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Atenolol: once-daily cardioselective beta blockade for angina pectoris G Jackson, J Schwartz, RE Kates, M Winchester and DC Harrison Circulation 1980;61;555-560 Circulation is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TX 72514 Copyright © 1980 American Heart Association. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 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 Subscriptions: Information about subscribing to Circulation is online at http://circ.ahajournals.org/subsriptions/ Permissions: Permissions & Rights Desk, Lippincott Williams & Wilkins, 351 West Camden Street, Baltimore, MD 21202-2436. Phone 410-5280-4050. Fax: 410-528-8550. Email: [email protected] Reprints: Information about reprints can be found online at http://www.lww.com/static/html/reprints.html Downloaded from circ.ahajournals.org at Dana Medical Library, University of Vermont on October 12, 2006 Atenolol: Once-daily Cardioselective Beta Blockade for Angina Pectoris GRAHAM JACKSON, M.B., JANICE SCHWARTZ, M.D., ROBERT E. KATES, PH.D., MARK WINCHESTER, M.D., AND DONALD C. HARRISON, M.D. SUMMARY The physiology, pharmacokinetics and efficacy of atenolol, a cardioselective,-adrenergic blocking agent, were evaluated in 10 patients with stable angina pectoris in a single-blind, dose-ranging study. After a 1-month control placebo period, atenolol was administered once daily at dosages of 25, 50, 100 and 200 mg for 2-week periods. All patients had fewer anginal attacks and consumed fewer nitroglycerin tablets than during the placebo period. Twenty-four-hour ambulatory ECG recordings showed a decrease in mean hourly heart rate throughout the dosing period, with preservation of diurnal variation. Maximal, symptom-limited, treadmill exercise tests performed 3 hours after drug ingestion showed significantly increased exercise time and decreased double products for all doses, but especially with 100-mg and 200-mg doses. Exercise time 24 hours after drug ingestion continued to show a decrease in maximum heart rate and double product, with 100mg and 200-mg doses again being most effective. Atenolol serum levels correlated with percent reduction in exercise heart rate and increased exercise time. Serum levels rose linearly, with an average elimination half-life of about 10 hours after chronic oral dosing. Thus, atenolol was an effective antianginal agent and suppressed resting and exercise-stressed heart rate for 24 hours after ingestion when given in a 100-mg or 200-mg dose once daily. Drug Dosage Administration THE BENEFICIAL EFFECTS of ,B-adrenergic blockade in the treatment of angina pectoris is well established.1' 2 The most widely used agent is propranolol. Since propranolol was introduced, various /3-adrenergic blocking agents with differing properties have been developed in an attempt to avoid the side effects of generalized A3 blockade. Atenolol, a cardioselective /3 blocker, is one of these newer agents. Because of initial favorable clinical reports in Europe,3-5 we undertook a dose-ranging and antianginal efficacy study of atenolol in patients with A single-blind protocol was used because of the risks reported with sudden withdrawal off/ blockade.6 All drug preparations (including placebo) were given as two identical tablets once daily at 8 a.m. Nitroglycerin was used for pain, but not for prophylaxis, throughout the trial. Placebo was given for the first 4 weeks of the 12-week protocol, which served as an initial control period. In subsequent 2-week periods, patients received 25 mg, 50 mg, 100 mg and 200 mg of atenolol daily. Drug compliance was checked by tablet count and measurement of serum drug levels. stable, exercise-induced angina. Materials and Methods Antianginal Assessment The patients kept a daily record of anginal attacks and