med. clinical experiences with propranololpmj.bmj.com/content/postgradmedj/41/479/526.full.pdf ·...

POSTGRAD. MED. J., (1965), 41, 526

CLINICAL EXPERIENCES WITH PROPRANOLOLE. M. M. BESTERMAN, M.A., M.D., M.R.C.P.

Cardiologist

D. H. FRIEDLANDER, M.B., M.R.C.P., M.R.C.P.ED.Registrar

Department of Cardiology, St. Mary's Hospital, London, W.2.

ADRENERGIC beta-receptors are responsible forthe cardiac effects of the sympathetic nervoussystem (Ahlquist, 1948). Pronethalol (Black andStephenson, 1962) first proved to be an effectivebeta-receptor blocking agent with little sympa-thomimetic activity. Limited clinical trialssuggested that pronethalol was of value inangina (Dornhorst and Robinson, 1962; Alleyneand colleagues, 1963; Barnett and Brandstater,1964), in arrhythmias including those attributedto digitalis (Stock and Dale, 1963) and thoseoccurring during anaesthesia (Payne and Senfield1964; Johnstone, 1964). The drug was alsoused in phaeochromocytoma (Dornhorst andLaurence, 1963), in hypertrophic obstructivecardiomyopathy (Harrison, Ross, Chidsey andBraunwald, 1963; Cohen, Effat, Goodwin,Oakley and Steiner, 1964), in hypertension(Prichard, 1964), in Parkinsonian tremor(Herring, 1964), and in metaraminol-treatedhypotension (Luria, Miller and Kaplan, 1964).However, the clinical use of pronethalol hasbeen limited by its side-effects in man and byits toxic properties in mice (Paget, 1963). Afurther analogue, propranolol (I.C.I. 45520;Inderal) (Black, Crowther, Shanks, Smith andDorhorst, 1964) did not appear to have theseundesirable properties. We are reporting ourexperiences with the clinical use of propranololwith particular reference to its use in arrhyth-mias, in angina pectoris and during anesthesia,and to its effect on the blood lipid picture andits toxicity.Material and Methods

Fifty-six patients were treated with propranololfor a variety of conditions. In thirty-eight patientsthe drug was used for its anti-arrhythmic properties,in sixteen it was given to patients suffering fromangina; it was also used in two patients with otherconditions. Of the fifty-six patients, forty-sevenreceived propranolol on a long-term basis in adosage that varied from 30 mg. to 80 mg. daily in3 or 4 divided doses. Up to 220 mg. was given ona single day. The longest duration of treatment wasten months.

Patients receiving propranolol were checkedclinically at frequenlt intervals and blood was takenfor certain haematological and biochemioal investi-

gations. These were: white blood count (WBC),transaminases (SGOT, SGPT) (Reitman and Frankel,1957), lactic dehydrogenase (LDH) (Wroblewski andLaDue, 1955), blood urea, bilirubin (by the methodof Malloy and Evelyn), alkaline phosphatase(autoanalyser) (Marsh, Fingerhut and Kirsch, 1959),and thymol turbidity (by the method of MacLaggan).Eleven of the patients on long-term propranolol

were also investigated for changes in certain bloodlipid fractions. Three of these patients were receivingthe drug for prevention of arrhythmias and theremainder were suffering from angina. The bloodsamples were taken either fasting from in-patients orwere taken at noon from out-patients who had hada light breakfast and rested for half-an-hour beforevenepuncture. In any one patient, all the sampleswere either taken as an in-patient or all the samplesas an out-patient. Blood was withdrawn from anantecubital vein without proximal constriction of thearm. The lipid fractions measured were as follows:total cholesterol by the method of Zak and Zlatkis(Leffler, 1960), phospholipids by the modified Bartlettmethod (Bartlett, 1959), triglycerides (Handel 4ndZilversmit, 1957) and free fatty acids by the tech-nique of Dole (1956).

Propranolol has been used during anesthesia infifty patients by Dr. H. L. T. Thornton and Dr. L.Strunin and we are grateful to them for some detailsof their results which we report in the section on theuse of propranolol in anaesthesia.ResultsReversion of Arrhythmias to Sinus Rhythm(10 patients)

Supraventricular Tachycardia. Ten episodesin five patients have been corrected. In allexcept one the patients were referred becausethe tachycardia had proved resistant to tbeusual forms of treatment. Two patients werein congestive cardiac failure due to the arrhyth-mia which had lasted for three and ten daysrespectively. In both patients sinus rhythm wasrestored after one oral dose of propranolol,10 mg. The largest oral dose needed in anyof the patients was 40 mg. One patient whodeveloped a supraventricular tachycardiaduring anaesthetic induction for cardiac surgeryhad undergone previous cardiac surgery andthe procedure had been made extremely difficultby recurrent tachycardia. With the secondoperation however 1 mg. of propranolol givenintravenously stopped the tachycardia and this

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BESTERMAN and FRIEDLANDER: Propranololdid not recur during a seven hour operation.Propanolol alone failed to revert a secondepisode of supraventricular tachycardia in onepatient but carotid sinus pressure, that hadbeen ineffective before the drug, causedreversion to sinus rhythm one hour after anoral dose of 20 mg.

