Antimalarials

Malaria is an infection that can be caused by a few different types of plasmodium species, which are single-celled parasites that are spread by mosquitoes. There are hundreds of types of Plasmodium species, but the five that cause malarial disease in humans are Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale, and Plasmodium knowlesi. Once the plasmodium gets into the bloodstream, it infects liver cells and red blood cells, which causes a variety of symptoms and sometimes even leads to death. We rely on groups of medications commonly known as antimalarials, in order to prevent and treat malaria.

Now, malaria is transmitted when a plasmodium-infected female of the Anopheles mosquito hunts for a blood meal in the evening and throughout the night. They’re kind of like tiny flying vampires, with the mosquito being drawn to carbon dioxide that gets breathed out, as well as bodily smells, like foot odor. At this point, the Plasmodium is in a stage of development called a sporozoite, waiting patiently in the mosquito’s salivary gland.

When the mosquito bites a person with its proboscis, the worm-like sporozoites spill out of the mosquito’s saliva and make it into the bloodstream. The sporozoites then travel to the liver, where they invade hepatocytes.

There, they begin asexual reproduction, also known as schizogony. Over the next 1-2 weeks, P. falciparum, P. malariae, and P. knowlesi sporozoites multiply asexually and mature into merozoites, while host hepatic parenchymal cells die. In contrast, Plasmodium vivax and Plasmodium ovale sporozoites enter into a dormant hepatic phase, where they are called hypnozoites. They can remain in this dormant phase for months to years until they wake up and begin schizogony.

In both cases, when the merozoites are released into the blood, they enter the erythrocytic phase, where they invade red blood cells. Once inside the red blood cell, Plasmodium feeds on hemoglobin via a process called endocytosis, where the parasite wraps its membrane around the hemoglobin, in order to bring the hemoglobin inside itself. The plasma membrane forms a bubble called a food vacuole where hemoglobin can be broken down. Plasmodium uses the globin proteins to fuel their growth, but the heme is toxic to them, so they are converted into insoluble hemozoin crystals. As the parasite feeds, it undergoes mitosis and differentiates into lots of merozoites, which then burst out of the red blood cell and enter back into circulation.

Now, instead of going into the erythrocytic phase again, some of the merozoites undergo gametogony, which is where they divide and give rise to gametocytes, which are little sausage -shaped sexual forms that can be either male or female. These gametocytes remain inside of a red blood cell, and can get sucked up by another female mosquito that bites the same malaria carrier.

The gametocytes can then fuse together inside the mosquito to form a zygote. This part of the plasmodium life cycle is called sporogony, and it’s sexual reproduction, as opposed to the schizogony or asexual reproduction that happened in the liver and red blood cells. The zygote then goes on to develop further, it becomes an ookinete and then an oocyst that ruptures in the mosquito’s gut, releasing thousands of sporozoites, which navigate their way into the mosquito's salivary gland in order to repeat the cycle all over again.

Symptoms of malaria correspond to the reproductive cycle that is unique for each plasmodium species. When the red blood cells burst at the end of the erythrocytic phase, tumor necrosis factor alpha and other inflammatory cytokines are released, which causes high fevers that typically occur in paroxysms or short bursts.

For example, Plasmodium malariae, fevers happen every 72 hours, and is called quartan fever, while for Plasmodium vivax and Plasmodium ovale, fevers happen every 48 hours, and these are called tertian fever. Now, since red blood cells are destroyed when merozoites are released, malaria also causes hemolytic anemia, with symptoms like extreme fatigue, headaches, jaundice, and splenomegaly.

Now, many of the antimalarial medications are quinoline derivatives like quinine, which is one of the earliest antimalarial medications derived from the bark of South American Cinchona trees. Other medications in this class include quinidine, chloroquine, mefloquine, and primaquine. These medications work by entering the plasmodium and accumulating in their food vacuoles. Here, they bind to heme and prevent it from being converted into hemozoin. Since heme is toxic to the Plasmodium, this eventually leads to their death.