Antimalarial Drugs
Antimalarial drugs
Four species of plasmodium typically cause
human malaria:
1. Plasmodium falciparum
2. P vivax.
3. P malariae.
4. P ovale.
Antimalarial drugs
Four species of plasmodium typically cause
human malaria:
1. Plasmodium falciparum
2. P vivax.
3. P malariae.
4. P ovale.
Life cycle of the malarial parasite, Plasmodium falciparum,
showing the sites of action of antimalarial drugs
Drug Classification
1. Tissue schizonticide
2. a blood schizonticide
Tissue schizonticide
Primaquine
•
Eradicates primary exoerythrocytic forms of P. falciparum and P.
vivax and the secondary exoerythrocytic forms of recurring
malarias (P. vivax and P. ovale).
•
Lead to radical cures of the P. vivax and P. ovale malarias, which
may remain in the liver in the exoerythrocytic form after the
erythrocytic form of the disease is eliminated.
•
The sexual (gametocytic) forms of all four plasmodia are
destroyed in the plasma or are prevented from maturing later in
the mosquito, thus interrupting the transmission of the disease.
•
[Note: Primaquine is not effective against the erythrocytic stage
of malaria and, therefore, is often used in conjunction with a
blood schizonticide, such as chloroquine, quinine, mefloquine, or
pyrimethamine.
Drug Classification
1. Tissue schizonticide
2. a blood schizonticide
Tissue schizonticide
Primaquine
•
Eradicates primary exoerythrocytic forms of P. falciparum and P.
vivax and the secondary exoerythrocytic forms of recurring
malarias (P. vivax and P. ovale).
•
Lead to radical cures of the P. vivax and P. ovale malarias, which
may remain in the liver in the exoerythrocytic form after the
erythrocytic form of the disease is eliminated.
•
The sexual (gametocytic) forms of all four plasmodia are
destroyed in the plasma or are prevented from maturing later in
the mosquito, thus interrupting the transmission of the disease.
•
[Note: Primaquine is not effective against the erythrocytic stage
of malaria and, therefore, is often used in conjunction with a
blood schizonticide, such as chloroquine, quinine, mefloquine, or
pyrimethamine.
Mechanism of action of primaquine
Metabolites of primaquine are believed to act
as oxidants that are responsible for the
schizonticidal action as well as for the
hemolysis and methemoglobinemia
encountered as toxicities.
Pharmacokinetics of Primaquine :
Primaquine is well absorbed on oral administration
It is rapidly oxidized to metablolietes which appear in
the urine
Adverse effects of Primaquine
Hemolytic anemia (in patients low levels of glucose-6-
phosphate)
Abdominal discomfort (with large doses) especially
when administered in combination with chloroquine
Methemoglobinemia
Granulocytopenia (rarely)
Primaquine is contraindicated during pregnancy.
All Plasmodium species may develop resistance to
primaquine
Pharmacokinetics of Primaquine :
Primaquine is well absorbed on oral administration
It is rapidly oxidized to metablolietes which appear in
the urine
Adverse effects of Primaquine
Hemolytic anemia (in patients low levels of glucose-6-
phosphate)
Abdominal discomfort (with large doses) especially
when administered in combination with chloroquine
Methemoglobinemia
Granulocytopenia (rarely)
Primaquine is contraindicated during pregnancy.
All Plasmodium species may develop resistance to
primaquine
Blood schizonticide
Chloroquine
•
The mainstay of antimalarial therapy, and it is
the drug of choice in the treatment of
erythrocytic P. falciparum malaria,
•
Chloroquine is less effective against P. vivax
malaria.
•
It is highly specific for the asexual form of
plasmodia.
•
Chloroquine is also effective in the treatment
of extraintestinal amebiasis
Blood schizonticide
Chloroquine
•
The mainstay of antimalarial therapy, and it is
the drug of choice in the treatment of
erythrocytic P. falciparum malaria,
•
Chloroquine is less effective against P. vivax
malaria.
•
It is highly specific for the asexual form of
plasmodia.
•
Chloroquine is also effective in the treatment
of extraintestinal amebiasis
Action of chloroquine on the formation of hemozoin by
Plasmodium species
Pharmacokinetics of Chloroquine
Chloroquine is rapidly and completely absorbed
following oral administration.
4 days of therapy suffice to cure the disease
The drug concentrates in erythrocytes, liver, spleen,
kidney, lung, melanin-containing tissues, and
leukocytes.
Some metabolic products have antimalarial activity.
The excretion by urine rate is enhanced as is
acidified.
Pharmacokinetics of Chloroquine
Chloroquine is rapidly and completely absorbed
following oral administration.
4 days of therapy suffice to cure the disease
The drug concentrates in erythrocytes, liver, spleen,
kidney, lung, melanin-containing tissues, and
leukocytes.
Some metabolic products have antimalarial activity.
The excretion by urine rate is enhanced as is
acidified.
