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Antihypertensive medications and renal disease. (Medication Review).

Hypertension is defined as blood pressure above 140/90 mmHg. It is estimated that approximately 50% to 60% of all dialysis patients experience hypertension, and it can be both a cause and result of end stage renal disease (ESRD) (Creigh, Milite, Sullivan, Rubin, & Stenzel, 1992). In 1999, approximately 100,000 patients developed ESRD as a result of hypertension, and approximately 23,000 people with hypertension develop ESRD each year (U.S. Renal Data System, 2001). While there exists conflicting data as to the direct effect of elevated blood pressure on mortality, hypertension in the ESRD patient has been associated with the development of left ventricular hypertrophy as well as many other cardiovascular complications (Horl & Horl, 2002). These cardiovascular complications are responsible for approximately 50% of all deaths among long-term dialysis patients (Horl & Horl, 2002).

Hypertension and ESRD

Several factors have been identified as potential causes for hypertension in patients with ESRD (Horl & Horl, 2002). Some possible causes include: volume overload, hormone imbalances, impaired nitric oxide dependent vasodilation, uremic toxins, correction of renal anemia, secondary hyperparathyroidism, dialysis regimen, and sodium intake.

Studies have found increased systolic blood pressure to be a stronger risk factor for the development of cardiovascular abnormalities than increased diastolic blood pressure. Other studies examining the difference in accuracy between predialysis and postdialysis blood pressure in predicting the risk of developing complications due to elevated blood pressure in the ESRD patient have shown that predialysis blood pressure best represents the average interdialytic arterial blood pressure. Thus, predialysis systolic blood pressure should be used when deciding whether or not to treat high blood pressure in the ESRD patient (Horl & Horl, 2002).

The National Heart, Lung, and Blood Institute (NHLBI) developed guidelines for the treatment of hypertension in both general and special populations. Their latest report, the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-VI) states that in patients with renal disease, blood pressure should be controlled to 125/75 mmHg (NHLBI, 1997). However, studies in dialysis patients have found that marked hypertension (systolic blood pressure >180) or hypotension (systolic blood pressure <110) could result in increased risk of mortality (Horl & Horl, 2002). Therefore, it is important to maintain stringent blood pressure control in the ESRD patient, using both pharmacological and nonpharmacological methods.

Nonpharmacologic Treatment of Hypertension

The nonpharmacologic treatment of hypertension can be just as if not more important than treatment with medications. Several nonpharmacologic interventions should be initiated in all patients with hypertension, including smoking cessation, weight loss, elimination of alcohol consumption, aerobic exercise, and control of the patient's electrolyte balance.

Sodium restriction. Sodium restriction is probably the most effective way for ESRD patients to control their blood pressure. Patients with ESRD should limit their dietary salt intake to less than 100 mmol/day (about six grams of table salt per day) (NHLBI, 1997). In addition, dialysate sodium concentration should be tailored to each patient such that a patient's sodium load remains low Horl & Horl, 2002). By reducing the sodium concentration in the body, ESRD patients will experience a reduction in extracellular volume resulting in blood pressure reduction. In most cases, sodium restriction is more effective than pharmacological treatment in reducing and controlling blood pressure in the ESRD patient.

Pharmacological Treatment of Hypertension

When nonpharmacologic methods employed to treat hypertension are insufficient, there are a variety of medications available to use in order to gain blood pressure control. However, it is important to note that each of these medications has adverse effects associated with them that must be monitored in addition to blood pressure in order to optimally treat the patient with ESRD.

Angiotensin-converting enzyme (ACE) inhibitors. Generally, ACE inhibitors are considered the best agents for patients with renal disease due to their reno-protective effects (NHLBI, 1997). Currently, there are 11 ACE inhibitors on the market (see Table 1). ACE is responsible for the conversion of angiotensin I to angiotensin II in blood vessels. Angiotensin II is a potent vasoconstrictor and also stimulates the production of aldosterone, furthering the hypertensive effect. ACE inhibitors act primarily by inhibiting the conversion of angiotensin I to angiotensin II leading to vasodilation that helps to decrease blood pressure. Most ACE inhibitors are taken once a day, with the exception of captopril, which is dosed two to three times a day, and enalapril, which is best dosed twice a day (Hawkins, Bussey, & Prisant, 1997).

