ANTIMALARIAL DRUGS INTRODUCTION:

Nearly 100 millions (10 crores) of people, all over the world, are attacked by malaria every year of which about 1% (mostly children) die. Malaria is caused by a protozoon, belonging to the sub-phylum of sporozoa and the genus plasmodium. Four species of plasmodium are clinically important: (1)P. vivax (2) P. falciparum (3) P. ovale and (4) P. malariae. Out of them, P .Vivax and p. falciparum are important. EFFECTS OF MALARIA Malaria parasites invade RBC causes hemolysis this is a major cause of anemia due to malaria. Hemolytic jaundice can develop . P. falciparum induced hemolysis is particularly more severe. In P. falciparum malaria, RBCs containing schizoints cling to the walls of capillaries of vital organs like brain/kidney. This can cause hypoxia of the organ concerned. Further, rupture of these schizoints containing RBCs cause further hypoxia leading to damage of the organ death may result. CLASSIFICATION OF ANTI-MALARIAL DRUGS: BASED ON CHEMICAL STRUCTURE 1. 4- aminoquinolines: chloroquine,Amodiaquine 2. Chincona alkaloids: Quinine 3. Quinoline-methanol: Mefloquine

4. Acridine: Mepacrine, Quinacrine 5. 8-Aminoquinolines: primaquine 6. Biguanides: proguanine 7. Diaminopyrimidines: pyrimethamine 8. Phenantherine-methanol: Halofanterine, Lumifanterine 9. Antibiotics: Tetracycline, Doxycycline, Clindamycin 10. Sulfonamides &Sulfones: Sulfadoxine&Dapsone

BLOOD SCHIZONTICIDES: These drugs destroy the blood schizonts (merozoitesschizontsmerozoites) and prevent erythrocyticschizogony to terminate the attack of malarial fever. These may be subgrouped as: (a) fast-acting high-efficacy blood schizonticides such as chloroquine, quinine, mepacrine, mefloquine, halofantrine, artemisinin and atovaquone. These can be used singly to terminate the attack of malaria promptly; (b) slowacting low-efficacy blood schizonticides such as pyrimethamine, proguanil, sulfonamides and tetracyclines. These can be used only in combination if the aim is to terminate the clinical attack. SPORONTOCIDES: These drugs make the gametocytes ineffective within the blood of the mosquito. Pyrimethamine and proguanil,which are blood schizonticides, are also sporontocides. SUPPRESSIVE PROPHYLAXIS (CHEMOPROPHYLAXIS):

 Drugs used for such purpose do not affect the hepatic phase of the malarial parasite but destroy the merozoites released from the liver so that early development of the erythrocytic stage is prevented. Such drugs are mainly blood schizonticides. Suppressive prophylaxis is employed during the periods of exposure to infected mosquitoes and for some weeks to follow.

SUPPRESSIVE CURE: If the suppressive prophylaxis is continued for a longer period, the hepatic phase of hypnozoitesbecomes extinct or exhausted . Thus if chloroquine 300 mg weekly is taken for 3 months, after the attack of P. vivax malaria or after leaving the endemic area, the hepatic phase of P. vivax become extinct. Suppressive cure is like a radical cure but by an extended suppressive prophylaxis therapy. CLINICAL CURE: The asexual erythrocyticschizogony state of malarial parasite is responsible for clinical symptoms (chills, rigor, fever) of malaria and therefore the blood schizontocides can be used to terminate an acute attack of malaria (clinical cure). The fast-acting high-efficacy bloodschizonticides such as chloroquine, quinine, mepacrine, mefloquine, artemisinin, halofantrine and atovaquone can be used singly to treat attacks of P. falciparium malaria where any delay in the treatment may be fatal. The slow-acting low-efficacy blood schizonticides such as proguanil, pyrimethamine with sulfadoxine and tetracyclines can also be used for clinical cure but these are rather used in combination.

Commonly used regimens are as under: Chloroquine (base) 600 mg stat as loading dose, followed by 300 mg after 8 hrs and then 300 mg daily for next 2 days. Relapses of P. vivax or P. ovale malaria are treated analogously like a primary attack. Pyrimethamine 75 mg + sulfadoxine 1500 mg as a single dose can be used alternatively in chloroquine intolerant/resistant cases. For resistant P. falciparum malaria, one of the following regimens may be used: Quinine 600 mg TDS for 7 days alone or along with pyrimethamine 75 mg + sulfadoxine 1500 mg single dose; or with doxycycline 100 mg OD for 7 days. Mefloquine 750 mg stat followed by 500 mg 12 hrs later. Artesunate (oral) 100 mg BD on first day followed by 100 mg OD for another five days; or artesunate (I.M or I.V) 120 mg on first day followed by 60 mg daily for another 4 days. Arteether (I.M) 150 mg once daily for 3 days. RADICAL CURE: Eradication of both exoerythrocytic as well as erythrocytic state of malarial parasite leads to radical cure of malaria. The drug that accomplishes radical cure in vivax malaria is primaquine administered as 15 mg orally daily for 15 days. Usually primaquine is given immediately after the use of chloroquine to achieve a high radical cure rate (primaquine phosphate as 26 mg = 15 mg base). TO PREVENT TRANSMISSION OF MALARIA: Though rarely used for this purpose (as their use in one infected person would not prevent widespread transmission of malaria in a population),

some drugs have gametocidalaction(e.g., primaquine in all species;proguanil and pyrimethamine in P. vivax and P. ovale only). By destroying the gametocytes the drug prevents the transmission of malaria by the mosquitoes.

