Antihypertensive Drugs

Chapter 25

Antihypertensive Drugs INDIVIDUAL AGENTS Angiotensin-Converting Enzyme Inhibitors Class Mechanisms of Action

The angiotensin-converting enzyme (ACE) inhibitors inhibit the activity of ACE, which converts angiotensin I (A-I) to the potent hormone angiotensin II (A-II). Because A-II plays a crucial role in maintaining and regulating blood pressure (BP) by promoting vasoconstriction and renal sodium and water retention, ACE inhibitors are powerful tools for targeting multiple pathways that contribute to hypertension, as shown in Table 25-1.

Class Members

There are currently more than 15 ACE inhibitors in clinical use. Each drug has a unique structure but they all have remarkably similar clinical effects. The pharmacodynamic properties of the ACE inhibitors are outlined in Table 25-2.

Class Renal Effects

ACE inhibitors have vast hemodynamic and nonhemodynamic effects that afford the kidney protection. The mechanisms by which this is achieved are outlined in Table 25-3. The antikaliuretic effect is typically transient but can be exacerbated by concomitant administration of potassiumsparing diuretics, supplements, and NSAIDs and should be monitored rigorously. The effectiveness of ACE inhibitors on angiotensin peptide levels depends on the responsiveness of renin secretion. When renin shows little increase in response to ACE inhibiton, the levels of A-II and its metabolites decrease markedly, with little change in A-I levels. Large increases in renin levels in response to ACE inhibition increase the levels of A-I and its metabolites, which can produce higher levels of A-II by uninhibited ACE and other pathways, thereby blunting the effect of ACE inhibition. This phenomenon is referred to as ACE escape, and may contribute to reduced ACE inhibitor efficacy when used chronically. The reduction of proteinuria is a key therapeutic goal in chronic kidney disease (CKD) management. All ACE inhibitors decrease urinary protein excretion in both normotensive and hypertensive patients with CKD of various origins.

511

512 Table 25-1

Antihypertensive Mechanism of Angiotensin-Converting Enzyme Inhibitors

# Vasodilatory bradykinins

Hypertension and the Kidney

# Peripheral vascular resistance

VI

Enhance vasodilatory prostaglandin synthesis Improve nitric oxide–mediated endothelial function Reverse vascular hypertrophy # Aldosterone secretion Induce natriuresis Augment renal blood flow Blunt sympathetic nervous system activity and pressor responses Inhibit norepinephrine and arginine vasopressin release Inhibit baroreceptor reflexes # Endothelin-1 levels Inhibit thirst Inhibit oxidation of cholesterol Inhibit collagen deposition in target organs

Table 25-2

Pharmacodynamic Properties of AngiotensinConverting Enzyme Inhibitors

Generic Name

Dose Range (mg)

Captopril Benazepril

Max Dose (mg)

Dosing Interval

Peak Response (hr)

12.5–50

150

bid/tid

1–2

10–20

40

qd

2–6

Duration Response (hr) 6–12 24

Enalapril

10–40

40

qd/bid

4–8

12–24

Quinapril

20–80

30

qd

2

24

Ramipril

qd/bid

3–6

24

qd

2–12

24

qd/bid

2–7

24

2.5–20

40

Trandolapril

2–4

8

Fosinopril

5–40

40

Perindopril

4–8

8

qd

3–7

24

20–40

40

qd

6–8

24

Lisinopril

Several mechanisms account for the reduction in proteinuria, including a decrease in glomerular capillary hydrostatic pressure, a decrease in mesangial uptake and clearance of macromolecules, and improved glomerular basement membrane permselectivity. Individual response rates vary widely and

Table 25-3

Potential Renoprotective Effects of Angiotensin-Converting Enzyme Inhibitors Associated Effects

Restore pressurenatriuresis relationship to normal

Results in natriuresis and lower arterial blood pressure; exaggerated response if restricted sodium intake

Inhibit tubule sodium resorption Decrease arterial pressure Decrease aldosterone production

Correlates with decreased potassium excretion

Decrease proteinuria

Variable individual response rates; antiproteinuric effects abolished by high salt intake

Improve altered lipid profiles Decrease renal blood flow Decrease filtration fraction Decrease renal vascular resistance Reduce scarring and fibrosis Attenuate oxidative stress and free radicals

are strongly influenced by drug dose and changes in dietary sodium. There is a clear dose-response relationship between increasing doses and reduction of proteinuria, independent of changes in BP, renal plasma flow, and glomerular filtration rate (GFR). Notably, the effect of ACE inhibitors on reduction of proteinuria is abolished with high salt intake. The ACE inhibitors have superior antiproteinuric efficacy compared with other classes of antihypertensive agents, with the exception of angiotensin receptor blockers (ARBs). The antiproteinuric effect is additive with the ARBs and does not depend on changes in creatinine clearance, GFR, or BP. Many patients with impaired renal function exhibit a reversible fall in GFR with ACE inhibitor therapy that is not detrimental. This fall in GFR occurs because of the hemodynamic changes, but the long-term reduction in perfusion pressure is renoprotective. Indeed, type 1 diabetic patients with the greatest initial decline in GFR have the slowest rate of loss of renal function over time. It should be emphasized that ACE inhibitors should not be withdrawn immediately if a modest increase in serum creatinine is noted; a 20% to

CH 25

Antihypertensive Drugs

Renoprotective Effects

513

514 30% decline in GFR can be expected and close monitoring is

Hypertension and the Kidney

warranted. The improvement in clinical outcome is not restricted to hypertensive patients. In normotensive diabetics, studies demonstrate that ACE inhibitors can normalize GFR, VI markedly reduce the progression of renal disease, and normalize microalbuminuria. In patients with an activated renin-angiotensin-aldosterone system (RAAS), ACE inhibitors cause a decrease in GFR and may be a cause of acute kidney injury. Patients with severe bilateral renal artery stenosis, unilateral stenosis of a solitary kidney, severe hypertensive nephrosclerosis, volume depletion, congestive heart failure, cirrhosis, or a transplanted kidney are at high risk for renal deterioration with ACE inhibitors. In these states of reduced renal perfusion related to low effective arterial circulating volume or flow reduced by an obstructed artery, the maintenance of renal blood flow and GFR is highly reliant on A-II-mediated increased efferent arteriolar vasoconstriction, and interruption of this causes a critical reduction in perfusion pressure, leading to dramatic reductions in GFR and urinary flow, worsening of renal ischemia, and in selected cases, anuria.

Class Efficacy and Safety

ACE inhibitors are recommended for initial monotherapy in patients with mild, moderate, and severe hypertension regardless of age, race, or gender, and are safe to use in patients with mild, moderate, and severe renal insufficiency. Black hypertensive patients have been found to respond less well to lower doses than whites, but higher doses are as effective. ACE inhibitors elicit an adequate response in 40% to 60% of patients and response rates are enhanced by salt restriction or the addition of low-dose hydrochlorothiazide (HCTZ). Addition of the diuretic has been shown to be more effective than increasing the dose of ACE inhibitors. ACE inhibitors are indicated as first-line therapy in hypertensive patients with heart failure and systolic dysfunction, those with type 1 diabetes mellitus and proteinuria, patients after myocardial infarction with reduced systolic function, and patients with left ventricular dysfunction. ACE inhibitors reduce ventricular hypertrophy independent of reduction in BP. Indeed, all hypertensive diabetic patients, even those with no evidence of nephropathy, should be given ACE inhibitors for cardiovascular risk reduction. Primary and secondary prevention trials have shown a reduction in myocardial ischemia and infarction, stroke, and cardiovascular death with the use of ACE inhibitors. ACE inhibitors may cause fetal or neonatal injury or death when used during the second and third trimesters of pregnancy; first trimester use has also been associated with major

Antihypertensive Drugs

congenital malformations. If a patient becomes pregnant during 515 treatment, the ACE inhibitor should be discontinued and alternative treatment commenced; termination of pregnancy should be left to the discretion of the patient and treatment team. Hyperkalemia rarely requires discontinuation of therapy and CH 25 is more likely to develop in patients with renal insufficiency or diabetes or those taking potassium-sparing drugs. The most common side effect of ACE inhibitors is a dry, hacking, nonproductive, and often intolerable cough that is reported in up to 20% of patients, thought to be secondary to hypersensitivity to bradykinins, which are normally degraded by ACE. This is managed by switching to an ARB (see later discussion). Angioedema is a rare but potentially life-threatening complication of ACE inhibitor therapy, thought to be due to tissue accumulation of bradykinins and inhibition of C1 esterase activity. It occurs in less than 0.2% of patients within hours of the first dose of ACE inhibitor or occasionally after prolonged use. First-dose hypotension occurs more commonly in volumedepleted states, patients with high-renin hypertension, and those with systolic heart failure. In elderly patients, ACE inhibitor therapy more frequently causes nocturnal hypotension. In high-risk patients, therapy should be initiated with lower doses and preferably after discontinuation of diuretics. Other complications include a metallic taste sensation, leucopenia, and anemia. Fatal agranulocytosis has been reported. ACE inhibitors have been demonstrated to interfere with the response to erythropoietin, an effect that has been utilized therapeutically for post-transplant erythrocytosis.

