Comparative Effects of Beta Adrenergic Blocking Drugs
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Thorax: first published as 10.1136/thx.30.1.9 on 1 February 1975. Downloaded from Thorax (1975), 30, 9. Comparative effects of beta adrenergic blocking drugs EDGAR SOWTON, D. S. DAS GUPTA1, and I. BAKER The Cardiac Department, Guy's Hospital, London SE] Sowton, E., Das Gupta, D. S., and Baker, I. (1975). Thorax, 30, 9-18. Comparative effects of beta adrenergic blocking drugs. Although many different beta blockers are now in clinical use, there is very little information concerning their relative efficacy, and it is still not clear what clinical importance should be attached to properties such as positive inotropic stimulation (intrinsic sympathomimetic activity or ISA) and membrane stabilizing action ('local anaesthetic effect' or 'quinidine-like effect'). In this report we compare the ability of patients with angina to exercise on a bicycle ergometer while receiving a series of commonly used beta blockers, and attempt to determine the impor- tance of ISA. The investigation is in four parts with the drugs given orally or intra- venously: statistical analysis of the results was carried out using standard methods, both parametric and non-parametric (Friedmann analysis of variance, Wilcoxon matched pairs signed ranks test) by two independent statisticians. copyright. The relevant properties of drugs included in this paper are summarized in Table I. Laboratory reports using many different animal preparations may differ from this assessment under specific conditions, and the Table is intended only as a guide to the generally accepted properties of these drugs when used clinically. Results for sotalol are included for reference in the first part of this paper but the drug was withdrawn http://thorax.bmj.com/ from clinical use and was not studied further. TABLE I steady-state erect exercise at 300 kpm/minute on a bicycle ergometer. Control measurements were Membrane Drug Trade Name Route given Activity ISA made 6 minutes after the start of the exercise, and changes were measured a fur- Propranolol Inderal IV and oral Yes No drug-induced Practolol Eraldin IV and oral Minimal Yes ther 6 minutes following intravenous injection of Alprenolol Aptin IV and oral Yes Yes on September 27, 2021 by guest. Protected Oxprenolol Trasicor IV and oral Yes Yes one of five beta-blocking drugs. The haemody- MJ 1999 Sotalol IV Minimal No namic results are shown in Fig. 1, illustrating that Pindolol (LB46) Visken Oral Minimal Yes there are considerable differences between these drugs, particularly with regard to practolol; it might be anticipated that these differences are HAEMODYNAMIC COMPARISONS OF DRUGS reflected in the clinical responses of patients with As a basis for subsequent assessment of doses and angina. consideration of importance of ISA we present here some haemodynamic results obtained by Hoy, Gibson, and Sowton which have previously COMPARISON OF DIFFERENT INTRAVENOUS DOSES been unpublished. Measurements of cardiac AT SEVERAL EXERCISE LEVELS output (dye dilution technique), intra-arterial Further data were obtained by comparing the pressure (via 1 mm Teflon tubes introduced per- inhibition of exercise tachycardia by four beta cutaneously into the brachial artery), and heart blocking drugs in groups of normal volunteers and rate (from ECG recordings) were taken during patients. The results are the mean from six sub- jects, and between groups there were no signifi- 'Present address- Department of Cardiology, University of Chicago Hospitals, 950 East 59th Street, Chicago, Illinois 60637, USA cant differences of heart rate at rest or at each 9 Thorax: first published as 10.1136/thx.30.1.9 on 1 February 1975. Downloaded from 10 E. Sowton, D. S. Das Gupta, and I. Baker been combined. The results are summarized in Table II. ficLav There is a tendency for these drugs to approach .I t) " Ra". - more closely the effect of propranolol as the exer- 2 1'.I .--.j cise level was increased, and also (with the excep- 1(} tion of sotalol) as the dose level was increased. ( t l. i !i l' Ii (-I.)L l , The molecular weights of the drugs are similar, I and so this milligram for milligram comparison approximates to a molecule for molecule basis. 11.I The relative potencies of the drugs differ con- 11 siderably and it is noteworthy that they differ S\ .; :.t - from values established in antagonism of an isoprenaline-induced tachycardia in laboratory I1 animals (cats) as determined by Barrett and ,., - Carter (1970) and shown in Table III. ~.R IjT} ul11, TABLE II i;\ '}1 F .,- COMPARATIVE SLOWING OF TACHYCARDIA DURING 4,'.-,I ERECT EXERCISE E t' (Propranolol effect = 100%) .; 0 r._ (I k-7.-- Exercise Level IV Dose Drug Rest Half Maximum Maximum 05 mg Propranolol 100 100 100 7 Practolol 70 30 30 z Alprenolol * 40 45 Sotalol * 50 30 copyright. 