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Pharmacologic Issues in Treating Hypertension in CKD
Pharmacologic Issues in Treating Hypertension in CKD Domenic A. Sica Antihypertensive drugs are prescribed to patients with CKD to slow down the rate of loss of residual kidney function; to reduce proteinuria, when present; and to protect other target organs from damage that is mediated by elevated blood pressure (BP). In most patients, a diuretic and a renin system blocking drug, such as an angiotensin-converting enzyme inhibitor, angiotensin receptor antagonist, or an aldosterone receptor antagonist are used. Often, 3 or more drugs are needed to achieve BP goals. Many drugs are eliminated through the kidney and in some cases dosage reductions are advisable to avoid adverse effects from high levels of medication. This article will review the various classes of antihypertensive drugs used in the management of high BP in patients with CKD, with an emphasis on pitfalls that arise when kidney function is impaired. Q 2011 by the National Kidney Foundation, Inc. All rights reserved. Key Words: Hypertension, Aldosterone receptor antagonsists (ARAs), Angiotensin receptor blockers (ARBs), Angiotensinconverting enzyme (ACE) inhibitors, Cardiovascular (CV)
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KD is both a cause and an effect of hypertension and is multifactorial in its development. Other than volume expansion, CKD-related hypertension is generally without qualifying characteristics of any consistency. Consequently, the order in which antihypertensive medications are given to patients with CKD and hypertension is arbitrary. Prescription practice for CKD-related hypertension should be mindful of the need for multiple drugs with a minimum of one being a properly dosed diuretic.1 It is not without reason that blood pressure (BP) goals for patients with hypertension and CKD are set at lower levels as compared with those for patients with essential hypertension, but it remains to be determined by how much the BP should be lowered in patients with hypertension and CKD.2 It also remains to be decided by how much the BP should be lowered for patients with proteinuric CKD as opposed to those with progressive CKD without proteinuria.3
Basis for Use of Antihypertensive Medications in CKD Antihypertensive medications are used in patients with CKD for several reasons. First, BP reduction slows down the progression rate of renal disease, irrespective of the type of medication (or medications) being used. Second, certain antihypertensive compounds, such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and aldosterone receptor antagonists (ARAs), significantly reduce protein excretion and in so doing further slow down the progression rate of renal disease above and beyond what is seen with BP reduction. Third, antihypertensive compounds, such as ACE inhibitors and ARBs, also have demonstrable cardiovascular (CV) protective effects. The latter is an From Division of Nephrology, Virginia Commonwealth University Health System, Richmond, VA. Address correspondence to Domenic A. Sica, MD, Division of Nephrology, Virginia Commonwealth University Health System, Richmond, VA 232980160. E-mail: [email protected] Ó 2011 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 doi:10.1053/j.ackd.2010.11.003
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important feature of drug therapy in CKD because these patients typically exhibit a high CV event-rate across the entire spectrum of CKD.
Pharmacologic Principles and Dosing Effects Dose-response effects exist for all classes of antihypertensive drugs, but BP responses to dose titration are most evident with diuretics, sympatholytics, a-blockers, and calcium channel blockers (CCBs). A major consideration in the pharmacodynamic dose-response relationship for an antihypertensive medication is the extent to which BP counterregulatory mechanisms are set in motion by lowering of BP. Acute and chronic BP reduction often activates an interlinked series of mechanisms to bring BP back toward previously raised values. Reflex increases in cardiac output, peripheral vasoconstriction, and salt and/or water retention can arise from baroreflex-mediated activation of the sympathetic and renin–angiotensin–aldosterone system. These counterregulatory responses are dose-dependent and most regularly crop up with nonspecific vasodilatory drugs (eg, hydralazine or minoxidil) or diuretics. It can prove to be quite difficult to approximate the extent to which counterregulatory systems are activated with antihypertensive medications in patients with CKD. A reliable sign of such ‘‘pseudotolerance’’ is loss of previously established BP control. In that regard, a 10% to 20% increase in heart rate induced by antihypertensive medication should prompt either a lowering of the dose of the provoking agent and/or the addition of a pulse rate lowering compound such as a b-blocker. Sodium retention, as the basis for loss of BP control, is easy to recognize when peripheral edema (with an accompanying weight gain) develops, although a lapse in control can still occur from volume expansion even in the absence of peripheral edema. If this is suspected, diuretic therapy can be increased or the class of diuretic changed to effect a small weight loss in the order of 1% to 2% of body weight.
Diuretics Diuretics remain a mainstay of therapy in the therapy of hypertension and/or volume overload in the presence
Advances in Chronic Kidney Disease, Vol 18, No 1 (January), 2011: pp 42-47
Pharmacologic Issues in Treating Hypertension
of CKD. By reducing extracellular fluid volume, they lower BP and thus are capable of potentiating the effects of ACE inhibitors, ARBs, and other antihypertensive agents including CCBs. Administration of thiazide-type diuretics once daily are recommended in CKD stages 1 to 3. There is limited information from controlled trials to guide diuretic dosing for BP control in CKD stages 4 and 5; therefore, such dosing is empiric and is often determined by the elimination of edema (if present) and less so by control of BP.4 As an example of the frequency of diuretic use in CKD, about 84% of the patients in the Reduction of Endpoints in non insulin-dependent diabetes mellitus (NIDDM) with the Angiotensin II Antagonist Losartan study (baseline serum creatinine level: approximately 1.9 mg/dL) were given diuretic therapy in addition to several other antihypertensive medications to achieve the BP goal of ,140/90 mm Hg.5,6 A similarly high proportion of patients received diuretic therapy to reach the target BP in the Irbesartan Diabetic Nephropathy Trial (baseline serum creatinine level: approximately 1.7 mg/dL.)7,8 The major outcomes data in stage 3 CKD and hypertension with diuretic therapy come from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, where the thiazide-type diuretic chlorthalidone was compared with the ACE inhibitor lisinopril and the CCB amlodipine. In a post hoc evaluation of the trial, patients were stratified at baseline into the following 3 glomerular filtration rate (GFR) groups: normal or increased ($90 mL/min/1.73 m2; n ¼ 8126), mild reduction (60-89 mL/min/1.73 m2; n ¼ 18,109), and moderate or severe reduction (,60 mL/min/1.73 m2; n ¼ 5662). Each stratum was analyzed for effects of the treatments on outcomes. The chlorthalidone-based regimen (dose range: 12.5-25.0 mg/d) was equally (if not superior) effective in reducing BP as compared with regimens based on lisinopril (dose range: 10-40 mg/d) and amlodipine (dose range: 5-10 mg/d); moreover, neither amlodipine nor lisinopril was superior to chlorthalidone in reducing the rate of development of ESRD or a 50% or more decrement in GFR.9 There remains some sort of artfulness to the correct use of diuretics in CKD, partly, because of the intimate relationship between GFR and diuretic response. Although a large dose of a thiazide diuretic will initiate a diuresis in patients with mild renal insufficiency, the response in patients with a GFR of ,50 mL/min is more limited, except for the thiazide-type diuretic metolazone10; however, in the setting of CKD, patients are not ‘‘resistant’’ to a thiazide diuretic per se; instead, the basis for failure of a thiazide-type diuretic is, in most instances, that they are not sufficiently potent for the needs of such patients. Patients receiving fixed-dose combination antihypertensive therapy containing a thiazide-type diuretic should be considered for conversion to a loop diuretic (together with whatever was the other component of the fixed-dose combination) when GFR values drop to
