Antihypertensive Drugs - Brenner and Rector's The Kidney, 8th ed

Brenner and Rector's The Kidney, 8th ed.

CHAPTER 45. Antihypertensive Drugs

Matthew R. Weir Donna S. Hanes David K. Klassen

		Pharmacology of the Nondiuretic Antihypertensive Drugs, 1596
		Angiotensin-Converting Enzyme Inhibitors, 1596
		Angiotensin II Type I Receptor Antagonists, 1603
		β-Adrenergic Antagonists, 1606
		Calcium Antagonists, 1611
		Central Adrenergic Agonists, 1619
		Central and Peripheral Adrenergic Neuronal Blocking Agents, 1621
		Direct-Acting Vasodilators, 1621
		Moderately Selective Peripheral α₁-Adrenergic Antagonists, 1623
		Peripheral α₁-Adrenergic Antagonists, 1623
		Renin Inhibitors, 1624
		Selective Aldosterone Receptor Antagonists, 1625
		Tyrosine Hydroxylase Inhibitor, 1626
		Selection of Antihypertensive Drug Therapy, 1626
		Goal Blood Pressure Selection, 1626
		Fixed-Dose Combination Therapy, 1627
		Choosing Appropriate Agents, 1628
		Refractory Hypertension, 1632
		Drug Treatment of Hypertensive Urgencies and Emergencies, 1633
		Parenteral Drugs, Direct-Acting Vasodilators, 1634
		Central α₂-Adrenergic Agonist, 1635
		Ganglionic Blocking Agent, 1635
		Angiotensin-Converting Enzyme Inhibitor, 1635
		α-Adrenergic Antagonist, 1636
		Calcium Antagonists, 1636
		Dopamine D₁-like Receptor Agonist, 1636
		Rapid-Acting Oral Drugs, 1636
		Clinical Considerations in the Acute Reduction of Blood Pressure, 1636

This chapter is divided into three major sections. The first section reviews the pharmacology of the nondiuretic antihypertensive drugs in order to provide clinicians with a complete overview of how to employ these therapies safely in practice ( Table 45-1 ). The first section also discusses the individual drug classes and highlights the class mechanism of action, class members, class renal effects, and class efficacy and safety. Individual similarities and differences both within and between classes are addressed.

The second section reviews clinical decision making with regard to the selection of antihypertensive therapy, blood pressure goals, considerations about choosing the first agent or using fixed-dose combination therapy, and how to deal with refractory hypertension.

The third section reviews the pharmacology of the parenteral and oral drugs available for the management of hypertensive urgencies and emergencies and discusses clinical considerations in the acute reduction of blood pressure.

TABLE 45-1 -- Pharmacology of Nondiuretic Antihypertensive Drugs

Angiotensin-converting enzyme inhibitors

		Sulfhydryl
		Carboxyl
		Phosphinyl

Angiotensin II type 1 receptor antagonists

		Biphenyl tetrazoles
		Nonbiphenyl tetrazoles
		Nonheterocyclics

β-Adrenergic and α₁- and β-adrenergic antagonists

Nonselective β-adrenergic antagonists

Nonselective β-adrenergic antagonists with partial agonist activity

		β₁-Selective adrenergic antagonists
		β₁-Selective adrenergic antagonists with partial agonist activity
		Nonselective β-adrenergic and α₁-adrenergic antagonists

Calcium antagonists

Direct-acting vasodilators

		Benzothiazepines
		Dihydropyridines
		Diphenylalkylamines
		Tetralines

Central α₂-adrenergic agonists

Central and peripheral adrenergic-neuronal blocking agents

Moderately selective peripheral α₁-adrenergic antagonists

Peripheral α₁-adrenergic antagonists

Peripheral adrenergic-neuronal blocking agents

Selective aldosterone receptor antagonists

Tyrosine hydroxylase inhibitors

Vasopeptidase inhibitors

PHARMACOLOGY OF THE NONDIURETIC ANTIHYPERTENSIVE DRUGS

Angiotensin-Converting Enzyme Inhibitors

Class Mechanisms of Action

The angiotensin-converting enzyme (ACE) inhibitors inhibit the activity of ACE, which converts the inactive decapeptide angiotensin I (AI) to the potent hormone angiotensin II (AII). Because AII plays a crucial role in maintaining and regulating blood pressure (by promoting vasoconstriction and renal sodium and water retention), the ACE inhibitors are powerful tools for targeting multiple pathways that contribute to hypertension. ACE inhibitors directly reduce the circulating and tissue levels of AII, blocking the potent vasoconstriction induced by the hormone ( Table 45-2 ).^[1] The resulting decrease in peripheral vascular resistance is not accompanied by changes in cardiac output or glomerular filtration rate (GFR); heart rate is unchanged or may be reduced in patients whose baseline heart rate is higher than 85 beats/min.^[2]

TABLE 45-2 -- Antihypertensive Mechanism of Action of Angiotensin-Converting Enzyme Inhibitors

↓ Peripheral vascular resistance

↓ Vasodilatory bradykinins

Enhance vasodilatory prostaglandin synthesis

Improve nitric oxide-mediated endothelial function

Reverse vascular hypertrophy

↓ Aldosterone secretion

Induce natriuresis

Augment renal blood flow

Blunt SNS activity and pressor responses

Inhibit NE and AVP release

Inhibit baroreceptor reflexes

↓ Endothelin-1 levels

Inhibit thirst

Inhibit oxidation of cholesterol

Inhibit collagen deposition in target organs

AVP, arginine vasopressin; NE, norepinephrine; SNS, sympathetic nervous system.

Reduction in systemic and local levels of AII also leads to effects beyond vasodilation that contribute to the antihypertensive efficacy of ACE inhibitors (see Table 45-1 ).^[3] Additional mechanisms include (1) inhibition of the breakdown of vasodilatory bradykinins catalyzed by ACE or kininase II (the hypotensive action of ACE inhibitors is blocked by bradykinin antagonists)^[4]; (2) enhancement of vasodilatory prostaglandin synthesis; (3) improvement of nitric oxide-mediated endothelial function^{[5] [6]}; (4) reversal of vascular hypertrophy^[7]; (5) decrease in aldosterone secretion; (6) augmentation of renal blood flow to induce natriuresis^[8]; (7) blunting of sympathetic nervous system activity^[9] through presynaptic modulation of norepinephrine release; (8) inhibition of postjunctional pressor responses to norepinephrine or AII^[10]; (9) inhibition of central AII-mediated sympathoexcitation, norepinephrine synthesis, and AVP release; (10) inhibition of centrally controlled baroreceptor reflexes, which results in increased baroreceptor sensitivity^[11]; (11) decrease in vasoconstrictor endothelin-1 levels^[12]; (12) inhibit thirst, inhibit oxidation of cholesterol,^[13] and inhibit collagen deposition in target organs.^[14]

Class Members

There are currently more than 15 ACE inhibitors in clinical use. Each drug has a unique structure that determines its potency, tissue receptor binding affinity, metabolism, and prodrug compound, but they have remarkably similar clinical effects ( Table 45-3 ).^[3] The drugs are classified into either sulfhydryl, carboxyl, or phosphinyl categories on the basis of the ligand that binds to the ACE-zinc moiety.

TABLE 45-3 -- Pharmacodynamic Properties of Ace Inhibitors

Drug Generic (Trade) Name	Initial Dose (Mg)	Usual Dose (Mg)	Maximum Dose (Mg)	Interval	Peak Response (H)	Duration of Response (H)
Alacepril (Cetapril)	12.5	12.5–100	100	qd	3	24
Captopril (Capoten)	12.5	12.5–50	150	bid/tid	1–2	6–12
Benazepril (Lotensin)	10	10–20	40	qd	2–6	24
Enalapril (Vasotec)	5	10–40	40	qd/bid	4–8	12–24
Moexipril (Univasc)	7.5	7.5–30	30	qd/bid	3–6	24
Quinapril (Accupril)	5	20–80	30	qd	2	24
Ramipril (Altace)	2.5	2.5–20	40	qd/bid	3–6	24
Trandolapri (Mavik)	1	2–4	8	qd	2–12	24
Fosinopril (Monopril)	5	5–40	40	qd/bid	2–7	24
Cilazapril (Dynorm)	2.5	2.5–10	10	qd/bid	6	8–10
Perendopril (Aceon)	4	4–8	8	qd	3–7	24
Spirapril (SCH 33844)	6	6	6	qd	3–6	24
Zofenopril (SQ 26991)	30	30–60	60	qd	—	—
Lisinopril (Zestril, Prinivil)	10	20–40	40	qd	6–8	24
Imidipril (TA 6366)	10	10–40	40	qd	5–6	24

Sulfhydryl Angiotensin-Converting Enzyme Inhibitors

Captopril is a sulfhydryl-containing ACE inhibitor that is available in tablets of 12.5, 25, 50, and 100 mg (see Tables 45-3 and 45-4 [3] [4]).^{[15] [16]} The usual starting dose in hypertension is 25 mg two to three times daily (see Table 45-2 ) and can be titrated at 1- to 2-week intervals.^[16] Captopril has 75% bioavailability, with peak onset occurring within 1 hour.^[16] The half-life is 2 hours; with chronic administration, the hemodynamic effects are maintained for 3 to 8 hours.^[15] Food may decrease captopril absorption by up to 54% but is clinically insignificant.^[17] Captopril is partially metabolized in the liver into an inactive compound; 95% of the parent compound and metabolites are eliminated in the urine within 24 hours. The elimination half-life increases markedly in patients with creatinine clearances less than 20 mL/min. Initial dosages should be reduced and smaller increments used for titration. Hemodialysis removes approximately 35% of the dose.

TABLE 45-4 -- Pharmacokinetic Properties of Ace Inhibitors

Drug	Absorption	Bioavailability (%)	Affected by Food	Peak Blood Level (H)	Elimination Half Life	Metabolism	*Excretion^[]**	Active Metabolites
Alacepril	—	70	—	1	1.9	L	U(70)	Captopril
Captopril	60–75	75	Yes	1	2	K	U	Inactive
Benazepril	35	>37	No	2–6	22	L/K	F/U	Benazeprilat
Enalapril	55–75	73	—	3–4	11–35	L/K	F/U	Enalaprilat
Lisinopril	25	6–60	—	1	12	K	U	Enalaprilat
Moexepril	>20	13–22	Yes	1.5	2–10	L/K	F(50)/U	Moexeprilat
Quinapril	60	50	Yes	1	25	K	U(50)	Quinaprilat
Ramipril	50–60	60	—	2–4	13–17	L/K	F/U	Ramiprilat
Trandolapril	70	10	No	2–12	16–24	L/K	F(66)/U	Trandalaprilat
Fosinopril	36	36	—	1	12	L/K/I	F/U	Fosinoprilat
Cilazapril	—	57–76	No	1–2	30–50	K	U(52)	Cilazaprilat
Spirapril	—	50	Yes	1	33–41	L	F(60)/U(40)	Spiraprilat
Perindopril	—	75	Yes	1.5	3–10	L	F/U(75)	Perindoprilat
Imidapril	—	40	—	3–10	10–19	L	U	Imidaprilat
Zofenopril	>80	96	Yes	5	5	K	F(26)/U(69)	Zofenoprilat

F, feces; I, intestine; K, kidney; L, liver; U, urine.

^*	Excretion values in parentheses are percentages.

Carboxyl Angiotensin-Converting Enzyme Inhibitors

Benazepril hydrochloride is a long-acting, non-sulfhydryl-containing, carboxyl ACE inhibitor that is available as 10- or 20-mg tablets alone or in combination with amlodipine. The usual initial dose is 10 mg daily, with maintenance doses of 20 mg to 40 mg daily. Some patients respond better to twice-daily dosing (see Tables 45-3 and 45-4 [3] [4]).^{[15] [18]} The onset of action occurs in 2 to 6 hours; maximal antihypertensive responsiveness occurs in 2 weeks. Benazepril is a prodrug that is rapidly bioactivated in the liver into the active benazeprilat compound, which is 200 times more potent than benazepril. The elimination half-life of benazeprilat is 22 hours. Benazeprilat is excreted primarily in the urine. Dialysis does not remove benazepril, but initial doses should be reduced to 10 mg and 5 mg in patients with creatinine clearances less than 60 and 30 mL/min, respectively.

Cilazapril is a nonsulfhydryl prodrug of the long-acting ACE inhibitor cilazaprilat.^{[15] [16]} The usual dose is 2.5 mg to 10 mg daily or in divided doses. After absorption, cilazapril is rapidly de-esterified in the liver to its active metabolite, cilazaprilat. The initial antihypertensive response occurs in 1 to 2 hours, peaks at 6 hours, and lasts for 8 to 12 hours.^[19] Doses should be reduced by 25% to 50% in renal failure.

Enalapril maleate is a nonsulfhydryl prodrug of the long-acting ACE inhibitor enalaprilat.^{[15] [16]} The oral preparations are available in tablets of 2.5, 5, 10, and 20 mg (see Tables 45-3 and 45-4 [3] [4]). The initial dose of enalapril is 5 mg once daily. The usual daily dose is 10 mg to 40 mg, singly or in divided doses. Initial responses occur in 1 hour, and the peak serum levels of enalaprilat are achieved in 3 to 4 hours. Enalapril undergoes biotransformation in the liver into the active compound, enalaprilat. Enalapril is excreted primarily in the urine. Doses should be reduced by 25% to 50% in patients with end-stage renal disease (ESRD).

Imidapril is the nonsulfhydryl prodrug of the long-acting ACE inhibitor imidaprilat. The usual daily dose is 10 mg to 40 mg (see Table 45-3 ). The peak response occurs in 5 to 6 hours and lasts for 24 hours (see Table 45-4 ). Imidapril is metabolized in the liver. The elimination half-life of the metabolites is 10 to 19 hours. No dose adjustments are necessary in patients with renal failure. It has a unique advantage over other ACE inhibitors in causing a lower incidence of cough.^[20]

Lisinopril is a nonsulfhydryl analog of enalaprilat.^{[15] [16] [21]} The initial dose is 10 mg/day, and the usual daily dose is 20 mg to 40 mg (see Tables 45-3 and 45-4 [3] [4]). The initial antihypertensive response occurs in 1 hour, peaks at 6 hours, and lasts for 24 hours. The maximal effect may not be seen for 24 hours. The elimination half-life is 12 hours. Lisinopril is not metabolized and is exclusively eliminated unchanged in the urine. Lisinopril is dialyzable, and patients may require supplemental doses. The initial dose should be reduced to 2.5 to 7.5 mg/day in patients with moderate to advanced renal failure.

Moexipril hydrochloride is the nonsulfhydryl prodrug of the ACE inhibitor moexiprilat. The usual daily dose is 7.5 mg to 30 mg in single or divided doses (see Table 45-3 ).^{[15] [16]} The oral bioavailability of moexipril is approximately 20%, and absorption is impaired by high-fat meals. The peak response occurs at 3 to 6 hours and lasts 24 hours (see Table 45-4 ). Moexipril is rapidly converted in the liver to moexiprilat, which is 1000 times more potent than the parent compound. Dosage should be reduced by 50% in renal failure.

Perindopril is a nonsulfhydryl prodrug of the long-acting ACE inhibitor perindoprilat.^{[15] [16]} The usual daily dose is 4 mg to 8 mg (see Table 45-3 ). The response peaks at 3 to 7 hours (see Table 45-4 ). A single dose has a duration of action of 24 hours. Perindopril undergoes extensive first-pass hepatic metabolism into the active metabolite, perindoprilat. Renal excretion accounts for 75% of the clearance. Dosage should be reduced by 75% and 50% in patients with creatinine clearances less than 50 and 10 mL/min, respectively.^[22]

Quinapril hydrochloride is a nonsulfhydryl, prodrug of the ACE inhibitor quinaprilat.^{[15] [16] [23]} The initial dose is 10 mg, and the usual daily dose is 20 mg to 80 mg and should be adjusted at 2-week intervals (see Table 45-3 ). Twice-daily therapy may provide a more sustained blood pressure reduction. The onset of action occurs in 1 hour; the peak response occurs in 2 hours and lasts for 12 to 24 hours (see Table 45-4 ). Quinapril is extensively metabolized in the liver into the active metabolite, quinaprilat. Renal excretion by way of filtration and active tubular secretion accounts for 50% of the clearance. Quinapril is not dialyzable. The dose should be reduced by 25% to 50% in patients with renal failure.

Ramipril is a potent, nonsulfhydryl prodrug of the ACE inhibitor ramiprilat.^{[15] [16]} Ramipril capsules are available in 1.25, 2.5, or 5 mg. The initial daily dose is 2.5 mg (see Table 45-3 ). The usual daily dose is 2.5 mg to 20 mg and can be titrated by doubling the current dose at 2- to 4-week intervals. Ramipril is well absorbed from the gastrointestinal tract; peak concentrations are achieved in 1 hour (see Table 45-4 ). Peak response occurs in 2 hours and lasts for 24 hours. Ramipril is extensively metabolized in the liver into the active metabolite, ramiprilat. The elimination half-life of the active compound is 13 to 17 hours and is prolonged with renal failure to almost 50 hours. The dosage should be reduced by 50% to 75% in patients with a creatinine clearance less than 50 mL/min.

Trandolapril is a nonsulfhydryl, ethyl ester prodrug of the ACE inhibitor trandolaprilat.^{[15] [16]} It is available in tablets of 1, 2, and 4 mg or in combination with verapamil. The usual starting dose is 1 to 2 mg/day (see Table 45-3 ). Trandolapril is only 10% bioavailable, and absorption is not affected by food (see Table 45-4 ).^[24] Trandolapril undergoes extensive first-pass hepatic metabolism into trandolaprilat. The peak serum concentrations of trandolaprilat occur within 2 to 12 hours; the duration of action is 24 hours but may reach up to 6 weeks. The recommended starting dose with creatinine clearance less than 30 mL/min is 0.5 mg.

Phosphinyl Angiotensin-Converting Enzyme Inhibitor

Fosinopril sodium is a nonsulfhydryl prodrug of the long-acting ACE inhibitor fosinoprilat.^{[15] [16] [25]} The usual daily dose is 5 mg to 40 mg (see Table 45-3 ). Maximal effects may not occur until 4 weeks. The initial response occurs in 1 hour, the peak response occurs in 2 to 7 hours, and the duration of response is 24 hours and is prolonged in ESRD (see Table 45-4 ). The elimination half-life of fosinoprilat is 11.5 to 12 hours. All metabolites are excreted in both the urine and feces. Hepatic biliary clearance increases significantly as renal function declines. Thus, the dosage must be reduced by 25% in patients with ESRD.

Class Renal Effects

There has been considerable interest in the ability of the ACE inhibitors to protect the kidney from the unrelenting deterioration that occurs with hypertension and renal insufficiency. The ACE inhibitors have vast hemodynamic and nonhemodynamic effects that afford such protection ( Table 45-5 ). In patients with hypertension, the ACE inhibitors have the ability to restore the pressure-natriuresis relationship to normal, allowing sodium balance to be maintained at a lower arterial blood pressure.^[26] In the setting of restricted sodium intake, the response is exaggerated. The mechanism responsible for this effect is direct inhibition of proximal, and possibly distal, tubule sodium reabsorption.^[27] The increase in renal excretory capacity plays a major role in the long-term antihypertensive activity of the drugs. Clinically, the increase in sodium excretion is transitory because the reduction in arterial pressure returns sodium excretion to normal. However, the maintenance of normal sodium excretion at lower arterial pressures correlates with increased excretion in the setting of hypertension.^[26] After several days, both inhibition of AII and aldosterone contribute to the natriuresis.^{[3] [28]} The long-term effects on water excretion are less certain. ACE inhibitors induce an initial increase in free water clearance, but there are no long-term changes in total body weight, plasma, or extracellular fluid volume. The decrease in aldosterone caused by ACE inhibition also correlates with decreased potassium excretion,^[28] particularly in patients with impaired renal function. The antikaliuretic effect appears to be transient but can be exacerbated by concomitant administration of potassium-sparing diuretics, supplements, and nonsteroidal anti-inflammatory drugs (NSAIDs) and should be monitored rigorously.

TABLE 45-5 -- Potential Renoprotective Effects of Angiotensin-Converting Enzyme Inhibitors

Restore pressure-natriuresis relationship to normal

Inhibit tubule sodium resorption

Decrease arterial pressure

Decrease aldosterone production

Decrease proteinuria

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

The effects of ACE inhibitors on angiotensin peptide levels depend on the responsiveness of renin secretion.^[29] All ACE inhibitors decrease AII, increase angiotensin 1-7 (a potential vasodilator), and increase plasma renin. When renin shows little increase in response to ACE inhibition, the levels of AII and its metabolites decrease markedly, with little change in the levels of AI. Large increases in renin levels in response to ACE inhibition increase the levels of AI and its metabolites. The increased levels of AI can produce higher levels of AII by uninhibited ACE and other pathways, thereby blunting the effect of reduced AII. This phenomenon is referred to as ACE escape and may contribute to reduced ACE inhibitor efficacy when used chronically.

The importance of tissue ACE specificity remains controversial. It is clear that local inhibition of ACE in the vascular wall and renal vessels contributes to the antihypertensive activity of the drugs. ACE inhibitor-induced changes in blood pressure correlate with the degree of renin-angiotensin system (RAS) inhibition in both plasma and tissues. The ACE inhibitors with the greatest tissue specificity, however, are associated with prolonged activity at the tissue level even after the serum ACE levels return to normal. Consequently, they are more efficacious at once-daily dosing. Other potential renoprotective effects noted in experimental models include attenuation of oxidative stress,^[30]scavenging of free radicals, and attenuation of lipid peroxidation.^[31] The clinical importance of these effects is under investigation.

Insofar as the degree of proteinuria correlates best with the rate of decline of renal function, and a decrease in proteinuria correlates better with renal protection than lowering blood pressure, reduction of proteinuria can have a substantial impact. All ACE inhibitors decrease urinary protein excre-tion^{[32] [33]} in normotensive and hypertensive patients with renal disease of various origins. Individual response rates vary from a rise of 31% to a fall of 100% and 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 that is not dependent on changes in blood pressure, renal plasma flow, or GFR. Furthermore, the effect of ACE inhibitors on reduction of proteinuria is abolished with high salt intake.

In normotensive diabetics, studies demonstrate that ACE inhibitors can normalize GFR, markedly reduce the progression of renal disease, and normalize microalbuminuria.^[34] This is discussed in depth in Chapter 36 . The effect is noted in the first month of therapy and is maximal at 14 months. Several mechanisms account for the reduction in urinary protein excretion: a decrease in glomerular capillary hydrostatic pressure, a decrease in mesangial uptake and clearance of macromolecules, and improved glomerular basement membrane permselectivity.^[3] 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 blood pressure.^{[35] [36]} The beneficial effect of ACE inhibition may not be enhanced by combined non-dihydropyridine CCA therapy beyond blood pressure lowering.^{[37] [38]}

Up to 0.7% of patients treated with captopril may develop proteinuria with total urinary protein excretion exceeding 1 g/day.^[15] In most cases, proteinuria subsides within 6 months whether or not captopril is continued, with no residual change in GFR. Renal biopsy specimens reveal a membranous nephropathy. The sulfhydryl group of captopril is thought to invoke an immune complex-mediated nephropathy similar to that which occurs with penicillamine.^[39]

The majority of the vasoconstrictor action of AII is confined to the efferent arteriole. ACE inhibitors preferentially dilate the efferent arteriole by reducing the systemic and intrarenal levels of AII. The effect is a reduction in intraglomerular capillary pressure. ACE inhibitors uniformly increase renal blood flow, decrease filtration fraction, have variable to no effect on GFR, decrease renal vascular resistance, reduce urinary protein excretion, and impair microvasculatory autoregulation,^{[40] [41]} in patients with hypertension. In patients with nondiabetic glomerular renal damage, acute ACE inhibitor administration causes a decrease of renal perfusion, glomerular filtration, and pressure and an increase of afferent resistances.^[42] Long-term administration is associated with a decrease in renal perfusion, with a tendency to higher filtration fraction and lower afferent resistances. Marked improvement in GFR occurs and is sustained for up to 3 years.^{[28] [43]} However, many patients with impaired renal function exhibit a reversible fall in GFR with ACE inhibitor therapy that is not detrimental. The GFR declines initially because of the hemodynamic changes, but the long-term reduction in perfusion pressure is renoprotective. Type 1 diabetic patients with the greatest initial decline in GFR have the slowest rate of loss of renal function over time.^[44] It should be emphasized that ACE inhibitors should not be withdrawn immediately if an increase in serum creatinine is noted; a 20% to 30% decline in GFR can be expected, and close monitoring is warranted.

A genetically inherited trait of disordered regulation of the RAS contributes to the pathogenesis of hypertension in approximately 45% of patients.^[45] Such patients have sodium-sensitive hypertension, abnormalities in the renal vascular responses to changes in sodium intake and AII, blunted decrements of renin release in response to saline or AII, and accentuated vasodilator responses to ACE inhibition^[45]; they have been termed nonmodulators. In these patients, ACE inhibition not only increases renal blood flow substantially more than it does in normal subjects but also restores the renal vascular and adrenal responses to AII, renin release, renal sodium handling, and blood pressure.^[46]

In patients with an activated RAS, ACE inhibitors cause a decrease in GFR and can precipitate acute renal failure. Patients with severe bilateral renal artery stenosis, unilateral renal artery 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.^{[47] [48]} These patients typically have a precipitous drop in blood pressure and deterioration of renal function when treated 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 dependent on increased efferent arteriolar vasoconstriction mediated by AII. Interruption of the increased tone causes a critical reduction in perfusion pressure and can lead to dramatic reductions in GFR and urinary flow, worsening of renal ischemia, and, in selected cases, anuria. The hemodynamic effect is reversible with cessation of therapy.

Class Efficacy and Safety

Angiotensin-converting enzyme inhibitors are recommended for initial monotherapy in patients with mild, moderate, and severe hypertension regardless of age, race, or gender.^[49] They are effective in diabetic patients, obese patients, and patients with renal transplants.^[50] They are safe to use in patients with mild, moderate, and severe renal insufficiency. In general, patients with high-renin hypertension and chronic renal parenchymal disease respond particularly well, presumably because they have inappropriately high intrarenal renin and AII levels. Black people with hypertension have been found to respond less well to lower doses than whites, but higher doses are as effective.^{[51] [52]} In most studies, ACE inhibitors elicit an adequate response in 40% to 60% of patients. An immediate fall in blood pressure occurs in 70% of patients. The enhanced efficacy of ACE inhibitors in the presence of salt restriction is paralleled by the additive effects of diuretic therapy. The addition of low-dose hydrochlorothiazide (HCTZ) enhances the efficacy more than 80%, normalizing blood pressure in another 20% to 25% of patients.^[53]Addition of the diuretic is more effective than increasing the dose of ACE inhibitor.^{[53] [54]} A growing area of interest is focusing on the benefit of using high-dose ACE inhibitors or the combination of ACE inhibitors with ARBs to prevent target organ damage. The results thus far are encouraging and both methods appear safe.^{[45] [56]}

Neither the duration nor the degree of blood pressure lowering is predicted by the effect on blood ACE or AII levels, and all ACE inhibitors appear to have comparable efficacy. The response may, in part, be due to interindividual variability of the ACE genotype. The activity of ACE is partially dependent on the presence or absence of a 287-base-pair element in intron 16, and this insertion-deletion (ID) polymorphism accounts for 47% of the total phenotypic variation in plasma ACE. DD subjects have the highest, ID subjects have intermediate, and II subjects have the lowest concentrations. Genotype also influences tissue ACE activity, but the clinical implications are under investigation.^{[52] [57]}

Angiotensin-converting enzyme inhibitors are indicated as first-line therapy in hypertensive patients with heart failure and systolic dysfunction, those with type 1 diabetes and proteinuria, after myocardial infarction with reduced systolic function, patients with CAD or atrial fibrillation, and patients with left ventricular dysfunction.^{[49] [58] [59]} ACE inhibitors reduce ventricular hypertrophy independent of the blood pressure lowering.^[60] All patients with diabetes, even without evidence of nephropathy, should be given ACE inhibitors for cardiovascular risk reduction.^{[61] [62] [63] [64] [65]} Clinical studies showed that ACE inhibitors improve endothelial dysfunction and cardiac and vascular remodeling, retard the progression of atherosclerosis, improve arterial distensibility, and reduce the risk of myocardial ischemia and infarction, stroke, and cardiovascular death in primary and secondary prevention^{[61] [66] [67]} trials. They are also associated with improved exercise performance in patients with hypertension and intermittent claudication,^[68] reduced pain perception, reduced perioperative myocardial ischemia, retarding the progression of aortic stenosis,^{[15] [69]} protect against cognitive decline,^[70] promote atrial structural remodeling^[71] and prolonged survival of arteriovenous polytetrafluoroethylene grafts.^{[72] [73]}

Angiotensin-converting enzyme inhibitors are contraindicated in patients with known renovascular hypertension or hypersensitivity to ACE inhibitors. ACE inhibitors may cause fetal or neonatal injury or death when used during the second and third trimesters of pregnancy.^{[49] [74]} Recent evidence suggests that first-trimester use is also associated with major congenital malformations.^[75] If a patient becomes pregnant during treatment, the ACE inhibitor should be discontinued and alternative treatment found; termination of pregnancy should be left to the discretion of the patient and treatment team.

