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EVALUATION OF THE ACUTE CARDIOVASCULAR EFFECTS OF CHLOROQUINE

TABLE OF CONTENTS

TITLE

DECLARATION

DEDICATION

ACKNOWLEDGEMENT

CONTENTS

LIST OF TABLE

LIST OF FIGURES

ABSTRACT.

CHAPTER ONE

HISTORY

CHEMISTRY

MECHANISM OF ANTIMALARIAL ACTION

ANTIMALARIAL ACTION

ANTI-INFLAMMATORY EFFECTS

ABSORPTION METABOLISM AND EXCRETION

THERAPEUTIC USES

TOXICITY

OBJECTIVES

CHAPTER TWO

MATERIALS AND METHODS

CHAPTER THREE

RESULTS

CHAPTER FOUR

DISCUSSION

CONCLUSION

REFERENCES

ABSTRACT

          Cardiovascular effects of chloroquine following intravenous (iv) administration of chloroquine were investigated by administering chloroquine alone or in combination with other, drugs, (carbachol, acctychroline and atropine). The animals were cannulated. Blood pressure and heart rate were pleasured following intravenous administration through the femoral vein of different doses of either chloroquine and or acetyl-chroline, carbachol and Atropine. The results were

  • Chloroquine decreased the cat mean arterial blood pressure significantly and to a less extend the heart rate after the administration of chloroquine intravenously in anesthesised casts.
  • Co-administraiton of acetyl-choline produced effects in the mean-blood pressure and heart rate more than those observed with either drugs.
  • It was also shown that carbachol produced similar effect with Acetyl-choline on co-administration, but Atropine has opposite effects to both drugus. The data therefore confirms the cardrovascular effect of intravenous chloroquine and indicate that Acetyl-choline.

CHAPTER ONE

INTRODUCTION

HISTORY: 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-N2H5

                      CH3

STRUTURE OF CHLOROQUINE

Chloroquine 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 PROPERTIES

MECHANISMS OF ANTIMALANAL ACTION

          The 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 et al. 1965, 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. 1980

ANTI – INFLAMMATORY EFFECTS

Choroquine 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 EXCRETION

Chloroquine is well absorbed by oral route in healthy subjects (GUSTAFSSAN et al 1983). And in children with uncomplicated falciparum malaria (Adelusi et al. 1982. Walker et al 1983). 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 et al 1972: kurodo 1962, lingvist et al 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.

The main organ of excretion of chloroquine and its major metabolite is the kidney. Chloroquine and its major metabolite is the kidney. Chloroquine has half-life of 15+ 6 days. Renal clearance ranged between 355 to 950 me/mis which comprised 51% of the total clearance (white 1985) it has been shown that there is no much remarkable difference in chloroquine pharmacokinectic between normal and malnourished individuals.

Tulpule and krisnaswancy 1983). It has been shown that the major unsual pharmakokinectic properties of chloroquine already demonstrated in caucasians has been confirm in Nigerians. These properties include an extremely large apparent volume of distribution and consequently a long half-life and slow – elimination, although the drug is efficiently cleared from plasma. The study has thus shown that there is no systemic difference between the pharmacokinetics of chloroquine in black Africans as compared to cuacasians (GUSTAFSSON et al 1983). Recent unpolished observation in Ghana also support the notion that Africans and Caucasians do not differ markedly with respect to chloroquine kenectics (Adlepon – Yamoak et al 1986) therapeutic uses: Malaria. Chloroquine in well tolerated doses is highly effective in terminating the acute attacks of vivax malaria, and when administratered chrorically. It acts as an effective suppressive agent. A complete cure was observed in fever and parasitema of acute attack of non resistance strains or falciparum malarial within 24 – 48 hours (Wester 1985). Cloroquine is effective in suppressing all types of malaria, except the resistant strains of P. Falciparum if chloroquine administration is continued too soon after P. vivax infection parasiterial may recur after days P. vivax infection parasiterial may recur after days (Catchpool 1984).

Other – uses: The important therapentic value of chloroquine in extra intestinal amlabiasis was first reported by canon in (1948, 1949 and Murgatrd & Kent. 1948. Chloroquine is highly effective in the treatment of fluke infection (Cathprol 1984). It eradicates hepatic amebiasis due to its, ability to accumulates in greater concentration in liver, but it is less effective than Emetine which has a direct toxic action of the myocardium.

TOXICITY: Chloroquine inhiubits pressor response to posterior hypothalamic stimulation the degree of inhibition ranged from 27- 45% (Egerakaya & Osunkwo 1986). Intoxification was associated with shock and convulsion (Good & shedder, 1982). Chloroquine cause flattening of the T-wave widening of the QRS complex, depression of the S-T segment of the electro – cardiogram and/or atrio – ventricular blockade (Looase Suwan et al 1986. Catchprol 1984. Chloroquine causes cardio-myopathy as characeterised by vacoular changes in the myocardium and congestive heart failure (Hughes et al 1971, Magnussen, and Olivasium, 1977). It has also been indicated that chloroquine induced decrease in myocardial contractility and hypotension via calcium channel blockade ( Ikhimivin et al, 1981, Ebeigbe & Aloamaka, 1982). Chloroquine is a protein myocardial depressant – depressed heart rate, lowered blood pressure and changes in the electro-cardiogramm were attributed to drug induced effect on myocardial contractility (Sofola & Adegoke, 1981), Salakor & Sango deyi, 1976). Early clinical investigation in patient with falaparm malaria suggested that the principal toxicity of intnavenously injected chloroquine was hypotension (Scott 1950), Mohr 1953, Mnorr 1953 and Laning 1955). Chloroquine on prolonged treatment causes visual loss which is not necessarity progressive if the drug is discontinued but appears to be irreversible (Ber stein and colleague (1963). These gentlemen also demonstrated that chloroquine is stored in the Iris and choronoid of laboratory animals in significantly higher concentration that in other tissues.

Objectives

It has been found that intravenously administered cvhloroquine even at therapeuty dose produced hypotension and bradycardia (Scot 1950). These effects have been attributed to the ability of chloroquine to block calcium ion influx into the myocardium as well as vascular smooth muscle (Ebeigbe and Alcamaka, 1982). Recent work done by Duru and colleagues demonstrated that sympathetic mediation may not be involved it is possible that the hypotension and decrease in cardiac contractility may be brought about by enhancement of parasympathetic influences on the heart and smooth muscles and hence this investigation.

          Therefore the objective of this study is to evaluate the effects of chloroquine on the parasympathetic influence on the heart and smooth muscles.

 The following will be determined.

  1. The effects of chloroquine at different doses on the cat mean arterial blood pressure and heart rate.
  2. The effects of the following drug combinations on the heart rate and mean arterial blood pressure
  3. Acetycholine and chloroquine
  4. Carbachol and chloroquine
  5. Atropine and chloroquine

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