CHILOROQUINE INDUCED HYPOTENSION EVALUATION OF CHOLINERGIC PARTICIPATION
TABLE OF CONTENT
List of figures
List of tables
Chapter one: introduction
Mechanism of antimalarial action
Precaution and contraindication
Chapter two: material and methods
Chapter three: Result
Chloroquine produces hypotension post intravenous administration in rats, cats and man. This effect has been attributed to blockade of calcium channels in the cardiac as well as other smooth muscles.
We have observed that pre-treatment with calcium gluconate did not return the blood pressure of drug treatment animals to normal suggesting that other mechanism (s) such as chlolinergic mediation may be involved and hence this investigation. Cats *1.7 – 3.0kg( were anesthetized with urethane, cannulated and the drug administered via the femoral vein. Chloroquine was administered in different doses either alone or in combination with therapeussure and heart rate were monitored using lectromed, type Mx2p, chloroquine procedure dose dependent hypotension in the cat following intravenous administration with less cardiac depressant effect. Coadministration of the drug and carbachol or acetycholine augumented the drug induced hypotensive effect and shortened that life of the animal. On the other hand coadministration of chloroquine and atropine attenuated the drug induced effect and shortened the life of the animal. On the other hand coadministration of chloroquine and atropine attenuated the drug induced effect and prolonged the life of the animal. These results indicate that chloroquine induced hypotensive effect involves chlonergic mechanism and suggest that intravenous coadministration of cholinometic drugs with chloroquine may not be advisable.
Chloroquine is one of a large series of 4- aminoquinolines. Russian as well as French scientists have investigated the antimalarial properties of the 4 – aminoquinolines (Rollo, 1980). Beginning in 1943, antimalarial research in the United states led to the synthesis of many 4 – aminoquinolines, the most potent of which was designated SN 7618 and later named chloroquine (Catchpool 1980).
Currently, chloroquine is the most widely prescribed antimalarial drug in the world (W.H.O, 1984). It is the treatment of choice for malaria caused by plasmodium Vivax, P. malariae, p. ovale and sensitive strains of p. Ealciparum.
Chlorequine is 7 – chloro – 4 – (4 – diethylamino – 1 methyl butyl amino) quinolone (Webster, 1985), The disphosphate is a white, bitter powered, soluble in water. The D, L, DL forms of chloroquine are indistinguishable in potency tests in Aves but the D isomer is somewhat less toxic than the L isomer (Berliner et al 1948). It is soluble in water at PH 4.5.
This solubility decreases at more alkaline of neutral PH (Catchpool – 1980).
FIG 1structure of chloroquine.
The above is the structure of chloroquine. It contains an alkyl side chain and a quinolone nucleus. The chlorine atom in the seventh position on the quinolone nucleus. The chlorine atom in the seventh position on the quinolone nucleus. The chlorine atom in the seventh position on the quinolone ring is crucial for antimalarial property (Webster 1985). Methyl substitution in position 3 of the quinolone reduces activity and additional methyl substitution in position 8 completely climinates activity (Berliner et al 1948; coatney et al 1953).
Congenars of chloroquine are amodiaquine, hydroxyl-chloroquine, amopyroquine and cycloquine (Wester 1985). Hydroxy-chloroquine is employed in place of chloroquine (Webster 1985). Hydroxyl-chloroquine is employed in place of chloroquine against normally sensitive strains of plasmodium parasite.
Amodiaquine is more potent than chloroquine both invivo and invitro against certain resistant strains of plasmodiumFalciparum (Rollo 1980).
Chloroquine is primarily an antimalarial agent (W.H.O. 1984). However it also possess several other pharmacological properties. ANTI INFALMMATORY EFFECTS – chloroquine has been demonstrated to possess anti inflammatory properties (Rollo el tal 1980). It is therefore employed occasionally to treat rheumatoid arthritis (Percival and meanock, 1968), and discoid lupus erythematosus. The mechanism of this action is not understood (Dubois 1978).
EFFECTS ON CARDIOVASCULAR SYSTEM – chloroquine has effects on cardiovascular system. These effects are more consistent with parenteral administration which results in high plasma levels.
Chloroquine produces significant and progressive fall in systolic blood pressure (Looaresuwan et al 1986). The fall in systolic blood pressures are accompanied by a rise in heart rate which paralleled the change in plasma chloroquine concentrations, (Looaresuwan et al 1986. Toxic doses of chloroquine depresses vasomotor function and induce ci9rculatory collapse, shock, respiratory paralysis and death. (catchpool 1982). On the electrocardiogram, chloroquine causes a prolongation of the Q R S complex, a depression of ST segment but no change in QT interval (Looaresuwan et al 1986).
Furthermore, chloroquine has no antagonistic action to the effect of adrenaline on the heart and blood vessels (Salako and Sangodey, 1976).
High plasma levels causes cardiac arrest as chloroquine depresses cardiac contractility and decreases vascular resistance (Marshall and Ojewale 1978). Ikhinmwin et al 1981; Ebeigbe and Aloamaka, 1982).