Side effects. Several major side effects are associated with ACE inhibitor use. The most important adverse effect to ESRD patients is an increase in serum creatinine. While ACE inhibitors are the preferred antihypertensive medication in patients with ESRD, the metabolism of the drug by the kidney can pose some challenges. It is very important to obtain baseline kidney function tests (blood urea nitrogen [BUN], serum creatinine) before initiating therapy. Patients with a baseline serum creatinine greater that 3 mg/dL should be administered ACE inhibitors with extreme caution. Increases in serum creatinine of greater than 1 mg/dL after initiation of therapy may indicate increased renal damage and should warrant discontinuation of therapy (Horl & Horl, 2002). Other serious side effects associated with ACE inhibitors include hyperkalemia, neutropenia, and angioedema, all of which can be life threatening. Patients should be educated to watch for symptoms of angioedema such as the swelling of the lips, tongue, and face, as well as any other area of the body. ACE inhibitors are also associated with a dry, nonproductive cough resulting from increased bradykinin levels in the lungs. Patients bothered by this cough should be switched to alternative therapies. Finally, ACE inhibitors are contraindicated in pregnancy due to their adverse effects on cartilage development in the fetus (Hawkins et al., 1997).

Angiotensin-receptor blockers (ARBs). ARBs lower blood pressure by blocking the binding of angiotensin II to its receptor in the tissues. By blocking angiotensin II binding, ARBs produce vasodilation and decreased production of aldosterone resulting in decreased blood pressure (Hawkins et al., 1997). Currently, there are five ARBs available on the market, candesartan (Atacand[R]), irbesartan (Avapro[R]), losartan (Cozaar[R]), telmisartan (Micardis[R]), and valsartan (Diovan[R]) (NHLBI, 1997).

Side effects. Many side effects with these agents are similar to those experienced with ACE inhibitors. The only difference in the adverse effect profile between these two classes of agents is that ARBs do not cause a non-productive cough and are less likely to cause hyperkalemia than ACE inhibitors (Hawkins et al., 1997).

Diuretics. Currently, there are four classes of diuretics (see Table 2). While the exact mechanism of action of these agents is unknown, they do cause volume depletion due to diuresis. With this diuresis, cardiac output decreases, which consequently results in decreased blood pressure. Initially, this reduction in cardiac output is accompanied by an increase in peripheral resistance. However, with chronic diuretic use, while plasma and extracellular volume returns to baseline, the peripheral vascular resistance seen in initial treatment falls below baseline resistance levels and is responsible for the maintenance of hypotensive effect (Hawkins et al., 1997).

In the general population, carbonic anhydrase inhibitors and potassium-sparring diuretics are not very effective unless they are used in combination with other agents. Of the two remaining classes, thiazide diuretics are considered better at decreasing blood pressure than loop diuretics (Hawkins et al., 1997). This, however, does not hold true in patients with a creatinine clearance less than 30 ml/min. In these patients, thiazide diuretics are generally ineffective in decreasing blood pressure and loop diuretics are frequently needed in high doses in order to produce the desired effect. Use of potassium-sparring diuretics should be avoided in patients with renal disease due to their potential to cause fatal hyperkalemia (Horl & Horl, 2002).

Side effects. The most common side effects associated with diuretic use are photosensitivity, hypokalemia, hypomagnesemia, hypercalcemia, hyperuricemia, and sexual dysfunction. Most agents also contain sulfonamide groups that may result in hypersensitivity reactions. Additionally, ESRD patients with existing heart disease should have their potassium and magnesium levels monitored regularly as therapy with other agents, such as digoxin, frequently used in these patients may increase the risk of developing these potentially fatal electrolyte imbalances. Patients that experience these electrolyte imbalances should be given the appropriate nutritional supplement to correct the deficits caused by therapy (Hawkins et al., 1997).

