Clinical perspective on celiprolol: Cardioprotective potential

Clinical perspective on celiprolol: Cardioprotective potential 8-Adrenergic blockers have had widespread use in the treatment of cardiovascular disease. Some agents of this class have been shown to reduce the incidence of total mortality, cardiovascular mortality, sudden death, and nonfatal reinfarction in survivors of acute myocardial infarction. The mechanism for this cardioprotective action is not known. Antiarrhythmic action and hemodynamic alterations have been suggested as possible mechanisms. An anticoagulant mechanism is another possiblity, although the antiplatelet effects of B-blockers are weak. It is now believed that antithrombotic effects may be related to the prevention of coronary artery plaque rupture and the subsequent propagation of an occlusive arterial thrombus rather than a direct anticoagulant action. The therapeutic ability &blockers to attenuate the hemodynamic consequences of catecholamine surgers, as they do in aortic dissection, may protect a vulnerable plaque from fracture, reducing the risk of coronary thrombosis, myocardial infarction, and death. Celiprolol, a third-generation ,f3,-selective adrenergic blocker with partial &agonist activity, is comparable to other @blockers in antihypertensive and antianginal activity. It has additional actions that may be beneficial to patients: (1) it does not adversely affect lipids and lipoproteins; (2) it does not appear to depress the myocardium in patients with left ventricular dysfunction; (3) it can lower serum fibrinogen levels; and (4) it can cause regression of myocardial mass in patients with left ventricular hypertrophy. (AM HEART J 1991;121:724-9.)

William

H. Frishman,

MD Bronx,

N.Y.

fl-Adrenergic-blocking drugs, one of the major pharmocologic advances of the twentieth century, are used in a wide spectrum of cardiovascular disorders including angina pectoris, arrhythmias, systemic hypertension, hypertrophic cardiomyopathy, mitral valve prolapse, and myocardial ischemia. These drugs also are helpful in many noncardiovascular conditions (e.g., migraine and glaucoma)1-3 and probably have more widespread application in clinical medicine than any other class of synthetic drugs. Their prominent cardiovascular effects are in decreasing heart rate, blood pressure, and myocardial contractility during rest and exercise, thereby reducing myocardial oxygen demand. Celiprolol, a long-acting PI-selective adrenergicblocking drug with partial &agonist activity and direct vasodilating activity, possesses a unique pharmacologic profile. In this review we reexamine the concept of adrenergic agonism and antagonism, the uses of P-blockers in hypertension and angina pectoris, and their potential use as cardioprotective agents. From

the Department

of Medicine,

Albert

Einstein

Reprint requests: William H. Frishman, MD, Einstein College of Medicine/Mont&ore Medical Rd., Bronx, NY 10461. 4/O/25418

724

College Hospital Center,

of Medicine. of the Albert 1825 Eastchester

The role of celiprolol assessed. ADRENERGIC

AGONISTS

as a cardiovascular AND

drug is also

ANTAGONISTS

In 1948 Ahlquist4 conceived the dual-adrenoreceptor hypothesis. Unable to explain the different effects of norepinephrine and epinephrine on the peripheral circulation (epinephrine being a peripheral dilator and norepinephrine a constrictor), he concluded that receptors for the circulating catecholamines differed; he called these LXand /3. About 20 years later Lands et a1.5 proposed another subdivision of P-adrenoceptors into 01 and & subtypes.5 Drugs affecting the Padrenoceptor are classified as selective (pi or Pz) or nonselective (mixed PI and /?z) agonists and antagonists. Adrenoceptors at both presynaptic (prejunctional) and postsynaptic (postjunctional) sites are the main targets for drugs that interact with the sympathetic nervous system. Apart from their effects on postsynaptic P-receptors, blockade of presynaptic P-receptors may be involved in the hemodynamic actions of /?-blocking drugs. Stimulation of presynaptic p-receptors is followed by an increase in the release of endogenous norepinephrine from postganglionic sympathetic fibers.6 Blockade of the presynaptic P-receptors should therefore diminish the amount of