15 mg Propranolol 100 100 100 Practolol 40 55 55 FIG. 1. Haemodynamic changes 6 minutes after 5 mg Alprenolol * 50 70 Sotalol 20 40 45 intravenous 8 blocker during erect exercise. 50 mg Propranolol 100 100 100 Practolol 40 60 75 Alprenolol 17 60 75 exercise level on placebo tests. Also, there were Sotalol 20 30 45 http://thorax.bmj.com/ no significant differences in mean age nor in the total amount of exercise performed after either *Heart rate faster than control level. placebo or active drugs. Preliminary results with two drugs have been presented elsewhere (Sowton, TABLE III ANTAGONISM OF ISOPRENALINE TACHYCARDIA IN CATS 1970). Each subject underwent an exercise test, in which the maximal work load was established, Drug Relative and on each of four subsequent days re-exercised Potencies Propranolol 100 at levels of one quarter, one half, three quarters, Alprenolol 103 and maximum tolerance. A warm-up period of Oxprenolol 187 on September 27, 2021 by guest. Protected Practolol 40 exercise, followed by 20 minutes' rest, preceded Sotalol 8 the definitive test on each occasion. At rest and Pindolol 2,480 for two minutes at each exercise level the heart rate was measured following intravenous injection of placebo (saline) and 0 5 mg, 15 mg and 5 mg COMPARATIVE INTRAVENOUS TRIAL IN ANGINA of active drug. Each investigation therefore con- The relative effects on exercise tolerance in 12 sisted of five exercise tests, during the last three patients with angina pectoris were studied using of which the subject had cumulative doses of intravenous injections of four beta blocking drugs 0 5 mg, 1X5 mg, and 5 mg of the test drug. Fig. 2 in doses based upon the results given above and a shows representative results following saline, consideration of the literature. These doses were: propranolol, practolol, and alprenolol injections. propranolol 5 mg, oxprenolol 5 mg, alprenolol The reduction in heart rate with propranolol 10 mg, and practolol 40 mg; in each case the was taken as 100% and the changes following manufacturers confirmed that these doses might other drugs were expressed proportionately. There be expected to produce similar improvement in were only minor differences in results for normal exercise tolerance. The drug solutions were pre- subjects or patients, and so these groups have pared in the Guy's Hospital pharmacy and the Thorax: first published as 10.1136/thx.30.1.9 on 1 February 1975. Downloaded from Comparative effects of beta adrenergic blocking drugs 11 PL ACEBO P ROPRANOLOL a0 4 .-- '---..g a0 .-.._..................... 0 5 - =~~~~~~~~- :e ;.-. n 0 14 a 3 Is I .0. O 20- a 0SOmg i I I 6 EXERCISE LEVlL ; " a- rw| EXERCISE LEVEL PRACTOLOL ALPRENOLOL I. i a0. 01.Smg 5' ~ ~ ~ ~ - I*Sm i ............e- ., .. - .*54m 51 .............---.... 6 oas -o_ copyright. 0a3 9 o i, U1 s i A i --- I -w- * s - - - w L a I -ig IV fAlleac" LIVLt EXERCISE LEVEL FIG 2. http://thorax.bmj.com/ trial was double-blind; the order of drugs was exercise was begun 3 minutes later at a work randomized, and all patients received all drugs. load of 200 kpm/minute. The work load was in- All patients had typical histories of angina pec- creased by 200 kpm/minute every 3 minutes until toris for the last three months and had abnormal anginal pain was produced; ECGs were continu- ECGs with typical ischaemic ST segment depres- ously monitored. Recordings were taken for 15 sion during exercise. There were 10 men and two seconds before the one-minute point and three- women with a mean age of 51 years; none had minute point at each work load, as well as at the on September 27, 2021 by guest. Protected hypertension, valve disease, asthma, or chronic onset of anginal pain. The patients were then bronchitis, or gave a history of heart failure. All allowed to rest again until heart rates had re- had agina graded 2 or 3 (moderate or severe) on turned to baseline values, and 20 ml of beta-block- a 4-point scale in which grade 4 represents angina ing solution was injected. The exercise test was occurring at rest (Balcon, Maloy, and Sowton, then repeated using the same protocol. Assessment 1968). The only other drug used was sublingual of exercise tolerance was made by calculating the nitroglycerine, which was not taken on the morn- total work performed before the onset of angina, ing of the investigations. and the improvement over saline values was taken Exercise testing was carried out according to as a measure of the drug effect. There were no a standardized protocol at 9 am on separate days complications during this investigation and no in the sitting position on a bicycle ergometer patient complained of side effects. (Elema-Schonander). An initial warm-up for 3 minutes at 200 kpm/minute was followed by rest RESULTS The mean increase in total work before until the heart rate had returned to control values pain was greatest with practolol (1,250 kpm) (typically 20 to 30 minutes).