Circulation-1975-Nies-6-15

SPECIAL ARTICLE

Clinical Pharmacology of PropranololBy ALAN S. NIES, M.D., AND DAVID G. SHAND, M.D.

ONE OF THE more significant advances incardiovascular therapeutics in the past decade

has been the introduction of 3-adrenergic blockingdrugs. This review is prompted by the expanding in-dications and more widespread use of this group ofdrugs. Although several compounds have beendeveloped, propranolol was the first to gain wideacceptance and remains the only one available forgeneral use in the United States. We shall thereforeconcentrate on the clinical pharmacology ofpropranolol and make only passing reference to someof the other drugs which, in time, will undoubtedlybecome available.

Determinants of Circulating Drug ConcentrationA fundamental principle of pharmacology is that a

drug's effect is a function of its concentration at thereceptor. However, when a given dose is administeredto patients, several factors govern the amount of drugthat eventually reaches its site of action which mayvary considerably from patient to patient. These dis-positional factors of absorption, distribution, andelimination therefore become as importanttherapeutically as does the effectiveness of the drugitself. For this reason great emphasis has recently beenplaced on measuring plasma drug concentrations, asthese are generally in equilibrium with drug at thereceptors. In the case of propranolol, it was soonrecognized that some six to ten times larger doses wererequired by mouth to match the effects of in-travenously administered drug. This occurs despitecomplete absorption across the gut' and is an un-avoidable consequence of the fact that the liver is themajor organ of elimination and removes drug from theportal blood before it can ever reach the systemic cir-culation, and thence its target organs. The removal ofdrug by the liver during its transfer from the gut toFrom the Division of Clinical Pharmacology, Departments of

Medicine and Pharmacology, Vanderbilt University MedicalSchool, Nashville, Tennessee.

Supported in part by Public Health Service Grant GM 15431.Address for reprints: Dr. Alan S. Nies, Division of Clinical Phar-

macology, Departments of Medicine and Pharmacology, VanderbiltUniversity Medical School, Nashville, Tennessee 37232.

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the systemic circulation has been termed presystemic(or "first pass") hepatic elimination. Because of thiseffect, the disposition of propranolol is criticallydependent on the route of administration. We shalltherefore consider the determinants of propranololconcentrations in the blood after intravenous ad-ministration before discussing the more complexsituation that arises following oral administration.Intravenous AdministrationThe three major biological determinants of

propranolol disposition are the activity of the drugmetabolizing enzymes in the liver, hepatic blood flow,and plasma-drug binding. The hepatic uptake processis so great that the hepatic extraction ratio for the drugis very large after intravenous administration of nor-mal therapeutic doses. An hepatic extraction in excessof 90% has been demonstrated directly in the dog2and by inference in man, as its clearance from theblood (about 1.2 L/min) approaches a value forhepatic blood flow.3 This very high hepatic extractionresults in a drug half-life in man of two to three hoursafter an i. v. dose. The apparent volume of distributionin blood is about 250 L. The relationship betweendrug clearance (Cl), apparent volume of distribution(Vd), and half-life (T/2) is given by

Cl = Vd x 0T693Because of the very high hepatic extraction ratio ofpropranolol, its clearance is sensitive to alterations inhepatic blood flow.4 Since the beta-blocking effects ofpropranolol result in reduced cardiac output,5 hepaticblood flow is lowered during administration of thisdrug and hepatic elimination is reduced.5 Thus dl-propranolol, by its pharmacologic action, affects itsown clearance by decreasing delivery of drug to theliver. Dextro-propranolol, which does not affecthepatic blood flow, is cleared more rapidly in the un-anesthetized monkey than the racemate.4 This effectmay explain the shorter half-life of d-propranolol thandl- or 1-propranolol in man.6 It has also been shownthat propranolol can decrease the elimination of otherhighly extracted compounds, like lidocaine, by reduc-ing hepatic blood flow.7 Although only investigated in