Volume

121

Number

2. Part

Table

Cardioprotective

2

I. Blood

pressure

and heart rate at the end of monotherapy

Baseline value

Change from baseline

Group

N

Supine diastolic BP (mm Hg) Supine systolic BP (mm Hg) Standing diastolic BP (mm Hg) Standing systolic BP (mm Hg) Supine HR (beats/min) Standing HR (beats/min)

P C P C P C P C P C P C

40 42 40

101 101 155

+ 1 k 1 * 2

-2 -6 0.4

42 40 42

151 100 100

k

2 -t 1 + 1

-6 -1 -5

40 42 40

150 146 75

-t- 3 i 2 i 2 78 + 2 80 zk 2

-2

Adapted from Frishman BP, blood pressure; HR.

WH, Flamebaum W, Schoenberger heart rate; C, celiprolol; P, placebo.

J. Am J Cardiol

of celiprolol

725

with celiprolol

Parameter

42 40 42

potential

81

+ 2

f 1 + 1 + 2

k

2 rc_ L + 1

f 2 -7 rt_2 -2 * 2 -7 -1 -6

t 1 -+ 2

f 1

Between group value 0.005’ 0.022* 0.016’ 0.025* 0.014*

0.009*

1989;63:839-42.

*p < 0.05.

norepinephrine released, leading to a weaker stimulation of postsynaptic a-receptors, an effect that would result in less vasoconstriction. It is not clear, however, whether or how presynaptic P-blockade contributes to a reduction in peripheral vascular resistance and the antihypertensive effects of o-blocking drugs. Celiprolol, for example, is a &-selective blocker that also stimulates @z-receptors and possesses vasodilator properties and in addition may have direct action on smooth muscle aside’ from that mediated through P-receptors. These unique characteristics make celiprolol useful in patients with hypertension with concomitant conditions. Through vasodilation the associated reductions in cardiac afterload might make celiprolol useful in cardiomyopathy. Because of its partial ,&-agonism, it may be used safely in patients with hypertension who have asthma and Raynaud’s disease. CLINICAL USES OF ,&ADRENERGIC-BLOCKING DRUGS Essential hypertension. P-Blockers in general are

safe, effective therapy for the treatment of systemic hypertension.2 However, their hemodynamics, side effect profiles, and dosing schedules vary markedly. Many patients with hypertension have narrowing of the systemic arteriolar resistance vessels, leading to increased systemic vascular resistance in all regional vascular beds. Arteriolar dilation of systemic resistance vessels is a useful target of therapy. Thus drugs that induce such vasodilation are advantageous, but because a decrease in systemic vascular resistance may produce activation of the sympathetic nervous system, including reflex tachycardia, systemic arteriolar vasodilation in the absence of cardiac

@-adrenoceptor blockade can result in augmented demands on myocardial oxygen consumption and associated side effects. Cardiac P-blockade can offset the reflex cardiac stimulation induced by peripheral vasodilation. When treating hypertension one should strive to control both resting and exercise blood pressure. Indeed the control of blood pressure during exercise may be more important in prevention of target organ damage.7 The increase in blood pressure associated with dynamic exercise is mediated largely through reflex &adrenoceptor stimulation of the heart, which results in increased cardiac output. These surges in blood pressure are modulated significantly by @blockade. Blood pressure also rises immediately before waking as a result of sympathoadrenal stimulation of arteriolar resistance vessels through (Yadrenoceptors and an increase in myocardial activity via ,&adrenoceptor stimulation. Thus the combination of selective /3-adrenoceptor blockade and the ability to dilate systemic arteriolar resistance vessels could be beneficial. The pharmacologic characteristics of celiprolol may provide advantages over conventional P-blockers used to treat hypertension. Unlike propranolol, for example, celiprolol decreases peripheral vascular resistance, reducing the tendency to cause coldness of the extremities.8 Bronchosparing properties resulting from its partial @a-agonism permit use in patients with reversible airways disease.g It does not have a significant effect on cardiac conduction other than a small increase in the atrioventricular nodal refractory period.lO The use of celiprolol in hypertension. In a multicenter, placebo-controlled, double-blind, random-

726

Frishman

American

Placebo

Titration

Single-blind

Double-blind

Run-in (wash-out)

February 1991 Heart Journal

3 tablets qd

1 Tablet @

1 tablet qd

Visits 1 Weeks 0 Fig. 42.)