nitroglycerin consumption. These records were reviewed by the investigators every 2 weeks, and side effects were noted. At each visit, supine and standing heart rates were determined from ECG recordings and blood pressures were measured using a standard sphygmomanometer. Only the data of the last week of each 2-week period were used for comparisons to avoid carry-over effects.7 Patients Ten patients, seven men and three women, with a mean age of 55 years (range 35-67 years) participated in the study. Each patient gave written consent after being informed of the details and objectives of the study, and the protocol was approved by the Stanford Medical Committee on the Use of Human Subjects in Research. All had had clinically stable exerciseinduced angina for 3 or more months. No patient had valvular heart disease, cardiac failure, obstructive airways disease, hypertension (resting diastolic pressure > 100 mm Hg), diabetes, or thyroid or renal disease. Exercise Testing During the second week of each treatment period, exercise testing was performed 3 hours and 24 hours after drug ingestion. No food, caffeine or nitroglycerin was consumed within the 2 hours before testing. With continuous ECG monitoring, patients exercised on a motor-driven treadmill until chest pain occurred (symptom-limited). The exercise test began at a constant grade of 10% at 1 mph, with 0.5-mph increments introduced every 3 minutes; a 12-lead ECG was recorded before testing and at 3-minute intervals, and three-lead ECGs were recorded each minute between the 3-minute recordings. The blood pressure was From the Division of Cardiology, Stanford University School of Medicine, Stanford, California. Supported in part by NIH training grant HL-07265, NIH research grant HL-21221, and by funds from I.C.I. Americas, Inc. Dr. Jackson is a Peel Medical Research Trust Traveling Fellow. Address for correspondence: Donald C. Harrison, M.D., Chief, Cardiology Division, Stanford University School of Medicine, Palo Alto, California 94305. Received June 28, 1979; revision accepted September 4, 1979. Circulation 61, No. 3, 1980. 555 VOL 61, No 3, MARCH 1980 CIRCULATION 556 recorded at rest and after 1 and 3 minutes of each treadmill stage. Changes in ST segments were measured during and after peak exercise. A downwardsloping depression of at least 1 mm persisting for 0.08 second or longer in at least five consecutive beats was considered indicative of ischemia. Monitoring was continued for a minimum of 6 minutes after exercise or until values returned to control levels. All anginal episodes stopped after cessation of exercise. WEEKLY ANGINA 12 ATTACK RATE L 1- 10 Ambulatory Monitoring During the second week of each 2-week period, a 24-hour ambulatory recording was performed. This monitoring period included both peak and trough treadmill tests. Patients were encouraged to engage in their normal daily activity and wore recorders on the same day of the week for each test. Avionics recording systems were used and the tapes were analyzed on the Stanford computer system.8 Heart-rate trends were examined throughout the 24-hour period. Serum Drug Levels Five ml of heparinized blood was drawn 3 hours (peak) and 24 hours (trough) after atenolol ingestion (concomitant with treadmill testing and ambulatory ECG monitoring). Serum atenolol concentrations were determined by a high-pressure liquid chromatographic method.9 8 z 6 \ \X \\\ 4 Anginal Attack Rate and Nitroglycerin Consumption The mean weekly incidence of angina and nitroglycerin consumption are shown in table 1 and figure 1. Compared with placebo, atenolol reduced the anginal attack rate during all periods of its administration (p < 0.001). A dose response was present with a decreasing number of attacks with increasing dosage. Atenolol at doses of 100 mg and 200 mg was significantly superior