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SPECIAL ARTICLE
Clinical Pharmacology of Propranolol
By ALAN S. NIES, M.D.,
AND
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ONE OF THE more significant advances in
cardiovascular therapeutics in the past decade
has been the introduction of 3-adrenergic blocking
drugs. This review is prompted by the expanding indications and more widespread use of this group of
drugs. Although several compounds have been
developed, propranolol was the first to gain wide
acceptance and remains the only one available for
general use in the United States. We shall therefore
concentrate on the clinical pharmacology of
propranolol and make only passing reference to some
of the other drugs which, in time, will undoubtedly
become available.
DAVID G. SHAND, M.D.
the systemic circulation has been termed presystemic
(or "first pass") hepatic elimination. Because of this
effect, the disposition of propranolol is critically
dependent on the route of administration. We shall
therefore consider the determinants of propranolol
concentrations in the blood after intravenous administration before discussing the more complex
situation that arises following oral administration.
Intravenous Administration
The three major biological determinants of
propranolol disposition are the activity of the drug
metabolizing enzymes in the liver, hepatic blood flow,
and plasma-drug binding. The hepatic uptake process
is so great that the hepatic extraction ratio for the drug
is very large after intravenous administration of normal therapeutic doses. An hepatic extraction in excess
of 90% has been demonstrated directly in the dog2
and by inference in man, as its clearance from the
blood (about 1.2 L/min) approaches a value for
hepatic blood flow.3 This very high hepatic extraction
results in a drug half-life in man of two to three hours
after an i. v. dose. The apparent volume of distribution
in blood is about 250 L. The relationship between
drug clearance (Cl), apparent volume of distribution
(Vd), and half-life (T½/2) is given by
Determinants of Circulating Drug Concentration
A fundamental principle of pharmacology is that a
drug's effect is a function of its concentration at the
receptor. However, when a given dose is administered
to patients, several factors govern the amount of drug
that eventually reaches its site of action which may
vary considerably from patient to patient. These dispositional factors of absorption, distribution, and
elimination therefore become as important
therapeutically as does the effectiveness of the drug
itself. For this reason great emphasis has recently been
placed on measuring plasma drug concentrations, as
these are generally in equilibrium with drug at the
receptors. In the case of propranolol, it was soon
recognized that some six to ten times larger doses were
required by mouth to match the effects of intravenously administered drug. This occurs despite
complete absorption across the gut' and is an unavoidable consequence of the fact that the liver is the
major organ of elimination and removes drug from the
portal blood before it can ever reach the systemic circulation, and thence its target organs. The removal of
drug by the liver during its transfer from the gut to
Cl = Vd x 0T693
Because of the very high hepatic extraction ratio of
propranolol, its clearance is sensitive to alterations in
hepatic blood flow.4 Since the beta-blocking effects of
propranolol result in reduced cardiac output,5 hepatic
blood flow is lowered during administration of this
drug and hepatic elimination is reduced.5 Thus dlpropranolol, by its pharmacologic action, affects its
own clearance by decreasing delivery of drug to the
liver. Dextro-propranolol, which does not affect
hepatic blood flow, is cleared more rapidly in the unanesthetized monkey than the racemate.4 This effect
may explain the shorter half-life of d-propranolol than
dl- or 1-propranolol in man.6 It has also been shown
that propranolol can decrease the elimination of other
highly extracted compounds, like lidocaine, by reducing hepatic blood flow.7 Although only investigated in
From the Division of Clinical Pharmacology, Departments of
Medicine and Pharmacology, Vanderbilt University Medical
School, Nashville, Tennessee.
Supported in part by Public Health Service Grant GM 15431.
Address for reprints: Dr. Alan S. Nies, Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt
University Medical School, Nashville, Tennessee 37232.