2 2

3 3

4 4

1 rrk:g

5 6

1

6 8

7 10

1. Study protocol. (From Frishman WH, Flamebaum W, SchoenbergerJ. Am J Cardiol1989;63:839-

ized, titration-to-effect study design, the efficacy of celiprolol was evaluated in 91 patients with mild-tomoderate systemic hypertension (supine diastolic blood pressure 95 to 114 mm Hg without medication). l1 A placebo-controlled run-in screening period of 4 weeks was used to establish baseline blood pressure. Patients were then randomly assigned to receive placebo (n = 46) or once-daily doses of celiprolol (n = 45), which was titrated every 2 weeks (200, 400, 600 mg/day) over a g-week period to achieve a reduction in supine diastolic blood pressure to I 90 mm Hg (Fig. 1). Blood pressure and heart rate at rest were measured three times each with patients in the supine position and then after standing for 2 minutes. Compared with placebo, celiprolol caused significant reductions in supine and standing diastolic blood pressures at the end of the study (Table I). The decrease in heart rate seen in patients treated with celiprolol was not clinically relevant, since no bradycardia was seen in any patients and mean heart rates remained > 70 beats/min. Angina pectoris. P-Blockers are widely accepted for the treatment of angina pectoris.3 More controversial has been the relative antianginal efficacy P-blockers with partial agonist activity.i2 Heart rate reduction is a major contributor to the antianginal effects of P-blockers, and since agents with partial agonist activity have minimal bradycardic actions, it has been suspected that they are less effective in treatment of patients with angina. However, results of compara-

tive trials show that celiprolol, which has partial agonist activity, is more effective than placebo13 and as effective as propranolo114, l5 and atenolol.i6, l7 The hemodynamic activity of celiprolol, however, differs from that of propranolol. The vasodilator activity of celiprolol could cause a lesser increment in end-diastolic volume than does propranolol, which causes more bradycardia. Celiprolol tends to cause a smaller increase in wall tension and myocardial oxygen consumption, which could offset its lesser bradycardic action. It also has been suggested but not proved that celiprolol may have a more favorable effect on coronary hemodynamics than does propranolol. A large multicenter trial compared once-daily doses of celiprolol(200,400, or 600 mg as necessary) with twice-daily dosesof propranolol (80,160, or 320 mg as necessary) in patients with chronic stable angina pectoris in a randomized, double-blind, titration-to-effect design. 14,I5 Established end points included time to onset of angina, time to moderately severe angina, and time to 1 mm ST segment depression on the ECG. The study showed that both celipro101 and propranolol are effective agents in improving exercise tolerance and reducing the frequency of attacks of angina. Celiprolol(400 mg daily) and atenolol (100 mg daily) were compared in a randomized, double-blind, crossover study.17 Again both drugs decreased the frequency of angina and increased exercise time and time to onset of 1 mm ST segment depression (Table II). Thus it appears that partial &-agonism does not

Volume Number

121 2, Part 2

Cardioprotective

interfere with the therapeutic effectiveness of celiprolol in treating angina pectoris. This property also may provide a margin of safety for patients with unacceptably low heart rates and for patients with left ventricular dysfunction. CARDIOPROTECTIVE