Overall, ACE inhibitors are well tolerated and have relatively neutral or beneficial metabolic effects. ACE inhibitors are associated with 8% to 11% reductions in low-density lipoprotein (LDL)-cholesterol and triglycerides and 5% increases in high-density lipoprotein (HDL)-cholesterol.^[76] They do not cause perturbations of serum sodium or uric acid. ACE inhibitors reduce the levels of plasminogen activator inhibitor-1 and may improve fibrinolysis.^[77]Hyperkalemia greater than 5.8 mmol/L rarely requires discontinuation of therapy and occurs in 2% of patients.^[49] It is more likely to develop in patients with renal insufficiency or diabetes or those taking potassium-sparing drugs. The effects on glucose metabolism are favorable.^[78] They may improve glucose tolerance by augmenting the insulin secretory response to glucose,^[78] and may help ameliorate obesity and hyperinsulinemia.^[79] Use of ACE inhibitors has clinically been associated with a 25% to 30% risk for developing diabetes.^[80] Several large clinical trials are currently underway to evaluate the clinical relevance of this finding.^[81] Many of the ACE inhibitors need dose adjustment in the presence of renal dysfunction ( Table 45-6 ).

TABLE 45-6 -- Antihypertensive Drugs Requiring Dose Modification^[*] in Renal Insufficiency: Estimated Glomerular Filtration Rate (Creatinine Clearance)

Drug	>50 ml/min	10–15 ml/min	<10 ml/min	Dialysis^[†]
Angiotensin-Converting Enzyme Inhibitors
1. Benazepril	No change	50%	25%	Negligible
2. Captopril	No change	50%	25%	(H) 50%
3. Cilazepril	No change	50%	25%	(H) 50%
4. Enalapril	No change	50%	25%	(H) 50%
5. Fosinopril	No change	No change	75%
6. Imidipril	No change	No change	—	—
7. Lisinopril	No change	50%	25%	(H) 50%
8. Moexipril	No change	50%	25%	—
9. Perindopril	No change	75%	50%	—
10. Quinapril	No change	50%	25%	—
11. Ramipril	No change	50%	25%	—
12. Trandolapril	No change	50%	25%	—
13. Zofenopril	No change	—	—	—
Angiotensin Receptor Blockers
1. Candesartan	No change	No change	No change	Negligible
2. Eprosartan	No change	No change	50%	Negligible
3. Irbesartan	No change	No change	—	Negligible
4. Losartan	No change	No change	No change	Negligible
5. Olmesartan	No change	—	—
6. Telmisartan	No change	No change	No change	Negligible
7. Valsartan	No change	No change	No change	—
Adrenergic Antagonists
1. Nadolol	No change	50%	25%	(H) 50%
2. Carteolol	No change	50%	25%	—
3. Penbutolol	No change	No change	50%	Negligible
4. Pindolol	No change	No change	50%	Negligible
5. Atenolol	No change	50%	25%	(H) 50%
6. Betaxolol	No change	No change	50%	(H) 50%
7. Bisoprolol	No change	50%	25%	Negligible
8. Acebutolol	No change	50%	30%–50%	(H) 50%
9. Celiprolol	No change	50%	Avoid	—
10. Nebivolol	No change	50%	—	—
Calcium Antagonists
Diltiazem	No change	No change	No change	Negligible
Verapamil	No change	No change	No change	Negligible
Nifedipine	No change	No change	No change	Negligible
Amlodipine	No change	No change	No change	Negligible
Felodipine	No change	No change	No change	Negligible
Isradipine	No change	No change	No change	Negligible
Manidipine	No change	No change	No change	Negligible
Nicardipine	No change	No change	No change	Negligible
Nisoldipine	No change	No change	No change	Negligible
Lacidipine	No change	No change	No change	Negligible
Lercanidipine	—
Ca Central α₂-Adrenergic or Imidazole I1-Agonists
Methyldopa	No change	No change	50%	(H) 50%
Clonidine	No change	50%	25%	Negligible
Moxonidine	No change	50%	—	—
Rilmenidine	No change	50%	25%	—
Peripheral Adrenergic-Neuronal Blocking Agents
Guanethidine	No change	No change	50% (avoid)	—
Guanadrel	No change	50%	25% (avoid)	—
Direct-Acting Vasodilators
Hydralazine	No change	No change	75%^[‡]	Negligible
Minoxidil	No change	50%	50%	(H and P) 50%
Tyrosine Hydroxylase Inhibitor
Metyrosine	No change	50%	25%	—
Selective Aldosterone Receptor Antagonists
Eplerenone	Dosage adjustment in renal failure unknown
	Caution in regard to hyperkalemia
Vasopeptidase Inhibitors
Omapatrilat	No dosage adjustment is necessary in renal failure.
	Limited pharmacokinetic studies in patients with mild to severe renal insufficiency suggest that no dose adjustment in required.^[34]

H, hemodialysis; P, peritoneal dialysis.

^*	Percent of total dose given.
^†	Replacement dose at end of dialysis (% of dose prescribed for patient with GFR < 10 mL/min).
^‡	Slow acetylators.

There are few class side effects, and they may occur with all ACE inhibitors. The newer agents appear to have a lower incidence of side effects, possibly because of the lack of the sulfhydryl moiety found in captopril. 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.^[82] The cough is thought to be secondary to hypersensitivity to bradykinins, which are inactivated by ACE, increases in prostaglandins; and accumulation of substance,^[80] a potent bronchoconstrictor.^{[3] [83]} The cough can begin initially or many months after therapy,^[84] is more common in women, and may disappear spontaneously.^[84] It may be more common in patients with bronchial hyperreactivity, but ACE inhibitors are safe in asthmatics.^[85] NSAIDs and sodium cromoglycate have been reported to improve the cough,^[86] but cessation of ACE therapy is the only absolute cure.

Angioedema is a rare but potentially life-threatening complication of ACE inhibitor therapy. It occurs in less than 0.2% of patients within hours of the first dose of ACE inhibitor or after prolonged use.^{[87] [88] [89]} Understanding of the mechanism of ACE inhibitor-induced angioedema is evolving and involves several components: tissue accumulation of bradykinin and inhibition of C1 esterase activity.^[87] Susceptible individuals typically have defects in non-ACE, non-kininase I pathways of bradykinin degradation.^{[87] [90]} Swelling confined to the face, mucous membranes, and lips usually resolves with discontinuation of therapy and may exacerbate obstructive sleep apnea.^[91]Involvement of the glottis and larynx requires management of the airway, epinephrine, H₂-blockers, corticosteroids, or fresh frozen plasma.^[15] This phenomena may not be a class effect, so safe administration with one agent may not be assumed to extend to all ACE inhibitors.

First-dose hypotension, with reduction of blood pressure up to 30%, has been reported with all ACE inhibitors with a frequency of up to 2.5% of patients. Hypotension occurs more commonly in volume-depleted states, patients with high-renin hypertension, and those with systolic heart failure. The hypotension is usually well tolerated but may be associated with syncope. In elderly patients, ACE inhibitor therapy more frequently causes nocturnal hypotension.^[92] The accompanying increase in plasma norepinephrine may explain the low incidence of orthostatic symptoms.^[92] In high-risk patients, therapy should be initiated with lower doses and preferably after discontinuation of diuretics. Rebound hypertension has not been reported with discontinuation of ACE inhibitors.

Side effects related to the chemical structure are more frequently seen with the sulfhydryl-containing captopril than with the other agents. Dysgeusia appears to be related to the binding of zinc by the ACE inhibitors. Approximately 2% to 4% of patients experience a diminution or loss of taste sensation that is associated with a metallic taste. It is usually self-limited and resolves in 2 to 3 months even with continued therapy. It may be severe enough to interfere with nutrition and cause weight loss.^[93] Cutaneous reactions are manifest as a nonallergic, pruritic maculopapular eruption that appears during the first few weeks of therapy; they may be associated with a fever or arthralgias and may disappear even with continuation of the ACE inhibitor. Leukopenia and anemia have been reported with ACE inhibitor therapy. Neutropenia (<1000 neutrophils/mm³) with myeloid hypoplasia occurs almost exclusively in patients with renal insufficiency, immunosuppression, collagen vascular diseases, or autoimmune diseases. It is associated with systemic and oral cavity infections common with agranulocytosis. Neutropenia occurs within 3 months of therapy and generally resolves 2 weeks after therapy is discontinued.^[15] Although usually reversible, it may be fatal.

Anaphylactoid reactions ranging from mild pruritus to bronchospasm and cardiopulmonary collapse have been reported in hemodialysis patients treated with ACE inhibitors who are dialyzed with high-flux polyacrylonitrile, cellulose acetate, or cuprophane membranes or patients receiving apheresis with dextran sulfate membranes.^[93] The frequency of reactions is unknown, but they occur within the first few minutes of treatment. Such membranes should be avoided in patients receiving ACE inhibitors.

Significant drug interactions with ACE inhibitors are few. AII stimulates the production of vasodilatory prostaglandins. Aspirin inhibits the production of vasodilator and antithrombotic prostaglandins. Theoretically, either agent may antagonize the effectiveness of the other. Studies show that aspirin doses of 100 mg/day or less do not negate the effects of ACE.^[94] Concomitant use of ACE inhibitors and cyclosporine may exacerbate renal hypoperfusion.^[15]Concomitant use of ACE inhibitors with trimethoprim may exaggerate hyperkalemia. Finally, ACE inhibitors have been demonstrated to interfere with the response to erythropoietin. Hemodialysis and renal transplant patients receiving erythropoietin frequently require higher doses to maintain adequate hematocrits.^[95] Consequently, ACE inhibitors can be used effectively to reduce post-transplantation erythrocytosis,^[96] but appear to have little effect on erythropoiesis in hemodialysis patients.^[97]

Angiotensin II Type I Receptor Antagonists

Class Mechanisms of Action

The AII receptor blockers (ARBs) allow more specific and complete blockade of the RAS than the ACE inhibitors because they circumvent all pathways that lead to the formation of AII. For example, AI is metabolized not only by ACE to form AII but also by chymase, cathepsin G, tissue plasminogen activator (t-PA), and other enzymes.^[98] AII can be formed at sites other than those in the systemic circulation such as the brain, kidney, and heart. Furthermore, long-term ACE inhibitor therapy is associated with a return of AII levels to baseline, possibly contributing to reduced efficacy. The ARBs selectively antagonize AII directly at the AT1 receptor regardless of the source of production. Because AII plays a crucial multifactorial role in maintaining and regulating blood pressure, blockade of the AT1 receptor with ARBs is a powerful tool for targeting multiple pathways that contribute to hypertension.

Like ACE inhibitors, ARBs directly block the vasoconstricting action of AII and cause a decrease in peripheral vascular resistance.^[99] The hypotensive effect is not accompanied by changes in cardiac output, heart rate, or GFR. Interruption of the binding of AII at the tissue level also leads to other effects beyond vasodilation that contribute to the antihypertensive effect (see Table 45-4 ).^[3] Additional mechanisms include (1) augmentation of renal blood flow and reduction of aldosterone release to induce natriuresis and attenuate the compensatory increase in sodium retention that accompanies a fall in blood pressure^[3]; (2) direct depression of tubule sodium reabsorption^{[100] [101]}; (3) improvement of nitric oxide-mediated endothelial function^[102]; (4) reversal of vascular hypertrophy^[102]; (5) blunting of sympathetic nervous system activity and presynaptic noradrenaline release; (6) inhibition of postjunctional pressor responses to NE or AII; (7) inhibition of central AII-mediated sympathoexcitation and vasopressin release^{[103] [104] [105]}; (8) inhibition of centrally controlled baroreceptor reflexes^[106]; (9) inhibition of central nervous system norepinephrine synthesis; (10) inhibition of thirst^[107]; and possibly inhibition of RAS-mediated actions on endothelin-1.^[108] The antihypertensive action of ARBs is dependent on activation of the RAS and is associated with clinically insignificant increases in circulating levels of AII.^[99] ARBs also increase bradykinin levels by antagonizing AII at its type I receptor and diverting AII to its counterregulatory type 2 receptor, which potentiates vasodilation.^[109] ARBs also increase the level of other angiotensin peptides, including angiotensin 1-7, AIII, and AIV, which can act on their respective receptors to modulate vasoconstriction, renal blood flow, and vascular hypertrophy.^{[110] [111] [112] [113] [114] [115]}

Class Members

The ARB class is composed of peptide and nonpeptide analogs that vary in structure, mechanism of receptor inhibition, metabolism, and potency. There are currently seven drugs in clinical use. Many of the newer drugs arose from modification of losartan, the first biologically active ARB oral agent. They are categorized according to the substitution of carboxylic and other moieties into several groups: the biphenyl tetrazoles (derivatives of losartan), nonbiphenyl tetrazoles, and nonheterocyclic compounds.^[3] They are also classified according to their ability to antagonize AII. The competitive (surmountable) antagonists shift the dose-response curve for AII-mediated contraction to the right without depressing the maximal response to AII. The noncompetitive (insurmountable) antagonists also depress the maximal response to AII. The variable effects of ARBs are mediated by differences in the interaction with allosteric binding sites on the receptor, dissociation of the drug-receptor complex, removal of the agonists from tissues, or the ability to modulate the amount of internalized receptors.^[116]

Biphenyl Tetrazole Derivatives

Candesartan cilexetil is an esterified prodrug imidazole that is rapidly and completely converted into the active 7-carboxylic acid candesartan (CV 11974) in the intestinal wall.^{[15] [16]} Candesartan is a selective, nonpeptide ARB noncompetitive (insurmountable) blocker with the highest receptor binding affinity with a slow detachment rate from the receptor ( Table 45-7 ). Consequently, the effects are long lasting and unlikely to be overcome by the up-regulation of AII that commonly accompanies AT1 receptor blockade. The initial dose is 16 mg daily, and the usual daily dose is 8 mg to 32 mg in one or two divided doses ( Table 45-8 ). The initial antihypertensive response occurs in 2 to 4 hours, peaks at 6 to 8 hours, and lasts 24 hours ( Table 45-9 ).^{[116] [117]} Radioreceptor assays demonstrate the presence of candesartan at the receptor site for periods longer than predicted from plasma half-life analysis, which correlates with the clinical observation of a sustained effect beyond 24 hours. Maximal response is achieved in 4 weeks. The terminal half-life of Candesartan is approximately 9 hours and is not affected by renal failure. No unchanged parent compound is detected in the serum or urine. Candesartan is not dialyzable.

TABLE 45-7 -- Pharmacokinetic Interactions between AT₁ Receptor Blockers and the Receptor

AT₁ Receptor	Receptor Antagonist Dissociation Rate	Affinity	Type of AT₁, Antagonism
Candesartan cilexetil (Candesartan)	Slow	280	Noncompetitive
Irbesartan	Slow	5	Noncompetitive
Valsartan	Slow	10	Noncompetitive
Telmisartan	Slow	10	Noncompetitive
Losartan	Fast	50	Competitive
Eprosartan	Fast	100	Competitive

TABLE 45-8 -- Pharmacodynamic Properties of Angiotensin Receptor Blockers

Drug Generic (Trade) Name	Initial Dose (Mg)	Usual Dose (Mg)	Maximum Dose (Mg)	Interval	Peak Response (H)	Duration of Response (H)
Eprosartan (Tevetan)	200	200–400	400	qd/bid	4	24
Irbesartan (Avapro)	150	150–300	300	qd	4–6, 14	24
Losartan (Cozaar)	50	50–100	100	qd/bid	6	12–24
Valsartan (Diovan)	80	80–160	300	qd	4–6	24
Candesartan (Atacand)	8	8–32	32	qd	6–8	24
Telmisartan (Micardis)	40	40–80	80	qd	3–6	24
Olmesartan (Benicar)	20	20–40	40	qd	1.4–2.8	24

TABLE 45-9 -- Pharmacokinetic Properties of Angiotensin Receptor Blockers

Drug	Absorption	Bioavailability (%)	Affected by Food	Peak Blood Level (H)	Elimination Half Life	Metabolism	*Excretion^[]**	Active Metabolites
Eprosartan	>80	13	No	4	6	L	F(70)/U(7)	Inactive
Irbesartan	>80	60–80	No	1.5–2	10–14	L/K	F(65)/U(20)	Inactive
Losartan	>80	25	No	1	4–9	L/K	F(60)/U(40)	Active
Valsartan	>80	25	Yes	2–4	6–9	L/K	F(83)/U(13)	Inactive
Candesartan	—	15	No	2–4	9	I/L/K	F(67)/U(33)	None
Telmisartan	—	42	Yes	0.5–1	24	L	F	Inactive
Olmesartan	—	26	No	1	12–18	I	F(50)/U(50)	Active

F, feces; I, intestine; K, kidney; L, liver; U, urine.

^*	Excretion values in parentheses are percentages.

Eprosartan is a nonpeptide, selective ARB that was modified to resemble AII more closely. It is a noncompetitive antagonist with a high affinity for the AT1 receptor (see Table 45-7 ).^{[15] [16]} The initial daily dose is 200 mg (seeTable 45-8 ). The usual daily dose is 200 mg to 400 mg. Eprosartan is rapidly absorbed, but absorption is delayed by food (see Table 45-9 ). The initial response occurs in 4 hours and lasts for 24 hours. The elimination half-life is 6 hours.^[118] Doses should be reduced by 50% in patients with renal failure.

Irbesartan is a nonpeptide specific imidazolinone derivative of losartan that acts as a noncompetitive AT1 receptor blocker with a very high receptor binding affinity (see Table 45-7 ).^{[15] [16] [119]} The initial dose is 150 mg daily. The usual daily dose is 150 mg to 300 mg. The initial response occurs in 2 hours. The peak response is bimodal; in hypertensive patients, peak responses occur in 4 to 6 hours and 14 hours, corresponding to the peak increases in plasma renin activity and AII levels.^[15] With continuous dosing, the maximal effect may not be seen for up to 6 weeks. The duration of action is 24 hours. Irbesartan is not dialyzable.

Losartan potassium is the prototype ARB. The tetrazole moiety on the biphenyl ring accounts for its oral activity and duration of action. It was the first orally active agent and is a competitive, nonpeptide selective AT1 receptor inhibitor with moderate receptor binding affinity (see Table 45-7 ).^{[15] [16] [120]} The usual starting dose is 50 mg once daily (see Table 45-8 ). Dose adjustments should be made at weekly intervals. The antihypertensive efficacy may be improved with divided doses. The usual daily dose is 50 mg to 100 mg. The potassium contents of the 25-, 50-, and 100-mg tablets are 0.054, 0.108, and 0.216 mEq, respectively. The oral bioavailability of losartan is 25% and is unaffected by food (see Table 45-9 ). The initial response occurs in 1 hour, peaks at 6 hours, and lasts for 24 hours. Only 5% of losartan is recovered unchanged in the urine, supporting extensive metabolism and biliary secretion. Neither the parent drug nor metabolites are removed by dialysis.

Olmesartan medoxomil is a selective, nonpeptide ARB prodrug that is rapidly and completely bioactivated by hydrolysis to olmesartan during absorption from the gastrointestinal tract.^[121] The initial dose is 20 mg, and the usual dose is 20 mg to 40 mg daily (see Table 45-8 ). The peak plasma concentration is reached in 1 hour (see Table 45-9 ). The blood pressure-lowering effect lasts for 24 hours and reaches a maximum at 2 weeks. Olmesartan is eliminated in a biphasic manner with a terminal half-life of 13 hours. Dosing and pharmacokinetics have not been studied in dialysis patients.

Nonbiphenyl Tetrazole Derivatives

Telmisartan incorporates a carboxylic acid as the biphenyl acidic group. Telmisartan is a nonpeptide, noncompetitive ARB with high specificity and receptor affinity.^{[15] [16] [122]} The usual starting dose is 40 mg, and the usual daily dose is 40 mg to 80 mg. The initial response occurs in 3 hours and is dose dependent (see Table 45-9 ). The duration of action is 24 hours but may be up to 7 days after discontinuation of the drug.^[15] Women typically achieve plasma levels two to three times higher than those of men, but this is not associated with differences in blood pressure response. Less than 3% of the drug is metabolized in the liver into inactive compounds. The elimination half-life is 24 hours. Telmisartan is not dialyzable, and dose adjustment is not necessary in patients with renal disease.

Nonheterocyclic Derivatives

Valsartan is a nonheterocyclic ARB in which the imidazole of losartan is replaced by an acetylated amino acid.^{[15] [16]} Valsartan is a noncompetitive antagonist with high specificity and receptor binding affinity (see Table 45-7 ). The initial starting dose is 80 mg once daily (see Table 45-8 ). The usual dose is 80 mg to 16 mg daily. The maximal blood pressure response is achieved after 4 weeks of therapy (see Table 45-9 ). The initial response occurs in 2 hours, peaks at 4 to 6 hours, and lasts 24 hours. Valsartan does not undergo significant metabolism. The elimination half-life is 6 to 9 hours and is not affected by renal failure.

Class Renal Effects

Intrarenal AII receptors are widely distributed in the afferent and efferent arterioles, glomerular mesangial cells, the inner stripe of the outer medulla, medullary interstitial cells,^[123] and on the luminal and basolateral membranes of the proximal and distal tubule cells, collecting ducts, podocytes, and macula densa cells.^[124] The majority of receptors are of the AT1 subclass. Circulating and predominantly locally produced AII interacts with the receptors; the complex is internalized and AII is released into the intracellular compartment, where it exerts its effects. Studies suggest that the majority of renal interstitial AII is formed at sites not readily accessible to ACE inhibition or is formed by non-ACE pathways.

Angiotensin receptor blockers antagonize the binding of AII and cause a number of intrarenal changes. The overall renal hemodynamic responses of AT1 receptor blockade are variable depending in the counteracting influences of the decrease in arterial pressure.^{[125] [126]} Decreases in systemic arterial pressure by ARBs may be associated with compensatory activation of the intrarenal sympathetic nervous system, resulting in decreased renal function. This effect is more pronounced during sodium-depleted states because activation of the RAS helps to maintain arterial and renal pressure. In contrast, direct intrarenal infusions of ARBs cause an increase in sodium excretion.^[127] The enhanced sodium excretion has been shown to be due to direct inhibition of sodium reabsorption by the proximal tubules but may also be due to hemodynamic changes in medullary blood flow and tubule absorption in distal nephron segments. Because AII blockade enhances the ability of the kidneys to excrete sodium, sodium balance can be maintained at lower arterial pressures. AII blockade also reduces tubuloglomerular feedback sensitivity^[128] by decreasing macula densa transport of sodium chloride to the afferent arteriole. This leads to increased delivery of sodium chloride to the distal segments for excretion without compensatory changes in GFR.

In addition to the natriuretic and diuretic actions, acute administration of some ARBs has been observed to induce reversible kaliuresis in salt-depleted normotensive subjects in the absence of changes in GFR.^[129] However, chronic AII receptor blockade does not cause appreciable changes in urinary electrolyte excretion or volume. The kaliuretic effect may be due to specific intrinsic pharmacologic effects of the losartan molecule.^[15]

Another property unique to the losartan molecule is induction of uricosuria. This effect is not seen with ACE inhibitors or other ARBs, including the active metabolite of losartan and does not appear to be related to inhibition of the RAS.^[130] Losartan has a greater affinity for the urate/anion exchanger than other antagonists and causes inhibition of urate reabsorption in the proximal tubule.^[131] The uricosuria is associated with a concomitant decrease in serum uric acid in normal subjects, hypertensive subjects, and patients with renal disease and kidney transplants.^[132] The effect occurs within 4 hours of drug administration and is dose dependent. Long-term administration reduces uric acid levels by approximately 0.4 mg/dL.^[133] The clinical implications of this effect are unknown. Concerns that increased uric acid supersaturation might perpetuate renal uric acid deposition have not been borne out clinically, as losartan simultaneously increases urinary pH, which protects against crystal nucleation.^[134] Conversely, the decrease in serum uric acid might be beneficial, as it has been suggested that hyperuricemia is a risk factor for renal disease progression and coronary artery disease.

Hypertensive patients treated with ARBs, with normal or impaired renal function, exhibit renal responses similar to or slightly greater than the responses of those treated with ACE inhibitors.^[135] In addition to decreases in systolic and diastolic blood pressure, patients demonstrate increases in renal blood flow and decreases in filtration fraction and renal vascular resistance with no substantial changes in GFR.^[136] These effects are probably a result of combined decreases in both pre- and postglomerular resistances. It has been suggested that elevated intrarenal AII levels in the presence of AT1 receptor blockade stimulates AT2 receptors, which can increase preglomerular vasodilator actions of bradykinin, cyclic guanosine monophosphate, and nitric oxide.^[137] ACE inhibitors can potentiate this effect.^[137] The clinical importance of this finding has yet to be established. AII blockade may significantly reduce GFR in underperfused kidneys. Patients with low perfusion pressures, dehydration, or renal artery stenosis may experience severe decreases in GFR, but less severe decreases than with ACE inhibitors.^[138] Under conditions of overperfusion, such as with hypertension associated with glomerulosclerosis and nephron loss or diabetes, AII blockade is protective. Such patients often have a suboptimal suppression of the RAS. The lowering of efferent arteriole resistance reduces intraglomerular hydrostatic pressure, attenuating the progression of renal injury, and increases renal sodium excretory capacity. In concert with the reduction in systemic arterial pressure, these actions may provide more renal protection than other classes of antihypertensive agents despite equivalent reductions of blood pressure.^{[139] [140] [141]}

In healthy and hypertensive patients, ARBs produce dose-dependent increases in circulating AII levels and plasma renin activity.^[142] The increases occur at the peak plasma drug levels and persist up to 24 hours; they remain elevated with chronic administration. Decreases in plasma levels of aldosterone have been reported but are variable. In normal subjects, the decreases coincide with the peak interval of ARB activity; in hypertensive patients with a fixed sodium diet, there are no significant changes in aldosterone from baseline.^{[3] [129]} Indeed, ARBs suppress the AII-mediated adrenal cortical release of aldosterone, but these effects appear to be quantitatively less important than the intrarenal suppression of AII action. Long-term AT1 receptor blockade does not appear to induce aldosterone escape.^[143]

Urinary protein excretion is significantly decreased with ARBs^[15] and parallels findings with ACE inhibitors. Antiproteinuric effects have been described in diabetic and nondiabetic patients and those with renal transplants.^[144]The time course of the antiproteinuric effect has a slow onset, and the dose-response curves differ from those of the antihypertensive effects: the maximal effect occurs at 3 to 4 weeks. Currently, the peak of the dose-response curve has not been determined. Whether the antiproteinuric effects are equivalent to or better than those of ACE inhibitors remains to be determined. They do appear to have additive and similar hemodynamic and antiproteinuric effects.^[145] In a number of trials, ACE I therapy or ARB therapy reduced proteinuria by up to 40%. Combined therapy resulted in a 70% reduction of proteinuria with no further changes in blood pressure.^{[146] [147]} Such findings suggest that the mechanism of the antiproteinuric effect may differ between the two classes. It is currently recommended that patients receiving ACE inhibitor therapy with persistent hypertension or proteinuria should be treated with angiotensin receptor antagonist therapy.^[148] This combination appears to reduce intrarenal AII and transforming growth factor b (TGF-β) levels more than high doses of either agent alone.^[149] The benefits of using ARBs for renoprotection and reduction of proteinuria are discussed in Chapter 36 .

