A COMPARATIVE STUDY OF THE EFFECTS OF OXPRENOL, ATENOL AND PROPRANOLOL ON SOME PHYSIOLOGICAL PARAMETERS IN HEALTH MAN
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A COMPARATIVE STUDY OF
THE EFFECTS OF OXPRENOL, ATENOL AND PROPRANOLOL ON SOME PHYSIOLOGICAL
PARAMETERS IN HEALTH MAN
CHAPTER ONE
1.1 INTRODUCTION AND LITERATURE REVIEW
Norepinephrine, epinephrine and other catecholamines
can cause either excitation or inhibition of smooth muscle, depending on the
site, the dose and the catecholamine chosen. Norepinephine is the most potent
excitatory catecholamine and has correspondingly low activity as an inhibitor.
Epinephrine is relatively potent as an excitor and as an inhibitor of smooth
muscle. On the basis of such observations, Ahlquist (1948) propounded a
hypothesis that two types of adrenoceptors exist: the alpha (α) and the beta
(β) adrenoceptors. This classification of receptors has been corroborated by
the findings that certain drugs selectively antagonize the alpha –
adrenoceptors whereas some other agents selectively antagonize the
beta-adrenoceptors. The alpha-adrenoceptors are divided into two types: alpha-1
and alpha-2 adrenoceptors. (Starke, 1977). There are also two types of
beta-adrenoceptors: beta-1 and beta-2 adrenoceptors (Lands et al 1967). There
are drugs that antagonize the activities of these adrenoceptors either
selectively or non-selectively. Hence we have drugs that antagonize both
alpha-1 and alpha-2 adrenoceptors (e.g. Phenoxybenzamine) and those that act
only on alpha-1 adrenoceptors (e.g. Prazosin). Starke et al (1975; Langer
1977). The beta-adrenoceptor antagonists (beta-blockers) may be divided into
beta-1 selective antagonists (e.g. atenolol) and non-selective antagonists with
affinity for both beta-1 and beta-2 adrenoceptors (e.g. Propranolol) (Levy and
Wilkenfeld, 1969). There are also drugs that antagonize both the alpha and
beta-adrenoceptors (e.g. Labetalol). (Brittain and Levy, 1976; Richards and
Prichards, 1978).
The first drug shown to produce a selective blockade
of beta-adrenoceptors was dichloroisoproternol (DCI) (Powell and Slater, 1958).
Studies with DCI made a substantial contribution to the understanding of
effects mediated by beta-adrenoceptors, but it was not used in man, largely
because it has a prominent beta-receptor stimulant action; that is, it is a
partial agonist. The initial report of the hypotensive effect of
beta-adrenoceptors blocking drugs appeared in 1964 (Prichard). Pronethalol was
administrated to some hypertensive patients and then to some normotensive
patients who were being treated for angina pectoris. A significant fall in
blood pressure was recorded after three months therapy. However, pronethalol
was withdrawn because of its carcinogenic effects in mice. The use of
Propranolol in hypertension was described later the same year.
The cardioselective or beta-1-adrenoceptor
antagonists include atenolol, and metoprolol. It is important to remember that
the selectivity of the beta-1-blockers is not absolute; larger doses of these
compounds will inhibit all beta-adrenoceptors (Prichard, 1978). The
non-selective beta-adrenoceptor antagonists include propranolol, nadolol,
oxprenolol, alprenolol, penbutolol, sotalol and timolol. The beta-blockers in
each group may exert two types of effects namely: membrane stabilizing activity
and intrinsic sympathomimetic activity.
It has been considered that large doses of some
beta-blockers have direct ‘depressing action’ (‘quinidine-like effect’,
‘membrane action’ local anaesthetic effect), on the hear in man. A membrane
action is seen with large doses in animals (Coltart, Gibsonand Shand, 1971). It
however has no relevance to treatment of hypertension and is certainly not
responsible for the haemodynamic effects of beta-adrenoceptor antagonists since
no significant membrane stabilizing activity occurs with clinically effective
doses of beta-blockers. The quinidine-like effects of beta blockers appear to
contribute little to the treatment of cardiac arrhythmias. Effective
concentrations of propranolol in blood are below those that cause membrane
stabilization. In addition beta-blockers without this property are also
effective anti-arrhythmic agents (Black and Prichard, 1973; Shand, 1975).
The clinical significance of Intrinsic
Sympathomimetic Activity (ISA) is controversial. From a theoretical point of
view it has been argued that the beta-blockers with ISA for example oxprenolol
and pindolol, may protect against development of cardiac failure (Imhof, 1976).
