EDITORIALS

Calcium Channel Blockers in Systemic Hypertension

WILLIAM H. FRISHMAN, MD, SHLOMO CHARLAP, MD, and ERIC L. MICHELSON, MD

Basic Mechanisms Increased vascular resistance is the hallmark of es-

tablished systemic hypertension. It has been proposed that a disturbance of cellular calcium metabolism plays a primary role in the development and mainte- nance of the elevated arteriolar tone.1-3 The pivotal role of calcium in determining the contractile state of vascular smooth muscle is well documenteda Actin- myosin interactions and contraction of the muscle cell result from phosphorylation of myosin by myosin ki- nase; activation of this enzyme is dependent on intra- cellular calcium reaching the concentration required for it to bind with calmodulin.

In spontaneously hypertensive rats, a reduced cal- cium uptake by the sarcoplasmic reticulum of smooth muscle cells, resulting in increased intracellular free calcium concentrations, supports a possible role for calcium in the pathogenesis of hypertension5 In- creased intracellular calcium concentrations have also been found in adipose tissue6 and platelets7 of those patients with essential hypertension. These and other studies1-3Jsg suggest that increased calcium concentra- tions are also present in smooth muscle cells of hyper- tensive patients and may contribute to the hyperten- sive state. Because the influx of calcium into cells is a major determinant of the intracellular free calcium concentration,2J0 inhibition of calcium entry into vas- cular smooth muscle appears to be a direct, and there- fore attractive, approach to the treatment of systemic hypertension.

Calcium channel blocking drugs cause selective in- hibition of transmembrane flux of calcium in excitable tissue.*l Their ability to block calcium-mediated elec- tromechanical coupling in contractile tissue reduces the contractile activity of the heart and also produces

From the Departments of Medicine of The Albert Einstein Col- lege of Medicine, Bronx, New York, The Long Island College Hospital, Brooklyn, New York, and the Lankenau Medical Re- search Center, Philadelphia, Pennsylvania. Manuscript re- ceived November 18,1985; revised manuscript received Febru- ary 13,1986, accepted February 14,1986.

Address for reprints: William H. Frishman, MD, Department of Medicine, Albert Einstein Hospital, 1825 Eastchester Road, Bronx, New York 10461.

arterial dilation in both the coronary and peripheral vascular beds; their inhibition of transmembrane cel- lular flow of calcium during the slow inward current depresses sinus node automaticity and both sinoatrial and atrioventricular conduction. Recognition of these properties has led to successful use of these agents in a variety of cardiovascular disorders, particularly myo- cardial ischemic syndromes, hypertrophic cardiomy- opathy and certain arrhythmias. Because drugs that induce systemic vasodilation can be expected to re- duce elevated arterial blood pressure, it is not surpris- ing that interest now focuses on use of the calcium blocking drugs in the medical management of systemic hypertension.

Experimental Evidence Experimental studies suggest that the calcium

channel blocking drugs decrease peripheral resistance in hypertension by specifically reversing a functional abnormality that is maintaining the hypertensive state, i.e., excessive intracellular calcium concentrations. Verapamil and nifedipine produce a greater relaxa- tion of blood vessels in spontaneously hypertensive rats than in normotensive rats.8,g Similarly, the fore- arm resistance vessels of patients with essential hy- pertension are more sensitive to the dilator action of verapamil than are those of normal subjects1 The demonstration of a direct relation between the degree of antihypertensive response to calcium blocking ther- apy and the height of pretreatment blood pressure with only minimal blood pressure reductions in nor- motensive subjects supports this concept,12J3 but does not distinguish these agents from most other antihy- pertensive drugs. However, a notable exception are the vasodilators, such as prazosin and nitroprusside, which will also cause blood pressure reductions in normotensive persons.

In addition to their calcium channel-mediated vas- cular effects, these drugs may also reduce pressure through antisympathetic actions at ol-adrenergic re- ceptorsl4 and through a natriuretic effect.15

Clinical Effectiveness Acute administration: The clinical effectiveness of

the calcium channel blocking drugs, particularly ni-

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150 EDITORIALS

fedipine, in the rapid treatment of patients with severe hypertension has been demonstrated.3J”J’ The drugs produce prompt and potent blood pressure-lowering effects, usually without untoward reactions. Blood pressure is reduced in direct relation to the magnitude of the pretreatment blood pressure, with profound hy- potensive responses rarely observed. Oral, sublingual (i.e., nifedipine] or parenteral (i.e., verapamil) formu- lations can be used, depending on the urgency of blood pressure control. The responses to either oral or sub- lingual preparations may be less predictable for acute blood pressure reduction. Nifedipine, and other dihy- dropyridine derivatives when they become available, may be the preferred calcium blockers for treatment of hypertensive emergencies because of their more po- tent vasodilator actions. Reflex cardiac stimulation precipitating angina or myocardial infarction, a poten- tial complication with other vasodilator drugs, is rarely seen because of the concomitant coronary vasodilator actions of the calcium channel blocking drugs. Nifedi- pine markedly reduces left ventricular afterload, mak- ing it effective in cases of severe hypertension compli- cated by congestive heart failure. Although the drug is generally safe in such situations, all calcium blocking drugs have negative inotropic actions and can exacer- bate heart failure in patients with significant left ven- tricular dysfunction. In patients with hypertension and a suspected dissecting aortic aneurysm, use of nifedi- pine alone is not recommended because the reflex sympathetic stimulation that the drug elicits may in- crease sheer forces in the aortic wall and possibly wid- en the dissection.