Like the ACE inhibitors, ARBs have multiple nonhemodynamic effects that may contribute to renoprotection. These include antiproliferative actions on the vasculature and mesangium, inhibition of TGF-b,^{[149] [150]} inhibition of atherogenesis^[151] and vascular deterioration,^[152] improved superoxide production and nitric oxide bioavailability,^[153] reduction of collagen formation, reduced mesangial matrix production, improved vascular wall remodeling, decreased vasoconstrictor effects of endothelin-1, improved endothelial function,^[152] reduction of oxidative stress, and protection from calcineurin inhibitor injury. The clinical importance of these effects is under investigation.

Class Efficacy and Safety

All AT1 receptor blockers have been demonstrated to lower blood pressure effectively and safely in patients with mild, moderate, and severe hypertension regardless of age, gender, or race.^{[154] [155] [156]} The recently completed Trial of Preventing Hypertension (TROPHY) study evaluated the feasibility of treating patients with pre-hypertension (defined as systolic BP 130-139 mm Hg, and diastolic pressure of 85-89 with the ARB, Candesartan. After 4 years, patients randomized to the ARB arm were significantly less likely to develop incident hypertension than those treated with placebo).^[157] Pre-hypertension is a predictor of cardiovascular risk, but whether this data will change clinical practice remains speculative. They are indicated as first-line monotherapy or add-on therapy for hypertension and are comparable in efficacy to other agents.^{[158] [159] [160]} They are safe and effective in patients with CKD (even when used in high doses), diabetes, heart failure, renal transplants, coronary artery disease (CAD), arrhythmias and left ventricular hypertrophy (LVH)^{[161] [162] [163] [164]} and have been shown to protect against hypertensive end-organ damage, such as LVH, stroke, ESRD, retinopathy, and possibly diabetes.^{[165] [166] [167] [168] [169]} Although they may not be the most efficacious agents in terms of blood pressure reduction in blacks, they are equally or more efficacious in offering target organ protection and arresting disease progression than agents that do not inhibit the RAS.^[170] Moreover, the antihypertensive activity is not attenuated by high-salt diets in blacks.^[159] In most patients, the ARBs offer blood pressure lowering comparable to that of all other classes, with an improved tolerability profile.^[171] ARBs provide effective control over a 24-hour period and are suitable for once-daily dosing.^[172]Response rates vary from 40% to 60%. They do not affect the normal circadian blood pressure variation.^[173] The long onset of action of 4 to 6 weeks avoids the first-dose hypotension and rebound hypertension commonly seen with other drugs. There is a dose-dependent response with newer agents, and losartan and valsartan have a relatively flat dose-response curve.^[174] Candesartan, irbesartan, and olmesartan may have the greatest efficacy with a longer duration of action because of their noncompetitive binding nature.^[175]

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. The ARBs may also abrogate the adverse metabolic effects of thiazides. Combination of ARBs and ACE inhibitors is safe and additive in reducing blood pressure and effectively suppressing sympathetic activity.^[176] Two large studies are currently under way to asses the effectiveness of combination therapy versus ACE-inhibitor alone therapy on cardiovascular outcomes in high risk patients.^{[45] [177]} Combination therapy with dihydropyridines has additive effects in reducing blood pressure and is well tolerated.^[178] ARBs are contraindicated in patients with known renovascular hypertension and may cause fetal or neonatal death when used during the second and third trimesters of pregnancy.

Overall, the ARBs have neutral metabolic effects and are superior to other classes with respect to tolerability. They do not cause hyper- or hyponatremia, and hyperkalemia is rare. 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 or diabetes or in those taking potassium-sparing drugs. ARBs tend to lower BNP levels which may explain their benefit in heart failure.^[179] ARBs have no effect on serum lipids in hypertensive patients but may improve the abnormal lipoprotein profile of patients with proteinuric renal disease as well as improve obesity-related morbidity.^{[180] [181]} ARBs have favorable effects on serum glucose and insulin sensitivity.^[182] Clinical trials comparing ARB-based therapy with other antihypertensives in patients with hypertension and LVH demonstrate a 25% reduced risk for the development of diabetes in the ARB group. The mechanism for this effect has not been defined.^{[166] [183]} Increased liver transaminases are occasionally reported, but the effects are usually transient despite continued therapy.^[15]

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. This is a major clinical advantage of the use of ARBs. The incidence of cough in patients with a history of ACE inhibitor-induced cough is no greater than in those receiving placebo.^[184] Similarly, the incidence of angioedema and facial swelling is no greater than with placebo, but they can occur.^[185] The most frequent side effects are headache (14%), dizziness (2.4%), and fatigue (2%), which occur at rates lower than those with placebo.^[186] ARB therapy not only does not worsen sexual activity but may improve it.^[187] Like ACE inhibitors, ARBs may cause minor decreases in serum hemoglobin; they may lower the hematocrit effectively in post-transplantation erythrocytosis.^[188] Drug interactions are uncommon, but as with ACE inhibitors, NSAIDS may blunt the natriuretic effect of ARBs.^[189] Acute reversible renal failure has been reported with AII receptor blockade therapy in salt-depleted patients. Thus, therapy should not be instituted in hypovolemic patients or in the setting of active diuresis.

β-Adrenergic Antagonists

Mechanisms of Action

These drugs exert their antihypertensive effects by attenuation of sympathetic stimulation through competitive antagonism of catecholamines at the β-adrenergic receptor.^[190] In addition to β-blockade properties, certain drugs have antihypertensive effects mediated through different mechanisms ( Table 45-10 ) including α₁-adrenergic blocking activity, β₂-adrenergic agonist activity, and perhaps effects on nitric oxide-dependent vasodilator action. Partial agonist activity is a property of certain β-adrenergic blockers that results from a small degree of direct stimulation of the receptor by the drug, which occurs at the same time that receptor occupancy blocks access of strongly stimulating catecholamines.^{[191] [192]} Whether the presence of partial agonist activity is advantageous or disadvantageous remains unclear. Drugs with partial agonist activity slow resting heart rate less than drugs that lack this pharmacologic effect.^[193] The exercise-induced increase in heart rate is similarly blocked by both groups of drugs.^[193] However, β-adrenergic blockers with nonselective partial agonist activity may reduce peripheral vascular resistance and cause less atrial ventricular conduction depression than drugs without partial agonist activity. The specificity of partial agonist activity for β₁- or β₂-receptors may also have a role in the antihypertensive response to a given drug.

TABLE 45-10 -- Pharmacodynamic Properties of β-Adrenergic Antagonists

Drug	β₁-Selectivity	Partial Agonist Activity	Membrane-Stabilizing Activity	α-Adrenergic Antagonist
Nadolol	0	0	0
Propranolol	0	0	+
Carteolol	0	+	0
Penbutolol	0	+	0
Pindolol	0	+	+
Labetalol	0	+	0	+
Carvedilol	0	0	+	+
Atenolol	+	0	0
Metoprolol	+	0	0
Betaxolol	+	0	+
Acebutolol	+	+	+
Celiprolol	+	0	0	+
Bisoprolol	+	0	0
Nebivolol	+	0	0

β-Adrenergic receptor blockers may be nonspecific and block both β₁- and β₂-adrenergic receptors, or they may be relatively specific for β₁-adrenergic receptors. β₁-Receptors are found predominantly in heart, adipose, and brain tissue, whereas β₂-receptors predominate in the lung, liver, smooth muscle, and skeletal muscle. Many tissues, however, have both β₁- and β₂-receptors, including the heart, and it is important to realize that the concept of a cardioselective drug is only relative.

β-Adrenergic blockers differ significantly in gastrointestinal absorption, first-pass hepatic metabolism, protein binding, lipid solubility, penetration into the central nervous system, and hepatic or renal clearance. β-Blockers eliminated primarily by hepatic metabolism have a relatively short plasma half-life; however, the duration of the clinical pharmacologic effect does not correlate well with plasma half-life in many of these drugs. Water-soluble drugs eliminated by the kidney may have longer half-lives. Bioavailability varies greatly.

Overall, the precise mechanism of the antihypertensive effect of β-adrenergic blockers remains incompletely understood. β₁-Adrenergic receptor blockade has generally been considered responsible for the blood pressure-lowering effect; however, β₂-receptor blockade has an independent antihypertensive effect.^[194] Inhibition of β₁-adrenergic receptors in the juxtaglomerular cells within the kidney may inhibit renin release. A direct action on the central nervous system with reduction in central nervous system sympathetic outflow may also be involved. Attenuation of cardiac pressor stimuli related to β-blockade may result in baroreceptor resetting. In additional, adrenergic neuron output may be blocked because of inhibition of β₂-adrenergic receptors at the vascular wall.

Nonselective β-Adrenergic Antagonists

Nadolol is a nonselective β-adrenergic blocking agent without partial agonist activity ( Table 45-11 ). The average adult dose is 40 mg to 80 mg given once daily, with a maximum daily dose of 320 mg ( Table 45-12 ). Nadolol is not appreciably metabolized, and elimination occurs predominantly in the urine and feces. Dose adjustment is indicated in patients with renal failure. Dosage intervals should be increased to 24 to 36 hours, 24 to 48 hours, and 40 to 60 hours in patients with creatinine clearances of 30 to 50 mL/min per 1.73 m², 10 to 30 mL/min per 1.73 m², and less than 10 mL/min per 1.73 m², respectively. Dose adjustment is not necessary in hepatic insufficiency. Hemodialysis reduces the serum concentration of nadolol, but specific recommendations for dosage during dialysis are not available.

TABLE 45-11 -- Pharmacokinetic Properties of β-Adrenergic Antagonists

Drug	Bioavailability (%)	Affected By Food	Peak Blood Level (H)	Elimination Half-Life (H)	Metabolism	*Excretion^[]**	Active Metabolites
Nadolol	20–40	No	2–4	20–24	—	U/F	—
Propranolol	16–60	Yes	—	3–4	L	—	—
Timolol	50–90	—	—	2–4	L	U(20)	—
Carteolol	84	Yes	—	5–8.5	L	—	—
Penbutolol	100	No	—	17–24	L	U	—
Pindolol	95	No	2	3–11	L	U(40)	—
Atenolol	40–60	Yes	—	14–16	—	U/F	—
Metoprolol	50	—	1.5–2	3–7	L	U	—
Betaxolol	78–90	No	2–6	12–22	L	U	—
Bisoprolol	90	—	2.3	9.6	L	U	—
Acebutolol	90	No	2–3	3–8	L	U	—

F, feces; L, liver; U, urine.

^*	Excretion values in parentheses represent percentages.

TABLE 45-12 -- Pharmacodynamic Properties of β-Adrenergic Antagonists

Drug	Initial Dose (Mg)	Usual Dose (Mg)	Maximum Dose (Mg)	Interval	Peak Response (H)	Duration of Response (H)
Nadolol	40	40–80	320	qd	—	—
Propranolol	40	80–320	640	bid	—	—
Timolol	10	20–40	60	bid	—	—
Carteolol	2.5	2.5–10	60	qd	6	24
Penbutolol	20	20–40	80	qd-bid	2	20–24
Pindolol	5	10–40	60	qd-bid	—	24
Atenolol	25	50–100	200	qd	3	24
Metoprolol	12.5–50	100–200	450	qd-bid	1	3–6
Betaxolol	10	10–40	40	qd	3	23–25
Bisoprolol	2.5	5–20	40	qd	2–4	24
Acebutolol	400	400–800	1200	qd	3	24

Propranolol is a noncardioselective β-adrenergic blocker (see Tables 45-11 and 45-12 [11] [12]). It has no partial adrenergic activity. The usual daily dosage range is 80 mg to 320 mg. It may be administered as a single daily dose if a long-acting preparation is used. The drug is metabolized by the liver. The major metabolite, 4-hydroxypropranolol, has β-adrenergic blocking activity. Renal excretion is less than 1%. Adjustment in renal failure is not necessary. Patients with liver disease may require variable dosage adjustments and more frequent monitoring.

Timolol is a nonselective β-adrenergic blocking agent without partial adrenergic activity (see Tables 45-11 and 45-12 [11] [12]). The recommended initial dose of timolol in the man agement of hypertension is 10 mg twice daily. The maintenance dose generally ranges from 20 mg to 40 mg daily. No dosage adjustment is necessary in patients with renal failure. Because timolol undergoes extensive hepatic metabolism, patients with liver disease may require a dosage adjustment and frequent monitoring. It is not removed by dialysis.

Carteolol is a long-acting nonselective β-adrenergic blocker (see Tables 45-11 and 45-12 [11] [12]).^{[195] [196]} It has moderate partial agonist activity.^{[197] [198]} Recommended dosing is 2.5 mg to 10 mg daily. Doses up to 60 mg/day have been utilized. Carteolol is eliminated primarily by the kidney. Dosage adjustment should be made for decreased renal function. The recommended dosing interval is 72 hours for creatinine clearances less than 20 mL/min per 1.73 m², and 48 hours for creatinine clearances between 20 and 60 mL/min per 1.73 m².

Penbutolol is a nonselective β-adrenergic blocking agent (see Tables 45-11 and 45-12 [11] [12]).^[195] It has low partial agonist activity. Usually, doses are 20 mg to 40 mg given either as a single dose or divided twice daily. Hepatic metabolism to inactive metabolites occurs with subsequent renal elimination. The optimal antihypertensive effect is seen at an average of 14 days after initiation of therapy. Dosage adjustments for patients with renal insufficiency are not recommended, but adjustment may be required for patients with hepatic insufficiency.

Pindolol is a nonselective β-adrenergic blocking agent with high partial agonist activity (see Tables 45-11 and 45-12 [11] [12]). The usual adult oral dose is 5 mg twice daily with incremental increases by 10 mg every 3 to 4 weeks. The maximum daily recommended dose is 60 mg. Approximately 40% of a dose of pindolol is excreted unchanged in the urine; 60% is metabolized in the liver. The drug half-life increases modestly in patients with renal impairment. Dosage adjustments do not appear be necessary. Dosage adjustments may be necessary in patients with severely impaired hepatic func-tion and in patients with concomitant cirrhosis and renal failure.

β₁-Selective Adrenergic Antagonists

Atenolol is a long-acting β₁-selective adrenergic blocking agent. It has no partial agonist activity. The usual dose is 50 mg to 100 mg once daily. It is eliminated approximately 50% by the kidneys and 50% excreted in the feces. Doses greater than 100 mg/day are unlikely to produce additional benefit. The time required to achieve the optimal antihypertensive effect is 1 to 2 weeks. Patients with moderate renal insufficiency should have the dose interval increased to 48 hours, and for patients with advanced renal disease dosing intervals should be increased to 96 hours. Atenolol is not significantly metabolized by the liver, and no dosage adjustment is necessary in patients with hepatic disease. The drug is removed by dialysis and a maintenance dose should be given after a dialysis treatment.

Metoprolol is a β₁-selective adrenergic blocker. There is no partial agonist activity. Extensive hepatic metabolism occurs, and 3% to 10% of the drug is excreted unchanged in the urine. The initial oral dose is 12.5 mg to 50 mg either once or twice daily, increasing to 100 mg to 200 mg twice daily. Sustained-released preparations may be substituted as a once-daily dose.

Betaxolol is a long-acting β₁-selective adrenergic blocking agent.^[199] There is no partial agonist activity. The usual oral dose for hypertension is 10 mg to 40 mg once daily. Therapy is typically started at a dose of 10 mg once daily. The majority of patients respond to 20 mg once daily. The time to achieve the optimal antihypertensive effect is approximately 1 to 2 weeks. Renal dysfunction results in a decrease in betaxolol clearance. Titration should begin at 5 mg once daily in those with severe renal impairment. It is metabolized predominantly in the liver with metabolites excreted by the kidney. Approximately 15% of the dose is recovered unchanged in the urine.

Bisoprolol is a long-acting β₁-selective adrenergic blocking agent.^[200] There is no partial agonist activity. The usual oral dose is 2.5 mg to 20 mg given once daily. Hepatic metabolism occurs with renal excretion of metabolites; however, 50% of the drug is excreted by the kidney unchanged. In patients with renal failure, the initial oral dose should be 2.5 mg once daily with careful monitoring in dose titration. The maximum recommended dose of bisoprolol in patients with renal failure is 10 mg/day. Similar dose reduction is also required for patients with hepatic insufficiency.

Acebutolol is a β₁-selective adrenergic blocking agent. It has low partial agonist activity. Doses of 400 mg to 1200 mg per day are effective in hypertension. The drug is metabolized to diacetolol, an active metabolite, with the parent com-pound being excreted both renally and in bile. Diacetolol is excreted mainly by the kidneys. Dose reduction of 50% to 75% is recommended for patients with advanced renal insufficiency.

Nonselective β-Adrenergic Antagonists with α-Adrenergic Antagonism or other Mechanisms of Antihypertensive Action

Labetalol is a nonselective β-adrenergic blocking agent.^[201] It also possesses selective α-adrenergic blocking activity (Tables 45-13 and 45-14 [13] [14]). It does have weak partial agonist activity. The blocking of β₁- and β₂-adrenergic receptors is approximately equivalent. In addition, labetalol is highly selective for postsynaptic α₁-adrenergic receptors. After an oral dose, the ratio of α₁- to β-blocking potency is approximately 1:3. With intravenous administration, the β-blocking potency seems more prominent. The usual initial doses in hypertension are 100 mg orally twice daily, increasing gradually to a maintenance dose of 200 mg to 400 mg twice daily. The drug is metabolized in the liver with 50% to 60% of a dose excreted in the urine and the remainder in the bile. Dosing adjustment is not required for any degree of renal failure. Chronic liver disease has been demonstrated to decrease the first-pass metabolism of labetalol. Dosage reduction is required in these patients to avoid excessive decreases in heart rate and supine blood pressure.

TABLE 45-13 -- Pharmacokinetic Properties of β-Adrenergic Antagonists with Vasodilatory Properties

Drug	Bioavailability (%)	Affected By Food	Peak Blood Level (H)	Elimination Half-Life (H)	Metabolism	*Excretion^[]**	Active Metabolites
Labetalol	25–40	Yes	1–2	5–8	L	U (50–60)	—
Carvedilol	25–35	No	1–1.5	6–8	L	F	—
Celiprolol	30–70	Yes	—	5–6	—	F/U	—
Nebivolol	12–96	No	2.4–3.1	8–27	L	—	—

F, feces; L, liver; U, urine.

^*	Excretion values in parentheses represent percentages.

TABLE 45-14 -- Pharmacodynamic Properties of β-Adrenergic Antagonists

Drug	Initial Dose (Mg)	Usual Dose (Mg)	Maximum Dose (Mg)	Interval	Peak Response (H)	Duration of Response (H)
Labetalol	100	200–800	1200–2400	bid	3	8–12
Carvedilol	6.25	12.5–25	50	bid	4–7	24
Celiprolol	200	200–600	—	qd	—	—
Nebivolol	5	5	—	qd	6	24

Carvedilol is a nonselective β-adrenergic blocking agent with peripheral α₁-blocking activity.^{[202] [203]} It no partial agonist activity (see Tables 45-13 and 45-14 [13] [14]). It is approximately equipotent in blocking β₁- and β₂-adrenergic receptors. Carvedilol is highly selective for postsynaptic α₁-adrenergic receptors. The ratio of α₁- to β₁-blocking activity is estimated to be 1:7.6. There is evidence that the therapeutic actions of carvedilol may be in part dependent on endogenous production of nitric oxide. For the management of hypertension, an initial oral dose of 6.25 mg twice daily is recommended and may be increased to 12.5 mg to 25 mg twice daily if needed. Dosing adjustments are not required for patients with renal insufficiency. Carvedilol is extensively metabolized in the liver, and dose reductions are suggested for patients with hepatic insufficiency.

Celiprolol is a β-blocker with several unique properties.^{[204] [205]} It is a β₁-adrenergic blocking agent with α₂-receptor blocking activity (see Tables 45-13 and 45-14 [13] [14]). Celiprolol also causes vasodilatation through β₂-receptor stimulation and possibly nitric oxide with a subsequent decrease in systemic vascular resistance. In contrast to other β-blockers, celiprolol does not appear to induce bronchospasm or have negative inotropic effects. It does have moderate partial agonist activity. The initial dose of celiprolol is 200 mg once daily. This can be increased to 400 mg to 600 mg once daily. Renal excretion is 35% to 42%. A 50% dose reduction is suggested in patients with a creatinine clearance of 15 to 40 mL/min per 1.73 m². It is not recommended for patients with a creatinine clearance of less than 15 mL/min per 1.73 m².

Nebivolol is a long-acting β₁-selective adrenergic antagonist (see Tables 45-13 and 45-14 [13] [14]).^{[206] [207] [208] [209] [210] [211] [212]} The compound is a 1 : 1 racemic mixture of two enantiomers, d-nebivolol and L-nebivolol. The actions of nebivolol are unique and unlike those of other β-blocking agents. These are attributed to the individual effects of the isomers. The β₁-adrenergic blocking effects are related to the d-isomer, whereas the L-isomer is essentially devoid of β-blocking properties at therapeutic doses. When administered alone, the L-isomer does not produce significant effects on blood pressure; however, the antihypertensive effects of the d-isomer are enhanced by the presence of the L-isomer. The hypotensive effects of the racemic mixture are associated with a decrease in peripheral vascular resistance.^[213] The mechanism by which the L-isomer enhances the hypotensive effects of the d-isomer is unclear. It has been suggested that L-nebivolol may potentiate the effects of endothelium-derived nitric oxide and induce decreases in blood pressure and peripheral vascular resistance. It has also been suggested that the L-isomer may inhibit norepinephrine actions at the presynaptic β-receptors. The initial oral dose is 5 mg once daily. The drug is metabolized in the liver. Both rapid and slow metabolizers have been identified. The half-life of nebivolol is 8 hours in rapid metabolizers and 27 hours in slow metabolizers. Reduced initial doses are recommended for patients with renal insufficiency.

Renal Effects of β-Adrenergic Blockers

Both α- and β-adrenergic receptors in the kidney mediate vasoconstriction and vasodilatation and renin secretion. β-Adrenergic blockers may influence renal blood flow and GFR through their effects on cardiac output and blood pressure in addition to direct effects on intrarenal adrenergic receptors. β-Adrenergic receptors have been localized to the juxtaglomerular apparatus in autoradiographic studies. β₂-Receptors predominate in the kidney. The degree of specificity of β- adrenergic blockers for β₁- and β₂-receptors might be expected to influence the effect on renal function, as might the degree of intrinsic partial agonist activity. In general, the acute administration of a β-adrenergic blocker usually results in reduction of GFR and effective renal plasma flow. This effect is independent of whether the drug has a β₁-selectivity or intrinsic partial agonist activity. Nebivolol, carvedilol, and celiprolol, however, have vasodilatory properties and have been shown to increase GFR and renal plasma flow.^[214] This may be mediated by increased synthesis of vasodilatory nitric oxide. Nadolol has been shown in some studies to increase renal plasma flow and glomerular filtration with intravenous administration; however, oral administration may result in decrements in blood flow and GFR. β₁-Selective drugs, when administered orally, tend to produce smaller reductions in GFR and renal plasma flow. The chronic use of propranolol has been characterized by a 10% to 20% decrement in renal plasma flow and GFR. The degree of reduction in GFR and renal plasma flow is modest and probably not of great clinical significance in most cases.

The fractional excretion of sodium has been observed to decrease by up to 20% to 40% in some studies of the acute renal effects of β-blockade. Combined α- and β-blockade with labetalol has shown little effect on renal hemodynamics.

β-Adrenergic antagonist therapy is usually associated with suppression of plasma renin activity.^[215] Long-term effects are, however, less well defined. The degree of partial agonist activity may have a direct effect on renin secretion regardless of the degree of β₁-selectivity of the adrenergic blocking agent, although not all studies have been consistent. The exercise-induced rise in plasma renin activity has been shown to be suppressed by β-blockade.^[216]

Efficacy and Safety of β-Adrenergic Antagonists

β-Adrenergic antagonists are effective therapy for the management of mild to moderate hypertension; however, their use as primary first-line therapy has become controversial.^[217] Largely as a result of data from the ALLHAT study, 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 type diuretic as appropriate initial therapy for most patients with hypertension.^{[49] [218]} The use of β-adrenergic antagonists is suggested largely as secondary therapy for patients with specific co-morbid conditions where β-adrenergic antagonists have been shown to be of specific value such as heart failure, post-myocardial infarction, or angina.^{[190] [219] [220] [221]} Meta-analyses have suggested that compared to therapy with other agents, the reduction in major cardiovascular events associated with β-adrenergic antagonist therapy is not seen in older patients.^[222] β-blockers should not be considered first-line therapy for older patients without specific indications for their use.^{[223] [224]} In younger patients primary β-blocker therapy is associated with protection from major cardiovascular events equivalent to therapy with diuretics. These recommendations are based on numerous randomized clinical trials comparing therapy with β-blockers to other agents. Messerli and colleagues^[225] examined 10 trials involving over 16,000 elderly patients randomly assigned to diuretics or β-blockers, or both. Diuretic therapy was associated with superior reduction in cerebrovascular events, fatal stroke, cardiovascular mortality, and all-cause mortality. In this analysis, β-blockers in elderly patients were effective in reducing cerebrovascular events and heart failure. This meta-analysis was complicated by the concurrent use of diuretics and β-blockers in 52% to 60% of patients.

Recent studies have suggested that β₁-selective blockers may have a slightly greater antihypertensive effect than nonselective agents. This may be in the range of 2 mm Hg to 3 mm Hg. It may be that β₂-blockade in some fashion blunts the antihypertensive effects of β₁-blockade. β₂ partial agonist activity may mediate peripheral vasodilator effects that could contribute to the antihypertensive action. A β₁-selective antagonist with partial agonist activity at the β₁-receptor may result in less hypotensive effect. The magnitude and clinical significance of these differences are unclear.

β-Adrenergic antagonists are useful therapy for patients in all ethnic groups.^{[226] [227] [228] [229]} Data from the Veterans Affairs Cooperative Study Group on antihypertensive agents has suggested that the antihypertensive response to beta-blocker therapy lower in older black patients. Other studies have also suggested that β-adrenergic blockers may be less efficacious in black than in white patients when compared with therapy with calcium channel blockers and diuretics.^{[226] [227] [230]} As a group, the drugs remain useful in black patients with significant reductions in blood pressure, particularly with more highly β₁-selective agents. β-Adrenergic blockers have been used to treat women with hypertension in the third trimester of pregnancy, although birth weights have been observed to be decreased. β-Adrenergic blockers are generally avoided in early pregnancy.^{[231] [232] [233]} Labetalol with α- and β-adrenergic blocking characteristics is, however, commonly used in pregnancy.

β-Adrenergic antagonists have been shown to have important effects on outcome in patients with coronary artery disease.^{[234] [235]} The use of a β-blocker following an acute myocardial infarction has been shown to reduce morbidity and mortality in multiple trials. Despite the clear evidence of benefit, β-blockers have been underutilized in this setting. When prescribed, they are often used in doses considerably lower than those proved to be effective in the clinical trials. In a survey of postinfarction β-blockade usage involving over 200,000 patients it was found that survival benefit from β-blockade was apparent regardless of systolic blood pressure, age, or ejection fraction.^[235]Patients with chronic obstructive pulmonary disease, which is commonly regarded as a contraindication to β-blockade, also had a significant decrease in the risk of death when treated with a β-blocker.^[235] Other studies have shown a 20% reduction in total mortality and a 32% to 50% reduction in sudden death with β-blocker therapy in patients who have suffered a myocardial infarction.^[234] For hypertensive patients with a previous myocardial infarction, β-adrenergic antagonists may be the drugs of choice for antihypertensive therapy.^{[49] [234] [236]}

Patients with coexisting heart failure and hypertension are an appropriate population for use of β-adrenergic antagonists.^{[237] [238]} The Cardiac Insufficiency Bisoprolol Study II demonstrated a 20% reduction in mortality in patients with moderate heart failure randomized to therapy with a β-blocker.^[239] Hospitalizations for heart failure were reduced and sudden death was reduced by 44%. Similar results were observed in a large randomized intervention trial utilizing metoprolol in patients with congestive heart failure. Over the long term, β-adrenergic blockers improve exercise tolerance, left ventricular geometry, and left ventricular structure and reduce myocardial oxygen demand. Whether β-adrenergic blockers have a role in the primary prevention of cardiac disease in hypertensive patients is less clear than their role in patients with preexisting cardiac disease, in whom the benefits are quite clear.^{[240] [241] [242]} Meta-analysis has shown β-blockade to be significantly associated with a reduced risk of stroke and congestive heart failure.^[240]

Agents with β₁-selectivity have a therapeutic advantage over nonselective β-adrenergic antagonists in the treatment of patients with bronchospastic airway disease, peripheral vascular disease, or diabetes mellitus.^{[191] [243]}Bronchoconstriction is mediated in part by β₂-adrenergic receptors in the airways. β-Blockade with nonselective agents can lead to increased airway resistance. This is less likely to occur in agents with β₁-selectivity. β₁-Selectivity is relative, however, and may be less apparent at higher doses. Patients with severe bronchospastic airway disease should not receive β-blockers. In patients with mild to moderate disease, β₁-selective agents may be used cautiously. Symptoms of peripheral vascular disease may be exacerbated by β-blocker therapy. Cold extremity and absent pulses have been described in patients with severe disease. Raynaud phenomenon has been reported with nonselective β-blockade. Blockade of β₂-receptor-mediated skeletal muscle vasodilatation as well as decreased cardiac output may contribute to vascular insufficiency.