to the 25-mg dose (p < 0.001), but there was no significant difference between the 50-mg and 100-mg doses or the 100-mg and 200mg doses. The 200-mg dose was more effective than the 50-mg dose (p < 0.005). Nitroglycerin consumption declined in a parallel, dose-related fashion. Com- 50 100 \ ID4\ 200 2 Statistical Analysis Data were analyzed for statistical significance by the repeated-measures analysis of variance. For variables where statistically significant (at the 5% level) dose-response relationships were detected, further comparison of mean responses at different dose levels was done using a matched-pairs t test. 125 - ----WEEKLY CONSUMPTION x NITROGLYCERIN 200 0 ATENOLOL PLACEBO FIGURE 1. Subjective data: weekly angina attack rate and nitroglycerin use among the 10 patients during placebo and atenolol periods. pared with placebo, all dosages decreased nitroglycerin consumption significantly (p < 0.001), with no significant difference between the 50-mg dose vs 100mg and 200-mg doses or the 100-mg dose vs the 200mg dose (table 1 and fig. 1). Exercise Data During the initial placebo period, peak and trough significantly different, verifying the reproducibility of the responses with the protocol (table 2). All atenolol doses significantly reduced resting and exercise heart rate at 3 hours (p < 0.001) and 24 hours (p < 0.001) after ingestion (table 3 and fig. 2). Atenolol was statistically most effective at 100- tests were not TABLE 1. Subjective Data Placebo Weekly angina attacks Weekly nitroglycerin consumption Values are mean - SEM. 12.1 8.0 2.2 2.6 25 50/100 25 mg 2.1 9.0 2.7 d= 1.5 Atenolol 100 mg 2.2 4.7 l1. 50 mg 5.4 2.3 1.2 2.3 1.3 200 mg 2.4 0.9 0.9 0.6 ATENOLOL FOR ANGINA PECTORIS/Jackson TABLE 2. Placebo Data al. et 557 ! AT REST Peak Trough 80 p Resting heart rate (beats/min) 72.2 2.3 78.7 118.7 4.7 114.6 4 3.4 NS 4.2 NS Exercise heart rate (beats/min) Resting SBP E 141.1 139.2 8.8 7.2 NS 25 7"50 cc (mm Hg) Resting DBP (mm Hg) 70 5I 60 _ - ON EXERCISE 120 1tOl25 * 50 .100 * 200 a ,100 100 _- cr 86.7 5.9 86.4 3.8 NS 50 163.9 384.5 7.7 30.3 NS NS 40 90 _ Exercise SBP (mm Hg) 167.0 * 8.8 413.5 - 34.9 Exercise time (sec) Exercise ST depression (mm) Double product 1.6 198.3 siEM. 1 - 0.3 16.4 1.7 187.8 0.3 14.5 NS NS Values are mean Abbreviations: SBP = systolic blood pressure; DBP = diastolic blood pressure; double product = exercise heart rate times systolic blood pressure divided by 100. mg and 200-mg doses, with no significant difference between the two. The maximal exercise double product (heart rate times systolic blood pressure) at the occurrence of chest pain was significantly reduced at peak and trough testing by all atenolol doses (p < 0.001), but the 100-mg and 200-mg doses were significantly more effective than the 25-mg or 50-mg doses (p < 0.001) (fig. 3). The amount of exercise necessary to produce angina 3 hours after drug ingestion was increased by all atenolol doses. At 24-hours after drug ingestion, however, only 50-mg (p < 0.01), 100-mg (p < 0.005) and 200-mg doses of atenolol (p < 0.001) showed significant improvement compared with placebo (fig. 3). ST depression was significantly reduced 3 hours after drug ingestion by 25-mg and 50- - PLACEBO PEAK 80 TROUGH L PLACEBO PEAK TROUGH FIGURE 2. The effect of atenolol dosage increments heart rate at peak and trough points. on doses (p < 0.05), but more markedly reduced for 100-mg and 200-mg doses compared with placebo (p < 0.01). The response to 25 mg of atenolol did not differ from the response to placebo. Only the 100-mg (p < 0.02) and 200-mg (p < 0.02) doses of atenolol produced significant reduction of ST depression 24 hours after drug ingestion. mg Twenty-four-hour Ambulatory ECGs The mean hourly heart rate was plotted against time for the full 24-hour period (fig. 4). All doses suppressed heart rate