Anti-malarial drugs

What is chloroquine used for?

Prophylaxis of malaria where the risk of resistance is lowest

What is the mechanism of action of chloroquine?

• After passive diffusion, neutral form chloroquine becomes trapped in the acidic parasitic digestive vacuole in the protonated form so it can’t leave.

• Chloroquine caps hemozoin molecules to prevent further biocrystallization of haem, → haem buildup.

• Chloroquine binds to haem to form a complex that is highly toxic to the cell and disrupts membrane function.

• Toxic concentrations of haem and the complex → cell lysis → parasite cell autodigestion

What other drugs interfere with the haem disposal mechanisms in infected erythrocytes?

Mefloquine, primaquine, quinine and lumefantrine

What is mefloquine used for?

To prevent and treat Malaria, particularly strains caused by Plasmodium falciparum and Plasmodium vivax

What is primaquine used for?

To eliminate the liver stages of P.vivax and P.ovale following chloroquine treatment

What is proguanil?

Pro drug that needs metabolising before it can be used

• A biguanide derivative that is converted to an active metabolite cycloguanil.

• The latter inhibits parasitic dihydrofolate reductase enzyme → Blocks biosynthesis of purines and pyrimidines, which are essential for DNA synthesis and cell multiplication.

• It is thought that proguanil itself may act on another target than dihydrofolate reductase

What is proguanil used for?

Normally used in combo with chloroquine for the prophylaxis of malaria

What is the problem with proguanil?

• Variable metabolism in the liver by cytochrome P450 isoenzymes of proguanil to cycloguanil.

• → clinical importance in poor metabolizers such as the Asian and African populations at risk for malaria infection as they may not achieve adequate therapeutic levels of the active compound, cycloguanil, even after multiple doses

What is pyrimethamine?

• It is a folic acid antagonist and inhibits the dihydrofolate reductase of plasmodia → blocks the biosynthesis of purines and pyrimidines.

• These are essential for DNA synthesis and cell multiplication

What is pyrimethamine used for?

Always used with sulfadoxine (in Fansidar) to treat uncomplicated, chloroquine resistant, P.falciparum malaria

What is artemisinin?

Chinese herb to treat malaria

Why is artesunate a good form to use to treat malaria?

It is an injectable so has a higher bioavailability as it goes straight into the blood where the issue is

How does artemether and lumefantrine work in combination with eachother to treat malaria?

• Artemether is metabolised into the active metabolite dihydroartemisinin. It works against the erythrocytic stages of P.falciparum by inhibiting nucleic acid and protein synthesis.

• Mechanism: interaction with heme, or ferrous ions, in the parasite food vacuole → cytotoxic radical species.

• Artemether has a rapid onset of action and is rapidly cleared from the body. (rapid symptomatic relief by reducing the number of malarial parasites?)

• Lumefantrine has a much longer half life and is believed to clear residual parasites

How does atovaquone work to treat malaria?

• Highly lipophilic

• Acts by selectively affecting mitochondrial electron transport and parallel processes such as ATP and pyrimidine biosynthesis.

• Does not cause myelosuppression (important for patients who have undergone bone marrow transplantation)

What is the mechanism of action of atovaquone?

• Interference with the haem disposal mechanisms

• Inhibition of parasitic dihydrofolate reductase

• Free radical formation and alkylation

• Interfering with parasitic mitochondrial electron transport - important because of drug resistance

What drugs can work together with atovaquone to treeat Falciparum malaria?

Quinine, mefloquine, proguanil

What causes benign (recurring) malaria and what is the treatment choice?

• Chloroquine is the drug of choice for the treatment of benign malarias (but resistance becoming widespread).

• Chloroquine alone is adequate for P. malariae infections but in the case of P. vivax and P. ovale, a radical cure (to destroy parasites in the liver and thus prevent relapses) is required. This is achieved with primaquine

How can people protect themselves against mosquito bites?

• Mosquito nets impregnated with permethrin provide the most effective barrier protection against insects; coils, mats and vaporised insecticides are also useful.

• Diethyltoluamide (DEET) in lotions, sprays or roll-on formulations is safe and effective when applied to the skin but the protective effect only lasts for a few hours.

• Long sleeves and trousers worn after dusk also provide protection.