Amlodipine, Enalapril, and Dependent Leg Edema in Essential Hypertension

Abstract

Abstract-Calcium channel blockers (CCBs) blunt postural skin vasoconstriction, an autoregulatory mechanism that minimizes gravitational increases in capillary pressure and avoids fluid extravasation when standing. To evaluate the dose-response relation between this pharmacological interference and dependent edema, a frequent side effect of CCBs during antihypertensive treatment, skin blood flow (laser Doppler flowmetry) at the dorsum of the foot, both supine and with the limb passively placed 50 cm below the heart level, and leg weight (Archimedes principle) were measured at baseline, during increasing doses of the dihydropyridine amlodipine (5 and 10 mg UID each for 2 weeks), and after drug withdrawal in 10 hypertensive men. Because angiotensin-converting enzyme inhibitors may attenuate ankle swelling by CCBs, those parameters were evaluated according to a similar design during amlodipine (10 mg UID) and enalapril (20 mg UID) combined (nϭ10). As a control, the effect of enalapril monotherapy (10 and 20 mg UID for 2 weeks each) was evaluated in a third series of patients (nϭ8). Amlodipine (5 mg UID) increased leg weight without modifying postural vasoconstriction (the percent skin blood flow decrease from horizontal to dependent position), which indicates that extravascular fluid shift was independent of postural skin vasoconstriction. At 10 mg UID, however, amlodipine blunted postural vasoconstriction and increased leg weight further, which suggests that skin blood flow autoregulation Key Words: calcium antagonists Ⅲ angiotensin-converting enzyme inhibitors Ⅲ blood flow Ⅲ vasoconstriction Ⅲ hypertension, essential P recapillary resistance in the skin of the foot rises on standing, thereby limiting the increase in capillary pressure resulting from gravitational increases in transmural pressure. 1,2 This autoregulatory vasoconstrictor mechanism is triggered by limb venous congestion and operates both through a locally evoked sympathetic axoaxonic reflex 1,2 and local myogenic factors, 3 with some minor participation of central mechanisms. 2 The postural vasoconstrictor response protects subcutaneous tissue from fluid extravasation during dependency and eventually dependent edema 1 ; its derangement, as in patients with peripheral vascular disease 4 and diabetes, 5 sets the stage for subcutaneous edema formation. 6 We have recently shown impaired postural skin blood flow control in patients with essential hypertension who were treated with calcium channel blockers (CCBs). 7 This pharmacological effect may contribute to ankle and/or pretibial edema in the absence of fluid retention, 8 a frequent, bothersome, and still not completely understood collateral effect of calcium antagonist drugs. 9 To test this hypothesis, we evaluated the relation between changes in postural skin vasomotion and objective measures of ankle swelling during treatment with graded doses of amlodipine, a dihydropyridine CCB. 10 On the basis of previous reports of reduced ankle swelling during association therapy with angiotensin-converting enz...

Effect of valsartan addition to amlodipine on ankle oedema and subcutaneous tissue pressure in hypertensive patients

“…13,14 The mechanisms by Valsartan-amlodipine combination and ankle oedema R Fogari et al which ARB may attenuate the CCB-induced oedema are not clear but possibly resemble those hypothesized for ACE-I. [4][5][6][7][8] Thus, RAAS blockade by both ACE-I and ARB is likely to result in venous capacitance vessels vasodilation with consequent intracapillary pressure normalization and reduced fluid exudation from the intracapillary space into the interstitium. The ability to affect the vasodilatory mechanism of the oedema produced by CCB seems to make not only ACE-I but also ARBs able to alleviate this side effect.…”

“…[1][2][3] The mechanisms underlying CCB-induced oedema, although not completely understood, possibly include: (a) an increase in capillary hydrostatic pressure, with consequent transcapillary fluid loss, that results from a relatively more pronounced vasodilation in precapillary than postcapillary resistance vessels; 4-6 (b) an interference with the local vascular control, probably the myogenic component, that operates to protect dependent vascular regions from increased fluid filtration. [7][8] With any form of oedema, most physicians add a diuretic to the antihypertensive treatment. Unfortunately, diuretics, either loop or thiazide, have little effect on CCB-induced oedema because they merely decrease fluid retention but do not affect the vasodilatory mechanism of the oedema, which is predominant with CCB.…”

Effect of benazepril addition to amlodipine on ankle oedema and subcutaneous tissue pressure in hypertensive patients

“…[8][9][10][11] Although the precise mechanisms causing the Ca-antagonist-induced oedema are still not completely understood, the most likely reason appears to be an increase in capillary hydrostatic pressure with consequent transcapillary fluid loss that results from a relatively more pronounced vasodilation in precapillary than postcapillary resistance vessels. [12][13][14] It has also been suggested that the Ca-antagonist-related oedema could be partly ascribed to interference by these drugs with the local vascular control (probably the myogenic component) that operates to protect dependent vascular regions from increased fluid filtration, 15,16 whereas sodium retention and activation of the renin-angiotensin system seem to play a minor role. 14,17 Most reports about the lower incidence of Caantagonist-induced ankle oedema with the addition of an ACE-I are generally based on a simple collection of reported side effects, that is, on subjective parameters rather than objective estimates of the magnitude of this effect.…”

A Noninferiority Comparison of Valsartan/Hydrochlorothiazide Combination Versus Amlodipine in Black Hypertensives

“…1 The maximum recommended dose of amlodipine, which is not uncommonly associated with pedal edema, often is required to control BP in black patients. 20 Equivalent BP lowering and better tolerability with valsartan/HCTZ compared with amlodipine would support use of this combination as an alternate, first-line therapy in blacks with hypertension.…”