Circulation, Volume 52, July 1975

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CLINICAL PHARMACOLOGY OF PROPRANOLOL

animals so far, such hemodynamic drug interactionsare of likely clinical relevance, especially in patientsrequiring acute intensive care with cardioactive drugsgiven intravenously.8The effect of plasma-binding of propranolol on

drug elimination differs from the traditional teachingthat decreased plasma-binding shortens half-life byincreasing free drug concentration available formetabolism. With propranolol, the hepatic extractionratio greatly exceeds the free drug fraction, and thusboth bound and free forms are available formetabolism and are extracted from plasma by theliver. With such nonrestrictive elimination, total drugclearance is unaffected by binding in the circulationand half-life is proportional to the "volume of dis-tribution" which is an index of tissue stores of a drug.The volume of distribution of propranolol increases asplasma-binding decreases because more drug escapesfrom the plasma into the tissues. Plasma-binding thusacts as a drug delivery system to the liver, and lowpropranolol plasma-binding lengthens half-life, andconversely, high binding shortens half-life.9' 10

Oral AdministrationAs a result of the anatomical arrangement of its

portal circulation, the liver can remove drug from theportal venous blood during its transfer from the gut tothe systemic circulation (fig. 1). The fraction of thedose removed during presystemic hepatic eliminationis equal to the hepatic extraction ratio, E, so that thefraction that passes on into the systemic circuit isgiven by (1 - E). The greater the extraction ratio, thesmaller will be the fraction of the dose that is availableto produce systemic effects. This fraction is termed thebioavailability of the drug. Drugs with high extrac-tions, like propranolol, can therefore never be fully

bioavailable even though their alimentary absorptionis complete. As might be predicted from its very highclearance after i.v. administration, the availability ofsmall single oral doses of propranolol is very small.However, as the single oral dose is increased aboveabout 30 mg, the avid removal process becomessaturated and hepatic extraction falls, resulting in alarger fraction of an oral dose reaching the systemiccirculation and a longer half-life, of three to six hours,in normal subjects.3 Furthermore, this avid hepaticuptake remains saturated throughout the usual six-hour dosage interval, so that drug concentrations inthe blood accumulate during chronic oral ad-ministration." Finally, when steady state is reachedduring continuous oral administration, drug concen-trations are essentially proportional to dose, in con-trast to the situation following single oral doses.3However, even during chronic oral administration ofthe hepatic extraction is still relatively high (0.5-0.8)so that only 20-50% of the dose reaches the systemiccirculation.Not only is the bioavailability low but it is highly

variable among patients. Plasma levels after oral ad-ministration vary more widely than those after in-travenous administration in the same subjects. 12 In ourclinical practice 20-fold differences in plasma concen-tration have been seen at the end of the dosage inter-val in patients receiving the same oral dose (fig. 2).Again, this is a necessary consequence of the largepresystemic elimination that occurs with highly ex-tracted drugs.` Thus, compared to patients with lowhepatic extraction ratios, those with higher extractionratios not only permit less drug to reach the systemiccirculation but also clear the drug more efficiently,resulting in even lower concentrations than thedifferences in extraction ratio might suggest.

L 1 -VE R-LIVER F . . . (1 .

INTRAVENOUS ORALFigure 1

Presystemic "first pass" effect. A diagrammatic representation of intravenous and oral administration of propranolol. Theshading represents drug concentration and the arrows represent route of administration. Since the major organ of elimina-tion is the liver, the drug can be extractedfrom portal venous blood prior to reaching the systemic circulation during oraladministration.