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,50 mL/min, only if BP control is inadequate and/or edema is present.4 Fixed-dose combination antihypertensive therapies with a thiazide-type diuretic component do not require a diuretic change in nonedematous patients with CKD and good BP control. An important consideration in the treatment of hypertension in CKD stages 4 and 5 is that a loop diuretic is only as useful as its ability to bring a patient to ‘‘target weight.’’ Patients with CKD have a 10% to 30% increase in extracellular fluid and blood volume, even in the absence of overt edema and commonly have a saltsensitive form of hypertension.11 Establishing a ‘‘target weight’’ in the patient with CKD who is not edematous can prove to be tricky; however, a gradual reduction in BP in a poorly controlled hypertensive that coincides with diuretic-related weight loss can be a useful clue that a ‘‘dry weight’’ is being reached.12 Potassium (K1)-sparing diuretics, such as spironolactone and eplerenone, are being used more frequently in the CKD population, based on their ability to lower BP while exhibiting a prominent antiproteinuric effect.13 The onset of action for spironolactone is characteristically slow, with a peak response at 48 hours or more after the first dose. This response lag most likely relates to the time needed for the active metabolites of spironolactone to reach steady-state plasma and/or tissue levels. Spironolactone can trigger a prominent natriuretic response when given to patients with cirrhosis/ascites or heart failure, particularly when combined with a loop and/or a thiazide-type diuretic14; however; it is not a particularly strong natriuretic agent, irrespective of CKD status, when given to nonedematous hypertensive subjects. The package label for both spironolactone and eplerenone are specific in that these drugs should not be used even with mild-to-moderate levels of renal insufficiency; however, use of an ARA in CKD is not merely a function of the level of renal function; rather, it should take into account the possibility of development of clinically relevant hyperkalemia.15 For most patients, the risk of developing hyperkalemia should not dissuade the prudent clinician from use of these compounds when indicated. Hyperkalemia should be considered a possibility in any patient receiving an ARA with or without an ACE inhibitor (or ARB). Hyperkalemia is best addressed preemptively with control of dietary K1 intake, elimination (or dosage reduction) of K1 supplements, and avoidance of nondiuretic K1-sparing compounds.16
ACE Inhibitors ACE inhibitors are frequently administered drugs in patients with CKD, usually given for the treatment of hypertension and/or for their cardiorenal protective effects. The BP lowering effect of ACE inhibitors is generally less in volume-expanded forms of hypertension, which is often the case in CKD. In patients with CKD, addition of a diuretic to an ACE inhibitor typically
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Sica
enhances the BP lowering response, and a goal BP of 130/ 80 mm Hg is currently recommended. This goal BP presumably addresses the optimal BP for both renal and CV protection; however, there is considerable debate on whether achieved BP values of ,130/80 mm Hg confer additional renal benefits in patients with CKD and, if so, whether any such favorable response is drug class specific. Currently, there is insufficient evidence to determine whether a J-shaped relationship exists for renal outcomes and achieved BP values of ,130/80 mm Hg. Most ACE inhibitors are exclusively renally cleared with occurrence of varying degrees of filtration and tubular secretion (organic anion secretory pathway).17 ACE inhibitors with dual routes of elimination, such as fosinopril and trandolapril, are those whose active diacid is both hepatically and renally cleared. This property of combined renal and hepatic elimination minimizes accumulation in CKD because dosing to steady state occurs. To date, a specific adverse effect has not been identified from ACE inhibitor accumulation, although cough has been suggested, but not proven, to be an ACE inhibitor side effect relating to drug concentrations. However, it is possible that the longer drug concentrations remain elevated—after a response to an ACE inhibitor has occurred—the more likely it is that BP, renal function, protein excretion, and K1 handling will be influenced. To this end, there is emerging support for treatment stratagems using high ACE inhibitor doses; however, the findings with such an approach have been variable.18-20 Presently, guidelines do not suggest titration of an ACE inhibitor or an ARB dose to a level higher than what might be necessary for BP control in
patients with CKD. If an ACE inhibitor dose is titrated upward in a patient with CKD and already wellcontrolled BP, it is a process undertaken on an empiric basis with an uncertain outcome. Mindful of such an approach, some patients are very sensitive to the effects of an ACE inhibitor, particularly those who have an activated renin–angiotensin–aldosterone system; therefore, even minimal degrees of ACE inhibitor accumulation can pose a problem.21 The major adverse consequences of ACE inhibitor accumulation then result in prolonged BP lowering, an often sharp fall in GFR, and/or a significant increase in serum K1 concentration. The mere fact that these physiologic and biochemical sequelae occur does not mandate permanent discontinuation of an ACE inhibitor. In many cases, the offending ACE inhibitor can be cautiously reintroduced particularly when issues of volume contraction are judiciously managed. The current product label recommendations, which suggest that ACE inhibitor doses should be reduced in moderate-to-severe CKD, vary somewhat from compound to compound (Table 1). These differing dosage recommendations are not particularly germane to the manner in which ACE inhibitors are used in patients with CKD. ACE inhibitors are typically titrated to effect when given to patients with CKD; therefore, it is contrary to clinical practice to reduce the dose of an ACE inhibitor simply because it is accumulating. As previously mentioned, if the ACE inhibitor effect—BP reduction—or the side effect—drop in GFR and/or hyperkalemia—occurs then the dose should be reduced if not temporarily discontinued. When the dose of a renally cleared ACE inhibitor is
Table 1. Elimination and Dosing Characteristics of ACE Inhibitors
Drug
Trade Name
Benazepril* Captopril†
Lotensin Capoten
Enalapril‡ Fosinopril† Lisinopril‡x Moexipril{ Perindopril£
Vasotec Monopril Prinivil, Zestril Univasc Aceon
Quinapril¢ RamiprilU
Accupril Altace
Trandolapril¤
Mavik
Usual Total Dose and/or Range (mg)—Renal Failure (Frequency Day) (Clcreat: 10-30 mL/min)
Usual Total Dose and/or Range (mg)—Renal Failure (Frequency Day) (Clcreat: 0-10 mL/min)
5 (1) 75% of normal dose (Clcreat: 10-50 mL/min) 2.5 No adjustment 5 (1) 3.75 (1)(Clcreat: ,40 mL/min) 2.0 (every other day) (Clcreat: 15-29 mL/min) 2.5 (1) 25% of normal dose (Clcreat: ,40 mL/min) 0.5 (1)
Same 50% of normal dose
Titrate to maximum of 40 mg
2.5 No adjustment 2.5 (1) Same 2.0 (on dialysis day) (Clcreat: ,15 mL/min) Same Same
Titrate to maximum of 40 mg Usual dose titration to effect
Same
Titrate to optimal response
*Novartis Pharmaceuticals Corp., Suffern, NY. †Bristol-Myers Squibb, New York, NY. ‡Merck and Co., West Point, PA. xAstra Zeneca, London, United Kingdom. {UCB Inc., Brussels, Belgium. £Solvay Pharmaceuticals, Inc., Brussels, Belgium. ¢Pfizer Inc., New York, NY. UMonarch Pharmaceuticals, Briston, TN. ¤Abbott Laboratories, Abbott Park, IL.
