CHAPTER 28 Antihypertensive Drugs
About 29% of Americans have hypertension, and it is the leading cause of cardiovascular disease worldwide.10 Careful examination of the prevalence of hypertension reveals that it is distributed disproportionately among subgroups in the U.S. population. Hypertension increases with advancing age, but its prevalence is much lower in women before menopause than in men of comparable age. There also seems to be a racial component to hypertension3: the prevalence is approximately 23% in whites and Mexican Americans but is 32% in African Americans.
Because of the asymptomatic nature of this disease, approximately one third of affected individuals are unaware of their condition. Isolated systolic hypertension affects more than 15% of all people older than 60 years. Studies suggest that only half of hypertensive patients receive pharmacologic treatment at all, and, of this fraction, only half have adequate control of blood pressure levels. Because the long-term consequences of hypertension (e.g., coronary artery disease, stroke, renal failure) are so devastating to health, screening programs are essential to detect the disease early so that treatment can be instituted before major complications ensue. Education of patients is also essential to ensure compliance with recommended therapy because of the insidious nature of the disease and because unpleasant side effects of the drugs used to treat it may cause the patient to feel better when not receiving medication. An individual is considered hypertensive if his or her systolic or diastolic arterial blood pressure (or both) is elevated above normal (i.e., systolic arterial pressure >140 mm Hg or diastolic arterial pressure >90 mm Hg).2
The severity of hypertension is classified as shown in Table 28-1. Hypertension can arise as a primary disease or as a result of an underlying illness. Essential hypertension is a term used to describe the presence of sustained, elevated blood pressure for which no cause is apparent. When this term was coined, it was believed that the elevation of blood pressure was essential to maintain organ perfusion in the affected patient. This idea is no longer widely accepted, but the term is still in use. Essential hypertension remains of unknown etiology and represents 80% to 90% of all cases of hypertension. Although much is known about the cardiovascular changes that occur as a consequence of prolonged elevation of blood pressure, no single pathologic change can be cited as the primary cause. Many theories abound regarding the causes of essential hypertension, some of which are discussed subsequently.
Secondary hypertension results from a known disorder, such as renal, vascular, or parenchymal disease, or from an endocrine disorder such as pheochromocytoma. Treatment of secondary hypertension usually consists of therapy for the underlying disease process. Hypertension may be systolic or diastolic, or both. Until more recently, less emphasis had been placed on the importance of systolic hypertension. More recent evidence indicates, however, its close association with untoward outcomes.23 Treatment of isolated systolic hypertension in elderly patients with an antihypertensive drug has been shown to reduce mortality rates, especially from stroke.14,19 The results are independent of mean arterial pressure. The risk of heart failure is also decreased with reduction in systolic hypertension.13 It has been suggested that the incidence of dementia is reduced as systolic pressure is reduced in elderly patients.16
In metabolic syndrome, hypertension is accompanied by abdominal obesity, hyperlipidemia with atherosclerosis, and hyperglycemia or insulin resistance or both.22 In this syndrome, hypertension is only one target of therapy. Questions that are still being explored are to what extent each sign of the syndrome is related and how.
Pressure in a hydraulic system is the product of flow through the system and the resistance to such flow. The relationships between mean arterial blood pressure (MAP), cardiac output (CO), and total peripheral resistance (TPR) can be described in the following equation:
CO is determined by the load presented to the heart (venous return or preload) and the inotropic and chronotropic state of the myocardium. TPR depends on the diameter and compliance (stiffness) of the arterioles. These factors are regulated by the resting vascular smooth muscle tone, intrinsic reactivity of the vasculature, vasoactive substances in the blood, and sympathetic nervous system activity. Another important factor in the governance of blood pressure is the blood volume, which is regulated by the kidneys. The interrelationships among all these factors are illustrated in Figure 28-1.
Blood pressure tends to remain at a constant value, and there are many physiologic control mechanisms to protect the organism from harmful perturbations in blood pressure. Two of the most important regulatory mechanisms are short-term control afforded by the sympathetic nervous system and long-term control, which is a function of the renal system.
