Anti-malarial drugs used now are mainly in the treatment of clinical attack of acute malaria severe or in preventive chemoprophylaxis. Chemotherapy targets the parasites. The majority of these drugs are blood schizonticidal agents that are effective against the erythrocytic stage of the plasmodia life cycle. Few drugs like primaquine affect the gametocytes.

Table of the summary of clinically used anti-malarial drugs.
 

INFECTION	DRUGS IN TREATMENT.	DRUGS IN CHEMOPROPHYLAXIS
All plasmodial infection	Chloroquine	Chloroquine or proguanil
Infection with Chloroquine-resistant P.falciparum.	(i)Mefloquine, (ii)Quinine + pyrimethamine-sulphadoxine(Fansidar) or Doxocycline or berberine (iii)Halofantrine	(i)  Mefloquine  (i)  Chloroquine + proguanil or pyrimethamine-dapsone(maloprim)
Chronic infection	Primaquine	Primaquine

 
 

The female Anopheles mosquito is the vector responsible for transmitting the parasite. Life cycle of the protozoa is complex occurring in man and in the mosquito. Its life cycle comprised of both the sexual and asexual forms. Sexual cycle is the mosquito, while the asexual cycle in man. The parasites enter the host’s blood stream as the mosquito bites for a blood meal, unaware to her. Within 30 minutes of the parasite’s sporozoites entering the bloodstream, they enter parenchymal cells of the liver (pre-erythrocytic stage lasting 10- 14 days in which they multiply. Hepatocytes ruptures to released merozoites that enter red blood cells. These form motile intracellular parasites, trophozoites (erythrocytic stage). Mitotic divisions occur in the cells giving rise to schizonts. These red cells ruptures, releasing mature merozoites. Meanwhile, continuos multiplication further produce more merozoites (schizogony). Other sporozoites remain in liver cell in a resting stage (hypnozoites) that can be activated in malarial relapses weeks or months later. Multiplication is at a phenomenal rate, a single vivax give rise to 250 millions in days. Some parasites fused to form gametocytes in red blood cell and their life cycle completes only in the mosquito.

Inside the mosquito, female and male come together to form a zygote- oocyte (sporocyst) Division and multiplication of the sporocyst takes place to produce many sporozoites. These then migrate to the salivary gland, waiting to re-infect again. Periodic episodes of fever correlates with periodic synchronised rupture of RBC with the release of merozoites and cell debris.

Malarial infection could also be transmitted through blood transfusion, shared syringes among drug abusers and organ transplantation.
 
 

CHLOROQUINE (4-AMINOQUINOLINE) has been the drug of choice in most parts of malaria endemic areas for some time until, resistant was developed by the notorious falciparum specie. It is a very potent schizonticidal drug against erythrocytic stage of all the 4 Plasmodium species. It has no effect on sporozoites, hypnozoites or gametocytes. It is a weak base, and concentrate itself in the parasites’ lysosome, possibly by a parasite-specific drug-concentrating mechanism. The by-product of the parasitic digestion of the haemoglobin, haem (ferriprotoporphorin 1X) is very toxic to the parasite. Plasmodial haem polymerase converts haem to harmless haemozoin (a red pigment associated with malaria). Chloroquine inhibits this enzyme and so a built up of haem kills the parasite by membranolytic action. Chloroquine also causes fragmentation of the parasite's RNA and intercalates in its DNA (Ward, S. A. 1988). Chloroquine is use for clinical cure and for suppression. In Chloroquine sensitive malaria, it reduces the fever and clears blood of parasites within 24 hours. This is a radical cure for P. falciparum infection, but not for P. ovale or P. vivax as there is always an exo-erythrocytic phase in which the hypnozoites may lead to a clinical relapse attack. In chemoprophylaxis, progaunil is combined to prevent this relapse. Chemoprophylaxis against the resistant strain P.falciparum, it is combined with maloprim. Completely unrelated to malaria, Chloroquine is also used for rheumatoid arthritis. Chloroquine is administered orally, unless where not feasible or in severe attack, then it is given by continuos intravenous infusion, frequent intramuscular or subcutaneous injection. It is completely absorbed and extensively distributed throughout the tissues. There is a slow release from the tissue and there on metabolised in the liver to be excreted in urine. Half-life of the drug is 50 hours, though 70% comes out intact drug. Unwanted effects are occasionally, nausea, vomiting, diarrhoea, psychoses, rashes, pruritis, dizziness, blurring vision, headache, and urticarial symptoms. Continues use of high doses could lead to irreversible retinopathies. Usually, these symptoms are not experience in the low doses of chemoprophylaxis (Simooya et al 1998).
 
 

QUININE (Quinoline-methanols) is an alkaloid derived from cinchona bark. Up until the development of Chloroquine, quinine was the first line of drug in the treatment of malaria. It is now taking its original place, since resistant has developed against Chloroquine. Quinine is a potent blood schizonticidal drug against the four plasmodia species. It is an erythrocytic drug and has no effect on the exo-erythrocytic phase or the gametocytic phase (Rimchala et al 196). Its mechanism of action is similar to Chloroquine, it causes cytotoxicity of the parasite by inhibiting plasmodial haem polymerase with the subsequent built up toxic haem. It also intercalates in parasite DNA. Clinical use of quinine is in acute attack of P.falciparum where there is a Chloroquine resistance. Given orally as a 7-day course. Tetracycline or fansidar follows the 7-day course. In severe P.falciparum infection, slow intravenous infusion. In some parts of the world or in patients who are vomiting, it administered parentally. It has antipyrexia activity, as well as clearing the blood of parasitaemia. It is well absorbed in the gut. 80% of it is bound to plasma protein. Half-life is 10 hours and it is metabolised in the liver and excreted in urine within 24 hours. Side effects are numerous and could be fatal. Depressant action on the heart, a mild oxytocic effects on the uterus in pregnancy. Slight blocking action on neuro muscular junction. Irritation of the gastric mucosa, nausea, vomiting, Cinchonism syndrome (tinnitus, headaches, blindness) and hypersensivity reactions. Sometimes hypotention in really high doses, cardiac dysrhythmias and severe CNS disturbances such as delirium and coma. Other times hypoglycaemia (stimulate insulin release), blood dyscrasias. Blackwater fever which is a rare but fatal case of acute haemolytic anaemia is associated with renal failure occur as result of quinine treatment of malaria or abuse for 'fever' (Rimchala et al 196).
 