Ventricular Tachycardia. Five episodes inthree patients have been corrected using oralpropranolol 20 mg. in four instances. The fifthepisode occurred during cardiac catheterisationand reverted within one minute of giving 5 mg.of propranolol intravenously. None of thesepatients with ventricular tachycardia was incongestive failure or markedly hypotensivewhen treated.

Atrial Flutter and Atrial Fibrillation. Onepatient with untreated thyrotoxicosis and atrialflutter was digitalised. In view of the rapidventricular rate propranolol was recommended.However, when treatment was started, atrialfibrillation had developed and, after three daystherapy, sinus rhythm was restored.No deliberate attempts have been made to

use propranolol for the restoration of sinusrhythm in atrial fibrillation and there is noevidence that propranolol is of any value inthis respect.

Ventricular Fibrillation. One case-history isrecorded.

A woman of 60 was being treated with sustainedaction isoprenaline for complete heart block andoccasional Adams-Stokes attacks. After threemonths on this drug she had a further syncopalepisode and was then given an extra tablet ofsustained action isoprenaline. After one hour thepatient started to have frequent syncopal attacksand was admitted to hospital where an electro-cardiogram demonstrated recurrent paroxysms ofventricular fibrillation. Over the succeeding twohours 60 mg. of propranolol were given, the first10 mg. intravenously. During this time the Adams-Stokes attacks diminished in frequency and finallyceased.

Prevention of Recurrent Arrhythmias(20 patients)Paroxysmal Supraventricular Tachycardia.

Five patients were treated with propranolol inan attempt to prevent frequently recurringepisodes of supraventricular tachycardia. Theinitial dose used was 10 mg. four times daily.Two of these patients are of special interestand are reported in some detail.A man of 23 presented with a history of recurrent

supraventricular tachycardia since infancy. HisEGG demonstrated an intermittent Wolff-Parkinson-White pattern when in sinus rhythm. He had signsof a congenital ventricular septal defect. When firstseen an attack of tachycardia had been present

for ten days and he was in gross congestive heartfailure. The arrhythmia was corrected with asingle oral dose of 10 mg. propranolol. In thepreceding three months he had not been free fromparoxysms for more than five days but on 40 mg.of propranolol daily he remained in sinus rhythmuntil the twelfth day of treatment when tachycardiarecurred. On the fifteenth day he was re-admittedand was given two slow intravanous injections of5 mg. of propranolol. After the second injectionhe reverted to sinus rhythm but thereafter oralpropranolol up to 220 mg. daily did not appearto have any affect on preventing or revertingparoxysms of tachycardia.A man of 60 presented with a twenty year history

of paroxysmal supraventricular tachycardia. Inthe months before treatment he was having one totwo attacks daily. The first observed episode wascorrected by 40 mg. of oral propranolol. Thereafterhe received 40 mg. of the drug daily and remainedfree of attacks for eighteen days. Between the 18thand 24th day of treatment the episodes recurredwith increasing frequency, and after the 24th dayin spite of increasing the dose of propranolol to100 mg. daily, the drug did not appear to haveany effect on the incidence or duration of theparoxysms.

In the three remaining patients, who hadless frequent episodes of tachycardia, pro-pranolol likewise failed as a long-term prophy-lactic agent.Paroxysmal Atrial Fibrillation. Two patients

were treated. In one, 30 mg. of propranololdaily prevented episodes of atrial fibrillation forone week, but thereafter up to 80 mg. dailyfailed to influence the incidence of the episodes.In the second patient, observed during threemonths of propranolol therapy, episodes offibrillation appeared to become less frequentbut the slower ventricular rate during theparoxysms provided relief and made recognitionof attacks less accurate.

Frequent Ectopic Beats. Propranolol wasused in three patients who had a history ofventricular ectopic beats for several years; onesuffered from chronic rheumatic and the otherfrom ischaemic heart disease. As both wereout-patients they were only seen at monthlyintervals and there was no reduction in theincidence of the ectopic beats. The thirdpatient developed frequent ectopic beats aftercholecystectomy; she had previously sufferedfrom this arrhythmia intermittently for manyyears. The post-operative ectopic beats wereabolished during the one week period of treat-ment and observation.

