O’Brien
28. 29.
30. 31.
32.
33.
34. 35.
36.
et al.
American
Gould B, Mann S, Davies AB, et al. Does placebo lower bloodpressure? Lancet 1981;2:1377. Drayer JIM, Weber MA, DeYoung JL, Brewer DD. Long-term BP monitoring in the evaluation of antihypertensive therapy. Arch Intern Med 1983;143:898. DuPont AG, van der Niepen P, Six RO. Placebo does not lower ambulatory blood pressure. Br J Clin Pharmacol1987;24:106. Conway J, Johnston J, Coats A, et al. The use of ambulatory blood pressure monitoring to improve the accuracy and reduce the numbers of subjects in clinical trials of antihypertensive agents. J Hypertens 1988;6:111. Cheung DG, Neutel JM, Smith DHG, et al. Absence of placebo effect on the whole-day ambulatory blood pressure (BP) (Abstract). Clin Pharmacol Ther 1990;47:200. Bellet M, Pagny J-Y, Chatellier G, et al. Evaluation of slow release nicardipine in essential hypertension by casual and ambulatory blood pressure measurements. Effects of acute versus chronic administration. J Hypertens 1987;5:599. Hills M, Armitage P. The two-period cross-over clinical trial. Br J Pharmacol 1979;8:7. Mann S, Millar-Craig MW, Balasubramanian V. Propranolol LA and ambulatory blood pressure. Br J Clin Pharmacoll980; 10:443-7. Gradman AH, Pangan P, Germain M. Lack of correlation between clinic and 24-hour ambulatory blood pressure in subjects participating in a therapeutic drug trial. J Clin Epidemiol 1989:42:1049-54.
Clinical drugs
pharmacology
37.
38. 39.
40.
41.
42.
43.
44. 45.
March 1991 Heart Journal
Fitzgerald DJ, O’Malley K, O’Brien ET. Reproducibility of ambulatory blood pressure recordings. In: Weber MA, Drayer JIM, eds. Ambulatory blood pressure monitoring. New York: Springer, 1984:71. Coats A, Conway J, Sleight P. Ambulatory monitoring, clinical trial size and precision. J Hypertens 1989;7(suppl6):S357. Rose M, McMahon GF. Some problems with antihypertensive drug studies in the context of the new guidelines. Am J Hypertens 1990;3:151. Cox JP, Ryan J, O’Brien E, O’Malley K. The effect of slow-release nicardipine on ambulatory and clinic blood pressure in mild hypertension. Br J Clin Pharmacol 1989;28:79. Conway J, Coats A. Value of ambulatory blood pressure monitoring in clinical pharmacology. J Hypertens 1989;7(suppl 3):S29. Cruickshank JM, Thorp JM, Sacharias FJ. Benefit and potential harm of lowering high blood pressure. Lancet 1987;1:581. Alderman MH, Ooi WL, Madhavan S, Cohen H. Treatmentinduced blood pressure reduction and the risk of myocardial infarction. JAMA 1989;262:920. Floras JS. Antihypertensive treatment, myocardial infarction and nocturnal myocardial ischaemia. Lancet 1988;2:994. Stanton AV, Atkins N, O’Malley K, O’Brien E. Circadian blood pressure and antihypertensive drugs. Am J Hypertens 1990;3:107A.
of vasodilatory
,&blocking
The clinical pharmacology of @adrenoceptor blockers is summarized. They have a variety of pharmacological actions on the B-adrenoceptors. For example, propranolol is a nonselective B-blocker with antagonist effects on both 81 and & receptors, atenolol is a selective j3,-antagonist, and celiprolol is a selective @,-antagonist, partial &-agonist. j3,-Receptor blockade tends to reduce heart rate, cardiac output, and arterial pressure while increasing periphdral vascular resistance, whereas &receptor blockade tends to be disadvantageous in causing bronchoconstriction and peripheral vasoconstriction. Selective bl-antagonist, Da-agonist activity would, therefore, appear to be particularly beneficial in offering the advantages of 8, blockade plus peripheral vasodilation. The @I- and &-receptor actions of drugs are not always clearly identifiable, as in the demonstration of celiprolol’s partial &agonist activity in human beings. This is because, in vivo, cardiovascular reflexes are intact and it has not, so far, been possible to remove endogenous catecholamines. This review summarizes various studies to investigate partial agonist activity, with particular emphasis on celiprolol. (AM HEART J 1991;121:1006-11.)
Robin G. Shanks, MD, DSc Belfast, Northern Ireland
From
the Department
University
of Therapeutics
Reprint requests: R.G. Shanks, cology, The Queen’s University burn Road, Belfast BT9 7BL, 4/O/26248
1006
and Pharmacology,
The Queen’s
of Belfast. Department of Therapeutics of Belfast, Whitla Medical Northern Ireland.
and Building,
Pharma97 Lis-
Many P-adrenoceptor blocking drugs, some of which may possess a variety of additional properties, have now been described and are used extensively for the treatment of a wide variety of diseases. Although it is 25 years since the introduction of propranolol, this
Volume Number
121 3, Part 2
Clinical pharmacology
drug is still widely used and is the standard with which other p-blocking drugs are compared. Propranolol is known as a nonselective @-blocker because it acts at both the @I- and ,&-receptor sites. The former action results in reduction of heart rate, cardiac output and arterial pressure, and an increase in peripheral vascular resistance, whereas blockade of 02 receptors may produce bronchoconstriction and peripheral vasoconstriction. The cardioselective blocking drugs (practolol, atenolol, and metoprolol), which are more correctly described as ,&-selective, are an improvement over the nonselective agents. They have less effect on airway resistance and do not inhibit the bronchodilatory effect of &agonists, yet they have the same hemodynamic effects as nonselective blockers. Both types of drug are effective in the treatment of hypertension even though peripheral vascular resistance is increased after their use, probably as a reflex response to the fall in cardiac output. The increase in vascular resistance and reduction in peripheral blood flow are the probable explanations for the occurrence of cold extremities, one of the most frequent adverse effects of these drugs. Attempts have been made to overcome this effect by the development of drugs that have a peripheral vasodilatory action either through blockade of a-adrenoceptors (labetalol) or through an agonist effect on the @s receptors (pindolol, dilevalol, celiprolol). This review will summarize some of the properties of the @s-agonist, celiprolol, in human beings. &ADRENOCEPTOR
BLOCKING
ACTIVITY
In an open study involving four healthy volunteers, celiprolol at doses of 100 mg orally and 10 mg intravenously significantly reduced the increases in heart rate and systolic blood pressure produced by the intravenous infusion of isoproterenol,l but did not prevent the reduction in diastolic blood pressure. These findings suggest that celiprolol is capable of selective blockade of ,6i receptors. Reduction of the increase in heart rate occurring during moderate to severe exercise has been widely used to determine blockade of cardiac P-adrenoceptors.2 Several studies have shown that intravenous and oral administration of celiprolol reduce exercise tachycardia. 3, 4 In a double-blind crossover study involving 12 healthy, normal male subjects who exercised on a treadmill 4 hours after oral administration of 100 mg atenolol and 400 mg celiprolol, there was a significant reduction in maximum exercise heart rate with no significant difference in the degree of inhibition of exercise tachycardia (RhonePoulenc Rorer Inc., data on file).