Others have regarded ISA as a side effect limiting the use of the drugs (Waal –
Manning, Simpson, 1975). It has been shown, however, that in the treatment of
hypertension and angina pectoris, drugs with ISA are as effective as
beta-blockers without this property, for example atenolol and propranolol
(Harry, 1975; Prichard, 1970; Thadani et al, 1980). In healthy subjects ISA
modified the haemodynamic response to beta-blockers, in that heart rate and cardiac
output were less with atendlol and propranolol than when beta-blockers with ISA
were used (Svendsen et al, 1980). Beta-blockers with ISA do not change the
total peripheral resistance index. Beta-blockers without ISA, on the other
hand, increase the total peripheral resistance, reflecting peripheral
vaso-constriction (Svendsen et al, 1981). The receptors involved in this action
are the peripheral beta-2-adrenoceptors.
Occasionally today one talks of the various
generations of beta-blockers. The ratio of beta-1- to beta-2- blocking potency
has been calculated as well as the significance of intrinsic sympathomimetic
activity or of membrane stabilizing effect. Some of these attempts have
demonstrated, to an extent, the superiority of one or the other representative
of the whole group in the treatment of high blood pressure.
1.2 MECHANISM OF ACTION OF BETA-ADRENOCEPTOR
BLOCKERS
The beta-adrenoceptor blocking drugs appear to lower
the blood pressure as a result of a variety of mechanisms involving beta-adrenoceptor
blockade. Blood pressure falls regardless of the presence or absence of the
associated properties. There have been a number of hypothesis to explain the
hypotensive effect of beta-adrenoceptor blocking agents, including a direct
action on the Central Nervous System (CNS), adrenergic neurone blockade,
anti-renin activity, an increase of vasodilator prostaglandins, effects
secondary to reduced cardiac output and resetting of baroreceptors secondary to
reduced pressor peaks from the reduction in cardiac activity.
i. Central Nervous System
Some observation in animals suggest a possible
central mode of action. Intra-arterial injection of propranolol into either the
carotid or vertebral artery in the anaesthetized dog produces a fall in blood
pressure of more rapid onset than if administered via the femoral artery
(Offferhaus and Van Zwieten, 1974). Several beta-adrenoceptor antagonists
(propranolol, atenolol, oxprenolol, pindolol, practolol and sotalol) when
injected into the cerebral ventricle of conscious normotensive cats have been
shown to produce a transient rise followed by a fall in blood pressure (Day and
Roach, 1974).
Some beta-adrenoceptor blocking drugs when
administered systemically penetrate the CNS and concentrations rapidly achieve
a steady state. However, in cats, for example, there was no evidence of
accumulation in the cerebrospinal fluid following two weeks administration of
oxprenolol compared to acute administration (Offerhaus and Van Zwieten, 1974).
Other experiments in cats using equivalent hypotensive doses of metoprolol and
atenolol have revealed up to a nine-fold higher concentration of metoprolol
compared to lipid insoluble atenolol (Offerhaus et al, 1975).
While beta-adrenoceptor drugs can influence central
sympathetic activity it is unlikely that this is the only explanation for their
anti-hypertensive action in man. Beta-adrenoceptor blocking drugs, such as
sotalol, that apparently do not cross the CNS still have an effective
antihypertensive effect in man.
ii. Adrenergic Neurone Blocking Action
The adrenergic neurone blocking effect that has been
observed in rats and rabbits has been found not only from racemic propranolol
but also with the d (+) isomer which is devoid of antihypertensive effects in
man. The fact that propranolol and other beta-adrenoceptor antagonists reduced
blood pressure in man without producing the postural hypotension characteristic
of the adrenergic neurone blocking drugs (Prichard and Gillam, 1969) also
indicates that an adrenergic neurone inhibition is not important.
iii. Renin Blocking Activity
Beta-adrenoceptor inhibition lowers plasma renin in
normotensives and hypertensives (Buhler et al, 1972) although the
beta-adrenoceptor stimulation is not the only factor involved in rennin release
(Bravo et al, 1974).
Buhler et al (1972) subdivided their hypertensive
patients prior to treatment into high, normal and low rennin groups according
to their ambulant peripheral rennin levels and daily urinary sodium excretion.
540mg Propranolol was given daily to all the patients. After a week’s therapy
it was found that the 12 high renin patients showed the greatest falls in blood
pressure, the 14 low renin level patients failed to show a significant fall in
pressure while the 23 patients with normal renin levels had intermediate falls
of blood pressure. There was a good overall correlation between the fall in
blood pressure and plasma renin activity. Propranolol, oxprenolol and cardio
selective agents atenolol and metoprolol and cardio selective agents atenolol and
metoprolol were studied in a further series of 137 patients (Buhler et al,
(1975) and the results of the previous investigators (Buhler et al, 1972) were
confirmed.