Adverse effect of Chloroquine
Higher doses, many more toxic effects occur, such
as gastrointestinal upset, pruritus, headaches, and
blurring of vision
Discoloration of the nail beds and mucous
membranes may be seen on chronic
administration.
electrocardiographic changes( because it has a
quinidine-like effect)
Dermatitis produced by gold or phenylbutazone
therapy.
Note:
Patients with psoriasis or porphyria should
not be treated with chloroquine, because an
acute attack may be provoked.
Adverse effect of Chloroquine
Higher doses, many more toxic effects occur, such
as gastrointestinal upset, pruritus, headaches, and
blurring of vision
Discoloration of the nail beds and mucous
membranes may be seen on chronic
administration.
electrocardiographic changes( because it has a
quinidine-like effect)
Dermatitis produced by gold or phenylbutazone
therapy.
Note:
Patients with psoriasis or porphyria should
not be treated with chloroquine, because an
acute attack may be provoked.
Blood schizonticide: Mefloquine
An effective single agent for suppressing and curing infections
caused by multidrug-resistant forms of P. falciparum.
Its exact mechanism of action remains to be determined, but
like quinine, it can apparently damage the parasite's embrane
Is absorbed well after oral administration and concentrates in
the liver and lung.
It has a long half-life (17 days) because of its concentration in
various tissues and its continuous circulation through the
enterohepatic and enterogastric systems.
The drug undergoes extensive metabolism. Its major excretory
route is the feces.
Adverse reactions at high doses range from nausea, vomiting,
and dizziness to disorientation, hallucinations, and depression.
Electrocardiographic abnormalities and cardiac arrest are
possible if mefloquine is taken concurrently with quinine or
quinidine.
Blood schizonticide: Mefloquine
An effective single agent for suppressing and curing infections
caused by multidrug-resistant forms of P. falciparum.
Its exact mechanism of action remains to be determined, but
like quinine, it can apparently damage the parasite's embrane
Is absorbed well after oral administration and concentrates in
the liver and lung.
It has a long half-life (17 days) because of its concentration in
various tissues and its continuous circulation through the
enterohepatic and enterogastric systems.
The drug undergoes extensive metabolism. Its major excretory
route is the feces.
Adverse reactions at high doses range from nausea, vomiting,
and dizziness to disorientation, hallucinations, and depression.
Electrocardiographic abnormalities and cardiac arrest are
possible if mefloquine is taken concurrently with quinine or
quinidine.
Blood schizonticides:
Quinine and quinidine
Interfere with heme polymerization, resulting
in death of the erythrocytic form of the
plasmodial parasite.
For These drugs are reserved severe
infestations and for malarial strains that are
resistant to other agents, such as chloroquine.
Taken orally, quinine is well distributed
throughout the body and can reach the fetus.
Alkalinization of the urine decreases its
excretion.
Blood schizonticides:
Quinine and quinidine
Interfere with heme polymerization, resulting
in death of the erythrocytic form of the
plasmodial parasite.
For These drugs are reserved severe
infestations and for malarial strains that are
resistant to other agents, such as chloroquine.
Taken orally, quinine is well distributed
throughout the body and can reach the fetus.
Alkalinization of the urine decreases its
excretion.
The major adverse effect of quinine
1. Cinchonism ( syndrome causing nausea,
vomiting, tinnitus, and vertigo).
2. Positive Coombs' test for hemolytic anemia
occurs (Quinine)
3. Quinine is fetotoxic
Drug interactions of quinine
Potentiation of neuromuscular-blocking agents
Elevation of digoxin levels if taken concurrently
with quinine
Quinine absorption is retarded when the drug
is taken with aluminum-containing antacids.
The major adverse effect of quinine
1. Cinchonism ( syndrome causing nausea,
vomiting, tinnitus, and vertigo).
2. Positive Coombs' test for hemolytic anemia
occurs (Quinine)
3. Quinine is fetotoxic
Drug interactions of quinine
Potentiation of neuromuscular-blocking agents
Elevation of digoxin levels if taken concurrently
with quinine
Quinine absorption is retarded when the drug
is taken with aluminum-containing antacids.
Blood schizonticide and sporontocide:
Pyrimethamine
Inhibits plasmodial dihydrofolate reductase at
much lower concentrations than those needed
to inhibit the mammalian enzyme.
The inhibition deprives the protozoan
oftetrahydrofolat cofactor required in the de
novo biosynthesis of purines and pyrimidines
It is also used against P. malariae and
Toxoplasma gondii.
If megaloblastic anemia occurs with
pyrimethamine treatment, it may be reversed
with leucovorin
Blood schizonticide and sporontocide:
Pyrimethamine
Inhibits plasmodial dihydrofolate reductase at
much lower concentrations than those needed
to inhibit the mammalian enzyme.
The inhibition deprives the protozoan
oftetrahydrofolat cofactor required in the de
novo biosynthesis of purines and pyrimidines
It is also used against P. malariae and
Toxoplasma gondii.
If megaloblastic anemia occurs with
pyrimethamine treatment, it may be reversed
with leucovorin