6
Circulation, Volume 52, July 1975
CLINICAL PHARMACOLOGY OF PROPRANOLOL
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animals so far, such hemodynamic drug interactions
are of likely clinical relevance, especially in patients
requiring acute intensive care with cardioactive drugs
given intravenously.8
The effect of plasma-binding of propranolol on
drug elimination differs from the traditional teaching
that decreased plasma-binding shortens half-life by
increasing free drug concentration available for
metabolism. With propranolol, the hepatic extraction
ratio greatly exceeds the free drug fraction, and thus
both bound and free forms are available for
metabolism and are extracted from plasma by the
liver. With such nonrestrictive elimination, total drug
clearance is unaffected by binding in the circulation
and half-life is proportional to the "volume of distribution" which is an index of tissue stores of a drug.
The volume of distribution of propranolol increases as
plasma-binding decreases because more drug escapes
from the plasma into the tissues. Plasma-binding thus
acts as a drug delivery system to the liver, and low
propranolol plasma-binding lengthens half-life, and
conversely, high binding shortens half-life.9' 10
Oral Administration
As a result of the anatomical arrangement of its
portal circulation, the liver can remove drug from the
portal venous blood during its transfer from the gut to
the systemic circulation (fig. 1). The fraction of the
dose removed during presystemic hepatic elimination
is equal to the hepatic extraction ratio, E, so that the
fraction that passes on into the systemic circuit is
given by (1 - E). The greater the extraction ratio, the
smaller will be the fraction of the dose that is available
to produce systemic effects. This fraction is termed the
bioavailability of the drug. Drugs with high extractions, like propranolol, can therefore never be fully
7
bioavailable even though their alimentary absorption
is complete. As might be predicted from its very high
clearance after i.v. administration, the availability of
small single oral doses of propranolol is very small.
However, as the single oral dose is increased above
about 30 mg, the avid removal process becomes
saturated and hepatic extraction falls, resulting in a
larger fraction of an oral dose reaching the systemic
circulation and a longer half-life, of three to six hours,
in normal subjects.3 Furthermore, this avid hepatic
uptake remains saturated throughout the usual sixhour dosage interval, so that drug concentrations in
the blood accumulate during chronic oral administration." Finally, when steady state is reached
during continuous oral administration, drug concentrations are essentially proportional to dose, in contrast to the situation following single oral doses.3
However, even during chronic oral administration of
the hepatic extraction is still relatively high (0.5-0.8)
so that only 20-50% of the dose reaches the systemic
circulation.
Not only is the bioavailability low but it is highly
variable among patients. Plasma levels after oral administration vary more widely than those after intravenous administration in the same subjects. 12 In our
clinical practice 20-fold differences in plasma concentration have been seen at the end of the dosage interval in patients receiving the same oral dose (fig. 2).
Again, this is a necessary consequence of the large
presystemic elimination that occurs with highly extracted drugs.` Thus, compared to patients with low
hepatic extraction ratios, those with higher extraction
ratios not only permit less drug to reach the systemic
circulation but also clear the drug more efficiently,
resulting in even lower concentrations than the
differences in extraction ratio might suggest.
1
L
LIVER
INTRAVENOUS
-V
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RF
.
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(1
.
ORAL
Figure 1
Presystemic "first pass" effect. A diagrammatic representation of intravenous and oral administration of propranolol. The
shading represents drug concentration and the arrows represent route of administration. Since the major organ of elimination is the liver, the drug can be extracted from portal venous blood prior to reaching the systemic circulation during oral
administration.
Circulation, Volume 52, July 1975
NIES, SHAND
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Figure 2
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Plasma propranolol levels (ng/ml) obtained during various doses of
the drug orally. Each dot represents the level of a single patient.
Note the wide range of values at a given dose.
Drug Half-life and Duration of Action
Perhaps one of the most important uses of
pharmacokinetic data is in devising appropriate
dosage regimens on the basis of drug half-life. There
has been some confusion concerning the relationship
of duration of action and half-life of beta-adrenergic
blocking drugs. Duration of action is determined by
the dose administered (or initial plasma concentration) as well as by drug half-life. Furthermore, drug
effect and plasma concentrations do not necessarily
decline in parallel. In the case of beta-blockade with
practolol14 and propranolol after intravenous administration,` the reduction in exercise heart rate is a
function of the logarithm of the plasma concentration.