Angiotensin II Type I Receptor Antagonists Class Mechanisms of Action

The angiotensin receptor blockers (ARBs) allow more specific and complete blockade of the RAAS than ACE inhibitors by selectively antagonizing A-II directly at the angiotensin type 1 (AT1) receptor. Because A-II plays a crucial, multifactorial role in maintaining and regulating BP, blockade of the AT1 receptor with ARBs is a powerful tool for targeting multiple pathways that contribute to hypertension. The hypotensive effects of ARBs are mediated through the same mechanisms as ACE inhibitors, as listed in Table 25-1. The pharmacodynamic properties of the ARBs are outlined in Table 25-4.

Class Renal Effects

A-II receptors are widely distributed within the kidney. The hemodynamic responses are achieved by mechanisms similar to those of ACE inhibitors, as described previously. Hypertensive patients treated with ARBs, with normal or slightly

516 Table 25-4

Hypertension and the Kidney

VI

Pharmacodynamic Properties of the Common Angiotensin II Receptor Blockers

Generic Name

Dose Range (mg)

Max Dose (mg)

Dosing Interval

Peak Response (hr)

Duration Response (hr)

Eprosartan

200–400

400

qd/bid

4

24

Irbesartan

150–300

300

qd

4–6

24

Losartan

50–100

100

qd/bid

6

12–24

Valsartan

80–160

300

qd

4–6

24

Candesartan

8–32

32

qd

6–8

24

Telmisartan

40–80

80

qd

3–6

24

Olmesartan

20–40

40

qd

1.4–2.8

24

impaired renal function, exhibit renal responses similar to, or slightly greater than, those treated with ACE inhibitors. In healthy and hypertensive patients, ARBs produce dosedependent increases in circulating A-II levels and plasma renin activity. Decreases in plasma levels of aldosterone have been reported but are variable. Angiotensin receptor blockade significantly decreases urinary protein excretion in a manner broadly similar to that observed with ACE inhibition. Antiproteinuric effects have been described in diabetic and nondiabetic patients and with renal transplant recipients. The maximal antiproteinuric effect occurs at 3 to 4 weeks. The antiproteinuric effects of ACE inhibitors and ARBs appear to be additive. In a number of trials, ACE inhibitor or ARB therapy reduced proteinuria by up to 40%; combination therapy resulted in a 70% reduction in proteinuria with no further changes in BP. Long-term renoprotection with these agents substantially retards the progression of renal disease and reduces overall mortality rate in patients with type 2 diabetes mellitus independent of changes in BP. Thus, the ARBs should be the foundation of therapy in patients with type 2 diabetes and nephropathy. It is recommended that patients receiving ACE inhibitor therapy with persistent hypertension or proteinuria should be considered for combined treatment with angiotensin receptor antagonist therapy. A property unique to the losartan molecule is induction of uricosuria. This effect is not associated with an increased risk of nephrolithiasis, nor is it observed with ACE inhibitors or other ARBs, and it is not related to inhibition of the RAAS. The decrease in serum uric acid may be beneficial, as it has been suggested that hyperuricemia is a risk factor for renal disease progression and coronary artery disease.

ARBs have multiple, nonhemodynamic effects that may 517 contribute to renal protection, including antiproliferative effects on the vasculature and mesangium, inhibition of atherogenesis, improved endothelial function, and reduction of oxidative stress. CH 25 All ARBs have been demonstrated to lower BP effectively and safely in patients with mild, moderate, and severe hypertension regardless of age, gender, or race. They are indicated as first-line monotherapy or add-on therapy for hypertension and are comparable in efficacy to ACE inhibitor therapy. They are safe and effective in patients with chronic kidney disease, diabetes, heart failure, renal transplants, coronary artery disease (CAD), and left ventricular hypertrophy (LVH), and have been shown to protect against hypertensive end-organ damage, such as LVH, stroke, endstage renal disease (ESRD), and possibly diabetes. Although they may not be the most efficacious agents in terms of BP reduction in black hypertensive patients, they are equally or more efficacious in offering target organ protection and arresting disease progression than agents that do not inhibit the RAAS. The long onset of action of 4 to 6 weeks avoids the firstdose hypotension and rebound hypertension commonly seen with other drugs. The addition of thiazide diuretics potentiates the therapeutic effect and increases response rates to 70% to 80%, and is more effective than increasing the dose of ARB. ARBs may cause fetal or neonatal death when used during the second and third trimesters of pregnancy. As with ACE inhibitors an abrupt decline in GFR may be observed in the setting of renal hypoperfusion; this typically responds to withdrawal of the drug or optimization of renal perfusion. In clinical trials, hyperkalemia occurs in less than 1.5% of patients and is comparable to that observed with ACE inhibitor therapy. It is more likely to develop in patients with renal insufficiency, those with diabetes, or those taking potassiumsparing drugs. ARBs tend to lower brain natriuretic peptide levels, which may explain their benefit in heart failure. They have no effect on serum lipids in hypertensive patients but may improve the abnormal lipoprotein profile of patients with proteinuric renal disease. Clinically relevant side effects are not observed more frequently than in placebo-treated patients. Because ARBs do not interfere with kinin metabolism, cough is rare and the incidence of cough in patients with a history of ACE inhibitor–induced cough is no greater than in those receiving placebo. Similarly, the incidence of angioedema and facial swelling is no greater than with placebo.

Antihypertensive Drugs

Class Efficacy and Safety

518 b-Adrenergic Antagonists

Mechanisms of Action

Hypertension and the Kidney

b-Adrenergic blocking drugs act via attenuation of sympathetic VI stimulation through competitive antagonism of catecholamines at the b-adrenergic receptor. In addition to b-blockade properties, certain drugs have antihypertensive effects mediated through several different mechanisms including a1-adrenergic blocking activity, b2-adrenergic agonist activity, and perhaps effects on nitric oxide–dependent vasodilator action. Partial agonist activity is a property of certain b-adrenergic blockers that results in less slowing of the resting heart rate; the overall clinical significance of this remains unclear. b-Adrenergic receptor blockers may be nonspecific and block both b1- and b2-adrenergic receptors, or they may be relatively specific for b1-adrenergic receptors. b1-Receptors are found predominantly in heart, adipose, and brain tissue, whereas b2-receptors predominate in the lung, liver, smooth muscle, and skeletal muscle. Many tissues, however, have both b1- and b2-receptors, including the heart, and it is important to realize that the concept of a cardioselective drug is only relative. b-Blockers differ significantly in terms of absorption, lipid solubility, and CNS penetrance and clearance; bioavailability varies greatly.

Class Members

The b-adrenergic antagonists are classified and reviewed on the basis of the following subclasses: nonselective b-adrenergic antagonism, nonselective b-adrenergic antagonism with partial agonist activity, and b1-selective adrenergic antagonism. Their pharmacodynamic properties are outlined in Table 25-5.

Renal Effects

Both a- and b-adrenergic receptors in the kidney mediate vasoconstriction, vasodilatation, and renin secretion. In general, the acute administration of a b-adrenergic blocker usually results in reduction of GFR. The degree of reduction in GFR is typically modest and not of clinical significance in most cases. b-Adrenergic antagonist therapy is usually associated with suppression of plasma renin activity.

Efficacy and Safety

b-Adrenergic antagonists are effective therapy for the management of mild to moderate hypertension; however, their use as a first-line agent has become controversial. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII) has strongly recommended a thiazide diuretic as appropriate initial therapy for most patients with hypertension.