Prevention of Relapse after Reversion ofAtrial Fibrillation by Direct Current Shock.Ten patients were given propranolol in anattempt to prevent relapse into atrial fibrillationafter direct current (DC) shock had been used

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POSTGRADUATE MEDICAL JOURNAL

TABLE 1PROPRANOLOL GIVEN IN AN ATTEMPT TO MAINTAIN

SINUS RHYTHM AFTER REVERSION OF ATRIAL FIBRILLATION BY D.C. SHOCKAge Diagnosis Duration A. Fib. Operation C.T.R. Present state52 M.S. 6 months Yes 54% S.R.-5 months49 M.S. 6 months Yes 50% Relapse-4 hours49 M.S. 13 months Yes 52% Relapse-3 weeks40 M.S. Parox 3 years Yes 53 % Relapse-2 months

Perm 5 weeks38 Mild M.S. Parox 6 months No 54% S.R.-2 months

Perm 5 weeks47 M.S., A.I. 5 weeks No 61% Relapse-10 weeks55 M.I., M.S. 2 years Yes (1962) 63% Off Propranolol

1st day-long PR56 "Lone" 5 months No 50% Off Propranolol

A.F. 2nd day-asthma53 M.S. 1 year Yes 50% Off Propranolol

1st day-long PR49 M.S. 1 year Yes 49% Relapse--4 weeksM.S. Mitral Stenosis. MI. Mitral Incompetence. A.I. Aortic Incompetence.C.T.R. Cardio-thoracic Ratio. A.F. Atrial Fibrillation.

to revert atrial fibrillation to sinus rhythm(Lown, Amarasingham and Neuman, 1962).Patients were given 40 mg. per day in fourdivided doses starting the day before reversionand continued for three months. The resultsare shown in Table 1. The drug was dis-continued in three cases, one because of anasthmatic wheeze, and two because of partialheart block. Of the other seven only two werein sinus rhythm at the end of a three monthperiod.Control of Heart Rate (6 patients)

Atrial Fibrillation. Propranolol was used intwo patients with atrial fibrillation and a rapidventricular rate despite adequate digitalization.In both cases the rate was reduced, in onefrom 140 to 110 and in the other from 120 to95 per minute.

Sinus Rhythm. Of 22 patients in sinusrhythm, the average heart rate before pro-pranolol was 92 and on treatment was 70beats per minute.Four patients with effort syndrome and sinus

tachycardia were treated. These patients allcomplained of palpitation and, in spite ofsedation, casual pulse rates recorded in theout-patient clinic averaged 130, 130, 110 and100 respectively. On treatment with propranololthe pulse rate slowed and averaged 85, 80, 87,and 70 respectively, and only one of the patientsstill noticed palpitation and she found thesymptom less marked. In one of these casestreatment was stopped and the heart rate thenincreased from 78 to 130. The slower rate wasrestored by further propranolol.Use in Anesthesia

Forty patients were given propranolol for

ventricular arrhythmias produced by anaestheticagents. Halothane was the anasthetic usuallyin use and ectopics were the commonestarrhythmia but occasionally short runs ofventricular tachycardia occurred. Parenteralpropranolol proved immediately effective inabolishing these arrhythmias and also thoseassociated with carbon dioxide retention and,in two cases, ectopic beats associated witha high serum potassium level. Propranolol alsoreduced the incidence of ectopic beats associatedwith intrathoracic surgery.

Propranolol was found to be useful in slowingthe heart rate in certain surgical situations.Tachycardia is produced by adrenaline-con-taining saline injected locally to define tissueplanes and this could be slowed effectively bypropranolol. One patient developed reflextachycardia during surgery in the region ofthe stellate ganglion and this was slowed bypropranolol. The tachycardia of thyrotoxicosisshowed some slowing with propranolol, and,if the tachycardia produced by atropinepremedications was too marked, propranololwas effective in producing some slowing.One patient under halothane anasthesia was

given a ganglion blocking agent to lower theblood pressure; subsequently 1 mg. of pro-pranolol was given and this produced a markedhypotension which proved difficult to correct.The dose used in all cases initially was 1 mg.

given slowly intravenously. The largest doseused was 3 mg. The drug was usually effectivewithin one minute.Use in Ischaemic Heart Disease (16 patients)

Sixteen patients with angina pectoris weretreated with 10 mg. of propranolol 3 or 4times daily, increasing to 20 mg. 4 times daily

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if there had been no beneficial effect. Noneof the sixteen showed significant objective orECG improvement. Five patients reported asubjective impression of improvements and theother eleven reported no change.We have not used propranolol in the treat-

ment of any acute coronary occlusive episode.Use in Cardiac Catheterisation

Five patients were given propranolol intra-venously to correct arrhythmias developingduring cardiac catheterisation. In four casesmultiple ventricular ectopic beats were reducedin number but not abolished. One case ofventricular tachycardia was restored to normalrhythm.Other Uses of PropranololTwo other patients have been treated with

long-term propranolol, one with hypertrophicobstructive cardiomyopathy, and one withthrombo-embolic pulmonary hypertension. Inneither case was there enough objective evidenceto show whether or not the drug was of benefit.Effect of Propranolol on Blood Lipid LevelsThe results obtained in the eleven patients

tested are summarized in Table 2. The"control" samples were taken either beforestarting propranolol or more than one weekafter discontinuing the drug. The "treatment"blood samples were taken at any time fromone day to ten months after starting the drug,and the duration of treatment at the time oftaking the first and last sample is shown ineach case.

