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PROJECT TOPIC: EVALUATION OF THE ACUTE CARDIOVASCULAR EFFECTS OF CHLOROQUINE

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CHAPTER ONEINTRODUCTIONHISTORY: chloroquine is the most widely prescribed antimalarial agent (WHO 1984). It was synthesised during world war II due to the shortage of quinine and also for the need to produced less toxic and more effective antimalarial drug. In 1945 it was found out that chloroquine had been synthesised and studied under the name RESOCHIN as early asds 1934 in Western Germany (Catchpool 1984). Chloroquine has been used for many decades in the prophylactic and treatment of malarial (Bruce-Chwalt 1982, Rollo 1980) and for the treatment of thematoid disease (Costae 1970).CHEMISTRY: Chloroquine is a 4-amino-quinoline compound namely T-Chloro-4-( 5 – diethyl-amino -1-methyl pentye – amino – quinolone (Thopson & Wevbel 1972).

H-C-CH2-CH2-CH2-N-2H5CH3STRUTURE OF CHLOROQUINEChloroquine posses quinolone ring with diamino alphatic side-chain. The chlorine atom at position 7 of the quinolone ring and the diamino alphatic side chain are crucial for the antr-malanal action of chloroquine (Catch pool 1984). Chloroquine diphosphate is a white. Bitter powder, soluble in water. Its solution is stable. It gives a brownish red colour when the solution in sulphuric acid is treated with a drop of potassium dichromate (100g/A) TS (WHO 1986). It has been isomer of chloroquine in mammals (Berliner et al 1948, Coatney and colleagues 1953).PHARMACOLOQUAL PROPERTIESMECHANISMS OF ANTIMALANAL ACTIONThe mechanism of plasmodicidal action of chloroquine is not completely understood. However a number of effects may contribute to its antimalarial action. It has been shown that the drug exerted its effect at least in poart by interacting with BNA molecules. (Shellenberg and Coatney (1980). In addition, chloroquine inlilits bNA polymerase markedly and RNA polymecrase less so. In back cases by interacting binding to the BNA primer (Allison, Colen and Yielding 1965). Stabilisation of the double helix is believed to occur by the formation of additional ionic bond between the substituted amino – side chain of chloroquine and the phosphate among of complementary strands of bNA across the monor goove (ALLISON et al 1966). Antimalarial activity of the 4-amino quinolone was maximal when there were 4 – carbon atoms occurring between the Nitrogen atoms in the side chain. A decrease or as increase in the number or carbon 0 atoms deceased the potency of the compounds (Ciak and Hann 1966). The second possible mechanism through which chloroquine mediate its plasmodicidal effect is via the active concentration of the drug in the plasmodium infested hefatocytes. The reason for the accumulation or chloroquine which due to its weak basic structure in plasmodium infested hepatocytes has been clarified. Recent postulates shows that aggregates of pernproto porphyrin ix released by parasive degradation of red blood cells served as receptor for chloroquine and related antimalrial agents and this accounted for the accumulation of the drug chon et al. 1980ANTI – INFLAMMATORY EFFECTSChoroquine and hydroxyl chloroquine have been used in the treatment or rhematoed arthritis and systemic lupuns erythomatosus since 1950 and their efficacy in inducing remission has been confirm in carefully controlled studies (Zvaifler; 1971). Chloroquine decreases Leukocyte chemotatis, inhibit bNA synthesis trap free radicals. Interferes with the replication of viruses and suppresses the responsiveness of T- lymphocytes to mitogens.ABSORPTION METABOLISM AND EXCRETIONChloroquine is well absorbed by oral route in healthy subjects (GUSTAFSSAN et al 1983). And in children with uncomplicated falciparum malaria (Adelusi, 1982). The decline in plasma et concentration after a single close is multiphasic with an extremely long-terminal elimination phase during which plasma concentration are measurable for up to three months. (GUSTAFSSON et al 1983) oral route of administration is impossible in seriously ill patients who are vomitting or comatose, that is those in most need of urgent treatment. Tissue distribution is extensive and there is concentration in the blood cells. The total apparent volume of distribution in consequently enormous – for plasma chloroquine. This has been extimated to be in order of 1000, kg-1 (Frisk- flomverg et al 1984) the time required to reach maximal plasma level after oral administration is 1-2 hours and dose not vary with changing the dose.Chloroquine is rapidly removed from the plasma after absorption. It is concentrated in tissues where active protein synthesis and cell multiplication are greatest. Chloroquine has been shown to accumulate in retina and skin melanin containing tissue (Grundman, 1972: kurodo 1962, lingvist, 1983). The large apparent volume of distribution is due to the high concentration of chloroquine in tissues and organs like the skin, Liver. Kidney, spleen and lungs. Adelusi and salako 1982, Lindguist 1973) the central nervous system content was reported to sjhow low concentration of chloroquine in malarial (Grundman, 1972). The level of the drug in the liver, spleen kidney and Leulukocyte was 200-700 times that in the plasma (Webster 1985). The volume of distribution values ranged from 116 to 285 L/kg. conforming extensive tissue binding and distribution (White 1985). Chloroquine undergoes a remarkable degradation in the body, the main metabolite is dosethyl chloroquine which accounts for one forth of the material appearing in the urine (Webster, 1985) it has been indicated that more than half the urinary product is pure chloroquine mechesney et al 1966. Bisle sethyl chloroquine a carbonxylic acid dervatrive was also found in small quantities Webster 1985). In man, the reported metabolite after single and rtepeated doses of chloroquine are mono desethylated chloroquine and bidesthyl chloroquine (Mcchsney et al 1962; Mechesney et al 1966. Prince evans et al 1979, Esscen and Afamefuna 1982). Of these bidesthyl chloroquine only constitute 10% of the total amount excreted in urine. 70% of a given chloroquine dose is reported to be excreted in the urine unchanged and 55% of a given dose chloroquine can be recovered after repeated doses (Mechesney et al 1966, Prince Evans et al 1979 and during chronic treatment (Frisk – Haolbertg et al 1983 Mono desethylated chloroquine is reported to have antimalarial activity (ROLLO 1980) hence its pharmakinectics are of importance.


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