compared with placebo. Atenolol 100 mg and 200 mg were the most effective 24 hours after drug ingestion (p < 0.001). The minimum and maximum heart rates are shown in table 4. The mean maximum heart rate during the placebo period was 119 beats/min. During administration of atenolol at 25, 50, 100 and 200 mg, the maximum heart rate was 103, 94, 89 and 88 beats/min, respectively, and oc- TABLE 3. Atenolol Exercise Data Resting heart rate (beats/min) Exercise heart rate (beats/min) Resting SBP (mm Hg) Resting DBP (mm Hg) Exercise SBP (mm Hg) Exercise time (sec) Exercise ST depression (mm) Double product 25 mg Peak Trough 62.1 70.9 2.1 *2.7 104.4 100.1 *3.6 131.7 *6.0 77.9 *3.7 -4.1 139.1 149.5 161.0 *7.5 477.2 *44.9 1.2 *0.3 151.0 *11.9 *7.5 81.6 *5.5 *7.7 407.5 *34.2 1.4 *0.3 170.0 13.8 50 mg Peak Trough 58.5 67.1 -3.0 i1.5 96.7 101.7 -3.1 -4.1 132.4 127.1 *6.4 -7.0 76.5 77.9 *2.5 *3.5 154.0 150.1 *9.1 *7.2 552.0 447.9 39.3 *35.7 1.06 1.5 *0.2 *0.3 159.0 147.0 *10.2 14.9 100 mg Peak Trough 54.3 61.5 -1.5 *2.9 89.5 99.4 *2.1 -3.9 128.0 130.8 *7.3 *5.5 76.4 75.2 *3.3 *4.1 143.9 153.1 -6.1 *9.0 527.5 459.0 *39.7 37.4 0.8 0.9 *0.3 *0.2 129.0 153.0 *8.0 13.4 Values are mean * SEM. Abbreviations: SBP = systolic blood pressure; DBP = diastolic blood pressure; double systolic blood pressure divided by 100. product 200 mg Peak Trough 60.7 60.8 *2.9 *2.9 88.1 96.9 *4.0 *2.5 127.1 127.4 -8.0 *7.5 74.4 70.3 *3.5 *3.9 145.1 155.0 *6.9 48.3 508.3 541.7 i 35.3 *38.5 0.7 1.2 0.4 *0.4 128.0 152.0 14.1 8.7 exercise heart rate times EXERCISE TIME (sec) ST DEPRESSION (mm) DOUBLE PRODUCT 550 1- 2.5 220 200 500 _- 200 _- FIGURE 3. Though exercise time was significantly prolonged at all peak levels, only 100-mg and 200-mg doses were significantly effective at trough levels. Similarly, the double product was more effectively reduced by 100-mg and 200-mg doses at trough points, as was the ST-segment depression. 2 100 450 H 50 180 _ 1.5 _ 25 400 _ 160 _ 1 350 _ 140 _ 0.5 PEAK TROUGH PLACEBO ATENOLOL (mg) _ o 120 300 PLACEBO PEAK TROUGH ATENOLOL (mg) PEAK TROUGH PLACEBO ATENOLOL (mg) curred at the time of treadmill exercise testing. The mean minimum heart rate for the placebo period was 55 beats/min, and occurred during sleep. During administration of 25, 50, 100 and 200 mg of atenolol, the mean minimum heart rates were 52, 52, 47 and 47 beats/min, respectively. Diurnal variation in heart rate was observed. Even with the higher atenolol doses, no heart rates less than 45 beats/min were recorded during the 24-hour period. Figure 5 is a typical R-R interval plot that shows the increase in R-R interval with increasing drug dosage and the narrowing of the range of intervals recorded during atenolol therapy. Drug Levels The mean peak steady-state serum atenolol concentrations were 117.4, 257.2, 437.2 and 916.5 ng/ml after 2-week administration of atenolol at doses of 25, 50, 100 and 200 mg, respectively (fig. 6). The peak serum levels increased linearly with increased dosage, T T 1 - l T - o PLACEBO 90 - n -be E -C : a 50 | ATENOLIOL 80 cc cr cc I VOL 61, No 3, MARCH 1980 CI RCULATION 558 70 _ 60 _ suggesting linear bioavailability and pharmacokinetics. The peak concentration during the 200-mg dosing protocol was as high as 2000 ng/ml in one patient. There was significant intersubject variability in peak serum concentrations, with an average coefficient of variation for all four doses of 55%. The mean trough steady-state serum atenolol concentrations were 23.0, 51.9, 67.8 and 103.7 ng/ml after the 2-week administration of atenolol at doses of 25, 50, 100 and 200 mg, respectively (fig. 6). The trough concentrations were 20.7 ± 10.6% (mean ± SD) of the peak level when all data pairs were considered. Though adequate blood samples were not obtained to permit calculation of disposition parameters, these data suggest an