of P-blockers
1007
SELECTlVEBLOCKADEOFfiRECEPTORS
Intravenous administration of isoproterenol in human beings produces an increase in heart rate that results mainly from stimulation of ,& receptors, and bronchodilation and peripheral vasodilation arise from stimulation of /& receptors. Practolol was the first drug to be described that selectively blocked Bladrenergic receptors.5 Several other drugs, of which the most widely used are atenolol and metoprolol, have now been developed which have this same selectivity of action. This property was, for some time, referred to as cardioselective blockade, but as the heart probably contains both Pi and @Zreceptors, it is more accurately described as &-selective blockade. Studies in animals have demonstrated that @l-selective blocking drugs inhibit the increase in heart rate but not the bronchodilation and vasodilation produced by isoproterenol.5 The same separation of responses, however, does not occur in human beings, there being little reduction in isoproterenol-induced tachycardia with doses of practolol that produce marked inhibition of exercise tachycardia.6 Atenolol and metoprolol, at dosages which reduce exercise tachycardia, have little or no effect on the responses because of stimulation of @s receptors by isoproternol.7 No studies have yet described the effects of celiprolol on exercise tachycardia and on responses to a &-agonist in the same subject group. A number of studies, however, have investigated the effects of celiprolol on the responses elicited by stimulation of 02 receptors. For example, in a study involving 12 patients with mild to moderate hypertension and reversible airways obstruction, 100 mg atenolol and 400 mg celiprolol were administered in a doubleblind manner for 4 weeks8 A single-dose challenge was performed after the first dose of placebo, atenolol, and celiprolol, and regular measurements made of forced expiratory volume in the first second of expiration (FEVl), forced vital capacity (FVC), and peak expiratory flow (PEF). At 3 hours, a 200 pg dose of inhaled salbutamol was administered and measurements repeated. The results, obtained from 10 patients, showed FEV1, FVC, and PEF to be significantly reduced by atenolol but unaltered by celiprolol. All three parameters were significantly increased by salbutamol with no difference in responses after the three treatments. Similar results have been described in other studies.g These observations indicate that celiprolol, at recommended therapeutic doses, does not block @Zreceptors and, thus, can be described as a selective /31antagonist.
1008 PARTIAL
Shanks AGONIST
American
ACTIVITY
The partial agonist activity of celiprolol has been clearly demonstrated both in vitro and in vivo in a variety of experimental models. Results from in vitro studies using human lymphocytes suggest that celiprolol may have partial agonist activity at 02 receptors.lO Demonstration of partial agonist activity in human beings has been more difficult because reflexes are intact, and it has not been possible to remove endogenous catecholamines. A number of studies in human beings have shown, however, that /3-adrenoceptor partial agonists differ from &antagonists by causing less reduction in supine heart rate and cardiac OutpuP? I2 and having flatter dose-response curves for reduction of exercise tachycardia.2, l3 Another method for investigating the partial agonist activity of P-blockers in human beings has recently been described. Heart rate normally falls during sleep to reach its lowest level after 6 hours.14 This is thought to be a result of a predominance of parasympathetic tone owing to withdrawal of sympathetic tone during sleep.15 This reduced sympathetic activity provides ideal conditions for demonstrating fl-agonism through an increase in heart rate. These studies involved healthy volunteers in whom heart rate during sleep was recorded using an Oxford Medilog 4-24 sensitive tape recorder (Oxford Medical Inc., Clearwater, Fla.). Heart rate during sleep was increased by pindolol, salbutamol, and xamoterol, and reduced by atenolol and propranolol.‘6 The increase in heart rate produced by salbutamol was abolished by concurrent administration of ICI 118551, which selectively blocks &.-adrenoceptors.17 The effect of xamoterol was unaffected by ICI 118551.18 These results demonstrate that heart rate during sleep can be increased by drugs with partial agonist activity at PI- (xamoterol) or &-adrenoceptors (salbutamol). The mechanism of the increase in heart rate with salbutamol may be the result of direct stimulation of /?2-adrenoceptors in the heart, or may be partly reflex caused by peripheral vasodilation. Stimulation of @2-adrenoceptors has been shown to augment physiologic finger tremor,lg and &-agonists would be expected to increase finger tremor. Both salbutamol and pindolol have been shown to increase finger tremor,16 which would indicate that at least part of the partial agonist activity of pindolol is at the /32-adrenoceptors. Studies in human beings have recently been completed that investigated the partial agonist activity of dilevalol, a nonselective &adrenoceptor blocking drug with vascular &-agonist and minimal a-antag-
March 1991 Heart Journal
onist activity in animals (B. A. MacLennon, et al., unpublished data). Six healthy male volunteers received single oral doses of 12.5,25,100,200,400, and 800 mg dilevalol and placebo in a randomized doubleblind study. Heart rate was recorded during sleep and, compared with placebo, dilevalol in doses of 100 mg and greater significantly increased heart rate. The maximum effect occurred after administration of 800 mg dilevalol (mean f SD, 68 * 5 beats/min) compared with placebo (60 t- 6 beats/min) at 8 hours. While these results indicate that dilevalol at doses of 100 mg and greater has partial agonist activity in human beings, they do not indicate if this results from activity at &- or &-sites. A second study was carried out involving 12 healthy male volunteers in a double-blind randomized design who received, at weekly intervals, single oral doses of 200 and 400 mg dilevalol, 10 mg pindolol, 80 mg propranolol, 8 mg salbutamol, and placebo (MacLennon BA, et al., unpublished data). Heart rate, cardiac output, blood pressure, forearm blood flow, and finger tremor were measured with subjects in the supine position before and at 30-minute intervals for 3 hours after treatment. Supine heart rate was reduced by propranolol, unchanged by dilevalol and pindolol, and increased by salbutamol. Compared with placebo, finger tremor was increased by dilevalol, pindolol, and salbutamol, and unaltered by propranolol. Forearm blood flow was not significantly altered by pindolol, propranolol, and 400 mg dilevalol, yet was significantly increased by 200 mg dilevalol and salbutamol. These results are consistent with dilevalol having partial agonist activity at /3z receptors. Similar studies are underway with celiprolol, but the results are not yet available. The unavailability of ICI 118551 for these studies has meant that other experimental approaches have been required to elucidate the role of 01 or 82 receptors in the partial agonist activity of celiprolol. Indirect evidence from other studies in human beings indicates that celiprolol may have partial agonist activity at the @zreceptors. For example, one study involved the 24-hour noninvasive recording of blood pressure and heart rate under ambulatory conditions in 15 patients with essential hypertension after double-blind administration of placebo and 400 mg celiprolol once daily for 1 month.20 On placebo, nighttime heart rate was reduced. During celiprolol treatment, however, heart rate was lower than with placebo during the day but was higher at night. The lower heart rate with celiprolol during the day can be attributed to blockade of sympathetic drive to the heart, and the higher night-time heart rate attributed
Volume Number
121 3, Part
Clinical
2
