Effect of Propranolol on Elevated Arterial Blood Pressure

Effect of Propranolol on Elevated Arterial Blood Pressure By DAVI W. RICHARDSO, M.D., JACK FREUD, M.D., ARTHUR S. GEAR, M.D., H. PAGE MAUCK, JR., M.D., AD LESTER W. PRESTO, B.S. Downloaded from http://circ.ahajournals.org/ by guest on July 5, 218 SUMMARY ineteen patients with moderately severe arterial hypertension received propranolol (12 mg daily), or chlorthalidone (1 mg daily), both medications together, and placebos in a double-blind crossover trial. Each treatment was given for 5 weeks; blood pressure was measured at weekly intervals. Propranolol alone reduced arterial pressure by 9/8 mm Hg, a statistically insignificant change. Use of chlorthalidone alone was accompanied by an average reduction in arterial blood pressure of 23/9 mm Hg. Both drugs together lowered blood pressure by 33/15 mm Hg. Heart rate was lower in regimens including propranolol; body weight and serum potassium and chloride concentration were lower and blood urea nitrogen and serum creatinine were higher in regimens containing chlorthalidone. Propranolol, in the dose given, is a less effective hypotensive drug than is chlorthalidone. Additional Indexing Words: Hypertension Chlorthalidone Potassium supplementation Weight PROETHALOL, an effective beta-adrenergic blocking agent, was observed to reduce arterial blood pressure in hypertensive patients being treated for angina pectoris.1 Subsequently Prichard and Gillam2 3 compared propranolol, another beta-adrenergic blocking drug, 12 to 64 mg/day, with previously administered methyldopa in 12 hypertensive patients and reported lower blood pressure during use of propranolol. Since in previous clinical trials2-6 the hypotensive effect of propranolol was not compared with that of placebo, we have evaluated the hypotensive efficacy of propranolol in comparison with that of inert tablets and a standard diuretic in trials in which neither physician nor pa- From Departments of Medicine and Biometry, Medical College of Virginia, Richmond, Virginia. Work was supported by grants from the Virginia Heart Association and from Ayerst Laboratories and Geigy Pharmaceuticals. Presented at the Fortieth Scientific Sessions of the American Heart Association, San Francisco, California, October 21, 1967. 534 Beta-adrenergic blockade Blood chemistry Heart rate tient knew which therapy was being administered. We have compared propranolol, 12 mg/day, placebo, chlorthalidone, 1 mg/ day, and the combination of propranolol and chlorthalidone as hypotensive agents in 19 hypertensive patients. The order of administration of drugs was randomized and unknown to patient or physician. Propranolol, 12 mg/ day, had only moderate hypotensive effect. Methods Twenty-two patients entered the study. One refused to return after the first week, one died 2 weeks before completion of the fourth period, and one was stopped before entering the fourth period which would have included chlorthalidone and potassium, a combination withdrawn by its manufacturer because of toxicity. Thus 19 patients, 5 male and 14 female, completed the entire study. The patients' ages ranged from 35 to 69 years. T.C., a 44-year-old egro man, had chronic nephritis manifest by persistent proteinuria, microscopic hematuria, cylinduria, and azotemia without pyuria or bacteriuria. G.W., a 57-year-old egro woman, had probable hyperparathyroidism, with intermittent hypercalcemia, a renal stone, and recurrent duodenal ulcer. She

PROPRAOLOL AD ELEVATED BLOOD PRESSURE 535 Downloaded from http://circ.ahajournals.org/ by guest on July 5, 218 did not have azotemia or infected urine. In the remainder, no cause for hypertension could be demonstrated despite multiple urinalyses, determination of urinary catecholamine excretion, intravenous pyelography, radioactive renography, multiple determinations of serum sodium, potassium, chloride and bicarbonate concentrations, and complete historical and physical examination. one of the patients had hemorrhagic or exudative retinopathy, congestive heart failure, edema, asthma, or gout. Six had chemical diabetes mellitus; none received insulin. Each patient had been followed in the hypertension clinic for months, and each had previously received