ToxicityHcamatology and BiochemistryThe results of tests carried out on patients

taking long-term propranolol are summarizedin Table 3.Three of these results caused some concern.

The two abnormal white counts, one of 14,000/cu. mm. (neutrophils 9.000) and one of15.000/cu. mm. (neutrophils 11.200). occuredfive weeks and seven months respectively afterstarting propranolol. Neither patient showedany other obvious cause for the leucocytosis,both had previous and subseauent normal whitecounts during continued therapy. The thirdresult that caused concern was a SGPT resultof 108 units/ml. The patient was a knownasthmatic and was receiving 30 mg. daily ofprooranolol as well as digoxin for paroxysmalatrial fibrillation. After four weeks the dosewas raised to 60 mg. daily. Four weeks latershe comnlained of some increase in breathless-ness and was found to be in atrial fibrillation

witn the JVP 3 cm. +. Her body weight hadincreased 4 lbs., her chest was clear clinicallyand on X-ray, wth no increase in heart size.It was on this day that her SGPT was 108units/mi. SGOT and urea the same day werenormal and continuing the same dose ofpropranolol together with an oral diureticimproved the breathlessness. All biochemicaltests proved normal on three subsequentoccasions.The remaining abnormal results were found

in situations in which there was another morelikely cause. Four of the abnormal SGPTresults occurred in two patients in congestivecardiac failure (from supraventricular tachy-cardia and thrombo-embolic pulmonary hyper-tension) and one of the SGPT results and theabnormal SGOT occurred immediately afterDC shock for conversion of atrial fibrillationto sinus rhythm. Eight of the abnormal bloodurea levels occurred in three patients in whomsimilar urea values were found while not onpropranolol. When one patient became hypo-tensive on propranolol his blood urea rose from40 to 50 mg./100 ml. The patient withthrombo-embolic pulmonary hypertension andcongestive failure presented another of theabnormal urea results and the abnormalbilirubin (2.4 mg./100 ml.). Finally the patientwho suffered multiple Adams-Stokes episodesproduced a blood urea of 54 mg./100 ml. anda SGPT of 45 units/ml. two days after theepisodes, but these subsequently returned tonormal despite continued propranolol therapy.Asthma (7 patients)Four patients with known bronchial asthma

were given long-term propranolol for cardiacconditions. None of them suffered an acuteepisode severe enough to need treatment. Onenoticed no difference in his breathing, twonoticed their breathing was a little "tighter"but not troublesome, and the fourth developedslight wheeze with rhonchi the day followingDC shock for reversion of his atrial fibrillationand propranolol was then discontinued.Three other patients, who suffered from

chronic bronchitis as well as angina pectoris,developed acute bronchitis while takingpropranolol. During the attack of bronchitisthey presented a mild wheeze with widespreadrhonchi. The wheeze and rhonchi disappearedafter control of the bronchitis with antibioticsand while continuing propranolol.Skin Lesions (2 patients)

Treatment in two cases was discontinuedbecause of skin reactions. Both patients com-plained of an itch felt on trunk and limbs two

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BESTERMAN and FRIEDLANDER: PropranololTABLE 3

TOXICITY TESTS ON PATIENTS TAKING PROPRANOLOL

No. ofEstimations

6175726266303128

Upper limitof normal

11,000/c. mm.40 U./ml.40 U./ml.500 U./ml.40 mg. /100 ml.0.8 mg./100 ml.15 Units4 Units

No. ofTest Patients

W.B.C. 21S.G.O.T. 27S.G.P.T. 27L.D.H. 23B1. Urea 24S. Bilirubin 14S. Alk. Phosphatase 15Thymol Turbidity 14

and seven weeks after commencing treatment.The irritation gradually increased over the nextthree weeks and in one case this then dis-appeared after stopping propranolol. The othercase then developed a fine scaly rash in thefollowing two weeks and this disappeared onstopping the drug.Gastro-lntestinal Side-Effects (2 patients)

In one patient nausea and vomiting occurredon the second day of treatment with propranolol40 mg. daily. This lasted a few hours and didnot recur on continuing the drug. Anotherpatient, who had been reverted to sinus rhythmby DC shock, became nauseated with vomitingwhen she developed congestive failure associatedwith relapse into atrial fibrillation; the pro-pranolol was discontinued but the nauseacontinued until her congestive failure wascontrolled.