Central nervous system symptoms of sedation, sleep disturbance, depression, and visual hallucinations have been reported with β-adrenergic blockade. Placebo-controlled studies have, however, suggested that depression and memory are not affected. Symptoms may be more common with lipid-soluble β-blockers. Sexual dysfunction has been reported but is less of a problem with β₁-selective non-lipid-soluble agents.^[244] Changes in cognitive function, both improvement and worsening, have been reported; however, there is no clear mechanism by which the symptoms may arise. Constipation, diarrhea, nausea, or indigestion may occasionally occur with β-blockers. These symptoms are probably less common with β₁-selective agents.

β-Adrenergic receptors have important effects on glucose metabolism. β-Adrenergic stimulation increases both glycogenolysis and gluconeogenesis from amino acids and glycerol and inhibits glucose utilization in the periphery. These effects result in impaired glucose tolerance and increased blood sugar in some diabetic patients. β-Blockade can result in blunting the effects of epinephrine secretion resulting from hypoglycemia resulting in hypoglycemia unawareness. Nonselective β-adrenergic blockers and to a lesser degree β₁-selective agents have been associated with the rise is serum potassium. Suppression of aldosterone and inhibition of β₂-linked sodium-potassium membrane transport skeletal muscle have been proposed as possible mechanisms. This effect is of limited clinical importance in patients with normal renal function and not taking other medications that may affect serum potassium levels.

β-Adrenergic blocking agents can affect lipid levels. Chronic use of β-adrenergic blockers has been associated with an increase in triglyceride levels and decrease in HDL-cholesterol. β-Blockers with increased β₁-selectivity or with partial agonist activity appear to have less effect on the lipid profile. Nonselective β-blockers without partial agonist activity may decrease HDL-cholesterol up to 20%, and increases in triglycerides of up to 50% have been reported. The effects of β-blockade on lipid metabolism are attributed primarily to modulation of lipoprotein lipase activity. Very low density lipoprotein (VLDL)-cholesterol and triglyceride metabolism is reduced in the setting of unopposed β-adrenergic stimulation of the lipoprotein lipase activity. Decreased VLDL metabolism results in decreases in HDL-cholesterol.

Abrupt withdrawal of β-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, which is a reflection of possible adrenergic receptor up-regulation during chronic sympathetic blockade. Gradual tapering of β-blockers decreases the risk of withdrawal. Withdrawal symptoms have been reported more commonly with abrupt discontinuation of relatively short-acting drugs. Withdrawal symptoms are relatively unusual with longer-acting agents.

Calcium Antagonists

Mechanisms of Action

Calcium antagonists (CAs) remain an important therapeutic class of medications for a variety of cardiovascular disorders.^{[245] [246]} Initially introduced in the 1970s as antianginal agents, they are now widely advocated as first-line therapy for hypertension.^[49] The pharmacologic effects of these drugs are related to their ability to attenuate cellular calcium uptake.^{[247] [248] [249] [250] [251]} CAs do not directly antagonize the effects of calcium, but they inhibit the entry of calcium or its mobilization from intracellular stores.

Calcium channels have binding sites for both activators and antagonists. The voltage-dependent L-type calcium channel is a multimeric complex composed of alpha 1, alpha 2, omega, beta, and gamma subunits.^[252] These channels have different binding sites for the various CAs and are regulated by voltage-dependent as well as receptor-dependent events involving protein phosphorylation and G protein coupling resulting from, for example, β-adrenergic stimulation.^[253] Each class of CA is quantitatively and qualitatively unique; they possess different sensitivity and selectivity for binding pharmacologic receptors as well as the slow calcium channel in various vascular tissues. Even within the dihydropyridine class, there is considerable pharmacologic variability.^[254] 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.

Calcium antagonists represent ideal antihypertensive agents because they uniformly lower peripheral vascular resistance in patients regardless of race, salt sensitivity, age, or comorbid conditions. There are at least three mechanisms whereby they lower blood pressure. First, CAs reduce peripheral vascular resistance by attenuating the calcium-dependent contractions of vascular smooth muscle. The contraction of vascular smooth muscle is dependent on the total cytosolic calcium concentration, which, in turn, is regulated by two distinct mechanisms. Depolarization of vascular smooth muscle tissue is dependent on the inward flux of calcium through voltage-sensitive L-type and T-type calcium channels. Hypertensive patients have an abnormal influx of calcium, promoting increased peripheral vascular resistance.^[247] Calcium released from the sarcoplasmic reticulum in response to extracellular calcium influx is a non-voltage-dependent pathway. Cytosolic calcium binds to calmodulin, initiating a sequence of cellular events that promotes the interaction between actin and myosin, resulting in smooth muscle contraction. Therefore, the importance of the calcium channels is their pivotal role of linking cell membrane electrical activity to biologic responses. Calcium influxes through L-type channels from extracellular sources and intracellular sources are both attenuated by CAs.^{[248] [245]}

Second, CAs decrease vascular responsiveness to AII and the synthesis and secretion of aldosterone.^[250] They also interfere with α₂-adrenergic receptor-mediated vasoconstriction and possibly α₁-adrenergic receptor-mediated vasoconstriction.^{[249] [256]} The maximal vasodilatory response measured by forearm blood flow appears to be inversely related to the patient's plasma renin activity and AII concentration. Thus, it is possible that there is a greater influence of the calcium influx-dependent vasoconstriction in patients with low-renin hypertension, such as blacks, explaining the clinical observation that CAs are often more potent than other agents in such groups.

Finally, the CAs may induce a mild diuresis. It is well known that, in particular, the dihydropyridines reduce preglomerular resistance and maintain or increase the GFR^[251] because of their preferential vasodilatory action on the renal afferent arteriole. Subsequently, decreased tubule sodium reabsorption and improved renal blood flow and natriuresis are observed. The sodium excretion rate tends to correlate with the reduction in blood pressure.

Antihypertensive activity has not uniformly been demonstrated to be secondary to changes in nitric oxide release. The vasorelaxant properties of nifedipine and verapamil appear to be nitric oxide independent, whereas those of amlodipine are partly NO dependent.^{[257] [258]} This effect of amlodipine is thought to be mediated by inhibition of local ACE and increases in vasodilatory bradykinins.^[258]

Class Members

Despite their shared mechanism of action, the CAs are a very heterogeneous group of compounds. They differ with respect to pharmacologic profile, chemical structure, pharmacokinetic profile, tissue specificity, receptor binding, clinical indications, and side effect profile ( Table 45-15 ). Two primary subtypes are distinguished on the basis of their behavior: dihydropyridines and nondihydropyridines. The nondihydropyridines are further divided into two classes: benzo-thiazepines (diltiazem) and diphenylalkylamines (verapamil). The distinctly different pharmacologic effects are summarized in Table 45-15 .

TABLE 45-15 -- Pharmacodynamic Properties of Calcium Antagonists

Drug Generic (Trade) Name	First Dose (Mg)	Usual Daily Dose (Mg)	Maximal Daily Dose (Mg)	Maximal Hypotensive Response (H)	Duration of Hypotensive Response (H)
Diltiazem (Cardizem)	60	60–120 tid/qid	480	2.5–4	8
Diltiazem SR (Cardizem SR)	180	120–240 bid	480	6	12
Diltiazem CD (Cardizem CD)	180	240–280 qd	480	—	24
Diltiazem XR (Dilacor XR)	180	180–480 qd	480	3–6	24
Diltiazem ER (Tiazac)	180	180–480 qd	480	6–10	24
Amlodipine (Norvasc)	5	5–10 qd	10	—	24
Felodipine (Plendil ER)	5	5–10 qd	20	2–5	24
Isradipine (DynaCirc)	2.5	2.5–5 bid	20	2–3	12
Isradipine CR (DynaCirc CR)	5	5–20 qid	20	2	7–18
Nicardipine (Cardene)	20	20–40 tid	120	1–2	8
Nicardipine SR (Cardene SR)	30	30–60 bid	120	2–6	12
Nifedipine (Procardia, Adalat)	10	10–30 tid/qid	120	0.5–1	4–6
Nifedipine GITS (Procardia XL)	30	30–90 qd	120	4–6	24
Nifedipine ER (Adalat CC)	30	30–90 qd	120	2–4	24
Nisoldipine (Sular)	20	20–40 qd	60	—	24
Verapamil (Calan, Isoptin)	80	80–120 tid	480	6–8	8
Verapamil SR (Calan SR, Isoptin SR)	90	90–240 bid	480	—	12–24
Verapamil SR Pellet (Veralan)	120	240–480 qd	480	—	24
Verapamil COER-24 (Covera-HS)	180	180–480 qHS	480	>4–5	24
Mibefradil (Posicor)	50	50–100 qd	100	2–4	17–25

CD, controlled diffusion; COER, controlled-onset extended release; GITS, gastrointestinal therapeutic system; SR, sustained release; XR and ER, extended release.

Although all CAs vasodilate coronary and peripheral arteries, the dihydropyridines are the most potent. Insofar as this subclass of CAs are membrane-active drugs, they exert a greater effect on the peripheral vessels than myocardial cells, which depend less heavily on the external calcium influx than vessels.^[248] Their potent vasodilatory action prompts a rapid compensatory increase in sympathetic nervous activity, mediated by baroreceptor reflexes creating a neutral or positive inotropic stimulus.^[259] Longer-acting dihydropyridines, however, do not appear to activate the sympathetic nervous system.^[260] In contrast, the nondihydropyridines are moderately potent arterial vasodilators but directly decrease AV nodal conduction and have negative inotropic and chronotropic effects, which are not abrogated by the reflex increase in sympathetic tone. Because of their negative inotropic action, they are contraindicated in patients with systolic heart failure. As expected, they are more effective at reduc-ing stress-induced cardiovascular responses than the dihydropyridines.^[261]

A clinically useful classification system for the CAs categorizes them by their duration of action into short-acting and long-acting agents (to be given once daily) ( Table 45-16 ). This schema is helpful because the short-acting agents are no longer recommended for the management of hypertension, because the stimulation of the sympathetic nervous system may predispose patients to angina, myocardial infarction, and stroke.^[262] The long-acting drugs are commonly divided into three generations. First-generation agents such as nifedipine have shorter half-lives and require multiple daily doses. Second-generation agents have been modified into sustained release formulations, requiring once-daily dosing. The third-generation agents have intrinsically longer plasma or receptor half-lives, possibly related to greater lipophilicity.^[263]

TABLE 45-16 -- Pharmacokinetic Properties of Calcium Antagonists

Drug	Oral Absorption (%)	First-Pass Effect	Bioavailability (%)	Peak Blood Level	Elimination Half-Life (H)	Metabolism/Excretion	Protein Binding	Active Metabolites
Diltiazem	98	50%	40	2–3 h	4–6	Liver/feces and urine	77–93	Yes
Diltiazem SR	>80	50%	35	6–11 h	5–7	Liver/feces and urine	77–93	Yes
Diltiazem CD	95	Extensive	35	10–14 h	5–8	Liver/feces and urine	77–93	Yes
Diltiazem XR	95	Extensive	41	4–6 h	5–10	Liver/feces and urine	95	Yes
Diltiazem ER	93	Extensive	40–60	4–6 h	10	Liver/feces and urine	95	Yes
Amlodipine	>90	Minimal	88	6–12h	30–50	Liver/urine	>95	Yes
Felodipine	>90	Extensive	13–18	2.5–5 h	11–16	Liver/urine	>95	No
Isradipine	>90	Extensive	15–25	1–2 h	8	Liver/feces and urine	>95	No
Isradipine CR	>90	Extensive	15–25	7–18 h	—	Liver/feces and urine	>95	No
Nicardipine	>90	Extensive	35	0.5–2 h	8.6	Liver/feces and urine	>95	No
Nicardipine SR	>90	Extensive	30	1–4 h	—	Liver/feces and urine	>95	No
Nifedipine	>90	20–30%	60	<30 min	2	Liver/urine	98	Yes
Nifedepine GITS	>90	25–35%	86	6 h	—	Liver/urine	98	Yes
Nifedipine ER	>90	25–35%	89	2.5–5 h; 6–12	7	Liver/urine	98	Yes
Nisoldipine	>85	Extensive	4–8	6–12 h	10–22	Liver/feces and urine	99	No
Verapamil	>90	70–80%	20–35	1–2 h	2.8–7.4	Liver/feces and urine	85–95	Yes
Verapamil SR	>90	70–80%	20–35	5–6 h	4–12	Liver/feces and urine	85–95	Yes
Verapamil SR pellet	>90	70–80%	20–35	7–9 h	12	Liver/feces and urine	85–95	Yes
Verapamil COER-24/CODAS	>90	70–80%	20–35	11 h	—	Liver/feces and urine	85–95	Yes

CD, controlled-diffusion; COER, controlled-onset extended release; GITS, gastrointestinal therapeutic system; SR, sustained release; XR and ER, extended release.

Benzothiazepines

Diltiazem hydrochloride is the prototype of the benzothiazepine CAs. Diltiazem is 98% absorbed from the gastrointestinal tract, but because of extensive first-pass hepatic metabolism, the bioavailability is only 40% compared with intravenous dosing^[15] (see Tables 45-15 and 45-16 [15] [16]). In vivo, the competitively inhibited liver isoenzyme CYP2D6 is the most important metabolic pathway, which probably accounts for the substantial proportion of drug interactions that occur with diltiazem.^[264] Rates of elimination are slower in elderly persons and those with chronic liver disease but unchanged with renal insufficiency.

Oral forms of diltiazem have been modified to improve delivery and currently include tablets, sustained-release (SR) capsules, controlled-diffusion (CD) capsules, Geomatrix extended-release (XR) capsules, extended-release (ER) capsules, and buccoadhesive formulations.^{[15] [265] [266] [268]} The usual starting dose in tablet form is 180 mg per day in three divided doses and may be titrated to a total dose of 480 mg per day (see Table 45-15 ).

The SR tablet release rate varies with the size of the matrix.^[265] Therefore, the long-acting preparations should not be divided. The usual daily dose is 120 mg to 240 mg, and peak response usually occurs in 6 hours. The CD capsules are composed of two types of diltiazem beads: 40% of the beads release the drug within 12 hours, and the remaining 60% release the drug over the next 12 hours.^[15] The usual daily dose is 240 mg to 480 mg. Approximately 95% of the drug is absorbed, peak plasma levels occur in 10 to 14 hours, and the plasma half-life is 5 to 8 hours but increases with increasing dose. The XR capsules contain a degradable “swellable” controlled-release matrix that slowly releases the drug over 24 hours. The usual daily dose is 180 mg to 480 mg. Ninety-five percent of the drug is absorbed. Onset of action occurs in 3 to 6 hours, and the half-life ranges from 5 to 10 hours. The ER capsules contain prolonged microgranules that dissolve at a constant rate. Peak blood levels are achieved after 4 to 6 hours, and bioavailability is 93%. The usual daily dose is 180 mg to 480 mg, with an elimination half-life of up to 10 hours. A buccoadhesive formulation has been developed to bypass the effects of the hepatic first-pass metabolism and improve bioavailability.^[266] The dissolution and diffusion of the bucco-adhesive hydrophilic matrices of diltiazem polymers provide reliable delivery for up to 10 hours. The optimal use of this vehicle is still under investigation.

Diphenylalkylamine

Verapamil hydrochloride, the oldest CA, is the prototype Diphenylalkylamine derivative. Verapamil inhibits membrane transport of calcium in myocardial cells, particularly the AV node, and smooth muscle cells, rendering it antiarrhythmic, antihypertensive, and a negative inotrope. It is available for oral administration in film-coated tablets containing 40, 80, or 120 mg of racemic verapamil HCl^[15] (see Table 45-15 ). The usual daily dose is 80 mg to 120 mg three times per day. The elimination half-life increases chronic administration and in elderly patients with renal insufficiency (see Table 45-16 ).

The SR caplets are available in scored 120-, 180-, and 240-mg forms. The usual antihypertensive dose is equivalent to the total daily dose of immediate-release tablets and can be given as 240 mg to 480 mg per day. Adequate antihypertensive response may be improved by divided twice-daily dosing.

The SR pellet-filled verapamil capsules are gel-coated capsules with an onset of action of 7 to 9 hours that is not affected by food. Peak concentrations are approximately 65% of those of immediate-release tablets, but the trough concentrations are 30% higher. The usual daily dose is 240 mg to 480 mg.

The controlled-onset, extended-release (COER) and chronotherapeutic oral drug absorption system (CODAS) tablets have unique pharmacologic properties and deliver verapamil 4 to 5 hours after ingestion. A delay coating is inserted between the outer semipermeable membrane and the active inner drug core. As the delay coating expands in the gastrointestinal tract, the pressure causes drug from the inner core to be released through laser-drilled holes in the outer membrane. This makes it ideal for nighttime dosing by providing maximal plasma levels in the early morning hours from 6 am to noon and minimizing nighttime diurnal blood pressure variations.^[267] A promising buccal drug formulation of 40 mg that significantly improves the bioavailability of verapamil is under investigation.^[268]

Of the 13 known metabolites of verapamil, norverapamil is the only one with cardiovascular activity; it has 20% of the potency of the parent compound. Renal excretion accounts for 70% of clearance and occurs within 5 days. The remainder is excreted in the feces. Clearance decreases with increasing age and decreasing weight.^[269] With chronic administration, there is a significant increase in bioavailability, possibly as a result of saturation of hepatic enzymes. Dose adjustment is necessary with hepatic but not renal failure; however, verapamil should be used with caution in patients who ingest large amounts of grapefruit juice or those with renal insufficiency taking concurrent AV nodal blocking agents.^[270]

Dihydropyridines

Nifedipine is a dihydropyridine CA that causes decreased peripheral resistance with no clinically significant depression of myocardial function. It has no tendency to prolong AV conduction, sinus node recovery, or slow sinus rate. This is a result of the reflex sympathetic stimulation triggered by vasodilation. Clinically, there is usually a small increase in heart rate and cardiac index. The labeling for immediate-release nifedipine capsules has been revised to recommend against using this dosage form for the management of chronic hypertension.^[15] In elderly persons, the immediate-release form has been associated with a greater than threefold increase in mortality compared with other antihypertensive agents, including other calcium channel blockers.^[271] In most patients, immediate-release nifedipine causes a modest hypotensive effect that is well tolerated. However, in occasional patients the hypotensive effect is profound and has resulted in myocardial infarction, stroke, and death. This effect appears to be more pronounced in patients taking concomitant β-blockers. Consequently, its use should be reserved for short periods but not in the setting of acute syndromes.^[15] The usual adult dose is 10 mg to 20 mg three times daily and can be titrated weekly (see Table 45-15 ). Nifedipine is rapidly and fully absorbed, and drug levels are detectable within 10 minutes of ingestion. Peak levels are achieved within 30 minutes and the half-life is 2 hours. There is no clinical advantage to bite-and-swallow or bite-and-hold sublingually.

Nifedipine is extensively metabolized in the liver then excreted in the urine. The majority of the population is reported to metabolize the drug rapidly. Nifedipine is 98% protein bound, so the dose should be adjusted in patients with hepatic insufficiency or severe malnutrition.

The extended-release tablets of nifedipine are available in 30-, 60-, and 90-mg doses. These tablets consist of an outer semipermeable membrane surrounding an active drug core. The core is composed of an inner active drug layer surrounded by an osmotically active, inert layer that forces dissolution of the drug core as it swells from gastrointestinal juice absorption. The drug is then slowly and steadily released over 16 to 18 hours. This method of delivery is referred to as the gastrointestinal therapeutic system or GITS formulation. The extended-release form should not be bitten or divided. The time to peak concentration is 6 hours, and plasma levels remain steady for 24 hours. The bioavailability of the extended-release tablet is 86% compared with immediate-release forms, and tolerance does not develop.^[272] Eighty percent of the metabolites are excreted in the urine. The remainder is excreted in the feces with the outer semipermeable membrane shell. The usual adult maintenance dose is 30 to 90 mg/day. Conversion from the immediate-release form to extended-release tablets can be done on an equal milligram basis.

A similar extended-release formulation is composed of a coat and a core (CC).^[15] The outer layer contains a slow-release form of nifedipine; the inner core is a fast-release preparation. Peak concentrations are reached within 2.5 to 5 hours, and there is a second peak after 6 to 12 hours as the inner core is released. When administered in this way, the half-life is extended from 2 to 7 hours. The usual daily dose is 30 mg to 90 mg and should be titrated by 30-mg increments in 7 to 14 days for maximal effect. Because of the unique delivery system, which provides a rapid-release core, peak plasma concentrations are not always reliable.^{[15] [275]} Ingestion of three 30-mg tablets simultaneously, but not two, results in a 29% higher peak plasma concentration than a single 90-mg tablet. Consequently, two tablets may be substituted for 60 mg, but substitution of 30-mg tablets to make 90 mg is not recommended.^{[15] [275]}

Amlodipine besylate is unique among the dihydropyridine CAs. It appears to bind to both dihydropyridine and nondihydropyridine sites to produce peripheral arterial vasodilation without significant activation of the sympathetic nervous system.^[274] The parent compound has substantially slower, but more complete, absorption than others in the class (see Table 45-16 ). After ingestion, amlodipine is almost completely absorbed, peak plasma concentrations are achieved in 6 to 12 hours, and the clinical response can be detected at 24 hours. Mean peak serum levels are linear, age independent, and achieved after 7 to 8 days of chronic dosing.^{[15] [277]} The elimination half-life is long, ranging from 30 to 50 hours, and is prolonged in elderly people.^[275] The long half-life permits once-daily dosing, and the hypotensive response may last up to 5 days.^[276] Ninety percent of amlodipine is metabolized in the liver. Ten percent is excreted unchanged; the metabolites are excreted primarily in the urine, but no dose adjustment is necessary with renal impairment. The minimum effective dose is 2.5 mg, particularly in elderly patients. Most patients require a dose of 5 mg to 10 mg per day.

Benidipine is a long-acting dihydropyridine CA that is available for the management of mild to moderate hypertension. It has several unique mechanisms of action.^[277] It has a high vascular selectivity, and inhibits L-, N-, and T- calcium channels. It is widely available in Japan, and has a proven safety record for use as an antihypertensive agent, renoprotective drug. The usual daily dose is 2 mg to 4 mg once daily, but can be increased to 4 mg twice daily in angina pectoris.

Felodipine is a dihydropyridine CA that is administered in extended-release tablets of 2.5, 5, and 10 mg (see Table 45-15 ).^[15] Felodipine is almost completely absorbed from the gastrointestinal tract with a time to peak concentration of 2 to 5 hours. There is extensive first-pass hepatic metabolism.^[15] Bioavailability is influenced by food. Large meals and the flavo noids in grapefruit juice increase the bioavailability by approximately 50%.^[278] The overall half-life is 11 to 16 hours. Felodipine is metabolized in the liver inactive metabolites, the majority of which are excreted in the urine. The usual daily dose is 2.5 mg to 10 mg, and titration can be instituted at 2-week intervals. The dose should be adjusted for hepatic, but not renal, insufficiency.

Isradipine is a dihydropyridine CA that is effective alone or in combination with other antihypertensive agents for the management of mild to moderate hypertension^[15] (see Table 45-15 ). Isradipine is rapidly and almost completely absorbed after oral administration. Extensive first-pass hepatic metabolism reduces bioavailability to less than 25%. The hypotensive effect peaks at 2 to 3 hours for the regular release form. The drug is active for 12 hours; however, the full antihypertensive response does not occur until 14 days. The usual daily dose is 2.5 mg to 5 mg two to three times daily. The onset of action of the SR formulation is achieved in 2 hours and lasts for 7 to 18 hours. The usual daily dose of the CR tablet is 5 mg to 20 mg. Isradipine is extensively protein bound. The elimination half-life is biphasic with a terminal half-life of 8 hours. Dosage adjustment is unnecessary in renal or liver failure.

Manidipine is a third-generation dihydropyridine CA structurally related to nifedipine.^{[281] [282] [283]} The usual adult dose is 10 mg to 20 mg once daily. Dosage should be adjusted at 2-week intervals. Manidipine is highly protein bound and extensively metabolized in the liver. Metabolism is impaired by grapefruit juice.^[282] Sixty-three percent of the drug is excreted in the feces. The peak plasma concentration occurs after 2 to 3.5 hours, with an elimination half-life of 5 to 8 hours. Dose adjustment is not necessary in renal failure.

Nicardipine hydrochloride is a dihydropyridine CA available as 20- and 40-mg immediate-release gelatin capsules or 30-, 45-, and 60-mg SR capsules.^[15] The usual daily dose is 20 mg to 40 mg three times daily for the immediate-release form and 30 mg to 60 mg twice daily for the SR preparation. When converting to the SR form, the previous daily total of immediate-release drug should be administered on a twice-daily regimen. Titration should be instituted no sooner than 3 days. Nicardipine is well absorbed orally but has only 35% systemic bioavailability because of extensive first-pass hepatic metabolism. The time to peak concentration is 30 minutes to 2 hours for immediate-release capsules and 1 to 4 hours for SR forms. The elimination half-life is 8.6 hours. Nicardipine is 100% oxidized in the liver to inactive pyridine metabolites. There is no evidence of microsomal enzyme induction. Metabolites are excreted primarily in the urine and feces. The parent compound is not dialyzable. Dose adjustments are necessary in hepatic, but not renal, insufficiency.

Nisoldipine is a dihydropyridine CA formulated as extended-release tablets of 10, 20, 30, and 40 mg (see Table 45-15 ).^[15] The initial starting dose is 20 mg and the usual maintenance dose is 20 mg to 40 mg given once daily, which can be titrated at weekly intervals. Bioavailability of nisoldipine drug is low and variable (4% to 8%). The coat-core design allows a full 24-hour effect after oral administration. The drug reaches therapeutic concentrations in 6 to 12 hours, and absorption is slowed by high-fat meals. The elimination half-life ranges from 10 to 22 hours. Nisoldipine is metabolized in the liver and intestine. Variable hepatic blood flow induced by the drug probably contributes to its pharmacokinetic variability. The majority of the metabolites are excreted in the urine, the remainder in the feces. Dose adjustments are necessary with hepatic, but not renal, impairment.

Lacidipine is a second-generation dihydropyridine CA available in tablet form. It is reported to be unusually potent and long acting, possibly because it diffuses deeper into lipid bilayer membranes. A unique attribute of this drug appears to be its greater vascular selectivity, but the clinical relevance of this remains unclear.^[283] The usual dose is 4 mg to 6 mg once daily and should be titrated at 2- to 4-week intervals.^[284] The duration of action is 12 to 24 hours. The elimination half-life is 12 to 19 hours. The parent compound is converted 100% by the liver into inactive fragments that are excreted primarily in the feces (70%) and the kidney. Dose adjustment is necessary in elderly persons and in patients with hepatic, but not renal, impairment.

