3. Malaria  Malaria is transmitted by the infected female Anopheles mosquito is caused by four species of plasmodium protozoa.  The four plasmodium species are 1)P. falciparum (Malignant Tertian, Subtertian). 2)P.vivax ( Benign Tertian Malaria ). 3)P. Malariae ( Quartan Malaria ). 4)P. ovale (Mild Tertian Malaria).

4. Malaria  Life cycle of malaria  Infection from plasmodia can cause anemia, pulmonary edema, renal failure, jaundice, shock, cerebral malaria, and if not treated in a timely manner, can result in death.

6. Types of Chemotherapy  Tissue Schizonticides.  These drugs eradicate the exoerythrocytic liver- tissue stages of the parasite which prevents the parasite's entry into the blood.  Drugs of this type are useful for prophylaxis.  Blood Schizonticides.  These drugs destroy the erythrocytic stages of parasites and can cure cases of falciparum malaria or suppress relapses..

7. Types of Chemotherapy  Gametocytocides.  Agents of this type kill the sexual forms of the plasmodia (gametocytes), which are transmittable to the Anopheles mosquito, thereby preventing transmission of the disease.  Sporontocides (sporozooiticides).  These drugs act against sporozoites and are capable of killing these organisms as soon as they enter the bloodstream following a mosquito bite.

8. Treatment of Malaria  2 classes of natural drugs played a role in the development of synthetic antimalarial drugs:- 4-quinolinemethanol derivatives The 9-aminoacridines

9. Treatment of Malaria  4-quinolinemethanol derivatives;  quinine (extracted from cinchona bark) was the first known antimalarial; its use began in Europe in the 17th century.  Recently, it has been employed to treat chloroquine resistant strains of P. falciparum.

10. Treatment of Malaria  The 9-Aminoacridines  9-aminoacridine it self has antibacterial activity while quinacrine (a derivative of 9-aminoacridine) posses weak antimalarial activity.

11. Treatment of Malaria  With the beginning of World War II, a massive effort was begun to search for synthetic alternatives to quinine and the development of more effective antimalarial agent than quinacrine.  This results in the following synthetic antimalarials. 4-aminoquinolones 8-aminoquinolones Quinoline-4-methanols

12. Treatment of Malaria  4-aminoquinolones;  chloroquine and hydrochloroquine, are structurally similar to the right half of quinacrine.

13. Treatment of Malaria

14.  8-aminoquinolones;  pamaquine and primaquine, retain the methoxyquinolone nucleous of quinine and quinacrine

15. Treatment of Malaria

16.  Quinoline-4-methanols;  mefloquine and halofantarine, show similarity to the 4-quinolonemethanol portion of quinine.

17. Treatment of Malaria

18. 4-Substituted quinolines

19.  This class includes 5-compounds: Quinine Chloroquine Hydroxychloroquine Mefloquine Halofantrine  They share structural similarity, have same mechanism of action and resistance.  They are rapidly acting blood schizonticides with activity against plasmodium in the erythrocytic stage.

20. Mechanism of action  Weak Base Hypothesis.  The 4-substituted quinolines are weak bases and are thought to accumulate in a location which is acidic.  Because the extracellular fluid of the parasite is at pH 7.4 the weak base will move toward a more acidic pH.  Once in the lysosome an acid/base reaction occurs elevating the pH in the lysosome which in turn reduces the parasite's ability to digest hemoglobin thus reducing the availability of amino acids.  It is generally believed that the 4-substituted quinolines disrupt hemoglobin digestion in sensitive organisms

21. Mechanism of resistance  The development of resistance is thought to be a spontaneous gene mutation leading to enhanced drug efflux thus leading to rapid removal of the drug from the organism and hence reduce the effectiveness of the drugs  Rapid metabolism of the antimalarial by resistant strains.  It has been shown that cyctochrome P-450 activity parallels increased resistant to specific drugs

22. Therapeutic Application  They rapidly acting blood schizonticides with activity against plasmodium in the erythrocytic stage.  The drug of choice for treatment of malaria caused by Plasmodium falcipamm, P. ovale, P. vivax, and P. malariae in regions infected by chloroquine-resistant P. falciparum is quinine with mefloquine and halofantrine as alternative treatment agents.  The 4-substituted quinolines, depending on the specific drug in question, may also be used for prophylaxis of malaria.  Two types of prophylaxis are possible, causal pro­ phylaxis (prevents the establishment of hepatic forms of the parasite) and suppressive prophylaxis (eradicates the erythrocytic parasites but has no effect on the hepatic forms)

23. Quinine  Quinine is the most prevalent alkaloid present in the bark extracts (about 5%) of cinchona.  Structure activity relationship:-  Four stereo-chemical centers exist in the molecule (at C-3, C-4, C-8, and C-9)  Quinine, absolute configuration of 3R:4S: 8S:9R, and Quinidine, absolute configuration of 3R:4S: 8R:9S, and their optical isomers all have antimalarial activity while their C-9 epimers are inactive.

