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A COMPARATIVE STUDY OF THE EFFECTS OF PRAZOSIN, ALPHA-METHYLDOPA, OXPRENOLOL AND PLACEBO ON SOME PHYSIOLOGICAL PARAMETERS IN HEALTHY MAN
Table of content
List of tables
List of Figures
Chapter one: Introduction and Literature Review
Chapter two: Methodology
2.3 safety and Precautions
2.4 Statistical Analysis
Chapter three: results
3.1 effect on Meal Blood Pressure
3.2 Effect on Mean heart Rate
3.3 Effect on Vital Capacity
3.5 Effect on 24 hour Urinary electrolyte concentrations.
Chapter four: discussion
This comparative study of the effect of acute administration of prazosin, alpha-methyldopa, oxprenolol and placebo was carried out in 6 healthy normotensive blacks. The study protocol was designed in accordance with the revised Helsinkin declaration (1975) on human experimentation. Each of the subjects report at the investigation unit at least 30 minutes prior to the scheduled time for study and rested on a couch. After taking the baseline blood pressure and heart are each of the received in a randomised order either prazosin 1mg, alpha-methyldopa 500mg orprenolol retard 80mg or a placebo in a single blind basis. The blood pressure and heart rate response after acute administration of either of the drug or placebo was measured at 0.5, 1.5, 2. 3. 4. 5. 6 and 8hours after administration. The effects on exercise induced tachycardia and lung volumes was estimated at 2, 4 and 6 hours after administration.
Our results show that prazosin, alpha-methyldopa and oxprenolol produced no significant effect on human blood pressure and supine heart rate compared to the placebo. However prazosin significantly increased erect heart rate when compared to placebo. All the drugs produced a significant inhibition of exercise-induced tachycardia but had no significant effect enforced vital capacity when compared to the placebo.
Hypertension has been defined as a state of abnormally high blood pressure for a given age and sex which manifests as a symptom complex in the course of many disorders (Goodhart, 1978). There are two types of hypertension, essential or primary hypertension and non-essential or secondary hypertension. In essential hypertension the cause of the disease is unknown whereas in non-essential hypertension the disease is secondary to a known disorder (Roper, 1978).
However, essential hypertension constitutes a greater part of hypertensive cases commonly seen. It has been shown to be associated with a number of factors that predispose to atheroma and vascular thrombosis (Anderson, 1978). Among these are heredity, obesity, diet and heavy cigarette smoking. On the other hand, non-essential hypertension has been traced to underling pathological conditions such as kidney disease, endocrine disorders and coarctation of the aorta (Macheod, 1978). In both essential and non-essential hypertension, increase in peripheral resistance to blood flow has been observed (Guyton, 1981).
Historically the reduction in increased sympathetic activity was one of the earliest pharmacological approaches to treat high blood pressure (Prichard, 1982). Hoever, the mechanism of action of most drugs used were not understood until after the first description of the existence of alpha- and beta-adrenocpetors by Ahquist (1948). This classification provided a basis for further research into the properties of these receptors and their relevance to blood pressure control.
In the light of most recent knowledge starke and Lange (1978) suggested a pharmacological classification of the alpha adrenocpetors into alpha1 and alpha2 on the basis of their relative affinities for agonists and antagonists. Beta-adrenoceptors were subdivided in a similar way into beta1 and beta2 by Lands et al (1967). These adrenoceptors are located in the central and peripheral nervous system where they mediate sympathetic effects that influence the blood pressure.
Reduction in blood pressure is largely determined by reduction in total peripheral resistance or cardiac output (Guyton, 1981). Pharmacologically the peripheral resistance to blood flow can be reduced by blockade of alpha-1 adrenoceptros on the blood follow can be reduced by blockade of alpha-1 adrenocpetors on the blood vessels, or by the stimulation of the alpha-2 adrenoceptors in the central nervous system. On the other hand. The cardiac out-put can be reduced by blockade of beta1 adrenoceptors on the heart. The reverse is also true. This discovery has been greatly exploited in the development of various classes of antihypertensive agents such as sympatholytic, vasodilators, angistensin converting enzyme inhibitors and diuretics.