Recommended Dose Titration (mg) in Renal Failure (Frequency Day)
Titrate to maximum of 15 mg
Pharmacologic Issues in Treating Hypertension
reduced in the setting of an excessive BP drop or a significant fall in GFR, the process of recovery can be a protracted one. This is consistent with the very slow elimination of such an ACE inhibitor when renal failure is present. Recovery of BP or renal function can often be hastened by careful volume repletion when intravascular volume contraction exists. Although parameters such as BP and renal function are sensitive to the concentration of an ACE inhibitor, hyperkalemia may be less so. When hyperkalemia occurs with an ACE inhibitor, a reduced dose or use of a nonaccumulating ACE inhibitor can be considered. When hyperkalemia persists and ACE inhibition remains critical—for example, ACE inhibitor treatment in heart failure—a K1 binding resin, such as polystyrene sulfonate, can be given.
Angiotensin Receptor Blockers Similar to ACE inhibitors, ARBs are generally less efficacious as monotherapy in the treatment of hypertension when CKD exists and often require addition of a diuretic to maximize their BP lowering effect. These drugs undergo appreciable hepatic elimination with the exception of candesartan, telmisartan, and the E-3174 metabolite of losartan, which are 40%, 60%, and 50% hepatically cleared, respectively. Among the ARBs, irbesartan and telmisartan undergo the greatest degree of hepatic elimination with .95% of their systemic clearance being hepatic. Valsartan and eprosartan are both approximately 70% cleared by the hepatic route.22 Also, like ACE inhibitors, the dose of an ARB given to a patient with CKD should be adjusted according to the degree to which BP is lowered and should not be based on arbitrarily maintaining certain blood levels. ARBs seem to increase serum K1 values less so as compared with ACE inhibitors in patients with CKD.23
Direct Renin Inhibitors Aliskiren is a highly specific in vitro inhibitor of human renin with half maximal inhibitory concentration (IC50) of 0.6 nmol/L. The capacity of this drug to reduce BP in patients with hypertension is similar to that seen with therapeutic doses of various ACE inhibitors or ARBs. Aliskiren is not renally cleared; therefore, dosage adjustment in CKD on the basis of pharmacokinetic considerations is unnecessary.24 Opinions vary considerably on the utility of aliskiren ranging from enthusiasm for an antihypertensive with a ‘‘novel’’ mechanism of action to a ‘‘non-plussed’’ attitude derived, partly, from the absence of outcomes data distinguishing this compound from either ACE inhibitors or ARBs. Pending availability of specific CV and renal outcomes data with aliskiren, there still remains the need to better understand how this compound fits in the management of patients with hypertension and CKD. The renal effects of aliskiren seem to be similar to those of an ACE inhibitor or an ARB. However, there does seem to be an additive anti-
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proteinuric effect when aliskiren is given together with an ARB.25
Calcium Channel Blockers CCBs are commonly used drugs in patients with CKD, as a result of the consistency of their BP lowering effect. Additionally, coronary artery disease is known to be common in patients with CKD and drugs in this class are effective coronary vasodilators. In general, the volume of distribution, protein binding, and plasma half-life of CCBs are comparable between patients with CKD and those with normal renal function; therefore, CCBs do not require dose adjustment in CKD because of pharmacokinetic considerations.26 Dihydropyridine and nondihydropyridine CCBs, such as verapamil and diltiazem, reduce BP similarly inpatients with CKD. Addition of a CCB to other drug classes, including diuretics or a different CCB sub-class, generally results in an additive response.27,28 The renal effects of CCBs are a matter of some debate. Much of the discussion concerning this drug class has centered on the divergent antiproteinuric effects of dihydropyridine and nondihydropyridine CCBs.29 Consistently greater reductions in proteinuria have been seen with nondihydropyridine CCBs, despite BP reduction comparable with that seen with dihydropyridine CCBs.30 This greater antiproteinuric effect with nondihydropyridine CCBs relegates dihydropyridine CCBs to a secondary treatment position in proteinuric CKD when these 2 CCB classes are being considered as treatment options without renin-angiotensin system (RAS) system blockade. When given in combination with either an ACE inhibitor or an ARB, the treatment advantage of a nondihydropyridine over a nondihydropyridine CCB in proteinuric CKD becomes less noteworthy.6 CCB-related side effects may be particularly troublesome when these drugs are used in patients with CKD. These patients tend to be constipated, which can be aggravated by verapamil. In addition, CCBs can cause peripheral edema, which is a type of vasodilatory edema not marked by weight gain. When a true volumeexpanded form of peripheral edema exists—as is often the case in CKD—and a CCB is administered, any intensification of edema cannot be considered an accurate reflection of the patient’s volume state unless it is coupled to additional weight gain.
Beta-blockers Beta-blockers are commonly used drugs in patients with CKD either for the treatment of hypertension and/or for their cardioprotective effects.31-33 The renoprotective effects of b-blockers in the CKD population have been established in several trials where they have been used as adjunctive therapy.33 The BP lowering effect of b-blockers is somewhat unpredictable in patients with CKD unless combined with a diuretic. There are limited
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Sica
Table 2. Elimination Characteristics of Beta-blockers Drug
Active Metabolites
Accumulation in Renal Disease
Acebutolol Atenolol Betaxolol Bisoprolol Carteolol Carvedilol Celiprolol Esmolol Labetalol Metoprolol Metoprolol-LA Nadolol Nebivolol Oxprenolol Penbutolol Pindolol Propranolol Propranolol-LA Sotalol Timolol
Yes No No No Yes Yes Yes No No No No No No No No No Yes Yes No No
Yes Yes Yes Yes Yes No No No No No No Yes No No No No No No Yes No
data to support preferential use of so-called third generation b-blockers, such as carvedilol and nebivolol, for the treatment of hypertension in patients with CKD. The selection of a b-blocker in a patient with CKD should occur with some knowledge of the elimination characteristics of the drug as well as whether the compound has active metabolites (Table 2).31 Systemic accumulation of renally cleared b-blockers in patients with CKD does not normally improve BP control; alternatively, b-blocker accumulation can be accompanied by concentrationdependent side effects. If such side effects occur, 2 treatment options exist; first, to continue the offending b-blocker with empiric dose reduction or second, to switch therapy to a hepatically cleared b-blocker. Generally, the latter option is the preferred clinical approach.
Central Alpha Agonists Sympathetic activation plays an important and distinct role in hypertension and target organ damage associated with CKD and provides the experimental underpinnings for use of central a-agonists, such as clonidine and guanfacine, in this population.34 Clonidine undergoes modest renal clearance and its plasma half-life is prolonged in CKD, although there are no specific recommendations for dosage adjustment in this population.35 Guanfacine differs from clonidine in that it is mainly hepatically cleared and does not exhibit accumulation kinetics in CKD. Clonidine is available in a transdermal delivery system, which is applied weekly.36 Use of this transdermal delivery system can facilitate BP control in the otherwise poorly compliant hemodialysis patient because it can be applied once weekly in a supervised manner in a dialysis unit setting.36,37 Patients who suddenly stop oral clonidine occasionally experience
rebound hypertension. This occurs less frequently in patients with CKD because of its delayed clearance. Although clonidine accumulates when its dose goes unadjusted in patients with CKD, ‘‘paradoxical hypertension,’’ a phenomenon that emerges at very high plasma clonidine levels, seems to not occur. In addition, clonidine-treated patients with CKD and sinus node dysfunction can develop significant bradycardia, a possible phenomenon that can occur independent of BP changes. In patients who are affected by this phenomenon, clonidine is best avoided or the dose should be significantly reduced.38 Central a-agonists have not been evaluated to determine whether they have unique CV or renoprotective effects in the CKD population beyond what might be expected with BP reduction; however, it is conceivable that treatment strategies targeting the sympathetic nervous system (SNS) can become an integral part of standard therapy in CKD to slow down disease-state progression.