EFFECTS

OF ,&BLOCKADE

The four major classes of antihypertensive agentsdiuretics, P-blockers, angiotensin-converting enzyme (ACE) inhibitors, and calcium antagonists-can effectively lower blood pressure. However, P-blockers are the only class that conclusively have a beneficial effect not only on mortality but also on reinfarction in survivors of an acute myocardial infarction.l’, lg Several mechanisms to explain this cardioprotective effect have been proposed. A substantial proportion of the reduction in mortality resulting from @-blocker treatment in survivors of myocardial infarction may be due to a decreased number of sudden deaths.20 This may be caused in part by a reduction in premature ventricular beats, fewer episodes of ventricular tachycardia, or the ability of /?-blockers to preserve serum potassium levels. 21 It is also believed that the antiischemic actions of p-blockers may contribute to their beneficial effects. Drugs that block ,f3-adrenergic receptors reduce the effects of catecholamines and decrease myocardial oxygen requirements by lowering systemic arterial pressure, heart rate, and myocardial contractility at rest and during exercise.22 Prevention of plaque rupture. It is now widely believed that infarction is a thrombotic event. Coronary thrombi large enough to be detected angiographically often are associated with tears (fissures) in the caps of atherosclerotic plaques.23s 24 The tears allow blood to penetrate into the arterial wall, leading to thrombus formation within the intima; this may be followed by propagation of thrombosis into the vessel lumen. Why plaque becomes susceptible to rupture is not known. Sudden increases in blood pressure precipitated by physical or mental stress and surges in sympathetic tone may produce hemodynamic changes that lead to plaque rupture. These surges in sympathetic nervous activity also may increase platelet aggregability and possibly coronary vascular tone. ,f3Blockade may modulate or attenuate the consequences of these sympathetic nervous system surges by inhibiting the effects of catecholamines on blood pressure, heart rate, and myocardial contractility. In other conditions in which blood pressure tears the plaque (e.g., acute dissection), @-blockers are known to protect the aorta possibly through their ability to reduce blood pressure and myocardial contractility. Spence25 reported that propranolol was

potential

of celiprolol

727

II. The effects of 2 weeksof treatment with celiprolol and atenolol on exerciseresponsein a randomized doubleblind crossoverstudy Table

Placebo Exercise time (set) Maximum ST segment depression (mm) Time to 1 mm ST segment depression (min) Double product at 1 mm ST depression/ 100

635 k 48 2.5 * 0.3 7il

727 + 52 1.9 * 0.3

746 !I 50* 2.0 I?- 0.3

10 k 1*

190 f 11

Adapted from McLenachan LM, 1988;61:53C. ‘p < 0.05: **p < 0.01; tp < 0.001. celiprolol; ttp < 0.001, difference

Celiprolol

Atenolol

Findlay

125 t 6f

IN, Henderson

difference between

between atenolol

10 f

1*

151 It l3**tt

E. Am J Cardiol

placebo and atenolol/ and celiprolol.

more likely to reduce the velocity of blood flow and the likelihood of nonlaminar blood flow in the aorta, thereby reducing turbulence and vortex formation, as heart rate X blood velocity product is a determinant of arterial blood flow disturbance. It is postulated that this P-blocker effect also may reduce the risk of endothelial damage and plaque rupture making subsequent coronary thrombosis less likely. Some P-blockers also have weak antiplatelet effects, which may prevent development or propagation of clots,26 as aspirin does. Thus, in terms of cardioprotection, the role of ,&blockers in protecting plaque from fissures may be important. POSSIBLE

ADVANTAGES

PATIENTS

WITH

OF

HYPERTENSION

CELIPROLOL WITH

IN CONCOMITANT

CONDITIONS Asthma. A PI-adrenergic blocker with &-stimulating activity may have advantages for the treatment of angina or hypertension in patients with asthma. Compared to a drug such as propranolol, drugs with &-selectivity (e.g., metoprolol) or a-blocking activity (e.g., labetalol) minimize the increase in airway resistance. Patients in whom asthma develops while they are taking a &-selective blocker respond to more readily to bronchodilation with a standard dose of a &-stimulant such as albuterol than do those taking a nonselective P-blocker such as propranolol. Celiprolol, which inhibits /31-adrenergic receptors and stimulates &receptors, may provide relative safety for patients with asthma who are receiving P-blocker therapy. Although &blockers are not generally prescribed for patients with asthma, this margin of safety may be beneficial for those patients in whom a diagnosis of asthma has not been made.

728

Frishman

Left ventricular

American

dysfunction

and hypertrophy.

