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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
6
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L
LIVER
INTRAVENOUS
-V
E
RF
. .
(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
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NIES, SHAND
8
600
C7
c
400
0
z
0
0
0
(I)
200
0*
n_
1
I
S
0l
0
40
20
6-HOURLY DOSE,mg
Figure 2
80
NIES, SHAND
10
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
DL- PROPRANOLOL
SUCCESS
FAI LURE
D-PROPRANOLOL
SUCCESS
FAILURE
11
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.
24
01
C,)
-Jr
0:
F-
CLL
;g
3
ir
:c
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
NIES, SHAND
12
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.
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
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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RG: The pharmacodynamics and metabolism of propranolol
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2. SHAND DG, EVANS GH, NIES AS: The almost complete hepatic
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4. NIEs AS, EVANS GH, SHAND DG: The hemodynamic effects of
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5. NIEs AS, EVANS CH, SHAND DG: Regional hemodynamic effects
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LD, NIES AS, BENDER HW, SHAND DC: Time required for
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28. THOMPSON FD, JOEKES AM, FOULKES DM: Pharmacodynamics
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15
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