By Matthew Cozier
Antimalarial drugs are those that are designed to prevent or cure malaria. There are two major classes of antimalarial drugs – tissue schizonticidal and blood schizonticidal drugs. This is because the malarial parasites Plasmodium spp. Live in the body in a variety of forms. There are four major subtypes of Plasmodium that cause malaria. Plasmodium vivax, Plasmodium malariae, Plasmodium falciparum & Plasmodium ovale. It is important to first understand the lifecycle of these microbes in order to discuss the current drug therapies against malaria.
Malaria presents a major challenge to economic and social development] in developing countries where approximately 515 million people are affected each year. The current strategies aimed at fighting malaria, as supported by the WHO and the Bill & Melinda Gates Foundation include developing new effective drug therapies against malaria, distributing them, decreasing the cost and providing these therapies to those in need.
Malaria is transferred from human to human by way of mosquitos enacting as vectors. If one mosquito bites a human, the exchange of saliva for blood allows the entry of a Plasmodium spp. Into the body, effectively penetrating the hosts primary defenses. At this point in the lifecycle, malarial microbes are refered to as sprozoites by which make their way to the liver through the circulatory system. Once they reach the liver, they may proliferate in numbers multiplying in numbers asexually and asymptomatically for a period of 6–15 days. Sometimes, at this stage, the malarial parasites form hypnozoites that are able to remain dormant for 6-12 months. Eventually, they move out of the liver and back into the bloodstream as Merozoites, specifically able to infect red blood cells (RBC's). The Merozoites cause the most damage to the blood reducing reducing the capacity of RBC's to carry oxygen around the body. Some Merozoites will turn into Gametocytes, that are taken up by the Mosquito in circulation. Once inside the mosquito these Gametocytes reproduce sexually and migrate to the salivary glands of the mosquito inducing salivary production and facilitating for its own spread once the mosquito bites another individual.
The immune system remains powerless against malaria since the parasites occupy the liver and erythrocytes, hiding from cells. In any case when malaria spends a relatively short period outside any cell of the body. This makes the potential use and production of a vaccine against malaria very unlikely. However the anti-malarial drugs are designed to target malaria at various stages of the lifestyle.
Blood Schizonticidal agents;
- Chloroquinine; affect on haem disposal, prevent digestion of hemoglobin and reducing supply of amino acids needed for parasite viability essentially we're starving their vital requirements to survive.
-- at high [] it prevents RNA and DNA synthesis
-- treatment of chloroquine senstivie malaria resistance with P.falciparin in most parts of the world increased expression of MDR-ABC transporters,
-- Oral IM, SC, IV forms of chloroquine available - does tend to concentrate in the affected cells
released slowly by the liver and metabolised by the liver
- Quinine dervived from cinchona bark binds malarial DNA inhibits haem polymerase works similar to chloroquininie does not affect the liver forms of malaria.
--The primary chemotherapeutic agent against falciparum, and may be used in combination with doxycycline or pyrimethamine in suladoxine.
-- Given in 7 day oral gcourses or slow IV infusion
-- Bolus dose, contraindicated due to risk of arrythmias Mefloquine;
-- Inhibits haem polymerase
-- Not generally used in australaia due to severe neuropsychotic reactions as part of their SE's. P
Proguanil and pyrimethamine
- prevents utilisation of folate
- inhibits conversion of dihydrofolate to tetrahydrofolate by dihydrofolate reductase
- High affinity for plasmodial enzyme than human form.
- Proguanil is used as an alternative to mefloquine pyrimethamine with sulphadoxine is used for the treatment of uncomplicated chlrooquinine-resitant p.falciparum with quinine.
- Few untoward effects.
Doxycyclie & tetracycline
- prevents ribosomal synthesis of proteins and hence replication of these parasites...
used in areas where methaquine and chloroquinine resistance is known...
Tissue Schozonitical agents;
- Rdical cures and attack parasties of the liver (hypnozoites)
- Effective against; P.Vivax and P.ovale
- Primaquinin
-- mechanism of action unknown
-- resistance rare
-- few unwanted SE's – only that of the GIT. Chemoprophylais;
-- start 1 week before entering area with malaria or 2-3 weeks if using mefloquinine
plus 4 weeks after leaving infected area
-- Block link between exo-erythrocytic and erythrocytic stages.
-- Prevent development of malarial attacks kill parasites as they emerge from the liver
They DON”T prevent primary infection of the liver...
Prevent transmission; destroy gametocytes primaquine, proguanil, pyrimethamine
The relative cost of these drugs is something to consider. New drugs such as Atovaquone may cost up to 5euro's for a tablet with adult doses consisting of in excess of 3 tablets per day.
These drug therapies are limited however in that they do not target the reservoir for infection which presides in the mosquito population. Non-pharmacological agents such as DDT have been used in the past to kill mosquitos. In addition, fly nets, repellants and avoiding swampy areas where these mosquitos live and breed is commonly recommended to prevent encouter with malaria.
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