Table 25-5 Generic Name

Pharmacodynamic Properties of b-Adrenergic Antagonists b1-Selectivity

Partial Agonist Activity

Usual Daily Dose (mg)

Max Dose (mg)

Interval

Duration of Response (hr)

Nadolol

0

0

40–80

320

qd

Propranolol

0

0

80–320

640

bid

—

Timolol

0

0

20–40

60

bid

—

Pindolol

0

þ

10–40

Labetolol*

0

þ (weak)

200–800

Atenolol

þ

0

50–100

200

qd

Metoprolol

þ

0

100–200

450

qd/bid

Bisoprolol

þ

0

5–20

Nebivolol*

þ

0

5

Acebutalol

þ

þ

400–800

1200 50

Carveldilol

0

0

3.125–25

Celiprolol

þ

0

200–600

*Denotes vasodilatory properties.

60

qd/bid

1200–1400

40

bid

qd —

—

—

24 8–12 24 3–6 24

qd

24

qd

24

bid

24

qd

—

519

520 The use of b-adrenergic antagonists is suggested largely as sec-

Hypertension and the Kidney

ondary therapy for patients with specific co-morbidities for which b-adrenergic antagonists have been shown to be of specific value, such as heart failure, postmyocardial infarction, VI and angina. Meta-analyses have suggested that compared to therapy with other agents, the reduction in major cardiovascular events associated with b-adrenergic antagonist therapy is not seen in older patients, and that b-adrenergic antagonists should not be considered first-line therapy for older patients without specific indications for their use. b-Adrenergic antagonists are useful therapy for patients in all ethnic groups, although evidence suggests that the antihypertensive response may be less in older black patients, and that b-adrenergic blockers may be less efficacious in black than in white patients when compared with therapy with calcium channel blockers and thiazides. b-Adrenergic blockers have been used to treat women with hypertension in the third trimester of pregnancy, although they are generally avoided in early pregnancy. The main side effects associated with b-adrenergic blockade include central nervous system symptoms of lethargy, sedation, sleep disturbance, depression, and visual hallucinations; sexual dysfunction in males; constipation, diarrhea, nausea, or indigestion; hyperkalemia; and impaired glucose tolerance. b-Blockade can also blunt the effects of epinephrine secretion resulting from hypoglycemia, which may result in hypoglycemia unawareness. Patients with severe bronchospastic airway disease should not receive b-adrenergic blockers. In patients with mild to moderate disease, b1-selective agents may be used cautiously. Symptoms of peripheral vascular disease may be exacerbated by b-blocker therapy. Abrupt withdrawal of b-adrenergic blockers may be associated with overshoot hypertension and worsening angina in patients with coronary artery disease; myocardial infarction has been reported. These withdrawal symptoms may be due to increased sympathetic activity, reflecting possible adrenergic receptor up-regulation during chronic sympathetic blockade. Gradual tapering of b-blockers decreases the risk of withdrawal. Chronic use of b-adrenergic antagonists has been associated with an increase in triglyceride levels and decrease in high-density lipoprotein (HDL) cholesterol, although those with increased b1-selectivity or with partial agonist activity appear to have less effect.

Calcium Antagonists Mechanisms of Action

Calcium antagonists (CAs) have emerged as an important therapeutic class of medications for a variety of cardiovascular disorders. Initially introduced in the 1970s as antianginal

Antihypertensive Drugs

agents, they are now widely advocated as first-line therapy for 521 hypertension. CAs do not directly antagonize the effects of calcium, but they inhibit the entry of calcium or its mobilization from intracellular stores. Each class of CA is quantitatively and qualitatively unique, possessing differential CH 25 sensitivity and selectivity for binding pharmacologic receptors as well as the slow calcium channel in various vascular tissues. This differential selectivity of action has important clinical implications for the use of these drugs and explains why the CAs vary considerably in their effects on regional circulatory beds, sinus and atrioventricular (AV) nodal function, and myocardial contractility. It further explains the diversity of indications for clinical use, ancillary effects, and side effects. CAs uniformly lower peripheral vascular resistance in patients regardless of race, salt sensitivity, age, or co-morbid conditions. CAs decrease vascular responsiveness to A-II, and the synthesis and secretion of aldosterone. Interestingly, the maximal vasodilatory response to the CAs is inversely related to the patient’s plasma renin activity. Thus, it is possible that these agents are of specific benefit in patients with low-renin hypertension, such as black hypertensive patients. CAs may also induce a mild diuresis.

Class Members

CAs are a very heterogeneous group of compounds and differ with respect to pharmacologic profile, pharmacokinetic profile, clinical indications, and side effect profile (Table 25-6).

Table 25-6

Generic Name Diltiazem Diltiazem SR

Pharmacodynamic Properties of Calcium Antagonists Usual Daily Dose (mg)

Max Dose (mg)

Dose Interval

Duration Response (hr)

60–120

480

tid/qid

120–240

480

bid

12

8

Amlodipine

5–10

10

qd

24

Felodipine

5–10

20

qd

24

Isradipine

2.5–10

20

bid

12

Nicardipine

20–40

120

tid

8

Nifedipine

10–30

120

tid/qid

4–6

Nifedipine ER

30–90

120

qd

Verapamil

80–120

480

tid/qid

Verapamil SR

90–240

480

bid

24 8 12–24

522 The two primary subtypes are the dihydropyridines (nifedi-

Hypertension and the Kidney

pine, felodipine, amlodipine, nicardipine, isradipine, nisoldipine) and nondihydropyridines. The nondihydropyridines are further divided into two classes: benzothiazepines (diltiazem) VI and diphenylalkylamines (verapamil). Although all CAs vasodilate coronary and peripheral arteries, the dihydropyridines are the most potent. Their potent vasodilatory action prompts a rapid compensatory increase in sympathetic nervous activity, mediated by baroreceptor reflexes creating a neutral or positive inotropic stimulus. Longer acting dihydropyridines, however, do not appear to activate the sympathetic nervous system. In contrast, the nondihydropyridines are moderately potent arterial vasodilators but directly decrease AV nodal conduction and have negative inotropic and chronotropic effects, not abrogated by the reflex increase in sympathetic tone. Because of their negative inotropic action, they are contraindicated in patients with systolic heart failure. Shortacting agents are no longer recommended for the treatment of hypertension as the powerful stimulation of the sympathetic nervous system by the vasodilation may predispose patients to angina, myocardial infarction, and stroke.

Class Renal Effects

There are multiple mechanisms whereby CAs alter or protect renal function, notably as natriuretics, vasodilators, and antiproteinuric agents. The natriuretic effect, apparently mediated by direct inhibition of renal tubule sodium and water absorption, appears to persist in the long term. The renal hemodynamic effects of CAs are variable. Experimentally, CAs improve GFR in the presence of the vasoconstrictors norepinephrine and A-II by preferentially attenuating afferent arteriolar resistance. Acute administration of CA results in little change or augmentation of the GFR and renal plasma flow, no change in the filtration fraction, and reduction of renal vascular resistance. The long-term effects of CAs on renal function are variable; some patients exhibit no change in GFR, but others exhibit an exaggerated increase in GFR and renal plasma flow. Variable antiproteinuric effects are also seen with respect to class of drug—some dihydropyridines increase protein excretion by up to 40%. In contrast, felodipine, diltiazem, and verapamil do not appear to have this effect and may lower protein excretion, possibly by also decreasing efferent arteriolar tone and glomerular pressure. The clinical implications remain to be determined. Studies have shown that in black hypertensive patients with mild to moderate renal insufficiency and proteinuria above 1 g/day, renoprotection with an ACE inhibitor far exceeds any effect of the dihydropyridine calcium channel blocker amlodipine, with which renal function may deteriorate. Hypertensive patients with

Class Efficacy and Safety

Approximately 70% to 80% of stage I and II hypertensive patients respond to monotherapy. In contrast to other vasodilators, the CAs attenuate the reflex increase of neurohormonal activity that accompanies reduction in BP, and in the long term they inhibit or do not change sympathetic activity. The CAs are effective in young, middle-aged, and elderly patients with all ranges of hypertension. CAs are equally efficacious in patients with a high or low plasma renin activity, regardless of sex, dietary salt intake, or race, although their effect is diminished in smokers. They are effective and safe in patients with hypertension and coronary artery disease and ESRD. The long-acting agents produce sustained systolic and diastolic BP reductions of 16 to 28 mm Hg and 14 to 17 mm Hg, respectively, with no appreciable development of tolerance. Among the different classes, the dihydropyridines appear to be the most powerful at reducing BP but may also be associated with greater activation of baroreceptor reflexes. Verapamil and to a lesser extent diltiazem exert greater effects on the heart and less vasoselectivity. They typically reduce heart rate, slow AV conduction, and depress contractility. CAs are

Table 25-7

Class Dihydropyridines

Renal Effects of Calcium Antagonists

Na+ Excretion ↑

GFR

Renal Blood Flow

↑ to $

↑ to $

Renal Vascular Resistance Proteinuria #

↑

Diltiazem

↑

↑ to $

↑ to $

#

/#

Verapamil

↑

↑ to $

↑ to $

#

↑

GFR, glomerular filtration rate.