Reduc-

tion of heart rate and blood pressure during exercise is believed to be the major therapeutic action of P-blockers in angina; however, other actions of conventional P-blockers may offset this beneficial effect. These include an increase in left ventricular volume, an increase in vascular resistance, and attenuation of the increase in contractility that normally accompanies exercise.27 Left ventricular hypertrophy induced by systemic hypertension appears to be a disease marker for increased cardiovascular morbidity and mortality.28 Once left ventricular hypertrophy develops, the heart gets stiffer and therefore may not relax as well. P-Blockers generally can cause regression in left ventricular hypertrophy, as determined by echocardiography, with or without an associated reduction in blood pressure.28 Given the associated beneficial effects of a P-blocker with partial /3z-agonism, celiprolol may be helpful in patients with systemic hypertension in whom left ventricular dysfunction and/or hypertrophy is a problem. Elevated lipids and lipoproteins. All vasodilatorsnot just P-blocking vasodilators-appear to have a lipid-neutral effect or a favorable effect on the lipid profile. If a patient is treated with a nonvasodilating &blocker, the lipid profile often deteriorates.2g One double-blind crossover study showed that atenolol, metoprolol, oxprenolol, and propranolol all reduced high-density lipoprotein cholesterol levels and raised triglyceride levels.30 Herrmann and Mayer3i and other investigators32, 33have shown that celiprolol causes slight but significant reductions in total cholesterol and significant reductions in serum triglyceride levels and possibly a slight increase in high-density lipoprotein cholesterol. Compared with conventional @-blockers, therefore, celiprolol has a more favorable effect on the lipid profile. This may be important in assessing its cardioprotective actions. Elevated fibrinogen levels. The Framingham study revealed that an elevated serum fibrinogen level is a risk factor for premature vascular disease.34 Herrmann and Mayer31 showed that long-term celiprolol therapy reduces serum fibrinogen levels, although the mechanism of this effect is not clear. They speculated that it may result from hemodilution caused by the vasodilator activity of celiprolol, which expands plasma volume, or from a decrease in cell rigidity. Increased coagulability could cause fibrinogen to be absorbed on that basis. This area requires further investigation. CONCLUSIONS

While the role of celiprolol in the secondary prevention of coronary heart disease requires further

February 1991 Heart .~ournat

investigation, its effects on lipids and lipoproteins may provide advantages in this area. Celiprolol appears to retain the advantages seen with earlier generations of the P-blocker class and yet has a unique pharmacologic profile in that it combines plselective antagonism with partial /?2 agonism and direct vasodilating activity. This combination can potentially alter the side effect profile typically associated with conventional P-blockers, especially in those patients with bronchospastic disease, peripheral artery disease, and hyperlipidemia. REFERENCES

1. Frishman WH. Beta-adrenoceptor antagonists: new drugs and new indications. N Engl J Med 1981;305:500-6. 2. Frishman WH. Clinical Pharmacology of the beta-adrenoceptor blocking drugs. 2nd ed. Norwalk, Conn: Appleton-Century-crofts, Inc, 1984. 3. Frishman WH. Beta-adrenergic blockers. Med Clin North Am 1988;72:37-82. 4. Ahlquist RP. A study of adrenotropic receptors. Am J Physiol 1948;153:586-600. 5. Lands AM, Arnold A, McAuliff JP, et al. Differentiation of receptor systems activated by sympathomimetic amines. Nature 1967;214:597-8. 6. Weinstock M. The presynaptic effect of beta-adrenoceptor antagonists on noradrenergic neurons. Life Sci 1976;19:145366. 7. Frishman WH. The beta adrenoceptor blocking drug. Int J Cardiol 1982;2:165-78. 8. Solomon T, Gensini G, Dator C, Caruso F. Celiprolol: a hemodynamic appraisal in comparison with propranolol. Br J Clin Pharmacol 1985;40:43A-4A. 9. Matthys H, Doshan HD, Ruhle KH, et al. The bronchosparing effect of celiprolol, a new betai, alphas receptor antagonist on pulmonary function of propranolol-sensitive asthmatics. J Clin Pharmacol 1985;25:354-9. 10. Estes NAM, Lin SK, Caruso FS, Solomon TA. Clinical cardiac electrophysiologic study of celiprolol. J Cardiovasc Pharmacol 1986;8(suppl 4):S116-18. 11. Frishman WH, Flamebaum W, Schoenberger J. Celiprolol in systemic hypertension. Am J Cardiol 1989;63:839-42. 12. Frishman WH. Pindolol: a new beta-adrenoceptor antagonist the partial agonist activity. N Engl J Med 1983;308:940-4. 13. Harston WE, Eff J, Capone P. A double-blind placebocontrolled study of celiprolol in the treatment of angina pectoris. Br J Clin Pratt 1985;39(suppl 40):55-61. 14. Frishman WH, Heiman M, Soberman J, et al. Comparison of celiprolol and propranolol in stable angina pectoris. Am J Cardiol 1991. (In press.) 15. Frishman WH, Soberman J, Eff J. A comparison of celiprolol to propranolol in angina pectoris: results of an international double-blind study [Abstract]. J Am Co11 Cardiol1986;9)suppl Ah192A. 16. Jackson NC, Lee PS, Taylor SH. A single blind randomized comparison of the 23 hour anti-angina1 efficacy of celiprolol versus atenolol. J Cardiovasc Pharmacol1986;8(suppl4):S 145 47. 17. McLenachan LM, Findlay IN, Henderson E. Atenolol and celiprolol for stable angina pectoris. Am J Cardiol 1988;61:52C. 18. Beta-Blocker Heart Attack Trial Research Group: A randomized trial of propranolol in patients with acute myocardial infarction. I. Mortality results. JAMA 1981;247:1707-14. 19. Norwegian Multicenter Study Group. Timolol-induced reduction in-mortality and reinfarction in patients surviving acute mvocardial infarction. N Engl J Med 1981:304:801-7. 20. Frishman WH, Laifer LI, Furberg CD. Beta-adrenergic blockers in the prevention of sudden death. In: Josephson ME, ed. Sudden cardiac death. Philadelphia: FA Davis, 1985:249-64.