Lercanidipine is a novel dihydropyridine CA whose molecular design imparts greater solubility within the arterial cellular membrane bilayer, conferring a 10-fold higher vascular selectivity than that of amlodipine.^[284] In contrast to amlodipine, it has a relatively short half-life but a long-lasting effect at the receptor and membrane level and is associated with significantly less peripheral edema.^[285] It is administered at a starting dose of 10 mg and increased to 20 mg as needed. It has a gradual onset of action and the effects last for 24 hours.^[286] Lercanidipine is unique among dihydropyridines in that it also appears to dilate the efferent renal arteriole.^[287]

Class Renal Effects

The potential benefits of CAs in acute and chronic kidney disease have been well described. There are multiple mechanisms whereby they alter or protect renal function, notably as natriuretics, vasodilators, and antiproteinuric agents ( Table 45-17 ). All CAs exert natriuretic and diuretic effects. Experimental studies and studies in humans with hypertension indicate that the increase in sodium excretion is, in part, independent of vasodilatory action or changes in GFR, renal blood flow, or filtration fraction. This is probably the result of changes in renal sodium handling that can potentiate the antihypertensive vascular effect. In normal subjects, CAs acutely increase sodium excretion, frequently in the absence of changes in blood pressure. In hypertensive subjects, acute administration of CAs uniformly increases sodium excretion 1.1- to 3.4-fold, the magnitude of which is not related to the decrement in blood pressure.^[288]

TABLE 45-17 -- Renal Effects of Calcium Antagonists

Class	Na Excretion	Glomerular Filtration Rate	Filtration Fraction	Renal Blood Flow	Renal Vascular Resistance	Proteinuria
Dihydropyridines	↑	↑ to ↔	—	↑ to ↔	↓	↑
Diltiazem	↑	↑ to ↔	—	↑ to ↔	↓	—↓
Verapamil	↑	↑ to ↔	—	↑ to ↔	↓	↑

The natriuretic effect appears to persist in the long term. Chronic administration of CAs to hypertensive patients results in a cumulative sodium deficit that is abruptly reversed with discontinuation of the drug. Natriuresis frequently occurs 3 to 6 hours after the morning dose,^[289] and the net negative sodium balance levels off after the first 2 to 3 days of administration but persists for the duration of therapy.^[290] There are no significant changes in long-term body weight, potassium, urea nitrogen, catecholamines, or GFR. Moreover, stimulation of renin release and aldosterone does not occur to an appreciable degree. It has been postulated that the natriuresis induced by CAs increases distal sodium delivery to the macula densa, suppressing renin release. Because AII mediates aldosterone synthesis by way of cytosolic calcium messengers, CAs blunt this response as well.^[291]

The mechanism whereby CAs induce natriuresis appears to be direct inhibition of renal tubule sodium and water absorption. Dihydropyridines increase urinary flow rate and sodium excretion without changing the filtered water and sodium load. Studies suggest that CAs may diminish sodium uptake at the amiloride-sensitive sodium channels.^[292] Inhibition of water reabsorption occurs distal to the late distal tubule. Proximal tubule sodium reabsorption may be inhibited by higher doses. One possible mediator of this effect is atrial natriuretic peptide. In human studies, CAs augment atrial natriuretic peptide release and potentiate its action at the level of the kidney. Other potential mediators are under investigation. What magnitude the natriuretic effects contribute to the antihypertensive response is unknown, but in contrast to other vasodilators, the changes attenuate the expected adaptive changes in sodium handling.

The renal hemodynamic effects of CAs are variable and depend primarily on which vasoconstrictors modulate renal vascular tone.^[293] Experimentally, CAs improve GFR in the presence of the vasoconstrictors norepinephrine and AII and others by preferentially attenuating afferent arteriolar resistance.^[294] The efferent arteriole appears to be refractory to these vasodilatory effects. Patients with primary hypertension appear to be more sensitive to the renal hemodynamic effects of CAs than normotensive subjects, and this effect is more pronounced with advancing kidney disease.^[295] 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. Chronic administration is not associated with significant changes in renal hemodynamics. The response is maximal in the presence of AII, which selectively causes postglomerular vasoconstriction. Clinically significant changes are counteracted by the reduction in renal perfusion pressure coincident with reduction of blood pressure.

The long-term effects of CAs on renal function are variable.^{[298] [299]} In hypertensive patients, the effects on renal hemodynamics vary. Some patients exhibit no change in GFR, whereas others have an exaggerated increase in GFR and renal plasma flow.^[293] Even normotensive patients with a family history of hypertension have an exaggerated hemodynamic response.^[298]

The antiproteinuric effects of CAs also vary with respect to the class of drug and the level of blood pressure reduction achieved.^[299] Some dihydropyridines increase protein excretion by up to 40%. It is not clear whether this is a result of hemodynamic vasodilation at the afferent arteriole resulting in increased glomerular capillary pressure, (as CAs directly impair renal autoregulation) changes in glomerular basement membrane permeability, or increased intrarenal AII. In contrast, felodipine, diltiazem, verapamil, and others do not appear to have this effect and may lower protein excretion, possibly by also decreasing efferent arteriolar tone and glomerular pressure.^[300] The clinical implications remain to be determined.

Large clinical trials underscore the controversy. In blacks with hypertension and mild to moderate renal insufficiency with proteinuria greater than 1 g per day, renoprotection with an ACE inhibitor far exceeded any effect of the dihydropyridine calcium channel blocker amlodipine. In the latter group of patients, renal function deteriorated.^[301] This effect was independent of blood pressure reduction and was more evident in proteinuric patients; it was also suggestive in patients with baseline proteinuria less than 300 mg per day. Hypertensive patients with diabetic nephropathy also fared considerably worse with amlodipine therapy than with an ARB.^[140] Patients experienced higher rates of progression of renal disease and all-cause mortality in the amlodipine and placebo group. This effect was also independent of blood pressure levels achieved. However, it should be emphasized that coadministration of a dihydropyridine with an ARB does not abrogate the ARB's protective effect on kidney function.^[139] It is postulated that selective dilation of the afferent arteriole favors an increase in glomerular capillary pressure that perpetuates renal disease progression.

Calcium antagonists have many nonhemodynamic effects that may also afford renoprotection ( Table 45-18 ).^[302] In addition to lowering blood pressure, they act as free radical scavengers; retard renal growth and kidney weight^{[305] [306]}; reduce the entrapment of macromolecules in the mesangium; attenuate the mitogenic actions of platelet-derived growth factor and platelet-activating factor^[304]; block mitochondrial overload of calcium^[305]; decrease lipid peroxidation; decrease glomerular basement membrane thickness; augment the antioxidant activities of superoxide dismutase, catalase, and glutathione peroxidase^[306]; inhibit metalloproteinase-1 and collagenolytic activity; suppress the expression of the angiogenic growth factors and suppress selections that are important for leukocyte adhesion to the vascular endothelium,^[307] vascular endothelial growth factor, fibroblast growth fa-ctor, TGF-b, and endothelial nitric oxide synthase^{[310] [311]}; prevent renal cortical remodeling and scarring improve fibrinolysis; and improve endothelial dysfunction (see Table 45-18 ).^{[295] [312] [313] [314]}

TABLE 45-18 -- Renal Protective Mechanisms of Calcium Antagonists

↓ Blood pressure

↓ Proteinuria

Free radical scavengers

↓ Kidney growth

↓ Mesangial molecule entrapment

Attenuate antigenic PDGF and PAF

Block mitochondrial calcium overload

↓ Lipid peroxidation

↓ GBM thickness

Augment antioxidant effects of SOD/catalase and GTP

Inhibit collagenic activity

Suppress angiogenic growth factors: VEGF, bFGF, TGF-β, and eNOS

Prevent renal cortical remodeling

Ameliorate cyclosporine toxicity

Block thromboxane- and endothelin cyclosporine-induced vasoconstriction

bFGF, basic fibroblast growth factor; eNOS, endothelial nitric oxide synthase; GTP, glutathione peroxidase; GBM, glomerular basement membrane; PAF, platelet-activating factor; PDGF, platelet-derived growth factor; SOD, super-oxide dismutase; TGF-β, transforming growth factor β; VEGF, vascular endothelial growth factor.

Because of their renal hemodynamic effects and inhibition of calcium-mediated injury, the CAs have the ability to attenuate various types of kidney damage, including radiocontrast-induced nephropathy and hypoperfusion ischemic injury such as occurs during cardiac surgery.^{[315] [316]} In experimental models, pretreatment with CA variably preserved GFR and renal blood flow.^[315] The clinical effectiveness of this class of drugs in these settings requires further evaluation.

Calcium antagonists represent an important treatment option for renal transplant recipients. Administration of CAs in the renal allograft perfusate and to renal allograft recipients reduces initial graft nonfunction by attenuating ischemic and reperfusion injury^[316] and preserves long-term renal function by protecting against cyclosporine nephrotoxicity and by contributing to immunomodulation.^{[319] [320]} Cyclosporine causes direct tubule injury and induces intrarenal vasoconstriction. The thromboxane- and endothelin-induced vasoconstriction of the afferent arteriole stimulated by cyclosporine is reversed by CA.^[319]

Class Efficacy and Safety

All CAs are considered initial antihypertensive agents and appear to be equally efficacious and safe.^{[49] [322]} CAs are particularly effective in stroke prevention.^{[223] [323]} Approximately 70% to 80% of patients in stage I and II respond to monotherapy. Up to 50% of unselected patients respond to monotherapy. In contrast to other vasodilators, the CAs attenuate the reflex increase of neurohormonal activity that accompanies reduction in blood pressure, and in the long term they inhibit or do not change sympathetic activity.^{[276] [324]} The long-acting agents produce sustained systolic and diastolic blood pressure reductions of 16 mm Hg to 28 mm Hg and 14 mm Hg to 17 mm Hg, respectively, with no appreciable development of tolerance.

The CAs are effective in young, middle-aged, and elderly patients with “white coat,” mild, moderate, or severe hypertension.^{[325] [326] [327] [328]} Their efficacy may be determined by genetic polymorphisms.^[327] CAs are equally efficacious in men and women, patients with a high or low plasma renin activity regardless of dietary salt intake, and black, white, and Hispanic patients.^[328] Their effect is diminished in smokers.^[329] They are effective and safe in patients with hypertension and coronary artery disease^[330] and ESRD.^[331] CAs have also been demonstrated to reduce adverse cardiovascular events and slow the progression of atherosclerosis in normotensive patients with CAD.^[332]

Among the different classes, the dihydropyridines appear to be the most powerful at reducing blood pressure but may also be associated with greater activation of baroreceptor reflexes.^[333] Dihydropyridines induce a shift in sympathovagal balance that favors sympathetic predominance compared with nondihydropyridines.^[261] In general, however, when compared with other vasodilators, CAs attenuate the reflex increase in sympathetic activity (increased heart rate, cardiac index, and plasma norepinephrine levels and renin activity).

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 ( Table 45-19 ). The second- and third-generation CAs consist of pharmacologically manipulated formulations whose half-lives are progressively longer.^[263]

TABLE 45-19 -- Hemodynamic Effects of Calcium Antagonists

	Arteriolar Dilation	Coronary Dilation	Cardiac Afterload	Cardiac Contractility	Myocardial O₂Demand	Cardiac Output	AV Conduction	CA Automaticity	Heart Rate Acute/Chronic	Activation of Baroreceptor Reflexes
Dihydropyridines	↑↑↑	↑↑↑	↓↓	↔	↓	↑↔	↔	↔	↑/↑	↑↔
Diltiazem	↑↑	↑↑↑	↓	↓	↓	↔	↓	↓↓	↓/↓↔	↔
Verapamil	↑↑	↑↑	↓	↓↓	↓	↔	↓↓	↓	↓/↓↔	↔

Calcium antagonists are contraindicated in patients with severely depressed left ventricular function (except perhaps amlodipine or felodipine), hypotension, sick sinus syndrome (unless a pacemaker is in place), second- or third-degree heart block, and atrial arrhythmias associated with an accessory pathway.^[15] The nardihydropyridines have been associated with heart block in hypercalcemic patients.^[334] They should not be used as first-line antihypertensive agents in patients with heart failure, after myocardial infarction, those with unstable angina, or blacks with proteinuria greater than 300 mg per day.^[301] 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.^[335]

The CAs are generally well tolerated and are not associated with significant impairments in glycemic control or sexual dysfunction. The rapid antihypertensive action of CAs may encourage compliance. Orthostatic changes do not occur because venoconstriction remains intact. Side effects are usually transient and are the direct result of vasodilation. Hypotension is most common with intravenous administration. The most common side effect of the dihydropyridines is peripheral edema. It is dose related and thought to be the result of uncompensated precapillary vasodilation, causing increased intracapillary hydrostatic pressure. The edema is not responsive to diuretics but improves or resolves with the addition of an ACE inhibitor, which preferentially vasodilates postcapillary beds and reduces intracapillary hydrostatic pressure.^[318] Other side effects related to vasodilation include headache, nausea, dizziness, and flushing, and occur more commonly in women. The nondihydropyridines verapamil and isradipine more commonly cause constipation and nausea. The gastrointestinal effects are directly related to inhibition of calcium-dependent smooth muscle contraction: reduced peristalsis and relaxation of the lower esophageal sphincter. Another common side effect of the dihydropyridines is gingival hyperplasia, which is exacerbated in patients taking concomitant cyclosporine. Dihydropyridines cause gingival inflammatory B cell infiltrates stimulated by bacterial plaque, immunoglobulins, and folic acid, creating growth of the gingiva.^[336] This can be controlled with regular periodontal treatment and reversed with discontinuation of the drug.^[337]

The CAs are notable among antihypertensive agents because of their metabolic neutrality. Insofar as calcium influx across beta cell membranes helps to regulate insulin release, CAs might predispose to low insulin levels. At usual therapeutic levels, CAs have no effect on serum glucose, insulin secretion, or insulin sensitivity in nondiabetic and diabetic subjects.^[338] They do not increase triglycerides or cholesterol and do not reduce HDL-cholesterol. CAs do not precipitate hyponatremia, hyper- or hypokalemia, or hyperuricemia. Therefore, they are ideal agents for patients with dysmetabolic syndromes or diabetes. Initial trials indicated that CAs were more efficacious in blacks and elderly persons or those with low-renin hypertension. However, they have been demonstrated to be equally efficacious in young and old patients, black and white patients, diabetic patients, and obese patients. In elderly patients with hypertension or coronary artery disease, verapamil may cause more bradycardia than other agents, but second- or third-degree heart block is not seen.^[330] In elderly patients receiving chronic ACE inhibitor therapy, the addition of verapamil can reverse ACE-induced increases in creatinine safely without further lowering blood pressure.^[339] CAs are safe and effective in elderly patients with stage I isolated systolic hypertension and can reduce progression to higher stages of hypertension.^[340] The latter may be a result of their ability to correct altered arteriole resistance vessels and endothelial function.^[341]

Properties beyond their antihypertensive actions make the CAs particularly useful in certain clinical situations. CAs not only lower arterial pressure but also have variable effects on cardiac function. All CAs are vasodilators and increase coronary blood flow. With the exception of the short-acting dihydropyridines, most CAs reduce heart rate, improve myocardial oxygen demand, improve ventricular filling, diminish ventricular arrhythmias, reduce myocardial ischemia, and conserve contractility,^{[344] [345]} making them ideal for patients with angina or diastolic dysfunction.^[330] Acutely, they improve diastolic relaxation; administered chronically, they reduce left ventricular wall thickness,^[344] may prevent the development of hypertrophy, and improve arterial compliance.^{[347] [348] [349]} This may be crucial in hypertensive patients insofar as LVH is one of the strongest risk predictors of cardiovascular morbidity and mortality.^[348] Verapamil may also be used for secondary cardioprotection to reduce reinfarction rates in patients intolerant of β-blockers, unless they have concomitant heart failure,^[349] and in patients with chronic headaches.^[350] The blood pressure-independent inhibition of atherogenesis by CAs may be another indication to use a CA, particularly in high-risk patients such as those with diabetes and ESRD.^{[353] [354]}

In general, the antihypertensive effects of CAs are enhanced more in combination with β-blockers or ACE inhibitors than with diuretics.^{[355] [356]} Perhaps this reflects the fact that CAs have intrinsic diuretic activity that cannot be further mobilized. In combination with ACE inhibitors, response rates approach 70% in patients with stage 1 to 3 hypertension.^[345] It is theorized that this particular combination (dihydropyridines and an ACE inhibitor), maximizes pre- and postcapillary vasodilation to lower peripheral vascular resistance.

The combination of dihydropyridine CA with β-blockers is efficacious and even desirable in selected patients. The CAs have the potential to blunt the adverse effects associated with β-blockade, such as vasoconstriction, and the β-blockers have the ability to attenuate the increased sympathetic stimulation induced by CAs. Concomitant therapy with β-blockers and nondihydropyridine CAs is potentially more dangerous, as they may have additive effects on suppressing heart rate, AV node conduction, and cardiac contractility ( Table 45-20 ). This combination may be particularly dangerous in patients with ESRD.

TABLE 45-20 -- Drug-Drug Interactions with Calcium Antagonists

Calcium Antagonist	Interacting Drug	Result
Verapamil	Digoxin	Digoxin levels by 50%–90%
Diltiazem	Digozin	Digoxin level by 40%
Verapamil	β-Blockers	AV nodal blockade, hypotension, bradycardia, asystole
Verapamil, diltiazem	Cyclosporine/tacrolimus and sirolimus	Cyclosporine levels by 25%–100%
Verapamil, diltiazem	Cimetidine	Verapamil and diltiazem levels by decreased metabolism
Verapamil	Rifampin/phenytoin	Verapamil levels by enzyme induction
Dihydropyridines	Amiodarone	Exacerbate sick sinus syndrome and AV nodal blockade
Dihydropyridines	α-Blockers	Excessive hypotension
Dihydropyridines	Propranolol	Increased propranolol levels
Dihydropyridines	Cimetidine	Increased area under the curve and plasma levels of calcium antagonist
Nicardipine	Cyclosporine	Cyclosporine levels by 40%–50%
Amlodipine	Cyclosporine	Cyclosporine levels by 10%
Felodipine	Flavinoids	Bioavailability by 50%
Diltiazem	Methylprednisone	Methylprednisone 0.5-fold
Nifedipine	Diltiazem	Nifedipine levels 100%–200%

Drug interactions are not uncommon (see Table 45-20 ). Concurrent use of a CA and amiodarone exacerbates sick sinus syndrome and AV block. Diltiazem, verapamil, and nicardipine have been shown to increase cyclosporine, including the microemulsion formulation, tacrolimus, and sirolimus levels by 25% to 100%.^[356] This interaction may be clinically useful to reduce the dosage and cost associated with immunosuppressive therapy. Frequent monitoring of calcineurin inhibitor levels is recommended. In contrast, nifedipine and isradipine have no effect on these concentra tions and can be used safely. Diltiazem is a potent inhibitor of CYP3A4, which is responsible for metabolism of methylprednisolone. Coadministration of diltiazem and methylprednisolone resulted in a greater than 2.5-fold increase in the steroid blood level and enhanced adrenal suppressive responses.^[357] Coadministration of diltiazem also increased nifedipine levels by 100% to 200%.^[358] This combination has additive antihypertensive efficacy and appears to be safe.^[359] Concomitant administration of CAs with the digitalis glycosides resulted in up to a 50% increase in serum digoxin concentrations, due to reduced renal clearance of digoxin. This appears to be a dose-dependent effect.^[360]

Several issues regarding the inherent safety of CAs have come under scrutiny. CAs may be associated with an increased risk of gastrointestinal hemorrhage, particularly in elderly persons.^[361] Diltiazem inhibits platelet aggregation in vitro, but the clinical relevance of this finding has not been substantiated. Nonetheless, it is prudent to use caution when co-administering CAs with NSAIDs, as NSAIDs may exacerbate the risk of bleeding and may antagonize the antihypertensive effects of CAs.^{[364] [365]} A similar concern regarding the possible relationship between CAs and cancer has not been substantiated.^[364]

The safety of CAs in treating cardiovascular diseases is no longer controversial. There is clear evidence that CAs reduce cardiovascular mortality and morbidity, particularly stroke; however, short-acting agents such as nifedipine have been associated with a small increased risk for myocardial infarction in meta-analyses^{[240] [367]} when compared with other agents. It is speculated that the disadvantageous activation of the renin-angiotensin and sympathetic nervous system induced by the short-acting agents may predispose to myocardial ischemia. 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 management of hypertension.

Central Adrenergic Agonists

Mechanisms of Action

Central adrenergic agonists act by crossing the blood-brain barrier and have a direct agonist effect on α₂-adrenergic receptors located in the midbrain and brainstem.^{[83] [368] [369] [370]} Binding to the more recently described I1-imidazoline receptors within the brain may also play a role in the inhibition of central sympathetic output.^{[369] [370] [371] [372] [373] [374] [375] [376] [377]} Drugs in this class bind to either the α-adrenergic receptors or the I1-imidazoline receptors with some degree of specificity ( Table 45-21 ). Moxonidine and rilmenidine have a 30-fold greater specificity for the I1-imidazoline receptor than the α-2 receptor. Clonidine, by contrast exhibits a fourfold greater specificity for the I1-imidazoline receptor compared to the α-2 receptor. The central side effects are felt to be largely related to α-2 binding. In addition to decreasing total sympathetic outflow, binding to these receptors results in increases in vagal activity. A reduction in catecholamine release and turnover as evidenced by decreased biochemical markers of noradrenergic activity such as plasma norepinephrine levels correlated with the magnitude of blood pressure decreases.

TABLE 45-21 -- Receptor Binding of Centrally Acting Antihypertensives

Drug	Receptor
Clonidine	α₂ + I₁
α-Methyldopa	α₂
Guanabenz	α₂
Guanfacine	α₂
Rilmenidine	I₁ > α₂
Moxonidine	I₁ > α₂

α₂, α₂-adrenergic receptor; I1, imidazole receptor.

Stimulation of both receptors types is probably mediated through the same neuronal pathways.^[375] The classical α₂-receptor agonists such as clonidine and α-methyldopa (acting through its active metabolite α-methylnoradrenaline) results in vasodilatation in the resistance vessels and hence a reduction in peripheral vascular resistance. As a result, blood pressure is reduced. In spite of the vasodilator action, reflex tachycardia generally does not occur, probably as a result of peripheral sympathetic inhibition.

Studies have shown that the selective I₁ receptor agonists moxonidine and rilmenidine are predominantly arterial vasodilators, resulting in a reduction in peripheral vascular resistance.^{[373] [374]} Moxonidine is associated with a reduction in plasma renin activity. The central α₂-adrenergic agonists may also stimulate peripheral α₂-adrenergic receptors. This effect predominates at high drug concentrations. These receptors mediate vasoconstriction, and this may result in a paradoxical increase in blood pressure.^[366] Overall, these drugs generally result in a decrease in peripheral vascular resistance, a slowing of heart rate, and either no change or a mild decrease in cardiac output.^{[376] [378]} Orthostatic hypotension is generally not a feature of these drugs. The pharmacokinetic and pharmacodynamic properties of these drugs are shown in Tables 45-22 and 45-23 [22] [23].

TABLE 45-22 -- Pharmacokinetic Properties of Central Adrenergic Agonists

Drug	Bioavailability (%)	Affected by Food	Peak Blood Level (H)	Elimination Half-Life (H)	Metabolism	*Excretion^[]**	Active Metabolites
Clonidine	50	—	—	7–16	L	F (30–50)	Methyldopao-sulfite
						U (24)
α-Methyldopa	65–96	—	1.5–5	6–23	L	F (22)	—
						U (65)
Guanabenz	75	—	2–5	7–10	L	F (16)	—
Guanfacine	80	—	1.4	17	L	U (40–75)	—
Rilmenidine	80–90	No	0.5	2–3	L	U (90)	—
Moxonidine	100	No	2	5.5	L	U (90)	—

F, feces; L, liver; U, urine.

^*	Excretion values in parentheses represent percentages.

TABLE 45-23 -- Pharmacodynamic Properties of Central Adrenergic Agonists

Drug	Initial Dose (Mg)	Usual Dose (Mg)	Maximum Dose (Mg)	Interval	Peak Response (H)	Duration of Response (H)
α-Methyldopa	250	250–300	3000	bid-qid	3–6	24–48
Clonidine	0.1	0.2–0.6	1.2	bid	2–4	6–10
Guanabenz	4	16–32	96	bid	2–4	6–8
Guanfacine	1	1–3	6	qd-bid	6	24
Moxonidine	0.2–0.3	0.2–0.4	0.6	bid	1.5–4	48–72
Rilmenidine	1	1–2	—	qd-bid	1–2	10–12

Class Members

Methyldopa is a methyl-substituted amino acid that is active after conversion to an active metabolite.^[366] This active metabolite, α-methylnorepinephrine, accumulates in the central nervous system and is selective for α₂-adrenergic receptors. The initial dose of methyldopa in hypertension is 250 mg two to three times daily. It may be increased at intervals of not less than 2 days until a therapeutic response is achieved. The usual maintenance dose is 500 mg to 2 g in 2 to 4 doses. Maximum recommended daily dose is 3 g. Initial response occurs within 3 to 6 hours after a dose. Peak response is at 6 to 9 hours. The drug is approximately 50% metabolized by the liver. Drug half-life is increased in renal failure. Excretion in the urine is largely in the form of an inactive metabolite. The dosing interval should be increased to every 12 to 24 hours in patients with severe renal failure. Approximately 60% of methyldopa is removed with hemodialysis. A supplemental dose is recommended after a dialysis treatment.

Clonidine is a central-acting α-adrenergic agonist.^{[368] [371] [372]} The usual oral dose is 0.1 mg twice daily adjusted as necessary in 0.1- to 0.2-mg increments. Usual maintenance dose is 0.2 to 0.6 mg once daily in two divided doses. Total doses above 1.2 mg daily are usually not associated with a greater effect. The onset of activity is 30 to 60 minutes after an oral dose. Peak antihypertensive activity occurs within 2 to 4 hours. The duration of the antihypertensive effect is 6 to 10 hours. The half-life of the absorbed drug is 6 to 23 hours. Hepatic metabolism to inactive metabolites is followed by renal excretion. Transdermal patches are available and may be applied on a once-weekly basis. The drug half-life with the transdermal patch is approximately 20 hours after removal of the patch. With a transdermal patch, steady-state drug levels are reached within approximately 3 days. Dosage adjustment is not needed for patients with any degree of renal dysfunction including severe renal failure. Approximately 5% of clonidine body stores are removed after a 5-hour dialysis treatment.

Guanabenz is an orally active central α₂-adrenergic agonist.^[366] The usual starting dose for management of hypertension is 4 mg twice daily. Dosages may be increased to 4 to 8 mg/day at 1- to 2-week intervals. Doses as high as 96 mg/day have been used. The usual onset of antihypertensive activity occurs within 60 minutes and the activity lasts approximately 10 to 12 hours. The drug is highly protein bound and extensively metabolized. Less than 1% of unchanged drug is excreted in urine. The half-life of the drug is 7 to 10 hours. Dose adjustment in renal failure is not necessary. It appears that dose reductions may be necessary in patients with severe hepatic insufficiency. Because of extensive protein binding, drug removal by dialysis or peritoneal dialysis is minimal.

Guanfacine is a centrally acting antihypertensive drug with actions similar to those of clonidine.^[366] Effective doses are 1 mg to 3 mg daily. Peak levels are noted between 1 and 4 hours. The drug half-life is approximately 17 hours. The drug is 70% protein bound. The drug is metabolized in the liver, with renal excretion of 40% to 75% as unchanged drug. Limited data are available on dosing in renal failure; however, dosage adjustments do not appear warranted.

Moxonidine is a central imidazole I₁ and α₂-receptor agonist.^{[372] [379] [380]} Serum concentration peaks are reached within 30 to 180 minutes. Ninety percent of the dose is excreted through the urine within 24 hours. Fifty percent of this is as unchanged drug. The average half-life is 2.2 to 2.3 hours. For the management of hypertension the starting dose is 0.2 mg to 0.4 mg per day. The dose may be increased after several weeks to 0.2 mg to 0.3 mg twice daily. The maximum daily dose is 0.6 mg. Selectivity for the I1-imidazoline receptor results in fewer central side effects such as dry mouth and sedation compared with those of clonidine. Drug clearance is delayed in renal impairment. Single doses of 0.2 mg and a maximum daily dose of 0.4 mg should not be exceeded in patients with renal failure.

