Calcium antagonists and beta blockers in the control of mild to moderate systemic hypertension, with particular reference to verapamil and propranolol

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<ul><li><p>Calcium Antagonists and Beta Blockers in the Control of Mild to Moderate Systemic Hypertension, </p><p>with Particular Reference to Verapamil and Propranolol </p><p>BRAMAH N. SINGH, MD, PhD, PERLITA REBANAL, RN, MARTHA PIONTEK, RN, and KOONLAWEE NADEMANEE, MD </p><p>The antianginal and antiarrhythmic role of calcium antagonists is well established. Recent preliminary studies have indicated that, like /3 blockers, calcium antagonists may produce short- and long-term hy- potensive effects in patients with mild to moderate essential hypertension. The pharmacologic proper- ties of calcium antagonists provide a clear rationale for their use in the control of essential hypertension. The comparative hypotensive effects of verapamil (80 to 160 mg 3 times a day) and propranolol (40 to 120 mg 3 times a day) were evaluated over 4 weeks, preceded by a 4-week placebo phase, in a double-blind protocol in 17 patients with mild to moderate hypertension. Verapamil (n = 10) re- duced the mean sitting systolic blood pressure by 10.7% (p </p></li><li><p>1OOD A SYMPOSIUM: CALCIUM ANTAGONISTS IN HYPERTENSION-FOCUS ON VERAPAMIL </p><p>pharmacologic similarities and differences between ,6 blockers and calcium antagonists. The second is to provide further evidence from a controlled double- blind study for the comparative efficacy of verapamil and propranolol in patients with mild to moderate hy- pertension. The third is to discuss the overall advan- tages and disadvantages of calcium antagonists and /3 blockers as hypotensive agents. </p><p>Pharmacologic Considerations The bulk of the pharmacologic effects of P-adrener- </p><p>gic blocking drugs can be attributed to the ability of these compounds to competitively block p adrenocep- tors. Structurally, these compounds are almost homo- geneous; minor structural differences have produced compounds of variable ,&amp;blocking potency, varied pharmacokinetics and different associated features such as intrinsic sympathomimetic activity, cardiose- lectivity and membrane-depressant propensities. Al- though such features may influence the overall ad- verse effects profile of an individual agent, they have little or no effect on their therapeutic efficacy, which results essentially from blockade of ,6 adrenoceptors. In contrast, calcium antagonists constitute a structural- ly heterogeneous group of compoundslO that share 2 significant properties: the ability to block the slow cal- cium channel in cardiac muscle and the ability to inhibit transmembrane fluxes of calcium in smooth muscle especially in the coronary and peripheral circulations.10 </p><p>Because of their often striking structural differences, individual calcium compounds may exhibit other pharmacologic actions (e.g., verapamil and diltiazem have noncompetitive sympatholytic actions], which may lead to a complex interplay with their intrinsic properties demonstrable in isolated tissues and the re- flex changes they may produce as a result of sympa- thetic activation caused by peripheral vasodilatation.1 Because of the reflex effects and the varying potencies </p><p>of different calcium antagonists to induce peripheral vasodilatation, the in vitro and in vivo actions of calci- um antagonists may differ markedly. This is particu- larly striking in atrioventricular (AV) nodal conduction and refractoriness. For example, as with 0 blockers, calcium antagonists such as verapamil, diltiazem, tia- pamil or gallopamil predictably lengthen AV conduc- tion and refractoriness both in vivo and in vitro. By contrast, the dihydropyridines (e.g., nifedipine and ni- cardipine) are potent depressants of AV nodal conduc- tion in isolated hearts, but this effect is nullified or even reversed by their reflex effectslo </p><p>It must be emphasized that while calcium antago- nists alter AV nodal conduction by blocking the slow- channel potentials in this structure, p blockers produce their negative dromotropic effects by altering the sym- pathetic impulse traffic in the AV node. Thus, the AV nodal effects of the 2 classes of compounds are likely to summate if they have similar effects individually (e.g., propranolol compared with verapamil or diltiazem). With dihydropyridines, concomitant fi blockade is likely to convert a potentially facilitatory action on the AV node to a depressant one. These electrophysiologic features of the various compounds are of therapeutic significance in the choice of an agent for the control of hypertension or ischemic syndromes in patients who may have preexisting conduction system disease. From the standpoint of control of hypertension, how- ever, the comparative cardiocirculatory effects of cal- cium antagonists and fi antagonists are the most rele- vant pharmacologic effects. </p><p>It is now well established that most /3 antagonists when administered intravenously or orally depress heart rate, cardiac output and indexes of ventricular contractility and increase the filling pressures of the ventricle. The characteristic hemodynamic