The introduction of these agents has significantly improved antihypertensive therapy. The benefit of antihypertensive therapy is primarily a reduction in the compications associated with hypertension (Macleod 1978). The beneficial effect of these agents has stimulated various research work into their actions in man after administration. However, for our purpose we shall only review previous studies on antihypertensive agents such as prazosin, alpha-methyldopa and oxprenolol, which are sympatholytic with different mechanisms of action.
Prazosin is a quinazolinee derivative synthesised by Hess and Constantine in an attempt to find a vasodilator with minimal; effects on cardiac output (Constantine 1974; and Hess 1974).
The pharmacolinetics of prazosin has been most recently reviewed by Vincent et al (1985). When given orally, prazosin is readily absorbed from the gastrointestinal tract. The rate and extent of absorption is not significantly affected by food (Verbeselt et al, 1976); and the extent of absorption is similar regardless of the formulation (Hobbs et al, 1978). The peak plasma concentration after administration of prazosin is dose related and occurs between 1 and 3 hours (Larochaelle et al, 1982). Prazosin is highly bound to plasma protein; possesses a large volume of distribution and a half-life of 2 to 4 hours in normotensives and hypertensive with normal renal function (Bateman et al, 1979; Rubin et al, 1981). It is largely metabolised in the Liver and exerted via the biliary tract as metabolites of less potency (Taylor et al, 1977).
MECHANISM OF ACTION
On the basis of additional knowledge of the two types of alpha-adrenoceptors, it is now known that prazosin acts mainly by competitive blockade of postsynaptic alpha-1 adrenoceptor in concentrations that do not block the presynaptic alpha-2 adrenocpetors. (Cambridge et al, 1977). By this blockade, prazosin inhibits the vasoconstrictor effect of circulation of noradrenaline, and therefore products a fall in blood pressure.
Antagonism of postsynaptic alpha-1 receptors on vascular smooth muscle of arteries and veins appears to be the basis of the cardiovascular actions of this drug in clinical practice. There is evidence to show that prazosin has no significant effect on alpha-2 or beta-2 adrenoceptors. Cambridge et al (1977) using rabbit pulmonary artery strips showed that prazosin has a marked affinity for the postsynaptic alpha-1 adrenoceptors and not alpha-2 or beta-2 adrenoceptors. This was supported by subsequent study by Cambridge et al, (1978) and Hornung et al, (1979).
The importance of this peripheral alpha1 adrenoceptor blockade is that prazosin cause’s hypotension without causing reflex tachycardia as conventional alpha-adrenoceptor blocking drugs such as phentolamine and phenoxybenzamine. As such, prazosin is preferred to phenotolamine and phenoxybenzamine in the treatment of hypertension.
Previously, alternative hypethesis were advanced to explain the action of prazosin. One of such was inhibition of central alpha-adrenocpetor. But wood no significant effect on blood pressure whereas injection of the drug peripherally produced a marked fall in blood pressure. Prazosin was also proposed to act by inhibition of phospodiesterase (Hess, 1975) or by inhibition of dopaminebeta hydroxylase (Frigon et al 1978). It is true that the inhibition of phosphodiesterase can case accumulation of cyclic AMP in vascular smooth muscle and hence vasodilatation but a major drewback to this hypothesis is that prazosin concentrations required to inhibit phosphodiesteriase far exceed those achieved therapeutically (Hess 1975, Scott et al, 1978). A similar objection allies to the hypothesis that prazosin acts by inhibition of beta-hylase to decrease nor adrenaline released (Frigon et al, 1978). The action of prazosin therefore appears to be essentially due to postsynaptic alpha-1 receptors blockade at the periphery.
Prazosin dilates both arteries and veins and reduces the blood pressure without causing much reflex tachycardia in normal or hypertensive patients as other vasodilators such as hydralazine, diazoxide and minoxidil (wood et al, 1977; komarek and cartheuseu, 1977). The reduction in blood pressure occurs at rest and during exercise. However, the fall in blood pressure is more in the erect than in the supine position (Brogden et al, 1977).
