On Exercise Tolerance in Patients with Angina Pectoris

Thorax: first published as 10.1136/thx.28.3.331 on 1 May 1973. Downloaded from

Thorax (1973), 28, 331.

Effects of a new cardioselective beta-adrenergic blocker (tolamolol) on exercise tolerance in patients with angina pectoris

N. K. SOOD and C. W. H. HAVARD Department of Medicine, Royal Northern Hospital, London

The effect of oral and intravenous tolamolol on exercise tolerance was assessed in 11 patients with angina pectoris. Patients were selected on the basis of an absence of placebo response and the reliable reproducibility of anginal pain and electrocardiographic changes with exercise on a constant load Schonander-Elema bicycle ergometer. The effect of tolamolol on exercise time and heart rate was compared with that of propranolol. Tolamolol was shown to increase exercise tolerance and the effect was comparable to that of propranolol. Tolamolol did not produce a significant increase in airways resistance nor were any untoward side effects noted. Since the beneficial effect of pronethalol in the when given by mouth a negative chronotropic and treatment of angina pectoris was demonstrated a positive inotropic effect have been demonstrated (Dornhorst and Robinson, 1962; Alleyne et al., in anginal subjects (Wilson et al., 1968). A single 1963; Apthorp, Chamberlain, and Hayward, 1964) blind trial (Wilson and Turner, 1968) and a

several new beta-adrenergic blocking compounds double blind trial (Wilson, Watson, Peel, and http://thorax.bmj.com/ have been introduced. Propranolol, the first clini- Turner, 1969) have demonstrated its effectiveness cally acceptable beta-blocker, has become estab- in reducing the severity and frequency of anginal lished in the treatment of angina (Gillam and attacks. Prichard, 1965; Hamer and Sowton, 1966; Wolf- Tolamolol is a new beta-adrenergic blocking son et al., 1966). Propranolol, however, reduces compound. In animal studies it has been found to myocardial contractility (Chamberlain, 1966; have a cardioselective action similar to that of Stephen, 1966) and causes an increase in airways practolol, and it is considerably more active resistance (McNeill, 1964) which limits its use in (Adam, 1972). It does not have the direct depres- patients with ischaemic heart disease associated sant action of propranolol on myocardial con- on September 30, 2021 by guest. Protected copyright. with asthma or chronic bronchitis. Practolol tractility (Hillis, 1973). It is, therefore, of con- (Eraldin) and oxprenolol (Trasicor) are more siderable clinical interest. This study was under- recent beta-blockers with a more cardioselective taken to assess the effects of tolamolol on anginal action. Initial studies with intravenous practolol subjects during bicycle ergometer exercise under showed encouraging results (Areskog and Adolfs- strictly controlled conditions. son, 1969) but long-term oral administration sug- gests that practolol is not as effective as propranolol in relieving the frequency of angina (Sandler MATERIALS AND METHODS and Clayton, 1970). This is probably due to the intrinsic sympathomimetic activity of practolol Patients were selected on the basis of the reliable repro- (Dunlop and Shanks, 1968). Furthermore, practo- ducibility of anginal pain and/or electrocardiographic lol has been shown to have negative inotropic changes with exercise on a constant load Schbnander- effects on the myocardium (Gibson and Sowton, Elema bicycle ergometer. Individuals with severe angina, a history of myocardial infarction in the pre- 1968; Sowton, Balcon, Cross, and Frick, 1968) vious six months, severe obstructive airways disease, and its use in patients with incipient cardiac or cardiac failure and those with intercurrent disease failure is not without risk (Sandler and Clayton, likely to interfere with performance on a bicycle 1970). Oxprenolol, intravenously, produces nega- ergometer were excluded. tive chronotropic and inotropic effects, although For preliminary selection each patient undertook a 331 Thorax: first published as 10.1136/thx.28.3.331 on 1 May 1973. Downloaded from

332 N. K. Sood and C. W. H. Havard prolonged phase of familiarization with the bicycle RESULTS ergometer and the requirements of the investigation. This was to ensure reproducibility of symptoms or The effects of different treatments on exercise time objective electrocardiographic changes with a standard and on heart rate at rest and after exercise are exercise test. Up to eight exercise tests were performed shown in Tables I and II. The results re-confirm during this phase. Exercise loads were selected to produce pain or ECG changes within 90 to 120 seconds. the lack of response to placebo in the subjects Chest lead V5 was continuously monitored. Patients selected for the trial. The increase in exercise were trained to stop exercise at the first sign of anginal tolerance with each of the active compounds ad- pain, or if instructed to do so when ECG changes sug- ministered is highly significant (P