INDIVIDUAL ANTIMALARIAL DRUGS

CHLOROQUINE: Chloroquine is a synthetic 4-aminoquinoline derivative available as chloroquine phosphate for oral use. PHARMACOKINETICS: Chloroquine can be given orally or by I.M injection or by slow I.V, infusion. It is almost completely absorbed from GIT. The drug is distributed widely and is extensively bound to liver and other body tissues including cornea and RBCs. It undergoes metabolism in the liver. It is mainly excreted in urine (70% as unchanged, 30% as metabolites). Initial half life is 3-4 days but as it is slowly released from the tissues the terminal half life may be extended to 1-2 months. MECHANISM OF ACTION: Chloroquine has a preferential accumulation in parasitised erythrocytes. Being a basic drug it diffuses freely into the parasite lysosome.

 Inside, at the acidic pH of the lysosome it gets ionised (impermeable) and gets trapped inside the parasite. Its accumulation in parasites food vacuoles, inhibits peptide formation and reduces the supply of amino acids necessary for parasite viability. ANTIMALARIAL ACTION AND CLINICAL USE: Asexual erythrocytic state (+); gametocidal (+) only in P. vivax and P. ovale, not for P. falciparum; pre- and exoerythrocytic state (-). Resistance to chloroquine among the strains of P. falciparum is most common and results due to mutations in putative chloroquine transporter (PfCRT). It is very effective in providing the clinical as well as radical cure of P. falciparum malaria not resistant tochloroquine. In P. vivax and P. ovale malaria it provides clinical cure but relapses usually occur unless chloroquine therapy is followed by primaquine (15 mg OD for 15 days). In addition to its antimalarial use, chloroquinehas been used in the treatment of rheumatoid arthritis and for amoebic abscess not responding to metronidazole. ADVERSE EFFECTS: Chloroquine is usually well tolerated in the does used for chemoprophylaxis. With doses used to treat the clinical attack of malaria, nausea, vomiting, dizziness, headache, urticaria and blurred vision may occur occasionally. Larger does sometimes may precipitate retinopathies.

 Bolus I.V injection of chloroquine may cause hypotension and T-wave abnormalities in ECG. CONTRAINDICATIONS AND DRUG INTERACTIONS: 1. Its use should be avoided in patients with retinal and visual field abnormalities. 2. Chloroquine aggravates the attacks of psoriasis or porphyriaand therefore contraindicated in such patients. 3. In G6PD deficient persons its use may result in haemolyticanaemia. 4. Ca2+ and Mg2+ containing antacids decrease its absorption. 5. Concomitant use of metoclopramide with chloroquine sometimes precipitates paradoxical extrapyramidal side effects. 6. Chloroquine is considered safe in pregnancy and in younger children above 2 years of age. AMODIAQUINE Amodiaquine is another 4-aminoquinoline derivative whose antimalarial spectrum and adverse effects are similar to chloroquine. It was withdrawn several years ago because of the risk of agranulocytosis(1:2000)and hepatotoxicity when the drug is used for chemoprophylaxis. Incidentally, this drug has been reintroduced in several countries not only because it is cheap but the chloroquine-resistant P. falciparum malaria generally responds to amodiaquine.

QUININE: Quinine is an alkaloid derived from cinchona bark and has been used in the treatment and prevention of malaria since 1820.

PHARMACOKINETICS: Quinine is usually given orally but can also be given by slow I.V infusion for severe P. falciparum malaria and in patients who are vomiting. It is well absorbed from GIT following oral ingestion. It is widely distributed in body tissues. It is primarily metabolised in liver and excreted in the urine. The plasma half life is 10-11hrs. MECHANISM OF ACTION; The mechanism by which it exerts its antimalarial action is not clear. Like chloroquine it inhibits the parasites haem polymerase but it is not so extensively concentrated in the malarial parasite aschloroquine does. It does not bind to parasites DNA at antimalarial doses. It is believed to act as a proptoplasmic poison to the parasite and poisons the parasites feeding mechanism and hampers the supply of amino acids and peptides. ANTIMALARIAL ACTION AND CLINICAL USE: Asexual erythrocytic state (+); gemetocidal activity (+) only in P. vivax and P. ovale but not for P. falciparum; pre- and exoerythrocytic state (-). Some resistance of P. falciparum malaria to quinine has been reported from Southeast Asian countries like Thailand, yet till date quinine is now the main antimalarial drug for treating chloroquine-resistant. P. falciparum malaria.

 Aside from its use as an antimalarial drug, quinine is also used to treat nocturnal leg cramps observed in the patients of varicose veins, diabetes and arthritis. Quinine + clindamycin are a first-line therapy for the treatment of babesiosistick-borne malaria like disease). ADVERSE EFFECTS: Being bitter in taste, compliance is poor. Being irritant to gastric mucosa can cause nausea and vomiting. Bolus I.V. administration can lead to hypotension and cardiac arrhythmias. Higher plasma levels lead to cinchonism- a toxic state characterized by sweating, tinnitus, blurred vision headache, diarrhea and cardiac arrhythmias. The former coma responds to glucose. Though pathogenesis is uncertain. Black water fever is a rare consequence of erratic use of quinine for fever due to other reasons. This type of hypersensitivity is manifested by marked haemolysis with renal failure and may result even during quinine therapy for malaria. CONTRAINDICATION AND DRUG INTERACTIONS : Persons having visual and auditory problems. Persons with cardiac abnormalities. Al 3+ and Mg 2+ containing antacids decrease its absorption.

 Quinine raises plasma levels of digoxin. Quinine should not be given concurrently with mefloquine, as both drugs adversely affect cardiac conduction.