Antimalarial Drugs

Antimalarial Drugs

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.


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

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.


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 membrane
 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.


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
END