It has been demonstrated that the cardiovascular effects of chloroquine is via interference with calcium ion influxes into the cell but it is less effective than verapamil (Efferekeya and Osunkwo, 1986). The cardiovascular toxicity of parenteral chloroquine is related to transiently high plasma concentrations occurring early in the distribution phase.
Thus the rate of administration is therefore a major determinant of toxicity, (Looaresuwan et al 1986).
OTHER EFFECTS – chloroquine hs also been shown to be effective against ameoiasis and thus is used in extraintesitnal ameobiasis (conan 1948, Murgatroyed and kent 1948). It is also used to treat porphyria cutomea tarda, solar urticarial and polymrphous light eruptions (Isaacson et al 1982).
MECHANISM OF ANTIMALARIAL ACTION
From early work, it was hypothesized that the drug exerts its effects, at least in part, by an interaction with DNA. Schellenberg and coatney (1960) showed that chlorouine inhibited incorporation of labelled phosphate (23p) into RNA and DNA. This was demonstrated in the DNA and ENA of plasmodium Gallinaceum, invitro and invivo and by plasmodiumberghei invotro (Rollo, 1980).
Chloroquine and its congenars have been shown to block the enzymatic synthesis of DNA and RNA in both mamalina and porotozoalk cells (Allison et al 1966)
Research Allison et al 1966 showed that chloroquine strongly intercalates double stranded DNA. Further, changes in several physical parameters were consistent with an intercalation of chloroquine with guanine containing double stranded DNA (Allison et al 1966). The drug has been reported to inhibit DNA premier (Allison 1965; cohen and Yielding, 1965). The selective toxicity for malarial parasites has been attributed to a chloroquine concentrating mechanism in the parasitized cell (chon et, al, 1980). Plasmodium – infected erythrocytes exposed to chloroquine rapidly concentrated the drug and also exhibited clumping of malarial pigment as parasite digested the haemoglobin of the host red cells.
It has been suggested that this clumping may in some way disrupt the amino acid metabolism of the parasite and lead to its death (earhurst et al 1972; peters, 1973). Both the concentration of the drug and clumping of the malarial pigment are processes which may be related because they are energy dependent, storable and competitively inhibited by antimalarials such as Amodiaquine, quinine, mefloquine, (choua et al, 1980). Recently it has been postulated that aggregates of ferrriprotoporphyrin ix released during degradation of haemoglobin by parasitized erythrocytes, may serve as a receptor for chloroquine and other antimalarials (chou et al, 1980) either ferriprotoporphyin ix or complexes of chloroquine with the porphyrin can cause membrane damage with lysis of trypanosomes, erythrocytes, or malarial parasites (meshnick et al, 1977; dutta and Fitch 1983; Fitch 1983).
However it is not clear if these agents (porphyrin and ferriprotoporphyrin ix) are physiological mediators of destruction of plamsmodia and/or red cell. Further, inhibition of ornithine decarboxylase, the rate limiting enzyme in polyamine biosynthesis, has recently been proposed as another possible mechanism of action of chloroquine (konigk and putfarken, 1983).
ABSROPTION, FATE, AND EXCRETION.
Chloroquine has complex pharmacokinetic properties. It is rapidly and almost completely absorbed from the gastrointestinal tract and less than 10% of the administered dose is found in the stool. This route of administration is not used in seriously ill patients who are vomiting or are comatose.
Parenteral administration is extensively used in such cases.
Intramuscular chloroquine has been associated with occasional death (Harris, 1955; Tuboku – Metzger, 1964; Williams, 1966; Geddes, 1970). Chloroquine is also administered intravenously in the tropies. W.H.O (1984) recommended that parenteral chloroquine should be used. Mean bioavailability of chloroquine is 78% for solution and 89% for tablets (Gustafsson et al 1983).
Highest plasma concentration occur in about 1 -2 hours after oral administration. Adelusi et al (1982), and walker et al (1983) have reported that chloroquine was well absorbed after oral administration to children with uncomplicated falciparum malaria. Early investigation to children with uncomplicated falciparum malaria. Early investigations of absorption and excretion in urine and plasma concentrations were very low suggesting extensive tissue binding (Berliner et al 1948). About very 55% of chloroquine in the plasma is bound to non-diffusible unidentified constituents.
Bergquist and Domeij – Nyberg (1983) have shown that chloroquine and monodesthyl chloroquine are extensively bound to platelets and granulocytes. This comprised about 80% of their total blood contents, suggesting that the drug may be localized in these cells. The plasma half-life of chloroquine ranges between 65 days to 60 days (white, 1985).
In animals, the drug concentrations ranging from 200 – 700 times the plasma concentrations (12drug/1 0- 25ug/1) may be found in the liver, lungs, kidney, spleen and melanocytes, the brain and spinal cord, in contrast contain only 10 – 30 times the concentrations present in plasma (grandma 1972).