Hypotension (3 patients)Three patients needed adjustment of the

dose of propranolol because of hypotension.A man of 50 with angina and multifocalventricular ectopic beats was given 30 mg. ofpropranolol daily for four months. His initialblood pressure was 150/90 mm. Hg. and at theend of the four months was 140/90. The dosewas raised to 40 mg. per day and after one weekthe pressure fell to 100/68. The dose was loweredagain to 30 mg. daily and the pressure returnedto 120/90.A man of 50 with angina was started on 30 mg.daily of propranolol. His initial pressure was

130/80 and after one week of treatment was 120/80.For the next week he received 40 mg. per day andhis blood pressure dropped to 100/60 but roseagain to 120/70 on reducing the dose of propranololto 30 mg. daily.A woman of 67 was being treated for paroxysmalatrial fibrillation with propranolol 40 mg. daily.Her initial blood pressure was 130/80 and it

remained at this level for two months. In thethird month of treatment the pressure graduallybecame lower and the drug was discontinued whenthe systolic level reached 80 mm. Hg. It later becameevident that she had impairment of hepatic functionfrom metastatic carcinoma.We did not use propranolol specifically for

the treatment of hypertension. Excluding the

No. of PatientsAbnormal withResults Abnormalities

2 21 17 51 1

11 61 10 00 0

three patients reported above, sufficient casualblood pressure readings were available forcomparison before and during treatment in18 patients with doses of propranolol from30 mg. to 80 mg. daily. The average pressurebefore treatment was 157/87 mm. Hg. andwhile taking propranolol was 151/87 mm. Hg.Congestive Heart Failure (7 patients)Three patients with congestive failure due to

long paroxysms of tachycardia recovered fromtheir failure with reversion to sinus rhythm.Two other patients with some degree of con-gestive failure were treated with propranololwithout any obvious deterioration. In onepatient who had suffered from left ventricularfailure due to acute cardiac infarction, pro-pranolol was later used to revert two episodesof ventricular tachycardia, occurring three andfour weeks after the initial infarct. Followingthe second episode of ventricular tachycardiahe was given propranolol 50 mg. daily bymouth. After six days he developed furtherischaemic pain and congestive failure and diedthe following day presumably from a secondcardiac infarct. One patient developed con-gestive failure when she relapsed into atrialfibrillation ten weeks after successful DCdefibrillation.The body weights of 22 patients measured

before starting propranolol, and during treat-ment with 30 mg. to 80 mg. daily for three toten months showed that 20 of these patients'weights remained constant (less than 4 lbs.change) but two showed a marked increase.These were both patients who receivedpropranolol 40 mg. per day following successfulconversion of atrial fibrillation to sinus rhythmby DC shock. In the three months of prophy-lactic treatment their weights increased by16 lbs. and 21 lbs. respectively. Their appetiteswere increased, there were no signs of congestivefailure, and chest X-rays showed no increasein heart size or of pulmonary venous congestion.




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Anticoagulant RegulationBecause one patient who was anticoagulated

developed haematuria ten days after startingpropranolol, we have reviewed the effect ofpropranolol on anticoagulant control. Sixteenpatients were receiving anticoagulants at thetime of starting propranolol and were undersatisfactory control. The patient mentionedabove was the only one who had a markedchange in the prothrombin time or anticoagulantrequirefnent during the first three weeks oftreatment.Treatment Discontinued

Toxic side effects necessitated withdrawal ofpropranolol in six patients: two developedrashes, one hypotension, and three followingDC shock defibrillation who developed partialheart block (2 cases) or asthma (1 case).Discussion

In our experience the greatest value ofpropranolol has been its acute anti-arrhythmicaction. Oral propranolol may now prove to,be the drug of choice for reversion of paroxysmsof supraventricular tachycardia.

Only one of these patients was very ill withcongestive failure, hypotension and vomiting,due to long-standing tachycardia and requiredintravenous therapy. Two doses of 5 mg. ofpropranolol were injected slowly, twentyminutes being taken over each injection withan hour between them and there were noapparent ill-effects. However this was our onlyexperience with this type of case and othershave reported near-fatalities with intravenouspropranolol in hypotensive patients with con-gestive failure (J. Somerville, personal com-munication, 1964). Extreme caution is neededin the intravenous use of propranolol inhypotensive patients and in general we preferDC shock.The treatment of choice in cases of ventricular

tachycardia is debatable and we must awaitfurther experience with propranolol and DCshock before the relative effectiveness andsafety of these methods can be compared withthose of procainamide and quinidine. When adrug can be given by mouth, propranololappears to be safe and effective. It is our policyat present to give propranolol to these patientsand to reserve DC shock for those who failto respond to propranolol and for those patientstoo ill to take the drug orally.The reversion of atrial fibrillation and flutter

to sinus rhythm we believe is best achieved

by use of DC shock (Lown and others, 1962;Oram and Davies, 1964; McDonald, Resnekovand O'Brien, 1964).The case of Adams-Stokes episodes associated

with paroxysmal ventricular fibrillation is ofinterest. The appearance of ventricularfibrillation in this patient was attributed toexcessive sustained action isoprenaline. With themore widespread use of this drug (Dack andRobbin, 1961; Fleming and Mirams, 1963) inthe treatment of heart block, this becomes asituation in which an effective beta-receptorblocking drug has an important role.