average elimination halflife for atenolol of about 10 hours. Side Effects and Toxicity Studies One patient developed mild congestive cardiac failure on 200 mg atenolol (with a peak serum drug concentration of 1000 ng/ml), but this resolved with dosage reduction and diuretic therapy. There were no changes in SGOT, Alk Phos, total bilirubin, FBS, uric acid, BUN, total protein, cholesterol, calcium, inorganic phosphate, albumin, LDH, hemoglobin, hematocrit or white blood count. Nine of the 10 patients have continued on long-term atenolol therapy with no complaints of vivid dreams, hallucinations, depression or insomnia. TABLE 4. Heart Rates Derived From 24-hour Ambulatory Recordings EG- 0 zW13 50 _ ,a,q _ 8 10 12 14 16 18 20 22 24 TIME OF DAY 2 4 6 8 FIGURE 4. Mean hourly heart rate for individual atenolol doses and placebo. Time of tablet ingestion is indicated by arrow. bpm = beats/min. Placebo Atenolol (25 mg) Atenolol (50 mg) Atenolol (100 mg) Atenolol (200 mg) Values are mean SEM. Minimum (beats/min) Maximum (beats/min) 55.1 52.2 50.3 47.0 47.3 118.7 103.5 94.3 88.8 87.7 - 1.0 1.5 1.4 0.8 1.7 4.1 4.2 2.0 4.1 4.4 ATENOLOL FOR ANGINA PECTORIS/Jackson et al. 5_ 1 1 1 1 ATENO L0L (200 mg) cJ z c O _- 1 5_ 1- 0 01 0L 5 0 ATENOLOL z (50 mg) 1 g 1 * 1 1 1 - | *l h,-1X | X 1 _ _ a z LU c-, LUJ 0. F ATENOLOL (100 mg) 01 ATENOLOL (25 mg) 0 5 7 1 12 1 1 1500 (40) 1750 PLACEBO 250 500 (120) 1000 1-250 (60) (48) R-R INTERVAL (msec) 750 (80) FIGURE 5. By plotting R-R interval against percent frequency of occurrence, the 24-hour heart rate control is illustrated. With increasing dosage, the plot moves to the right, indicating improved 24-hour heart rate control. Discussion Beta-adrenergic antagonists are well established in the treatment of angina pectoris. The major beneficial effect is achieved through reduction of myocardial oxygen consumption, primarily by decreasing exercise heart rate and blood pressure.'0 11 As the mechanism of action of these drugs is competitive inhibition of fl receptors, little difference in antianginal benefit of equipotent doses of individual agents would be expected once the maximum reduction of peak exercise heart rate is achieved.10 Propranolol, one of the most widely used of the /3 blockers, has several clinical disadvantages: first, a relatively short pharmacokinetic half-life (4-6 hours), which has prompted (perhaps unnecessarily) frequent dosing intervals;12 second, nonspecific f/ blockade with potential pulmonary and peripheral vascular effects; and third, central nervous system side effects (which now constitute a compelling reason for discontinuing /-blocker therapy).'3 Atenolol, like propranolol, has a pure f antagonist action'4' 1' but lacks intrinsic sympathomimetic activity and membrane-stabilizing activity.'3 Potential advantages of atenolol include its cardioselective / blockade,'8' 17 a plasma half-life of 6-10 hours and a pharmacodynamic half-life of 18 hours,15' 18 and the lack of significant penetration into the central nervous system'5 (personal communication: Imperial Chemical Corporation Laboratory). A single oral dose of atenolol in normal volunteers has produced blockade of exercise-induced tachycardia for at least 24 hours after ingestion.'8'20 At least one preliminary antianginal study has shown that atenolol given twice daily is as effective as propranolol7 and that for op- 559 timal dosages, atenolol was effective once daily.3 Another antianginal study reported that atenolol was more effective than practolol.' Neither sedative effects21 nor decreased reaction times22 after atenolol administration have been reported. Although vivid dreams have been sporadically reported during atenolol therapy,23 they occur much less frequently than with propranolol. In a report of patients who had nightmares, hallucinations and insomnia on d blockers, almost