to partial agonist activity when sympathetic activity is low. This partial agonist activity could be either at 01 or 0.2 receptors. &Adrenergic receptors are present in bronchial smooth muscle, and stimulation produces bronchodilation. In healthy volunteers, selective and nonselective P-blockers have little effect on airway resistance.21 In contrast, a large proportion of asthmatic patients develop bronchoconstriction after administration of a @mtagonist owing to blockade of the p2 receptors in bronchial smooth muscle. At therapeutic doses, the more &-selective drugs have consistently caused less bronchoconstriction than nonselective drugs. 22,23 It has been argued that partial agonist activity might be useful for patients with asthma, but this has been difficult to assess.24 It is important to differentiate between the effects of a /3blocking drug with partial agonist activity on resting airways function in a large group of patients and the occasional development of severe bronchoconstriction in a few patients. In the current context, the effects of antihypertensive drugs on airways are examined to determine whether there is evidence of partial agonist activity rather than whether they are safer than drugs without such activity. More than 20 studies have examined the effects of celiprolol on airways resistance. For example, the effects of 40 mg propranolol, 100 mg atenolol, 200 and 400 mg celiprolol, and placebo were compared in 24 asthmatic patients. 25 Propranolol produced a significant reduction in FEVi, there was little change after placebo and atenolol, and after both doses of celiprolol, increasesin FEVl occurred. Similar differences between celiprolol, atenolol, and propranolol have been described elsewhere.g, 26a27 These studies suggest that there are differences between the effects of celiprolol and atenolol on airway resistance that indicate not only the absence of a bronchoconstrictor effect but even of bronchodilation. Although the studies do not throw any light on the mechanism of such an effect, it may result from partial agonist activity at 02 receptors. Both nonselective and Pi-selective blockers have similar hemodynamic effects, characterized by reduced heart rate, cardiac output and arterial pressure, and increased calculated peripheral resistance.28 The increase in peripheral resistance results from a reflex increase in response to the fall in cardiac output or arterial pressure, and from &-receptor blockade in peripheral blood vessels. It is generally accepted that the effects of partial agonists are different from conventional &blockers in that they may give smaller reductions in supine heart rate and
pharmacology
of @-blockers
1009
cardiac output with little change in calculated peripheral resistance. 28 These effects could result from the partial agonist activity at&receptors resulting in active vasodilation. The hemodynamic effects of celiprolol have been investigated in several studies. For example, intravenous administration to hypertensive patients generally produces a fall in arterial pressure and little change in heart rate, cardiac output, total peripheral resistance, and peripheral blood flo~.~’ Another study involved six hypertensive patients who were given celiprolol, 200 to 400 mg/day for 5 to 7 days, and nine hypertensive patients given nadolol, 80 to 360 mg/day for 6 to 10 days.30 Both drugs reduced mean arterial pressure, but heart rate was reduced by nadolol and not by celiprolol; forearm blood flow was reduced by nadolol and increased by celiprolol; and forearm vascular resistance was unaltered by nadolol and reduced by celiprolol. These results indicate a difference in the effects of the two drugs that may result from peripheral vasodilation effected by celiprolol as a result of partial agonist activity at 02 receptors. Partial agonist activity at PI receptors produces a different hemodynamic profile; thus xamoterol and epanolol, which are both PI-selective with marked and moderate PI-agonist activity, respectively, do not reduce arterial pressure.31 CONCLUSIONS
Celiprolol is a @-adrenergic blocker characterized by selective blockade of /31 receptors and partial agonist activity at @2receptors. These properties enable it to retain the benefits of &-receptor blockade in angina and hypertension while having the advantages of partial &-agonist activity in preventing adverse effects on pulmonary function and the peripheral circulation. These latter effects may reduce the incidence of cold extremities in patients during treatment and may also have a more favorable hemodynamic effect on the heart.32 A number of studies have shown that the effects of celiprolol on lipids may be different from other P-blocking drugs. It is now generally agreed that nonselective and &-receptor selective drugs, devoid of partial agonist activity, increase plasma levels of triglyceride and the triglyceride fraction of very low-density lipoprotein cholesterol, and reduce highdensity liproprotein (HDL) cholesterol and the HDLI low-density liproprotein (LDL) ratio.33* 34 ,i3-Blocking drugs with partial agonist activity have a less pronounced effect on lipids. It has been suggested that these changes in lipids may have adverse effects that
1010
Shanks
would increase associated coronary risk and, thus, counteract their beneficial blood pressure lowering effects.35, 3fi Several studies have investigated the effects of celiprolol on lipids. In one study, five different pblockers (atenolol, propranolol, celiprolol, mepindolol, and bisoprolol) were each administered for 2 years to 99 males with mild to moderate hypertension.37 They all produced similar reductions in blood pressure and had no significant effect on total cholesterol and LDL cholesterol. Propranolol caused the greatest increase in triglycerides and the greatest decrease in HDL cholesterol; the effects of atenolol were similar but less marked. Bisoprolol and mepindolol increased triglyceride levels and did not significantly alter HDL cholesterol. Celiprolol, unlike any of the other &blockers, decreased triglyceride and increased HDL cholesterol levels. It is not known if the difference in effect of celiprolol on lipids is the result of its partial &-agonist activity, but it is clearly worthy of further study. REFERENCES
1. Bereman H. Tabassi D. Rasser W. et al. Circulatorv effects of isoprenaline as influenced by the new beta-receptor blocking agent celiprolol in healthy volunteers. Arzneimittelforschung 1983;33:53. McDevitt DG. The assessment of @adrenoceptor blocking drugs in man. Br J Clin Pharmacol 1977;4:413. Mancia G. The central and peripheral hemodynamics of celiprolol. AM HEART J 1988;116:1405. McLenachan JM, Wilson J, Dargie HJ. Improved left ventricular function during exercise: a comparison of celiprolol and atenolol. AM HEART J 1988,16:1453. 5. Dunlop D, Shanks RG. Selective blockade of adrenoceptor beta receptors in the heart. Br J Pharmacol 1968;32:20. 6. Brick I. Hutchinson KJ. McDevitt DG. et al. Comoarison of the effects of ICI 50172 and propranolol on the cardiovascular responses to adrenaline, isoprenaline and exercise. Br J Pharmacol 1968;34:127. 7. Pringle TH, Riddell JG, Shanks RG. A comparison of the cardioselectivity of five @-adrenoceptor blocking drugs. J Cardiovast Pharmacol 1988;11:543. 8. van Zyl AI, Jennings AA, Bateman ED, Opie LH. Comparison of respiratory effects of two cardioselective beta blockers, celiprolol and atenolol, in asthmatics with mild to moderate hypertension. Chest 1989;95:209. 9. Matthys H, Doshan HD, Rtihle K-H, et al. The bronchosparing effects of celiprolol, a new beta-l alpha-2-receptor antagonist on pulmonary function of propranolol sensitive asthmatics. .J Clin Pharmacol 1985;25:354. 10. Riddell dG, Shanks RG, Brogden RN. Celiprolol, a preliminary review of its pharmacodynamic and pharmacokinetic properties and its therapeutic use in hypertension and angina pectoris. Drugs 1987;34:438. 11. Svendsen TL, Trap-Jensen J, Bliddal J, et al. Acute haemodynamic effects of five @-adrenoceptor blocking agents in man: the significance of selectivity and intrinsic sympathomimetic activity. Acta Med Stand 1979;625:26. 12. Svendsen TL, Hartling 0, Trap-Jensen J. Immediate haemodynamic effects of pr&altero< a new adrenergic 01 receptor agonist, in healthy volunteers. Eur J Clin Pharmacol 1980;18:219.