Beta-blockers. Beta-adrenergic receptors (beta-1 and beta-2) can be found in many parts of the body, such as the brain, lungs, and heart. While there are several hypotheses regarding how beta-blockers reduce blood pressure, the exact mechanism by which they do so is unknown. However, among the beta-blockers currently available (see Table 3), there exist differentiating factors that affect which therapy is chosen for each patient. The first factor is cardioselectivity. These agents, which include bisoprolol, metoprolol, atenolol, and acebutolol, are thought to selectively target the beta-receptors in the cardiovascular system and, thus, are safer to use in patients with asthma or chronic obstructive pulmonary disease due to the fact that exacerbations occur when the beta-1 receptors found in the lungs are blocked. Next are the agents with intrinsic sympathomimetic activity, including pindolol, penbutolol, carteolol, and acebutolol. These agents are partial beta-receptor agonists and, thus, do not affect resting heart rate, cardiac output, and peripheral blood flow. Finally, propranolol, sotolol, and acebutolol also possess anti-arrhythmic effects and can be used in patients with certain arrhythmias (Hawkins et al., 1997).

Side effects. The most serious side effects associated with beta-blockers include bradycardia, bronchospasm (in patients with existing lung disease), and the development of congestive heart failure. Patients initiating beta-blocker therapy should be closely monitored for the development of these adverse effects. Additionally, beta-blockers have been associated with adverse effects on lipid profiles and glucose tolerance. Patients should be closely monitored for these effects by obtaining baseline blood chemistries and periodic follow-up blood chemistries (Hawkins et al., 1997). Finally, some patients receiving beta-blocker therapy may experience sexual dysfunction necessitating a discontinuation in therapy (Hawkins et al., 1997).

[Alpha.sub.2]-receptor agonists. Agents in this class reduce blood pressure by stimulating the [alpha.sub.2]-receptor in the brain resulting in decreased heart rate, cardiac output, peripheral resistance, plasma renin activity, and decreased baroreceptor reflexes (Hawkins et al., 1997). These agents are among the oldest indicated for the treatment of hypertension and include clonidine (Catapres[R]), guanabenz (Wytensin[R]), guanfacine (Tenex[R]), and methyldopa (Aldomet[R]), all of which are available generically.

Side effects. With chronic use, these agents can cause sodium and fluid retention, which can pose serious problems for the ESRD patient. Additionally, [alpha.sub.2]-receptor agonists may cause sedation and dry mouth, although these symptoms typically resolve with chronic use. Abrupt cessation of these drugs can result in "rebound hypertension," characterized by sudden increases in blood pressure to above pre-treatment levels. Finally, methyldopa has been associated with hemolytic anemia and other liver abnormalities, such as hepatitis. Patients receiving this medication should have periodic liver function tests as well as Coomb's test to detect the onset of these disorders (Hawkins et al., 1997).

[Alpha.sub.1]-receptor antagonists. These agents selectively block the [alpha.sub.1]-receptor in the periphery resulting in arterial and venous dilation, thereby lowering blood pressure. However, these agents are only useful in the treatment of mild hypertension due to the fluid and sodium retention that develops at higher doses. Agents in this class, doxazosin (Cardura[R]), prazosin (Minipress[R]), and terazosin (Hytrin[R]), are available generically and are most useful in patients with benign prostatic hypertrophy due to their ability to reduce prostate size (Hawkins et al., 1997).

Side effects. These medications are extremely likely to cause hypotension, in some cases resulting in syncope, particularly with the first few doses. Patients taking these agents should be educated to take them at bedtime and to rise slowly from sitting or laying-down positions (to minimize hypotensive effects). Additionally, patients receiving this class of agents should be tapered upwards towards treatment doses to avoid severe hypotensive reactions (Hawkins et al., 1997).

Calcium channel blockers. Calcium channel blockers reduce blood pressure by blocking the entry of calcium into cardiac and smooth muscle cells. This leads to a relaxation of the muscle resulting in vasodilation and, consequently, a reduction in blood pressure. There are two major classes of calcium channel blockers, dihydropyridines and non-dihydropyridines (see Table 4). The differences between these two classes are in the type of receptor in which they target. Drugs in the dihydropyridine class typically cause peripheral vasodilation, while medications in the non-dihydropyridine class mediate their effect by altering atrioventricular conduction in the heart. It is important to note that immediate-release nifedipine has been associated with extreme hypotension and should not be used regularly for the treatment of hypertension (Hawkins et al., 1997).