Thus, this effect declines as a linear function of time as
the plasma concentration declines exponentially (i.e.,
first order). It is therefore to be expected that drug
effect should decline less rapidly than plasma concentration when exercise tachycardia is used to judge
efficacy. On the other hand, the efficacy of propranolol
can be determined from the antagonism of
isoproterenol-induced tachycardia. This antagonism is
competitive and therefore can be overcome by increasing isoproterenol dosage, that is, the
dose/response curve for isoproterenol is shifted to the
right in parallel fashion by propranolol. Such an effect
can be quantified by calculation of the dose ratio (DR)
for isoproterenol (the dose needed for a given
response in the presence of propranolol divided by
that found under control conditions). When betaadrenergic blockade is defined by the dose ratio to
isoproterenol (DR), then log (DR-1) is a function of
log plasma propranolol concentration.'6 In this case
(DR-1) theoretically falls in parallel with plasma con-
centration and both decline exponentially with time
consistent with the data of Paterson et al.'
It should be mentioned that over the range of dose
ratios usually achieved clinically, a plot of dose ratio
against log plasma concentration is in fact essentially
linear,'5 and deviations appear only at low drug concentrations.17 While these considerations may seem
somewhat esoteric, they do serve to show how an inappropriate measure of drug efficacy can lead to
erroneous conclusions concerning the duration of
drug action. It may be concluded that, excluding the
effects of active metabolites, there is no evidence that
the effects of beta-adrenergic blockade become dissociated from the plasma drug levels, and it is
generally accepted that patients should be maintained
at minimally effective plasma levels at the end of a
dosage interval.
The half-life of propranolol in normal subjects
depends on the route and duration of drug administration but is always short and rarely exceeds six
hours. Accordingly, the recommended oral dosage interval was set at about six hours. Although few
systematic studies have been made, there are several
reasons to believe that longer intervals with larger
doses could be used, so that effective levels would still
be present at the time another dose is administered,
with the proviso that the higher peak levels were not
associated with toxicity. Since occurrence of toxicity is
not related to dosage, it would seem possible to
administer the drug less often to individual patients,
especially when compliance is a problem. Indeed investigators have recently found adequate antihypertensive effect with twice daily propranolol administration. 18, 19
Interest in the duration of beta blockade has
heightened recently with the suggestion by Viljoen et
al.20 that the effect of propranolol may take some time
to dissipate and that coronary artery surgery is unsafe
for two weeks after withdrawal. While their opinion is
shared by some, others have disagreed.2' 22 Two
groups have investigated this problem in surgical
patients. Faulkner et al.23 could not detect propranolol
or note any effects on atrial muscle response to
norepinephrine 48 hours after drug withdrawal. These
findings were extended by Coltart et al.24 who showed
that neither metabolites nor the drug were detectable
as early as 12-24 hours postwithdrawal. More important perhaps are several anecdotal reports that severe
arrhythmia, angina, and even infarction can occur
following withdrawal. 25-27 The important question
may well be whether it is advisable to discontinue
propranolol at all in such cases. Until the argument is
resolved each case should be treated individually and
drug withdrawal carefully monitored in a hospital. If
the patient's condition worsens it may well be safer to
Circulation, Volume 52, July 1975
CLINICAL PHARMACOLOGY OF PROPRANOLOL
operate while minimally effective doses of propranolol are present.
Effects of Disease
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An important consideration in drug elimination is
the presence of disease. In the case of propranolol,
drug half-life is known to be prolonged by a reduction
in liver blood flow, decreased activity of the hepatic
enzymes, and by reduced plasma drug-binding.