Acute administration of prazosin casues a moderate increase in heart rate as well as an increase in cardiac index (Lund Johansen, 1975).
In asthmatics, Barnes (1981) and Barnes et al, (1980) found that the number of alpha-receptors increased on the brochial smooth muscle. However, their blockade no clinically significant bronchodilator.
The interaction of prazosin with propranolol is controversial. Elliot et al, (1981) found that concurrent propranolol administration increase the severity and duration of postural hypotensive response to prazosin. Strokes et al, (1974) found no interaction between prazosin and beta-receptor blockers. However, Rubin et al, (1980) found that indomethacin prevented the fise in plasma renin activity seen with prazosin alone and in some of the subjects studied prazosin-induced blood pressure reduction was attenuated.
The therapeutic uses and side effects of prazosin has been reviewed by stanaszek (1983). Prazosin has been used in the treatment of mild, moderate or severe essential hypertension. It is either given alone or with a diuretic. It is also used in the treatment of congestive heart failure because it produces a balance vasodilatation of veins and arteries thereby reducing the cardiac preload and afterload.
The most important side effects of prazosin in hypertensive patients is the ‘’first dose effects’’ an acute symptom complex characterised by dizziness, faintness and palpitation. In a study of 10 hypertensive receiving a single oral dose of prazosin 5mg, Rabin and Blaschke (1980) demonstrated that the first dose effect was due to severe hypertension, impairment of venous return and bradycardia. Rubin et al (1980) and side man et al, (1982) confirm this is in a similar study. This dose related occurrence can be minimised by starting treatment with an initial low dose. Other side effects of prazosin include headache, drowsiness and weakness.
Unlike prazosin, alpha-methyldopa is a centrally acting antihypertensive agent.
When given orally about 50% of the drug is absorbed. It is subject to first pass intestinal metabolism. About 66% of the drug is excreted unchanged via the kidney while some are excreted as conjugates or decarboxylase derivatives (myhere et al, 1972). There is individual variability in both the quantity absorbed and the distribution of the metabolites.
MECHANISM OF ACTION
Alpha-methyldopa is known to act centrally. In the central nervous system, it is metabolically converted by decarboxylation and B-hydroxylation to alpha-methyindoradrenaline (Dollery 1965). When released, alpha-methynoradrenaline selectively stimulates the central alpha2 adrenoceptors and this inhibits the sympathetic output to the peripheral vessels. The resultant reduction in peripheral resistance leads to reduction in blood pressure (Dollery, 1965).
There iks evidence to show that alpha-methyldopa acts centrally and that alpha-methylndonadrenaline is the active agent. Inhibition of dopa decarboxylase centrally abolishes the hypotensive response to alpha-methyidopa (Henning 1969; Day et al, 1973). It has also been shownb that alpha-methylnoradrenaline produces more hypotension than its precussors when administered centrally (Heise and Kroneberg 1972).
The effects of alpha-methldopa are antagonised by small doses of amphetamine – like drugs (Schild, 1980).
Alpha-methyldopa produces a reduction in sympathetic outflow to the peripheral blood vessels leading to a reduction in vascular resistance to blood flow. The resultant fall in blood pressure is as great in the lying as in the standing position. This fall in blood pressure is maximal within 4 to 6 hours after oral administration.
A number of studies in patients with mild to moderate essential hypertension have compared the antihypertensive effect of prazosin with that of alpha-methyldopa. Brogden et al, (1977) showed that prazosin and alpha-methyldopa appeared to produce a comparable antihypertensive effect when both drugs are adjusted to achieve optimal control of blood pressure. The antihypertensive effect of prazosin, and alphamethyldopa were also found to be comparable to one another by whelton et al, (1979); Nanivandekar and Kulkarni (1981).
Alpha-methyldopa is used in the treatment of mild to moderate hypertension. It is frequently used in the control of hypertension in pregnancy since it has no significant effect on the foetus (Schild, 1980).