Propranolol has proved less effective whengiven in an attempt to maintain sinus rhythmin patients with paroxysmal arrhythmias. Thetwo case histories of such patients suggesttolerance of propranolol developing betweenthe twelfth and twenty-fourth day of treatment.Similarly in one of the cases of paroxysmalatrial fibrillation, propranolol appears tobecome ineffective after one week. Stock andDale (1963) noted this lack of maintenanceof improvement when using pronethalol, andin cases treated by 'bilateral upper dorsal sym-pathectomy, a similar "escape" from treatmenthas been noted (White, Smithwick and Simeone,1952).We have therefore abandoned propranolol

as a prophylactic agent in recurrent arrhythmias.It is of interest that D. A. Chamberlain(personal communication) has reported twocases who had temporary relief only after asympathectomy and have now been treated witha beta-blocking drug for 18 months withsustained improvement and have no apparenttendency to "escape". Likewise our limitedexperience with frequent ectopic beats suggeststhat propranolol is of no value for long-termcontrol. However there is little doubt that thetemporary foci of ectopic beats can becontrolled by propranolol. Multiple ectopicbeats following acute cardiac infarction havenot been treated with propranolol owing to thetheoretical hazards of depressing myocardialfunction. If these risks should prove moretheoretical than real, this situation would bean indication for the use of the drug.The use of propranolol as a prophylacticagent after DC shock reversion of atrialfibrillation to sinus rhythm has also provedineffective. The disappointing results sum-marized in Table 1 taken together with ourdoubts concerning the drug's sustained effectand the report of Tsolakas, Davies and Oram(1964) have caused us to abandon the use ofpropranolol for this purpose.

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BESTERMAN and FRIEDLANDER: PropranololPropranolol has proved of value in slowing

a rapid ventricular rate in two patients withatrial fibrillation who were fully digitalised.No tolerance or "escape" has been seen in thiscircumstance. However some such patients maybe in border-line heart failure and the use ofthe drug might then be dangerous. Stock andDale (1963) reported increasing heart failuredue to beta-receptor blockade.

Propranolol slowed the heart rate of patientsin sinus rhythm as did pronethalol (Dornhorstand Robinson, 1962). This action was likewisesustained over a period (in one of our patientsup to eight months). We are unable to explainthe sustained effects of propranolol in sinustachycardia and atrial fibrillation as opposedto its diminishing efficacy in paroxysmalarrhythmias and long-standing ectopic beats.The value of propranolol in angina pectoris

is not as yet known and must await the resultsof a controlled series. The drug appears toimprove exercise tolerance in some anginalpatients in acute experiments (Hamer, Grand-jean, Melendez and Sowton, 1964), and in adouble-blind trial using 20 patients Srivastava,Dewar and Newall (1964) reported long-termpropranolol showed "sufficient promise tojustify a more extended trial." The results inour 16 patients with angina were disappointing,but it must be noted that they received 30 to80 mg. daily whereas the present recommendeddose of propranolol for this type of patientis 90 to 180 mg. per day. However two of our16 patients developed hypotension at a doselevel well below 80 mg. daily, and we believethat the higher doses should be approachedwith caution.We have had little experience of the use of

propranolol in other conditions. There is littledoubt of the important place of beta blockadein the treatment of digitalis arrhythmias andto cover surgery in phaeochrome tumours.Propranolol may have a place in the diagnosisof these tumours (Paton, 1964) and in thetreatment of hypertension (Prichard and Gillam,1964). Other possible situations of which wehave little personal experience include its usein hypertrophic obstructive cardiomyopathy, topotentiate the action of nor-adrenaline andmetaraminol in the treatment of hypotension,and to reduce Parkinsonian tremor.

Pilkington, Lowe, Robinson and Titterington(1962) showed that the rise in plasma free fattyacids produced by adrenaline infusion wasabolished by pronethalol but not by the alpha-receptor blocking agent phenoxybenzamine.Recently Muir, Chamberlain and Pedroe (1964)showed that in short-term experiments prone-

thalol caused a reduction in the mobilisationof non-esterified fatty acids and that the bloodlevels of non-esterified fatty acid fell duringand after exercise. As this action of adrenalineon fatty acid release appeared to be a "beta"effect we investigated various lipid fractions inpatients on long-term propranolol therapy.These patients were mostly suffering fromischaemic heart disease and no significantchanges were seen in the lipid fractionsmeasured. However a rise of free fatty acidwas observed in three out of seven patientson long term treatment (over 2 months),including the only two cases on the drug foras long as nine months.We did not find that patients on long-term

propranolol developed abnormal transaminaselevels as was reported by Tsolakas and others(1964). We agree with McNeill (1964) thatpropranolol should be given with caution inpatients with bronchial asthma though it isnot completely contraindicated. In additionlong-term propranolol may be hazardous inpatients with chronic bronchitis.

Production of a skin rash was one of thedisadvantages of pronethalol (Alleyne andcolleagues, 1963) but this was usually of anerythematous or urticarial type. Our twopatients developed a slowly increasing irritationwhich in one case eventually developed into afine scaley rash. In both cases the symptomimproved immediately on withdrawing the drugand we believe that it was a true propranololside-effect. Gastro-intestinal upset was anotherof the major drawbacks of treatment withpronethalol but not with propranolol, and wedo not believe that propranolol was causativein the two patients who developed nausea inour series.