American
March 1991 Heart Journal
13. O’Connor PC, Arnold JMO, Brown AN. Human pharmacokinetic and pharmacodynamic studies on RO 31-1118, a new B-adrenoceptor antagonist. Br J Clin Pharmacol1985;19:319. 14. Kleitman N. Sleep and wakefulness. Chicago: University of Chicago Press, 1963. 15. Baust W, Bohnert B. The regulation of the heart rate during sleep. Exp Brain Res 1969;7:169. 16. McCaffrey PM, Riddell JG, Shanks RG. An assessment of the partial agonist activity of RO 31-1118, flusoxolol and pindolol in man. Br J Clin Pharmacol 1987;24:571. 17. Arnold JMO, O’Connor PC, Riddell JG, et al. Effects of the betan-adrenoceptor antagonist ICI 118551 on exercise tachycardia and isoprenaline-induced beta adrenoceptor responses in man. Br J Clin Pharmacol 1985;19:619. 18. McCaffrev PM. Riddell JG. Shanks RG. The selectivitv of xamoteroi, prenalterol and salbutamol as assessed by their effects in the presence and absence of ICI 1185.51. J Cardiovasc Pharmacol 1988;11:543. 19. MacLennon BA, McCullough PJ, McDermott BJ, et al. The selectivity of the partial agonist activity of dilevalol in man. (Submitted for publication.) 20. Parati G, Pomidossi G, Casadei R, et al. Evaluation of the antihypertensive effect of celiprolol by ambulatory blood pressure monitoring. Am J Cardiol 1988;61:27C. 21. Tattersfield AE. Beta adrenoceptor antagonists and respiratory disease. J Cardiovasc Pharmacol 1968;8(suppl 4):35. 22. Benson MK, Berrill WT, Cruickshank JM, Sterling GS. A comparison of four beta adrenoceptor antagonists in patients with asthma. Br J Clin Pharmacol 1978;5:415. 23. Astrom H. Comparison of the effects on airway conductance of a new selective beta-adrenergic blocking drug, atenolol and propranolol in asthmatic subjects. Stand J Respir Dis 1975;56:292. 24. McDevitt DG. Beta-adrenoceptor blocking drugs and partial agonist activity. Is it clinically relevant? Drugs 1983;25:331. 25. Doshan HD, Rosenthal RR, Brown R, et al. Celiprolol, atenolol and propranolol: a comparison of pulmonary effects in asthmatic patients. J Cardiovasc Pharmacol 1986;8(suppl 4):105. 26. Mathys H, Doshan HD, Riihle K-H, et al. Bronchosparing properties of celiprolol, a new 01, CQ blocker, in propranololsensitive asthmatic patients. J Cardiovasc Pharmacol 1986;8(suppl 4):40. 27. Rosenthal F, Silke B, Capone P. A comparison of celiprolol and atenolol in the treatment of hypertension. Br J Clin Pratt 1985;39(suppl 40):76. 28. Man in’t Veld AJ. Schalekamn MADH. How intrinsic svmpathomimetic activity modulates the haemodynamic responses to fl-adrenoceptor antagonists. A clue to the value of their antihypertensive mechanism. Br J Clin Pharmacoll982; 1332456. 29. Gensini G, Dator C, Esente P, et al. Comparison of the acute haemodynamic effects of intravenous celiprolol and propranolo1 in patients with suspected coronary disease. J Cardiovasc Pharmacol 1986;8(suppl 4):83. 30. Mancia G, Grassi G, Parati G, et al. Effects of celiprolol on reflex control of the cardiovascular system in essential hypertension. 3 Cardiovasc Pharmacol 1!%6:8(suPd 4):67. G, Sampieri L, Cuspidi C, et al. Do& /3l:selective ag31. Leonetti onist activity interfere with the antihypertensive efficacy of 81-selective blocking drugs? J Hypertens 1985;3(suppl3):243. 32. Taylor SH. Beta blocking drugs and myocardial function. J Cardiovasc Pharmacol 1986;(suppl 4):75. 33. Krone W, Niigele H. Effects of antihypertensives on plasma lipidsand lipoprotein metabolism. AM HEART J 1988;116:1729. RJ. /3 Blockers, lipids and coronary atherosclerosis: 34. Northcote fact or fiction? Br Med J 1588;296:731. 35. Weinbereer MH. Antihvpertensive therapv and linids. Paradoxical influences on c&liovascular disease risk. km J Med 1986;8O(suppl 2A):64. 36. Editorial. Antihypertensive drugs, plasma lipids and coronary disease. Lancet 1980;1:19. ~2
Volume Number
121 3, Part
Clinical pharmacology
2
37. Fogari R, Zoppi antihypertensive vast Pharmacol
A, Pasotti C. Plasma therapy with different 1989;14(suppl 7):28.
DISCUSSION Question. Can you enlighten
lipids during chronic p-blockers. J Cardio-
me on what the difference is between celiprolol and dilevalol? Does celiprolol just have greater partial agonist activity or a higher intrinsic activity at the j32 receptor? Dr. Shanks. No, celiprololis cardioselective anddilevalol is not. Dilevalol blocks both pi and p2 receptors. Question. I was thinking particularly of differences in activity at the & receptor? Dr. Shanks. Professor Mancia has data that show dilevalol to have partial agonist activity at 02 receptors and celiprolol probably has also, but I do not know if anyone has shown any difference in the effects of the two drugs.
of &blockers
1011
Question. I should like to know if there is any relationship between these drugs and changes in the endocrine system, the renin-angiotensin system, prostaglandins, and the kallikrein-kinin system. Are there any data about the relationship between these &blockers and changes in the other systems that also participate in blood pressure control? Dr. Shanks. I do not know of any comparative study on the effects of, say, celiprolol and atenolol on the parameters that you have mentioned. Question. Do you know of any study with respect to circulating catecholamine? Owing to the possible p2 activation of presynaptic receptors, it might be expected that circulating catecholamine could be increased. Dr. Shanks. I do not know of the result of any study although that does not mean to say that there is no such study.