effects of </p><p>25 20 R PA PiW no C.I. LVEF CSF MVO, SVA PVR SW, </p><p>HR LVEDP Cl SW LV WI LVdp/dt m </p><p>+ 50, + 45% TIMOLOL : 1.0 mg paou </p><p>FIGURE 1. Hemodynamic effects of intravenously administered ti- molol in patients with coronary artery disease undergoing diagnos- tic cardiac catheterization. Note that p blockade induces an in- crease in mean pulmonary artery pressure (PA), systemic vascular resistance (SVR), left ventricular end-diastolic pressure (LVEDP), but a decrease in heart rate (HR), cardiac index (Cl), left ventrlcu- lar work index (LV WI) and left ventricular dP/dt (an index of contractility). Although not shown here, fi blockade produces a decrease in coronary sinus flow and in coronary arteriolar resistance. </p><p>FIGURE 2. Effects of intravenous verapamil (10 mg) on systemic and coronary hemodynamic indexes and left ventricular ejection fraction (LVEF) in patients with coronary artery disease. The most striking effect is a decrease in systemic vascular resistance (SVR) and mean aortic pressure (Ao) with the preservation of cardiac index (Cl). The increase in the mean pulmonary capillary wedge pressure (PCW) denotes some reduction in contractility but LVEF is unaffected. The increase in coronary sinus flow (CSF) is consistent with the coronary vasodilator effects of the calcium antagonist. Based on data in reference 11. </p></li><li><p>P-blocking compounds as exemplified by the proper- cular resistance and reflex sympathetic effects. The ties of timolol are shown in Figure 1. These drugs may currently available data suggest that the most signifi- also reduce coronary blood flow commensurate with cant mechanism mediating the hypotensive effect of the reduction in myocardial oxygen demand. When calcium antagonists is peripheral dilatation. However, given intravenously, they may increase systemic vas- experience is limited with the hemodynamic actions of cular resistance, which, however, decreases during calcium antagonists after prolonged oral therapy. long-term oral administration of these agents owing to We investigated the comparative effects of long- the sustained reduction in cardiac output. The latter term administration of verapamil and propranolol on may contribute significantly to the hypotensive action ventricular function in patients with known coronary of the p antagonists. artery disease.14 The effects of the 2 compounds on </p><p>In contrast to the action of /3 blockers, the most strik- heart rate, blood pressure and left ventricular ejection ing hemodynamic effects of calcium antagonists con- fraction determined by radionuclide ventriculography sist of a predictable and consistent reduction in sys- at rest and during exercise on a bicycle ergometer temic vascular resistance accompanied by either no were compared. The mean data are summarized in change or an increase in cardiac output.lO Further, Figures 3 and 4. In patients with relatively well-pre- unlike fi blockers, calcium antagonists reduce coro- served ventricular function, neither drug had a signifi- nary vascular resistance with a tendency for the coro- cant effect on left ventricular ejection fraction at rest. nary sinus flow to increase. Some of the agents may Both drugs prevented the decrease in the ejection frac- produce a slight increase in the filling pressures of the tion induced by exercise, undoubtedly owing to their ventricle presumably owing to impairment of contrac- antiischemic actions. However, the @blockade caused tility, but this is of little hemodynamic consequence by propranolol led to a significant attenuation of the unless the overall ventricular performance is severely heart rate and systolic blood pressure induced by exer- impaired.ll The typical hemodynamic changes pro- cise, while the corresponding changes induced by cal- duced by calcium antagonism as exemplified by intra- cium antagonism with verapamil were modest. Similar venous verapamil are illustrated in Figure 2. The alter- differences have also been found between other p ations produced by diltiazem are very similar.lzJ3 blockers and calcium antagonists. They are of clinical With dihydropyridines, the hemodynamic response is relevance in so far as patients other than those with dominated by a greater reduction in the systemic vas- coronary artery disease [e.g., those with hypertension] </p><p>REST n = 15 patients </p><p>200 T SYSTOLIC BL?OD PRESSURE </p><p>1 </p><p>February 26, 1986 THE AMERICAN JOURNAL OF CARDIOLOGY Voiume 57 rOlD </p><p>2 140 </p><p>I </p><p>s; 120 </p><p>G loo </p><p>g 80 </p><p>HEART RATE </p><p>i n = I5 patients </p><p>I\ I I P</p></li><li><p>102D, A SYMPOSIUM: CALCIUM ANTAGONISTS IN HYPERTENSION-FOCUS ON VERAPAMIL </p><p>treated with these 2 classes of drugs are likely to re- spond to physical exercise somewhat differently. For example, with p blockade, exercise capacity is likely to be more severely limited than it is with calcium antagonists. </p><p>Comparative Hypotensive Effects of Verapamil and Propranolol </p><p>The data presented here are based on a double- blind, placebo-controlled comparative evaluation of the hypotensive potency of verapamil and propranolol in patients with mild to moderate systemic hyperten- sion (140/90 