antihypertensive drugs. Each had diastolic blood pressure averaging 88 mm Hg or more during five weekly visits while receiving placebo tablets, save for one patient whose blood pressure averaged 143/8 mm Hg prior to randomization and 15/85 during the randomization placebo period. All patients carried on their usual work without restriction of diet or exercise. Each patient was seen at weekly intervals for 3 weeks. At each visit the patient was weighed and arterial pressure was recorded by one of two nurses who made all measurements throughout the study. Patients lay for 1 minutes in a quiet room, after which blood pressure was measured three times in the supine position and three times in the standing position. Heart rate was recorded with the patients supine. Pills remaining in the bottles issued the previous week were counted in an attempt to ensure that medication was taken properly, and the patient was reminded how to take the medications. At 3- week intervals, blood was drawn for hemoglobin concentration, white cell count, autoanalyzer estimation of urea nitrogen and of serum concentrations of creatinine, sodium, potassium, chloride, bicarbonate, bilirubin, alkaline phosphatase and glutamic-oxalacetic transaminase. At the first five weekly visits, each patient received sufficient medicaments for him to take one dummy capsule of chlorthalidone twice daily and one dummy tablet of propranolol three times daily in the ensuing week. Thereafter, each received treatment for 5 weeks with each of the four possible combinations: (1) both medications dummy; (2) both active (propranolol, 4 mg for use thrice daily, and chlorthalidone, 5 mg for use twice daily); (3) active chlorthalidone, 5 mg for use twice a day and dummy pro- Table 1 Comparison of Arterial Pressures in Lying Position Between the Initial Placebo Period (Single-Blind) and the Treatment Placebo Period* (Randomized; Double-Blind) Age Treatment Systolic (mm Hg) Diastolic (mm Hg) Patient (yr) Sex Race placebo period Initial Treatment Initial Treatment D.C. J.H. L.G. M.T. G.W. P.A. T.C. S.M. P.T. E.P. C.H. C.B. L.S. P.H. A.R. M.C. L.W. E.A. C.A. 4 F 49 M 4 F 35 F 49 F 55 M Average for period 45 M 52 F 43 F 5 F Average for period 44 F 67 F 54 M 69 F 37 F 55 F Average for period 49 F 45 F 46 M Average for period Overall averages *Period = 5 weeks. w Second Second Second Second Fourth Fourth Fourth 142.8 229.5 159.4 154.9 21.7 169.6 (177.8) 26. 168. 164.3 144. (17.6) 133. 143. 187.6 196.5 152.7 165. (163.) 184.3 131.1 215.9 (177.1) (171.5) 148.8 216. 164.1 153.5 22.8 182.3 (18.9) 191.1 167.2 161.2 148.2 (166.9) 131.9 15.4 188. 193.8 152.2 16.8 (162.8) 199.2 137.7 198.1 (178.3) (172.3) 88.8 119.9 97.2 99.7 12.3 17.3 (15.5) 121.9 12.4 96.5 96.3 (14.3) 88.1 8.4 112.6 113.7 113.7 11. (13.1) 94.8 94.3 136.9 (18.7) (15.) 93. 125.7 99.9 11.2 126.2 114. (11.) 115. 98.9 97.5 14.3 (13.9) 87.8 84.2 121.3 114. 112.3 18.3 (14.7) 96. 99.2 129. (18.1) (16.7)

536 RICHARDSO ET AL. Arterial Blood Pressure-Lying Table 2 Position Downloaded from http://circ.ahajournals.org/ by guest on July 5, 218 Treatment week Dummy* Propranololt Chlorthalidonet Propranolol plus chlorthalidone Dummy Propranolol Chlorthalidone Propranolol plus chlorthalidone 164.82 153.83 146.42 142.5 13.4 99.17 92.78 92.28 Second week week Systolic pressure 17.8 172.57 162.35 162.8 147.1 141.5 143.5 139.8 Diastolic pressure 15.18 16.68 97.2 95.45 97.5 94.37 94.18 91.2 Fourth week Fifth week 172.95 172. 165.84 162.82 144.37 148.56 138.46 138.73 18.37 98.18 96.91 9.63 16.7 98.67 97.74 92.11 Means not connected by vertical lines are significantly different (P <.5). *1 inert tablet resembling propranolol three times daily plus 1 inert tablet resembling chlorthalidone twice daily. tpropranolol, 4 mg, three times daily plus 1 dummy chlorthalidone tablet twice daily. *Chlorthalidone, 5 mg, and KC1,.5 g, twice daily plus 1 dummy propranolol tablet three times daily. Propranolol, 4 mg, three times daily plus chlorthalidone, 5 mg, twice daily. Table 3 Average Arterial Blood Pressure-Standing Position Treatment week Second week week Systolic pressure Dummy* 162.25 165.4 17.5 Propranololt 153.77 161.55 16.75 Chlorthalidonet 142.47 143.22 137.5 Propranolol plus 136.31 14.13 135.43 chlorthalidone