Rilmenidine is a centrally acting imidazole receptor and α₂-adrenergic receptor agonist.^{[372] [375] [381] [382] [383] [384] [385]} Rilmenidine binds preferentially to central I1-imidazoline receptors in the brainstem. At higher doses, rilmenidine can bind and activate central α₂-adrenergic receptors. Antihypertensive effects occur within 1 hour after a single 1-mg dose. The duration of action is 10 to 12 hours. Peak concentration after oral dosing is at approximately 2 hours. Steady-state plasma levels are reached by day 3. Rilmenidine is eliminated primarily unchanged in the urine. In chronic renal failure, clearance of the drug is decreased. The usual oral dose is 1 mg once or twice daily. Dose reductions are required for patients with renal dysfunction. Patients with advanced renal disease should have the dose decreased to 1 mg every other day.

Renal Effects of Central α₂-Adrenergic Agonists

Central α₂ and I1-imidazoline receptor agonists have little if any clinically important effect on renal plasma flow, GFR, or the renin-angiotensin-aldosterone axis (RAAS). The fractional excretion of sodium is unchanged. Body fluid composition and weight are not altered. A water diuresis may be associated with guanabenz, through inhibition of central release of vasopressin or altered renal responsiveness to vasopressin. These agents may result in decreased renal vascular resistance mediated by a decrease in preglomerular capillary resistance related to decreased levels of circulating catecholamines.

Antihypertensive Efficacy and Safety

The antihypertensive efficacy of this class of drugs has been confirmed in large numbers of patients. These agents have been shown to be effective monotherapy for hypertension.^[366] Additive effects are associated with addition of a diuretic. They have been shown to be effective in both young and old patients, and the effects do not differ in racial groups. Moxonidine and rilmenidine have been associated with decreased plasma glucose levels and may improve insulin sensitivity. They may also decrease in total cholesterol, LDL, and triglycerides.^{[386] [387] [388]} These agents may pay a role in management of the metabolic syndrome. These agents may also be of benefit in patients with congestive heart failure. Treatment with rilmenidine and moxonidine has been shown to reverse LVH and improve arterial compliance. This effect was associated with a reduction in plasma atrial natriuretic peptide levels. Stimulation of α₂-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 α₂-adrenergic activation is dry mouth related to a decrease in salivary flow. This is due to a centrally mediated inhibition of cholinergic transmission. Clonidine in high doses may precipitate a paradoxical hypertensive response related to stimulation of postsynaptic vascular α₂-adrenergic receptors.^[366] Methyldopa has been associated with a positive direct Coombs test with or without hemolytic anemia.^[366] The α₂-adrenergic agonists are associated with sexual dysfunction and may produce gynecomastia in men and galactorrhea in both men and women.

Abrupt cessation of α₂-adrenergic blockers may result in rebound hypertension. This occurs 18 to 36 hours after cessation of short-acting agents.^[387] Patients may have tachycardia, tremor, anxiety, headache, nausea, and vomiting. This syndrome may be related to down-regulation of the α₂-adrenergic receptors in the central nervous system associated with chronic therapy. The agents that have higher specificity for the I₂ receptor appear to have significantly fewer central nervous system effects such as dry mouth and drowsiness. Rebound hypertension secondary to abrupt withdrawal has not been associated with moxonidine or rilmenidine.

Central and Peripheral Adrenergic Neuronal Blocking Agents

Mechanisms of Action and Class Member

Reserpine, a rauwolfia alkaloid, reduces blood pressure by lowering the activity of central and peripheral noradrenergic neurons. Reserpine blocks noradrenaline and dopamine uptake into storage granules of noradrenergic neurons. The result is noradrenaline depletion. A similar effect is seen in central dopaminergic and serotoninergic neurons. In doses currently used for hypertension, the major effect of reserpine is in the central nervous system. Reserpine results in a rapid reduction in cardiac output, heart rate, and peripheral vascular resistance. Enhanced vagal activity may be involved as well. Tolerance to the antihypertensive effects of reserpine does not occur.

Reserpine is used in initial doses of 0.1 mg to 0.25 mg daily.^[388] Approximately 40% of an oral dose is absorbed. The half-life is 50 to 100 hours. Extensive hepatic metabolism occurs; 1% is recovered as unchanged compound in the urine. Maximal clinical effect is observed 2 to 3 weeks after initiation of therapy. No dosage adjustment is necessary for patients with renal insufficiency. Dosage supplementation is not required after hemodialysis.

Renal Effects

Glomerular filtration rate and renal plasma flow are not affected by reserpine therapy. Renal vascular resistance may be reduced, perhaps mediated through decreased sympathetic stimulation of vascular α-adrenergic receptors. Significant effects on the RAAS have not been observed. Renal handling of sodium and potassium is unchanged.

Efficacy and Safety

Reserpine has been shown to be effective therapy as a single agent or in combination with HCTZ.^{[390] [391]} This has been observed in numerous large and small trials including the Veterans Administration Cooperative Study, the Hypertension Detection and Follow-up Program, and the Multiple Risk Factor Intervention Trial. Reserpine used in combination with a diuretic has shown comparable efficacy to combinations of β-blockers and diuretics. In these studies, the dose of reserpine was between 0.1 mg and 0.3 mg daily. This is many times lower than the doses used in the 1960s that led to a reputation of a poor side effect profile. The most common side effect of reserpine is nasal congestion, which is reported in 6% to 20% of patients. Unlike other side effects, it does not appear to decrease with lower doses of drug, and it is felt to be related to cholinergic effects of the drug. Increased gastric motility and gastric acid secretion can occur; however, the incidence of dyspepsia or peptic ulcer disease with reserpine is not greater than that with other antihypertensive drug treatments. Inability to concentrate, sedation, sleep disturbance, and depression have been reported. Other side effects include weight gain, increased appetite, and sexual dysfunction. Early suggestions that reserpine causes breast cancer in women were not confirmed.

Direct-Acting Vasodilators

Mechanisms of Action

The direct-acting vasodilators reduce systolic and diastolic blood pressure by decreasing peripheral vascular resistance. The drugs act directly on vascular smooth muscle with selective vasodilatation of the arteriolar resistance vessels and have little or no effect on the venous capacitance vessels. There is no effect on the functioning of carotid or aortic baroreceptors. The vasodilating effects have thought to involve inhibition of calcium uptake to the cells. 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 and possibly by direct effects on renal tubules. The arteriolar dilatation produced by these drugs causes a decrease in cardiac afterload, and the absence of venodilation leads to an increase in venous return to the heart, producing an elevated preload. These combined effects result in increased cardiac output. The pharmacokinetic and pharmacodynamic properties of these drugs are shown in Tables 45-24 and 45-25 [24] [25].

TABLE 45-24 -- Pharmacokinetic Properties of Direct-Acting Vasodilators

Drug	Bioavailability (%)	Affected by Food	Peak Blood Level (H)	Elimination Half-Life (H)	Metabolism	*Excretion^[]**	Active Metabolites
Hydralazine	20–50	No	1–2	1.5–8	L	U (3–14) F (3–12)	—
Minoxidil	90–100	—	1	4.2	L	U (90) F (3)	Glucuronide

F, feces; L, liver; U, urine.

^*	Excretion values in parentheses represent percentages.

TABLE 45-25 -- Pharmacodynamic Properties of Direct-Acting Vasodilators

Drug	Initial Dose (Mg)	Usual Dose (Mg)	Maximum Dose (Mg)	Interval	Peak Response (H)	Duration of Response (H)
Hydralazine	10	200–400	400	bid-qid	1	3–8
Minoxidil	2.5	10–20	40	qd-qid	4–8	10–12

Class Members

Initial oral doses of hydralazine 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 per 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 infusion. The elimination half-life is 1.5 to 8 hours and varies with acetylation rate in the liver. Both slow and fast acetylators have been described. Onset of action is approximately 1 hour. 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. No dosage supplement is required following hemodialysis or peritoneal dialysis (see Table 45-6 ).

Minoxidil is more potent than hydralazine. For severe hypertension the initial recommended dose is 5 mg as a single daily dose, increasing to 10 to 20 or 40 mg in single or divided doses. Minoxidil is usually used in conjunction with salt restriction and diuretics to prevent fluid retention. Concomitant therapy with a β-adrenergic blocking agent is often required to control tachycardia related to minoxidil use. Onset of the antihypertensive effect occurs within 30 to 60 minutes. Peak response is at 4 to 8 hours. The drug is 90% metabolized by the liver. The glucuronide metabolite has reduced pharmacologic effects but does accumulate in patients with ESRD. Renal excretion is 90%. Dosage adjustments may be required in patients with renal failure, although the mean daily doses required to control blood pressure have been reported to be similar in patients with normal renal function and those with renal failure (see Table 45-6 ).

Renal Effects of Direct-Acting Vasodilators

Hydralazine and minoxidil both increase juxtaglomerular cell secretion of renin. This is associated with elevations of AII and aldosterone. Chronic use is associated with return of plasma aldosterone levels to baseline. Retention of salt and water may be due to direct drug effects on the proximal convoluted tubule. Renal vascular resistance is decreased in relation to relaxation of resistance vessels. GFR and renal plasma flow are preserved.

Efficacy and Safety

Although minoxidil has been used to treat mild to moderate hypertension, it is commonly reserved for severe or intractable hypertension. When added to a diuretic and a β-blocker, minoxidil is generally well tolerated. Hypertrichosis is common. Pericarditis and pericardial infusions have been described. An increase in left ventricular mass has been reported. This may be due to adrenergic hyperactivity. Similar findings have been observed with hydralazine. Apart from adrenergic activation and fluid retention, chronic treatment with hydralazine has been associated with the development of systemic lupus erythematosus. 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 has been estimated that between 6% and 10% of patients receiving high doses of hydralazine for more than 6 months develop hydralazine-induced lupus. It occurs most frequently in women and rarely in blacks. This syndrome occurs primarily in slow acetylators. The syndrome is reversible when hydralazine is discontinued but may require months for complete clearing of symptoms. Hydralazine has been frequently used to treat pregnancy-associated hypertension.

Endothelin Receptor Antagonists

Endothelin receptor antagonists may have future implications in the management of hypertension. Endothelin is among the most potent endogenous vasoconstrictors known.^[390] It also enhances mitogenesis and induces extracellular matrix formation.^[390] It is thought to be involved in vascular remodeling and end-organ damage in several different cardiovascular conditions.^[391] As a result of these understandings, development of blockers for endothelin receptors is an attractive target.

Class Mechanism of Action and Class Members

An effort to explore the utility of endothelin reception antagonists in the management of hypertension is logical given the fact that endothelin is such a powerful vasoconstrictor. The two primary receptor sites: ET_A and ET_B can be selectively blocked with different chemicals, or both sites can be blocked simultaneously. These compounds function as specific vasodilators.

Originally these compounds were studied in patients with heart failure or pulmonary hypertension.^{[394] [395] [396] [397] [398]} Results of the studies in pulmonary hypertension have been encouraging.^{[396] [397] [398]} Bosentan, a mixed ET_A/ET_B receptor antagonist, has shown important promise. It has shown improvement in exercise capacity, hemodynamic parameters and World Health Organization functional class over one year. It has been hypothesized that selective ET_A receptor antagonists might offer greater benefits in systolic heart failure patients compared to non-selective agents such as bosentan. It is thought that simulation of ET_B receptors by endothelin-induced release of nitric oxide and prostaglandins may lead to vasorelaxation. ET_B receptors may also regulate the clearance of endothelin from the circulation.^[397] Thus, some consider selective ET_A receptor blockers as a better therapeutic strategy.^[398]Other studies with endothelin blockers in heart failure have not been encouraging, particularly when used in conjunction with other approved therapies.^{[394] [395]}

Bosentan has been studied in the management of hypertension. A large placebo-controlled trial lasting 4 weeks demonstrated a dose-dependent reduction in blood pressure when dosed from 100 mg once daily up to 1000 mg twice daily compared with placebo.^[399] The mean reduction of diastolic blood pressure of 5.8 mm Hg across all doses at or above 5 mg per day, was nearly identical to that seen with 20 mg of enalapril. The most common side effects were peripheral edema, flushing, headache, and some alterations in liver enzymes.

Darusentan, a selective ET_A receptor antagonist, has also been studied in a large placebo-controlled trial comparing doses of 10 mg to 100 mg per day over a 6-week period.^[400] Placebo-subtracted reductions in blood pressure were best with the 100 mg dose and approximated 11.3 mm Hg. However, this dose was associated more with reports of headache, flushing, and peripheral edema compared to the lower doses. There was no evidence of alteration in hepatic enzymes.

Class Renal Effects

Endothelin receptor antagonists have been studied in the development of acute and chronic renal failure in different experimental models.^[401] However, the investigation of endothelin receptor antagonism in models of kidney disease are few. One long study compared bosentan in comparison to, and in combination with the ACE inhibitor enalapril. Comparable reductions in blood pressure occurred with each therapy, whereas bosentan was less effective in preventing the development of proteinuria compared to the ACE inhibitor.^[402] What is unknown is whether the selective blockage of ET_A versus ET_B receptor will provide greater opportunity for using endothelin receptor antagonists as a means of not only controlling blood pressure, but also mitigating renal ischemia, and reducing proteinuria.

Class Efficacy and Safety

Despite the blood pressure reduction evident with these drugs, clinical progress in defining the therapeutic index with bosentan and Darusentan or other compounds is not yet evident. Whether this is related to concerns about tolerability, competing products with a better tolerability profile, or the teratogenic potential of endothelin receptor blockade as shown in experimental models is unknown. These drugs ultimately may also have a particular benefit in patients with more resistant forms of hypertension.

Moderately Selective Peripheral α₁-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. Phenoxybenzamine is a moderately selective peripheral α₁-adrenergic antagonist. Its specificity for the α₁-adrenergic receptor is 100 times greater than that for the α₂-adrenergic receptor.

Class Members

Phenoxybenzamine is a long-acting α-adrenergic blocking agent. This agent irreversibly and covalently binds to the α-receptors only. β-Receptors and the parasympathetic system are not affected by phenoxybenzamine. Total peripheral resistance is decreased and cardiac output increases with phenoxybenzamine. Phenoxybenzamine is also believed to inhibit the uptake of catecholamines into both adrenergic nerve terminals and extraneural tissues. 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. The final dose should be determined by blood pressure response. Phenoxybenzamine may be administered with a β-blocking agent if tachycardia becomes excessive during therapy. The pressor effects of a pheochromocytoma must be controlled by α-blockade before β-blockers are initiated. With oral use the pheochromocytoma symptoms are decreased after several days. Oral bioavailability is 20% to 30%. The drug is extensively metabolized by the liver. Administration of phenoxybenzamine to patients with renal impairment should be done cautiously. Specific dosage recommendations are not available.

Phentolamine is an α-adrenergic blocking agent that produces peripheral vasodilatation and cardiac stimulation with a resulting fall in blood pressure 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. Drug is not absorbed well orally. Half-life is 19 minutes. The drug is metabolized by the liver with 10% excreted in the urine as unchanged drug.

Renal Effects

Phenoxybenzamine has no clear effect on the renin-angiotensin-aldosterone axis. Blood volume and body weight are not altered. Salt and water retention does not occur. GFR and effective renal plasma flow would be expected to increase. Renal vascular resistance probably decreases in proportion to the degree of blockade of α-adrenergic receptors.

Efficacy and Safety

Phenoxybenzamine is used primarily as an agent to counteract the excessive α-adrenergic tone associated with pheochromocytoma. Tachycardia may result from α-adrenergic blockade, which unmasks β-adrenergic effects with epinephrine-secreting tumors. This may be controlled with concurrent use of a β-adrenergic antagonist. α-Adrenergic blockade must be initiated prior to β-adrenergic blockade to avoid paradoxical hypertension. Side effects of phenoxybenzamine are sedation, weakness, nasal congestion, hypertension, and tachycardia.

Peripheral α₁-Adrenergic Antagonists

Mechanisms of Action

Drugs of this class, including doxazosin, prazosin, and terazosin, are selective antagonists of the postsynaptic α₁-adrenergic receptor. With these drugs, the increases in arteriolar and venous tone mediated by norepinephrine released from sympathetic nerve terminals and acting at the α₁-adrenergic receptor located postjunctionally in the blood vessel wall are blunted. The affinity of these drugs for the α₂-receptor is very low. Because of the selective α₁ action, there is no interference with the negative feedback control mechanisms mediated by the prejunctional α₂-receptors. As a result, the reflex tachycardia associated with blockade of the presynaptic α₂-receptor is decreased substantially. The pharmacokinetic and pharmacodynamic properties of these drugs are shown in Tables 45-26 and 45-27 [26] [27].

TABLE 45-26 -- Pharmacokinetic Properties of Peripheral α₁-Adrenergic Antagonists

Drug	Bioavailability (%)	Affected By Food	Peak Blood Level (H)	Elimination Half-Life (H)	Metabolism	*Excretion^[]**	Active Metabolites
Doxazosin	62–69	No	2–5	9–22	L	F (63–65) U (1–9)	—
Prazosin	—	No	1–3	2–4	L	F	—
Terazosin	90	Yes	1	12	L	F (45–60) U (10)	—

F, feces; L, liver; U, urine.

^*	Excretion values in parentheses represent percentages.

TABLE 45-27 -- Pharmacodynamic Properties of Peripheral α₁-Adrenergic Antagonists

Drug	Initial Dose (Mg)	Usual Dose (Mg)	Maximum Dose (Mg)	Interval	Peak Response (H)	Duration of Response (H)
Doxazosin	1	8	16	qd-qid	4–8	24
Prazosin	1	6–15	20	bid-qid	½–1½	10
Terazosin	1	5	20	qd-bid	3	24

Class Members

Doxazosin is a selective long-acting α₁-adrenergic antagonist. The initial antihypertensive dose is 1 mg daily. This can be titrated up to a maximum of 16 mg daily. Maximal antihypertensive effect is seen 4 to 8 hours after a single dose. The drug is highly plasma protein bound and extensively metabolized. The majority of the administered dose is excreted in the feces. The estimated half-life is from 9 to 22 hours. Doxazosin pharmacokinetics are not altered in patients with renal impairment. The drug should be used with caution in patients with advanced liver dysfunction.

Prazosin is a selective α₁-adrenergic antagonist structurally related to doxazosin and terazosin. Oral dosing is 3 mg to 20 mg per day. A first-dose phenomenon with postural hypertension resulting in palpitations, tachycardia, and potentially syncope has been associated with prazosin. This can be minimized by limiting the initial dose to 1 mg at bedtime. Full therapeutic effects are seen within 4 to 8 weeks after initiation of therapy. Peak serum levels are reached 1 to 3 hours after an oral dose. The drug is highly protein bound. The elimination half-life is 2 to 4 hours. There is extensive hepatic metabolism followed by renal excretion of a very small amount of unchanged drug. Dosage adjustment is not required for patients with renal failure. Patients with significant liver disease may require a dose adjustment and more frequent monitoring.

Terazosin is a selective long-acting α₁-adrenergic antagonist. It has structural similarities to prazosin and doxazosin. The initial dose is 1 mg orally at bedtime with titration to 5 mg daily. Doses of 10 mg to 20 mg orally have been given. Peak serum levels following oral administration occur within 1 hour. The half-life is approximately 12 hours. Terazosin is extensively metabolized in the liver and eliminated primarily through the biliary tract. Renal insufficiency does not affect the pharmacokinetics of terazosin and dosage adjustment is not required. Patients with severe hepatic insufficiency may require dosage adjustments.

Renal Effects

Glomerular filtration rate and renal blood flow are maintained during long-term treatment with prazosin. In some studies there was a slight increase in renal blood flow. Renal vascular resistance may be reduced, perhaps mediated by a reduction in preglomerular capillary resistance related to inhibition of α₁-mediated vasoconstriction. Urinary protein excretion has been reported to be reduced. The RAAS is not significantly affected by specific α₁-adrenergic antagonists. The extracellular fluid volume has been reported to be increased, and the fractional excretion may be decreased.

Efficacy and Safety

Comparative clinical studies of the efficacy of α₁-adrenergic blockers have shown that the antihypertensive responses are similar to those of other antihypertensives.^[403] This conventional viewpoint has come under criticism with results of the ALLHAT study in which patients receiving doxazosin as their initial antihypertensive drugs were found to have poorer blood pressure control than those receiving a chlorthalidone-based treatment.^[404] In this study, patients receiving doxazosin had no difference in the primary outcomes of fatal coronary heart disease or nonfatal myocardial infarction but did have higher rates of stroke and congestive heart failure.^[405] The data from the ALLHAT study has resulted in a reassessment of the appropriateness of the use of doxazosin or other peripheral α-1 adrenergic antagonists as primary hypertensive therapy. The use of these drugs as secondary agents in the management of hypertension has also declined.

Prazosin has been shown to increase insulin sensitivity. There are potentially beneficial effects of α₁-blockers on lipid metabolism.^{[145] [405] [408] [409] [410]} These drugs have been consistently shown to result in a modest reduction in total and LDL-cholesterol and a small increase in HDL-cholesterol. This metabolic benefit may be linked to the beneficial effect on insulin responsiveness leading to increased peripheral glucose uptake.

The most important side effect of α₁-adrenergic receptor blockers is the first-dose orthostatic hypotension effect resulting in lightheadedness, palpitations, and occasional syncope. It is related to the drug effect on the venous capacitance vessels resulting in venous dilatation and inadequate venous return. It may occur with peak drug levels 30 to 90 minutes after the first dose. It can be minimized by initiating therapy with a small dose taken at bedtime.^[409] This effect can be exacerbated in patients with underlying autonomic insufficiency. α₁-Adrenergic antagonists are also used for symptomatic management of prostatic hypertrophy. Prostatic smooth muscle has significant α₁-adrenal receptors. Blockade of these receptors results in smooth muscle relaxation within the prostate.^{[412] [413] [414]}

Renin Inhibitors

The compounds in development include aliskiren, zankiren, and remikiren. However, due to problems with oral bioavailability, a decision was made by the makers to cancel development programs with the exception of aliskiren.

Class Mechanism of Action and Class Member

Aliskiren was designed through a combination of molecular modeling techniques and crystal structure elucidation.^[413] It is a potent and specific inhibitor of human renin in vitro (IC50 = 0.6 nmol/L). It is the first in a new class of orally effective, non-peptide, low-molecular-weight renin inhibitors for the management of hypertension.^{[416] [417]} Renin inhibition interferes with the first and rate-limiting step in the renin enzyme cascade: interaction of renin with its substrate angiotensinogen. The renin blockade step is attractive for hypertension therapeutics in large part due to the remarkable specificity of renin for its substrate.^[416] This specificity reduces the likelihood of unwanted interactions and possibly also side effects. In addition, unlike ACE inhibitors or angiotensin receptor blockers, which lead to a reactive rise in renin and associated angiotensin peptides, only renin inhibition renders the renin angiotensin system quiescent. Although aliskiren has low inherent bioavailability (2.6%), it is potent in reducing blood pressure, and has an effective half-life of 40 hours.^[417] The drug is not actively metabolized by the liver, and is primarily excreted in the urine, with the majority of it as unchanged drug. Cytochrome p450 enzymes are not involved in the metabolism of aliskiren. Thus, the possibility of clinical significant cytochrome p450 inhibition by aliskiren is unlikely.^[418]

Class Renal Effects

Renin inhibitors offer substantial promise for renal protection in that they provide not only blood pressure reduction, but also an opportunity to attenuate the activity of the renin angiotensin system without a reactive increase in renin or other angiotensin peptides. Experimental studies have demonstrated the utility of aliskiren in providing renal protection in hypertensive diabetic nephropathy in double transgenic (Ren-2) rats. This is a model of activated tissue renin angiotensin system. After the animals were made diabetic with streptozotocin, rats were treated with vehicle or aliskiren by osmotic mini-pumps. Aliskiren not only lowered systolic blood pressure, but it also prevented albuminuria development and reduced urinary excretion of TGF-beta. Gene expression of TGF-beta was significantly suppressed.^[419] In another study, these same investigators compared aliskiren and enalapril in the same model of Ren-2 double transgenic rats without diabetes.^[420] Both therapeutic strategies significantly reduced blood pressure and urinary albumin excretion for the duration of therapy. However, even after stopping therapy, both the renin inhibitor and the ACE inhibitor maintained reduction of both urinary TGF-beta excretion and albuminuria.^[420] In another experimental study, aliskiren was compared with the angiotensin receptor blocker valsartan in the same model of Ren-2 double transgenic rat, which because of its overexpression of human renin and angiotensinogen genes, develops rapid cardiovascular and renal disease. Both the aliskiren and the valsartan demonstrated an important opportunity to lower blood pressure, reverse left ventricular hypertrophy and albuminuria, and delay the onset of death.^[421] On the basis of these studies, it was suggested by the investigators that the renin inhibitor provides comparable renal protection as an ACE inhibitor or an angiotensin receptor blocker that extends beyond the dosing interval of the drug.

Preliminary data in humans indicate that aliskiren reduces proteinuria in conjunction with blood pressure.^[416] Longer-term studies will be needed to evaluate the utility of both the antihypertensive and the antiproteinuric effect in providing renal protection in humans. Renal vascular response curves to either ACE inhibition or renin inhibition at the top of the dose response curve indicates greater improvement in renal blood flow with the renin inhibitor despite similar changes in blood pressure.^[416] These data suggest the renin inhibitor may be more effective than ACE inhibitor in blocking angiotensin II formation. These preliminary observations may have some clinical significance.

Class Efficacy and Safety

Clinical trials of aliskiren have demonstrated a dose-dependent efficacy in reducing both systolic and diastolic blood pressure. In an 8-week double blind placebo controlled trial, aliskiren was studied in doses from 150 mg to 600 mg per day.^[422] The placebo-corrected reduction in sitting systolic blood pressure was approximately 10 mm Hg to 11 mm Hg for both the 300 mg and 600 mg dose. Also evaluated in the same study was irbesartan, an angiotensin receptor blocker, in a dose of 150 mg. This provided comparable blood pressure reduction as aliskiren in a dose of 150 mg. Other clinical studies have confirmed the antihypertensive efficacy of aliskiren in comparison to placebo, or with other active therapies like the angiotensin receptor blocker, losartan. As expected, blood pressure reduction was comparable with the active agents. The only observed difference was suppression of plasma renin activity and angiotensin I and II levels with aliskiren, but increased levels with angiotensin receptor blocker therapy.

The tolerability of aliskiren is comparable to that of placebo with a relatively low incidence of adverse events with all doses tested in the 150 mg to 600 mg range.^[422] Aliskiren treatment was comparable in tolerability to an angiotensin receptor blocker, or placebo, with a low discontinuation rate and no statistical difference in the incidence of different types of adverse events, with the exception of some diarrhea at the 600 mg dose.

Aliskiren has also been studied with hydrochlorothiazide for the management of hypertension.^[423] In a small clinical trial, all patients received aliskiren 150 mg once daily for three weeks. If patients had day time ambulatory blood pressure monitoring above 130/80 mm Hg, they were given hydrochlorothiazide (HCTZ) 25 mg for an additional 3 weeks. Adding 25 mg HCTZ resulted in an additional 10 mm Hg of systolic blood pressure reduction. Not surprisingly, there was no difference between the plasma renin activity between the patients receiving aliskiren with HCTZ or aliskiren alone. Other studies are underway currently to evaluate the use of aliskiren in conjunction with an angiotensin receptor blocker for lowering both blood pressure and proteinuria.

Selective Aldosterone Receptor Antagonists

Class Mechanism and Class Member

Potassium-sparing diuretics are discussed in the previous chapter, including spironolactone, a nonselective aldosterone receptor antagonist. However, eplerenone is a selective aldosterone receptor antagonist that is the first in its class to be evaluated for its antihypertensive and cytoprotective properties. It may have antihypertensive effects distinct from its diuretic properties.

Eplerenone is a 9a, 11a epoxy derivative of spironolactone. It is approximately 24 times less potent in blocking mineralocorticoid receptors than spironolactone. However, it is substantially more selective than spironolactone and has little agonist activity for estrogen and progesterone receptors.^[424] Therefore, it is associated with a lower incidence of gynecomastia, breast pain, and impotence in men and diminished libido and menstrual irregularities in women. Time to peak concentration is 1 to 2 hours. No significant accumulation occurs with multiple-dose administration. It appears well absorbed, but absolute (oral versus intravenous) data are not available. Specific data on protein binding and metabolism are unavailable. Its elimination half-life is 3.5 to 5.0 hours.