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NIES, SHAND

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Plasma propranolol levels (ng/ml) obtained during various doses ofthe 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 ActionPerhaps one of the most important uses of

pharmacokinetic data is in devising appropriatedosage regimens on the basis of drug half-life. Therehas been some confusion concerning the relationshipof duration of action and half-life of beta-adrenergicblocking drugs. Duration of action is determined bythe dose administered (or initial plasma concentra-tion) as well as by drug half-life. Furthermore, drugeffect and plasma concentrations do not necessarilydecline in parallel. In the case of beta-blockade withpractolol14 and propranolol after intravenous ad-ministration,` the reduction in exercise heart rate is afunction of the logarithm of the plasma concentration.Thus, this effect declines as a linear function of time asthe plasma concentration declines exponentially (i.e.,first order). It is therefore to be expected that drugeffect should decline less rapidly than plasma concen-tration when exercise tachycardia is used to judgeefficacy. On the other hand, the efficacy of propranololcan be determined from the antagonism ofisoproterenol-induced tachycardia. This antagonism iscompetitive and therefore can be overcome by in-creasing isoproterenol dosage, that is, thedose/response curve for isoproterenol is shifted to theright in parallel fashion by propranolol. Such an effectcan be quantified by calculation of the dose ratio (DR)for isoproterenol (the dose needed for a givenresponse in the presence of propranolol divided bythat found under control conditions). When beta-adrenergic blockade is defined by the dose ratio toisoproterenol (DR), then log (DR-1) is a function oflog plasma propranolol concentration.'6 In this case(DR-1) theoretically falls in parallel with plasma con-

centration and both decline exponentially with timeconsistent with the data of Paterson et al.'

It should be mentioned that over the range of doseratios usually achieved clinically, a plot of dose ratioagainst log plasma concentration is in fact essentiallylinear,'5 and deviations appear only at low drug con-centrations.17 While these considerations may seemsomewhat esoteric, they do serve to show how an in-appropriate measure of drug efficacy can lead toerroneous conclusions concerning the duration ofdrug action. It may be concluded that, excluding theeffects of active metabolites, there is no evidence thatthe effects of beta-adrenergic blockade become dis-sociated from the plasma drug levels, and it isgenerally accepted that patients should be maintainedat minimally effective plasma levels at the end of adosage interval.The half-life of propranolol in normal subjects

depends on the route and duration of drug ad-ministration but is always short and rarely exceeds sixhours. Accordingly, the recommended oral dosage in-terval was set at about six hours. Although fewsystematic studies have been made, there are severalreasons to believe that longer intervals with largerdoses could be used, so that effective levels would stillbe present at the time another dose is administered,with the proviso that the higher peak levels were notassociated with toxicity. Since occurrence of toxicity isnot related to dosage, it would seem possible toadminister the drug less often to individual patients,especially when compliance is a problem. Indeed in-vestigators have recently found adequate an-tihypertensive effect with twice daily propranolol ad-ministration. 18, 19

Interest in the duration of beta blockade hasheightened recently with the suggestion by Viljoen etal.20 that the effect of propranolol may take some timeto dissipate and that coronary artery surgery is unsafefor two weeks after withdrawal. While their opinion isshared by some, others have disagreed.2' 22 Twogroups have investigated this problem in surgicalpatients. Faulkner et al.23 could not detect propranololor note any effects on atrial muscle response tonorepinephrine 48 hours after drug withdrawal. Thesefindings were extended by Coltart et al.24 who showedthat neither metabolites nor the drug were detectableas early as 12-24 hours postwithdrawal. More impor-tant perhaps are several anecdotal reports that severearrhythmia, angina, and even infarction can occurfollowing withdrawal. 25-27 The important questionmay well be whether it is advisable to discontinuepropranolol at all in such cases. Until the argument isresolved each case should be treated individually anddrug withdrawal carefully monitored in a hospital. Ifthe patient's condition worsens it may well be safer to


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operate while minimally effective doses of propran-olol are present.Effects of DiseaseAn 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 reductionin liver blood flow, decreased activity of the hepaticenzymes, and by reduced plasma drug-binding.Patients with heart failure and liver disease should beexpected to handle the drug abnormally, though it isrecognized that the drug is contraindicated in heartfailure. In patients with liver disease, propranololhalf-life is variable: it may be relatively normal orprolonged to as much as 35 hours in cirrhotic patientswith surgically-induced portocaval anastomoses andreduced plasma drug-binding.3 In addition, suchpatients will have very high oral bioavailability ofdrugs such as propranolol since the presystemichepatic elimination is bypassed by the porto-systemicshunt.

