calcium channel blockers in systemic hypertension
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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-
fedipine, in the rapid treatment of patients with severe hypertension has been demonstrated.3JJ 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 verapamils 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