AntiMalaria

Thianti Sylviningrum
Tujuan Pembelajaran
• Setelah mengikuti kuliah,mahasiswa dapat :
a. Menjelaskan sifat dari Plasmodia sp.
b. Menjelaskan patofisiologi infeksi Plasmodia sp.
c. Menjelaskan jenis-jenis antimalaria
d. Menjelaskan mekanisme kerja antimalaria
e. Menjelaskan aplikasi klinis dari antimalaria
dengan mempertimbangkan
farmakodinamika,farmakokinetika,efek
samping,indikasi dan kontraindikasi serta
interaksi obat
Plasmodia sp
• Four species of plasmodia infect humans:
a. Plasmodium vivax
b. Plasmodium falciparum
c. Plasmodium ovale
d. Plasmodium malariae
• The insect vector is the female Anopheles
mosquito
ANTIMALARIAL DRUGS
• preventing mosquito bites
• clothes that cover much of the skin and using
insect repellents
• Drugs used in the treatment of malaria may have
several sites of action:
a. drugs used to treat the acute attack of malaria
act on the parasites in the blood; they can cure
infections with parasites (e.g. Plasmodium
falciparum) that have no exoerythrocytic stage
b. drugs used for chemoprophylaxis (causal
prophylactics) act on merozoites emerging from
liver cells
c. drugs used for radical cure are active against
parasites in the liver
d. some drugs act on gametocytes and prevent
transmission by the mosquito
Drugs used to treat the acute attack
• Blood schizonticidal agents
• act on the erythrocytic forms of the plasmodium
• P. falciparum or P. malariae : cure
• P. vivax or P. ovale : suppress the actual attack
• quinoline-methanols (quinine and
mefloquine)
• Various 4-aminoquinolines (chloroquine)
• the phenanthrene halofantrine
• agents that interfere the synthesis of folate
(sulfones)
• agents that interfere with its action
(pyrimethamine and proguanil), as well as
the hydroxynaphthoquinone compound
atovaquone
• tetracycline and doxycycline for
combination
Drugs used for chemoprophylaxis
• causal prophylactic drugs
• block the link between the exoerythrocytic stage
and the erythrocytic stage
• Drugs : chloroquine, mefloquine, proguanil,
pyrimethamine, dapsone and doxycycline
• given to individuals who intend travelling to an
area where malaria is endemic
Drugs that effect a radical cure
• Tissue schizonticidal agents effect
• acting on the parasites in the liver
• 8-aminoquinolines (e.g. primaquine and
tafenoquine)
• destroy gametocytes
Drugs used to prevent transmission
• 4-AMINOQUINOLINES : chloroquine
• effective against the erythrocytic forms of all four
plasmodial species
• does not have any effect on sporozoites, hypnozoites
or gametocytes
• mechanism of action that is not fully understood
• preventing digestion of haemoglobin by the parasite
• inhibits haem polymerase-the enzyme that
polymerises toxic free haem to haemozoin-
rendering it harmless to the parasite
• disease-modifying antirheumatoid drug
• Plasmodium falciparum is now resistant to
chloroquine
• enhanced efflux of the drug from parasitic
vesicles as a result of mutations in plasmodia
transporter genes
• generally administered orally
• concentrated in parasitised red cells
• metabolised in the liver and excreted in the
urine
• unwanted effects:nausea,vomiting, dizziness and
blurring of vision, headache and urticarial
symptoms,retinopathies, hypotension fatal
dysrhythmias.
• considered to be safe for use by pregnant women
QUINOLINE-METHANOLS
• Quinine
• effective against the erythrocytic forms of all four
species of plasmodium
• Mechanism of action like chloroquine
• bolus intravenous administration is contraindicated
because of the risk of cardiac dysrhythmias
• Unwanted effects : bitter taste, irritant to the gastric
mucosa , plasma exceeds 30-60μmol/l,
'cinchonism'-characterised by nausea, dizziness,
tinnitus, headache and blurring of vision-is likely to
occur
• Excessive plasma levels of quinine can result in
hypotension, cardiac dysrhythmias and severe
CNS disturbances such as delirium and coma
• blood dyscrasias & hypersensitivity reactions
• resistance to quinine is conferred by increased
expression of plasmodial drug efflux
transporters.
• Mefloquine :
• a blood schizonticidal quinoline- methanol
compound active against P. falciparum and P.
vivax
• frequently combined with pyrimethamine
• The antiparasite action is associated with
inhibition of the haem polymerase
• It has a slow onset of action and a very long
plasma half-life (up to 30 days)
• Unwanted effects : gastrointestinal
disturbances, severe neuropsychiatric reactions
• contraindicated in pregnant women or in those
liable to become pregnant within 3 months of
stopping the drug
PHENANTHRENE-METHANOLS
• Halofantrine :
• a blood schizonticidal drug
• It is active against strains of P. falciparum that
are resistant to chloroquine, pyrimethamine and
quinine
• It is effective against the erythrocytic form of P.
vivax but not the hypnozoites
• Cross-resistance between halofantrine and
mefloquine in falciparum infections has been
reported
• Absorption is substantially increased by a fatty
meal, and elimination is in the faeces.
• Unwanted effects : Abdominal pain,
gastrointestinal disturbances, headache, a
transient rise in hepatic enzymes and cough
occur,pruritus, changes in cardiac rhythm,
DRUGS AFFECTING THE SYNTHESIS OR
UTILISATION OF FOLATE
• Antifolate drugs are classified into type 1 and
type 2 compounds :
a. The type 1 antifolates are the sulfonamides
(sulfadoxine) and the sulfones (dapsone)
b. The type 2 antifolates include drugs such as
pyrimethamine and proguanil, which prevent
the utilisation of folate in the conversion of
dihydrofolate to tetrahydrofolate by inhibiting
dihydrofolate reductase
• They have a slow action against the erythrocytic
forms of the parasite
• proguanil is believed to have an additional effect
on the initial hepatic stage but not on the
hypnozoites of P. vivax
• The half-life of proguanil is 16 hours. It is a
prodrug and is metabolised in the liver to its
active form, cycloguanil
• Unwanted effects : pyrimethamine-dapsone
combination : haemolytic anaemia,
agranulocytosis and eosinophilic alveolitis.
• The pyrimethamine-sulfadoxine combination :
skin reactions, blood dyscrasias and allergic
alveolitis
• In high doses, pyrimethamine may inhibit
mammalian dihydrofolate reductase and cause a
megaloblastic anaemia
8-AMINOQUINOLINES
• primaquine
• against the liver hypnozoites
• does not affect sporozoites and has little if any
action against the erythrocytic stage of the
parasite
• it has a gametocidal action and is the most
effective antimalarial drug for preventing
transmission of the disease in all four species of
plasmodia
• Dose-related gastrointestinal symptoms can
occur
• large doses may cause methaemoglobinaemia
with cyanosis.
• This antimalarial drug can, however, cause
haemolysis in individuals with an X
chromosome-linked genetic metabolic
condition-glucose 6-phosphate dehydrogenase
deficiency-in red cells.
ANTIBIOTICS USED IN MALARIA
• doxycycline and tetracycline