Diastolic pressure Dummy 113.87 114.5 117.25 Propranolol 17.95 19.72 16.37 Chlorthalidone 15.7 15.37 13.4 Propranolol plus 11.7 12.46 99.62 chlorthalidone Fourth week Fifth week 168.25 159.3 138.72 133.37 117.42 17.72 14.19 98.65 17.56 158.14 142.63 132.95 116.49 18.28 13.93 98.32 Means not connected by vertical lines are significantly different (P <.5). *1 inert tablet resembling propranolol three times daily plus 1 inert tablet resembling chlorthalidone twice daily. tpropranolol, 4 mg, three times daily plus 1 dummy chlorthalidone tablet twice daily. *Chlorthalidone, 5 mg, and KC1,.5 g, twice daily plus 1 dummy propranolol tablet three times daily. Propranolol, 4 mg, three times daily plus chlorthalidone, 5 mg, twice daily.

Downloaded from http://circ.ahajournals.org/ by guest on July 5, 218 PROPRAOLOL AD ELEVATED BLOOD PRESSURE 537 pranolol; and (4) dummy chlorthalidone and active propranolol, 4 mg for use thrice daily. The tion to the experimental procedure. drugs, rather than lapse of time or habitua- order of administration was randomized and unknown to patient and observers. During the The blood pressure associated with each period when chlorthalidone was given without regimen is summarized in tables 2 and 3 and propranolol, potassium chloride, 5 mg, was figure 1. Propranolol, 4 mg three times a added to each chlorthalidone capsule in order day, reduced blood pressures with the patient to observe the effect of potassium supplementation on serum potassium concentration. Blood Hg, systolic and diastolic, as compared with in the lying down position by 9 and 8 mm pressure during that period in the double-blind crossover in which the patient received both placebo. Statistically significant reduction in dummies was used as the control pressure, diastolic pressure attributable to propranolol against which drug effects were compared. Analysis of variance for a randomized block design7 was no evidence of greater hypotensive effect occurred only in 2 of the 5 weeks. There (that is, each patient was considered as a complete block) was performed separately for each in the fifth than in the first week of propranolol administration. Chlorthalidone alone, 5 treatment period and each variable. Subsequently, Duncan's multiple-range test8 was used to mg twice a day, reduced pressure an average determine the statistical significance of the observed response differences among all treatment LYIG pairs. All patients were interviewed at each visit, after blood pressure and pulse had been recorded. 17r - *'----. o special effort was made to have a particular physician interview a x ---- particular patient throughout the study; in fact, each patient was seen by 16 H x ~x all four physicians at some time. Physicians were dv oe Ke instructed to ask at each visit about anv discomfort or change in daily habit; about sleepiness, 15 H A diarrhea, shortness of breath, swelling, and dizziness; and to record all symptoms. At the end of the study, all recorded symptoms were tabulated -o 14 H by study period without knowledge of which LALJ drug was received in any period. They were then retabulated by drug regimen. 3 (1) *-* Dummy Results x--x Propronolol A-A Chlorthalidone Effects on Arterial Pressure 12 H o--o P a C The effect on blood pressure of the ~: patients' KR habituation to the examination was observed I I1O by comparing the average pressure during the initial 5-week pre-randomization period of placebo administration with the average 1 X. - pressure during the "treatment" 5-week period in the double-blind trial in which the * - o_ X. patient received placebos. Table 1 shows the 9 data for each patient. In none of the four IE placebo periods during the double-blind comparison was the group average pressure sig- 1 2 3 4 5 WEEKS OF TREATMET nificantly different from the average pressure Figure 1 during the pre-randomization period. It is Arterial pressure, recorded in the supine position, on thus reasonable to assume that the changes each regimen. Each point is the average for 19 patients. The four regimens were placebo, propranolol, in blood pressure observed during administration of active drugs are the result of the pranolol plus chlorthalidone 12 mg daily, chlorthalidone, 1 mg daily, and pro- (P&C).