Patients with heart failure and liver disease should be
expected to handle the drug abnormally, though it is
recognized that the drug is contraindicated in heart
failure. In patients with liver disease, propranolol
half-life is variable: it may be relatively normal or
prolonged to as much as 35 hours in cirrhotic patients
with surgically-induced portocaval anastomoses and
reduced plasma drug-binding.3 In addition, such
patients will have very high oral bioavailability of
drugs such as propranolol since the presystemic
hepatic elimination is bypassed by the porto-systemic
shunt.
In the presence of renal disease half-life is relatively
unaffected and in some cases is even shortened.28 The
shortened half-life and higher plasma concentrations
reported in renal failure29 probably reflect a reduced
volume of distribution resulting from loss of muscle
mass.
Drug Concentration and Effect
The most important clinical problem is that of the
very great variation in propranolol dosage required in
patients being treated for the same condition. For example, patients with angina and hypertension may
require as much as 2000 mg daily, while some respond
to as little as 40 mg. If we can determine that variable
bioavailability accounts for the wide range of dosage
required for clinical effect, the question of appropriate
dosage could be answered by monitoring plasma concentrations and adjusting the dose accordingly. In
order to establish a therapeutic range of plasma
propranolol concentration we must examine the
evidence showing that the effects of propranolol are
indeed a function of its plasma concentration and exclude other explanations for dosage variation such as
the involvement of active metabolites and differences
in receptor sensitivity. Finally and most important,
the mechanism of action of the drug in treating a
diversity of conditions must be considered, as it is by
no means established that all the drug's effects are the
result of peripheral beta-blockade.
Beta-adrenergic Blockade
In attempting to relate plasma concentrations of an
antagonist drug like propranolol to its effects, a
suitable test stimulus is required. Both isoproterenol
and exercise-induced tachycardia have been investigated. 17-1, 30-38 Several groups have demonstrated
Circulation, Volume 52, July 1975
9
that the isoproterenol dose ratio, i.e., the amount of
shift of the isoproterenol dose-response curve, is a
predictable function of plasma propranolol concentration.16' 31 This test procedure has been standardized32 and is useful to determine relative potencies for
comparison of beta-adrenergic blocking drugs, but
suffers the disadvantage that there is no fixed end
point because there is no limit to the amount of isoproterenol that can be given. Thus, with isoproterenol as the stimulus, the dose ratio becomes a continuous variable within the limits of toxicity of the antagonist.
For endogenous stimuli, there should be a limit to
the degree of beta-adrenergic stimulation achievable.
It was therefore important to assess the effects of beta
blockers on an endogenous beta-adrenergic stimulus,
and exercise-induced tachycardia was investigated by
Coltart and Shand who compared the effects of three
doses of propranolol and a placebo.15 They demonstrated that there was a maximum attainable degree of
blockade in the sense that increasing the dose of
propranolol produced no further reduction in heart
rate at all exercise grades studied.15 As might be expected from a competitive antagonist, the effects of a
submaximal dose of propranolol could be overcome by
increasing the severity of the exercise, that is, more
drug would be required to produce a given effect in
subjects who exercise more strenuously. Although this
was clearly a cause of individual variation in dose requirements, doubling the submaximal dose was
sufficient to give a maximal effect in each case.
The study by Coltart and Shand showed that there
was a straight line relationship between block of exercise tachycardia and the log of plasma propranolol
concentration, but that the propranolol level
associated with a given effect two hours after a single
oral dose was one half that required after intravenous
administration. 15 A ready explanation for this discrepancy is available from the data of Paterson et al.1
who showed that an active metabolite of propranolol,
4-hydroxypropranolol, can be detected in the plasma
only after oral administration. This metabolite is not
measured by the standard propranolol assay, but since
it is equipotent to propranolol34 and achieves approximately the same circulating concentrations as the
parent drug shortly after an oral dose,' the effects of
the metabolite will add to those of propranolol. Thus
the presence of this metabolite produced after single
oral, but not intravenous doses, of propranolol can account for the twofold difference in effective
propranolol concentration by the two routes of administration. While the presence of an active
metabolite clearly makes interpretation of plasma
concentrations of the parent drug difficult, recent
evidence suggests that this may not be a problem with
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the clinical use of propranolol. Thus, 4-hydroxypropranolol has a shorter half-life than propranolol' so
that by the end of a six hour dosage interval all of the
effects of a single dose of the drug can be accounted
for by the parent compound.3' In addition, during
chronic oral administration, propranolol accumulates
in the plasma, and as early as two hours after the dose,
most of the resultant effect can be accounted for by
propranolol itself. If an active metabolite is present,
its contribution to beta-adrenergic blockade is
minor.3' This is supported by the data of Bodem et
al.'6 who found levels of at least 100 ng/ml were required for maximal effect after chronic oral administration, the same amount that is required after
i.v. administration in which no active metabolite can
be detected in plasma.