Alpha-blockers The pharmacokinetics of the peripheral a-blockers prazosin, terazosin, and doxazosin are not appreciably altered in the setting of CKD; therefore, when used in the presence of renal failure it is not necessary to adjust their dose on a pharmacokinetic basis. Compounds in this class are not appreciably dialyzed. These compounds are effective add-on therapies for resistant hypertension and as such are often used in patients with CKD and hypertension39-41; Peripheral a-adrenergic antagonist therapy shows evidence of an antiproteinuric effect; however, it does not show signs of BP-independent renoprotective effects in patients with CKD. The efficacy of peripheral a-adrenergic antagonists in the treatment of hypertension is limited by their tendency to cause salt-and-water retention and thus increase plasma volume, a process that may be more evident at higher doses and in patients with CKD; therefore, these drugs are most effective when given together with diuretic therapy.42
Conclusions Hypertension seen in association with CKD can prove to be quite difficult to treat. Most typically, several drug regimens are required with some particular emphasis placed on the correct use of diuretic therapy. ARAs are being more commonly considered as treatment options in this patient population, partly, on the basis of the frequent contributory role of aldosterone to the hypertensive profile in this patient population. Renally cleared drugs need to have dose adjustments made according to the individual compounds dose-response characteristics for BP reduction and side effect development. At the end of the day, hypertension can be controlled in most patients with CKD, but the process of obtaining BP goals is one that is in a constant state of evolution in
Pharmacologic Issues in Treating Hypertension
that the defining characteristics of the disease often change as renal failure progresses.
References 1. Sica D, Carl D. Pathologic basis and treatment considerations in chronic kidney disease-related hypertension. Semin Nephrol. 2005;25:246-251. 2. Lewis JB. Blood pressure control in chronic kidney disease: is less really more? J Am Soc Nephrol. 2010;21:1086-1092. 3. Appel LJ, Wright JT Jr, Greene T, et al. Intensive blood-pressure control in hypertensive chronic kidney disease. N Engl J Med. 2010;363:918-929. 4. Kidney Disease Outcomes Quality Initiative (K/DOQI). K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis. 2004;43 (suppl 1):S1-S290. 5. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861-869. 6. Bakris GL, Weir MR, Shanifar S, et al. Effects of blood pressure level on progression of diabetic nephropathy: results from the RENAAL study. Arch Intern Med. 2003;163:1555-1565. 7. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851-860. 8. Berl T, Hunsicker LG, Lewis JB, et al. Cardiovascular outcomes in the irbesartan diabetic nephropathy trial of patients with type 2 diabetes and overt nephropathy. Ann Intern Med. 2003;138:542-549. 9. Rahman M, Pressel S, Davis BR, et al. Cardiovascular outcomes in high-risk hypertensive patients stratified by baseline glomerular filtration rate. Ann Intern Med. 2006;144:172-180. 10. Sica DA. Metolazone and its role in edema management. Congest Heart Fail. 2003;9:100-105. 11. Mitch WE, Wilcox CS. Disorders of body fluids, sodium and potassium in chronic renal failure. Am J Med. 1982;72:536-550. 12. Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension. 2008;51:1403-1419. 13. Sica DA. The risks and benefits of aldosterone antagonists. Curr Heart Fail Rep. 2005;2:65-71. 14. Santos J, Planas R, Pardo A, et al. Spironolactone alone or in combination with furosemide in the treatment of moderate ascites in nonazotemic cirrhosis. A randomized comparative study of efficacy and safety. J Hepatol. 2003;39:187-192. 15. Sica DA. Eplerenone: a new aldosterone receptor antagonist: are the FDA’s restrictions appropriate. J Clin Hypertens (Greenwich). 2002;4:441-445. 16. Sica DA. Hyperkalemia risk in chronic kidney disease: deterrent to the use of aldosterone receptor antagonism or not. Hypertension. 2009;53:749-750. 17. Sica DA. Kinetics of angiotensin converting enzyme inhibitors in renal failure. J Cardiovasc Pharmacol. 1992;20(suppl 10):S13-S20. 18. Haas M, Leko-Mohr Z, Erler C, Mayer G. Antiproteinuric versus antihypertensive effects of high-dose ACE inhibitor therapy. Am J Kidney Dis. 2002;40:458-463. 19. Tobe SW, Dai MO. Outcomes of antiproteinuric RAAS blockade: high-dose compared with dual therapy. Curr Hypertens Rep. 2009;11:345-353. 20. Ruggenenti P, Mise N, Pisoni R, et al. Diverse effects of increasing lisinopril doses on lipid abnormalities in chronic nephropathies. Circulation. 2003;107:586-592.