Antihypertensive Drugs

diabetic nephropathy also fare considerably worse with amlo- 523 dipine therapy than with an ARB both in terms of renoprotection and overall mortality. However, co-administration of amlodipine with an ARB does not abrogate the protective effect on kidney function. It is postulated that selective dila- CH 25 tion of the afferent arteriole favors an increase in glomerular capillary pressure that perpetuates renal disease progression. CAs represent an important treatment option for renal transplant recipients. Administration of CAs may help preserve long-term renal function by protecting against cyclosporine nephrotoxicity and, possibly, by contributing to immunomodulation (Table 25-7).

524 contraindicated in patients with severely depressed left ven-

Hypertension and the Kidney

tricular function (except perhaps amlodipine or felodipine), hypotension, sick sinus syndrome (unless a pacemaker is in place), second- or third-degree heart block, and atrial arrhythVI mias associated with an accessory pathway. They should not be used as first-line antihypertensive agents in patients with heart failure, patients after myocardial infarction, those with unstable angina, or blacks with proteinuria greater than 300 mg/day. Conversely, CAs are indicated, and may be preferred, in patients with metabolic disorders such as diabetes, peripheral vascular disease, and stable ischemic heart disease. They may also be ideal agents for elderly hypertensive patients because they tend to lower the risk of stroke more than other classes. The CAs are generally well tolerated and are not associated with electrolyte derangements, significant perturbations of glycemic balance, lipemic control, or sexual dysfunction. Orthostatic changes do not occur because venoconstriction remains intact. The most common side effect of the dihydropyridines is peripheral edema. It is a result of uncompensated precapillary vasodilation and is not responsive to diuretics but may improve with the addition of an ACE inhibitor, which preferentially vasodilates postcapillary beds. Other side effects related to vasodilation include headache, nausea, dizziness, and flushing. The nondihydropyridines verapamil and isradipine more commonly cause constipation and nausea. Another common side effect of the dihydropyridines is gingival hyperplasia, exacerbated in patients taking concomitant cyclosporine. Properties beyond their antihypertensive actions make the CAs particularly useful in certain clinical situations. CAs not only lower arterial pressure but increase coronary blood flow. With the exception of the short-acting dihydropyridines, most CAs reduce heart rate, improve myocardial oxygen demand, improve ventricular filling, and conserve contractility, making them ideal for patients with angina or diastolic dysfunction. Verapamil may also be used for secondary cardioprotection to reduce reinfarction rates in patients intolerant of b-blockers unless they have concomitant heart failure. In general, the antihypertensive effects of CAs are enhanced more in combination with b-blockers or ACE inhibitors than with diuretics. Concomitant therapy with b-blockers and nondihydropyridine CAs, however, is potentially dangerous as they may have additive effects on suppressing heart rate, AV node conduction, and cardiac contractility, especially in patients with ESRD. Drug interactions are not uncommon. Concurrent use of a CA and amiodarone exacerbates sick sinus syndrome and AV block. Diltiazem, verapamil, and nicardipine have been shown

Antihypertensive Drugs

to increase cyclosporine, tacrolimus, and sirolimus levels by 525 25% to 100% by inhibiting the cytochrome P4503A4 isoenzyme, which metabolizes the calcineurin inhibitors. Concomitant administration of nifedipine, diltiazem, nicardipine, and verapamil with the digitalis glycosides results in up to a 50% CH 25 increase in serum digoxin concentrations. CAs may be associated with an increased risk of gastrointestinal hemorrhage, particularly in elderly persons. There is clear evidence that CAs reduce cardiovascular mortality and morbidity rates, particularly for stroke; however, short-acting agents such as nifedipine have been associated with a small increased risk for myocardial infarction in meta-analyses when compared with other agents. Currently, there is no evidence to prove the existence of either additional beneficial or detrimental effects of CAs on coronary disease events, including fatal or nonfatal myocardial infarctions and other deaths from coronary heart disease. Because of a potential risk, however, as well as simplicity and improved compliance, longer-acting agents should be considered over short-acting CAs for the treatment of hypertension.

Central Adrenergic Agonists Mechanisms of Action

Central adrenergic agonists act by crossing the blood-brain barrier and have a direct effect on a2-adrenergic receptors located in the midbrain and brainstem, or the more recently described I1 imidazole receptors. In addition to decreasing total sympathetic outflow, binding to these receptors results in increases in vagal activity. Clonidine is a stimulant of both a2- and I1 receptors, while a-methlydopa acts on the former. The classical a2-receptor agonists such as clonidine and a-methyldopa trigger vasodilatation in resistance vessels and hence a reduction in peripheral vascular resistance and BP. Despite the vasodilatory action, reflex tachycardia generally does not occur due to peripheral sympathetic inhibition. The selective I1 receptor agonists moxonidine and rilmenidine are predominantly arterial vasodilators, resulting in a reduction in peripheral vascular resistance. Moxonidine is also associated with reduction in plasma renin activity. The central a2-adrenergic agonists may also stimulate peripheral a2-adrenergic agonists, which mediate vasoconstriction, resulting in a paradoxic increase in BP.

Class Renal Effects

Central a2-agonists and imidazole I1 agonists have little, if any, clinically important effect on renal plasma flow, GFR, or the RAAS. These agents may result in decreased renal

526 vascular resistance mediated by a decrease in preglomerular

capillary resistance related to decreased levels of circulating catecholamines.

Hypertension and the Kidney

VI Antihypertensive Efficacy and Safety These agents have been shown to be effective monotherapy for hypertension in all age and racial groups. Additive effects are associated with the addition of a diuretic. Moxonidine and rilmenidine have been associated with decreased plasma glucose levels and may improve insulin sensitivity, and may also decrease total cholesterol, low-density lipoprotein (LDL), and triglycerides, suggesting a role in the management of the metabolic syndrome. These agents may also be of benefit in patients with congestive heart failure; treatment with moxonidine and rilmenidine has been shown to reverse LVH and improve arterial compliance, with an associated decrease in plasma atrial natriuretic levels. Stimulation of a2-adrenergic receptors in the central nervous system induces several side effects of these drugs, including sedation and drowsiness. The most common side effect related to a2-adrenergic activation is dry mouth due to a centrally mediated inhibition of cholinergic transmission. Clonidine in high doses may precipitate a paradoxic hypertensive response related to stimulation of postsynaptic vascular a2-adrenergic receptors. Methyldopa has been associated with a positive direct Coombs test with or without hemolytic anemia. The a2-adrenergic agonists are associated with sexual dysfunction and may produce gynecomastia in men and galactorrhea in both men and women. Abrupt cessation of a2-adrenergic blockers may result in rebound hypertension, tachycardia, tremor, anxiety, headache, nausea, and vomiting within 18 to 36 hours.

Direct-Acting Vasodilators Mechanisms of Action

The direct-acting vasodilators reduce systolic and diastolic BP by decreasing peripheral vascular resistance. Decreases in arterial pressure are associated with a fall in peripheral resistance and a reflex increase in cardiac output. Sodium and water retention is promoted secondary to the stimulation of renin release.

Class Members

Hydralazine is a direct-acting arteriole vasodilator. Initial oral doses in hypertension should be 10 mg four times daily increasing to 50 mg four times daily over several weeks. Patients may require doses of up to 300 mg/day. Dosing can be changed to twice daily for maintenance. The drug may also be used as an intravenous bolus injection or as a continuous

Antihypertensive Drugs

infusion. Oral absorption is 50% to 90% of the dose and the 527 drug is up 90% protein bound. Patients with mild to moderate renal insufficiency should have the dosing interval increased to every 8 hours. In severe renal failure, the dose interval should increase to every 8 to 24 hours. CH 25 Minoxidil is a direct vasodilator. It is more potent than hydralazine and induces a more marked activation of adrenergic drive. For severe hypertension the initial recommended dose is 5 mg as a single daily dose, increasing to 10 to 20 mg or 40 mg in single or divided doses. Minoxidil is usually used in conjunction with salt restriction and diuretics to prevent sodium retention. Concomitant therapy with a b-adrenergic blocking agent is often required to prevent increases in heart rate. The elimination half-life varies with the acetylation rate in the liver, and both slow and fast acetylators have been described. Renal excretion is 90%. Dosage adjustments may be required in patients with renal failure, although the mean daily doses required to control BP have been reported to be similar in patients with normal renal function.