538 RICHARDSO ET AL. 2 * - Lying o - Standing + 1 o Downloaded from http://circ.ahajournals.org/ by guest on July 5, 218 i44 (5). (I) -1 - -2 _ -3 _ -4 _ Zrz. -5 _- -6 _- * a I 88 * 8-7 _ Propronolol 4mg/ tid I & a 8 Chlortholidone 5mg / bid. m m S. 8 Propronolol Chlortholidone Figure 2 The changes in systolic arterial pressure observed in individual patients during active drug regimens. The horizontal line at zero represents each patient's pressure during the second through fifth weeks of placebo medication in the double-blind trial. Each point represents the change in blood pressure observed in one patient during the second through the fifth week on the indicated regimen, and is the mean of 12 measurements, three each week. Closed circles show changes in supine and open circles changes in standing blood pressure. of 23/9 mm Hg as compared with the placebo. Propranolol and chlorthalidone together reduced pressure an average of 33/15 mm Hg below that observed during administration of the placebo. Blood pressure was not significantly lower during administration of propranolol and chlorthalidone together than with chlorthalidone alone. The effects of drug regimens on blood pressure in the standing position were similar to those observed in the supine position (tables 2 and 3). Figures 2 and 3 show the changes of systolic and diastolic

PROPRAOLOL AD ELEVATED BLOOD PRESSURE 539 ffi +1~ r- LAJ 1~ IH -1 IF -2 I 8 1 o I 8 oo _ S fb *~~ ~ 8 9. *. A v v 8 % Downloaded from http://circ.ahajournals.org/ by guest on July 5, 218-3 -4j (-4 * - Lying o - Standing Propronolol 4mg/tid Changes in diastolic arterial pressure regimens. See legend for figure 2. Heart Rate in Treatment Period week Second week Drug HR Drug HR C 79.2 C 83.9 D 76.8 D 75.1 C+P 71.3 C+P 68.6 P 65. P 65.8 Chlorthalidone 5mg /bid Figure 3 observed in individual patients during active drug Table 4 8 Propronolol Chlortholidone Fourth week Fifth week week Drug HR Drug HR (Incomplete C 84.1 C 77.8 data not D 76.4 D 77.4 analyzed) C + P 66.2 C + P 68.2 P 64.1 P 67.6 Means not connected by the same vertical line are significantly different (P <.5)- Duncan's multiple range test. Abbreviations: HR = heart rate; D = dummy; P = propranolol; C = chlorthalidone; and C + P = chlorthalidone plus propranolol. pressure in individual patients associated with each active drug regimen. Heart Rate, Weight, and Blood Chemistry The heart rate was consistently lower in the two regimens which included propranolol (table 4). Sinus rhythm was present in all subjects throughout the study. In each week of the treatment period, there was a significant (P <.5) difference among the body weights (table 5). For all treatment weeks the weights during the two chlorthali-

54 RICHARDSO ET AL. Weight (lb) in Treatment Period Table 5 week Second week week Drug Weight Drug Weight Drug Weight P 167.4 P 167.8 P 166.6 D 165.7 D 165.4 D 166. C 163. C+P 163.8 C + P 163.2 C + P 162.8 C 162.8 C 162.4 Fort wee Fourth week Drug Weight P 166.8 D 165.4 C+P 163.7 C 162.3 Fitwe Fifth week Drug Weight P 166.6 D 165.8 C+P 164.9 C 163.2 Means not connected by the same vertical line are significantly different (P <.5) Duncan's multiple range test. Abbreviations: D = dummy; P - propranolol: C -- chlorthalidone; and C + P - chlorthalidone plus propranolol. Downloaded from http://circ.ahajournals.org/ by guest on July 5, 218 Clinical Laboratory Data: Fifth Table 6 Week of Each Treatment Period Blood urea nitrogen Chloride Biliruhin, direct Blood urea nitrogen Bilirubin, direct (mg/1 ml) C+P 25.2 C 24. P 2. D 18.4 Creatinine (mg/1 ml) C+P 1.56 C 1.52 P 1.38 D 1.35 Sodium (meq / L) D 143.8 p 143. CC+P 142.8 142. Potassium (meq / L) p 4.31 D 4.28 C 3.9 C+P 3.891 Chloride (meq/l) P 