Anti malarial drugs

Anti-malarial drugs

Malaria is an acute infectious disease caused by four species of the protozoal genus Plasmodium. The parasite is transmitted to humans through the bite of a female Anopheles mosquito, which thrives in humid, swampy areas. Malaria is the one of the most serious threats to human health throughout the world, preventing and curing this parasitic disease still depends predominantly on the administration of a small number of drugs whose efficacy is continually threatened by the emergence of drug-resistant parasite populations.

Malaria is caused by protozoan parasites of the genus Plasmodium, four species of which are now known to infect humans, P. vivax, P. falciparum, P. malariae, P. ovale and P. knowlesi.

Malarial parasites exhibit complex lifecycles in both of their hosts, with clinical symptoms arising from cycles of erythrocytic invasion, growth and division, followed by cell lysis and reinvasion. Plasmodium falciparum is the most dangerous species, causing an acute, rapidly fulminating disease that is characterized by persistent high fever, orthostatic hypotension, and massive erythrocytosis. Plasmodium vivax causes a milder form of the disease. Plasmodium malariae is common to many tropical regions, but Plasmodium ovale is rarely encountered.

Life cycle of the malaria parasite: When an infected mosquito bites, it injects Plasmodium sporozoites into the bloodstream. The sporozoites migrate through the blood to the liver, where they form cyst-like structures containing thousands of merozoites. Upon release, each merozoite invades a red blood cell, becoming a trophozoite and using hemoglobin as a nutrient. The trophozoites multiply and become merozoites. Eventually, the infected cell ruptures, releasing heme and merozoites that can enter other erythrocytes. Alternatively, released merozoites can become gametocytes, which are picked up by mosquitoes from the blood they ingest. The cycle thus begins again, with the gametocytes becoming sporozoites in the insect.

Drug therapy basing on the life cycle of parasite:

Tissue schizonticide: Primaquine:

Primaquine is an 8-aminoquinoline that eradicates primary exo-erythrocytic forms of P. falciparum and P. vivax and the secondary exo-erythrocytic forms of recurring malarias. The sexual (gametocyte) 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. Quinine, chloroquine, mefloquine or pyrimethamines are also used to treat.

Mechanism of action: Metabolites of Primaquine act as oxidants that are responsible for the schizonticidal action as well as for the hemolysis and methemoglobinemia encountered as toxicities.

Pharmacokinetics: On oral administration Primaquine is well absorbed and is not concentrated in tissues and appear in the urine.

Adverse effects: abdominal discomfort, occasional methemoglobinemia, Granulocytopenia and agranulocytosis are rarely seen.

Contraindication: During pregnancy.

 Blood schizonticide: Chloroquine

Chloroquine is a synthetic 4-aminoquinoline that has been the mainstay of anti-malarial therapy, and it is the drug of choice in the treatment of erythrocyte P. falciparum malaria, except in resistant strains. Chloroquine is less effective against P. vivax malaria. It is highly specific for the asexual form of plasmodia.

Mechanism of action: After traversing the erythrocytic and plasmodial membranes, chloroquine is concentrated in the organism's acidic food vacuole, primarily by ion trapping. It is in the food vacuole that the parasite digests the host cell's hemoglobin to obtain essential amino acids. However, this process also releases large amounts of ferriprotoporphyrin IX (soluble heme), which is toxic to the parasite. To protect itself, the parasite ordinarily polymerizes the heme to hemozoin (a pigment), which is sequestered in the parasite's food vacuole.

Chloroquine specifically binds to heme, preventing its polymerization to hemozoin. The increased pH and the accumulation of heme result in oxidative damage to the membranes, leading to lyses of both the parasite and the red blood cell. The binding to heme and prevention of its polymerization appear to be a crucial step in the drug's anti-plasmodial activity, and this may represent a unifying mechanism for such diverse compounds as chloroquine, quinidine, and mefloquine.

Pharmacokinetics: Chloroquine absorbed rapidly and completely by oral administration. It has a very large volume of distribution because the drug concentrates in melanin-containing tissues, erythrocytes, liver, spleen, lung, kidney and leukocytes and it also penetrates into the central nervous system and traverses the placenta. Excreted through urine.

Adverse effects: Headaches, pruritus, gastrointestinal upset and blurred vision.

 Blood schizonticide: Mefloquine:

It can apparently damage the parasite's membrane. Mefloquine appears to be promising as an effective single agent for suppressing and curing infections caused by multidrug-resistant forms of P. falciparum. Mefloquine is absorbed well after oral administration and concentrates in the liver and lung. The drug undergoes extensive metabolism. Its major excretory route is the feces.

Adverse effects: hallucinations, nausea, vomiting, dizziness to disorientation and depression.

Blood schizonticides: Quinine and quinidine

Quinine and its stereoisomer quinidine, interfere with heme polymerization, resulting in death of the erythrocytic form of the plasmodial parasite. Taken orally, quinine is well distributed throughout the body and can reach the fetus. Alkalinization of the urine decreases its excretion.

Adverse effect: Tinnitus, nausea, vomiting and vertigo.

 Blood schizonticide: Artemisinin

Artemisinin is derived from the qinghaosu plant, which has been used in Chinese medicine for more than two millennia in the treatment of fevers and malaria. Artemisinin is available for the treatment of severe, multidrug-resistant P. falciparum malaria. Its anti-malarial action involves the production of free radicals within the plasmodium food vacuole, following cleavage of the drug's endoperoxide bridge by heme iron in parasitized erythrocytes. It is also bind covalently to and damage specific malarial proteins. They are metabolized in the liver and are excreted primarily in the bile.

Adverse effects: Nausea, vomiting, diarrhea, neurotoxicity and prolongation of the QT interval.

Blood schizonticide and sporontocide: Pyrimethamine

 Pyrimethamine is an anti-folate agent frequently employed to affect a radical cure as a blood schizonticide. It also acts as a strong sporonticide in the mosquito's gut when the mosquito ingests it with the blood of the human host. Pyrimethamine inhibits plasmodial dihydrofolate reductase3 at much lower concentrations than those needed to inhibit the mammalian enzyme. The inhibition deprives the protozoan of tetrahydrofolate cofactor required in the de novo biosynthesis of purine and pyrimidine and in the interconversions of certain amino acids. Pyrimethamine alone is effective against P. falciparum.

Anti-malarial, plasmodium, blood.