28. 29.
30. 31.
32.
33.
34. 35.
36.
et al.
American
Gould B, Mann S, Davies AB, et al. Does placebo lower bloodpressure? Lancet 1981;2:1377. Drayer JIM, Weber MA, DeYoung JL, Brewer DD. Long-term BP monitoring in the evaluation of antihypertensive therapy. Arch Intern Med 1983;143:898. DuPont AG, van der Niepen P, Six RO. Placebo does not lower ambulatory blood pressure. Br J Clin Pharmacol1987;24:106. Conway J, Johnston J, Coats A, et al. The use of ambulatory blood pressure monitoring to improve the accuracy and reduce the numbers of subjects in clinical trials of antihypertensive agents. J Hypertens 1988;6:111. Cheung DG, Neutel JM, Smith DHG, et al. Absence of placebo effect on the whole-day ambulatory blood pressure (BP) (Abstract). Clin Pharmacol Ther 1990;47:200. Bellet M, Pagny J-Y, Chatellier G, et al. Evaluation of slow release nicardipine in essential hypertension by casual and ambulatory blood pressure measurements. Effects of acute versus chronic administration. J Hypertens 1987;5:599. Hills M, Armitage P. The two-period cross-over clinical trial. Br J Pharmacol 1979;8:7. Mann S, Millar-Craig MW, Balasubramanian V. Propranolol LA and ambulatory blood pressure. Br J Clin Pharmacoll980; 10:443-7. Gradman AH, Pangan P, Germain M. Lack of correlation between clinic and 24-hour ambulatory blood pressure in subjects participating in a therapeutic drug trial. J Clin Epidemiol 1989:42:1049-54.
Clinical drugs
pharmacology
37.
38. 39.
40.
41.
42.
43.
44. 45.
March 1991 Heart Journal
Fitzgerald DJ, O’Malley K, O’Brien ET. Reproducibility of ambulatory blood pressure recordings. In: Weber MA, Drayer JIM, eds. Ambulatory blood pressure monitoring. New York: Springer, 1984:71. Coats A, Conway J, Sleight P. Ambulatory monitoring, clinical trial size and precision. J Hypertens 1989;7(suppl6):S357. Rose M, McMahon GF. Some problems with antihypertensive drug studies in the context of the new guidelines. Am J Hypertens 1990;3:151. Cox JP, Ryan J, O’Brien E, O’Malley K. The effect of slow-release nicardipine on ambulatory and clinic blood pressure in mild hypertension. Br J Clin Pharmacol 1989;28:79. Conway J, Coats A. Value of ambulatory blood pressure monitoring in clinical pharmacology. J Hypertens 1989;7(suppl 3):S29. Cruickshank JM, Thorp JM, Sacharias FJ. Benefit and potential harm of lowering high blood pressure. Lancet 1987;1:581. Alderman MH, Ooi WL, Madhavan S, Cohen H. Treatmentinduced blood pressure reduction and the risk of myocardial infarction. JAMA 1989;262:920. Floras JS. Antihypertensive treatment, myocardial infarction and nocturnal myocardial ischaemia. Lancet 1988;2:994. Stanton AV, Atkins N, O’Malley K, O’Brien E. Circadian blood pressure and antihypertensive drugs. Am J Hypertens 1990;3:107A.
of vasodilatory
,&blocking
The clinical pharmacology of @adrenoceptor blockers is summarized. They have a variety of pharmacological actions on the B-adrenoceptors. For example, propranolol is a nonselective B-blocker with antagonist effects on both 81 and & receptors, atenolol is a selective j3,-antagonist, and celiprolol is a selective @,-antagonist, partial &-agonist. j3,-Receptor blockade tends to reduce heart rate, cardiac output, and arterial pressure while increasing periphdral vascular resistance, whereas &receptor blockade tends to be disadvantageous in causing bronchoconstriction and peripheral vasoconstriction. Selective bl-antagonist, Da-agonist activity would, therefore, appear to be particularly beneficial in offering the advantages of 8, blockade plus peripheral vasodilation. The @I- and &-receptor actions of drugs are not always clearly identifiable, as in the demonstration of celiprolol’s partial &agonist activity in human beings. This is because, in vivo, cardiovascular reflexes are intact and it has not, so far, been possible to remove endogenous catecholamines. This review summarizes various studies to investigate partial agonist activity, with particular emphasis on celiprolol. (AM HEART J 1991;121:1006-11.)
Robin G. Shanks, MD, DSc Belfast, Northern Ireland
From
the Department
University
of Therapeutics
Reprint requests: R.G. Shanks, cology, The Queen’s University burn Road, Belfast BT9 7BL, 4/O/26248
1006
and Pharmacology,
The Queen’s
of Belfast. Department of Therapeutics of Belfast, Whitla Medical Northern Ireland.
and Building,
Pharma97 Lis-
Many P-adrenoceptor blocking drugs, some of which may possess a variety of additional properties, have now been described and are used extensively for the treatment of a wide variety of diseases. Although it is 25 years since the introduction of propranolol, this
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drug is still widely used and is the standard with which other p-blocking drugs are compared. Propranolol is known as a nonselective @-blocker because it acts at both the @I- and ,&-receptor sites. The former action results in reduction of heart rate, cardiac output and arterial pressure, and an increase in peripheral vascular resistance, whereas blockade of 02 receptors may produce bronchoconstriction and peripheral vasoconstriction. The cardioselective blocking drugs (practolol, atenolol, and metoprolol), which are more correctly described as ,&-selective, are an improvement over the nonselective agents. They have less effect on airway resistance and do not inhibit the bronchodilatory effect of &agonists, yet they have the same hemodynamic effects as nonselective blockers. Both types of drug are effective in the treatment of hypertension even though peripheral vascular resistance is increased after their use, probably as a reflex response to the fall in cardiac output. The increase in vascular resistance and reduction in peripheral blood flow are the probable explanations for the occurrence of cold extremities, one of the most frequent adverse effects of these drugs. Attempts have been made to overcome this effect by the development of drugs that have a peripheral vasodilatory action either through blockade of a-adrenoceptors (labetalol) or through an agonist effect on the @s receptors (pindolol, dilevalol, celiprolol). This review will summarize some of the properties of the @s-agonist, celiprolol, in human beings. &ADRENOCEPTOR
BLOCKING
ACTIVITY
In an open study involving four healthy volunteers, celiprolol at doses of 100 mg orally and 10 mg intravenously significantly reduced the increases in heart rate and systolic blood pressure produced by the intravenous infusion of isoproterenol,l but did not prevent the reduction in diastolic blood pressure. These findings suggest that celiprolol is capable of selective blockade of ,6i receptors. Reduction of the increase in heart rate occurring during moderate to severe exercise has been widely used to determine blockade of cardiac P-adrenoceptors.2 Several studies have shown that intravenous and oral administration of celiprolol reduce exercise tachycardia. 3, 4 In a double-blind crossover study involving 12 healthy, normal male subjects who exercised on a treadmill 4 hours after oral administration of 100 mg atenolol and 400 mg celiprolol, there was a significant reduction in maximum exercise heart rate with no significant difference in the degree of inhibition of exercise tachycardia (RhonePoulenc Rorer Inc., data on file).