Moment-to-moment control of blood pressure largely depends on baroreflexes, in which sympathetic nervous system output to the heart, resistance vessels, and capacitance vessels is adjusted in response to feedback from baroreceptors in the carotid sinus and aortic arch. These baroreceptors respond to mechanical stretch (increased pressure) by increasing the firing rate of sensory neurons that innervate blood pressure control areas of the central nervous system (CNS). If blood pressure increases, the resultant increased activity of these sensory neurons inhibits efferent sympathetic nervous system activity, reducing heart rate, vascular tone, and blood pressure. Conversely, if blood pressure suddenly decreases, baroreceptor output is reduced, allowing increased peripheral sympathetic discharge. This reflex is responsible for the maintenance of blood pressure during rapid stresses to cardiovascular homeostasis, as induced by a change in posture.
Long-term stresses on the maintenance of blood pressure (e.g., alterations in water and salt intake) are handled by the kidneys. A change in blood pressure is sensed by the kidneys as a corresponding change in renal perfusion pressure. This disturbance invokes two compensatory mechanisms. First, the tubular reabsorption of Na+ and water either decreases (in high perfusion pressure) or increases (in low perfusion pressure). This alteration adjusts blood volume and secondarily changes CO to bring blood pressure back to normal. The kidneys also influence resistance vessel tone more directly by releasing renin (activating the renin-angiotensin system) when renal perfusion is diminished. The resultant increase in vasoactive angiotensin peptides increases peripheral vascular resistance by causing vasoconstriction. Angiotensin peptides also promote volume retention by increasing the release of aldosterone and contribute to muscular hypertrophy and other structural changes in the heart and vasculature (collectively referred to as remodeling).4
The physiologic mechanisms that control blood pressure are important in the treatment of hypertension in two respects. First, each of these mechanisms represents a potential therapeutic target for reducing blood pressure in a hypertensive patient. Second, because these mechanisms are in place to prevent changes in blood pressure, they become activated in an attempt to restore blood pressure to its former (high) level when steps are taken to reduce the hypertension.
The physical findings of a patient with essential hypertension usually reveal that CO is normal and TPR is elevated. In a hypertensive patient, the baroreceptor reflexes function normally, but have been “reset” to maintain MAP at a higher than normal value. The reasons for this shift are not yet understood and are the subject of intensive research. It is evident that there is a genetic component to essential hypertension and that certain risk factors lead to a worsening of blood pressure elevation (Box 28-1). In many patients, long-term cardiovascular complications of hypertension can be controlled solely by making appropriate lifestyle changes.
Although the cause of essential hypertension is unknown, it is well established that high blood pressure leads to cardiovascular and renal disease. Elevated blood pressure is directly correlated with overall mortality (Figure 28-2). It is accepted that reducing the blood pressure in hypertensive patients reduces the risk of cardiovascular events including myocardial infarction and stroke, and kidney failure.23,26 The damage caused by decades of elevated arterial pressure can be seen in the form of left ventricular hypertrophy, medial thickening of arteries, and nephropathy.18,26 These changes contribute to the development of diseases such as congestive heart failure, coronary artery disease, stroke, aneurysm, and renal failure (Box 28-2). Numerous clinical trials have shown a reduction in morbidity and mortality rates after pharmacologic reduction in blood pressure in hypertensive patients.
(Adapted from The Society of Actuaries and the Association of Life Insurance Medical Directors of America: Blood pressure study 1979, Boston, 1980, The Society.)
Diabetic patients are particularly vulnerable to targeted organ damage resulting from hypertension. The current standard of care dictates that antihypertensive therapy be prescribed in diabetics whose blood pressure is in the high-normal range or above (see Table 28-1). Angiotensin-converting enzyme (ACE) inhibitors are most commonly used for this purpose because of their well-documented protective effects in diabetic patients.4,21
Treatment of essential hypertension consists of therapy aimed at reducing the blood pressure into the normal range. As shown in Figure 28-1, many factors play a role in the determination of blood pressure, and consequently pharmacologic agents with diverse mechanisms of action can be used singly or in combination to treat essential hypertension. Antihypertensive agents can be categorized according to their mechanism of action and therapeutic use: diuretics, drugs affecting angiotensin, Ca++ channel blockers (CCBs), drugs affecting sympathetic function, direct-acting vasodilators, and miscellaneous drugs. Because the basic pharmacologic properties of many drugs useful in treating hypertension are discussed elsewhere, only pharmacologic features pertinent to the treatment of hypertension are discussed in detail in this chapter. Figure 28-3 shows the major sites of action of antihypertensive agents.
Thiazide diuretics are currently among the most widely used drugs for the initial management of essential hypertension. K+-sparing diuretics are commonly used together with thiazides for their additive effect and to prevent thiazide-induced hypokalemia. Thiazide diuretics may be used alone or in combination with other antihypertensive drugs. Loop diuretics such as furosemide are also useful as adjunctive agents in refractory hypertension.