Propranolol-induced hypotension presents aserious drawback in the use of this drug inchronic ischaemic heart disease. When used,dosage increments of only 10 mg. weekly shouldbe given and the blood pressure levels shouldbe measured regularly. The drug should notbe used in anginal patients with a low pressure.Pronethalol is known to reduce cardiacoutput at rest (Dornhorst and Robinson, 1962)and was found to precipitate heart failure onoccasions (Stock and Dale, 1963). Theoreticallythere is no reason why propranolol should nothave the same effect although, as reported, weexperienced little trouble from patients develop-ing congestive heart failure.

SummaryPropranolol has been used in the treatment

of a variety of conditions in 54 patients.




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534 POSTGRADUATE MEDICAL JOURNAL September, 1965

It was found to be of value in the reversionof supraventricular and ventricular tachycardiato sinus rhythm, but proved disappointingwhen given as prophylactic therapy to patientswith paroxysmal arrhythmias. Similarly itproved ineffectual as a prophylactic drug tomaintain sinus rhythm after DC shock reversionof atrial fibrillation.

Propranolol was effective in slowing the heartrate in both sinus tachycardia and atrialfibrillation and proved of benefit in patientswith "effort syndrome."

In angina pectoris in a small uncontrolledseries, results did not suggest that propranololwas of value.

In a further 50 patients given propranololduring anesthesia it was found to be of valuein abolishing ventricular arrhythmias and inslowing the heart rate in certain circumstances.The dangers of propranolol are immediate

hypotensive reactions following parenteral use,notably in shocked subjects, and delayedhypotensive responses when used as long-termoral therapy, especially in patients withischaemic heart disease. Heart failure maytheoretically be aggravated by the drug andbronchospasm has been observed in asthmaticand bronchitic subjects under treatment.Addendum.-Since this paper was written,

propranolol has been used with apparentbenefit in the following situation: a patientdeveloped ventricular fibrillation associatedwith an acute coronary occlusion and wassuccessfully reverted to sinus rhythm usinginternal DC defibrillation. However return ofventricular fibrillation occurred twice in thefollowing twenty minutes requiring further DCshock. Intravenous propranolol (2 mg.) wasthen administered and sinus rhythm was main-tained and the patient survived.

We are indebted to Dr. L. T. Thornton and Dr.L. Strunin for details of their anmsthetic experiencesin the use of propranolol, to the British HeartFoundation for a grant and to Miss G. Faulkner forcarrying out the blood lipid estimations, to Dr. B. J.Houghton who carried out the other biochemicalestimations, and to Dr. R. H. E. Grant of I.C.I.Pharmaceuticals Division for advice and for thesupply of propranolol.

REFERENCESAHLQUIST, R. P. (1948): A Study of the Adrenotropic

Receptors, Amer. J. Physiol., 153, 586.ALLEYNE, G. A. O., DICKINSON, C. J., DORNORSr,A. C., FULTON, R. M., GREEN, K. G., HILL, I. D.,HURSr, P., LAURENCE, D. R., PILKINGTON, T.,PRICHARD, B. N. C., ROBINSON, B., and ROSENHEIM,M. L. (1963): Effect of Pronethalol in AnginaPectoris, Brit. med. J., ii, 1226.

BARNETr, A. J., and BRANDSTATER, M. E. (1964):Pronethalol (Alderlin) A Beta Adrenergic Inhibitor,Med. J. Aust., 51, 714.

BARTLETT, G. R. (1959): Colorimetric Assay inMethods for Free and Phosphorylated GlycericAcids, J. biol. Chem., 234, 466.

BLACK, J. W., CROWTHER, A. F., SHiKs, R. G.,SMITH, L. H., and DORNHORST, A. C. (1964):A New Adrenergic Beta-Receptor Antagonist,Lancet, i, 1080.

BLACK, J. W., and STEPHENSON, J. S. (1962):Pharmacology of a New Adrenergic Beta-Receptor-Blocking Compound, Nethalide, Ibid, ii, 31 1.

COHEN, J., EFFAT, H., GOODWIN, J. F., OAKLEY,C. M., and STEINER, R. E. (1964): HypertrophicObstructive Cardiomyopathy, Brit. Heart J., 26, 16.

DACK, S., and ROBBIN, S. R. (1961): Treatment ofHeart Block and Adams-Stokes Syndrome withSustained-Action Isoproterenol, J. Amer. med. Ass.,176, 505.

DOLE, V. P. (1956): A Relation between Non-Esterified Fatty Acids in Plasma and the Meta-bolism of Glucose, J. clin. Invest., 35, 150.

DORNHORST, A. C., and LAURENCE, D. R. (1963):Use of Pronethalol in Phaeochrome Tumours, Brit.med. J., ii, 1250.

DORNHORST, A. C., and ROBINSoN, B. F. (1962):Clinical Pharmacology of a Beta-AdrenergicBlocking Agent (Nethalide), Lancet, ii, 314.