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21. Schoolwerth A, Sica DA, Ballermann BJ, Wilcox CS. Renal considerations in angiotensin converting enzyme inhibitor therapy. Circulation. 2001;104:1985-1991. 22. Sica DA. Renal handling of angiotensin receptor blockers: clinical relevance. Curr Hypertens Rep. 2003;5:337-339. 23. Bakris GL, Siomos M, Richardson D, et al. ACE inhibition or angiotensin receptor blockade: impact on potassium in renal failure. VAL-K Study Group. Kidney Int. 2000;58:2084-2092. 24. Vaidyanathan S, Bigler H, Yeh C, et al. Pharmacokinetics of the oral direct renin inhibitor aliskiren alone and in combination with irbesartan in renal impairment. Clin Pharmacokinet. 2007;46: 661-675. 25. Parving HH, Persson F, Lewis JB, Lewis EJ, Hollenberg NK, AVOID Study Investigators. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med. 2008;358:2433-2446. 26. Sica DA, Gehr TW. Calcium-channel blockers and end-stage renal disease: pharmacokinetic and pharmacodynamic considerations. Curr Opin Nephrol Hypertens. 2003;12:123-131. 27. Chrysant SG, Chrysant C, Trus J, Hitchcock A. Antihypertensive effectiveness of amlodipine in combination with hydrochlorothiazide. Am J Hypertens. 1989;2:537-541. 28. Sica DA. Current concepts of pharmacotherapy in hypertension: combination calcium channel blocker therapy in the treatment of hypertension. J Clin Hypertens (Greenwich). 2001;3:322-327. 29. Agodoa LY, Appel L, Bakris GL, et al. Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial. JAMA. 2001;285:2719-2728. 30. Bakris GL, Weir MR, Secic M, et al. Differential effects of calcium antagonist subclasses on markers of nephropathy progression. Kidney Int. 2004;65:1991-2002. 31. Frishman WH, Alwarshetty M. Beta-adrenergic blockers in systemic hypertension: pharmacokinetic considerations related to the current guidelines. Clin Pharmacokinet. 2002;41:505-516. 32. McCullough PA, Sandberg KR, Borzak S, et al. Benefits of aspirin and beta-blockade after myocardial infarction in patients with chronic kidney disease. Am Heart J. 2002;144:226-232. 33. Bakris GL. Role for beta-blockers in the management of diabetic kidney disease. Am J Hypertens. 2003;16(9 Pt 2):7S-12S. 34. Schlaich MP, Socratous F, Hennebry S, et al. Sympathetic activation in chronic renal failure. J Am Soc Nephrol. 2009;20:933-939. 35. Lowenthal DT, Affrime MB, Meyer A, et al. Pharmacokinetics and pharmacodynamics of clonidine in varying states of renal function. Chest. 1983;83(suppl 2):386-390. 36. Sica DA, Grubbs R. Transdermal clonidine: therapeutic considerations. J Clin Hypertens (Greenwich). 2005;7:558-562. 37. Ross EA, Pittman TB, Koo LC. Strategy for the treatment of noncompliant hypertensive hemodialysis patients. Int J Artif Organs. 2002;25:1061-1065. 38. Byrd BF III, Collins HW, Primm RK. Risk factors for severe bradycardia during oral clonidine therapy for hypertension. Arch Intern Med. 1988;148:729-733. 39. Black HR, Sollins JS, Garofalo JL. The addition of doxazosin to the therapeutic regimen of hypertensive patients inadequately controlled with other antihypertensive medications: a randomized, placebo-controlled study. Am J Hypertens. 2000;13(5 Pt 1):468-474. 40. Yasuda G, Hasegawa K, Kuji T, et al. Effects of doxazosin on ambulatory blood pressure and sympathetic nervous activity in hypertensive Type 2 diabetic patients with overt nephropathy. Diabet Med. 2005;22:1394-1400. 41. Mori Y, Matsubara H, Nose A, et al. Safety and availability of doxazosin in treating hypertensive patients with chronic renal failure. Hypertens Res. 2001;24:359-363. 42. Bryson CL, Psaty BM. A review of the adverse effects of peripheral alpha-1 antagonists in hypertension therapy. Curr Control Trials Cardiovasc Med. 2002;3:1-7.
C
KD is both a cause and an effect of hypertension and is multifactorial in its development. Other than volume expansion, CKD-related hypertension is generally without qualifying characteristics of any consistency. Consequently, the order in which antihypertensive medications are given to patients with CKD and hypertension is arbitrary. Prescription practice for CKD-related hypertension should be mindful of the need for multiple drugs with a minimum of one being a properly dosed diuretic.1 It is not without reason that blood pressure (BP) goals for patients with hypertension and CKD are set at lower levels as compared with those for patients with essential hypertension, but it remains to be determined by how much the BP should be lowered in patients with hypertension and CKD.2 It also remains to be decided by how much the BP should be lowered for patients with proteinuric CKD as opposed to those with progressive CKD without proteinuria.3
Basis for Use of Antihypertensive Medications in CKD Antihypertensive medications are used in patients with CKD for several reasons. First, BP reduction slows down the progression rate of renal disease, irrespective of the type of medication (or medications) being used. Second, certain antihypertensive compounds, such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and aldosterone receptor antagonists (ARAs), significantly reduce protein excretion and in so doing further slow down the progression rate of renal disease above and beyond what is seen with BP reduction. Third, antihypertensive compounds, such as ACE inhibitors and ARBs, also have demonstrable cardiovascular (CV) protective effects. The latter is an From Division of Nephrology, Virginia Commonwealth University Health System, Richmond, VA. Address correspondence to Domenic A. Sica, MD, Division of Nephrology, Virginia Commonwealth University Health System, Richmond, VA 232980160. E-mail: [email protected] Ó 2011 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 doi:10.1053/j.ackd.2010.11.003
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important feature of drug therapy in CKD because these patients typically exhibit a high CV event-rate across the entire spectrum of CKD.
Pharmacologic Principles and Dosing Effects Dose-response effects exist for all classes of antihypertensive drugs, but BP responses to dose titration are most evident with diuretics, sympatholytics, a-blockers, and calcium channel blockers (CCBs). A major consideration in the pharmacodynamic dose-response relationship for an antihypertensive medication is the extent to which BP counterregulatory mechanisms are set in motion by lowering of BP. Acute and chronic BP reduction often activates an interlinked series of mechanisms to bring BP back toward previously raised values. Reflex increases in cardiac output, peripheral vasoconstriction, and salt and/or water retention can arise from baroreflex-mediated activation of the sympathetic and renin–angiotensin–aldosterone system. These counterregulatory responses are dose-dependent and most regularly crop up with nonspecific vasodilatory drugs (eg, hydralazine or minoxidil) or diuretics. It can prove to be quite difficult to approximate the extent to which counterregulatory systems are activated with antihypertensive medications in patients with CKD. A reliable sign of such ‘‘pseudotolerance’’ is loss of previously established BP control. In that regard, a 10% to 20% increase in heart rate induced by antihypertensive medication should prompt either a lowering of the dose of the provoking agent and/or the addition of a pulse rate lowering compound such as a b-blocker. Sodium retention, as the basis for loss of BP control, is easy to recognize when peripheral edema (with an accompanying weight gain) develops, although a lapse in control can still occur from volume expansion even in the absence of peripheral edema. If this is suspected, diuretic therapy can be increased or the class of diuretic changed to effect a small weight loss in the order of 1% to 2% of body weight.