Class Renal Effects

Hydralazine and minoxidil both increase the secretion of renin and therefore cause elevations of A-II and aldosterone. Retention of salt and water may be due to direct drug effects on the proximal convoluted tubule. GFR and renal plasma flow are unaffected.

Efficacy and Safety

Minoxidil is commonly reserved for severe or intractable hypertension. When added to a diuretic and a b-blocker, minoxidil is generally well tolerated. Hypertrichosis is common. Pericarditis and pericardial infusions have been observed. An increase in left ventricular mass has been reported, possibly due to adrenergic hyperactivity. Chronic treatment with hydralazine has been associated with the development of systemic lupus erythematosus (6–10% of patients receiving high doses of hydralazine for >6 months). Generally, the syndrome occurs early in therapy, but it can occur after many years of treatment. A positive antinuclear antibody titer is used to confirm a clinical diagnosis of lupus. It occurs primarily in slow acetylators. The syndrome is reversible when hydralazine is discontinued but may require months for complete clearing of symptoms. Hydralazine has frequently been used to treat pregnancy-associated hypertension.

Endothelin Receptor Antagonists The development of endothelin receptor antagonists heralds promise for the future management of hypertension, as

528 endothelin is one of the most potent vasoconstrictors known, and is also thought to be involved in vascular remodeling and end-organ damage.

Hypertension and the Kidney

VI Mechanisms of Action and Class Members Endothelin receptor antagonists were originally studied in the management of pulmonary hypertension and heart failure, with encouraging results. The two primary receptor sites ETA and ETB can be either selectively or simultaneously blocked. It has been hypothesized that selective ETA receptor antagonists might offer greater benefits in systolic heart failure patients. Bosentan, a mixed ETA/ETB receptor antagonist, and Darusentan, a selective ETA receptor antagonist, have both been studied in the treatment of hypertension, and have shown dose-dependent reductions in BP. Common side effects include peripheral edema, flushing, headache, and liver enzyme derangement.

Class Renal Effects

The effects of endothelin receptor antagonists on the kidney have not been extensively investigated. When compared to the ACE inhibitor enalapril, although comparable in terms of BP reduction, bosentan was less effective in preventing the development of proteinuria.

Class Efficacy and Safety

Despite the BP reduction evident with these drugs, clinical progress in defining the therapeutic index with endothelin receptor antagonists is as yet unknown.

Moderately Selective Peripheral a1-Adrenergic Antagonists Mechanisms of Action

The nonselective agents phentolamine and phenoxybenzamine have an occasional role in hypertension management. Phentolamine is utilized parenterally, and the longer acting agent phenoxybenzamine has been used orally for the management of hypertension associated with pheochromocytoma.

Class Members

Phenoxybenzamine irreversibly binds to the a-receptors, lowering peripheral resistance and increasing cardiac output. The usual oral dose of phenoxybenzamine for pheochromocytoma is 10 mg twice daily, gradually increasing every other day to doses ranging between 20 and 40 mg two or three times a day. A b-blocker may be administered if tachycardia becomes excessive during therapy; however, the pressor

Renal Effects

Phenoxybenzamine has no clear effect on the renin-angiotensin-aldosterone axis. Salt and water retention does not occur. GFR and effective renal plasma flow would be expected to increase, and renal vascular resistance to decrease in proportion to the degree of blockade of a-adrenergic receptors.

Efficacy and Safety

Tachycardia may result from a-adrenergic blockade, which unmasks b-adrenergic effects with epinephrine-secreting tumors. This may be controlled with concurrent use of a b-adrenergic antagonist. a-Adrenergic blockade must be initiated prior to b-adrenergic blockade to avoid paradoxic hypertension. Side effects of phenoxybenzamine are sedation, weakness, nasal congestion, hypertension, and tachycardia.

Peripheral a1-Adrenergic Antagonists Mechanisms of Action

Drugs of this class (doxazosin, prazosin) are selective for the postsynaptic a1-adrenergic receptor. Because of the selective a1 action the reflex tachycardia associated with blockade of the presynaptic a2-receptor is decreased substantially.

Renal Effects

GFR and renal blood flow are maintained during long-term treatment with these agents. Renal vascular resistance may be reduced. No dosage adjustment is necessary in patients with renal disease.

Efficacy and Safety

Patients receiving doxazosin as their initial antihypertensive drug have been found to have poorer BP control compared to those receiving a chlorthalidone-based treatment. In clinical studies, patients receiving doxazosin had no difference in

Antihypertensive Drugs

effects of a pheochromocytoma must be controlled by a-blockade 529 before b-blockers are initiated. With oral use, symptoms of pheochromocytoma decrease after several days. Administration of phenoxybenzamine to patients with renal impairment should be done cautiously. Specific dosage recommendations CH 25 are not available. Phentolamine is an a-adrenergic blocking agent that produces peripheral vasodilatation in cardiac stimulation with a resulting fall in BP in most patients. The drug is used parenterally. The usual dose is 5 mg repeated as needed. The onset of activity with intravenous dosing is immediate. The drug is metabolized in the liver, with 10% excreted in the urine as unchanged drug.

530 fatal coronary heart disease or nonfatal myocardial infarction

Hypertension and the Kidney

but did have higher rates of stroke and congestive heart failure compared to diuretic-based regimens. There are potentially beneficial effects of a1-blockers on lipid metabolism. These VI drugs have been consistently shown to result in a modest reduction in total and LDL cholesterol and a small increase in HDL cholesterol. Prazosin has been shown to increase insulin sensitivity. The most important side effect of a1-adrenergic receptor blockers is the first-dose orthostatic hypotension effect resulting in lightheadedness, palpitations, and occasional syncope. This effect can be exacerbated in patients with underlying autonomic insufficiency and may be minimized by initiating therapy with a small dose taken at bedtime. a1-Adrenergic antagonists are also used for symptomatic treatment of prostatic hypertrophy.

Renin Inhibitors The development of renin inhibitors has been limited by difficulty with oral bioavailability, and as a result development on several drugs was canceled.

Class Mechanism of Action and Class Member

Aliskiren is a potent and specific inhibitor of human renin in vitro, and is the first in a new class of orally effective renin inhibitors. Aliskiren is potent in reducing BP and has an effective half-life of 40 hours. It is not actively metabolized by the liver and is primarily excreted in the urine.

Class Renal Effects

Renin inhibitors offer substantial promise for renoprotection in that they not only provide BP reduction, but also attenuation of the activity of the renin-angiotensin system, without a reactive increase in renin or other angiotensin peptides. Animal studies have suggested that aliskiren provides comparable renoprotection as an ACE inhibitor or an ARB. Preliminary data in humans indicate that aliskiren reduces proteinuria in conjunction with BP. There appears to be greater improvement in renal blood flow with the renin inhibitor when compared to ACE inhibitors, suggesting that it may be more effective in blocking A-II formation. Longer-term studies are required, however.

Class Efficacy and Safety

Clinical trials of aliskiren have shown a dose-dependent efficacy in reducing both systolic and diastolic BP, and BP reduction comparable to ARB therapy, although with suppression of

plasma renin activity and angiotensin I and II levels. The tol- 531 erability of aliskiren is comparable to that of placebo, with a relatively low incidence of adverse events with all doses tested in the 150 to 600 mg range, with the exception of some diarrhea at the 600 mg dose. CH 25

Class Mechanism and Class Member

Eplerenone is a selective aldosterone receptor antagonist that may have antihypertensive effects distinct from its diuretic properties. Although it is a much less potent mineralocorticoid receptor blocker than spironolactone, it is much more specific and has little agonist activity for estrogen and progesterone receptors. Therefore, it is associated with a lower incidence of gynecomastia, breast pain, and impotence in men and diminished libido and menstrual irregularities in women.

Class Renal Effects

Selective aldosterone receptor antagonism may be renoprotective independent of its effects on BP. Both experimental and clinical studies have demonstrated that A-II may be the primary mediator of the RAAS associated with progression of renal disease. Despite having no observable effects on glomerular hemodynamics, selective aldosterone receptor antagonism therapy may provide an incremental opportunity to protect the kidney in addition to ACE inhibitor or A-II receptor blocker therapy by inhibiting the effects of aldosterone that persist despite therapy with these drugs.