all noted a reversal of these side effects after changing to atenolol.24 The protocol was designed to establish the presence or absence of adequate A blockade throughout the 24hour period after the oral administration of atenolol once daily. Reduction of peak exercise heart rate was evaluated through treadmill stress testing 3 and 24 hours after atenolol ingestion at the time of peak and trough serum atenolol levels. Twenty-four-hour ambulatory electrocardiographic recordings monitored the heart rates under resting conditions and normal daily activity to exclude major swings in heart rate control. To assess the antianginal efficacy of atenolol, we measured anginal attack rate, consumption of nitroglycerin and changes in exercise tolerance in each patient. By correlating serum atenolol levels with anginal relief and exercise tolerance, we hoped to define the optimum therapeutic dosing range, dosage interval and the therapeutic antianginal serum concentration range. Our results show that in stable angina, atenolol significantly reduces the frequency of anginal attacks X 1100 1000 900 E 800 zO 700 H z 600 W 0 Z 500 0 - - - - ojC0 4002 W H300 <~~~~ DOSE ADMINISTERED (mg) FIGURE 6. Peak (filled circles) and trough (open circles) steady-state serum atenolol concentration as a function of dose. Each point represents the mean ± SEM of the subjects. 560 CIRCULATION and nitroglycerin consumption, with 100-mg and 200mg doses being the most effective. The results from 24-hour ambulatory electrocardiographic monitoring showed good control of heart rate throughout the 24hour dosing period with preservation of the normal nighttime bradycardia. Atenolol significantly prolonged the duration of exercise at the time of peak serum levels and significantly reduced the peak exercise heart rate, double product and ST depression. Though all dose increments significantly reduced exercise heart rate at trough serum levels, only the 50-mg, 100-mg and 200-mg doses significantly increased exercise time when compared with placebo. In these studies, the serum concentration of atenolol related to the magnitude of the effect and can be used as a dosing guideline. We found a mean trough serum concentration of about 70 ng/ml was necessary to insure adequate therapeutic benefit throughout the 24hour dosing interval. This level was achieved with a chronic oral dose of 100 mg once daily. Our studies show that atenolol is a potent antianginal agent. We observed that adequate 24-hour heart rate control is possible with 50-mg, 100-mg or 200-mg doses administered once daily. When only the hemodynamic variables are considered, there is no significant difference between the 50-mg, 100-mg and 200-mg dosages. Regarding anginal relief, the 200-mg dosage was superior to the 50-mg dosage (p < 0.005), but did not significantly differ from the 100-mg dosage, although four patients subjectively benefited most from the 200-mg dosage. This report supports the initial choice of 100 mg of atenolol for antianginal benefit and increase in exercise tolerance when given once daily. If this dose is well tolerated, advancement to 200-mg/day for optimal therapeutic effect may be required, depending on the clinical response. Cardioselectivity is relative and does not imply complete cardiospecificity; therefore, caution is advised with the administration of any 3 blocker to patients with bronchospastic disorders. In addition, the atenolol dosage or the dosage interval may need to be altered in the presence of renal impairment because excretion is almost entirely via the kidneys. Nonetheless, with its reduced side effects, cardioselectivity and once-daily dosing schedule, atenolol shows promise of significant advantages over currently available 3 blockers. Acknowledgments The authors thank Gail Yee, Sally Mancini, Inez Rodriguez, Cay Fotopolos