Diuretics Diuretics remain a mainstay of therapy in the therapy of hypertension and/or volume overload in the presence
Advances in Chronic Kidney Disease, Vol 18, No 1 (January), 2011: pp 42-47
Pharmacologic Issues in Treating Hypertension
of CKD. By reducing extracellular fluid volume, they lower BP and thus are capable of potentiating the effects of ACE inhibitors, ARBs, and other antihypertensive agents including CCBs. Administration of thiazide-type diuretics once daily are recommended in CKD stages 1 to 3. There is limited information from controlled trials to guide diuretic dosing for BP control in CKD stages 4 and 5; therefore, such dosing is empiric and is often determined by the elimination of edema (if present) and less so by control of BP.4 As an example of the frequency of diuretic use in CKD, about 84% of the patients in the Reduction of Endpoints in non insulin-dependent diabetes mellitus (NIDDM) with the Angiotensin II Antagonist Losartan study (baseline serum creatinine level: approximately 1.9 mg/dL) were given diuretic therapy in addition to several other antihypertensive medications to achieve the BP goal of ,140/90 mm Hg.5,6 A similarly high proportion of patients received diuretic therapy to reach the target BP in the Irbesartan Diabetic Nephropathy Trial (baseline serum creatinine level: approximately 1.7 mg/dL.)7,8 The major outcomes data in stage 3 CKD and hypertension with diuretic therapy come from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, where the thiazide-type diuretic chlorthalidone was compared with the ACE inhibitor lisinopril and the CCB amlodipine. In a post hoc evaluation of the trial, patients were stratified at baseline into the following 3 glomerular filtration rate (GFR) groups: normal or increased ($90 mL/min/1.73 m2; n ¼ 8126), mild reduction (60-89 mL/min/1.73 m2; n ¼ 18,109), and moderate or severe reduction (,60 mL/min/1.73 m2; n ¼ 5662). Each stratum was analyzed for effects of the treatments on outcomes. The chlorthalidone-based regimen (dose range: 12.5-25.0 mg/d) was equally (if not superior) effective in reducing BP as compared with regimens based on lisinopril (dose range: 10-40 mg/d) and amlodipine (dose range: 5-10 mg/d); moreover, neither amlodipine nor lisinopril was superior to chlorthalidone in reducing the rate of development of ESRD or a 50% or more decrement in GFR.9 There remains some sort of artfulness to the correct use of diuretics in CKD, partly, because of the intimate relationship between GFR and diuretic response. Although a large dose of a thiazide diuretic will initiate a diuresis in patients with mild renal insufficiency, the response in patients with a GFR of ,50 mL/min is more limited, except for the thiazide-type diuretic metolazone10; however, in the setting of CKD, patients are not ‘‘resistant’’ to a thiazide diuretic per se; instead, the basis for failure of a thiazide-type diuretic is, in most instances, that they are not sufficiently potent for the needs of such patients. Patients receiving fixed-dose combination antihypertensive therapy containing a thiazide-type diuretic should be considered for conversion to a loop diuretic (together with whatever was the other component of the fixed-dose combination) when GFR values drop to
43
,50 mL/min, only if BP control is inadequate and/or edema is present.4 Fixed-dose combination antihypertensive therapies with a thiazide-type diuretic component do not require a diuretic change in nonedematous patients with CKD and good BP control. An important consideration in the treatment of hypertension in CKD stages 4 and 5 is that a loop diuretic is only as useful as its ability to bring a patient to ‘‘target weight.’’ Patients with CKD have a 10% to 30% increase in extracellular fluid and blood volume, even in the absence of overt edema and commonly have a saltsensitive form of hypertension.11 Establishing a ‘‘target weight’’ in the patient with CKD who is not edematous can prove to be tricky; however, a gradual reduction in BP in a poorly controlled hypertensive that coincides with diuretic-related weight loss can be a useful clue that a ‘‘dry weight’’ is being reached.12 Potassium (K1)-sparing diuretics, such as spironolactone and eplerenone, are being used more frequently in the CKD population, based on their ability to lower BP while exhibiting a prominent antiproteinuric effect.13 The onset of action for spironolactone is characteristically slow, with a peak response at 48 hours or more after the first dose. This response lag most likely relates to the time needed for the active metabolites of spironolactone to reach steady-state plasma and/or tissue levels. Spironolactone can trigger a prominent natriuretic response when given to patients with cirrhosis/ascites or heart failure, particularly when combined with a loop and/or a thiazide-type diuretic14; however; it is not a particularly strong natriuretic agent, irrespective of CKD status, when given to nonedematous hypertensive subjects. The package label for both spironolactone and eplerenone are specific in that these drugs should not be used even with mild-to-moderate levels of renal insufficiency; however, use of an ARA in CKD is not merely a function of the level of renal function; rather, it should take into account the possibility of development of clinically relevant hyperkalemia.15 For most patients, the risk of developing hyperkalemia should not dissuade the prudent clinician from use of these compounds when indicated. Hyperkalemia should be considered a possibility in any patient receiving an ARA with or without an ACE inhibitor (or ARB). Hyperkalemia is best addressed preemptively with control of dietary K1 intake, elimination (or dosage reduction) of K1 supplements, and avoidance of nondiuretic K1-sparing compounds.16
ACE Inhibitors ACE inhibitors are frequently administered drugs in patients with CKD, usually given for the treatment of hypertension and/or for their cardiorenal protective effects. The BP lowering effect of ACE inhibitors is generally less in volume-expanded forms of hypertension, which is often the case in CKD. In patients with CKD, addition of a diuretic to an ACE inhibitor typically
44
Sica
enhances the BP lowering response, and a goal BP of 130/ 80 mm Hg is currently recommended. This goal BP presumably addresses the optimal BP for both renal and CV protection; however, there is considerable debate on whether achieved BP values of ,130/80 mm Hg confer additional renal benefits in patients with CKD and, if so, whether any such favorable response is drug class specific. Currently, there is insufficient evidence to determine whether a J-shaped relationship exists for renal outcomes and achieved BP values of ,130/80 mm Hg. Most ACE inhibitors are exclusively renally cleared with occurrence of varying degrees of filtration and tubular secretion (organic anion secretory pathway).17 ACE inhibitors with dual routes of elimination, such as fosinopril and trandolapril, are those whose active diacid is both hepatically and renally cleared. This property of combined renal and hepatic elimination minimizes accumulation in CKD because dosing to steady state occurs. To date, a specific adverse effect has not been identified from ACE inhibitor accumulation, although cough has been suggested, but not proven, to be an ACE inhibitor side effect relating to drug concentrations. However, it is possible that the longer drug concentrations remain elevated—after a response to an ACE inhibitor has occurred—the more likely it is that BP, renal function, protein excretion, and K1 handling will be influenced. To this end, there is emerging support for treatment stratagems using high ACE inhibitor doses; however, the findings with such an approach have been variable.18-20 Presently, guidelines do not suggest titration of an ACE inhibitor or an ARB dose to a level higher than what might be necessary for BP control in
patients with CKD. If an ACE inhibitor dose is titrated upward in a patient with CKD and already wellcontrolled BP, it is a process undertaken on an empiric basis with an uncertain outcome. Mindful of such an approach, some patients are very sensitive to the effects of an ACE inhibitor, particularly those who have an activated renin–angiotensin–aldosterone system; therefore, even minimal degrees of ACE inhibitor accumulation can pose a problem.21 The major adverse consequences of ACE inhibitor accumulation then result in prolonged BP lowering, an often sharp fall in GFR, and/or a significant increase in serum K1 concentration. The mere fact that these physiologic and biochemical sequelae occur does not mandate permanent discontinuation of an ACE inhibitor. In many cases, the offending ACE inhibitor can be cautiously reintroduced particularly when issues of volume contraction are judiciously managed. The current product label recommendations, which suggest that ACE inhibitor doses should be reduced in moderate-to-severe CKD, vary somewhat from compound to compound (Table 1). These differing dosage recommendations are not particularly germane to the manner in which ACE inhibitors are used in patients with CKD. ACE inhibitors are typically titrated to effect when given to patients with CKD; therefore, it is contrary to clinical practice to reduce the dose of an ACE inhibitor simply because it is accumulating. As previously mentioned, if the ACE inhibitor effect—BP reduction—or the side effect—drop in GFR and/or hyperkalemia—occurs then the dose should be reduced if not temporarily discontinued. When the dose of a renally cleared ACE inhibitor is
Table 1. Elimination and Dosing Characteristics of ACE Inhibitors
Drug
Trade Name
Benazepril* Captopril†
Lotensin Capoten
Enalapril‡ Fosinopril† Lisinopril‡x Moexipril{ Perindopril£
Vasotec Monopril Prinivil, Zestril Univasc Aceon
Quinapril¢ RamiprilU
Accupril Altace
Trandolapril¤
Mavik
Usual Total Dose and/or Range (mg)—Renal Failure (Frequency Day) (Clcreat: 10-30 mL/min)
Usual Total Dose and/or Range (mg)—Renal Failure (Frequency Day) (Clcreat: 0-10 mL/min)
5 (1) 75% of normal dose (Clcreat: 10-50 mL/min) 2.5 No adjustment 5 (1) 3.75 (1)(Clcreat: ,40 mL/min) 2.0 (every other day) (Clcreat: 15-29 mL/min) 2.5 (1) 25% of normal dose (Clcreat: ,40 mL/min) 0.5 (1)
Same 50% of normal dose
Titrate to maximum of 40 mg
2.5 No adjustment 2.5 (1) Same 2.0 (on dialysis day) (Clcreat: ,15 mL/min) Same Same
Titrate to maximum of 40 mg Usual dose titration to effect
Same
Titrate to optimal response
*Novartis Pharmaceuticals Corp., Suffern, NY. †Bristol-Myers Squibb, New York, NY. ‡Merck and Co., West Point, PA. xAstra Zeneca, London, United Kingdom. {UCB Inc., Brussels, Belgium. £Solvay Pharmaceuticals, Inc., Brussels, Belgium. ¢Pfizer Inc., New York, NY. UMonarch Pharmaceuticals, Briston, TN. ¤Abbott Laboratories, Abbott Park, IL.