Chronic administration: The different pharmaco- logic properties of the various calcium channel block- ing drugs, most notably nifedipine and other dihydro- pyridines, compared with verapamil and diltiazem, may be most evident in their respective roles for long- term therapy of chronic arterial hypertension. All cal- cium blocking drugs induce systemic arterial vasodila- tion; dihydropyridines are the most potent agentsll

Notwithstanding their precise mechanism of ac- tion, previous vasodilators generally have been rele- gated to the “third line” of antihypertensive therapy, to be given in combination with diuretic drugs and sym- patholytic agents. When used alone, many vasodilators induce reflex stimulation of the sympathetic and re- nin-angiotensin systems, resulting in adverse effects and loss of antihypertensive action. Investigators have found nifedipine and other short-acting dihydropy- ridines to have a similar profile of adverse reac- tions.l3,18J9 However, the activation of reflex homeo- static mechanisms does seem to decline over time.*Jg Whether antihypertensive efficacy diminishes with long term nifedipine therapy is a matter of controver- sy; most investigators find that pharmacologic toler- ance is not a problem.z0-23

Verapamil and diltiazem, which are less potent va- sodilators than nifedipine, appear to be effective anti- hypertensive drugs and are well tolerated.24-26 Vera- pamil and diltiazem have direct negative inotropic and chronotropic properties that are more evident clinical- ly, and apparently contribute to a different hemody-

namic profile. Verapamil also has antisympathetic and, possibly, central nervous system-mediated ef- fects that may further enhance its antihypertensive activity.14J7

Tolerability and safety: The few studies comparing the different calcium blocking drugs as monotherapy in the treatment of chronic hypertension suggest that the drugs have comparable hypotensive effects; only their side effect profiles are different.28929 The most common adverse effect reported with verapamil is constipation; with diltiazem there is occasional gastro- intestinal upset or ankle edema. With nifedipine, an- kle edema and palpitations may be observed. The mechanism of ankle edema with calcium channel blocking drugs is not known, but may relate to precap- illary vasodilation and increased capillary leak. The negative chronotropic, dromotropic and inotropic ef- fects of verapamil and diltiazem are less common, but potentially more serious. The depressant action of ve- rapamil and diltiazem on the sinus and atrioventricu- lar nodes is rarely a problem except in patients with sick sinus syndrome and conduction defects. Only in patients with significant left ventricular dysfunction does verapamil’s negative inotropic action have bear- ing. However, calcium channel blocking drugs gener- ally improve ventricular diastolic function, and pre- liminary investigations suggest that calcium blocking drugs may regress or prevent the progression of left ventricular hypertrophy. 14,30 Initial complaints of flushing, headache and ankle edema are frequently reported with use of nifedipine, sometimes leading to withdrawal of therapy, but these are less of a problem with long term use. Pharmacologic tolerance to the drugs has been reported infrequently.20 The drugs ap- pear to have no adverse renal effects in patients with normal renal function,31932 although there is a report of nifedipine causing acute reversible deterioration of renal function in patients with chronic renal insuffi- ciency.33 Because these drugs are metabolized in the liver, in the presence of advanced hepatic disease the dosage of calcium channel blocking drugs must be adjusted accordingly. Major pharmacologic drug in- teractions are not clinically important, with a few nota- ble exceptions. Verapamil treatment transiently in- creases digoxin levels approximately 50 to 7O%, and a reduction in digoxin dosage may be appropriate for the first week when initiating verapamil. Conversely, ve- rapamil treatment may cause a reduction in lithium levels, and cimetidine use may increase verapamil levels.