On the other hand, there is considerable evidence
against the effects on renin being the predominant mechanism of the
antihypertensive action of beta-blockers. Several investigators have failed to
find a relationship between the fall in blood pressure and pretreatment levels
of plasma renin (Leonetti et al, 1975; Morgan et al, 1975). Morgan et al (1975)
observed similar falls in blood pressure with low, normal and high renin
patients. Additionally, relatively small doses of propranolol whichc suppress
plasma renin levels have little effect on blood pressure. It has been suggested
that renin suppression may be important in lowering blood pressure when
beta-adrenoceptor antagonists are given to patients taking vasodilators as they
do reverse the rise in renin which results from the ingestion of vasodilators
(Pettinger and Mitchell, 1976).
In conclusion, while the fall in blood pressure in
some patients with high renin levels may be due, at least in part, to the
antirenin activity of beta-blockers, overall, the present evidence cannot be
regarded as more than indicating the possibility that the antirenin activity of
beta-blockers is the main mechanism of their anti-hypertensive effect.
iv. Effect on Plasma Volume
Tarazi et al (1971) observed that propranolol
reduced plasma volume in a series of 14 hypertensive patients although this
failed to correlate with the fall in blood pressure. Blood pressure fall in
some patients without a fall in plasma volume. Julius et al (1972) noted a fall
in plasma volume after acute intravenous propranolol but as others had shown
before, blood pressure did not fall. Other investigators have found an increase
in plasma volume after the administration of beta-adrenoceptor blocking drugs.
Propranolol 30mg a day increased plasma volume after one month despite a fall
in blood pressure (Gordon, 1976). Larger doses of propranolol (40mg 3 times
daily) produced inconsistent effects with a fall in blood pressure in seven (7)
and no change or an increase in the remaining six (6) patients. (Brave et al,
1975). The evidence therefore suggests that it is unlikely that changes in
plasma volume are of major importance in the hypotensive action of
beta-adrenoceptor antagonists.
Other mechanisms which has been proposed for the
action of beta-blockers include increase of vasodilator prostaglandins, effects
secondary to reduced cardiac output and resetting of baro-receptors secondary
to reduced pressor peaks from the reduction in cardiac activity.
The beta-blockers after a hesitant start have now
become first line drugs in the treatment of Caucasian hypertensive patients and
their use is continuing to increase. How they lower the blood pressure is yet
to be ascertained. Drugs with such varied actions, as beta-blockers, may well
lower blood pressure by more than one mechanism. In some cases one of the many
effects may be of overriding importance e.g. reducing plasma renin in patients
with high plasma renin level.
1.3 OXPRENOLOL
Oxprenolol is a non selective beta-adrenoceptor
antagonist. It exhibits Intrinsic Sympathomimetic Activity (ISA) and also has a
considerable membrane stabilizing effect which in potency is about half of
lignocaine.
PHARMACOLOGICAL
PROPERTIES:
Schlesinger and Barzilay (1980) working on the
effect of oxprenolol on patients with essential hypertension found that there
was a significant reduction in heart rate and systolic and diastolic blood
pressure in both supine and erect positions after treatment for 4 weeks. Also a
significant reduction in forced expiratory volume in second (FEV1) was observed
and this was due to the inhibition of brnchodilation, (beta-2 effect) by
oxprenolol.
ABSORPTION, METABOLISM
AND EXCRETION
Oxprenolol is appreciably absorbed when taken
orally. Like propranolol, it is subject to first pass effect, hence its short
elimination half life which is about 2 hours.
Oxprenolol is considerably bound to plasma proteins.
It is virtually completely metabolized in the liver before excretion in the
urine as metabolites of less potency compared to the parent drug.
TOXICITY AND SIDE
EFFECTS
The minor side effects of exprenolol include nausea,
vomiting, dizziness, and mild diarrhea. Owing to its effect on the bronchioles,
oxprenolol may precipitate severe bronchoconstriction in predisposed patients.
Hence it is contra indicated in asthma patients.
THERAPEUTIC USES:
Oxprenolol is used in the treatment of hypertension.