Class Efficacy and Safety

Eplerenone lowers BP when administered at 25, 50, or 200 mg twice daily in a dose-dependent fashion. Clinical trials also demonstrated that eplerenone has antihypertensive activity that is additive with that of either an ACE inhibitor or A-II receptor blocker. In diabetic hypertensive patients with microalbuminuria, adding eplerenone to ACE inhibitor therapy reduces proteinuria more than using the ACE inhibitor alone, independent of effects on BP. The advantage of eplerenone over spironolactone in clinical practice is probably related to fewer endocrine side effects because of more selective aldosterone receptor antagonism.

Tyrosine Hydroxylase Inhibitor Mechanisms of Action and Class Member

Metyrosine, the only drug in this class, blocks the rate-limiting step in the biosynthetic pathway of catecholamines via

Antihypertensive Drugs

Selective Aldosterone Receptor Antagonists

532 inhibition of tyrosine hydroxylase, the enzyme responsible for

Hypertension and the Kidney

conversion of tyrosine to dihydroxyphenylalanine. In patients with pheochromocytomas, metyrosine reduces catecholamine synthesis by up to 80%. This results in decreased total periphVI eral resistance and increased heart rate and cardiac output. The recommended initial dose of metyrosine is 250 mg four times daily, increasing by 250 to 500 mg daily, to a maximum of 4 g/day. Metyrosine is primarily eliminated unchanged in the urine; dose reduction is appropriate in patients with renal failure.

Efficacy and Safety

Metyrosine is used in the perioperative management of pheochromocytoma. Hypertension and reflex tachycardia may result from vasodilatation, and may be minimized by volume expansion. Side effects include sedation, changes in sleep patterns, and extrapyramidal signs. Metyrosine crystals have been noted in the urine in patients receiving high doses; patients should maintain a generous fluid intake.

SELECTION OF ANTIHYPERTENSIVE DRUG THERAPY Blood pressure is only one of many surrogate markers of risk contributing to cardiovascular disease; the optimal goal BP for different patients may be somewhat different, depending on coexistent cardiovascular risk factors. Therefore, the treatment of high BP and the estimation of goal BP necessitate careful individualization for each patient.

Choosing Appropriate Agents The choice of initial therapy in hypertension depends on a variety of factors including patient age, gender, race, obesity, and coexistent cardiovascular or renal disease. The major considerations for initial therapy in older patients should take into account the major pathophysiologic problem, which is an increase in peripheral vascular resistance. Systolic hypertension, a wide pulse pressure, diastolic dysfunction, reduction in cardiovascular baroreceptor reflex function, and a propensity for orthostasis are characteristic. Ideal therapeutic strategies for these patients include low dose of HCTZ, 12.5 to 25 mg/day. Thiazide diuretics function primarily as vasodilators and are particularly effective in controlling systolic BP. Thiazide diuretics also facilitate vasodilation with other therapeutic classes, particularly those that block the RAAS, and they can be utilized together as fixed-dose combinations.

Antihypertensive Drugs

Calcium channel blockers are also useful vasodilators in older 533 patients. They are much better tolerated in the lower half of their dosing range, and are quite effective even in the presence of a high-salt diet. a-Blockers may be useful in older men with benign prostatic hypertrophy. ACE inhibitors are also effective CH 25 vasodilators in older patients. b-Blockers may impair baroreceptor responses in older patients and worsen orthostasis and should be used with caution. Treatment of isolated systolic hypertension in older patients frequently requires multiple drugs. Regardless of the agents that are utilized, a slow careful titration approach is recommended, preferably not more frequently than every 3 months. Differences in gender may be important with regard to the selection of antihypertensive therapy. Women should avoid the use of ACE inhibitors and ARBs in pregnancy because of their possible teratogenic effects. Optimal therapy in a pregnant woman includes a-methyldopa, hydralazine, or b-blockers as they have a proven safety record with minimal risk of teratogenic effects. The treatment of pregnancyrelated hypertension is discussed further in Chapter 24, The Kidney in Hypertension and Pregnancy. In women with osteoporosis, thiazide diuretics are ideal agents because they antagonize calciuria and facilitate bone mineralization. Women experience more cough with ACE inhibitors and more pedal edema with calcium channel blockers compared with men. Race may play a role in the choice of antihypertensive agents. Blacks typically present with hypertension at an earlier age, have more substantial elevations in BP, and experience earlier development of target organ damage than similar demographically matched white counterparts. In addition, significant racial differences in the response to antihypertensive medications exist, possibly due to higher salt sensitivity in black patients. In general, thiazide diuretics and calcium channel blockers have more robust antihypertensive properties in lower doses in blacks than other commonly used therapeutic classes. Higher doses of ACE inhibitors or ARBs are frequently required in order to achieve the same level of BP reduction as seen in other racial groups. It is not uncommon for multiple drugs to be required to reach the target BP. Consequently, fixed-dose combinations may prove to be most useful in this population group as part of the strategy to simplify the approach. Hispanic and Asian populations do not appear to have different hypertensive responses to commonly used drugs compared with whites. Obese hypertensive patients frequently have other medical problems that complicate their hypertensive management. b-Blockers may be helpful in diminishing sympathoadrenal drive. Vasodilators, such as HCTZ and ACE inhibitors, ARBs,

534 and calcium channel blockers, are useful for reducing periph-

Hypertension and the Kidney

eral vascular resistance. Combinations of these drugs may also be helpful. Because of the tendency toward expanded plasma volume, thiazide diuretics can be helpful as they provide an VI opportunity to cause both vasodilation and mild volume reduction. Frequently, these patients require multiple drugs to achieve BP goals, and simplification strategies are important. Given the increased frequency of cardiovascular risk clustering phenomena in these patients, drug therapies that are metabolically neutral are ideal. In patients with coronary artery disease, it is important to remember that the majority of coronary artery perfusion occurs during diastole. Hence, pharmacotherapy should be targeted toward slowing heart rate in order to enhance perfusion during diastole. b-Blockers and heart rate–lowering calcium channel blockers, such as nondihydropyridines, are ideal in this respect. Agents that block the RAAS are the most effective in reducing LVH. In patients with heart failure, it is important to use an echocardiogram to distinguish between diastolic and systolic dysfunction. The treatment of diastolic dysfunction should include therapies that facilitate ventricular relaxation and reduce heart rate (b-blockers and calcium channel blockers). With systolic dysfunction, drugs that block the RAAS are more suitable to provide both preload and afterload reduction. b-Blockers are also helpful in addition to ACE inhibitors. In patients with kidney disease, optimal control of hypertension is an integral component of management to prevent progression of renal disease. RAAS blockers such as ACE inhibitors and ARBs provide greater renoprotection compared with other commonly used antihypertensives. The benefit of these drugs, in part, resides in their effects to facilitate efferent glomerular arteriolar dilation by antagonizing the effects of A-II as they lower BP. Sufficient diuretics should be employed to control blood volume; when the serum creatinine reaches 2 mg/dL volume reduction is more amenable to loop diuretics than thiazide diuretics.

Refractory Hypertension Refractory hypertension is a term used to characterize hypertension that fails to respond to what the clinician considers an adequate antihypertensive regimen. True refractory hypertension is unusual, and a methodologic approach should be taken to help achieve BP control in these patients. A variety of factors interfere with the ability to normalize BP, the most important of which is noncompliance. This problem derives from many factors including inadequate education, poor

Antihypertensive Drugs

clinician-patient relationship, lack of understanding about 535 side effects, and the complexity of multidrug regimens. Pseudohypertension is commonly observed in older hypertensive patients who have hardened atherosclerotic arteries, which are not easily compressible. This interferes with aus- CH 25 cultatory measurements of BP and greater apparent pressure is required to compress the sclerotic vessel than the intra-arterial BP requires. Another common cause of pseudohypertension is improper measurement. This occurs when the BP is taken with an inappropriately small cuff in people with large arm circumference. Because of the substantial proportion of hypertensive patients who are obese, it is critical to have the appropriate cuff size for determining auscultatory pressure. Some clinicians may view white coat hypertension as a cause of refractory hypertension. This is an area of contentious debate in that elevated office readings, despite lower home readings, still provide important predictive value for the development of cardiovascular events. Some clinical studies indicate that patients with so-called white coat hypertension also have LVH and may not have an appropriate nocturnal dip in BP. Volume overload is an important and common cause of refractory hypertension. It may be related to excessive salt intake or inability of the kidney to excrete an appropriate salt and water load because of either endocrine abnormalities or intrinsic renal disease. Salt sensitivity is particularly common in patients of African-American descent. A careful clinical examination coupled with judicious use of either thiazide or loop diuretics is critical in achieving ideal blood volume in order to restore the antihypertensive efficacy of most classes of drugs. It is also appropriate to consider educating the patient about avoiding foods that are rich in salt content, such as processed foods. Drug-related causes of refractory hypertension are common and need to be carefully assessed in each patient. Perhaps the most common drugs that cause refractory hypertension are over-the-counter preparations of sympathomimetics such as nasal decongestants, appetite suppressants, and NSAIDs. Unfortunately, patients may not always recognize overthe-counter preparations as a medication. Therefore, careful questioning specifically focusing on these types of medications should be routine during the evaluation for refractory hypertension. In addition, oral contraceptives, ethanol, cigarettes, and cocaine can be complicating factors that interfere with the ability of medications to lower BP. Obesity is an oft-overlooked cause of refractory hypertension and is commonly associated with obstructive sleep apnea. Nighttime ventilation techniques enhance the control of BP. Secondary causes of hypertension might also be considered as a cause of refractory hypertension. CKD and renal vascular