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SELECTlVEBLOCKADEOFfiRECEPTORS
Intravenous administration of isoproterenol in human beings produces an increase in heart rate that results mainly from stimulation of ,& receptors, and bronchodilation and peripheral vasodilation arise from stimulation of /& receptors. Practolol was the first drug to be described that selectively blocked Bladrenergic receptors.5 Several other drugs, of which the most widely used are atenolol and metoprolol, have now been developed which have this same selectivity of action. This property was, for some time, referred to as cardioselective blockade, but as the heart probably contains both Pi and @Zreceptors, it is more accurately described as &-selective blockade. Studies in animals have demonstrated that @l-selective blocking drugs inhibit the increase in heart rate but not the bronchodilation and vasodilation produced by isoproterenol.5 The same separation of responses, however, does not occur in human beings, there being little reduction in isoproterenol-induced tachycardia with doses of practolol that produce marked inhibition of exercise tachycardia.6 Atenolol and metoprolol, at dosages which reduce exercise tachycardia, have little or no effect on the responses because of stimulation of @s receptors by isoproternol.7 No studies have yet described the effects of celiprolol on exercise tachycardia and on responses to a &-agonist in the same subject group. A number of studies, however, have investigated the effects of celiprolol on the responses elicited by stimulation of 02 receptors. For example, in a study involving 12 patients with mild to moderate hypertension and reversible airways obstruction, 100 mg atenolol and 400 mg celiprolol were administered in a doubleblind manner for 4 weeks8 A single-dose challenge was performed after the first dose of placebo, atenolol, and celiprolol, and regular measurements made of forced expiratory volume in the first second of expiration (FEVl), forced vital capacity (FVC), and peak expiratory flow (PEF). At 3 hours, a 200 pg dose of inhaled salbutamol was administered and measurements repeated. The results, obtained from 10 patients, showed FEV1, FVC, and PEF to be significantly reduced by atenolol but unaltered by celiprolol. All three parameters were significantly increased by salbutamol with no difference in responses after the three treatments. Similar results have been described in other studies.g These observations indicate that celiprolol, at recommended therapeutic doses, does not block @Zreceptors and, thus, can be described as a selective /31antagonist.
1008 PARTIAL
Shanks AGONIST
American
ACTIVITY
The partial agonist activity of celiprolol has been clearly demonstrated both in vitro and in vivo in a variety of experimental models. Results from in vitro studies using human lymphocytes suggest that celiprolol may have partial agonist activity at 02 receptors.lO Demonstration of partial agonist activity in human beings has been more difficult because reflexes are intact, and it has not been possible to remove endogenous catecholamines. A number of studies in human beings have shown, however, that /3-adrenoceptor partial agonists differ from &antagonists by causing less reduction in supine heart rate and cardiac OutpuP? I2 and having flatter dose-response curves for reduction of exercise tachycardia.2, l3 Another method for investigating the partial agonist activity of P-blockers in human beings has recently been described. Heart rate normally falls during sleep to reach its lowest level after 6 hours.14 This is thought to be a result of a predominance of parasympathetic tone owing to withdrawal of sympathetic tone during sleep.15 This reduced sympathetic activity provides ideal conditions for demonstrating fl-agonism through an increase in heart rate. These studies involved healthy volunteers in whom heart rate during sleep was recorded using an Oxford Medilog 4-24 sensitive tape recorder (Oxford Medical Inc., Clearwater, Fla.). Heart rate during sleep was increased by pindolol, salbutamol, and xamoterol, and reduced by atenolol and propranolol.‘6 The increase in heart rate produced by salbutamol was abolished by concurrent administration of ICI 118551, which selectively blocks &.-adrenoceptors.17 The effect of xamoterol was unaffected by ICI 118551.18 These results demonstrate that heart rate during sleep can be increased by drugs with partial agonist activity at PI- (xamoterol) or &-adrenoceptors (salbutamol). The mechanism of the increase in heart rate with salbutamol may be the result of direct stimulation of /?2-adrenoceptors in the heart, or may be partly reflex caused by peripheral vasodilation. Stimulation of @2-adrenoceptors has been shown to augment physiologic finger tremor,lg and &-agonists would be expected to increase finger tremor. Both salbutamol and pindolol have been shown to increase finger tremor,16 which would indicate that at least part of the partial agonist activity of pindolol is at the /32-adrenoceptors. Studies in human beings have recently been completed that investigated the partial agonist activity of dilevalol, a nonselective &adrenoceptor blocking drug with vascular &-agonist and minimal a-antag-
March 1991 Heart Journal
onist activity in animals (B. A. MacLennon, et al., unpublished data). Six healthy male volunteers received single oral doses of 12.5,25,100,200,400, and 800 mg dilevalol and placebo in a randomized doubleblind study. Heart rate was recorded during sleep and, compared with placebo, dilevalol in doses of 100 mg and greater significantly increased heart rate. The maximum effect occurred after administration of 800 mg dilevalol (mean f SD, 68 * 5 beats/min) compared with placebo (60 t- 6 beats/min) at 8 hours. While these results indicate that dilevalol at doses of 100 mg and greater has partial agonist activity in human beings, they do not indicate if this results from activity at &- or &-sites. A second study was carried out involving 12 healthy male volunteers in a double-blind randomized design who received, at weekly intervals, single oral doses of 200 and 400 mg dilevalol, 10 mg pindolol, 80 mg propranolol, 8 mg salbutamol, and placebo (MacLennon BA, et al., unpublished data). Heart rate, cardiac output, blood pressure, forearm blood flow, and finger tremor were measured with subjects in the supine position before and at 30-minute intervals for 3 hours after treatment. Supine heart rate was reduced by propranolol, unchanged by dilevalol and pindolol, and increased by salbutamol. Compared with placebo, finger tremor was increased by dilevalol, pindolol, and salbutamol, and unaltered by propranolol. Forearm blood flow was not significantly altered by pindolol, propranolol, and 400 mg dilevalol, yet was significantly increased by 200 mg dilevalol and salbutamol. These results are consistent with dilevalol having partial agonist activity at /3z receptors. Similar studies are underway with celiprolol, but the results are not yet available. The unavailability of ICI 118551 for these studies has meant that other experimental approaches have been required to elucidate the role of 01 or 82 receptors in the partial agonist activity of celiprolol. Indirect evidence from other studies in human beings indicates that celiprolol may have partial agonist activity at the @zreceptors. For example, one study involved the 24-hour noninvasive recording of blood pressure and heart rate under ambulatory conditions in 15 patients with essential hypertension after double-blind administration of placebo and 400 mg celiprolol once daily for 1 month.20 On placebo, nighttime heart rate was reduced. During celiprolol treatment, however, heart rate was lower than with placebo during the day but was higher at night. The lower heart rate with celiprolol during the day can be attributed to blockade of sympathetic drive to the heart, and the higher night-time heart rate attributed