 

MEFLOQUINE (Quinoline-methanols) interferes with transportation of haemoglobin products and other substances from the host cell to the parasite’s food vacuole. (Hellgren et al 1997), (Weidekamm et al 1998). Resistance has been reported, but if combined with Chloroquine or quinine, that is overcome. Mefloquine is a blood schizonticidal of the erythrocytic malaria as well kill hypnozoites if given as a combination treatment with primaquine. Taken orally, is rapidly absorbed. Though it has a slow onset of action, it is very long acting with a plasma half-life of 30 days. It used for uncomplicated Chloroquine-resistant falciparum malaria and as a short-term chemoprophylaxis when entering Chloroquine resistant zones. (Contraindicated in pregnant women or people taking precision tests. Transient CNS toxicity, giddiness, convulsions, insomnia, neuropsychiatric reactions, gastrointestinal disturbances. Symptoms are mild in chemoprophylaxis (Hellgren et al 1997).
 
 

HALOFANTRINE (PHENANTHRENE-METHANOL) is a blood schizonticidal against the erthrocytic P.falciparum resistant to Chloroquine. Also P.vivax erythrocytic but not the hypnozoites. Use to treat acute form of uncomplicated, multiresistant falciparum malaria and as a ‘stand by’ drug if chemoprophylaxis fails and there is no medical aid available. If taken orally, it is slowly and irregularly absorbed (aided by a fatty meal), with a peak plasma concentration at 4-6 hours later. Half-life is 1-2 days and elimination through faeces. Toxicity includes abdominal pain, gastrointestinal disturbances headache, a transient rise in hepatic enzymes, cough (pruritus), slight dysrhythmias, and a reports of sudden cardiac deaths, haemolytic anaemia and convulsions (Nosten et al 1993, Simooya et al 1998).
 
 

FOLATE ANTAGONISTS Are drugs that affect the synthesis and utilisation of folate. Pyrimethamine (2,4,diaminopyrimidine) and progaunil. They act by inhibiting the dihydrofolate reductase necessary for synthesis of tetrahydrofolate, a precursor in the parasite DNA synthesis. They have similar structures to trimethoprim (of the pteridine ring of dihydrofolate reductase) and so able to block its activity.

Sulphonamide (e.g. sulphadoxine) and sulphones (dapsone) act by competing for enzyme, dihydropteroate synthetase with para-aminobenzoic acid and therefore inhibit folate synthesis. They act on erythrocytic P.falciparum, but not sporozoites or hypnozotess. It is a mobbed up treatment after a 7-day course of quinine in acute attack of chloroquine resistant falciparum malaria. It is a prohpylaxis for chloroquine resistant strain P.falciparum or P.vivax, progaunil or pyrimethamine- dapsone (fansidar) is combined with Chloroquine to prevent transmission by killing gametocytes. Orally administered, are slow but well absorbed primethamine has a half life of 4 days, proguanil-16 hours, dapsone-24-48 hours (with some entero-hepatic recycling). Large doses of pyrimethamine- dapsone cause haemolytic anaemia and aglanulocytosis. Pyrimethamine- sulphadoxine may cause serious skin reactions and blood discrasias and so is now withdrawn. Pyrimethamine occasionally results in skin rashes and higher doses starts to affect human dihydrofolate releases leading to megaloblastic anaemia. (Folate supplement is given in pregnancy and it reduces its efficacy) (Nwanynwu et al 1996, Basco et al1998).
 
 

PRIMAQUINE (8-aminoquinolines) is the drug for radical cure. It is a potent tissue schizonticidal drug affecting the mitochondria of the exo-erythrocytic forms and gametocytes of an avian form of P.falciparum. It dose not have any effect on the erythrocytic forms, sporozoites or hypnozoites, therefore it is not a radical cure to vivax and ovale malaria. It is rapidly absorbed and metabolised, taken orally. Primaquine is given as its base, 15 mg/day for 14 days Half-life is 3-6 hours. Main unwanted effect is due to an inherited genetic metabolic condition- a deficiency of glucose-6-phosphate dehydrogenase in the red blood cell. Large doses of primaquine would results in methaemaglobinaemia with cyanosis haemolysis.
 
 

ANTIBIOTICS (tetracycline and doxycycline) are often combined with pyrimethamine or quinine for 100% cure. Doxicyclin is contraindicated in pregnant and nursing women and children under 12 years old.
 
 

Prophylactic drugs blocked the link between the exo- erythrocytic and the erythrocytic stage, thus prevent the development of clinical attacks. Travellers take it one week before entering endemic zones and carry on taking one month after leaving. Non of the chemoprophylaxis is a 100% yet and some may have slight side effects that hinder compliance.
 
 

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