536 disease are not uncommon and are easily investigated. Addi-

Hypertension and the Kidney

tional endocrine abnormalities include hyperaldosteronism, pheochromocytoma, or hypo- or hyperthyroidism and hyperparathyroidism; rarely, aortic coarctation can be a cause of VI refractory hypertension. Often patients with subtle hyperaldosteronism will respond to the addition of a selective aldosterone receptor blocker. Strategies to control BP in patients with refractory hypertension should first deal with issues related to compliance, simplifying the medical regimen, and ensuring that side effects are not playing a role. Subsequently, one can evaluate the medications and try to choose those that work well with one another to facilitate a nearly additive antihypertensive response. Most drugs reduce systolic BP by approximately 8 to 10 mm Hg. Consequently, it is not unusual for patients who are 40 or 50 mm Hg from goal systolic BP to require four or five medications or possibly even more. One should also be careful to be sure that volume excess is controlled and that there are no drug-drug interactions or clinical situations that would promote diuretic resistance such as excessive salt intake.

DRUG TREATMENT OF HYPERTENSIVE URGENCIES AND EMERGENCIES The terms hypertensive urgency and hypertensive emergency are used loosely in clinical practice with a great deal of overlap. The distinction between the two is important because the management approach is substantially different. A hypertensive emergency is a clinical syndrome in which severe hypertension results in ongoing target organ damage manifested by encephalopathy, retinal hemorrhage, papilledema, acute myocardial infarction, stroke, or acute renal dysfunction. Any delay in control of BP may lead to irreversible sequelae, including death. Hypertensive emergencies are unusual but require immediate hospitalization in an intensive care unit, with careful and judicious use of intravenous vasodilators to lower systolic and diastolic BP cautiously to approximately 140/90 mm Hg (Table 25-8). In contrast, hypertensive urgencies are clinical situations in which a patient has a marked elevation in BP (>200/130 mm Hg) but no evidence of ongoing target organ damage. These patients can be managed cautiously on an outpatient basis (Table 25-9).

Parenteral Drugs, Direct-Acting Vasodilators Diazoxide is a pure arterial dilator that is used primarily in the treatment of acute hypertensive emergencies. The “minibolus”

Table 25-8

Parenteral Drugs Used in the Treatment of Hypertensive Emergencies

Class

Drug

Dose (max)

Onset of Action

Peak Effect

Duration of Action

Direct-acting vasodilators

Diazoxide

7.5–30 mg/min infusion or 1 mg/kg bolus q 5–15 min (300 mg max) 0.5–1 mg/min infusion or 10–50 mg IM 5–100 mg/min 0.25–10 mg/kg/min infusion

1–5 min

30 min

4–12 hr

1–5 min

10–80 min

3–6 hr

1–2 min Immediate

2–5 min 1–2 min

3–5 min 2–5 min

Hydralazine Nitroglycerine Nitroprusside b1-Adrenergic antagonist

Esmolol

250–500 mg/min  1 (loading), then 50–100 mg/kg/min  4 (maintenance); to max maintenance dose 300 mg/kg/ min

1–2 min

5 min

10–30 min

a1- and b1-Adrenergic antagonist

Labetolol

2 mg/min infusion or 0.25 mg/kg

5 min

10 min

3–6 hr

Ganglionic blockers

Trimethaphan

0.5–10 mg/min infusion bolus over 2 min (max 300 mg)

Immediate

1–2 min

5–10 min

ACE inhibitor

Enalaprilat

0.625–5 mg bolus over 5 min every 6 hr

5–15 min

1–4 h

6 hr Continued

537

538 Table 25-8

Parenteral Drugs Used in the Treatment of Hypertensive Emergencies—Cont’d

Class

Drug

Dose (max)

Onset of Action

Peak Effect

Duration of Action

Peripheral a-adrenergic antagonist

Phentolamine

0.5–1 mg/min infusion or 2.5–5 mg bolus

Immediate

3–5 min

10–15 min

Calcium antagonist

Nicardipine

5–15 mg/hr

5–10 min

45 min

50 hr

Dopamine D1-like receptor antagonist

Fenoldopam

0.01–1.6 mg/min constant infusion

5–15 min

30 min

5–10 min

Central a2-agonist

Methyldopa

250–500 mg bolus every 6 hr (max 2 g)

2–3 hr

3–5 hr

6–12 hr

ACE, angiotensin-converting enzyme.

Table 25-9

Rapidly Acting Oral Drugs Used in the Treatment of Hypertensive Urgencies Peak Effect (hr)

Duration of Action (hr)

Onset of Action

Labetolol

100–400 mg every 12 hr (max 2400 mg)

1–2 hr

2–4

8–12

Clonidine

0.2 mg initially, then 0.1 mg/hr (max 0.8 mg)

30–60 min

2–4

6–8

Diltiazem

30–120 mg every 8 hr (max 480 mg)

<15 min

2–3

8

Enalapril

2.5–10 mg every 6 hr

<60 min

4–8

Captopril

12.5–25 mg every hr (max 150 mg)

<15 min

1

6–12

Prazosin

1–5 mg every 2 hr (max 20 mg)

<60 min

2–4

6–12

Drug

12–24

(1 mg/kg administered at intervals of 5–15 minutes) and the continuous infusion of diazoxide have become the preferred methods of administration to avoid excessive reduction in BP. Diazoxide acts rapidly, and the BP effect persists up to 12 hours. It has a plasma half-life of 17 to 31 hours. In renal disease, the plasma half-life is prolonged, and dose reduction is required. Concurrent administration of a b-adrenergic antagonist can control reflex tachycardia. Transient hyperuricemia and hyperglycemia occur in the majority of patients, and the blood glucose level should be monitored. Hydralazine is a direct-acting vasodilator and may be given intramuscularly or as a rapid intravenous bolus injection. It acts rapidly, and the BP effect persists up to 6 hours. It is less potent than diazoxide, and the BP response is less predictable. It may also cause a reflex increase in heart rate, and sodium and water retention. Sodium nitroprusside is the most potent of the parenteral vasodilators, and it dilates both arteriolar resistance and venous capacitance vessels. It has the advantages of being immediately effective when given as an infusion and of having an extremely short duration of action, which permits minute-to-minute adjustments in BP control. Disadvantages of nitroprusside therapy include the need for intra-arterial BP monitoring, the need to protect the solution from light

CH 25

Antihypertensive Drugs

Dosage (maximal)

539

540 during infusion, and the potential for toxic effects from meta-

Hypertension and the Kidney

bolic side products. Nitroprusside is rapidly metabolized to cyanide and then to thiocyanate. Thiocyanate is largely excreted in the urine; it has a plasma half-life of 1 week in norVI mal subjects and accumulates in renal insufficiency. Toxic concentrations of cyanide or thiocyanate may occur if nitroprusside infusions are given for more than 48 hours or at infusion rates greater than 2 mg/kg/min; the maximal dose rate of 10 mg/kg/min should not last more than 10 minutes. Toxic manifestations include air hunger, hyperreflexia, confusion, and seizures. Lactic acidosis and venous hyperoxemia are laboratory indicators of cyanide intoxication. The drug should be promptly discontinued and levels of cyanide measured. Nitroprusside is hemodialyzable. Intravenous nitroglycerin produces, in a dose-related manner, dilation of both arterial and venous beds. At lower doses, its primary effect is on preload; at higher infusion rates, afterload is reduced. Nitroglycerin may also dilate both epicardial coronary vessels and their collaterals, increasing blood supply to ischemic regions. Effective coronary perfusion is maintained provided that BP does not fall excessively or heart rate does not increase significantly. Nitroglycerin has an immediate onset of action but is rapidly metabolized to dinitrates and mononitrates. Patients with normal or low left ventricular filling pressure or pulmonary wedge pressure may be hypersensitive to the effects of nitroglycerin. Therefore, continuous monitoring of BP, heart rate, and pulmonary capillary wedge pressure must be performed to assess the correct dose. Intravenous nitroglycerin may be the drug of choice in the treatment of the patient with moderate hypertension associated with coronary ischemia. The principal side effects are headache, nausea, and vomiting. Tolerance may develop with prolonged use.

