Lecture 26 Flashcards
How is malaria caused?
Through injection by an anopheles mosquito of protozoan parasites of the genus plasmodium, 5 species (falciparum, vivax, malariae, ovale and knowlesi) cause disease in humans, spreading to the liver where they mature and infect red blood cells
What are the three guidelines from the WHO for malaria control?
Early diagnosis which is difficult in countries which may not always have access to lab facilities to do a blood smear
Treatment with effective antimalarials which may expensive for poor nations
selective use of preventative measures including vector control where it can be sustained
What is important in potential targets for antimalarial therapies?
Must constitute essential features of the parasites life cycle
Must use targets and processes different enough from humans that the drug is not toxic
What were the two origins of antimalarial therapy?
Qinghaosu (Artemesia annua) which has been used as a herbal medicine in china for over 2000 years
Cinchona bark fro a tree brought over from south america by the spanish
What was the key compound isolated from cinchona bark?
Quinine which was the main alkaloid in the bark of the cinchona tree (quinidines were also present but these have cardiac complications by stopping the QT interval of the heart)
Not sure how the mechanism of this compound is achieved but may involve binding to DNA to stop nucleic acid synthesis or inhibtion of haem digestion
What was the first synthetic antimalarial developed?
PAMAQUINE in WW1
This was highly effective against the avian model, but not effective against the human strain and was toxic to humans
What is chloroquine?
Compound based of the quinine structure which accumulates in the parasites food vacuoles to interfere with haem digestion
This compound is effective against blood stages, relatively safe but does have the problem of having resistant malarial strains
What is amodiaquine??
A compound based of chloroquine structure but with an aromatic ring to fix the floppy aliphatic chain and an OH group to increase activity
This is effective against the blood stages of malaria and some chloroquine resistant strains but has an unacceptable risk of toxicity to granulocytes and the liver
What is primaquine?
A compound active against liver stages of vivax
mechanism of action involves oxidative stress in the parasite, effective against other life cycle stages however it is too toxic and causes haemolysis and methaemoglobinamia
What is mefloquine?
An antimalarial which has minor side effects of nausea, dizzyness and difficulty sleeping these do not last long or require stopping of treatment
however it is not recommended for use if there is a known allergy, history of epilepsy, severe psychiatric disorders or cardiac conduction abnormalities
What is pyronaridine?
Pyronaridine is a potential replacement for chloroquine but too expensive so cheap generic alternatives are needed
What is proguanil?
A prodrug which is metabolized to cycloguanil in order to be effective against erythrocytic and liver stages of P.Falciparum
Mecahnism occurs through inhbition of dihydrofolate reductase and therefore inhibition of DNA synthesis
Can be taken as a prophylactic (before exposure) but acts too slowly to operate as a cure
How can sulfones/sulfonamides be used to combat malaria?
Solones (Dapsone) and sulfonamides (sulfadoxine) inhibit dihydropteroate synthase which is involved in folate synthesis leading to a flow on effect in pyrimidine and DNA synthesis
Act too slowly on their own but may be combined with proguanil and pyrimethamine which acts at different pathways of the same pathway
How are artemisinin derivatives useful against malaria?
They are highly effective, rapid, have limited toxicity and are cheap
BUT usage must be carefully managed to avoid resistance developing
What are the risks of fake artesunates?
Found in south east asia
caused many deaths amongthose who would have survived if an authentic drug had been given
May result in inappropriate dosage levels leading to resistance emerging