13.3 D 13.2 C 99.8 C+P 99.5 Carbon dioxide (mm/l) C+P 26.4 C 26.3 D 25.5 P 25.4 SGOT (Karmen units) C+P 21.3 C 2.6 D 19. P 18.4 Alkaline phosphatase (Bessey-Lowry units) P 1.69 C 1.47 C+ P 1.42 D 1.29 (mg/1 ml) C+P.17 P.94 C.6 D.58 Bilirubin, total (mg! 1 ml) C+P.334 P.321 C.31 D.27 count White cell (cell / mm3) P 6952i D 6511 C 6327 C+P 628 Hemoglobin (gl 1 ml) C 13.62 D 13.39 C+P 13.34 P 12.98 Means not connected by the same vertical line are significantly differenct (P <.5)- Duncan's multiple range test. Abbreviations: D - dummy; P - propranolol; C - chlorthalidone; and C + P - chlorthalidone plus propranolol. done regimens were slightly less, but the rum potassium and chloride were lower. There statistical significance of these differences was no difference between the serum potaswas more definitive in the earlier weeks. sium levels for the chlorthalidone regimen Blood chemical and hematological analy- and for the combined chlorthalidone and proses are shown in table 6. During the adminis- pranolol regimen; in the former regimen,.5 g tration of the two chlorthalidone regimens, of potassium chloride was incorporated into concentration of blood urea nitrogen and each capsule of chlorthalidone. serum creatinine were higher; those for se- o significant differences among the four Circulation, Volume XXXVII, April 19(38

PROPRAOLOL AD ELEVATED BLOOD PRESSURE 541 Possible Side Effects Table 7 Downloaded from http://circ.ahajournals.org/ by guest on July 5, 218 Symptom Headache Dizziness Dyspnea Cough and wheezing Fatigue Sleepiness ausea Placebo o. * Pt. t 11 6 4 3 1 1 2 1 4 1 1 3 Propranolol o. Pt. 6 3 6 2 5 3 *o. = umber of times symptom was recorded. tpt. - umber of patients who developed this symptom. regimens were noted with respect to blood hemoglobin, white cell count, serum carbon dioxide content, bilirubin concentration, nor serum glutamic-oxalacetic transaminase and alkaline phosphatase. Side Effects Table 7 presents the number of times a symptom occurred during each regimen, and the number of patients who experienced each symptom. Headache occurred most frequently during placebo administration and least frequently in regimens containing chlorthalidone. Dizziness, on the other hand, occurred least frequently during the placebo period, and most frequently during administration of chlorthalidone. Dyspnea, cough, and wheezing occurred more frequently in regimens containing propranolol, with or without chlorthalidone. Fatigue occurred more often with regimens containing chlorthalidone or propranolol than with placebo. Other recorded symptoms, mentioned by only one or two patients each, included nocturia, present in all four regimens; angina pectoris, also present in all four regimens; urinary urgency, diarrhea, indigestion, nocturnal leg cramps, and stuffy nose. Discussion Propranolol in a dose of 4 mg three times daily caused an average blood pressure reduction of 9 mm Hg systohic and 8 mm Hg diastolic. These changes are statistically insignificant. The modest effect of propranolol is similar to that found by Waal,4 who ob- 4 3 3 2 2 2 Chlorthalidone and KC1 o. Pt. 2 2 9 6 2 1 1 1 3 3 6 5 3 3 Propranolol and chlorthalidone o. Pt. 2 2 7 5 9 7 served an average decrease in blood pressure of 12/6 mm Hg when propranolol, 45 to 15 mg/day, was added to other antihypertensive medication in 89 hypertensive patients. Similarly, Richards5 found an average decrease in pressure of 11/12 mm Hg in nine patients with elevated arterial pressure during administration of propranolol, 15 to 3 mg/day for 8 to 15 weeks. Paterson and Dollery6 compared the effects of propranolol, 8 mg/ day, propranolol, 24 mg/day, and hydrochlorthiazide, 5 mg/day, on 11 hypertensive patients who received each regimen