Recommended Dose Titration (mg) in Renal Failure (Frequency Day)
Titrate to maximum of 15 mg
Pharmacologic Issues in Treating Hypertension
reduced in the setting of an excessive BP drop or a significant fall in GFR, the process of recovery can be a protracted one. This is consistent with the very slow elimination of such an ACE inhibitor when renal failure is present. Recovery of BP or renal function can often be hastened by careful volume repletion when intravascular volume contraction exists. Although parameters such as BP and renal function are sensitive to the concentration of an ACE inhibitor, hyperkalemia may be less so. When hyperkalemia occurs with an ACE inhibitor, a reduced dose or use of a nonaccumulating ACE inhibitor can be considered. When hyperkalemia persists and ACE inhibition remains critical—for example, ACE inhibitor treatment in heart failure—a K1 binding resin, such as polystyrene sulfonate, can be given.
Angiotensin Receptor Blockers Similar to ACE inhibitors, ARBs are generally less efficacious as monotherapy in the treatment of hypertension when CKD exists and often require addition of a diuretic to maximize their BP lowering effect. These drugs undergo appreciable hepatic elimination with the exception of candesartan, telmisartan, and the E-3174 metabolite of losartan, which are 40%, 60%, and 50% hepatically cleared, respectively. Among the ARBs, irbesartan and telmisartan undergo the greatest degree of hepatic elimination with .95% of their systemic clearance being hepatic. Valsartan and eprosartan are both approximately 70% cleared by the hepatic route.22 Also, like ACE inhibitors, the dose of an ARB given to a patient with CKD should be adjusted according to the degree to which BP is lowered and should not be based on arbitrarily maintaining certain blood levels. ARBs seem to increase serum K1 values less so as compared with ACE inhibitors in patients with CKD.23
Direct Renin Inhibitors Aliskiren is a highly specific in vitro inhibitor of human renin with half maximal inhibitory concentration (IC50) of 0.6 nmol/L. The capacity of this drug to reduce BP in patients with hypertension is similar to that seen with therapeutic doses of various ACE inhibitors or ARBs. Aliskiren is not renally cleared; therefore, dosage adjustment in CKD on the basis of pharmacokinetic considerations is unnecessary.24 Opinions vary considerably on the utility of aliskiren ranging from enthusiasm for an antihypertensive with a ‘‘novel’’ mechanism of action to a ‘‘non-plussed’’ attitude derived, partly, from the absence of outcomes data distinguishing this compound from either ACE inhibitors or ARBs. Pending availability of specific CV and renal outcomes data with aliskiren, there still remains the need to better understand how this compound fits in the management of patients with hypertension and CKD. The renal effects of aliskiren seem to be similar to those of an ACE inhibitor or an ARB. However, there does seem to be an additive anti-
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proteinuric effect when aliskiren is given together with an ARB.25
Calcium Channel Blockers CCBs are commonly used drugs in patients with CKD, as a result of the consistency of their BP lowering effect. Additionally, coronary artery disease is known to be common in patients with CKD and drugs in this class are effective coronary vasodilators. In general, the volume of distribution, protein binding, and plasma half-life of CCBs are comparable between patients with CKD and those with normal renal function; therefore, CCBs do not require dose adjustment in CKD because of pharmacokinetic considerations.26 Dihydropyridine and nondihydropyridine CCBs, such as verapamil and diltiazem, reduce BP similarly inpatients with CKD. Addition of a CCB to other drug classes, including diuretics or a different CCB sub-class, generally results in an additive response.27,28 The renal effects of CCBs are a matter of some debate. Much of the discussion concerning this drug class has centered on the divergent antiproteinuric effects of dihydropyridine and nondihydropyridine CCBs.29 Consistently greater reductions in proteinuria have been seen with nondihydropyridine CCBs, despite BP reduction comparable with that seen with dihydropyridine CCBs.30 This greater antiproteinuric effect with nondihydropyridine CCBs relegates dihydropyridine CCBs to a secondary treatment position in proteinuric CKD when these 2 CCB classes are being considered as treatment options without renin-angiotensin system (RAS) system blockade. When given in combination with either an ACE inhibitor or an ARB, the treatment advantage of a nondihydropyridine over a nondihydropyridine CCB in proteinuric CKD becomes less noteworthy.6 CCB-related side effects may be particularly troublesome when these drugs are used in patients with CKD. These patients tend to be constipated, which can be aggravated by verapamil. In addition, CCBs can cause peripheral edema, which is a type of vasodilatory edema not marked by weight gain. When a true volumeexpanded form of peripheral edema exists—as is often the case in CKD—and a CCB is administered, any intensification of edema cannot be considered an accurate reflection of the patient’s volume state unless it is coupled to additional weight gain.
Beta-blockers Beta-blockers are commonly used drugs in patients with CKD either for the treatment of hypertension and/or for their cardioprotective effects.31-33 The renoprotective effects of b-blockers in the CKD population have been established in several trials where they have been used as adjunctive therapy.33 The BP lowering effect of b-blockers is somewhat unpredictable in patients with CKD unless combined with a diuretic. There are limited
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Sica
Table 2. Elimination Characteristics of Beta-blockers Drug
Active Metabolites
Accumulation in Renal Disease
Acebutolol Atenolol Betaxolol Bisoprolol Carteolol Carvedilol Celiprolol Esmolol Labetalol Metoprolol Metoprolol-LA Nadolol Nebivolol Oxprenolol Penbutolol Pindolol Propranolol Propranolol-LA Sotalol Timolol
Yes No No No Yes Yes Yes No No No No No No No No No Yes Yes No No
Yes Yes Yes Yes Yes No No No No No No Yes No No No No No No Yes No
data to support preferential use of so-called third generation b-blockers, such as carvedilol and nebivolol, for the treatment of hypertension in patients with CKD. The selection of a b-blocker in a patient with CKD should occur with some knowledge of the elimination characteristics of the drug as well as whether the compound has active metabolites (Table 2).31 Systemic accumulation of renally cleared b-blockers in patients with CKD does not normally improve BP control; alternatively, b-blocker accumulation can be accompanied by concentrationdependent side effects. If such side effects occur, 2 treatment options exist; first, to continue the offending b-blocker with empiric dose reduction or second, to switch therapy to a hepatically cleared b-blocker. Generally, the latter option is the preferred clinical approach.