24. Quinine  Modification of the secondary alcohol at C-9, through oxidation, esterification, or similar processes, diminishes activity.  The quinuclidine portion is not necessary for activity; however, an alkyl tertiary amine at C-9 is important.

25. Chloroquine (Aralen)  Structure-activity relationships:-  Chloro at the eight position increased activity while alkylation at C-3 and C-8 diminished activity.  The replacement of one of its N-Ethyl groups with hydroxyethyl produced hydroxychloroquin, a compound with reduced toxicity.

26. Chloroquine (Aralen)  It is commonly administered as the racemic mixture.  It is an excellent suppressive agent for treating acute attacks of malaria caused by P. vivax and P. ovale and is effective for cure and as a suppressive prophylactic for treatment of P. malariae and susceptible P. falciparum.  It is for treatment of rheumatoid arthritis, discoid lupus erythematosus and photosensitivity diseases

27. Mefloquine (Lariam)  Mefloquine is only available in an oral dosage form.  Mefloquine is an effective suppressive prophylactic agent against P. falciparum.  The drug also has high efficacy against falciparum malaria with a low incidence of re­crudescence.  The drug is in effective against sexual forms of the organism

28. Mefloquine (Lariam)  The side effects:  neuropsychiatric, gastrointestinal (nausea, vomiting, and diarrhea), dermatologic (rash, pruritus, and urticaria), and cardiovascular (bradycardia, arrhythmias, and extrasystoles).

29. Halofantrine (Hafan)  It is an alternative drug for treatment of both chloroquine-sensitive and chloroquine-resistant P. falciparum malaria.  The drug is metabolized via N-dealkylation to the desbutylhalofantrine which is several times more active than the administered drug

30. 8-Aminoquinolines

31. Pamaquine and Primaquine  Pamaquine was first introduced for treatment of malaria in 1926 and has been replaced with primaquine.  Primaquine is active against latent tissue forms of P. vivax and P. ovale and is active against the hepatic stages of P. falciparum.  The drug is not active against erythrocytic stages of the parasite, but does possess gametocidal activity against all strains of plasmodium.

32. Pamaquine and Primaquine  Primaquine is the drug of choice for treatment of relapsing vivax and ovale forms of malaria and will produce a radical cure of the condition.  It is recommended to be combined with chloroquine to eradicate the erythrocytic stages of malaria.  Primaquine is not given for long-term treatment because of potential toxicity and sensitization (especially with patients have glucose-6-phosphate dehydrogenase deficiency, In these cases hemolytic anemia may develop).

33. Pyrimethamine

34.  Pyrimethamine (Daraprim) is a potent inhibitor of dihydrofolate reductase  It has a significantly higher affinity for binding to the dihydrofolate reductase of plasmodium than host enzyme and as a result has been used to selectively treat plasmodium infections.  Combined with sulfadoxine (long acting sulfonamide) and quinine for treatment and prevention of chloroquine-resistant malaria (Plasmodium faldparum, P. ovale, P. vivax, and P. malaria).  Pyrimethamine is a blood schizonticide without effects on the tissue stage of the disease

35. Atovaquone-proguanil  Atovaquone was originally developed as an antimalarial, but because of the high failure rate (30%), it is not prescribed as a single chemical entity but, rather, is used to treat pneumocystis

36. Atovaquone-proguanil  alovaquone has been combined with proquanil as an effective prophylactic and therapeutic antimalarial  The two drug together (Malarone) exhibit synergy in which proguanil reduces the effective concentration of atovaquone needed to damage the mitochondrial membrane and atovaquone increases the effectiveness of proguanil.

37. Artemisinins

38.  Mechanism of Action. The artemisinins appear to kill the parasite by a free radical mechanism producing oxidative damage to the parasites membrane.  These compounds have gametocytocidal activity as well as being active against late stage parasites and trophozoites