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to partial agonist activity when sympathetic activity is low. This partial agonist activity could be either at 01 or 0.2 receptors. &Adrenergic receptors are present in bronchial smooth muscle, and stimulation produces bronchodilation. In healthy volunteers, selective and nonselective P-blockers have little effect on airway resistance.21 In contrast, a large proportion of asthmatic patients develop bronchoconstriction after administration of a @mtagonist owing to blockade of the p2 receptors in bronchial smooth muscle. At therapeutic doses, the more &-selective drugs have consistently caused less bronchoconstriction than nonselective drugs. 22,23 It has been argued that partial agonist activity might be useful for patients with asthma, but this has been difficult to assess.24 It is important to differentiate between the effects of a /3blocking drug with partial agonist activity on resting airways function in a large group of patients and the occasional development of severe bronchoconstriction in a few patients. In the current context, the effects of antihypertensive drugs on airways are examined to determine whether there is evidence of partial agonist activity rather than whether they are safer than drugs without such activity. More than 20 studies have examined the effects of celiprolol on airways resistance. For example, the effects of 40 mg propranolol, 100 mg atenolol, 200 and 400 mg celiprolol, and placebo were compared in 24 asthmatic patients. 25 Propranolol produced a significant reduction in FEVi, there was little change after placebo and atenolol, and after both doses of celiprolol, increasesin FEVl occurred. Similar differences between celiprolol, atenolol, and propranolol have been described elsewhere.g, 26a27 These studies suggest that there are differences between the effects of celiprolol and atenolol on airway resistance that indicate not only the absence of a bronchoconstrictor effect but even of bronchodilation. Although the studies do not throw any light on the mechanism of such an effect, it may result from partial agonist activity at 02 receptors. Both nonselective and Pi-selective blockers have similar hemodynamic effects, characterized by reduced heart rate, cardiac output and arterial pressure, and increased calculated peripheral resistance.28 The increase in peripheral resistance results from a reflex increase in response to the fall in cardiac output or arterial pressure, and from &-receptor blockade in peripheral blood vessels. It is generally accepted that the effects of partial agonists are different from conventional &blockers in that they may give smaller reductions in supine heart rate and
pharmacology
of @-blockers
1009
cardiac output with little change in calculated peripheral resistance. 28 These effects could result from the partial agonist activity at&receptors resulting in active vasodilation. The hemodynamic effects of celiprolol have been investigated in several studies. For example, intravenous administration to hypertensive patients generally produces a fall in arterial pressure and little change in heart rate, cardiac output, total peripheral resistance, and peripheral blood flo~.~’ Another study involved six hypertensive patients who were given celiprolol, 200 to 400 mg/day for 5 to 7 days, and nine hypertensive patients given nadolol, 80 to 360 mg/day for 6 to 10 days.30 Both drugs reduced mean arterial pressure, but heart rate was reduced by nadolol and not by celiprolol; forearm blood flow was reduced by nadolol and increased by celiprolol; and forearm vascular resistance was unaltered by nadolol and reduced by celiprolol. These results indicate a difference in the effects of the two drugs that may result from peripheral vasodilation effected by celiprolol as a result of partial agonist activity at 02 receptors. Partial agonist activity at PI receptors produces a different hemodynamic profile; thus xamoterol and epanolol, which are both PI-selective with marked and moderate PI-agonist activity, respectively, do not reduce arterial pressure.31 CONCLUSIONS
Celiprolol is a @-adrenergic blocker characterized by selective blockade of /31 receptors and partial agonist activity at @2receptors. These properties enable it to retain the benefits of &-receptor blockade in angina and hypertension while having the advantages of partial &-agonist activity in preventing adverse effects on pulmonary function and the peripheral circulation. These latter effects may reduce the incidence of cold extremities in patients during treatment and may also have a more favorable hemodynamic effect on the heart.32 A number of studies have shown that the effects of celiprolol on lipids may be different from other P-blocking drugs. It is now generally agreed that nonselective and &-receptor selective drugs, devoid of partial agonist activity, increase plasma levels of triglyceride and the triglyceride fraction of very low-density lipoprotein cholesterol, and reduce highdensity liproprotein (HDL) cholesterol and the HDLI low-density liproprotein (LDL) ratio.33* 34 ,i3-Blocking drugs with partial agonist activity have a less pronounced effect on lipids. It has been suggested that these changes in lipids may have adverse effects that
1010
Shanks
would increase associated coronary risk and, thus, counteract their beneficial blood pressure lowering effects.35, 3fi Several studies have investigated the effects of celiprolol on lipids. In one study, five different pblockers (atenolol, propranolol, celiprolol, mepindolol, and bisoprolol) were each administered for 2 years to 99 males with mild to moderate hypertension.37 They all produced similar reductions in blood pressure and had no significant effect on total cholesterol and LDL cholesterol. Propranolol caused the greatest increase in triglycerides and the greatest decrease in HDL cholesterol; the effects of atenolol were similar but less marked. Bisoprolol and mepindolol increased triglyceride levels and did not significantly alter HDL cholesterol. Celiprolol, unlike any of the other &blockers, decreased triglyceride and increased HDL cholesterol levels. It is not known if the difference in effect of celiprolol on lipids is the result of its partial &-agonist activity, but it is clearly worthy of further study. REFERENCES
1. Bereman H. Tabassi D. Rasser W. et al. Circulatorv effects of isoprenaline as influenced by the new beta-receptor blocking agent celiprolol in healthy volunteers. Arzneimittelforschung 1983;33:53. McDevitt DG. The assessment of @adrenoceptor blocking drugs in man. Br J Clin Pharmacol 1977;4:413. Mancia G. The central and peripheral hemodynamics of celiprolol. AM HEART J 1988;116:1405. McLenachan JM, Wilson J, Dargie HJ. Improved left ventricular function during exercise: a comparison of celiprolol and atenolol. AM HEART J 1988,16:1453. 5. Dunlop D, Shanks RG. Selective blockade of adrenoceptor beta receptors in the heart. Br J Pharmacol 1968;32:20. 6. Brick I. Hutchinson KJ. McDevitt DG. et al. Comoarison of the effects of ICI 50172 and propranolol on the cardiovascular responses to adrenaline, isoprenaline and exercise. Br J Pharmacol 1968;34:127. 7. Pringle TH, Riddell JG, Shanks RG. A comparison of the cardioselectivity of five @-adrenoceptor blocking drugs. J Cardiovast Pharmacol 1988;11:543. 8. van Zyl AI, Jennings AA, Bateman ED, Opie LH. Comparison of respiratory effects of two cardioselective beta blockers, celiprolol and atenolol, in asthmatics with mild to moderate hypertension. Chest 1989;95:209. 9. Matthys H, Doshan HD, Rtihle K-H, et al. The bronchosparing effects of celiprolol, a new beta-l alpha-2-receptor antagonist on pulmonary function of propranolol sensitive asthmatics. .J Clin Pharmacol 1985;25:354. 10. Riddell dG, Shanks RG, Brogden RN. Celiprolol, a preliminary review of its pharmacodynamic and pharmacokinetic properties and its therapeutic use in hypertension and angina pectoris. Drugs 1987;34:438. 11. Svendsen TL, Trap-Jensen J, Bliddal J, et al. Acute haemodynamic effects of five @-adrenoceptor blocking agents in man: the significance of selectivity and intrinsic sympathomimetic activity. Acta Med Stand 1979;625:26. 12. Svendsen TL, Hartling 0, Trap-Jensen J. Immediate haemodynamic effects of pr&altero< a new adrenergic 01 receptor agonist, in healthy volunteers. Eur J Clin Pharmacol 1980;18:219.