In the presence of renal disease half-life is relativelyunaffected and in some cases is even shortened.28 Theshortened half-life and higher plasma concentrationsreported in renal failure29 probably reflect a reducedvolume of distribution resulting from loss of musclemass.

Drug Concentration and EffectThe most important clinical problem is that of the

very great variation in propranolol dosage required inpatients being treated for the same condition. For ex-ample, patients with angina and hypertension mayrequire as much as 2000 mg daily, while some respondto as little as 40 mg. If we can determine that variablebioavailability accounts for the wide range of dosagerequired for clinical effect, the question of appropriatedosage could be answered by monitoring plasma con-centrations and adjusting the dose accordingly. Inorder to establish a therapeutic range of plasmapropranolol concentration we must examine theevidence showing that the effects of propranolol areindeed a function of its plasma concentration and ex-clude other explanations for dosage variation such asthe involvement of active metabolites and differencesin receptor sensitivity. Finally and most important,the mechanism of action of the drug in treating adiversity of conditions must be considered, as it is byno means established that all the drug's effects are theresult of peripheral beta-blockade.Beta-adrenergic Blockade

In attempting to relate plasma concentrations of anantagonist drug like propranolol to its effects, asuitable test stimulus is required. Both isoproterenoland exercise-induced tachycardia have been in-vestigated. 17-1, 30-38 Several groups have demonstratedCirculation, Volume 52, July 1975

that the isoproterenol dose ratio, i.e., the amount ofshift of the isoproterenol dose-response curve, is apredictable function of plasma propranolol concen-tration.16' 31 This test procedure has been standard-ized32 and is useful to determine relative potencies forcomparison of beta-adrenergic blocking drugs, butsuffers the disadvantage that there is no fixed endpoint because there is no limit to the amount of iso-proterenol that can be given. Thus, with isopro-terenol as the stimulus, the dose ratio becomes a con-tinuous variable within the limits of toxicity of the an-tagonist.

For endogenous stimuli, there should be a limit tothe degree of beta-adrenergic stimulation achievable.It was therefore important to assess the effects of betablockers on an endogenous beta-adrenergic stimulus,and exercise-induced tachycardia was investigated byColtart and Shand who compared the effects of threedoses of propranolol and a placebo.15 They demon-strated that there was a maximum attainable degree ofblockade in the sense that increasing the dose ofpropranolol produced no further reduction in heartrate at all exercise grades studied.15 As might be ex-pected from a competitive antagonist, the effects of asubmaximal dose of propranolol could be overcome byincreasing the severity of the exercise, that is, moredrug would be required to produce a given effect insubjects who exercise more strenuously. Although thiswas clearly a cause of individual variation in dose re-quirements, doubling the submaximal dose wassufficient 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 exer-cise tachycardia and the log of plasma propranololconcentration, but that the propranolol levelassociated with a given effect two hours after a singleoral dose was one half that required after intravenousadministration. 15 A ready explanation for this dis-crepancy is available from the data of Paterson et al.1who showed that an active metabolite of propranolol,4-hydroxypropranolol, can be detected in the plasmaonly after oral administration. This metabolite is notmeasured by the standard propranolol assay, but sinceit is equipotent to propranolol34 and achieves ap-proximately the same circulating concentrations as theparent drug shortly after an oral dose,' the effects ofthe metabolite will add to those of propranolol. Thusthe presence of this metabolite produced after singleoral, but not intravenous doses, of propranolol can ac-count for the twofold difference in effectivepropranolol concentration by the two routes of ad-ministration. While the presence of an activemetabolite clearly makes interpretation of plasmaconcentrations of the parent drug difficult, recentevidence suggests that this may not be a problem with