Side effects. The most commonly seen side effects associated with medications in the dihydropyridine class are peripheral edema, hypotension, constipation, and flushing. Patients taking these medications should be counseled to rise slowly from sitting or laying down to prevent falls that may occur from dizziness. Diltiazem and verapamil have been associated with adverse effects such as constipation, bradycardia, atrio-ventricular block, and congestive heart failure (Hawkins et al., 1997).

Vasodilators. Agents in this class include hydralazine (Apresoline[R]) and minoxidil (Loniten[R]). They exert their effect on blood pressure by causing direct arteriolar smooth muscle relaxation, thus reducing myocardial contractility (Hawkins et al., 1997).

Side effects. The numerous adverse effects associated with these medications have resulted in their decreased use for the treatment of hypertension. Patients receiving these medications may experience angina, particularly if they have underlying cardiac disease. Patients taking hydralazine may experience lupus-like syndrome characterized by rash, drug fever, peripheral neuropathy, hepatitis, and visual disturbances. Development of this adverse effect cad be reversed before progressing to full systemic lupus erythematosus if the therapy is discontinued quickly enough. Patients treated with minoxidil may experience increased hair-growth on the face, arms, back, and chest as well as pericardial effusion and electrocardiogram changes (Hawkins et al., 1997).

Combination medications. There are many agents available that combine two antihypertensive medications into one dosage form. These medications help to simplify a patient's medication regimen in that the patient only takes one pill rather than multiple pills. Table 5 contains a list of agents available as combination products. The mechanisms of action, side effects, warnings, and precautions for the combination products are the same as those previously discussed for the individual products.

Summary

Patients with ESRD are likely to have hypertension as a comorbid condition. The management of hypertension must involve nonpharmacologic as well as pharmacologic treatment. In most cases, nonpharmacologic treatment, including severe sodium restriction, smoking cessation, elimination of alcohol intake, and weight reduction, can significantly lower blood pressure in the ESRD patient. If these methods remain insufficient, then a variety of pharmacologic treatment options exist, with ACE inhibitors and diuretics being the most common medical agents employed. Treating hypertension in this patient population, while extremely challenging, greatly reduces the risk of developing cardiac disease, thereby, reducing the risk of mortality.

The Medication Review section of the Nephrology Nursing Journal presents information on medications administered to individuals with nephrologic disorders. Readers wishing to contribute to this column should contact Kim Bremer, department editor, for assistance. For specific guidelines, see any February issue of the Nephrology Nursing Journal. The opinions and assertions contained herein are the private views of the contributors and do not necessarily reflect the views of the American Nephrology Nurses' Association.
Table 1
ACE Inhibitors Currently Available
in the United States

Generic Name   Trade Name

Benazepril     Lotensin[R]
Captopril      Capoten[R] *
Enalapril      Vasotec[R] *
Fosinopril     Monopril[R]
Lisinopril     Prinivil[R] or Zestril[R]
Moexepril      Univasc[R]
Perindopril    Aceon[R]
Quinapril      Accupril[R]
Ramipril       Altace[R]
Trandolapril   Mavik[R]

* Generic formulations available
Table 2
Commonly Used Diuretic Agents Currently
Available in the United States

Generic Name                    Trade Name

Loop Diuretics
Bumetanide                      Bumex[R] *
Ethacrynic acid                 Edecrin[R]
Furosemide                      Lasix[R] *
Torsemide                       Demadex[R]

Thiazide Diuretics
Chlorthalidone                  Hygroton[R] *
Hydrochlorothiazide             Hydrodiuril[R],
Microzide[R] *
Indapamide                      Lozol[R] *
Metolazone                      Zaroxolyn[R]

Potassium-Sparing Diuretics
Spironolactone                  Aldactone[R] *
Triamterene                     Dyrenium[R] *