Beta-blockers cause unwanted effects due to alterations in peripheral blood
flow. These have included an awareness of cold limbs, an increase in
intermittent claudication and peripheral gangrene (Rodger et al 1975; Frohlich
et al 1969; Simpson 1974; Vale and Jeffreys 1978). There is evidence that this
problem may be reduced by using oxprenolol instead of propranolol (Roberts et
al 1977). In a controlled trial designed to compare the effect of oxprenolol
and propranolol on Resting Forearm Blood Flow (RFBF) when administrated acutely
and chronically in patients with essential hypertension, it was shown that a
reduction in RFBF after acute administration and after 2 weeks’ therapy occurs
with both drugs, the reduction being greater and more prolonbged with
propranolol than with oxprenolol. It was also shown that total peripheral
resistance was not changed by oxprenolol whereas propranolol increased the
total peripheral resistance. It is likely that exprenolol is exerting a
different effect because of its ISA either by direct stimulation of the
peripheral beta-adrenergic receptors or, reflexly in consequence of it causing
a lesser reduction of the cardiac output than prepranolol (Malcolm, 1982).
Hence it could be concluded that in hypertensive patients with peripheral
vascular disease, oxprenolol is safer milligram for milligram than propranolol.
Also in bradycardia and in situations in which a decrease in cardiac output is
inappropriate or if the beta-blocking effect is required during physical and
psychic stress, a beta-blocker with ISA might be advantageous.
1.4 ATENOLOL
Atenolol is a selective beta-1-adrenoceptor
antagonist which is mainly used in the treatment of hypertension. Atenolol
lacks both Intrinsic Sympathomimetic Activity (ISA) and membrane stabilizing
activity. Its chemical structure is shown in fig. 1.
PHARMACOLOGICAL
PROPERTIES
Fuller and Vallance (1982) found that Atenolol
reduces FEV1 and blood pressure in normotensive subjects after acute
administration. Leoneti et al (1982) were able to show that blood pressure
decrease was very significant during the first day of hypertensive therapy with
atenolol and was unchanged after seven and fourteen days of chronic treatment.
The degree of blood pressure reduction was very similar in both supine and
erect positions. The bradycardiac effect was already at its maximum during the
first day of therapy with atenolol and no further changes were observed during
the study. Atenolol also reduced the pressor increament during exercise.
Atenolol could therefore, be said to have a prompt and long lasting action.
ABSORPTION, METABOLISM
AND EXCRETION
Atenolol is appreciably absorbed when administered
orally. It is about 20 – 30% bound to plasma proteins and eliminated largely
unchanged by the kidney (Rubin et al, 1982). It’s elimination half-life is
about 7 hours.
Atenolol is beta-1 selective and has a long
half-life. Among the beta-adrenoceptor antagonists these two properties are the
ones likely to have the greatest clinical relevance. Indeed long duration of
action offers the possibility of reducing the number of daily administration of
a drug and it has been shown that the compliance of hypertensive patients to
treatment is inversely proportional to the frequency of drug administration
(Finnerty et al, 1973).
TOXICITY, SIDE EFFECTS
AND PRECAUTIONS
No appreciable inhibition of bronchodilatation has
been noticed with atenolol and there is no convincing evidence that atenolol
augments hypoglycaemia. However, atenolol has to be used with caution in
asthmatics and diabetics receiving insulin or hypoglycaemic drugs.
As with all beta-blockers atenolol should be used if
there is a risk of congestive heart failure unless the patient is monitored
closely.
THERAPEUTIC USES
The relative selectivity of atenolol is the basis
for its therapeutic advantage over less selective agents (Ablad et al 1973).
Atenolol is mainly used in the treatment of hypertension and angina pectoris.
It’s selective beta-1 adrenoceptor blocking activity makes it preferable to
propranolol for use in patients with mild obstructive airways disease.
1.5 PROPRANOLOL
Propranolol was the first beta-adrenoceptor
antagonist to come into wide clinical use. It is a highly potent non-selective
beta-adrenoceptor antagonist (blocks both beta-1 and beta-2 adrenoceptors
competitively). It does not exhibit any ISA but has a quinidine – like action.
The chemical structure is shown in fig. 1.
PHARMACOLOGICAL
PROPERTIES:
a. Cardiovascular System:
The major effect of propranolol on the cardiovascular system is due to its
actions on the heart. Propranolol decreases heart rate and cardiac output,
prolongs mechanical systole and slightly decreases blood pressure in resting
subjects (Robin et al, 1967). The effects on cardiac output and heart rate are
more prominent during exercise. Peripheral resistance is increased as a result
of compensatory sympathetic reflexes, and blood flow to all tissues except the
brain is decreased (Nies et al, 1973).