Diuretics reduce plasma volume by increasing Na+ and water excretion. Initially, this effect reduces blood pressure by decreasing CO. With time, CO and extracellular fluid volume return toward normal values, but the hypotensive effect persists because of a reduction in peripheral resistance. It is probable that electrolyte changes in vascular smooth muscle account for the vasodilation. For a complete discussion of diuretics used in the treatment of hypertension, see Chapter 27.
The role played by the renin-angiotensin system in hypertension has received much attention in recent years.4,25 Renin catalyzes the conversion of angiotensinogen, a glycoprotein found in the blood, to angiotensin I, a decapeptide with little cardiovascular activity (see Figure 28-3). Angiotensin I is activated by conversion to the octapeptide angiotensin II. This reaction is catalyzed by ACE, otherwise known as dipeptidyl carboxypeptidase or peptidyl dipeptidase. Under its designation as kininase II, ACE is also the enzyme that inactivates bradykinin.
Angiotensin II is metabolized by aminopeptidase enzymes to yield the less active and shorter lived heptapeptide angiotensin III. Increased renin activity leads to heightened production of angiotensin II and angiotensin III, vasoconstriction of peripheral arterioles, and elevation of blood pressure. Angiotensin peptides stimulate thirst and the secretion of aldosterone and antidiuretic hormone; the resultant increase in extracellular fluid and electrolytes augments the direct pressor effects. Angiotensin II also influences sympathetic nervous system function centrally and peripherally to increase cardiac activity and peripheral vascular resistance.
Patients with essential hypertension can be divided into three groups according to their renin-Na+ index (i.e., plasma renin activity relative to Na+ excretion). Approximately 15% of patients have renin concentrations higher than normal, 25% have renin concentrations lower than normal, and the remaining 60% exhibit normal renin titers. Renin titers tend to decrease with age. African American and elderly individuals tend to have a higher incidence of low-renin hypertension.
The percentage of hypertensive patients with normal renin activity may be misleading because renin release is ordinarily depressed as the result of increased blood pressure. Renin release may still be inappropriately high even in the “normal” group. Although angiotensin II may be the main causative agent in high-renin hypertension and may be a factor in the normal-renin hypertension group, other influences are implicated in low-renin hypertension, and these may contribute to normal-renin hypertension as well.
Pharmacologic intervention to reduce blood pressure theoretically can be anywhere along the angiotensin system—from the release of renin by the kidney juxtaglomerular cells, to the formation of angiotensin peptides, to the binding of angiotensin II and angiotensin III to receptors in vascular smooth muscle and other effector sites. In the following discussion, attention is limited to drugs whose primary mechanism of action is interference with renin synthesis, renin activity, conversion of angiotensin I to angiotensin II, or action of angiotensin II at its receptor. Other antihypertensive drugs also affect the renin-angiotensin system, however. β-Adrenergic receptor antagonists inhibit renin release by acting at β1-adrenergic receptors in the juxtaglomerular apparatus of the kidney. Undesired reflex actions can also occur in which diuretics and direct-acting vasodilators stimulate renin release. Studies indicate that, regardless of the specific drug regimen, treatment of hypertension eventually tends to restore renin to normal levels, whether it was initially high or low.
ACE inhibitors are among the most commonly used drugs for the treatment of essential hypertension. Captopril, the first drug of this class to be developed, was specifically designed to disrupt the renin-angiotensin pathway. Its structure is shown in Figure 28-4. Captopril differs from other ACE inhibitors because it contains a sulfhydryl group. Enalapril, lisinopril, and most of the other ACE inhibitors have an amino acid substitution. Fosinopril contains a phosphorus linkage.
Drugs that inhibit ACE block the conversion of angiotensin I to angiotensin II (Figure 28-5; see Figure 28-3).4 ACE inhibitors markedly decrease blood concentrations of angiotensin II and induce an immediate decrease in blood pressure. They may also act to maintain the lowered blood pressure by elevating bradykinin (a potent vasodilator) concentrations in the blood (see Figure 28-5). (As previously mentioned, ACE, as kininase II, is responsible for the breakdown of bradykinin.) ACE inhibitors have an antihypertensive effect even in patients without high renin activities. Over the course of several weeks, blood pressure is progressively reduced, mainly through decreased peripheral resistance, with little effect on CO or renal blood flow. Salt and water retention is not induced, and orthostatic hypotension and tachycardia are not problems.
