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A SINGLE BLIND CROSS-OVER STUDY OF THE EFFECTS OF SOME BETA ADRENOCEPTOR ANTAGONISTYWS AND DIAZEPAM ON EXERCISE TOLERANCE, HEART RATE AND BLOOD PRESSURE IN HEALTHY AFRICAN SUBJECTS.
TABLE OF CONTENT
LIST OF TABLES
LIST OF FIGURES
2.3 STATISTICAL ANALYSIS
3.1 EFFECTS ON THE HEART RATE
3.2 EFFECTS ON MAXIMAL EXERCISE TOLERANCE TIME
3.3 EFFECTS ON BLOOD PRESSURE
This study was undertaken to determine the effects of single oral doses of 40mg propranolol, 50mg atenolol, 50mg metoprolol, 5mg diazepam and placebo on the following physiological parameters:
Six healthy black adult males were recruited to undertake the study. They were aged between 19-22 years and were all non-smokers. One of the subjects however withdrew due to some illness. The study was done in a randomised, single-blind crossover design. Three days where allowed between treatments for was out of the previous drugs.
Results obtained from this study show that these drugs did not have any significant effects on blood pressure when compared with placebo. This was true for both resting diastolic and systolic blood pressure and blood pressure after maximal exercise.
There was a significant reduction in maximal significant effect resting heart rate (P> 1.0). On maximal exercise time, there was no significant difference between the drugs used and placebo (P> 1.0).
The findings are discussed into what is currently known about the effects of beta-adrenoceptor blockers on exercise tolerance and the racial difference in response to beta adrenoceptor blockers.
Since adrenoceptors were classified into alpha and beta (Alquist, 1948) with subsequent sub-division of beta-adrenoceptors into beta 1 and beta 2 by lands and co-workers in 1967, several therapeutically useful betadrenoceptor antagonists have been developed. At the present time, beta blockers constitute one of the most widely studied and clinically used group of drugs worldwide.
Beta blockers have been tried in a wide variety of conditions and are of established benefit in thyrotoxicosis, anxiety, essential tremor, migraine and glaucoma. However, their major therapeutic usefulness is in the management of cardiovascular disorders namely; hypertension, cardiac arrythmaias, angina pectoris and secondary prophylaxis after myocardial infarction.
Though extensively studied, several aspects of the pharmacology of the beta blockers remain unclarified. For instance, it takes 4-8 weeks to achieve maximal antihypertensive effect on beta blocker therapy. Their main mechanism of action in this condition is uncertain. Suggested possibilities include: an effect on the central nervous system, an adrenergic neurone blocking effect, an anti-renin effect, an effect secondary to reduced cardiac output and finally a mechanism consequent on resetting of barareceptors. The study described in this dissertation was designed to investigate some unsettled aspects of the pharmacology beta blockers. Before going on to discuss these issues, as well as the objectives of the study, it would seem appropriate to give a brief outline of the relevant pharmacology of the drugs used.
1,2 relevant pharmacology of drugs used.
1.2.1 atenolo (Ternomin)
Atenolol is a cardioselective (beta 1) adrenoceptor blocker. Like propranolol, it lacks partial agonist activity (PAA). It is also lipid insoluble and hence does not cross the blood brain barrier. Atenolol is a very effective antihypertensive agent.
Atenolol is well absorbed after an oral dose. It is however poorly bound to protein. It undergoes clinination largely by the kidneys. Atenolol has a half-life of 5.25 hours. (Rubin et al, 1982).
Although atenolol is cardiscelective, its use in asthma and diabetes should be with care (Weiner, N. 1980).
1.2.2 metoprolol (Betaloc, Lopressor).
Like aternolol, mertoprolol is a cardioselective beta 1 adrenoceptor antagonist. Metoprolol inhibiyts the ionotropic and chromnotropic effects of isoprenaline. (Weiner, N 1980)
Metoprolol is well absorbed from the gastro intestinal tract following oral administration. However, like propranolol, it undergoes first pass hepatic metabolism so that only 40% of the active drug reaches circulation. Peak concentration of the drug is attained in plasma 90 minutes after administration. (Brogen et al, 1977).
