calcium antagonists and beta blockers in the control of mild to moderate systemic hypertension, with...
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Calcium Antagonists and Beta Blockers in the Control of Mild to Moderate Systemic Hypertension,
with Particular Reference to Verapamil and Propranolol
BRAMAH N. SINGH, MD, PhD, PERLITA REBANAL, RN, MARTHA PIONTEK, RN, and KOONLAWEE NADEMANEE, MD
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
1OOD A SYMPOSIUM: CALCIUM ANTAGONISTS IN HYPERTENSION-FOCUS ON VERAPAMIL
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.
Pharmacologic Considerations The bulk of the pharmacologic effects of P-adrener-
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 ,&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
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
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
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.
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
25 20 R PA PiW no C.I. LVEF CSF MVO, SVA PVR SW,
HR LVEDP Cl SW LV WI LVdp/dt m
+ 50, + 45% TIMOLOL : 1.0 mg paou
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.
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-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
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]
REST n = 15 patients
200 T SYSTOLIC BL?OD PRESSURE
February 26, 1986 THE AMERICAN JOURNAL OF CARDIOLOGY Voiume 57 rOlD
i n = I5 patients
I\ I I P
102D, A SYMPOSIUM: CALCIUM ANTAGONISTS IN HYPERTENSION-FOCUS ON VERAPAMIL
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.
Comparative Hypotensive Effe