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NIES, SHAND

the clinical use of propranolol. Thus, 4-hydroxy-propranolol has a shorter half-life than propranolol' sothat by the end of a six hour dosage interval all of theeffects of a single dose of the drug can be accountedfor by the parent compound.3' In addition, duringchronic oral administration, propranolol accumulatesin the plasma, and as early as two hours after the dose,most of the resultant effect can be accounted for bypropranolol itself. If an active metabolite is present,its contribution to beta-adrenergic blockade isminor.3' This is supported by the data of Bodem etal.'6 who found levels of at least 100 ng/ml were re-quired for maximal effect after chronic oral ad-ministration, the same amount that is required afteri.v. administration in which no active metabolite canbe detected in plasma.While it is the consensus that there is a clear

relationship between plasma propranolol concentra-tion and effect in any given individual, there is someinterindividual variation in the plasma level requiredto produce a given effect. For example, George et al.33found as much as a fourfold difference in normals.Zacest and Koch-Weser'7 have described two pop-ulations of hypertensive patients, one of which re-quired 2.5 times the propranolol concentration toachieve comparable isoproterenol antagonism duringchronic oral administration, in spite of the fact thatwithin each population the correlation between drugconcentration and effect was excellent. The less sen-sitive subjects also tended to show higher plasmalevels with a given oral dose, and it was suggested thatthey might produce less 4-hydroxypropranolol. 17While this conclusion seems unlikely in view of theliterature already cited, a final judgment will only bepossible if a dependable technique of measuring thisunstable active metabolite becomes available.

Variations in receptor sensitivity might also be acause of the interindividual variation, and George etal.35 have shown that after i.v. administration in dogs,when no 4-hydroxypropranolol was present andplasma propranolol concentrations were comparable,those animals most sensitive to isoproterenol were alsomost sensitive to propranolol.

Another explanation for differences in response to agiven plasma level of propranolol is variation inplasma drug-binding. Data obtained from cardiactissue in vitro suggest that with propranolol, as withother drugs, only the unbound fraction of drug hasaccess to the receptor and is active (Faulkner, Boerthand Shand, unpublished observations). In man thebulk (> 90%) of propranolol in plasma is protein-bound and hence inactive, and yet both free andbound propranolol are measured by the plasmapropranolol assay. Small differences in plasma-binding can result in substantial variation in free drug

concentration. In normal subjects the plasma bindingof propranolol varies from 90% to 95%.9 While thismay seem a trivial individual difference, in fact thefree or active drug will vary from 5% to 10%, and thistwofold variation is a factor which might account for amodest individual variation in the effectiveness of agiven total drug concentration.

Therapeutic EffectsFinally, we should consider the evidence that all the

effects of propranolol have a common mechanism. Inthis context plasma drug concentration measurementscan supply valuable clues. Animal studies have shownthat propranolol can decrease the rate of rise of thecardiac action potential, an effect which has beendescribed as nonspecific myocardial depression or"quinidine-like" activity and this property is oftenquoted as contributing to the antiarrhythmic effect ofthe drug clinically. However, evidence is availablethat these nonspecific effects do not contribute impor-tantly to the therapeutic or adverse effects withpropranolol in man. In vitro data indicates that 10,000ng/ml are required to slow the rate of rise of the ac-tion potential of human papillary muscle.36 As plasmadrug binding in vivo would lower effective free con-centrations by a factor of 10-20, it would seem thatthe quinidine-like effect requires concentrations twoor three orders of magnitude higher than those givingbeta-blockade, and such concentrations are unlikely toever occur in patients even with the largest dosesemployed clinically.Supportive evidence is obtained from the use of the

