Malaria chemo

Question 1

List the Biochemical targets for Malaria Chemotherapy

Answer 1

Nucleic acid replication, nucleic acid and protein synthesis and haemoglobin by-products

Question 2

Describe the modes of action of the quinine –based drugs

Answer 2

Quinine-based (DNA replication)
The antimalarials based on the quinine structure, including quinine itself, chloroquine and mefloquine (larium) are thought to intercalate between the base pairs of the parasite DNA. This interferes with DNA replication. Are associated with frequent side effects (chinchonism) at therapeutic doses

Quinine-based (Protein synthesis)
Parasite protein synthesis requires essential amino acids derived from the host plasma or from the degradation of haemoglobin. The toxic by-product of this degradation, haeme, is polymerised by the parasite to form non-toxic haemazoin which can form crystals. Chloroquine (and co.) inhibits this degradation, binding to the breakdown products and preventing the formation of haemozoin - creating an environment highly toxic to the parasite.

Question 3

Explain why there is continual demand for new anti-malarial drugs

Answer 3

Plasmodium falciparum is particularly adept at developing resistance to antimalarial drugs, rendering them useless in some areas.
New antimalarials are required for treatment

Question 4

Discuss strategies to prolong the useful life of anti-malarial drugs.

Answer 4

The use of monotherapies makes the development of drug resistance more likely
The useful lifespan of new antimalarials can be prolonged if they are administered in combination with other new drugs.

e.g.
Coverage rates of appropriate diagnosis and treatment of malaria low and the use of artemisinin monotherapy very high in remote areas in Cambodia
This reflects the fragmented nature of Cambodia’s health system, and the reliance placed by these communities on informal vendors from whom artemisinin monotherapies are widely available

Question 5

Describe the modes of action of anti-folates

Answer 5

Antifolate (inhibit folate pathway)
Plasmodia cannot take up folate from host blood cells and have to synthesise all folate needed for DNA synthesis from scratch
PABA is essential in the synthesis of folate in plasmodia
One class of anti-folates, sulphonamides, mimics PABA and competitively binds to an enzyme involved in the pathway, thereby blocking subsequent reactions
This is a problem for the parasite - but not the patient who can get folate (vitamin B9) from their diet
An enzyme in the later part of the folate pathway, dihydrofolate reductase (DHFR) produces reduced folate co-factors - important for the synthesis of certain amino acids (for protein synthesis) and for the synthesis of nucleotides (for nucleic acid synthesis)
DHFR is the target of another class of anti-folate drugs e.g. pyrimethamine, proguanil, trimethroprim

Question 6

Describe the mode of action of artemisinin

Answer 6

Artemisinin is unlike any drug used before, its mode of action is still being explored
it has a strange endoperoxide group which is normally very unstable
when it comes into contact with Fe2+ in haemozoin (parasite-modified haem of haemoglobin), it “explodes” releasing oxygen radicals which interact with membrane proteins, damaging the membrane and killing the parasite
there are also reports that it may affect Ca2+ levels in the parasite by inhibiting a calcium pump