volume Number

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21. Frishman WH, Lazar EJ. Reduction of mortality, sudden death, and nonfatal reinfarction with beta-adrenergic blockers in survivors of acute myocardial infarction: a new hypothesis regarding the cardioprotective action of beta-adrenergic blockade. Am J Cardiol 1990;66(suppl):G66-G70. 22. Frishman WH, Furherg DC, Friedewald WT. Beta-adrenergic blockade for survivors of acute myocardial infarction. N Engl J Med 1984;310:830-6. 23. Richardson PD, Davies MJ, Born GVR. Influence of plaque configuration and stress distribution on fissuring of coronary atherosclerotic plaques. Lancet 1989;2:941-4. 24. Davies MJ, Thomas AC. Thrombosis and acute coronary artery lesions in sudden cardiac ischemic death. N Engl J Med 1984;310:1137-40. 25. Spence JD. Effects of hydralazine versus propranolol on blood velocity in patients with carotid stenosis. Clin Sci 1983;65:913. 26. Weksler BB, Gillick M, Pink J. Effect of propranolol on platelet function. Blood 1977;49:185-96. 27. McLenachan J, Wilson J, Dargie H. Improved left ventricular function during exercise: a comparison of celiprolol and atenolol. AM HEART J 1989:116(Part 2):1435-6.

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potential

of

celiprolol

729

28. Hachamovitch R, Sonnenblick EH, Strom JA, Frishman WH. Left ventricular hypertrophy in hypertension and the effects of antihypertensive drug therapy. Curr Probl Cardiol 1988;13:375-421. 29. Leren P, Helgeland A, Holme I, et al. Effect of propranolol and prazosin on blood lipids. Lancet 1980;2:4-6. 30. Day JL, Metcalfe J, Simpson N, Lowenthal L. Adrenergic mechanisms in the control of plasma lipids in man. Am J Med 1984;76:94-6. 31. Herrmann JM, Mayer EO. A long-term study of the effects of celiprolol on blood pressure and lipid-associated risk factors. AM HEART J 1988;116:1416-21.

32. Janka HU, Ptescjke J, Stand1 A, Mehnert H. Carbohydrate and lipid metabolism under beta-blocker therapy with celiprolol. Arzneimittelforschung 1983;33:76-9. 33. Hitzenberger G. The effects of the beta-adrenoceptor blocking agent, celiprolol, on blood lipids. Br J Clin Pratt 1985;36(suppl 40):86-7. 34. Kannel WB. Hypertension: relationship with other risk factors. Drugs 1986;31(suppl l):l-11.