While it is the consensus that there is a clear
relationship between plasma propranolol concentration and effect in any given individual, there is some
interindividual variation in the plasma level required
to produce a given effect. For example, George et al.33
found as much as a fourfold difference in normals.
Zacest and Koch-Weser'7 have described two populations of hypertensive patients, one of which required 2.5 times the propranolol concentration to
achieve comparable isoproterenol antagonism during
chronic oral administration, in spite of the fact that
within each population the correlation between drug
concentration and effect was excellent. The less sensitive subjects also tended to show higher plasma
levels with a given oral dose, and it was suggested that
they might produce less 4-hydroxypropranolol. 17
While this conclusion seems unlikely in view of the
literature already cited, a final judgment will only be
possible if a dependable technique of measuring this
unstable active metabolite becomes available.
Variations in receptor sensitivity might also be a
cause of the interindividual variation, and George et
al.35 have shown that after i.v. administration in dogs,
when no 4-hydroxypropranolol was present and
plasma propranolol concentrations were comparable,
those animals most sensitive to isoproterenol were also
most sensitive to propranolol.
Another explanation for differences in response to a
given plasma level of propranolol is variation in
plasma drug-binding. Data obtained from cardiac
tissue in vitro suggest that with propranolol, as with
other drugs, only the unbound fraction of drug has
access to the receptor and is active (Faulkner, Boerth
and Shand, unpublished observations). In man the
bulk (> 90%) of propranolol in plasma is proteinbound and hence inactive, and yet both free and
bound propranolol are measured by the plasma
propranolol assay. Small differences in plasmabinding can result in substantial variation in free drug
concentration. In normal subjects the plasma binding
of propranolol varies from 90% to 95%.9 While this
may seem a trivial individual difference, in fact the
free or active drug will vary from 5% to 10%, and this
twofold variation is a factor which might account for a
modest individual variation in the effectiveness of a
given total drug concentration.
Therapeutic Effects
Finally, we should consider the evidence that all the
effects of propranolol have a common mechanism. In
this context plasma drug concentration measurements
can supply valuable clues. Animal studies have shown
that propranolol can decrease the rate of rise of the
cardiac action potential, an effect which has been
described as nonspecific myocardial depression or
"quinidine-like" activity and this property is often
quoted as contributing to the antiarrhythmic effect of
the drug clinically. However, evidence is available
that these nonspecific effects do not contribute importantly to the therapeutic or adverse effects with
propranolol in man. In vitro data indicates that 10,000
ng/ml are required to slow the rate of rise of the action potential of human papillary muscle.36 As plasma
drug binding in vivo would lower effective free concentrations by a factor of 10-20, it would seem that
the quinidine-like effect requires concentrations two
or three orders of magnitude higher than those giving
beta-blockade, and such concentrations are unlikely to
ever occur in patients even with the largest doses
employed clinically.