FLEMING, H. A., and MIRAMS, J. A. (1963): AClinical Trial of a Sustained-Action Preparationof Isoprenaline in the Treatment of Heart-Block,Ibid, ii, 214.

HAMER, J., GRANDJEAN, T., MELENDEZ, L., andSoWTON, G. E. (1964): Effect of Propranolol(Inderal) in Angina Pectoris, Brit. med. J., ii, 720.

HANDEL, E. V., and ZILVERSMIT, D. B. (1957):Micromethod for the Direct Determination ofSerum Triglycerides, J. Lab. clin. Med., 50, 152.

HARRISON, D. C., Ross, J., JUN., CHIDSEY, C. A., andBRAUWALD, E. (1963): Hemodynamic Effects ofBeta-Adrenergic Blockade in Hypertrophic Sub-aortic Stenosis, Clin. Res., 11, 167.

HERRING, A. B. (1964): Action of Pronethalol onParkinsonian Tremor, Lancet, ii, 892.

JOHNsTONE, M. (1964): Beta-Adrenergic Blockadewith Pronethalol During Anmsthesia, Brit. J.Anaesth., 36, 224.

LEFFLER, H. H. (1960): Lipids and the SteroidHormones in Clinical Medicine. Edited bySunderman and Sunderman, Philadelphia: J. B.Lippincott.

LOWN, B., AMARASINGHAM, R., and NEUMAN, J.(1962): New Method for Terminating CardiacArrhythmias, J. Amer. med. Ass., 182, 548.

LURIA, M. H., MILLER, A. J., and KAPLAN, B. M.(1964): Successful Therapy of Prolonged Hypo-tension with an Adrenergic Beta-Receptor BlockingAgent, Circulation, 24, 494.

MCDONALD, L., RESNEKOV, L., and O'BRIEN, K.(1964): Direct-Current Shock in Treatment ofDrug-resistant Cardiac Arrhythmias, Brit. med. J.,i, 1468.

McNEILL, R. S. (1964): Effect of a Beta-Adrenergic-Blocking Agent, Propranolol, on Asthmatics,Lancet, ii, 1101.

MARCH, W. H., FINGERHUT, B., and KIRSCH, E.(1959): Adaptation of an Alkaline PhosphataseMethod for Automatic Colorimetric Analysis, Clin.Chem., 5, 119.

MUIR, G. G., CHAMBERLAIN, D. A., and PEDROB, D. T.



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(1964): Effects of Beta-Sympathetic Blockade onNonesterified-fatty-acid and Carbohydrate Meta-bolism at Rest and during Exercise, Lancet, ii,930.

ORAm, S., and DAVIES, J. P. H. (1964): FurtherExperience of Electrical Conversion of AtrialFibrillation to Sinus Rhythm, Ibid, i, 1294.

PAGET, C. E. (1963): Carcinogenic Action ofPronethalol, Brit. med. J., ii, 1266.

PATON, D. M. (1964): Beta-receptor Blockade in theDiagnosis of Phaeochromocytoma, Lancet, ii, 1125.

PAYNE, J. P., and SENFIELD, R. M. (1964): Pronethalolin Treatment of Ventricular Arrhythmias DuringAnesthesia, Brit. med. J., i, 603.

PILKINGToN, T. R. E., LowE, R. D., ROBINSON, B. F.,and TI1TERINGTON, E. (1962): Effect of AdrenergicBlockade on Glucose and Fatty-acid Mobilisationin Man, Lancet, ii, 316.

PRICHARD, B. N. C. (1964): Hypotensive Action ofPronethalol, Brit. med. J., i, 1227.

PRICHARD, B. N. C., and GILLAM, P. M. S. (1964):

Use of Propranolol (Inderal) in Treatment ofHypertension, Ibid, ii, 725.

RErrMAN, S., and FRANKEL, S. (1957): A ColorimetricMethod for the Determination of Serum GlutamicOxalacetic and Glutamic Pyruvic Transaminases,Amer. J. clin. Path., 28, 56.

SRIVASTAVA, S. C., DEWAR, H. A., and NEWELL, D. J.(1964): Double-blind Trial of Propranolol (Inderal)in Angina of Effort, Brit. med. J., ii, 724.

STOCK, J. P. P., and DALE, N. (1963): Beta-AdrenergicReceptor in Cardiac Arrhythmias, Ibid, ii, 1230.

TSOLAKAS, T. C., DAVIES, J. P. H., and ORAM, S.(1964): Propranolol in Attempted Maintenance ofSinus Rhythm after Electrical Defibrillation,Lancet, ii, 1064.

WHITE, J. C., SMITHwICK, R. H., and SIMEoNE, F. A.(1952): The Autonomic Nervous System, 3rd ed.New York: MacMillan.

WROBLEWSKI, F., and LADUE, J. S. (1955): SerumGlutamic Oxalacetic Transaminase Activity as anIndex of Liver Cell Injury, Ann. intern. Med.,43, 345.



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