Effects of tolamolol on exercise tolerance in patients with angina pectoris 333 the compounds administered. No untoward side lol, and 101 % with oral tolamolol. The percentage effects were recorded. There were no significant increment with propranolol is higher than that of changes in the blood count, liver function tests or previous reports using exercise tolerance (Areskog urinalysis. and Adolfsson, 1969; Hamer, Grandjean, Melen- Of the eight patients in whom FEV1 was dez, and Sowton, 1964). This is due to the method measured, it was slightly lower in five, higher in of testing which produced an early end point to two, and remained unaltered in one (Table III). exercise and any increase in exercise tolerance therefore became proportionally large. TABLE III The present study shows that tolamolol in- creases the exercise tolerance of patients with FEV, angina pectoris. Furthermore, doses of tolamolol Patient _ Before i.v. Tolamolol After i.v. Tolamolol capable of blocking cardiac beta receptors do not 1 350 3-40 produce a significant increase in airways resistance 2 3-10 3-25 in patients who do not suffer from asthma. This is 3 3-20 2-80 4 2-65 2 40 an important advantage over propranolol. Further 5 3130 3 25 6 3 15 295 studies are now required to confirm the clinical 7 2-80 2-90 efficacy of this drug in the long-term treatment of 8 3130 3 30 Mean 3-125 303 angina pectoris. We are grateful to Dr. Douglas Chamberlain for helpful advice and to Mr. Michael Curwen for statis- DISCUSSION tical help.

A method of exercise testing to assess the anti- anginal effect of tolamolol was chosen because this provides more useful data and more reliable results than a carefully designed double blind trial REFERENCES in which it is always difficult to exclude a placebo Adam, K. R. (1972). Personal communication. http://thorax.bmj.com/ response and other factors beyond the control of Alleyne, G. A. O., Dickinson, C. J., Dornhorst, A. C., and Fulton, R. M., Green, K. G., Hill, 1. D., Hurst, P., the investigator (Cole Goldberg, 1967; Datey Laurence, D. R., Pilkington, T., Prichard, B. N. C.. and Dalvi, 1970; Redwood et al., 1971). All Robinson, B., and Rosenheim, M. L. (1963). Effect of patients showing any placebo response were ex- pronethalol in angina pectoris. Brit. med. J., 2, 1226. cluded from the investigation. While it is uncer- Apthorp, G. H., Chamberlain, D. A., and Hayward, G. W. tain how the results obtained with bicycle ergo- (1964). The effects of sympathectomy on the electro- cardiogram and effort tolerance in angina pectoris. Brit. metry relate to everyday activity, this technique Heart J., 26, 218. has the virtue of reproducibility under controlled Areskog, N. H., and Adolfsson, L. (1969). Effects of a cardio- on September 30, 2021 by guest. Protected copyright. conditions. Our results show that both proprano- selective beta-adrenergic blocker (I.C.I. 50172) at lol and tolamolol are effective in increasing exer- exercise in angina pectoris. Brit. med. J., 2, 601. cise tolerance in patients with angina pectoris. The Chamberlain, D. A. (1966). Haemodynamic effects of beta- favourable effects of tolamolol are comparable to adrenergic blockade in man. Cardiologia, 49, Suppl. 2, p. 27. those of propranolol and are evident following Cole, R. E., and Goldberg, R. I. (1967). Timed-release both oral and parenteral administration. The dif- pentaerythritol tetranitrate and placebo in the manage- ference in exercise tolerance between oral and ment of angina pectoris. Curr. ther. Res., 9, 551. intravenous tolamolol (P<0-005) may be due to Datey, K. K., and Dalvi, C. P. (1970). Anti anginal drugs, the difference in effective doses of the drug. It is their evaluation by double blind trial. Angiology, 21, 520. possible that smaller effective doses were given Dornhorst, A. C., and Robinson, B. F. (1962). Clinical pharmacology of a beta-adrenergic-blocking agent parenterally compared to the standard oral dose (nethalide). Lancet, 2, 314. of 200 mg given to all patients. Dunlop, D., and Shanks, R. G. (1968). Selective blockade of The mechanism of action of tolamolol involves adrenoceptive beta receptors in the heart. Brit. J. blockade of cardiac sympathetic beta receptors. Pharmacol., 32, 201. Haemodynamic studies have now shown that Gibson, D., and Sowton, E. (1968). Effects of I.C.I. 50172 in although it has a slight negative inotropic effect, man during erect exercise. Brit. med. J., 1, 213. this is not associated with a reduction in cardiac Gillam, P. M. S., and Prichard, B. N. C. (1965). Use of propranolol in angina pectoris. Brit. med. J., 2, 337. contractility (Hillis, 1973). The mean percentage Hamer, J., Grandjean, T., Melendez, L., and Sowton, G. E. increase in effort tolerance in our studies was 74% (1964). Effect ofpropranolol (Inderal) in angina pectoris: with propranolol, 81 % with intravenous tolamo- preliminary report. Brit. med. J., 2, 720. Thorax: first published as 10.1136/thx.28.3.331 on 1 May 1973. Downloaded from

334 N. K. Sood and C. W. H. Havard

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