FIGURE 28-5 The role of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) in treating hypertension. ACEIs block the major, but not the only, synthetic pathway to angiotensin II. ACEIs also increase the concentration of bradykinin and other tachykinins, leading to vasodilation and some undesirable effects. ARBs block the effect of angiotensin II by whatever synthetic pathway because they block the AT1 receptor and the response to AT1 receptor stimulation. The ARBs do not block the AT2 receptor. This is considered a benefit of ARBs because the AT2 receptor mediates vasodilation, inhibition of growth and proliferation, and apoptosis. Angiotensin-converting enzyme (ACE) located in tissues is less affected by ACEIs. Enzymes are underlined. GFR, Glomerular filtration rate.
The reduction in angiotensin II concentrations as a result of ACE inhibition leads to a decrease in aldosterone secretion, which results in an increase in Na+ and water excretion. Correspondingly, there is a net increase in the reabsorption of K+ in the kidney tubule. Hypokalemia is not an adverse effect of ACE inhibitors. K+ supplements and K+-sparing diuretics should not be used concurrently with ACE inhibitors to avoid hyperkalemia. With long-term ACE inhibitor therapy, deleterious cardiovascular remodeling may be reduced or even reversed.4,5,26 ACE inhibitors are also renoprotective and because of this are useful drugs in patients with chronic renal disease and diabetes. The presence of high normal (or above normal) blood pressure and diabetes is a clear indication for the use of an ACE inhibitor.
The onset of action of captopril is rapid, and the duration of effect is short, requiring administration two to three times daily. Its elimination half-life is approximately 2 hours. Because food in the gastrointestinal tract significantly reduces the absorption of captopril, the drug should be taken 1 hour before meals. Approximately 40% of captopril is metabolized in the liver, and most of the metabolites and the parent drug are excreted by the kidney.
Lisinopril is less well absorbed than captopril, resulting in peak plasma concentrations after approximately 7 hours. The slow elimination half-life of roughly 12 hours permits single daily dosing of the drug. Lisinopril is excreted unchanged in the urine.
Enalapril (see Figure 28-4) is a prodrug that must be hydrolyzed in the liver to become fully active. Its absorption is not influenced by food, and it has a longer duration of effect than captopril. The active metabolite enalaprilat, with a plasma half-life of 11 hours, provides for the extended action. Enalaprilat is not absorbed from the gastrointestinal tract but is effective after intravenous administration; it has been marketed for such use in patients unable to take drugs orally. Other ACE inhibitors with an esterified carboxyl side chain are also activated (by hydrolysis) in the liver to “prilat” metabolites that avidly bind to ACE and provide durations of effect sufficient for single daily dosing. The other ACE inhibitors are listed at the end of this chapter. They differ primarily in their pharmacokinetic properties.
The most frequent side effect of the ACE inhibitors is coughing, which occurs in 20% of patients.4 Altered or reduced taste sensation is also common, especially with captopril. These adverse effects may disappear after continued use. The significance of reported cases of proteinuria is not established at this time. Other adverse effects that have been documented are skin rash; angioedema of the face, mucous membranes of the mouth, or extremities; and flushing, pallor, and hypotension. Angioedema is a serious condition that demands withdrawal of the drug. Hyperkalemia and neutropenia may rarely occur.
ACE inhibitors may cause renal insufficiency in patients with bilateral renal stenosis. The mechanism is the reduction of renal angiotensin II production, leading to a disproportionate dilation of efferent renal blood vessels compared with afferent vessels. This vascular imbalance results in a significant decline in the glomerular filtration rate. ACE inhibitors can help preserve renal function in diabetic patients.4,26 ACE inhibitors have the beneficial effect of reducing proteinuria in patients with some renal diseases.
Although ACE inhibitors are not known to be teratogenic during the first trimester of pregnancy, they can cause significant developmental defects and fetal death later on. After pregnancy has been established, discontinuance or substitution with another antihypertensive agent is mandatory.
