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.
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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
DECLARATION
DEDICATION
ACKNOWLEDGEMENT
LIST OF TABLES
LIST OF
FIGURES
ABSTRACT
CHAPTER ONE
1.1
INTRODUCTION
1.2
RELEVANT PHARMACOLOGY OF DRUG USED
1.2.1
ATENOLOL
1.2.2
METOPROLOL
1.2.3
PROPRANOLOL
1.2.4
DIAZEPAM
1.3
BACKGROUND AND OBJECTIVES OF THIS
STUDY
1.3.1
EFFECT OF BETA BLOCKERS ON MUSCLE
AND EXERCISE TOLERANCE
1.3.2
RACIAL DIFFERENCES IN RESPONSE OF
BETA BLOCKADE
1.3.3
EFFECTS OF DIAZEPAM ON EXERCISE
TOLERANCE
1.3.4
AIMS OF THIS STUDY
CHAPTER TWO
2.0 METHODOLOGY
2.1 SUBJECTS
2.3 STATISTICAL
ANALYSIS
CHAPTER
THREE
3.0 RESULTS
3.1 EFFECTS
ON THE HEART RATE
3.2 EFFECTS
ON MAXIMAL EXERCISE TOLERANCE TIME
3.3 EFFECTS
ON BLOOD PRESSURE
CHAPTER
FOUR
4.1 DISCUSSION
4.2 CONCLUSION
APPENDIX 1
APPENDIX 2
REFERENCES
ABSTRACT
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:
(1) Blood
pressure and heart rate.
(2) Maximal
exercise tolerance time.
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.
Chapter one
1.1 Introduction
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)
Pharmacological properties
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.
Pharmacokinetics
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).
Side effects
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)
Pharmacokinetics
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.
Side effects
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).
Pharmacological properties
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).
Pharmacokinetics
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).
Pharmacokinetics
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).
Side effects
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.
Therapeutic Uses
1.
Supraventricular and Ventricular
arrhythmias.
2.
Hypertension.
3.
Angina pectoris.
1.2.4 DIAZEPAM
Diazepam is a commonly used
benzodiazepine. It is used mainly in the treatment of an
Anxiety, convulsions and
hypnosedation.
Pharmacological properties
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).
Pharmacokinetics
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).
Side effects
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.
1.3 BACKGROUND
AND OBJECTIVES OF THIS STUDY
1.3.1
effects of beta blockers on muscle
and exercise tolerance
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).
1.3.2
racial differences in response to
Beta Receptor Blockade
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.
1.3.3
effects of Diazepam on exercise
tolerance
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).
1.4 aims
of this study
1.
to determine the effects of a
single therapeutic dose of propranolol, metoprolol, atenolol and diazepam on
heart rate, blood pressure and maximal exercise tolerance time.
2.
To compare the results obtained in
this study with available data.
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