Carbonic-Anhydrase Inhibitors
Acetazolamide                   Diamox[R] *

* Generic formulations available
Table 3
Commonly Used Beta-blockers Available in the
United States

Generic Name   Trade Name

Acebutolol     Sectral[R] *
Atenolol       Tenormin[R] *
Bisoprolol     Zebeta[R] *
Metoprolol     Lopressor[R] *, Toprol XL[R]
Nadolol        Corgard[R] *
Propranolol    Inderal[R] *, Inderal LA[R]

* Generic formulations available
Table 4

Commonly Used Calcium Channel Blockers
in the United States

Generic Name           Trade Name

Dihydropyridines
Amlodipine             Norvasc[R]
Felodipine             Plendil[R]
Nifedipine             Procardia XL[R] *, Adalat CC[R] *

Non-Dihydropyridines
Verapamil              Isoptin SR[R] *, Calan SR[R] *
Diltiazem              Cardizem SR[R] *, Dilacor XR[R] *

* Generic formulations available
Table 5
Medications Available as Combination Products in
the United States

Generic Name                      Trade Name

ACE inhibitor/Hydrochlorothiazide Combinations
Benazepril/hydrochlorothiazide    Lotensin HCT[R]
Captopril/hydrochlorothiazide     Capozide[R] *
Enalapril/hydrochlorothiazide     Vaseretic[R] *
Lisinopril/hydrochlorothiazide    Prinzide[R], Zestoretic [R]
Moexepril/hydrochlorothiazide     Uniretic[R]
Quinapril/hydrochlorothiazide     Accuretic[TM]

ACE inhibitor/Calcium Channel Blocker Combinations
Benazepril/amlodipine             Lotrel[R]
Enalapril/diltiazem               Teczem[R]
Enalapril/felodipine              Lexxel[R]
Trandolapril/verapamil            Tarka[R]

ARB/Hydrochlorothiazide Combinations
Losartan/hydrochlorothiazide      Hyzaar[R]
Telmisartan/hydrochlorothiazide   Micardis HCT[R]
Valsartan/hydrochlorothiazide     Diovan HCT[R]

Beta-blocker/Diuretic Combinations
Atenolol/chlorthalidone           Tenoretic[R] *
Bisoprolol/hydrochlorothiazide    Ziac[R] *
Metoprolol/hydrochlorothiazide    Lopressor HCT[R]
Nadolol/bendroflumethiazide       Corzide[R]
Propranolol/hydrochlorothiazide   Inderide[R] *, Inderide LA[R]
Timolol/hydrochlorothiazide       Timolide[R]

* Generic formulations available


References

Creigh, J.S., Milite, C., Sullivan, J.E, Rubin, A.L., & Stenzel, K.H. (1992). Hypertension is not adequately controlled in hemodialysis patients. American Journal of Kidney Diseases, 19, 453.

Hawkins, D.W., Bussey, H.I., & Prisant, L.M. (1997). Hypertension. In J.T. DiPiro, R.L. Talbert, G.C. Yee, G.R. Matzke, B.G. Wells, & L.M. Posey (Eds.), Pharmacotherapy : A pathophysiologic approach (3rd ed.) (pp. 195-218). Stamford, CT: Appleton and Lange.

Horl, M.P. & Horl, W.H. (2002). Hemodialysis-associated hypertension: Pathophysiology and therapy. American Journal of Kidney Diseases, 39, 227.

McKevoy, G.K. (Ed). (2001). AHFS drug information. Bethesda, MD: American Society of Health-System Pharmacists.

National Heart, Lung, and Blood Institute (NHLBI). (1997). The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Bethesda, MD: The National Institutes of Health.

U.S. Renal Data System. (2001). Annual data report. Bethesda, MD: The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases.

Lida Andrews, PharmD, is Managed Care Pharmacy Resident, Walgreens Health Initiatives, Deerfield, IL.

Matthew A. Gibbs, PharmD, is Regional Clinical Manager, Walgreens Health Initiatives, Deerfield, IL.
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Author:Andrews, Lida; Gibbs, Matthew A.
Publication:Nephrology Nursing Journal
Geographic Code:1USA
Date:Aug 1, 2002
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