Propranolol reduces sinus rate, decreases the
spontaneous rate of depolarization of ectopic pacemakers and slows conduction
in the atria and in the A.V node hence its use in the treatment of some cardiac
arrhythmias.
b. Metabolic Effects:
Propranolol inhibits glycogenolysis in the heart and the skeletal muscles. The
effects on hepatic glycogenolysis are dependent on species.
c. Other Effects:
The most important response to beta-blockade outside the cardiovascular system
is that of the bronchi and the bronchioles. Adrenergic bronchodilatation is
mediat ed by beta-2-adrenoceptors. Propranolol consistently increases airways
resistance. This effect is small and of no clinical significance in normal
individuals but it can be marked and potentially dangerous in asthmatics
(Nicholascu et al, 1972). Because bronchodilatation is a beta-2-adrenergic
response, selective beta-1-blockers, such as atenolol, are much less likely than
propranolol to induce bronchoconstriction and they have been used in asthmatics
with minimal effects on airway resistance. (Formgren, 1972).
ABSORPTION, METABOLISM
AND EXCRETION
Propranolol is almost completely aborbed following
oral administration. However much of the administered drug is metabolized by
the liver during the first passage through the portal circulation and only up
to about 30% reaches the systemic circulation. The degree of hepatic extraction
of propranolol is less as the dose is increased. Also somewhat less of the drug
is removed during the first circulation through the liver after repeated
administration than after the initial dose, which accounts for a gradual
increase in the half-life of the drug on chronic oral administration (about 4
hours) compared with the half-life of the initial oral dose (about 3 hours)
(Shand, 1975).
Propranolol is about 90 – 95% bound to plasma
proteins metabolized before excretion in the urine (Hayes and Cooper, 1971).
One of the products of hepatic metabolism is 4-hydroxypropranolol. This
metabolite is an active compound and is produced predominantly when the drug is
administered orally. Other metabolic products that have been identified in the
urine include naphthoxylactic acid, isopropylamine and propanol glycol. A
considerable fraction of propranolol is apparently glucuronide conjugates
(Shand, 1975).
Abrupt withdrawal of propranolol therapy may give
rise to a withdrawal syndrome. This may be due to the supersensitivity of
beta-adrenoceptors. Some patients may experience severe exacerbation of angina
attacks and patients being treated for hypertension may have a life-threatening
rebound of high blood pressure to levels that can exceed pretreatment levels.
Hence withdrawal of propranolol therapy should be gradual.
Propranolol causes an increase in airways resistance
which can be life-threatening in asthmatics. Asthma is therefore an absolute
contra indication to the use of propranolol.
Propranolol augments the hypoglycaemic action of
insulin by reducing the compensatory effect of sympathoadrenal activation and
masks the tachycardia that is an important sign of developing hypoglycaemia.
Therefore uncontrolled diabetes is an absolute contra indication to propranolol
therapy.
Other minor side effects that have been reported
include nausea, vomiting, diarrhea, and constipation. CNS side effects includes
vivid dreams, night mares and depression.
THERAPEUTIC USES
1.
In the treatment of
hypertension, it is usually combined with a diuretic. It is also frequently
used as an adjunct to treatment with a vasodilator in order to minimize reflex
tachycardia.
2.
It is used in the
management of both supraventricular and ventricular arrhythmia.
3.
Angina pectoris
prophylaxis.
4.
Hypertrophic
obstructive cardiomyopathies.
5.
Hyperthyroidism
(especially in thyroid crisis).
6.
As a prophylaxis in
migraine therapy.
1.6 SCOPE OF THE PROJECT
Beta-adrenoceptor antagonists are widely used in the
treatment of ischaemic heart disease and hypertension. It has been widely
reported in the literature that there are profound racial differences in the
responsiveness to both selective and non-selective beta-adrenoceptor
antagonists. (Venter and Joubert, 1984; Salako et al, 1979; Abson et al, 1981).
However, the factors underlying these differences have not been clearly
defined. Beta-blockade can be assessed from effects on:
i.
Blood pressure and heart rate;
ii.
Exercise-induced
tachycardia;
iii.
Lung volumes and
iv.
24 hour urinary
electrolyte output (The Na+/K+ ATPase regulating
potassium movement across the cell membrane is regulated by a
beta-2-adrenoceptor (Struthers and Reid, 1982).
Because there is a scarcity of published studies in
healthy blacks this study was undertaken to assess the physiological and
biochemical effects of standard doses of oxprenolol, atenolol and propranolol.
The results were later compared to published results among age and sex matched
caucasians with a view to determining any differences in responsiveness. As
drug levels were not measured, their pharmacokinetics were not compared.
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