Supportive evidence is obtained from the use of the
d-isomer of propranolol which is devoid of betablocking properties yet which retains the nonspecific
"quinidine-like" effects.36 Coltart et al.37 found that
four patients who had responded to i.v. infusion of dlpropranolol with abolition of premature ventricular
beats failed to respond to the d-isomer even though
higher plasma concentrations were achieved (60-75
ng/ml with dl-propranolol compared with 180-310
ng/ml with d-propranolol: fig. 3). The failure of
dextro-propranolol to suppress ventricular ectopic
beats follows published experience with dextroisomers of other beta-adrenergic blocking drugs38 and
with the antiarrhythmic efficacy of beta-adrenergic
blocking drugs which do not have quinidine-like
effects.39 The findings conflict, however, with the
results of Howitt et al.40 who reported that racemic
and dextro-propranolol had approximately equivalent
effects on supraventricular and ventricular ectopic
beats and tachycardia. The reason for this discrepancy
is not clear, but it may reflect differences in the
etiology of the arrhythmias studied or the criteria by
which effectiveness was assessed. Nevertheless, the
over-all results support the conclusion that proCirculation, Volume 52, July 1975
CLINICAL PHARMACOLOGY OF PROPRANOLOL
F
DL- PROPRANOLOL
SUCCESS
FAI LURE
D-PROPRANOLOL
SUCCESS
FAILURE
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model the quinidine-like effects are probably important. However the fact that the doses used are much
higher than those effective in man46 indicates that extrapolation of findings in acute digitalis toxicity in
animals to those appearing during chronic administration of the glycosides in man should be done only with
great caution.
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Figure 3
Effect of d-propranolol (circles) or dl-propranolol (triangles) on
ventricular contractions. Dl-propranolol was infused intravenously until the arrhythmia was abolished (closed symbols) or
until 20 mg was given. Plasma levels were obtained when the
arrhythmia was abolished or at the end of the infusion. In four
patients responding to dl-propranolol, d-propranolol was infused to
a dose of 40 mg intravenously with no effect on the arrhythmia.
Plasma levels obtained are in the upper half of the figure. Sinus rate
at rest is in the lower half of the figure. The slowing of sinus rate is
indicative of 3-adrenergic blockade which does not occur with dpropranolol.
premature
pranolol is an antiarrhythmic drug of clinical importance by virtue of its beta-adrenergic blocking activity, and that its nonspecific effects play no more
than a minor part.
A similar conclusion can be reached in other
situations for which propranolol is used. Dextropropranolol is not effective in angina or hypertension41' 42 while beta-adrenergic blockers without
quinidine-like activity are effective.41 43- These considerations also support the contention that the nonspecific cardiac depressant effects contribute little to
precipitation of heart failure in patients. Rather, the
drug's action in blocking reflex beta-adrenergic
stimulation which compensates for incipient failure is
an effect of any beta-adrenergic blocker and not
related to nonspecific effects. It should be mentioned
that in animals the i.v. doses of dl- and d-propranolol
required to reverse acute ouabain-induced arrhythmias are about the same (1-3 mg/kg), and in this
Circulation, Volume 52, July
1975
Hypertension is another condition in which consideration of dose is important and in which
mechanism of action is unclear. There is little doubt
that propranolol is an effective antihypertensive in
patients with essential hypertension, and offers the
great advantage of lowering both supine and standing
pressure equally. There is a great deal of controversy,
however, as to the mechanism of action and the type
of patients likely to respond. Recently, Buhler et
al.47' 48 suggested that patients with initially high renin
activity responded best to modest doses (average 240
mg daily) and that the antihypertensive effect was
related to the reduction of plasma renin activity that
the drug produces. Although plasma propranolol concentrations were not measured, the doses used would
likely be associated with levels of about 100 ng/ml
levels which were found by Michelakis and
McAllister49 to be associated with lowered plasma
renin activity (PRA).
Despite the enormous appeal of this specific approach to the treatment of a definable subset of
hypertensives, there is some contradictory evidence.
Several workers have failed to confirm specificity, in
that the hypotensive effects of the drug were not
associated with the fall in PRA.50 Further, the large
clinical experience in Europe51"53 suggests that most
patients will respond provided large enough doses are
given (up to 2000 mg daily). There are several explanations for the need of high doses in some patients.
Either compliance was poor, the patients were inadvertently overtreated, or large doses were required
to give the high plasma levels needed to produce
hypotension by an effect other than that on PRA.