d-isomer of propranolol which is devoid of beta-blocking properties yet which retains the nonspecific"quinidine-like" effects.36 Coltart et al.37 found thatfour patients who had responded to i.v. infusion of dl-propranolol with abolition of premature ventricularbeats failed to respond to the d-isomer even thoughhigher plasma concentrations were achieved (60-75ng/ml with dl-propranolol compared with 180-310ng/ml with d-propranolol: fig. 3). The failure ofdextro-propranolol to suppress ventricular ectopicbeats follows published experience with dextro-isomers of other beta-adrenergic blocking drugs38 andwith the antiarrhythmic efficacy of beta-adrenergicblocking drugs which do not have quinidine-likeeffects.39 The findings conflict, however, with theresults of Howitt et al.40 who reported that racemicand dextro-propranolol had approximately equivalenteffects on supraventricular and ventricular ectopicbeats and tachycardia. The reason for this discrepancyis not clear, but it may reflect differences in theetiology of the arrhythmias studied or the criteria bywhich effectiveness was assessed. Nevertheless, theover-all results support the conclusion that pro-


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Figure 3Effect of d-propranolol (circles) or dl-propranolol (triangles) onpremature ventricular contractions. Dl-propranolol was infused in-travenously until the arrhythmia was abolished (closed symbols) oruntil 20 mg was given. Plasma levels were obtained when thearrhythmia was abolished or at the end of the infusion. In fourpatients responding to dl-propranolol, d-propranolol was infused toa dose of 40 mg intravenously with no effect on the arrhythmia.Plasma levels obtained are in the upper half of the figure. Sinus rateat rest is in the lower half of the figure. The slowing of sinus rate isindicative of 3-adrenergic blockade which does not occur with d-propranolol.

pranolol is an antiarrhythmic drug of clinical im-portance by virtue of its beta-adrenergic blocking ac-tivity, and that its nonspecific effects play no morethan a minor part.A similar conclusion can be reached in other

situations for which propranolol is used. Dextro-propranolol is not effective in angina or hyperten-sion41' 42 while beta-adrenergic blockers withoutquinidine-like activity are effective.41 43- These con-siderations also support the contention that the non-specific cardiac depressant effects contribute little toprecipitation of heart failure in patients. Rather, thedrug's action in blocking reflex beta-adrenergicstimulation which compensates for incipient failure isan effect of any beta-adrenergic blocker and notrelated to nonspecific effects. It should be mentionedthat in animals the i.v. doses of dl- and d-propranololrequired to reverse acute ouabain-induced arrhyth-mias are about the same (1-3 mg/kg), and in thisCirculation, Volume 52, July 1975

model the quinidine-like effects are probably impor-tant. However the fact that the doses used are muchhigher than those effective in man46 indicates that ex-trapolation of findings in acute digitalis toxicity inanimals to those appearing during chronic administra-tion of the glycosides in man should be done only withgreat caution.

Hypertension is another condition in which con-sideration of dose is important and in whichmechanism of action is unclear. There is little doubtthat propranolol is an effective antihypertensive inpatients with essential hypertension, and offers thegreat advantage of lowering both supine and standingpressure equally. There is a great deal of controversy,however, as to the mechanism of action and the typeof patients likely to respond. Recently, Buhler etal.47' 48 suggested that patients with initially high reninactivity responded best to modest doses (average 240mg daily) and that the antihypertensive effect wasrelated to the reduction of plasma renin activity thatthe drug produces. Although plasma propranolol con-centrations were not measured, the doses used wouldlikely be associated with levels of about 100 ng/mllevels which were found by Michelakis andMcAllister49 to be associated with lowered plasmarenin activity (PRA).

Despite the enormous appeal of this specific ap-proach to the treatment of a definable subset ofhypertensives, there is some contradictory evidence.Several workers have failed to confirm specificity, inthat the hypotensive effects of the drug were notassociated with the fall in PRA.50 Further, the largeclinical experience in Europe51"53 suggests that mostpatients will respond provided large enough doses aregiven (up to 2000 mg daily). There are several ex-planations for the need of high doses in some patients.Either compliance was poor, the patients were in-advertently overtreated, or large doses were requiredto give the high plasma levels needed to producehypotension by an effect other than that on PRA.Failure to comply has been ruled out in eight patientsselected from Prichard's experience whose bloodpressure was controlled with 400-2000 mg daily asoutpatients, in that high plasma levels, from 125-2000ng/ml, were measured (Prichard and Shand, un-published observations).