Available evidence suggests that the antihyperten- sive efficacy of the calcium blocking drugs is compara- ble to that of existing first-line therapies.12J5v26s31,34 It is in this context that calcium channel blocking therapy represents a most noteworthy advance in the manage- ment of hypertension. Calcium blocking drugs offer an alternative treatment to /3-adrenergic blocking drugs in patients in whom that group of drugs is contraindicat- ed by existing asthma or peripheral vascular disease, insulin-requiring diabetes, or in whom reduction of exercise capacity and fatigue may become unaccept- able. Hypokalemia, hyperuricemia and impairment of

July 1, 1986 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 58 159

g$fJcose tolerance seen with diuretic drugs are not ob- served with calcium blocking drugs. Unlike some P- blocking drugs and the thiazides, calcium blocking agents do not have adverse effects on serum lipopro- teins.35 In contrast to other vasodilator drugs, calcium blocking drugs usually do not give rise to sodium or water retention, and may even cause natriuresis.36 As noted earlier, however, ankle edema, apparently be- cause of local hemodynamic changes, is not uncom- mon with nifedipine and related drugs. There are no reports of the drugs inducing lupus syndrome, as occa- sionally occurs with hydralazine.

The concomitant use of p-blocking therapy virtual- ly abolishes any nifedipine-induced increases in heart rate or plasma renin activity, while producing further decreases in blood pressure.18J2 Combination verapa- mil//3-blocking therapy for the treatment of hyperten- sion should be used with caution because of the com- mon negative inotropic and chronotropic actions of these drugs, although there is evidence that the drugs used together have potent hypotensive effects and the risk of adverse reactions is small when patients with- out sinus node and conduction disease or left ventricu- lar dysfunction are selected for therapy.37 The hypo- tensive effects of calcium blocking and diuretic drugs appear to be additive. 2*,38 Moreover, it appears that both diuretic and calcium channel blocking drugs are most efficacious in the same patient populations, typi- cally those often associated with low renin states: black patients and the elderly.

Nifedipine may be of value as long-term treatment when used as third-line therapy in the treatment of hypertension that is difficult to control. The drug has been successful when other third-line agents, such as hydralazine and minoxidil, were ineffective or pro- duced troublesome side effects.3J7,3g Apparently, its antihypertensive actions are maintained during chronic use as part of a multidrug regimen. A reported advantage of nifedipine is that it also improves myo- cardial relaxation. This takes on importance in pa- tients with long-standing hypertension who frequently have evidence of diastolic dysfunction.3g The limited experience with combination nifedipine/vasodilator therapy suggests that such a combination has very po- tent hypotensive effects. Since precipitous decreases in blood pressure may result, caution is advised in administration. Use of verapamil or diltiazem as third- line antihypertensive agents has not been formally in- vestigated, but should prove useful.

Calcium blocking drugs may be the preferred agents in older patients and in those with low renin activity, in whom one may wish to avoid diuretic thera- py and in whom P-blocking therapy may be relatively ineffective; P-blocking drugs would appear more use- ful in the younger patients and in patients with high renin levels.12 Calcium blocking drugs are apparently effective in the black persons,21r35 whereas P-blocking drugs have been found effective less consistent- ly.21JO~41 In fact, calcium channel blocking drugs are probably effective in patients typically responding best to a diuretic drug. Thus, for the patient with car- diovascular disease and adequate systolic ventricular

function, calcium channel blocking therapy may be an attractive initial monotherapeutic step.

In addition, the antianginal and antiarrhythmic properties of the calcium blocking drugs may allow their use as monotherapy in patients with hyperten- sion and coexisting coronary artery disease42s43 or su- praventricular arrhythmias. A disadvantage of calci- um channel blocking drugs for hypertension has been their short duration of pharmacologic action, which often necessitates their administration 3 times daily for antihypertensive efficacy, although a twice-daily regi- men may be sufficient in some cases.24 The availability of long-acting compounds like nitrendipine, or slow- release preparations of shorter-acting drugs that can allow once-daily dosing, should lead to more wide- spread use of the drugs for hypertension. A slow-re- lease preparation of nifedipine, now being evaluated, should reduce that drug’s incidence of side effects because of the lower peak drug concentrations. Dil- tiazem has been tested successfully in long-acting, sustained-release form.26 Verapamil in its regular for- mulation and in a new sustained-release preparation, suitable for twice- and perhaps once-daily dosing, has received a favorable review by the Cardio-Renal Ad- visory Panel of the FDA for the treatment of systemic hypertension, and may be the first calcium channel blocking drug approved for this indication. The clini- cal data bases in hypertension for diltiazem, nifedi- pine and the new dihydropyridines, nicardipine and nitrendipine, have been submitted to the FDA for review.

Conclusion: Calcium channel blocking drugs pro- vide a new conceptual approach to treatment of sys- temic hypertension. Clinical investigation suggests an important role for these drugs in treatment of mild, moderate and severe hypertension. For patients with concomitant disorders, as well as patients traditionally treated with diuretic drugs, calcium channel blocking therapy represents an attractive alternative. However, although the available calcium channel blocking drugs have many actions in common, they are distinct chem- ically and have different pharmacologic profiles and ancillary properties. Moreover, the higher cost of cal- cium blocking drugs compared with diuretic drugs and other antihypertensive agents may limit their use to patients in whom advantages in efficacy, adverse ef- fects and compliance are shown.

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