Review
Paper
Clinical Experience With Angiotensin Receptor Blockers With Particular Reference to Valsartan Steven G. Chrysant, MD, PhD;1 George S. Chrysant, MD2
The angiotensin II receptor blockers (ARBs), are highly selective for the AT1 subtype and will block the effects of angiotensin II on peripheral vessels. Several short- and long-term studies have shown these agents to be safe and effective antihypertensive drugs. Since monotherapy of hypertension may be ineffective in lowering the blood pressure to goal, the use of an ARB, especially in combination with a diuretic or another medication, is frequently necessary to bring the blood pressure 98
94–97
0.13 L/kg
308 L
53–93 L
34 L
17 L
500 L
17 L
26
7
Unknown
4
35–50
0.49–0.91
13
In this review, clinical experience with ARBs will be discussed and will focus on valsartan, alone and in combination with hydrochlorothiazide (HCTZ) in the treatment of hypertension, and cardiovascular and renal diseases. MECHANISM OF ACTION OF THE ARBS The seven ARBs approved by the Food and Drug Administration for treatment of hypertension are listed with their pharmacokinetic profiles in Table I. These ARBs exert their effect by selectively blocking the angiotensin II type 1 (AT1) receptor, thus interfering with the action of AII on vascular smooth muscle and its adverse cardiovascular remodeling effects. AII is primarily generated by the classical ACE pathway, but alternate pathways also exist (Figure 1). In contrast to ACEIs, ARBs block the AII action at the AT1 receptor level and, therefore, are indifferent to the pathway by which AII is generated. This is clinically important since up to 40% of tissue AII in the blood vessels, heart, and kidneys is produced through the alternate pathways and mostly through the action of chymase.4–6 This could account for the fact that AII levels, after being suppressed initially by ACEIs, begin to rise later and almost return to their baseline levels.13 These biological differences between ACEIs and ARBs suggest that ARBs may be the preferred drugs for initiating antihypertensive therapy or even substituting previously used ACEIs. ARBs, by selectively blocking the AT1 receptors, allow the free-floating AII to stimulate the unoccupied angiotensin II type 2 (AT2) receptors, and thus induce their beneficial effects (Figure 1, Table II). Valsartan is one of the ARBs that has a high affinity for the AT1 receptor, and binds to it insurmountably. This affinity, compared
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with other ARBs, is as follows: candesartan > irbesartan > valsartan/telmisartan > losartan > eprosartan.14 This, perhaps, explains the long duration of action of candesartan, irbesartan, valsartan, and telmisartan and their suitability for once-daily (q.d.) administration. Monotherapy of hypertension with valsartan and other members of its class results in about 50% control of BP and does not differ from monotherapies with other antihypertensive drugs. When an ARB, ACEI, or a β-blocker is combined with a diuretic, BP control is achieved in over 70% of patients.15,16 THERAPEUTIC EFFICACY OF VALSARTAN, VALSARTAN/HCTZ, AND SIMILAR COMBINATIONS OF OTHER ARBS IN HYPERTENSIVE PATIENTS Several double-blind, randomized, placebo-controlled studies testing the antihypertensive effectiveness and safety of valsartan as monotherapy have been reported. Initial studies used 10 mg, 20 mg, 40 mg, 80 mg, 160 mg, and 320 mg of valsartan q.d. with office measurements or, in some studies, 24-hour ambulatory BP measurements.17–20 The dose of valsartan producing the greatest BP reduction was 80 mg o.d. or higher.17–20 The results of one of these studies for both sitting diastolic blood pressure (SiDBP) and sitting systolic blood pressure (SiSBP) are depicted in Figure 2 (panels A and B, respectively).17 As expected the levels of plasma AII and plasma renin activity were elevated (Figure 3 [panels A and B, respectively]). The hypotensive effect of valsartan 80 mg/d was similar to equipotent doses of other antihypertensive drugs, both in the young and elderly.15–22 In a multicenter study, 501 elderly hypertensive patients were treated with
VOL. VI NO. VIII AUGUST 2004
The Journal of Clinical Hypertension (ISSN 1524-6175) is published monthly by Le Jacq Communications, Inc., Three Parklands Drive, Darien, CT 06820-3652. Copyright ©2004 by Le Jacq Communications, Inc., All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Sarah Howell at
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Table II. Functions of Angiotensin II Receptors Type 1 (AT1) and Type 2 (AT2) AT1 RECEPTOR
AT2 RECEPTOR
Most important Always expressed in adults Mediates vasoconstriction Increases renal tubular sodium reabsorption Increases cell growth Decreases endothelial function Stimulates connective tissue deposition Facilitates LDL transport to media through, possibly, the LOX-1 receptor
Less important A fetal receptor expressed in adults during stress or injury Mediates vasodilation Decreases renal tubular sodium reabsorption Inhibits cell growth Improves endothelial function Inhibits connective tissue deposition No known effect on cholesterol transport
LDL=low-density lipoprotein; LOX=oxidized low-density lipoprotein
either valsartan 40 mg q.d. (n=334) or lisinopril 2.5 mg q.d. (n=167) and were followed for 1 year. Both valsartan and lisinopril could be uptitrated to 80 mg and 20 mg, respectively, and low-dose HCTZ could be added, if necessary, for better BP control. Both drug regimens produced significant decreases in SiDBP and SiSBP with a response rate of 81% and 87% for the valsartan or lisinoprilbased regimen, respectively, at 52 weeks.22 Valsartan/HCTZ Combination The combination of valsartan 80–160 mg/d with HCTZ 12.5–25 mg/d has been tested in patients with essential hypertension in short, doubleblind,23–26 short-term open-label,27,28 and longterm open-label studies.29,30 The data from these studies are shown in Table III. Combination therapy, as expected, resulted in a greater BP reduction and greater response to treatment than monotherapy. The combination of valsartan/HCTZ 80/12.5 mg/d was as effective as valsartan/HCTZ 160/12.5 mg/d; valsartan/HCTZ 80/25 mg/d, or 160/25 mg/ d and resulted in greater BP reductions, although these were not statistically significant.22,23 Two of these studies extended the double-blind observation period of patients treated with valsartan/HCTZ 80/12.5–25 mg/d to 2-year29 and 3-year open-label extensions30 with ongoing BP control and good tolerability. Black hypertensive patients are usually resistant to monotherapy with ACEIs, ARBs, or β-blockers possibly because they have low renin hypertension, but the addition of a diuretic usually reverses this resistance and results in BP reduction similar to that in whites.31 ADVERSE EVENTS—DRUG INTERACTIONS The most commonly reported clinical adverse events with ARBs are dizziness, headache, and fatigue, which are no different than placebo-treated patients. VOL. VI NO. VIII AUGUST 2004
Cough or angioedema are rare with the use of ARBs in contrast to ACEIs, and ARBs can be used as an alternative to ACEIs for patients who develop cough without angioedema. With respect to the metabolic adverse events, mild hypokalemia (K+