to 180 to 200/110 to 115 mm Hg]. </p><p>Methods Patient selection and protocol design: The criteria </p><p>for entry into the study included a diastolic pressure between 95 and 114 mm Hg determined from 3 consec- utive recordings. Patients with a history of diabetes mellitus, heart failure, AV block or bronchial asthma were excluded. Patients in whom withdrawal from monoamine oxidase inhibitors, antiarrhythmic agents and psychotropic drugs was not possible were also excluded. All subjects were men, mean age 56 years (range 35 to 74). </p><p>200 </p><p>160 3 </p><p>80 </p><p> BASE- VERAPAMIL LINE 120mg tid </p><p>BASE- PRO- LINE PRANOLOL </p><p>160mg tid </p><p>FIGURE 5. Effects of verapamil and propranolol on the mean sitting systolic blood pressure. Data represent mean f standard deviation. </p><p>200 - </p><p>180- </p><p>160- </p><p>cn l40- </p><p>: 120- </p><p>E loo- 80- </p><p>60- </p><p>40- </p><p>20- n- </p><p>11 </p><p>- </p><p>1 T :.:.:; :.:.:.:...:.: in N=,O ;i$$$$ p;&gt;:.,.:.:.:.:.,. ..,.......... -:.. :.:.:.:.:.:.:.: :.:. :::i:i:;:;:;:;.::; </p><p>~ </p><p>I::::::::::::::::::: : :.:.&gt;&gt;,.;:,,::: :~~~~:~~~;;~:::;:~: </p><p>;~~~~~~~;$~21~~;~ .i::::;::.::i:</p></li><li><p>February 26, 1986 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 57 lQJ0 </p><p>propranolol had a significantly lower mean posttreat- ment (p </p></li><li><p>104D A SYMPOSIUM: CALCIUM ANTAGONISTS IN HYPERTENSION-FOCUS ON VERAPAMIL </p><p>There have been a number of open-label studies that have suggested that verapamil might have signifi- cant hypotensive effects in patients with mild to mod- erate hypertension. 5,~ Of particular interest have been the findings of Gould et a1,17 who analyzed the effects of verapamil by ambulatory blood pressure monitor- ing after 6 weeks of drug therapy at a dosage of 120 to 160 mg 3 times a day. A consistent reduction in blood pressure was found over 24 hours but especially dur- ing the daytime, with the preservation of the shape of the circadian pattern of blood pressure variation. The drug was also found to produce an overall reduction in blood pressure with dynamic and isometric exercise, with a reduction in heart rate but without the develop- ment of postural hypotension. In recent years several studies have suggested that verapamil has hypotensive potency that compares favorably with that of many other commonly used antihypertensive compounds such as /3 blockers,15J8-21 a-methyldopa,2z reserpinez3 and diuretics.15 </p><p>Verapamil versus ,6 blockers in hypertension: Our data indicate that verapamil and propranolol in a blinded study exerted approximately equipotent ef- fects in patients with mild to moderate hypertension, although there appeared to be a trend for a slightly greater potency with the calcium antagonist. In this respect, our experience is similar to that of Leonetti et alazO They compared the effects of 120 and then 160 mg 3 times a day of verapamil to propranolol60 and then 80 mg 3 times a day (each drug regimen lasting for 6 weeks) in 31 patients with moderate essential hyper- tension. Both the drugs produced a significant reduc- tion in systolic and diastolic blood pressures, both in the supine and the upright positions. As in our current study, the fall in the blood pressure induced by vera- pamil was slightly but not significantly greater than that produced by propranolol, and there was a greater bradycardic effect with the p blocker than with the calcium antagonist. Doyle et aPgJ1 have reported a similar double-blind crossover of verapamil(l20 mg 3 times a day for 6 weeks] and pindolol(7.5 mg 2 times a day for 6 weeks] and of verapamil(160 mg 2 times a day for 6 weeks) and labetalol (200 mg 2 times a day for 6 weeks]. They found that verapamil was equally as ef- fective as pindolol and labetolol in lowering the high systolic and diastolic pressures. It was of interest that the echocardiographic assessment of cardiac output revealed that the salutary effects of verapamil were accompanied by a slight increase in cardiac output. This indicated that, unlike the ,8 blockers, the hypoten- sive effect of verapamil was due entirely to a decrease in peripheral vascular resistance in line with the drugs peripheral vasodilator actions. The differing mechanisms of action of p blockers and calcium antag- onists clearly raises the possibility of their combined use in the control of essential hypertension, a thera- peutic concept that is well established in the control of chronic stable angina.Z4J5 </p><p>Therapeutic implications: Our data and those con- tained in the published reports on the effects of vera- pamil clearly establish the role of this reference calci- um antagonist in the control of mild and moderate </p><p>essential hypertension. The results have indicated that as a single agent verapamil is at least as effective as propranolol in this setting. The question has therefore arisen as to the circumstances in which the agent might be preferable to p blockers. In our own studies, the adverse effect profile of the 2 classes of compounds could not be evaluated critically because of the small number of patients studied. However, from the experi- ence that has accrued in the tre...</p></li></ul>