Losartan (as losartan potassium) was the first orally active angiotensin II receptor antagonist to be introduced (Figure 28-6). Other angiotensin II antagonists include candesartan, eprosartan, irbesartan, telmisartan, and valsartan. These nonpeptide analogues of angiotensin bind to the angiotensin II receptor and competitively inhibit the action of angiotensin II and angiotensin III.4,6 They are selective inhibitors of the AT1 receptor, the angiotensin receptor subtype that accounts for the major physiologic effects of angiotensin II. The effect is to inhibit the consequences of AT1 receptor stimulation without affecting potentially beneficial effects mediated by the AT2 receptor (see Figure 28-5).23 As is the case with ACE inhibitors, AT1 receptor blockers reduce the blood pressure and the tissue remodeling seen in hypertension and reduce organ damage resulting from hypertension.4,15,26
Losartan has a half-life of only 1.5 hours, but it is metabolized to an active metabolite with a longer half-life. Valsartan has a plasma half-life of 6 hours; it is excreted in the bile largely in the unchanged form. The half-lives for the other angiotensin II blockers range from 6 hours for eprosartan to 24 hours for telmisartan. The selectivity of angiotensin II antagonists avoids some of the side effects of ACE inhibitors, such as coughing and angioedema, because the bradykinin pathway is not affected by the angiotensin II antagonists (see Figure 28-5). Orally effective angiotensin II receptor antagonists now constitute a major drug group for treating hypertension.5
The renin inhibitor aliskiren has been approved for use in the United States as a once-daily treatment for stage 1 hypertension (see Table 28-1). Aliskiren binds with high specificity to the proteolytically active site of human renin.21 Renin is the rate-limiting step in the renin-angiotensin system, so inhibition of this enzyme provides a logical control point for pharmacologic intervention. Aliskiren reduces circulating concentrations of angiotensin I and angiotensin II, producing a decrease in systolic and diastolic blood pressure, comparable to reductions seen with ACE inhibition or AT receptor antagonism. Early reports on toxicity are favorable. Based on the mechanism of action, expected adverse events include hyperkalemia and hypotension. Aliskiren administration produces hyperreninemia owing to a compensatory increase in renin release. This effect is not clinically significant. Aliskiren does not interfere with ACE-induced catabolism of bradykinin, and it is not expected that cough or angioedema would be produced by this class of drugs (as seen in ACE inhibitors). Similar to other inhibitors of the renin-angiotensin system, aliskiren is contraindicated in patients with bilateral renal artery stenosis and during pregnancy. Aliskiren has a poor bioavailability and is greater than 90% excreted unchanged in the feces, so minimal drug metabolism interactions are expected from this drug.
Verapamil, diltiazem, and nifedipine were the first CCBs to be marketed. The pharmacologic features of nifedipine and its dihydropyridine congeners, including amlodipine, felodipine, isradipine, nicardipine, nimodipine, nisoldipine, and nitrendipine, are addressed in this chapter. Other CCBs are discussed in Chapters 24 and 26.
All CCBs prevent Ca++ influx into smooth and cardiac muscle cells. The potency of these drugs for each of these actions varies, however, producing some important clinical distinctions between the dihydropyridines and verapamil and diltiazem. These latter two drugs inhibit Ca++ influx into vascular smooth muscle and the heart with roughly the same potency. The effect of verapamil and diltiazem is to reduce blood pressure by vasodilation and reduced CO. Dihydropyridines such as nifedipine are much more potent at inhibiting Ca++ influx at vascular smooth muscle than in the heart. At clinically relevant plasma concentrations, nifedipine produces a pronounced vasodilation with little direct effect on cardiac function. Reflex tachycardia is a common side effect with dihydropyridines but is almost never seen with verapamil and diltiazem. CCBs are contraindicated in patients with cardiac conduction defects and in heart failure. CCBs are useful drugs for treating low-renin hypertension.
Dihydropyridines enhance the glomerular filtration rate and renal blood flow. Some patients taking dihydropyridines develop pedal edema. This condition does not result from fluid retention but rather from precapillary dilation. Renal Na+ excretion may be enhanced. The antihypertensive effect and an apparent direct renoprotective effect of these drugs may make them useful in treating chronic renal failure.
The plasma half-lives of most CCBs (diltiazem, isradipine, nicardipine, nifedipine, and verapamil) are 2 to 8 hours. The half-lives of the others are as follows: amlodipine, 30 to 50 hours; felodipine, 10 to 16 hours; nimodipine, 1 to 2 hours; nisoldipine, 7 to 12 hours; and nitrendipine, 10 to 20 hours. Long-term therapy may be associated with some increase in half-lives for some CCBs.
The elimination half-life and duration of action influence the clinical use of these agents. The short time course of nimodipine, along with its relative ability to cross the blood-brain barrier, limits the drug’s suitability for the treatment of chronic disease but permits its use to prevent vasospasm subsequent t/>