Failure to comply has been ruled out in eight patients
selected from Prichard's experience whose blood
pressure was controlled with 400-2000 mg daily as
outpatients, in that high plasma levels, from 125-2000
ng/ml, were measured (Prichard and Shand, unpublished observations).
Consideration of all the available data suggests that
propranolol may have two modes of action as an antihypertensive one lowering PRA level and one acting on the central nervous system. Recently, some
evidence has been accumulating in animals that
propranolol may act on the central nervous system to
produce hypotension.54' ` Lowering of PRA requires
only modest doses giving plasma levels in the range of
50-100 ng/ml. A similar, peripheral effect potentiates
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the action of hydralazine by preventing the reflex
tachycardia and PRA elevation56 and that of diuretics
by limiting the consequent rise in PRA.`7 The possible
effect on the central nervous system may require high
doses and is presumably capable of lowering pressure
in patients with low plasma renin levels. While
definitive studies are still required, the hypothesis is
attractive since its confirmation would resolve the apparent conflict in the data. In the case of the treatment
of angina pectoris, it is unclear why some patients obtain further relief from doses larger than necessary to
produce effective beta blockade.58 It is interesting that
angina, hypertension, and arrhythmia are not disease
entities but rather signs and symptoms which are
likely associated with variable pathophysiology and
the elucidation of the mechanism of action of a drug
like propranolol may provide clues to the underlying
disease process and aid in the definition of subsets of
patients with a common syndrome.
While the multiple effects of the factors that have
been discussed make it difficult to define a therapeutic
plasma propranolol concentration with great precision, all the published data would suggest that 100
ng/ml should confer a very high degree of blockade of
cardiac receptors and will be essentially maximal for
some patients. Significant beta blockade is produced
by lower propranolol levels which appear to be
sufficient for therapeutic effects in many patients. If
plasma levels are measured at the end of a dosage interval, these should represent the low end of the range
of plasma levels and should not be affected by the
presence of 4-hydroxypropranolol, which will
probably have dissipated. Similar concentrations in
the range of 50-100 ng/ml have been associated with
reduction in plasma renin activity,49 prevention of
reflex tachycardia due to hydralazine,7' 56 abolition of
sensitive ventricular arrhythmias,37 alleviation of
anginal pain,59 60 mild hypertension,17' 56 and in patients
with hypertrophic cardiomyopathy.61-62 A further fact
in support of this therapeutic range is that in all conditions save hypertension, propranolol is effective after
the intravenous administration of modest doses (1-5
mg) which actually give lower plasma concentrations than those recommended. Finally, of all the
variables, differences in bioavailability appear to be
the greatest and therefore probably the most important in determining variable dosage requirements.
Adverse Reactions
The adverse reactions to propranolol are not related
to dose63' 64 but appear with small doses early in the
course of treatment. Thereafter, dosage can usually be
increased without fear of dramatic or sudden toxicity.
The life-threatening adverse reaction is one of sudden
and profound hypotension resulting from heart failure
or heart block. As mentioned, such an effect results
from the sudden blockade of reflex sympathetic tone
which has maintained cardiac output in the face of a
failing myocardium. It is most commonly seen following rapid i.v. administration in the intensive care of
very sick patients. Until recently, the use of
propranolol in acute myocardial infarction was
therefore contraindicated. However, experimental
data in animals has suggested that beta-adrenergic
blockade may reduce the size of infarction.`6
Clinically, however, early results on the effects of
propranolol on mortality in the presence of myocardial infarction were conflicting and this whole area is
the subject of intensive investigation. Until the
problem is resolved we feel that propranolol should be
avoided in this situation.
The greater safety of other beta-adrenergic blocking drugs has received much publicity, some, in our
opinion, unjustified. Two of the pharmacological
properties other than beta-blockade that have been
considered important are intrinsic sympathomimetic
(or partial agonist) activity and quinidine-like effects.
