency before primaquine is prescribed.
Primaquine should be avoided in pregnancy because the fetus is relatively G6PD-deficient and thus at risk of
hemolysis.

COMPLICATION OF MALARIA
Cerebral Malaria
Coma is a characteristic and ominous feature of falciparum malaria and, despite treatment, is
associated with death rates of ~20% among adults and 15% among children. Th onset may be
gradual or sudden following a convulsion. Cerebral malaria manifests as diffuse symmetric
encephalopathy.

Hypoglycemia
Hypoglycemia, an important and common complication of severe malaria, is associated with a
poor prognosis and is particularly problematic in children and pregnant women. Hypoglycemia
in malaria results from a failure of hepatic gluconeogenesis and an increase in the
consumption of glucose by both the host and, to a much lesser extent, the malaria parasites.
To compound the situation, quinine, which is still widely used for the treatment of both severe
and uncomplicated falciparum malaria, is a powerful stimulant of pancreatic insulin secretion.
Hyperinsulinemic hypoglycemia is especially troublesome in pregnant women receiving
quinine treatment.

Acidosis
Acidosis, an important cause of death from severe malaria, results from accumulation of
organic acids. Hyperlactatemia commonly coexists with hypoglycemia. Acidotic breathing,
sometimes called respiratory distress, is a sign of poor prognosis.

Noncardiogenic Pulmonary Edema


Adults with severe falciparum malaria may develop noncardiogenic pulmonary edema even
after
several days of antimalarial therapy. The pathogenesis of this variant of the adult respiratory
distress syndrome is unclear. The mortality rate is >80%. This condition can be aggravated by
overly vigorous administration of IV fluid. Noncardiogenic pulmonary edema can also develop
in otherwise uncomplicated vivax malaria, where recovery is usual.
Renal Impairment
Acute kidney injury is common in severe falciparum malaria, but oliguric renal failure is rare
among children. The pathogenesis of renal failure is unclear but may be related to erythrocyte
sequestration and agglutination interfering with renal microcirculatory flow and metabolism.
Clinically and pathologically, this syndrome manifests as acute tubular necrosis. Renal cortical
necrosis never develops.

Hematologic Abnormalities
Anemia results from accelerated RBC removal by the spleen, obligatory RBC destruction at
parasite schizogony, and ineffective erythropoiesis. In severe malaria, both infected and
uninfected RBCs show reduced deformability, which correlates with prognosis and
development of anemia. Splenic clearance of all RBCs is increased. Anemia is a common
consequence of antimalarial drug resistance, which results in repeated or continued infection.
Slight coagulation abnormalities are common in falciparum malaria, and mild
thrombocytopenia is usual

Liver Dysfunction
Mild hemolytic jaundice is common in malaria. Severe jaundice is associated with P. falciparum
infections; is more common among adults than among children; and results from hemolysis,
hepatocyte injury, and cholestasis. Hepatic dysfunction contributes to hypoglycemia,
lactic acidosis, and impaired drug metabolism.

Other Complications HIV/AIDS and malnutrition predispose to more severe malaria in


nonimmune individuals; malaria anemia is worsened by concurrent infections with intestinal
helminths, hookworm in particular. Septicemia may complicate severe malaria, particularly in
children.