b1-Selective Adrenergic Antagonist Esmolol hydrochloride is a short-acting b1-selective adrenergic antagonist used in the management of hypertensive emergencies (see Table 25-8). Efficacy should be assessed after the 1-minute loading dose and 4 minutes of maintenance infusion. If an adequate therapeutic effect is observed, the maintenance infusion should be maintained. If an adequate therapeutic effect is not observed, the same loading dose can be repeated for 1 minute followed by an increased maintenance rate of infusion. Extravasation of esmolol hydrochloride may cause serious local irritation and skin necrosis. Esmolol shares all of the toxic potential of the b1-adrenergic antagonists previously discussed. Esmolol may be particularly useful for the treatment of

Labetalol The a1- and b-adrenergic antagonist labetalol may be given by either repeated intravenous injection or slow continuous infusion (see Table 25-8). The maximal BP-lowering effect is within 5 minutes of the first injection. The drug should be administered to patients in the supine position to avoid symptomatic postural hypotension. It has been proved to be safe and useful in hypertensive urgencies and emergencies in pregnant women.

Ganglionic Blocking Agent Trimethaphan camsylate blocks transmission of impulses at both sympathetic and parasympathetic ganglia, and is used exclusively for the treatment of hypertensive emergencies. It has an immediate onset of action when administered as a continuous infusion (see Table 25-8). The resulting dramatic reduction of BP requires intra-arterial monitoring. The main disadvantage is that the drug must be administered with the patient supine to avoid profound postural hypotension. It has been shown to be useful for acute BP reduction in patients with acute aortic dissection. Other disadvantages include the potential for tachyphylaxis after sustained infusion (48 hours), the appearance of side effects associated with parasympathetic and sympathetic blockade, and histamine release.

a-Adrenergic Antagonist Phentolamine mesylate is a nonselective a-adrenergic antagonist used primarily in the treatment of hypertension associated with pheochromocytoma. It has a rapid onset of action when administered intravenously as either a bolus or a continuous infusion (see Table 25-8). The duration of action is 10 to 15 minutes. It has a plasma half-life of 19 minutes; approximately 13% of a single dose appears in the urine as unchanged drug. Adverse effects include those associated with nonselective a-adrenergic blockade, as discussed previously.

Antihypertensive Drugs

postoperative hypertension and hypertension associated with 541 coronary insufficiency. Esmolol is hydrolyzed rapidly in blood, and negligible concentrations are present 30 minutes after discontinuance. The de-esterified metabolite of esmolol is eliminated by the kidney; it should therefore be used cautiously in CH 25 patients with renal insufficiency.

542 Calcium Antagonists

Hypertension and the Kidney

Nicardipine hydrochloride, a dihydropyridine CA, is administered by slow continuous infusion resulting in a dose-depenVI dent decrease in BP. Onset of action is within minutes; 50% of the ultimate decrease occurs in 45 minutes, but a final steady state does not occur for about 50 hours (see Table 25-8). Discontinuation of infusion is followed by a 50% offset of action in 30 minutes, but gradually decreasing antihypertensive effects exist for about 50 hours. It has been shown to be safe and effective in pediatric hypertensive emergencies.

Dopamine D1-like Receptor Agonist Fenoldopam mesylate is a dopamine D1-like receptor agonist used for acute hypertensive treatment. Elimination half-life is 5 minutes, and steady-state concentrations are reached within 20 minutes. Clearance of the active compound is not altered by ESRD or hepatic disease. Side effects include reflex increase in heart rate, increase in intraocular pressure, headache, flushing, nausea, and hypotension.

Hypertensive Urgency and Rapid-Acting Oral Drugs A more gradual, progressive reduction in systemic BP may be achieved after the oral administration of drugs with rapid absorption. These drugs include (1) the a1- and b-adrenergic antagonist labetalol, (2) the central a2-adrenergic agonist clonidine, (3) the CAs diltiazem and verapamil, (4) the ACE inhibitors captopril and enalapril, (5) the postsynaptic a1-adrenergic antagonist prazosin, and (6) a combination of oral therapies. The doses and pharmacodynamic effects of rapid-acting oral drugs used commonly in the treatment of hypertensive urgencies are given in Table 25-9. Note that rapid-acting oral dihydropyridine CAs such as sublingual nifedipine are no longer recommended as they may cause large and unpredictable reductions in BP with resultant ischemic events.

Clinical Considerations in the Acute Reduction of Blood Pressure The acute reduction of BP carries the risk of impairing blood supply to vital structures such as the brain and heart. Consequently, every effort should be made to avoid excessive

Antihypertensive Drugs

reduction of BP. Short-term, rapid reduction of BP may 543 decrease cerebral blood flow sufficiently to precipitate ischemia and infarction in patients with chronic hypertension. This may be particularly important in patients with atherosclerotic disease of the cerebral blood vessels in whom there CH 25 may be areas of uneven cerebral perfusion. Sudden drops in BP can also interfere with coronary perfusion during diastole and result in myocardial ischemia, infarction, or arrhythmia. In addition, rapid reduction of BP may result in a reflex increase in heart rate, which would also interfere with coronary perfusion. For these reasons, careful, cautious, and controlled reduction in BP is necessary in these patients. For most hypertension emergencies, a parenteral drug such as sodium nitroprusside is ideal. However, if the patient has coronary disease, intravenous nitroglycerin or esmolol, or both, is a useful approach as they can induce coronary dilation or slow heart rate, respectively. Intravenous nicardipine could also be used because it facilitates coronary vasodilation. Patients with acute aortic dissection are best treated with a b-adrenergic antagonist plus nitroprusside or a ganglionic blocker such as trimethaphan. Patients with hypertensive encephalopathy or central nervous system hemorrhage may be best treated with drugs that do not cause cerebral vasodilation such as hydralazine, nitroprusside, nicardipine, or fenoldopam. Fenoldopam may be helpful in patients with kidney diseases, as it maintains renal blood flow (Table 25-10).

544 Table 25-10

Antihypertensives Requiring Dose Modification* in Renal Insufficiency: Estimated Glomerular Filtration Rate (Creatinine Clearance)

Class

Drug

10–15 mL/min (%)

<10 mL/min (%)

Dialysis (%){

ACE inhibitors

Benazepril Captopril Cilazepril Enalapril Fosinopril Lisinopril Perindopril Quinapril Ramipril Trandolapril

50 50 50 50 No change 50 75 50 50 50

25 25 25 25 75 25 50 25 25 25

Negligible (H) 50 (H) 50 (H) 50 — (H) 50 — — — —

ARBs

Candesartan Eprosartan Irbesartan Losartan Olmesartan Telmisartan Valsartan

No No No No — No No

change change

No 50 — No — No No

Nadolol Carteolol Penbutolol Pindolol Atenolol

50 50 No change No change 50

25 25 50 50 25

b-Adrenergic antagonists

change change change change

change change change change

Negligible Negligible Negligible Negligible — Negligible — (H) 50 — Negligible Negligible (H) 50

Bisoprolol Acebutolol Celiprolol Nebivolol

50 50 50 50

25 30–50 Avoid —

Negligible (H) 50 — —

Calcium antagonists

No adjustment required

—

—

—

Central a2-adrenergic agonists

Methyldopa

No change

50

(H) 50

or Imidazole I1 agonists

Clonidine

50

25

Negligible

Peripheral adrenergic-neuronal blockers

Guanethidine

No change

(Avoid)

—

Direct-acting vasodilators

Hydralazine Minoxidil

No change 50

75{ 50

Negligible (H & P) 5%

Selective aldosterone receptor antagonists

Eplerenone

Dosage adjustment unknown

Caution with hyperkalemia

—

Tyrosine hydroxylase inhibitor

Metyrosine

50

25

—

*Percent of total dose given. { Replacement dose at end of dialysis (% of dose prescribed when GFR < 10 mL/min). { Slow acetylators. ACE, angiotensin-converting enzyme; ARBs, angiotensin receptor blockers; H, hemodialysis; P, peritoneal dialysis.

545