Central Alpha Agonists Sympathetic activation plays an important and distinct role in hypertension and target organ damage associated with CKD and provides the experimental underpinnings for use of central a-agonists, such as clonidine and guanfacine, in this population.34 Clonidine undergoes modest renal clearance and its plasma half-life is prolonged in CKD, although there are no specific recommendations for dosage adjustment in this population.35 Guanfacine differs from clonidine in that it is mainly hepatically cleared and does not exhibit accumulation kinetics in CKD. Clonidine is available in a transdermal delivery system, which is applied weekly.36 Use of this transdermal delivery system can facilitate BP control in the otherwise poorly compliant hemodialysis patient because it can be applied once weekly in a supervised manner in a dialysis unit setting.36,37 Patients who suddenly stop oral clonidine occasionally experience
rebound hypertension. This occurs less frequently in patients with CKD because of its delayed clearance. Although clonidine accumulates when its dose goes unadjusted in patients with CKD, ‘‘paradoxical hypertension,’’ a phenomenon that emerges at very high plasma clonidine levels, seems to not occur. In addition, clonidine-treated patients with CKD and sinus node dysfunction can develop significant bradycardia, a possible phenomenon that can occur independent of BP changes. In patients who are affected by this phenomenon, clonidine is best avoided or the dose should be significantly reduced.38 Central a-agonists have not been evaluated to determine whether they have unique CV or renoprotective effects in the CKD population beyond what might be expected with BP reduction; however, it is conceivable that treatment strategies targeting the sympathetic nervous system (SNS) can become an integral part of standard therapy in CKD to slow down disease-state progression.
Alpha-blockers The pharmacokinetics of the peripheral a-blockers prazosin, terazosin, and doxazosin are not appreciably altered in the setting of CKD; therefore, when used in the presence of renal failure it is not necessary to adjust their dose on a pharmacokinetic basis. Compounds in this class are not appreciably dialyzed. These compounds are effective add-on therapies for resistant hypertension and as such are often used in patients with CKD and hypertension39-41; Peripheral a-adrenergic antagonist therapy shows evidence of an antiproteinuric effect; however, it does not show signs of BP-independent renoprotective effects in patients with CKD. The efficacy of peripheral a-adrenergic antagonists in the treatment of hypertension is limited by their tendency to cause salt-and-water retention and thus increase plasma volume, a process that may be more evident at higher doses and in patients with CKD; therefore, these drugs are most effective when given together with diuretic therapy.42
Conclusions Hypertension seen in association with CKD can prove to be quite difficult to treat. Most typically, several drug regimens are required with some particular emphasis placed on the correct use of diuretic therapy. ARAs are being more commonly considered as treatment options in this patient population, partly, on the basis of the frequent contributory role of aldosterone to the hypertensive profile in this patient population. Renally cleared drugs need to have dose adjustments made according to the individual compounds dose-response characteristics for BP reduction and side effect development. At the end of the day, hypertension can be controlled in most patients with CKD, but the process of obtaining BP goals is one that is in a constant state of evolution in
Pharmacologic Issues in Treating Hypertension
that the defining characteristics of the disease often change as renal failure progresses.
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21. Schoolwerth A, Sica DA, Ballermann BJ, Wilcox CS. Renal considerations in angiotensin converting enzyme inhibitor therapy. Circulation. 2001;104:1985-1991. 22. Sica DA. Renal handling of angiotensin receptor blockers: clinical relevance. Curr Hypertens Rep. 2003;5:337-339. 23. Bakris GL, Siomos M, Richardson D, et al. ACE inhibition or angiotensin receptor blockade: impact on potassium in renal failure. VAL-K Study Group. Kidney Int. 2000;58:2084-2092. 24. Vaidyanathan S, Bigler H, Yeh C, et al. Pharmacokinetics of the oral direct renin inhibitor aliskiren alone and in combination with irbesartan in renal impairment. Clin Pharmacokinet. 2007;46: 661-675. 25. Parving HH, Persson F, Lewis JB, Lewis EJ, Hollenberg NK, AVOID Study Investigators. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med. 2008;358:2433-2446. 26. Sica DA, Gehr TW. Calcium-channel blockers and end-stage renal disease: pharmacokinetic and pharmacodynamic considerations. Curr Opin Nephrol Hypertens. 2003;12:123-131. 27. Chrysant SG, Chrysant C, Trus J, Hitchcock A. Antihypertensive effectiveness of amlodipine in combination with hydrochlorothiazide. Am J Hypertens. 1989;2:537-541. 28. Sica DA. Current concepts of pharmacotherapy in hypertension: combination calcium channel blocker therapy in the treatment of hypertension. J Clin Hypertens (Greenwich). 2001;3:322-327. 29. Agodoa LY, Appel L, Bakris GL, et al. Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial. JAMA. 2001;285:2719-2728. 30. Bakris GL, Weir MR, Secic M, et al. Differential effects of calcium antagonist subclasses on markers of nephropathy progression. Kidney Int. 2004;65:1991-2002. 31. Frishman WH, Alwarshetty M. Beta-adrenergic blockers in systemic hypertension: pharmacokinetic considerations related to the current guidelines. Clin Pharmacokinet. 2002;41:505-516. 32. McCullough PA, Sandberg KR, Borzak S, et al. Benefits of aspirin and beta-blockade after myocardial infarction in patients with chronic kidney disease. Am Heart J. 2002;144:226-232. 33. Bakris GL. Role for beta-blockers in the management of diabetic kidney disease. Am J Hypertens. 2003;16(9 Pt 2):7S-12S. 34. Schlaich MP, Socratous F, Hennebry S, et al. Sympathetic activation in chronic renal failure. J Am Soc Nephrol. 2009;20:933-939. 35. Lowenthal DT, Affrime MB, Meyer A, et al. Pharmacokinetics and pharmacodynamics of clonidine in varying states of renal function. Chest. 1983;83(suppl 2):386-390. 36. Sica DA, Grubbs R. Transdermal clonidine: therapeutic considerations. J Clin Hypertens (Greenwich). 2005;7:558-562. 37. Ross EA, Pittman TB, Koo LC. Strategy for the treatment of noncompliant hypertensive hemodialysis patients. Int J Artif Organs. 2002;25:1061-1065. 38. Byrd BF III, Collins HW, Primm RK. Risk factors for severe bradycardia during oral clonidine therapy for hypertension. Arch Intern Med. 1988;148:729-733. 39. Black HR, Sollins JS, Garofalo JL. The addition of doxazosin to the therapeutic regimen of hypertensive patients inadequately controlled with other antihypertensive medications: a randomized, placebo-controlled study. Am J Hypertens. 2000;13(5 Pt 1):468-474. 40. Yasuda G, Hasegawa K, Kuji T, et al. Effects of doxazosin on ambulatory blood pressure and sympathetic nervous activity in hypertensive Type 2 diabetic patients with overt nephropathy. Diabet Med. 2005;22:1394-1400. 41. Mori Y, Matsubara H, Nose A, et al. Safety and availability of doxazosin in treating hypertensive patients with chronic renal failure. Hypertens Res. 2001;24:359-363. 42. Bryson CL, Psaty BM. A review of the adverse effects of peripheral alpha-1 antagonists in hypertension therapy. Curr Control Trials Cardiovasc Med. 2002;3:1-7.