for 6 weeks. Arterial pressure (lying) was 13/5 mm Hg higher with propranolol, 24 mg/day, and 14/6 mm Hg higher with propranolol, 8 mg/ day, than with hydrochlorthiazide. Though Prichard and Gillam3 have suggested that prolonged administration (4 weeks or more) of propranolol produces greater reduction of arterial pressure than is seen in the first 3 weeks, our results with those of Waal4 and of Paterson and Dollery6 show no greater hypotensive effect after 5 or 6 weeks of propranolol than after 1 to 3 weeks. Addition of potassium chloride,.5 g twice a day, to chlorthalidone had no noticeable effect on serum potassium concentration. Thus, there seems little reason for administration of capsules combining potassium, at least in this dose, with chlorthalidone. Analysis of side effects suggests that reduction in blood pressure lessened the prevalence of headache in this group of patients 5 6 7 1 3 4 51

Downloaded from http://circ.ahajournals.org/ by guest on July 5, 218 542 with mild to moderate hypertensive disease. The greater frequency with which dyspnea and wheezing occurred while patients were taking propranolol is in keeping with known effects of the drug, which blocks adrenergic bronchodilation and, by reducing adrenergic stimulation of the heart, favors cardiac decompensation. In no patient were symptoms severe enough to require alteration of medication. One patient died in the fourth week period of the study, while taking propranolol alone. She was a 52-year-old egress with recurrent ventral hernia which had previously been repaired surgically without prolonged success. The hernia protruded one day, producing pain and vomiting for 2 hours, and then reduced itself spontaneously. She stopped taking propranolol that day. Two days later the hernia protruded again, and she entered the hospital with abdominal pain, vomiting, and hypotension. The hernia could not be reduced. Shock and puhnonary edema followed, and the patient died 36 hours later with continued pulmonary edema. Permission RICHARDSO ET AL. for autopsy was not given. The contribution of propranolol to her death is uncertain. Infusion of isoproterenol resulted in tachycardia and reduction in arterial pressure, suggesting that beta-adrenergic blockade was not present. References 1. PRIcEun, B.. C.: Hypotensive action of pronethalol. Brit Med J 1: 1227, 1964. 2. PmcHARw, B.. C., AD GILLAM, P. M. S.: Use of propranolol in the treatment of hypertension. Brit Med J 2: 725, 1964. 3. PiCuHARD, B.. C., AD GILLAM, P. M. S.: Propranolol in hypertension. Amer J Cardiol 18: 387, 1966. 4. WAAL, H. J.: Hypotensive action of propranolol. Clin Pharmacol Ther 7: 588, 1966. 5. RcHADs, F. A.: Propranolol in hypertension. Amer J Cardiol 18: 384, 1966. 6. PATERSO, J. W., AD DOLLERY, C. T.: Effect of propranolol in mild hypertension. Lancet 2: 1148, 1966. 7. BAILEY,. T. J.: Statistical Methods in Biology. London, English Universities Press, 1959, p. 18. 8. STEEL, R. G. D., AD ToRRIE, J. H.: Principles and Procedures of Statistics. ew York, McGraw-Hill Book Co., 196, p. 17. Circulation, Volume XXXVII, Aprl 1968

Effect of Propranolol on Elevated Arterial Blood Pressure DAVID W. RICHARDSO, JACK FREUD, ARTHUR S. GEAR, H. PAGE MAUCK, JR. and LESTER W. PRESTO Downloaded from http://circ.ahajournals.org/ by guest on July 5, 218 Circulation. 1968;37:534-542 doi: 1.1161/1.CIR.37.4.534 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright 1968 American Heart Association, Inc. All rights reserved. Print ISS: 9-7322. Online ISS: 1524-4539 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circ.ahajournals.org/content/37/4/534 Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation is online at: http://circ.ahajournals.org//subscriptions/