Metaprolol is metabolised to hydroxylated o-demethylated compounds which lack significant pharmacological effects. It has an elimination half-life of 3 hours.
Metoprolol has been found to impair glucose tolerance in diabetic patients since it inhibits the beta receptor mediated release of insulin. Metoprolol also reduced forced expiratory volume (FEEV1) in asthmatic patients. This effect is however less than that caused by propranolol. High doses of metoprolol will therefore result in the exacervbation of broncho constriction in asthma. It is therefore only used in asthmatics when a beta 2 adrenergic agonist is administered along with it (Brodden et al, 1977).
1.2.3 propranolol (Indernal, Avlocardin)
Propranolol is a non-selective beta adrenoceptor blocker. It lacks partial agonist activity (PAA).
Propranolol has the ability to block both beta 1 and beta 2 receptors. It is therefore contraindicated in asthma and diabetes. Propranonol produces some major effects on the cardiovascular system, its main effect being on the heart. It decreases heart rate and cardiac output. It prolongs mechanical systole and slightly decreases blood pressure in resting subjects (Rubin et al, 1967; Helfant et al 1971). The effects of propranolol become more evident in exercise where there is a reflex sympathetic rise in peripheral resistance and a decreae in blood flow to all tissues except the brain. (Nies et al, 1973). Propranolol is also known to inhibit glycogenolysis in the liver and skeletal muscle. (Koch et al, 1981).
Propranolol is extensively absorbed after oral dosage and then undergoes extensive first past metabolism so that only a third of the administered drug reaches the blood stream. It has a half-life of 3-5 hours. (Evans et al, 1973b). It is 90-95% bound to plasma protein (Evans et al, 1973a). Propranolol is mainly broken down into 4 hydroxy-propranolol which has some beta adrenergic blocking properties. However, the latter’s half-life is very short when compared with propranolol. (Fitzgerald and O’ Donnel, 1971).
Propranolol is extensively absorbed after oral dosage and then undergoes extensive first past metabolism so that only a third of the administered drug reaches the blood stream. It has a half-life of 3-5 hours. (Evans et al, 1973b).
Propranolol is mainly broken down into 4 hydroxypropranolol which has some beta adrenergic blocking properties. However, the latter’s half-life is very short when compared with propranolol. (Fitzgerald and)’ Donnel, 1971).
Propranolol causes an increase in airway resistance and is therefore contraindicated in asthma. This is due to its beta 2 blocking property.
It can also precipitate heart failure, although this is rare and is seen more in patients with compromised hearts.
Propranolol reduces the4 effect of sympathoadrenal compensatory mechanism and therefore augments the hypoglycaemic actions of insulin. It is contra-indicated in diabetes.
Other side effects are nausea, vomiting, constipation and mild diarrhoea (Crecentbalt and Shader, 1972). There could also be insomnia, dizziness, lassitude and depression.
Diazepam is a commonly used benzodiazepine. It is used mainly in the treatment of an
Anxiety, convulsions and hypnosedation.
On the skeletal muscle, diazepam causes relaxation. The effects of diazepam in causing muscle relaxation is taken advantage of in its use in certain spastic states. The effects of diazepam on the skeletal muscle may account for muscle weakness felt on administration of diazepam.
When given intravenously, there may be a slight decrease in blood pressure and a reflex increase in heart rate. (Elliot et al, 1971).
It is well absorbed after oral administration. Peak concentrations in plasma are attainee in an hour, but less so in children – between 15 – 30 minutes.
The plasma concentration remains high after 6-12 hours following administration. This is attributable to enterohepatic circulation. (Morselli, 1977).
Diazepam is metabolised to nordiazepam which is also active and this may extend its half-life two fold. (Harvey, C.H.; 1980).