The mineralocorticoid receptor forms part of the steroid/thyroid/retinoid/orphan-receptor family of nuclear transactivating factors.^[425] When unbound, these receptors are in an inactive multiprotein complex of chaperones. Upon binding aldosterone, the chaperones are released and the receptor hormone complex is translocated into the nucleus, where it binds to hormone response elements on DNA and interacts with transcription initiation complexes, which ultimately modulates gene expression.^[426] In the kidney, mineralocorticoid receptors are located primarily in the epithelial cells of the distal nephron. These receptors bind physiologic glucocorticoids and mineralocorticoids with similar affinity. Activation of mineralocorticoid receptors by aldosterone results in activation of epithelial sodium channels, which leads to a rapid increase in sodium and water reabsorption and promotes the tubule secretion of potassium.^{[429] [430]} A persistent increase in sodium balance does not occur despite continued stimulation of mineralocorticoid receptor by aldosterone.^[428] The mechanism of this escape phenomenon has not been fully elucidated.

There is evidence that indicates the presence of biologic activity of mineralocorticoid receptors in nonepithelial tissues.^[429] These receptors have been identified in blood vessels of the heart and the brain and may be involved in vascular injury and repair responses.^{[432] [433]} It has been reported that aldosterone mediates fibrosis and collagen formation through up-regulation of AII receptor responsiveness.^[429] Aldosterone increases sodium influx in vascular smooth muscle and inhibits norepinephrine uptake in vascular smooth muscle and myocardial cells.^[432] It also directly participates in vascular smooth muscle cell hypertrophy. Consequently, clinical trials have been started to validate the hypothesis that aldosterone receptor antagonism may inhibit vascular, myocardial, and renal injury.

Class Renal Effects

Selective aldosterone receptor antagonism may have benefits for the kidney independent of its effects on blood pressure. Both experimental and clinical studies have demonstrated that AII is probably the primary mediator of the RAAS that is associated with progression of renal disease.^{[435] [436]} The relative importance of aldosterone within this cascade has been the subject of experimental and clinical studies. Hyperaldosteronism and adrenal hypertrophy are common observations in remnant kidney models and correlate with progressive loss of renal function.^[433] Investigators demonstrated that hypertension, proteinuria, and structural injury were less prevalent in the subtotally nephrectomized rats that underwent adrenalectomy despite large doses of replacement glucocorticoids.^[435] Other investigators have demonstrated that aldosterone infusion could reverse the renal protective effects of the ACE inhibitor in stroke-prone spontaneously hypertensive rats.^[436] Interestingly, in this model, the renal injury induced by aldosterone was independent of blood pressure increases, suggesting a toxic tissue effect of aldosterone. Other experimental studies indicated that aldosterone receptor antagonism can prevent the development of proteinuria.^[436]

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 AII receptor blocker therapy by inhibiting the effects of aldosterone that persist despite therapy with these drugs.

Class Efficacy and Safety

Eplerenone lowers blood pressure in a dose-dependent fashion when administered at 25, 50 or 200 mg twice daily.^[437] Changes in blood pressure were greater with twice-daily dosing (50 mg twice a day = -11.7 mm Hg systolic reduction) as opposed to a single daily dose (100 mg daily = -7.9 mm Hg systolic blood pressure reduction) in 24-hour ambulatory measurements.^[437]

Clinical trials also demonstrated that eplerenone has antihypertensive activity that is additive with that of either an ACE inhibitor or AII receptor blocker.^[438] Additional reductions in blood pressure were 6.0 mm Hg systolic with the ACE inhibitor and 6.6 mm Hg with the AII receptor blocker. Another clinical trial demonstrated that in diabetic hypertensive patients with microalbuminuria, adding eplerenone to ACE inhibitor therapy was capable of reducing proteinuria more than the ACE inhibitor alone independent of blood pressure reduction.^[439]

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

Metyrosine, the only drug in this class, blocks the rate-limiting step in the biosynthetic pathway of catecholamines. Metyrosine inhibits tyrosine hydroxylase, the enzyme responsible for conversion of tyrosine to dihydroxyphenylalanine. This inhibition results in decreased levels of endogenous catecholamines. In patients with pheochromocytomas, metyrosine reduces catecholamine biosynthesis by up to 80%. This results in a decrease in total peripheral vascular resistance. Heart rate and cardiac output increase because of the vasodilatation.

Class Members

The recommended initial dose of metyrosine is 250 mg four times a day orally. This may be increased by 250 mg to 500 mg every day until a maximum of 4 g per day is given. Following oral absorption, metyrosine is eliminated primarily unchanged in the urine. The half-life is 7.2 hours. Dosage reduction is appropriate in patients with renal failure.

Renal Effects

Little information is available on the renal affects of metyrosine. On the basis of its mechanism of action, which would be to counteract the renal effects of excessive circulating catecholamines, renal plasma flow and glomerular filtration would probably increase. Renal vascular resistance would be expected to decrease.

Efficacy and Safety

Metyrosine is used in the preoperative or intraoperative management of pheochromocytoma. Hypertension and reflex tachycardia may result from vasodilatation. These effects can 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; occasional patients have been noted to have diarrhea.

SELECTION OF ANTIHYPERTENSIVE DRUG THERAPY

Goal Blood Pressure Selection

Numerous factors confound the management of high blood pressure. The treatment is often delayed many years because the disease process is frequently asymptomatic. Consequently, it is not uncommon to have subclinical or even clinically evident target organ damage at the initiation of treatment. Moreover, the mechanistic underpinnings of high blood pressure are not well elucidated, and frequently the use of pharmacotherapy is simply based on what brings the “numbers” down and not necessarily what may be well tolerated or what may be best for preventing the development of cardiovascular disease or renal disease.

The whole purpose of treating blood pressure elevation is to prevent the development of cardiovascular events. In that sense, blood pressure is nothing more than one of many surrogate markers of risk contributing to cardiovascular disease. Consequently, the word “hypertension” is a nebulous concept. A factual definition of hypertension would be the level of blood pressure at which there is a greater net attributable risk for cardiovascular disease. Thus, the optimal goal blood pressure for different patients may be somewhat different depending on coexistent cardiovascular risk factors. The management of high blood pressure is much more complex than we once assumed it to be, and the estimation of goal blood pressure must be carefully individualized for each patient.

Clinicians must ask themselves three major questions: How low should you go? What drugs should you use? What are the best strategies for facilitating the attainment of goal blood pressure?

The question of how low you should go is not an easy one to answer as there are so many different aspects of patients' care that require consideration. Observational data indicate the advantages of lower systolic and diastolic blood pressure, preferably below 120/80 mm Hg.^{[442] [443]} This was defined as normal in JNC 7 simply because it was the level of blood pressure least likely to be associated with development of cardiovascular events.^[49] However, treated blood pressures at the same levels as observed blood pressures may not provide the same cardiovascular risk reduction. This may be particularly important when treating blood pressure to lower goals as recommended for patients with target organ damage or diabetes.^[49] Consequently, more effort is needed to study the advantages of treated blood pressures below 140/90 mm Hg, which has been the traditional “gold standard.”

Whether one should treat the systolic, diastolic, or pulse pressure is another important consideration. This is particularly true when one considers the vast number of patients with isolated systolic hypertension who have been traditionally assumed to have normal blood pressure because their diastolic pressure was below 90 mm Hg. Interventional trials demonstrate the advantage of lowering systolic blood pressure.^{[444] [445] [446]} In fact, evidence from three large clinical trials on the management of isolated systolic hypertension indicates a consistent benefit related to reduction in congestive heart failure, myocardial infarction, and stroke with control of systolic blood pressure to an intermediate goal of less than 160 mm Hg and preferably a final goal of less than 140 mm Hg.^{[444] [445] [446]}

Epidemiologic data have also demonstrated the importance of pulse pressure (systolic diastolic blood pressure) in predicting cardiovascular events.^{[447] [448] [449]} It correlates directly with the risk of myocardial infarction and the development of LVH. Because the measurement of diastolic blood pressure is frequently difficult in older patients with vascular disease, the exact assessment of pulse pressure may not always be possible. Consequently, relying on the systolic blood pressure may give the clinician a more realistic opportunity to gauge the adequacy of antihypertensive therapy. It is important to realize that the management of systolic blood pressure may provide one of the most important opportunities to provide cardiovascular risk reduction, particularly in patients with lower diastolic pressures who have a wider pulse pressure.

Decision making about identifying goal blood pressure should focus primarily on the patient's age, target organ damage, and associated cardiovascular risk factors. In JNC 7, the recommendation to choose a goal of less than 130/80 mm Hg was suggested for patients with kidney disease (glomerular filtration rate estimated below 60 ml/min) or diabetes because these patients had already manifested target organ damage or had risk factors that markedly increased their risk for cardiovascular events. Unfortunately, these recommendations are not always adhered to, as many of these patients have multiple medical problems that require pharmacotherapy, and the addition of medications to intensify treatment of high blood pressure is viewed as untenable.

Decisions about which drug or drugs should be employed for a given patient require careful consideration and individualization. As discussed later, this may depend on age, gender, race, obesity, and associated cardiovascular or renal disease. Clinical trials in patients with vascular disease, heart disease, or kidney disease have demonstrated the important therapeutic advantage of drugs that block the RAAS, either the ACE inhibitor^{[450] [451]} or the AII receptor blocker,^{[452] [453] [454] [455] [456] [457] [458] [459]} to prevent progression of cardiac or renal disease as part of a multidrug regimen to lower blood pressure. These drugs should be part of every antihypertensive regimen in patients with heart disease or kidney disease unless there are specific contraindications.^[450] Although these drugs provide important risk reduction opportunities, they are not a substitute for achieving control of blood pressure.

Fixed-Dose Combination Therapy

With the shift in emphasis for treatment from the diastolic to both the systolic and diastolic blood pressure^[49] and the lower blood pressure goals being recommended, particularly in patients with target organ damage, there is a substantial increase in the complexity of medical regimens. Most available antihypertensive drugs, when appropriately dosed, reduce systolic blood pressure about 8 mm Hg to 10 mm Hg. Therefore, the number of drugs needed to reach goal blood pressure can probably be predicted by dividing the number 10 into the difference between current and goal systolic blood pressure. In many patients, this may require three or four drugs. Ideally, medications that are long acting, capable of being taken once daily, and well tolerated and preferably work well with other medications to facilitate blood pressure control should be employed. In addition, there has been a marked increase in the number of fixed-dose combination antihypertensive drugs that are available in the marketplace, in large part to facilitate compliance by reducing the complexity of the antihypertensive regimen ( Table 45-28 ).

TABLE 45-28 -- Fixed-Dose Combination Therapy

Class	Combination	Trade Name
β-Adrenergic blockers and diuretics	Atenolol 50–100 mg/chlorthalidone 25 mg	Tenoretic
	Bisoprolol 2.5–10 mg/HCTZ 6.25	Ziac^[*]
	Metoprolol 50–100 mg/HCTZ 25–50 mg	Lopressor HCT
	Nadolol 40–80 mg/bendroflumethiazide 5 mg	Corzide
	Propranolol 40–80 mg/HCTZ 25 mg	Inderide
	Propranolol ER 80–160 mg/HCTZ 50 mg	Inderide LA
	Timolol 10 mg/HCTZ 25 mg	Timolide
ACEIs and diuretics	Benazepril 5–20 mg/HCTZ 6.25 mg–25 mg	Lotensin HCT
	Captopril 25–50 mg/HCTZ 15–25 mg	Capozide^[*]
	Enalapril 5–10 mg/HCTZ 12.5–25 mg	Vaseretic
	Lisinopril 10–20 mg/HCTZ 12.5–25 mg	Zestoretic; Prinzide
Angiotensin II receptor blocker and diuretic	Losartan 50–100 mg/HCTZ 12.5–25 mg	Hyzaar, Hyzaar DS
	Valsartan 80–320 mg/HCTZ 12.5–25 mg	Diovan HCT
	Eprosartan 600 mg/HCTZ 12.5–25 mg	Teveten HCT
	Irbesartan 150–300 mg/HCTZ 12.5–25 mg	Avalide
	Telmisartan 40–80 mg/HCTZ 12.5–25 mg	Micardis HCT
	Candesartan 16–32 mg/HCTZ 12.5–25 mg	Atacand HCT
	Olmesartan 20–40 mg/HCTZ 12.5–25 mg	Benicar HCT
Calcium antagonists and ACEIs	Amlodipine 2.5–10 mg/benazepril 10–20 mg	Lotrel
	Verapamil 180–240 mg/trandolapril 1–4 mg	Tarka
Calcium antagonists and angiotensin II receptor blockers	Amlodipine 5–10 mg/valsartan 160–320 mg	Exforge
	Amlodipine 5–10 mg/olmesartan 20–40 mg	Azor
Other combinations	Clonidine HCI 0.1–0.3 mg/chlorthalidone 15 mg	Combipres
	Deserpidine 0.25–0.5	Enduronyl (Forte)
	Guanethidine 10 mg/HCTZ 25 mg	Esimil
	Hydralazine 25–100/HCTZ 25–50 mg	Apresazide
	Hydralazine 25 mg/reserpine 0.1 mg/HCTZ 15 mg	Ser-Ap-Es; Unipres; Tri-Hydroserpine
	Methyldopa 250 mg/chlorothiazide 150–250 mg	Aldoclor
	Methyldopa 250–500 mg/HCTZ 30–50 mg	Aldoril
	Prazosin 1–5 mg/polythiazide 0.5 mg	Minizide
	Rauwolfia 50 mg/bendroflumethiazide 4 mg	Rauzide
	Reserpine 0.125 mg/chlorthalidone 25 mg	Demi-Regroton
	Reserpine 0.125 mg/chlorothiazide 250–500 mg	Diupres
	Reserpine 0.125 mg/HCTZ 25–50 mg	Hydropres; Hydroserpine
	Reserpine 0.125 mg/hydroflumethiazide 50 mg	Salutensin (-Demi)
	Reserpine 0.25 mg/polythiazide 2 mg	Renese-R
	Reserpine 0.1 mg/trichlormethiazide 2–4 mg	Metatensin

Adapted from Chobanian AV, Bakris GL, Black HR, et al: Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 42:1206–1252, 2003.

ACEI, angiotensin-converting enzyme inhibitor; ER, extended release; HCT, HCTZ; hydrochlorothiazide; LA, long acting.

^*	Approved for initial therapy of hypertension.

Drugs that block the RAAS system, such as ACE inhibitors, AII receptor blockers, or β-blockers, can be prescribed with a low dose of HCTZ (6.25 mg or 12.5 mg). The advantage of the low-dose HCTZ is that it nearly doubles the antihypertensive effects of the parent drug without adding any toxicity to the regimen.^[452] Fixed-dose combinations of an ACE inhibitor and calcium channel blocker are also available. Clinical studies have demonstrated that these drugs are also additive in their ability to lower diastolic and systolic blood pressure.^[453] Moreover, there is good clinical evidence that the ACE inhibitor antagonizes the development of pedal edema, which is not uncommonly seen with the calcium channel blocker.^[454] Fixed-dose combinations of an angiotensin II receptor blocker and a calcium channel blocker will soon be available. Fixed-dosed combinations are now recommended in the JNC 7 report as a first line approach for the management of hypertension in patients whose systolic blood pressure goal is more than 20 mm Hg from current levels.^[49] However, most fixed-dose combinations are not approved by the FDA for initial treatment.

Considerations for physicians about how to consolidate and simplify pharmacotherapy for the control of blood pressure are of great interest given the complexity of the current multidrug regimens that many patients require. Giving four drugs in two pills is possible with available fixed-dose combinations. This is an important goal as many patients frequently require eight to ten medications for control of their various medical problems, including diabetes, dyslipidemia, and angina. High blood pressure is a disease that is largely asymptomatic, and consequently the therapeutic approach should be simple, effective, and well tolerated.

Choosing Appropriate Agents

This section of the chapter considers initial therapy in various types of patients depending on age, gender, race, obesity, and coexistent cardiovascular or renal disease. These considerations are primarily generalizations based on clinical experience and should not be viewed as rigorous guidelines. Because each patient is different, variation in the approach is frequently necessary.

The major considerations for initial therapy in older patients ( Table 45-29 ) should take into account the major pathophysiologic problem, which is an increase in peripheral vascular resistance. With associated proximal aortic stiffening, there are frequently an increase in systolic blood pressure, a decrease in diastolic pressure, and a wider pulse pressure.^[446] There are also an associated reduction in cardiovascular baroreceptor reflex function, greater blood pressure lability, and consequent propensity for orthostasis.^[458] Older patients also tend to have hypertrophic cardiomyopathy with impaired diastolic function, which may impair cardiac output.^[459]

TABLE 45-29 -- Considerations for Initial Therapy in Older Patients

Clinical Observations	Pharmacologic Considerations
Decreased vascular compliance and peripheral vascular resistance	Vasodilation (e.g., HCTZ, ACEI, ARB, CCB, α-blockers)
Isolated systolic hypertension and wide pulse pressure	Vasodilation (e.g., HCTZ, CCB)
Reduction of cardiovascular baroreflex function with blood pressure Lability.	Avoid sympatholytics and volume depletion. Use β blockers cautiously.
Orthostatic hypotension	Consider using short-acting meds (<8 h duration) at bedtime during recumbency
Reduced metabolic capability	Adjust all medications for renal/hepatic function—start at half dose
Prostatic hypertrophy	α-Blockers
More than 20 mm Hg from systolic goal	Fixed-dose combination (ACEI/HCTZ, ARB/HCTZ, ACEI/CCB, BB/HCTZ, ARB/CCB)

HCTZ, thiazide diuretic; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CCB, calcium channel blocker.

Ideal therapeutic strategies for these patients are vasodilators, preferably a low dose of HCTZ, 12.5 mg to 25 mg per day. Thiazide diuretics function primarily as vasodilators and have minimal long-term effects on blood volume. In low doses, they are well tolerated and cause minimal problems related to glycemia control, potassium homeostasis, and cholesterol metabolism.^{[462] [463]} They are particularly effective in controlling systolic blood pressure.^[462]Their biologic half-life extends well beyond their pharmacologic half-life.

Thiazide diuretics also facilitate vasodilation with other therapeutic classes, particularly those that block the RAAS.^[452] They can be utilized together as fixed-dose combinations.

Calcium channel blockers are also useful vasodilators in older 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, perhaps owing to their natriuretic effects^[463] or intrinsic vasodilatory effects.^{[466] [467]} α-Blockers may be useful in older men with benign prostatic hypertrophy because they facilitate prostatic urethral relaxation and improve urinary stream. ACE inhibitors and AII receptor blockers are also effective vasodilators in older patients. They are well tolerated, and their efficacy is enhanced with low-dose thiazide diuretic therapy.^[452] β-Blockers may impair baroreceptor responses in older patients and worsen orthostasis and should be used with caution.

Older patients have a greater likelihood of orthostasis than younger patients. As many as 18% of untreated elderly patients with hypertension may have a decrease of systolic blood pressure greater than 20 mm Hg after standing for 1 to 3 minutes.^[466] Older patients may also have pseudohypertension, which may interfere with a true determination of blood pressure.^[467] Consequently, three position blood pressures should always be employed during initiation and titration of medications. If recumbent blood pressures remain elevated, short-acting medications taken before bedtime such as clonidine or captopril may be useful in controlling blood pressure overnight.

Management 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. A careful assessment of the metabolic and excretory routes of the drugs as well as possible drug-drug interactions is recommended because older patients frequently have impaired metabolic function.

Differences in gender ( Table 45-30 ) may be important with regard to the selection of antihypertensive therapy.^[468] Men and women benefit equally with more intensive control of blood pressure resulting in a reduction in risk of cardiovascular events.^[469] In general, men have a decreased resting heart rate, a longer left ventricular injection fraction time, and an increased pulse pressure when stressed compared with women.^[468] Women tend to have reduced peripheral vascular resistance and greater blood volume than men.^[468] They also have a lower likelihood of coronary disease before menopause. However, when menopause occurs or in the presence of diabetes, women assume the same risk for coronary disease as men.^[468]

TABLE 45-30 -- Considerations for Initial Therapy Based on Gender

Clinical Observations	Pharmacologic Considerations
Men have resting heart rate, longer LVEF time, pressure compared with women	Vasodilation (e.g., HCTZ, ACEI, ARB, CCB) stressed pulse
Women have TPR and blood volume compared with men	Vasodilation, heart rate reduction, may need diuresis (HCTZ, ACE inhibitor, ARB, β-blocker, CCB)
Postmenopausal women more frequently have CAD with atypical chest pain	Antianginal; heart rate reduction (β-blocker, CCB)
Osteoporosis	Antagonize calciuria (HCTZ)
Pregnancy	Avoid teratogenic drugs (ACEI, ARB).
	Avoid drugs that may cause ureteroplacental insufficiency (loop diuretics). Optimal choices: α-methyldopa, hydralazine, β-blocker
Women report more pedal edema with CCB and cough with ACEI than men	Adjust dose or discontinue drug
More than 20 mm Hg systolic goal	Fixed-dose combination (ACEI/HCTZ, BB/HCTZ, ARB/HCTZ, ACEI/CCB, ARB/CCB)

ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CCB, calcium channel blocker; HCTZ, thiazide diuretic; CAD, coronary artery disease; HR, heart rate; LVEF, left ventricular ejection fraction; TPR, total peripheral resistance.

Vasodilation is always a good choice for treatment, as elevated peripheral vascular resistance is almost always involved in blood pressure elevation regardless of gender. Thiazide diuretics, ACE inhibitors, AII receptor blockers, and calcium channel blockers are all effective treatments. Many patients require two or more of these drugs, and fixed-dose combinations can be used.

Women should avoid the use of ACE inhibitors and AII receptor blockers in pregnancy because of their possible teratogenic effects. Calcium channel blockers may delay labor. Optimal therapy in a pregnant woman should remain α-methyldopa, hydralazine, or β-blockers as they have a proven safety record with minimal risk of teratogenic effects.

In women with osteoporosis, thiazide diuretics are ideal agents because they antagonize calciuria and facilitate bone mineralization.^[470]

Women experience more cough with ACE inhibitors and more pedal edema with calcium channel blockers compared with men.^[471] These differences in side effects may require adjustment in dose or switching medications. Interestingly, despite differences in the underlying pathophysiologic mechanisms of high blood pressure between genders, there does not appear to be a substantial difference in response rate to similar doses of commonly used antihypertensive drugs.

Ethnicity may play a role in choice of antihypertensive agents ( Table 45-31 ). Blacks frequently present with high blood pressure at an earlier age and have more substantial elevations in blood pressure and earlier development of target organ damage than similar demographically matched white counterparts.^{[230] [474] [475]} Ethnic differences in the response to antihypertensive medications have been demonstrated in numerous clinical trials.^[230] The mechanisms for these differences are not yet elucidated but appear to be independent of dietary salt or potassium.^[464] Some investigators have suggested possible genetic differences in renal sodium handling, yet this has not been conclusively demonstrated in clinical trials. Despite this observation, blacks frequently display blood pressure salt sensitivity.^[474] A careful assessment of the dose response of different medication classes, adjusting for differences in dietary sodium consumption and body mass index between races, has not been performed.

TABLE 45-31 -- Considerations for Initial Therapy in Black Patients

Clinical Observations	Pharamacologic Considerations
High peripheral vascular resistance with associated reduction in Salt	Vasodilation (e.g., HCTZ, ACEI, CCB, ARB) cardiac output sensitivity
	Natriuresis (HCTZ, ACE inhibitor, ARB, CCB). Reduce salt intake
Variable increase in blood volume (perhaps greater in some patients diuretic)	Natriuresis, diuresis (HCTZ; if creatinine >2.0, loop relative to peripheral vascular resistance)
More than 20 mm Hg from systolic goal	Fixed-dose combination therapy (ACEI/HCTZ, BB/HCTZ, ARB/HCTZ, ACEI/CCB, ARB/CCB)

ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; BB, β-blocker; CCB, calcium channel blocker; HCTZ, thiazide diuretic.

In general, thiazide diuretics and calcium channel blockers have been demonstrated to have more robust antihypertensive properties in lower doses in blacks than other commonly used therapeutic classes.^{[466] [467] [477]} Drugs that block the RAAS are effective in blacks, but higher doses are frequently required in order to achieve the same level of blood pressure as seen in nonblacks.^{[466] [467] [478]} As in most population groups, elevated peripheral vascular resistance contributes to blood pressure elevation. Some investigators have suggested that blacks have a modest volume component contributing to blood pressure elevation that may also contribute to antihypertensive drug resistance.^[474] It is not uncommon for multiple drugs to be required to reach goal blood pressure given the greater degree of blood pressure elevation and somewhat different patterns in the antihypertensive responses. Consequently, fixed-dose combinations may prove to be most useful in this population group as part of the strategy to simplify the approach.

Hispanics and Asians do not appear to have different hypertensive responses to commonly used drugs compared with Caucasians.^{[230] [466]} Consequently, there do not appear to be any reasons to treat these ethnic groups differently from Caucasians.

Obese patients with hypertension frequently have other medical problems that complicate their hypertensive management ( Table 45-32 ).^{[466] [479]} They tend to have a hyperdynamic circulation, increased peripheral vascular resistance, expanded plasma volume, and, like blacks, tend to have greater sensitivity to the influence of dietary salt in raising blood pressure.

TABLE 45-32 -- Considerations for Initial Therapy in Obese Patients with Hypertension

Clinical Observations	Pharmacologic Considerations
Hyperdynamic circulation	Reduce heart rate and sympathoadrenal outflow (β-blocker)
Increased peripheral vascular resistance	Vasodilation (e.g., HCTZ, ACEI, ARB, CCB)
Salt sensitivity	Natriuresis (HCTZ, ACEI, ARB, CCB). Reduce salt intake
Expanded plasma volume	Diuresis (HCTZ). Reduce salt intake
Hypoventilation	Sleep study to evaluate the need for positive-pressure ventilation at night
More than 20 mm Hg from systolic goal	Fixed-dose combination (ACEI/HCTZ, BB/HCTZ, ARB/HCTZ, ACEI/CCB, ARB/CCB)

ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; BB, β-blocker; CCB, calcium channel blocker; HCTZ, thiazide diuretic.

β-blockers may be helpful in diminishing sympathoadrenal drive. Vasodilators, such as HCTZ and ACE inhibitors, ARBs, and calcium channel blockers, are useful for reducing peripheral 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 both an opportunity to cause vasodilation and mild volume reduction. Frequently, these patients require multiple drugs to achieve blood pressure 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. One also should use β-blockers carefully as they may increase the likelihood of weight gain and may compromise glucose tolerance.^{[466] [480]}

Patients with hypertension and cardiac disease need tailored approaches, as the medications used to control blood pressure are all quite different with regard to their effects on the heart ( Table 45-33 ). 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. β-blockers and heart rate-lowering calcium channel blockers, such as nondihydropyridines, would be ideal in this respect.

TABLE 45-33 -- Considerations for Initial Therapy in Patients with Heart Disease

Clinical Observations	Pharmacologic Considerations
Angina	Reduce heart rate and induce coronary vasodilation (reduce heart rate 20% or 60–65 bpm) (β-blocker, nitrates, CCB).
Left ventricular hypertrophy	Reduce systolic blood pressure (HCTZ, ACEI, CCB, ARB). Avoid nonspecific vasodilator or therapies that result in reflex heart rate.
Systolic dysfunction	Reduce afterload and preload natriuresis (ACEI, HCTZ, ARB). Antineurohormonal agents, β-blocker, spironolactone.
Diastolic dysfunction	Improve myocardial compliance, reduce heart rate, avoid volume depletion (β-blocker, CCB, ACEI, ARB, avoid loop diuretics).
Myocardial infarction	Reduce heart rate (β-blocker, ACEI).
More than 20 mm Hg from systolic goal	Fixed-dose combination therapy (ACEI/HCTZ, BB/HCTZ, ARB/HCTZ, ACEI/CCB, ARB/CCB).

ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; BB, β-blocker; CCB, calcium channel blocker; HCTZ, thiazide diuretic.