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13. O’Connor PC, Arnold JMO, Brown AN. Human pharmacokinetic and pharmacodynamic studies on RO 31-1118, a new B-adrenoceptor antagonist. Br J Clin Pharmacol1985;19:319. 14. Kleitman N. Sleep and wakefulness. Chicago: University of Chicago Press, 1963. 15. Baust W, Bohnert B. The regulation of the heart rate during sleep. Exp Brain Res 1969;7:169. 16. McCaffrey PM, Riddell JG, Shanks RG. An assessment of the partial agonist activity of RO 31-1118, flusoxolol and pindolol in man. Br J Clin Pharmacol 1987;24:571. 17. Arnold JMO, O’Connor PC, Riddell JG, et al. Effects of the betan-adrenoceptor antagonist ICI 118551 on exercise tachycardia and isoprenaline-induced beta adrenoceptor responses in man. Br J Clin Pharmacol 1985;19:619. 18. McCaffrev PM. Riddell JG. Shanks RG. The selectivitv of xamoteroi, prenalterol and salbutamol as assessed by their effects in the presence and absence of ICI 1185.51. J Cardiovasc Pharmacol 1988;11:543. 19. MacLennon BA, McCullough PJ, McDermott BJ, et al. The selectivity of the partial agonist activity of dilevalol in man. (Submitted for publication.) 20. Parati G, Pomidossi G, Casadei R, et al. Evaluation of the antihypertensive effect of celiprolol by ambulatory blood pressure monitoring. Am J Cardiol 1988;61:27C. 21. Tattersfield AE. Beta adrenoceptor antagonists and respiratory disease. J Cardiovasc Pharmacol 1968;8(suppl 4):35. 22. Benson MK, Berrill WT, Cruickshank JM, Sterling GS. A comparison of four beta adrenoceptor antagonists in patients with asthma. Br J Clin Pharmacol 1978;5:415. 23. Astrom H. Comparison of the effects on airway conductance of a new selective beta-adrenergic blocking drug, atenolol and propranolol in asthmatic subjects. Stand J Respir Dis 1975;56:292. 24. McDevitt DG. Beta-adrenoceptor blocking drugs and partial agonist activity. Is it clinically relevant? Drugs 1983;25:331. 25. Doshan HD, Rosenthal RR, Brown R, et al. Celiprolol, atenolol and propranolol: a comparison of pulmonary effects in asthmatic patients. J Cardiovasc Pharmacol 1986;8(suppl 4):105. 26. Mathys H, Doshan HD, Riihle K-H, et al. Bronchosparing properties of celiprolol, a new 01, CQ blocker, in propranololsensitive asthmatic patients. J Cardiovasc Pharmacol 1986;8(suppl 4):40. 27. Rosenthal F, Silke B, Capone P. A comparison of celiprolol and atenolol in the treatment of hypertension. Br J Clin Pratt 1985;39(suppl 40):76. 28. Man in’t Veld AJ. Schalekamn MADH. How intrinsic svmpathomimetic activity modulates the haemodynamic responses to fl-adrenoceptor antagonists. A clue to the value of their antihypertensive mechanism. Br J Clin Pharmacoll982; 1332456. 29. Gensini G, Dator C, Esente P, et al. Comparison of the acute haemodynamic effects of intravenous celiprolol and propranolo1 in patients with suspected coronary disease. J Cardiovasc Pharmacol 1986;8(suppl 4):83. 30. Mancia G, Grassi G, Parati G, et al. Effects of celiprolol on reflex control of the cardiovascular system in essential hypertension. 3 Cardiovasc Pharmacol 1!%6:8(suPd 4):67. G, Sampieri L, Cuspidi C, et al. Do& /3l:selective ag31. Leonetti onist activity interfere with the antihypertensive efficacy of 81-selective blocking drugs? J Hypertens 1985;3(suppl3):243. 32. Taylor SH. Beta blocking drugs and myocardial function. J Cardiovasc Pharmacol 1986;(suppl 4):75. 33. Krone W, Niigele H. Effects of antihypertensives on plasma lipidsand lipoprotein metabolism. AM HEART J 1988;116:1729. RJ. /3 Blockers, lipids and coronary atherosclerosis: 34. Northcote fact or fiction? Br Med J 1588;296:731. 35. Weinbereer MH. Antihvpertensive therapv and linids. Paradoxical influences on c&liovascular disease risk. km J Med 1986;8O(suppl 2A):64. 36. Editorial. Antihypertensive drugs, plasma lipids and coronary disease. Lancet 1980;1:19. ~2
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37. Fogari R, Zoppi antihypertensive vast Pharmacol
A, Pasotti C. Plasma therapy with different 1989;14(suppl 7):28.
DISCUSSION Question. Can you enlighten
lipids during chronic p-blockers. J Cardio-
me on what the difference is between celiprolol and dilevalol? Does celiprolol just have greater partial agonist activity or a higher intrinsic activity at the j32 receptor? Dr. Shanks. No, celiprololis cardioselective anddilevalol is not. Dilevalol blocks both pi and p2 receptors. Question. I was thinking particularly of differences in activity at the & receptor? Dr. Shanks. Professor Mancia has data that show dilevalol to have partial agonist activity at 02 receptors and celiprolol probably has also, but I do not know if anyone has shown any difference in the effects of the two drugs.
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Question. I should like to know if there is any relationship between these drugs and changes in the endocrine system, the renin-angiotensin system, prostaglandins, and the kallikrein-kinin system. Are there any data about the relationship between these &blockers and changes in the other systems that also participate in blood pressure control? Dr. Shanks. I do not know of any comparative study on the effects of, say, celiprolol and atenolol on the parameters that you have mentioned. Question. Do you know of any study with respect to circulating catecholamine? Owing to the possible p2 activation of presynaptic receptors, it might be expected that circulating catecholamine could be increased. Dr. Shanks. I do not know of the result of any study although that does not mean to say that there is no such study.