Consideration of all the available data suggests thatpropranolol may have two modes of action as an an-tihypertensive one lowering PRA level and one act-ing on the central nervous system. Recently, someevidence has been accumulating in animals thatpropranolol may act on the central nervous system toproduce hypotension.54' ` Lowering of PRA requiresonly modest doses giving plasma levels in the range of50-100 ng/ml. A similar, peripheral effect potentiates

DL- PROPRANOLOL D-PROPRANOLOLF11


NIES, SHAND

the action of hydralazine by preventing the reflextachycardia and PRA elevation56 and that of diureticsby limiting the consequent rise in PRA.`7 The possibleeffect on the central nervous system may require highdoses and is presumably capable of lowering pressurein patients with low plasma renin levels. Whiledefinitive studies are still required, the hypothesis isattractive since its confirmation would resolve the ap-parent conflict in the data. In the case of the treatmentof angina pectoris, it is unclear why some patients ob-tain further relief from doses larger than necessary toproduce effective beta blockade.58 It is interesting thatangina, hypertension, and arrhythmia are not diseaseentities but rather signs and symptoms which arelikely associated with variable pathophysiology andthe elucidation of the mechanism of action of a druglike propranolol may provide clues to the underlyingdisease process and aid in the definition of subsets ofpatients with a common syndrome.While the multiple effects of the factors that have

been discussed make it difficult to define a therapeuticplasma propranolol concentration with great preci-sion, all the published data would suggest that 100ng/ml should confer a very high degree of blockade ofcardiac receptors and will be essentially maximal forsome patients. Significant beta blockade is producedby lower propranolol levels which appear to besufficient for therapeutic effects in many patients. Ifplasma levels are measured at the end of a dosage in-terval, these should represent the low end of the rangeof plasma levels and should not be affected by thepresence of 4-hydroxypropranolol, which willprobably have dissipated. Similar concentrations inthe range of 50-100 ng/ml have been associated withreduction in plasma renin activity,49 prevention ofreflex tachycardia due to hydralazine,7' 56 abolition ofsensitive ventricular arrhythmias,37 alleviation ofanginal pain,59 60 mild hypertension,17' 56 and in patientswith hypertrophic cardiomyopathy.61-62 A further factin support of this therapeutic range is that in all condi-tions save hypertension, propranolol is effective afterthe intravenous administration of modest doses (1-5mg) which actually give lower plasma concentra-tions than those recommended. Finally, of all thevariables, differences in bioavailability appear to bethe greatest and therefore probably the most impor-tant in determining variable dosage requirements.

Adverse ReactionsThe adverse reactions to propranolol are not related

to dose63' 64 but appear with small doses early in thecourse of treatment. Thereafter, dosage can usually beincreased without fear of dramatic or sudden toxicity.The life-threatening adverse reaction is one of suddenand profound hypotension resulting from heart failure

or heart block. As mentioned, such an effect resultsfrom the sudden blockade of reflex sympathetic tonewhich has maintained cardiac output in the face of afailing myocardium. It is most commonly seen follow-ing rapid i.v. administration in the intensive care ofvery sick patients. Until recently, the use ofpropranolol in acute myocardial infarction wastherefore contraindicated. However, experimentaldata in animals has suggested that beta-adrenergicblockade may reduce the size of infarction.`6Clinically, however, early results on the effects ofpropranolol on mortality in the presence of myocar-dial infarction were conflicting and this whole area isthe subject of intensive investigation. Until theproblem is resolved we feel that propranolol should beavoided in this situation.The greater safety of other beta-adrenergic block-