Left ventricular hypertrophy is evidence of the chronicity and magnitude of blood pressure elevation. All drugs that lower blood pressure except the direct-acting vasodilators effectively cause LVH to regress.^[479] Thus, most antihypertensives can be useful in this regard. Some trials indicate that drugs that block the RAAS may be more effective in reducing LVH than other drugs.^[479] A large-scale clinical trial demonstrated that the ARB losartan was more effective in reducing overall cardiovascular morbidity and mortality (primarily related to reduction in the incidence of stroke) in patients with hypertension and LVH than a β-blocker-based antihypertensive regimen.^[450]

If patients have dyspnea, it is important to use an echocardiogram to distinguish between diastolic and systolic dysfunction. The management 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 and diminish sympathoadrenal response.^[480] β-blockers are also helpful in these patients in addition to ACE inhibitor therapy. Diuretic therapy should be used to adjust blood volume as necessary.

In patients with kidney disease ( Table 45-34 ), blood pressure control is more complex to manage in that they not only have an increased vascular resistance but also frequently have increased blood volume contributing to the hypertensive process.^[481] Understandings about renal autoregulation provide some insight into appropriate levels of blood pressure control and the relative importance of different kinds of antihypertensive drugs in preserving renal function.

TABLE 45-34 -- Considerations for Initial Therapy in Patients with Renal Disease^[*]

Clinical Observations	Pharmacologic Considerations
Increased blood volume (common in glomerular diseases)	Reduce blood volume (HCTZ, loop diuretic if creatinine >2.0)
Decreased blood volume (common in tubular diseases)	May need salt supplementation
Increased peripheral vascular resistance	Vasodilation (ACEI, CCB, ARB)
Proteinuria	Reduce proteinuria (ACEI, ARB, NDCCB) (blood pressure systolic ≤130 mm Hg)
Diabetes with proteinuria	Control blood pressure and glycemia (ACEI if type 1, ARB if type 2 (blood pressure systolic <130 mm Hg)
More than 20 mm Hg from systolic goal	Fixed-dose combination therapy (ACEI/HCTZ, BB/HCTZ, ACEI/CCB, ARB/HCTZ, ARB/CCB) Use of HCTZ depends on renal function

NDCCB, nondihydropyridine calcium channel blocker; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; BB, β-blocker; CCB, calcium channel blocker; HCTZ, thiazide diuretic.

^*	All medications adjusted according to renal function.

The glomerular circulation operates optimally at one half to two thirds of the systemic blood pressure.^[482] Preglomerular vasoconstriction is necessary to step systemic pressure down to glomerular capillary pressure levels that are optimal for filtration yet low enough to avoid mechanical injury to the filtering apparatus.^{[484] [485]} The efferent glomerular arteriole also serves an important purpose. It vasoconstricts during situations of diminished effective arterial blood volume to maintain adequate pressure for glomerular filtration. With the development of vascular disease, the afferent glomerular arteriole does not vasoconstrict properly, allowing transmission of systemic blood pressure into the glomerulus. A clinical clue that could indicate failure of autoregulation is the presence of microalbumin or protein in the urine. Under these circumstances, systemic blood pressure should be reduced more substantially to minimize the risk of mechanical injury to the glomerulus. In JNC 7, recommended systolic blood pressure was less than 130 mm Hg in patients with renal disease.^[49] It is possible that even lower pressures may be necessary for optimal delay of progression of renal disease, particularly in the presence of proteinuria and in patients with diabetes.

Drugs that block the RAS such as ACE inhibitors^{[450] [451]} and ARBs^{[454] [455] [456]} provide a more consistent opportunity to reduce progression of renal disease as part of an intensive blood pressure-lowering strategy compared with other commonly used antihypertensive drugs. The benefit of these drugs resides, in part, in their effects to facilitate efferent glomerular arteriolar dilation by antagonizing the effects of AII as they lower blood pressure.^[484]Thus, there is a more consistent reduction in both systemic and glomerular capillary pressure. Additional medications can be added to these drugs to facilitate better blood pressure control and also help reduce glomerular capillary pressure and proteinuria. Sufficient diuretics to control blood volume should also be employed. When the serum creatinine reaches 2 mg/dl, volume reduction is more amenable to the use of loop diuretics as opposed to thiazides, which are more effective as peripheral vasodilators.

Some investigators have questioned the safety of using calcium channel blockers in patients with kidney disease given their preferential effects on dilating the afferent glomerular arteriole.^[37] Some studies have demonstrated that they can increase proteinuria despite lowering blood pressure.^[485] However, if these drugs are given with either ACE inhibitors or ARBs, which dilate the efferent glomerular arteriole, there is no clinical evidence that they are detrimental and worsen progression of renal disease. If anything, lower blood pressure achieved with these drugs in combination may provide a better opportunity to protect against the loss of kidney function.

Antiproteinuric strategies should be considered in patients with kidney disease as reduction in proteinuria with specific antihypertensive drugs, such as ACE inhibitors or ARBs, is beneficial in retarding progression of renal disease.^{[488] [489]}

Refractory Hypertension

Refractory hypertension is a term used to characterize high blood pressure that fails to respond to what the clinician feels is an adequate antihypertensive regimen ( Table 45-35 ).^[488] Thus, the definition can vary substantially from clinician to clinician. There are a variety of factors that interfere with the ability of what is deemed to be appropriate antihypertensive therapy to normalize blood pressure. Perhaps most important is nonadherence to therapy. Noncompliance is common and is one of the most serious problems that interfere with attaining goal blood pressure. It has many sources, including inadequate education, poor clinician-patient relationship, lack of understanding about side effects, and the complexity of multidrug regimens. The health care provider should make every effort to establish whether or not compliance with therapy is part of the problem before pursuing other potential explanations for refractory hypertension. If noncompliance is eliminated, a methodologic approach can be used to help diagnose the cause of refractory hypertension and then correct it.

TABLE 45-35 -- Causes of Refractory Hypertension

Pseudoresistance

	1.	“White-coat hypertension” or office elevations
	2.	Pseudohypertension in older patients
	3.	Use of small cuff on very obese arm

Nonadherence to therapy

Volume overload

Drug-related causes

	1.	Doses too low
	2.	Wrong type of diuretic
	3.	Inappropriate combinations
	4.	Drug actions and interactions
		Sympathiomimetics
		Nasal decongestants
		Appetite suppressants
		Cocaine
		Caffeine
		Oral contraceptives
		Adrenal steroids
		Licorice (may be found in chewing tobacco)
		Cyclosporine, tacrolimus
		Epoetin
		Antidepressants
		Nonsteroidal anti-inflammatory drugs

Concomitant conditions

	1.	Obesity
	2.	Sleep apnea
	3.	Ethanol intake of >1 oz (30 mL) per day
	4.	Anxiety, hyperventilation

Secondary causes of hypertension

		Renovascular hypertension
		Primary aldosteronism
		Pheochromocytoma
		Hypothyroidism
		Hyperthyroidism
		Hyperparathyroidism
		Aortic coarctation
		Renal disease

Pseudohypertension may also be a cause of refractory hypertension. This is most commonly observed in older hypertensive patients who have hardened atherosclerotic arteries, which are not easily compressible. This interferes with auscultatory measurements of blood pressure. It is also known as the Osler phenomenon.^[467] Because of the conformational changes of the vessels, greater apparent pressure is required to compress the sclerotic vessel than the intra-arterial blood pressure requires.

Another common cause of pseudohypertension is improper measurement. This occurs when the blood pressure 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. The bladder within the cuff should encircle at least 80% of the arm in order to provide an accurate determination.

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 blood pressure.^{[491] [492]}

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.

Increasing dietary salt offsets the antihypertensive activities of all antihypertensive medications.^[464] Some patients are more salt sensitive than others. Salt sensitivity is common in patients of African American descent. It is also a more common problem in patients with renal disease and congestive heart failure. A careful clinical examination coupled with judicious use of either thiazide or loop diuretics (depending on the level of renal function) 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.^[491] In addition, oral contraceptives, immunosuppressants such as cyclosporine, and even some antidepressants can raise blood pressure. Caffeine, licorice, and even erythropoietin may also raise blood pressure. Unfortunately, patients may not always recognize over-the-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, ethanol, cigarettes, and cocaine can be complicating factors that interfere with the ability of medications to lower blood pressure.

Some medications may interfere with the antihypertensive activity of other drugs. For example, NSAIDs interfere with the antihypertensive activity of diuretics and ACE inhibitors.^[488] Interestingly, only the antihypertensive effects of calcium channel blockers appear to be immune to the effects of NSAIDs.^[492] Drug-drug interactions that can interfere in drug absorption, metabolism, or the pharmacodynamics of concomitantly administered drugs can also interfere with antihypertensive activity.

Concomitant medical conditions can also interfere with the ability of medications to control blood pressure. Obesity is an often overlooked cause of refractory hypertension because it is commonly associated with the obesity hypoventilation syndrome, obstructive sleep apnea.^[493] Nighttime ventilation techniques such as continuous positive airway pressure enhance the control of blood pressure.^[493]

Secondary causes of hypertension might also be considered as a cause of refractory hypertension. These can be divided into two groups: either renal parenchymal and renal vascular or endocrine. Renal parenchymal and renal vascular diseases are not uncommon (90% of the total). A chemistry profile and urinalysis facilitate diagnosis of renal disease, whereas a renal vascular assessment with a Doppler or direct imaging technique determines whether renal vascular hypertension is present. Additional endocrine abnormalities include hyperaldosteronism, pheochromocytoma, or hypo- or hyperthyroidism and hyperparathyroidism; rarely, aortic coarctation can be a cause of refractory hypertension. Occult hyperaldosteronism should be screened for with a plasma aldosterone plasma renin activity ratio. In a recent retrospective study, a more widespread use of the PACRA ratio in hypertensive patients resulted in a 1.3-fold to 6.3-fold increase in the annual detection rate of primary aldosteronism (1% to 2% before screening, and 5% to 10% after screening). Although these results are complicated by selection bias, they are indicative that this type of screening should be considered in resistant hypertensives despite the fact that it is often unusual to find an adenoma.^[494] Often patients with subtle hyperaldosteronism will respond to the addition of a selective aldosterone receptor blocker to their antihypertensive regimen.

Strategies to control blood pressure in patients with refractory hypertension should first deal with issues related to compliance, simplifying the medical regimen, and being sure 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 blood pressure by approximately 8 mm Hg to 10 mm Hg. Consequently, it is not unusual for patients who are 40 mm Hg or 50 mm Hg from goal systolic blood pressure 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, impaired drug bioavailability, impaired diuretic secretion by the proximal tubule, increased protein binding in the tubule lumen, or reduced GFR. Both pseudohypertension and secondary causes of hypertension should be eliminated as possibilities. True refractory hypertension is unusual, and a methodologic approach should be taken to help facilitate blood pressure control in these patients because lack of control puts these patients at greater risk for cardiovascular complications.

DRUG TREATMENT OF HYPERTENSIVE URGENCIES AND EMERGENCIES

It is important to distinguish between hypertensive urgency and emergency ( Table 45-36 ). These terms 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.

TABLE 45-36 -- Hypertensive Emergencies

Hypertensive encephalopathy^[*]

Acute aortic dissection^[*]

		Central nervous system bleeding^[*]
		Intracranial hemorrhage
		Thrombotic cerebrovascular accident
		Subarachnoid hemorrhage

Acute left ventricular failure refractory to conventional medical therapy^[*]

Myocardial ischemia or infarction associated with persistent chest pain^[*]

Accelerated or malignant hypertension^[†]

Toxemia of pregnancy: eclampsia^[*]

Renal failure or insufficiency^[†]

Hypertension associated with hyperadrenergic states^[*]

		Pheochromocytoma
		Interaction between monoamine oxidase inhibitors and tyramine-containing foods
		Interaction between an α-adrenergic agonist and a nonselective β-adrenergic antagonist
		After abrupt withdrawal of clonidine or guanabenz
		After severe body burns
		Neurogenic hypertension

Hypertension in the surgical patient^[†]

		Associated with postoperative bleeding
		After open heart or vascular surgery
		Preceding emergency surgery
		After kidney transplantation

Hypertension in the diabetic patient with retinal hemorrhage^[*]

^*	Considered by some authors to be a true hypertensive emergency.
^†	Considered by some authors to be a hypertensive urgency.

A hypertensive emergency is a clinical syndrome in which marked elevation in blood pressure results in ongoing target organ damage in the body. This can be manifested by encephalopathy, retinal hemorrhage, papilledema, acute myocardial infarction, stroke, or acute renal dysfunction. Any delay in control of blood pressure may lead to irreversible sequelae, including death.

These syndromes are unusual but require immediate hospitalization in an intensive care unit, with careful and judicious use of intravenous vasodilators to lower systolic and diastolic blood pressure cautiously to approximately 140/90 mm Hg.

Hypertensive urgencies are clinical situations in which a patient may have marked elevation in blood pressure (greater than 200/130 mm Hg) yet no evidence of ongoing target organ damage. These patients can be treated with rapid-onset drugs such as captopril or clonidine and be observed cautiously with long-acting medications on an outpatient basis as progressive restoration of more appropriate blood pressure level is attained. Thus, the history and physical examination are the critical factors in delineating the difference between these two syndromes. The decision about whether to hospitalize the patient in an intensive care unit and use intravenous medication or to observe the patient carefully and use oral medications to facilitate better blood pressure control depends in large part on the presence or absence of ongoing target organ injury.

A variety of different antihypertensive therapeutic classes are effective in the treatment of hypertensive emergencies. These drugs can be given parenterally and include the direct-acting vasodilators, diazoxide, hydralazine, nitroprusside, and nitroglycerin; the β₁-selective adrenergic antagonist esmolol; the α- and β-adrenergic antagonist labetalol; the central adrenergic methyldopate; the ganglionic blocking agent trimethaphan; the ACE inhibitor enalaprilat; the peripheral α-adrenergic blocker phentolamine; the calcium channel blocker nicardipine; and the dopamine D₁-like receptor agonist fenoldopam mesylate.

Parenteral Drugs, Direct-Acting Vasodilators

Diazoxide is a benzothiadiazine drug that is used primarily in the treatment of acute hypertensive emergencies.^{[497] [498]} It is a pure arterial dilator. The “minibolus” (1 mg/kg administered at intervals of 5 to 15 minutes) and the continuous infusion of diazoxide have become the preferred methods of administration to avoid excessive reduction in blood pressure. Diazoxide acts rapidly, and the blood pressure effect persists up to 12 hours. It has a plasma half-life of 17 to 31 hours, 20% is eliminated unchanged in the urine, and the remainder undergoes hepatic metabolism to inactive metabolites. In renal disease, the plasma half-life is prolonged, and dose reduction is required.

Because diazoxide relaxes smooth muscle at peripheral arterioles, reduction in blood pressure is accompanied by an increase in cardiac output and heart rate, which in susceptible patients can provoke cardiac ischemia. Concurrent administration of a β-adrenergic antagonist controls these reflex vasodilatory responses. Transient hyperuricemia and hyperglycemia occur in the majority of patients. Consequently, the blood glucose level should be monitored. Salt and water retention also occurs, and concurrent diuretic administration is often required. Diazoxide and its metabolites are removed by hemodialysis and peritoneal dialysis, but clearance is relatively low because of its extensive protein binding.

Hydralazine is a direct-acting vasodilator and may be given intramuscularly as a rapid intravenous bolus injection ( Table 45-37 ). It acts rapidly, and the blood pressure effect persists up to 6 hours.^{[497] [498]} It is less potent that diazoxide, and the blood pressure response is less predictable. It may also cause a reflex increase in heart rate and sodium and water retention.

TABLE 45-37 -- Parenteral Drugs Used in the Treatment of Hypertensive Emergencies

Drug	Dosage (Maximal)	Onset of Action	Peak Effect	Duration of Action
Direct-Acting Vasodilators
Diazoxide	7.5–30 mg/min infusion or 1 mg/kg bolus q5–15 min	1–5 min	30 min	4–12h
				(300 mg)
Hydralazine	0.5–1.0 mg/min infusion or 10–50 mg intramuscularly	1–5 min	10–80 min	3–6 h
Nitroglycerine	5–100 μg/min infusion	1–2 min	2–5 min	3–5 min
Nitroprusside	0.25–10 μg/kg/min infusion	Immediate	1–2 min	2–5 min
β₁-Adrenergic Antagonist	250–500 μg/min × 1(loading dose), then 50–100 μg/kg/min × 4 (maintenance); maintenance dose may be increase to maximum 300 mg/kg/min	1–2 min	5 min	10–30 min
α₁- and β-Adrenergic Antagonist
Labetalol	2 mg/min infusion or 0.25 mg/kg	5 min	10 min	3–6 h
Central α₂-Agonist
Methyldopa	250–500 mg bolus every 6 hr (2 g)	2–3 h	3–5 h	6–12 h
Ganglionic Blockers
Trimethaphan	0.5–10 mg/min infusion bolus over 2 min (300 mg)	Immediate	1–2 min	5–10 min
Angiotensin-Converting Enzyme Inhibitor
Enalaprilat	0.625–5.0 mg bolus over 5 min q6h	5–15 min	1–4 h	6 h
Peripheral α-Adrenergic Antagonist
Phentolamine	0.5–1.0 mg/min infusion or 2.5–5.0 mg bolus	Immediate	3–5 min	10–15 min
Calcium Antagonist
Nicardipine	5–15 mg/ h	5–10 min	45 min (∼50%)	50 h
Dopamine D₁-Like Receptor Agent
Fenoldopam	0.01–1.6 μg/min constant infusion	5–15 min	30 min	5–10 min

Sodium nitroprusside is the most potent of the parenteral vasodilators.^{[497] [498]} Nitroprusside acts on the excitation-contraction coupling of vascular smooth muscle by interfering with the intracellular activation of calcium. Unlike diazoxide and hydralazine, nitroprusside 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 blood pressure control (see Table 45-37 ). Disadvantages of nitroprusside therapy include (1) the need for intra-arterial blood pressure monitoring, (2) the need for the drug to be prepared fresh every 4 hours, (3) the need to protect the solution from light during infusion, and (4) the potential for toxic effects from metabolic side products. Nitroprusside is not excreted intact. It is rapidly metabolized to cyanide and thiocyanate through a reaction with hemoglobin, which yields methemoglobin and an unstable intermediate that dissociates to release cyanide. The major elimination pathway of cyanide is conversion in the liver and kidney to thiocyanate. Back-conversion of thiocyanate to cyanide may occur. Thiocyanate is largely excreted in the urine; it has a plasma half-life of 1 week in normal 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 appearance of drug unresponsiveness may reflect an increase in the concentration of free cyanide. 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 blood pressure 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 (see Table 45-37 ). Because nitroglycerin is absorbed by many plastics, dilution should be performed only in glass parenteral solution bottles. Nitroglycerin is also absorbed by polyvinyl chloride tubing; non-polyvinyl chloride intravenous administration sets should be used.

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 blood pressure, 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 because it provides collateral coronary vasodilation, a property not seen with the other direct-acting arteriolar vasodilators. The principal side effects are headache, nausea, and vomiting. Tolerance may develop with prolonged use.

β₁-Selective Adrenergic Antagonist

Esmolol hydrochloride is a short-acting β₁-selective adrenergic antagonist. Esmolol hydrochloride concentrate for injection must be diluted to a final concentration of 10 mg/mL. Extravasation of esmolol hydrochloride may cause serious local irritation and skin necrosis. Esmolol shares all of the toxic potential of the β₁-adrenergic antagonists previously discussed.

After intravenous injection of a loading dose of 250 to 500 mg/kg and then infusion of a maintenance dose ranging from 50 to 100 mg/kg/min, steady-state blood concentrations are achieved within 5 minutes (see Table 45-37 ). Efficacy should be assessed after the 1-minute loading dose and 4 minutes of maintenance infusion. If an adequate therapeutic effect is observed (as assessed by blood pressure and heart rate response), 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.

Esmolol has pharmacologic actions similar to those of other β₁-selective adrenergic antagonists; it produces negative chronotropic and inotropic activity. It has been used to prevent or treat hemodynamic changes induced by surgical events, including increases in systolic and diastolic blood pressure and double product heart rate times systolic blood pressure. Esmolol may be particularly useful for the treatment of postoperative hypertension and hypertension associated with coronary insufficiency.^{[497] [498]} Esmolol is hydrolyzed rapidly in blood, and negligible concentrations are present 30 minutes after discontinuance. Because the kidneys eliminate the de-esterified metabolite of esmolol, the drug should be used cautiously in patients with renal insufficiency.

α₁- and β-Adrenergic Antagonists

The α₁- and β-adrenergic antagonist labetalol chloride may be given by either repeated intravenous injection or slow continuous infusion^{[497] [498]} (see Table 45-37 ). The maximal blood pressure-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. The adverse side effects of labetalol have been discussed previously. It has been proved to be safe and useful in hypertensive urgencies and emergencies in pregnant women.

Central α₂-Adrenergic Agonist

Methyldopate hydrochloride is a central α₂-adrenergic agonist that may be administered intravenously as a bolus infusion (see Table 45-37 ). It has a delayed onset of action and peak effect, and its effect on blood pressure is unpredictable. The adverse side effects of methyldopa have been discussed previously.

Ganglionic Blocking Agent

Trimethaphan camsylate is a ganglionic blocking agent; it blocks transmission of impulses at both sympathetic and parasympathetic ganglia by occupying receptor sites and by stabilizing the postsynaptic membranes against the action of acetylcholine liberated from presynaptic nerve endings. Peripheral vascular resistance is decreased, heart rate is usually increased, and cardiac output is decreased because of venous dilation and peripheral pooling of blood. Trimethaphan is used exclusively for the treatment of hypertensive emergencies.^{[497] [498]} It has an immediate onset of action when administered as a continuous infusion (see Table 45-37 ). The resulting dramatic reduction of blood pressure 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 blood pressure reduction in patients with acute aortic dissection. Other disadvantages include (1) the potential for tachyphylaxis after sustained infusion (48 hours); (2) the appearance of side effects associated with parasympathetic and sympathetic blockade; and (3) histamine release.

Angiotensin-Converting Enzyme Inhibitor

Enalaprilat, the active metabolite of the oral ACE inhibitor enalapril, is administered as a slow intravenous infusion for 5 minutes (see Table 45-37 ) in an intravenous dose that is approximately one fourth of an oral dose. Onset of action occurs within 15 minutes, and the maximal effect is within 1 to 4 hours.^[497] The duration of action is about 6 hours. Adverse effects of enalapril have been discussed previously. In patients with renal insufficiency, the initial dose should be no more than 0.625 mg.

α-Adrenergic Antagonist

Phentolamine mesylate is a nonselective α-adrenergic antagonist used primarily in the treatment of hypertension associated with pheochromocytoma.^{[497] [498]} It has a rapid onset of action when administered intravenously as either a bolus or a continuous infusion (see Table 45-37 ). 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 α-adrenergic blockade, as discussed previously.

Calcium Antagonists

Nicardipine hydrochloride, a dihydropyridine CA, is administered by slow continuous infusion at a concentration of 0.1 mg/mL; each 1-mL ampule (25 mg) should be diluted with 240 mL of a compatible intravenous fluid (not including sodium bicarbonate or lactated Ringer injection), resulting in 250 mL of solution at a concentration of 0.1 mg/mL. There is a dose-dependent decrease in blood pressure. 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 45-37 ). Discontinuation of infusion is followed by a 50% offset of action in 30 minutes, but gradually decreasing antihypertensive effects exist for about 50 hours. Adverse effects of nicardipine have been discussed previously. It has been shown to be safe and effective in pediatric hypertensive emergencies.^{[500] [501]}

Dopamine D₁-like Receptor Agonist

Fenoldopam mesylate, a dopamine D₁–like receptor agonist, is formulated as a solution to be diluted for intravenous infusion for acute hypertensive treatment.^{[502] [503]} It is a rapid-acting vasodilator by functioning as an agonist for dopamine D₁-like receptors and has moderate affinity for α₂-adrenoreceptors.

Fenoldopam is a racemic mixture in which the R-isomers are responsible for the biologic activity. It has vasodilatory effects on coronary, renal, mesenteric, and peripheral arteries in experimental studies; however, not all vascular beds respond uniformly. In humans, it has been shown to increase renal blood flow in both hypertensive and normotensive subjects.

It comes in 1-mL ampules that contain 10 mg of fenoldopam and is diluted for administration as a constant infusion at a rate of 0.01 to 1.6 mg/kg/min (see Table 45-37 ). It produces steady-state plasma concentrations proportional to its infusion rate. 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. About 90% of infused fenoldopam is eliminated in urine and 10% in feces. Elimination is largely by conjugation, not involving cytochrome P-450 enzymes. There are no data on drug-drug interactions.

Side effects include reflex increase in heart rate, increase in intraocular pressure, headache, flushing, nausea, and hypotension.

Rapid-Acting Oral Drugs

A more gradual, progressive reduction in systemic blood pressure may be achieved after the oral administration of drugs having rapid absorption.^[502] These include (1) the α₁- and β-adrenergic antagonist labetalol; (2) the central α₂-adrenergic agonist clonidine; (3) the CAs diltiazem and verapamil; (4) the ACE inhibitors captopril and enalapril; (5) the postsynaptic α₁-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 emergencies are given in Table 45-38 . Note that rapid-acting oral dihydropyridine CAs such as sublingual nifedipine are no longer recommended as they may cause large and unpredictable reductions in blood pressure with resultant ischemic events.^[503]

TABLE 45-38 -- Rapid-Acting Oral Drugs Used in the Treatment of Hypertensive Emergencies

Drug	Dosage (Maximal)	Onset of Action	Peak Effect	Duration of Action
α₁- and β-Adrenergic Antagonist
Labetalol	100–400 mg q12h (2400 mg)	1–2h	2–4 h	8–12 h
Central α₂-Agonist
Clonidine	0.2 mg initially, then 0.1 mg/h (0.8 mg)	30–60 min	2–4 h	6–8 h
Calcium Antagonist
Diltiazem	30–120 mg q8h (480 mg)	<15 min	2–3 h	8 h
Verapamil	80–120 mg q8h (480 mg)	<60 min	2–3 h	8 h
Angiotensin-Converting Enzyme (ACE) Inhibitors
Captopril	12.5–25 mg qh (150 mg)	<15 min	1 h	6–12 h
Enalapril	2.5–10 mg q6h (40 mg)	<60 min	4–8 h	12–24 h
α₁-Adrenergic Antagonist
Prazosin	1–5 mg q2h (20 mg)	<60 min	2–4 h	6–12 h

Clinical Considerations in the Acute Reduction of Blood Pressure

The acute reduction of blood pressure carries the risk of impairing blood supply to vital structures such as the brain and the heart. Consequently, every effort should be made to avoid excessive reduction of blood pressure. The risk of over-reduction of blood pressure in a rapid fashion was evidenced in a review published by Grossman and colleagues^[503] linking the use of sublingual nifedipine capsules with stroke and heart attack in hypertensive subjects. Because this approach is variable and rapid, clinicians were unable to set a lower limit of blood pressure achieved with therapy.

Cerebral blood flow is normally carefully autoregulated such that sufficient perfusion is maintained during lower levels of blood pressure and perfusion is diminished during states of chronic hypertension to avoid cerebral edema. With chronic hypertension, the short-term, rapid reduction of blood pressure may decrease cerebral blood flow sufficiently to precipitate ischemia and infarction. This may be particularly important in patients with atherosclerotic disease of the cerebral blood vessels in whom there may be areas of uneven cerebral perfusion. Although drugs that do penetrate the blood-brain barrier, such as hydralazine, sodium nitroprusside, and nicardipine, dilate cerebral vessels and may lessen the likelihood of ischemia, intrinsic vascular disease may render some areas more ischemic than others with blood pressure reduction. In addition, potent cerebral vasodilators could conceivably cause a rise in intracranial pressure, creating the potential for cerebral edema and possible herniation.

Sudden drops in blood pressure can also interfere with coronary perfusion during diastole and result in myocardial ischemia, infarction, or arrhythmia. In addition, rapid reduction of blood pressure may result in a reflex increase in heart rate, which would also interfere with coronary perfusion during diastole. For these reasons, careful, cautious, and controlled reduction in blood pressure 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 as it facilitates coronary vasodilation. Patients with acute aortic dissection are best treated with a β-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 a hydralazine, nitroprusside, nicardipine, or fenoldopam. Fenoldopam may be helpful in patients with kidney diseases, as it maintains renal blood flow.

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