The side effects are mainly extensions of its pharmacological properties and include; ataxia, drowsiness and psychomotor impairment.
Diazepam has additive effects when taken with other central nervous system depressants like alcohol. It could also cause confusion in the elderly.
muscular fatigue and exhaustion may be an effect of beta blockers and a variety of other drugs (Editorial, lancet, 1980; Cruickshank, 1981). This effect of beta blockers was assessed by determining maximal work capacity (Anderson et al, 1979) or perceived exertion. (Pearson et al, 1979). They found that an impairment was produced by both selective and non-selective beta receptor blockers.
The factors that might be responsible for this muscle dysfunction may be due to a reduction in limb perfusion. During exercise or stress, sympathetic stimulation of the predominantly beta 2 receptors in the peripheral arteries causes vasodilation. This will result in a decrease in peripheral resistance, fall in diastolic pressure and an increase in perfusion of limbs and muscles (Johnson, 1975; Herwaarden et al, 1977). It is therefore obvious that blockade of the beta receptors will produce the opposite effects.
The reduction in perfusion of the limbs and muscle will produce a decrease in the supply of oxygen, glucose and fatty acid and will greatly decrease lactic acid removal.
The beta receptor blockers also have some metabolic effects which may also be significant. (Southbrier et al, 1981).
The beta blockers impair glycogenolysis in the liver and muscle (Koche et al, 1982). Also the beta receptors (mainly beta 2) are involved in mobilisation of glucose as occurs in hypoglycaemia (Kendall, 1981a). Hence, the beta blockers especially the non-selective beta blockers, will impair the recovery from hypoglycaemia. (Deacon and Barnett, 1976; Newman, 1976; Hanson et al, 1977).
The usefulness of beta receptor blockers in the management of hypertension is not in dispute (Princhard et al, 1969). However, their usefulness in the Negro race has been a subject of dispute (Seedat, Y.K. and Ready, J., 1971). Work done so far, although relatively few have shown a relatively reduced potency of beta receptor blockers in blacks as compared to whites.
One reason that might be responsible for the observed differences in response to beta blockers between blacks and whites lies in the fact that normotensive as w3ell as hypertensive black patients have lower renin activates than whites. (Kem, et al, 1973). However, the role of plasma renin in predicting the effectiveness of beta blockers still remains unsettled. (Nillson et al, 1979; Amery et al, 1977).
There are also reports that the relative variations noticed between blacks and whites may be due to an increased cyclic adenosine monophosphate activity in the lymphocytes of blacks. (Venter et al, 1985). Various workers have shown that peripheral blood lymphocytes possess an adenylate cyclase system which is identical to beta 2 adrenoceptors in lungs and other tissues. It has also been shown that the lymphcytic beta 2 can be stimulated by beta agonists like isoprenalol and blocked by beta receptor antagonists like propranolol (Coleman & Somerville, 1979). It is therefore being suggested that the higher level of CAMP in the lymphocytes of blacks suggest a higher beta 2 activity, both at rest or on stimulation. If this applies to the vascular beta 2 receptors, it then becomes imperative the normal dose of beta blockers may not produce effects similar to those obtained in whites when taken by blacks.
diazepam produces muscle relaxation by acting selectively on polysynaptic rather than monosynaptic pathway in the central nervous system. It potentiates presynaptic inhibition in the spinal cord by enhancement of GABA-ergic transmission. Diazepam is not truly GABA-mimetic and does not produce any effects when GABA is depleted. Also certain inhibition GABA synthesis like thiopsemicarbazone will inhibit the effects of diazepam. It is also suggested that the stimulation of the effects GABA may be as a result of an antagonism of a protein that inhibits the binding of GABA to tis receptors (Costa et al, 1978; Guidotti et al, 1878). It has been shown that the muscle relaxant effects of any of the benzodiapine correlates with their ability to bind to protein (Bastrup et al, 1977; Mohlen and Okada, 1978; Septh et al; 1978).
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