Chloroquine binding to plasma proteins is relatively the same in rheumatoid and kwashiorkor patients as in malaria patients (Buchanan and van der walt, 1977; walker et al 1983). Chloroquine is also concentrated in melanin containing tissues, like the retina and skin Grundma et al, 1 1972, kuroda 1962; Indquist 1973).
Chloroquine in the whole blood is about3 – 10 time4s higher than those in plasma, serum chloroquine concentrations are considerably higher than plasma values.
Chloroquine undergoes appreciable biotransformation, the principal metanbolite is monodesethyl chloroquine (MDEC) which is (.25%) of the parent drug and unrelated metabolites in urine. Bisdesethyl-chloroquine, a carboxylic acid derivative and other uncharacterised metabolites are also parent in urine.
MDEC concentrations ranged between 35% to 57% of the parent compound concentrations (Walker et al 1983).
Excretion of chloroquine is quite slow but since it is a base acidification of urine increases its excretion while alkanization decreases it (Goodman 1985). With administration of a single dose, plasma concentrations and urinary excretion reach a plaeau after 10 days.
Excretion in urine accounted for 55% of oraly administered drug and 23% MDEC, the principal biologically active metabolite (Mechaesney et al 1967). The mean renal clearance is 412ml/min which comprised of 51% of the total clearance. There have been reports of the drug in human nails after long periods.
Gustafesson et al (1983) studied disposition of chloroquine, after intravenous and oral administration using high pressure liquid chronomatography method of analysis. Chloroquine was detectable in plasma for 52 days and in urine for up to 119 days following a single dose.
The common toxic manifestations of chloroquine observed at therapeutic doses include gastrointestinal upsets, pruritus, mild and transient headache, visual disturbances. Others are vertigo, malaise, anorexia, and urticarial (Catchpool, 1980). Upon prolonged administration of high doses of chloroquinre, side effects like exfoliate lessions of the skin, alopecia or graying of the hair occur (chatpool 1980).
All these symptoms usually disappears when the drug is discontinued and are reduced by taking chloroquinre after meals (Alving et al 1948) other serious toxic manifestations of chloroquine administration include toxic psychloses with hallucination and peripheral neuropathies with loss of reflexes and muscle powe4r in the lower limbs.
Chloroquine has been implicated to have a teratogenic effect (cordero and wolfe, 1985). Work has shown that tchloroquine causes congenital deafness and mental retardation (Cordero and wolfe, 1985).
Chloroquine has been shown to cross the placental of pregmenat rats and accumulate in the eyes and inner ear of the foetus (cordero and wolfe 1985). Long term treatment can cause irreversible retinopathy in man. This complication has been attributed to the deposition of chloroquine in melanin rich tissues (Bernstein et al 1963).
It can be avoided if the daily dose is 250mg or less, (dubois, 1978; Olansky, 1982). Rarely, neuropsychiastric discturbances, including unintentional suicide may be related to overdosage (Good and Shader, 1982).
Chloroquine has neither prophylactic nor radically curative value in human vivax malaria. Chloroquine is usually highly effective in t4erminating parasitemia and fever of acute attacks of non-resistant strains of p Falciparum within 24 to 48 hours (catchpool 1982). Complete cures are due to the fact that p Falciparum has no secondary tissue stages of plasmodia (Berliner 1948, Davidson, 1981).
Although chloroquine is primarily an antimalarial drug, it also has effect on their systems. It is anti-inflammatory in doses larger than those used for malaria.
The drug is thus used in rheumatoid arthritis and discoid lupus erythematosus. The mechanism of this action is not understood (Dubois 1978). Chloroquine is laos used to treat extraintesitnal ameobiasis (conan 1948, Murgatroyed and kent 1948).
It has also been employed to treat rheumatoid arthritis (peraval and meanock 1968).
PRECAUTIONS AND CONTRAINDICATIONS
Hepatic chloroquine concentrations is about 200 to 700 times that in plasma. Therefore the drug is used withy caution is the presence of hepatic ideas. Research has shown that concomitant use of Gold, phenylbutazone and chloroquine causes dermatitis (Rollo et al 1980).
For patients on long term, large some therapy opthalmological examination is recommended before and periodically during treatment (Percival and Meanock, 1968; Good and shader, 1982).
MARSHALL AND Ojewale, (1978) and Ikhinwin et al (1981) showed that chloroquine depressed cardiac contractility and decreases vascular resistance by interfering with calcium ion influx into the cell. Also looaresuwan et al (1986) reported that parenteral chloroquine caused a slight but significant fall in systolic blood pressure (B.P).
Recently evidence suggests that the sympathetic nervous system may not be involved (Duru et al, 1987). Equally important is that stimulation of parasympathetic nervous system could produce hypotensive effect.
Therefore, this study is aimed at investigating if the hypotensive and cardiodepressive effect of chloroquine are mediated via parasympathetic stimulation by evaluating the effects of chloroquine when given alone or in combination with Acetylcholine, carbachol and Atropine.
CHLOROQUINE INDUCED HYPOTENSION EVALUATION OF CHOLINERGIC PARTICIPATION