Lecture 26- Anti-malarials

Question 1

How are the malarial parasites spread?

Answer 1

By female mosquitoes of genus Anopheles whilst taking a blood meal.

Question 2

Describe the malaria life cycle?

Answer 2

1. Mosquito picks up the parasite from a infected person.
2. The mosquito injects the parasite into a new host it is about to attack. Malarial parasites are called sporozoites.
3. Sporozoites enter the liver and undergo asexual reproduction. Products of asexual reproduction= merozoites
4. Merozoites enter RBC and digest the Hb in red blood cell. Red blood cells burst and release more merazoite. Therefore more red blood cells are affected and the disease spreads.
5. The parasite senses you are about to die. So the parasite starts producing gametocyes which enter into the mosquito again to be infecting the next person.

Question 3

What are the potential targets for anti-malarial therapy?

Answer 3

• essential features of the parasite life cycle.
• be parasite specific so that selective toxicity can occur

Question 4

Describe the anti-malarial drug quinine?

Answer 4

• it is derived from the bark of Cinchona tree.
• Active against erythrocytic stages of the parasites
• Its mode of action may involve binding to DNA and stopping synthesis of nucleic acids and inhibition of haem digestion.

Question 5

Give an example of a synthetic anti-malarial and its properties?

Answer 5

Pamaquine

• Pamaquine is active against avian malaria
• Toxic in humans.
• Found effective against the vivax relapses.

Question 6

Describe chloroquine?

Answer 6

• Based on quinine structure
• Accumulates in the food vacuole of the parasite
• Interferes with haem digestion
• Effective against blood stages
• Relatively safe
• Resistance a problem

Question 7

Describe Amodiaquine?

Answer 7

• Effective against blood stages- more effective than chloroquine
• Risk of toxicity towards granulocytes and the liver.

Question 8

Describe Primaquine?

Answer 8

• Active against liver stages of P.vivax
• Mechanism of action- oxidative stress in the parasite
• Effective against other stages in the life cycle but it is too toxic.
• Causes haemolysis and methaemoglobinamia.

Question 9

Describe mefloquine?(Lariam)

Answer 9

• Good actions
• Minor side-effects- nausea, dizziness but do not require stopping the drug.
• Not recommended for use if a history of epilepsy, psychiatric disorders or cardiac conduction abnormalities.

Question 10

Describe Pyronaridine?

Answer 10

• Replacement for chloroquine
• Too expensive
• Requires new routes for synthesis.

Question 11

Describe proguanil?

Answer 11

• prodrug- may or may not require metabolic activation to cycloguanil
• Effective against erythrocytic and liver stages of P. falciparum
• Inhibits dihydrofolate reductase and hence DNA synthesis.
• Used as a prophlactic(ie should be given before exposure to the parasite for it to be effective)
• Too slow for a cure.
• stops the production of gametocytes in mosquito.

Question 12

Describe sulfonamides/ sulfone?

Answer 12

• Inhibit dihydropteroate synthase-involved in folate, hence pyrimidine and DNA synthesis.
• Act too slowly on their own but act synergistically with proguanil and pyrimethamine - always used in combination therapy

Question 13

Describe Artemisinin derivatives?

Answer 13

• Highly effective
• Rapid
• Limited toxicity
• CHEAP
• Inappropriate use leads to resistance and toxicity. So artemisinin is usually given with another anti-malarial drug.