We have already discussed the fact that the clinical
effects, both positive and negative, of quinidine-like
action are probably unimportant. The quinidine-like
action of these drugs may play at most a minor role in
the development of heart failure. While intrinsic activity of some drugs has been shown, since tachycardia
in reserpinized animals can be produced, a positive
chronotropic effect has never been shown in man. In
addition, there is also an excellent correlation between
reduction in rate and cardiac output, irrespective of
whether the drug used shows this property or not.66
The one exception is practolol, which is relatively
cardio-selective with less influence on peripheral
receptors in the circulation and in the bronchial
smooth muscle. With practolol, there is almost no
reduction in cardiac output at rest though bradycardia
is obvious.66 Whether this favorable property results
from intrinsic activity or cardio-selectivity is unclear.
Intrinsic activity does not appear to be important to
the pharmacology of nonselective agents, and in fact,
cardiac output is lowered by another cardio-selective
agent, ICI 66082.
At the present time, it is impossible to make a judgment on the possible role that some of the newer
agents may play. Certainly they all appear effective in
the same conditions. In terms of safety, all the
evidence suggests that profound cardiovascular
collapse is due to beta-blockade, a property that is
shared by all nonselective drugs, and that lack of
appearance of this serious side effect with these newer
agents is due as much to the fact that i.v. administration in sick patients is now avoided as to their particular pharmacology. The one clearly desirable
Circulation, Volume 52, July 1975
CLINICAL PHARMACOLOGY OF PROPRANOLOL
property is cardioselectivity which allows betablocking drugs to be used in asthma. Whether other
subtle differences in the properties of these agents will
make them more desirable as therapeutic agents
remains to be seen.
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Summary
This review of recent developments in the clinical
pharmacology of beta-adrenergic blocking drugs has
emphasized the individual variability in patient
response and how a knowledge of drug disposition can
provide some explanation for this. Plasma level estimates may be helpful in overcoming these variables
and can be of some help clinically, provided their
limitations are clearly understood, and they are not
used to replace accurate clinical assessment in the individualization of patient therapy. From the practical
point of view, treatment should be started with small
doses (e.g., 40-80 mg daily), which can be increased
stepwise until the desired effect is obtained or until
320 mg daily are administered. If only a partial
response has been obtained (for example, in the treatment of angina), it would seem reasonable to increase
the dose further. If there has been little or no effect,
then a plasma concentration determination at the end
of the usual dosage interval may be useful. Levels at
this time of 100 ng/ml or greater are strongly
suggestive of a therapeutic failure inasmuch as this
represents a very high degree of beta-adrenergic
blockade and therapeutic effects are usually seen at
plasma levels below this level. Several alternate drugs
are available for the treatment of arrhythmias or
hypertension and surgery can be considered in the
case of angina and obstructive cardiomyopathy. In
this context it should be emphasized that in only two
rare conditions (i.e., arrhythmia due to pheochromocytoma and obstructive cardiomyopathy) can
propranolol be considered the drug of first choice. If
plasma levels of less than 100 ng/ml are found, then
poor bioavailability or lack of compliance are possible
causes of apparent therapeutic failure and may be distinguished by increasing the dosage when failure to
increase plasma concentration may indicate poor compliance.
In the treatment of hypertension, it would seem
premature not to try diuretics as a first choice of treatment or to confine the drug's use to those patients
with high plasma renin activity. At the present time
we would favor adding hydralazine to the regimen in
patients who had failed to respond to propranolol at a
plasma concentration of 100 ng/ml. This should be
sufficient to overcome the reflex effects of the
vasodilator and avoids the problem of poor patient
compliance when very large doses are administered.
However, should the hypothesis that high plasma
Circulation, Volume 52, July 1975
13
renin activity be associated with increased cardiovascular morbidity and mortality67 be confirmed,
then the ability of propranolol to lower plasma renin
may make it a most desirable therapy irrespective of
its hypotensive effects.
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A S Nies and D G Shand
Circulation. 1975;52:6-15
doi: 10.1161/01.CIR.52.1.6
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