and Gary Sanders for their technical assistance; -Helena Kraemer for statistical consultation; Gale Pickering and Cathy Cassady for the manuscript preparation; and Dr. Howard Burchell for his editorial assistance. References 1. Harrison DC: Circulatory Effects and Clinical Uses of Beta- VOL 61, No 3, MARCH 1980 adrenergic Blocking Drugs. Amsterdam, Excerpta Medica, 1972 2. Alderman EL, Davies RO, Crowley JJ, Lopes MG, Brooker JZ, Friedman JP, Graham AG, Matlof HM, Harrison DC: Dose response effectiveness of propranolol for the treatment of angina pectoris. Circulation 51: 964, 1975 3. Jackson G, Harry JD, Robinson C, Kitson D, Jewitt DE: Comparison of atenolol with propranolol in the treatment of angina pectoris with special reference to once daily administration of atenolol. Br Heart J 40: 998, 1978 4. Roy P, Day L, Sowton E: Effect of a new 0-adrenergic blocking agent, atenolol (Tenormin), on pain frequency, trinitrin consumption, and exercise ability. Br Med J 3: 195, 1975 5. Erikssen J, Osvik K, Dedichen J: Atenolol in the treatment of angina pectoris. Acta Med Scand 201: 579, 1977 6. Shand DG: Propranolol withdrawal. N Engl J Clin Prac 27: 331, 1973 7. Jackson G, Atkinson L, Oram S: Double-blind comparison of tolamolol, propanolol, practolol and placebo in the treatment of angina pectoris. Br Med J 1: 708, 1975 8. Spitz AL, Fitzgerald JW, Harrison DC: Ambulatory arrhythmic quantification by a correlation technique. In Computers in Cardiology. IEEE Computer Society, Long Beach, California, 1977, pp 225-233 9. Yee YG, Rubin P, Blaschke TF: Atenolol determination by high-pressure liquid chromatography and fluorescence detection. J Chromatog 171: 357, 1979 10. Jackson G, Atkinson L, Oram S: Reassessment of failed betablocker treatment in angina pectoris by peak exercise heart rate measurements. Br Med J 3: 616, 1975 11. Robinson BF: Relation of heart rate and systolic blood pressure to the onset of pain in angina pectoris. Circulation 35: 1073, 1967 12. Thadani V, Parker JO: Propranolol in the treatment of angina pectoris. Comparison of duration of action in acute and sustained oral therapy. Circulation 59: 571, 1979 13. Forrest NA: Oxprenolol and a thiazide diuretic together in the treatment of essential hypertension - a large general practice study. Br J Clin Prac 27: 331, 1973 14. Harry JD: The demonstration of atenolol as a betaadrenoceptor blocking drug in man. Postgrad Med J 53 (suppl 3): 65, 1977 15. Barrett AM: The pharmacology of atenolol. Postgrad Med J 53 (suppl 3): 158, 1977 16. Fitzgerald JD: Why another beta-antagonist. Postgrad Med J 53 (suppl 3): 52, 1977 17. Astrom H: Comparison of the effects on airway conductance of a new selective beta-adrenergic blocking drug, atenolol, and propranolol in asthmatic subjects. Scand J Resp Dis 56: 292, 1975 18. McAinsh J: Clinical pharmacokinetics of atenolol. Postgrad Med J 53 (suppl 3): 74, 1977 19. Shanks RG, Kelly JG, Carruthers SG, McDevitt DG: Correlation of reduction of exercise heart rate with blood levels of atenolol after oral and intravenous administration. Postgrad Med J 53 (suppl 3): 70, 1977 20. McDevitt DG, Kelly JG, Johnston GD, Shanks RG: Investigation of chronic dosing regimens of atenolol. Postgrad Med J 53 (suppl 3): 79, 1977 21. Betts TA, Blake A: The psychotropic effects of atenolol in normal subjects: preliminary findings. Postgrad Med-J 53 (suppl 3): 151, 1977 22. Bayliss PFG, Duncan SM: The effects of atenolol and methyldopa on simple tests of central nervous function. Br J Clin Pharmacol 2: 527, 1975 23. Simpson WT: Nature and incidence of unwanted effects with atenolol. Postgrad Med J 53 (suppl 3): 162, 1977 24. Henningsen NC, Mattiasson I: Long-term clinical experience with atenolol - a new selective A3- 1 -blocker with few side effects from the central nervous system. Acta Med Scand 205: 61, 1979