The main side effect of alpha-methyldopa is drowsiness, but headache, dizziness and weakness may occur initially. At toxic doses, sedation, vertigo and psychic depression may occur
Oxprenolol is a non-selective beta-adrenoceptor blocker. Beta-blocking drugs were initially used in the treatment of angina pectoris, arrhythmias and phaechromocytoma. They were later employed in the treatment of hypertension and this has now become a major indication for the use of these drugs, (Prichard 1982)).
The pharmacokinetics of oxprenolol and other beta blockers has already been stablished (Godman, 1980). When given orally, oxprenolol is almost completely absorbed but only 33% of the drug reaches the systemic circulation. In the circulation oxprenolol is less bound to plasma protein compared to propranolol which is the prototype in this group. It has a half-life of about 2 hours and is largely metabolised in the liver and excreted via the kidney (Godman, 1980).
MECHANISM OF ACTION
It is known that oxprenolol and other beta blockers appear to lower blood poressure as a result of their beta adrenoceptor blocking action at various parts of the body. What is not well known is the specific site of action that is very crucial to their hypotensive effect. Several proposals have been advanced. Among these are; a direct action of the central nervous system, anti-renin activity, an increase in vasodilator prostaglandins and a reduction in cardia output. These proposals have been reviewed by Prichard (1982) and their limitations examined. However, oxprenolol and other beta-blockers may as well lower blood pressure by one or more of the above mechanisms in view of the complex nature of blood pressure control in man.
The most important effect of oxprenolol is on the heart where it causes reduction in cardiac output and heart rate as a result of beta adrenoceptor blockade. The decrease in cardiac output an heart rate is profound during exercise (Goodman 1980) Robin et al, (1967); Helfant et al, (1971) observed that ocprenlol produced a slight decrease in blood pressure in resting subjects. However, schilesinger and Barzilag (1980) observed that oxprenolol produced a significant reduction in heart rate and blood pressure in patients with essential hypertension on chronic treatment.
Beta-blocking drugs such as oxprenolol and pindolol possess intrindix sympathomimetic activity (ISA) as opposed to other beta blockers such as propranolol and atenolol. The importance of ISA is that, drugs with this property reduce blood pressure without causing excessive bradycardia as drugs without ISA (Makom, (1982).
Oxprenolol because of its bronchoconstrictor effect increases resistance to airflow. In the study by Schlesinger and Barzilag (1980) oxprenolol was found to reduce the forced expiratory volume in Isecond (FEV1) in hypertensive patients. It should therefore be used with caution in patients with obstructive airway disease or asthma.
Beta-blocking drugs such as propranolol and satolol has been reported to alter the ability of the kidney to eliminate sodium in normal subjects (Prichard, 1982). This is because of its effect on the Na-k ATase which regulates the exchange of sodium and potassium across the tubular membrane.
Beta-blocking drugs such as oxprenolol and propranolol are used in the treatment of hypertension of moderate severity especially in combination with diuretics. However oxprenolol is preferred to pronolol in the treatment of hypertension when there is need to avoid severe bradycardia (Malcom, 1982). Oxprenolol is also preferred t opropranolol in patients with peripheral vascular disease (Robert et al, 1977).
The treatment of essential hypertension with beta-blockers may be accompanied by cold extremities, peripheral gangrene, fatigue and dizziness. However, there is evidence that sides effects such as cold extremities and peripheral gangrene may be reduced with drugs with ISA. In a compatrative study of pateints with essential hypertension receiving propranolol and oxprenolol, Robert et al (1977) found that propranolol increased the total peripheral resistance while oxprenolol did not.
SCOPE OF PROJECT
There have been several reports in the literature about racial difference in the effectiveness of beta-blockers and prazosin in the management of hypertension in Negroes, although there has not been sufficient information to explain these differences venter and Joubert, 1984). However, comparative studies on the response to prazosin, alpha-methydopa and oxprenolol in this racial group are scarce. This study is therefore designed to examine the effects of standard doses of prazosin, alpha-methydopa and oxprenolol in blacks with respect to physiological responses of blood pressure heart rate, exercise induced tachycardia and forced vital capacity. In addition, to examine biochemical changes accompanying their mechanism of hypotension by measureing 24 hour urinary electrolytes.
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