ing drugs has received much publicity, some, in ouropinion, unjustified. Two of the pharmacologicalproperties other than beta-blockade that have beenconsidered important are intrinsic sympathomimetic(or partial agonist) activity and quinidine-like effects.We have already discussed the fact that the clinicaleffects, both positive and negative, of quinidine-likeaction are probably unimportant. The quinidine-likeaction of these drugs may play at most a minor role inthe development of heart failure. While intrinsic ac-tivity of some drugs has been shown, since tachycardiain reserpinized animals can be produced, a positivechronotropic effect has never been shown in man. Inaddition, there is also an excellent correlation betweenreduction in rate and cardiac output, irrespective ofwhether the drug used shows this property or not.66The one exception is practolol, which is relativelycardio-selective with less influence on peripheralreceptors in the circulation and in the bronchialsmooth muscle. With practolol, there is almost noreduction in cardiac output at rest though bradycardiais obvious.66 Whether this favorable property resultsfrom intrinsic activity or cardio-selectivity is unclear.Intrinsic activity does not appear to be important tothe pharmacology of nonselective agents, and in fact,cardiac output is lowered by another cardio-selectiveagent, ICI 66082.

At the present time, it is impossible to make a judg-ment on the possible role that some of the neweragents may play. Certainly they all appear effective inthe same conditions. In terms of safety, all theevidence suggests that profound cardiovascularcollapse is due to beta-blockade, a property that isshared by all nonselective drugs, and that lack ofappearance of this serious side effect with these neweragents is due as much to the fact that i.v. administra-tion in sick patients is now avoided as to their par-ticular pharmacology. The one clearly desirable


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property is cardioselectivity which allows beta-blocking drugs to be used in asthma. Whether othersubtle differences in the properties of these agents willmake them more desirable as therapeutic agentsremains to be seen.

SummaryThis review of recent developments in the clinical

pharmacology of beta-adrenergic blocking drugs hasemphasized the individual variability in patientresponse and how a knowledge of drug disposition canprovide some explanation for this. Plasma level es-timates may be helpful in overcoming these variablesand can be of some help clinically, provided theirlimitations are clearly understood, and they are notused to replace accurate clinical assessment in the in-dividualization of patient therapy. From the practicalpoint of view, treatment should be started with smalldoses (e.g., 40-80 mg daily), which can be increasedstepwise until the desired effect is obtained or until320 mg daily are administered. If only a partialresponse has been obtained (for example, in the treat-ment of angina), it would seem reasonable to increasethe dose further. If there has been little or no effect,then a plasma concentration determination at the endof the usual dosage interval may be useful. Levels atthis time of 100 ng/ml or greater are stronglysuggestive of a therapeutic failure inasmuch as thisrepresents a very high degree of beta-adrenergicblockade and therapeutic effects are usually seen atplasma levels below this level. Several alternate drugsare available for the treatment of arrhythmias orhypertension and surgery can be considered in thecase of angina and obstructive cardiomyopathy. Inthis context it should be emphasized that in only tworare conditions (i.e., arrhythmia due to pheo-chromocytoma and obstructive cardiomyopathy) canpropranolol be considered the drug of first choice. Ifplasma levels of less than 100 ng/ml are found, thenpoor bioavailability or lack of compliance are possiblecauses of apparent therapeutic failure and may be dis-tinguished by increasing the dosage when failure toincrease plasma concentration may indicate poor com-pliance.

In the treatment of hypertension, it would seempremature not to try diuretics as a first choice of treat-ment or to confine the drug's use to those patientswith high plasma renin activity. At the present timewe would favor adding hydralazine to the regimen inpatients who had failed to respond to propranolol at aplasma concentration of 100 ng/ml. This should besufficient to overcome the reflex effects of thevasodilator and avoids the problem of poor patientcompliance when very large doses are administered.However, should the hypothesis that high plasmaCirculation, Volume 52, July 1975

renin activity be associated with increased car-diovascular morbidity and mortality67 be confirmed,then the ability of propranolol to lower plasma reninmay make it a most desirable therapy irrespective ofits hypotensive effects.

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A S Nies and D G ShandClinical pharmacology of propranolol.

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright 1975 American Heart Association, Inc. All rights reserved.

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