pharmacologic management of systemic hypertension in blacks

Pharmacologic Management of Systemic Hypertension in Blacks

MATTHEW R. WEIR, MD, and ELIJAH SAUNDERS, MD

This article contrasts the characteristics of essential hypertension found in the black population with that seen in the nonblack population. Socioeconomic and pathophysiologic factors are discussed. Dfffer- ent pharmacofoglc classes of drugs are compared for their effectiveness in treating the black hypertensive patient. Because black hypertensives tend to have saft-sensitfve, low-renin hypertension coupled

wfth decreased cardiac output and hfgh perfpheral vascular resistance, an ideal antihypertensive should have natrfuretic effects but atso the physiologic capabilfty of reducing vascular resistance. Such an ideal hypertensive drug would be able to lower systemic blood pressure while improving organ perfusion and function.

(Am J Cardiol 1988;61:46H-52H)

H ypertension is more prevalent in the black population than in the nonblack population. The prevalence of hypertension among blacks in the United States is 38.2% compared with 23.3% among nonb1acks.l Ap- proximately 25% of the black population has uncontrolled hypertension compared with 16% of the nonblack population .2 Blacks have an abnormally high rate of ischemic heart disease mortality and have 3 to 4 times the rate of fatal stroke found in the overall Unit- ed States population2

The reasons hypertension in the black population displays such alarming statistics remains unknown. However, because the black, hypertensive population can be younger and manifest earlier cardiovascular disease, unphysiologic selections of antihypertensive agents could lead to more adverse effects, reduce the quality of life and lead to noncompliance. The traditional stepped-care therapy of diuretics, /3 blockers and vasodilators disregards certain clinical, hemodynamic and biochemical factors that can have significant impact on long-term morbidity and mortality in black patients with hypertension.

This study will discuss the characteristics of hypertension in the black population and contrast the avail- able classes of antihypertensive medications and their usefulness for the black patient. The major classes of

From the Divisions of Nephrology and Hypertension, Depart- ment of Internal Medicine, University of Maryland Hospital, Baltimore, Maryland.

Address for reprints: Matthew R. Weir, MD, Renal Division, University of Maryland Hospital, 22 South Greene Street, Balti- more, Maryland 21201.

drugs to be discussed include diuretics, ,6 blockers, adrenergic inhibitors, nonspecific vasodilators, angiotensin-converting enzyme [ACE) inhibitors and calcium channel blockers.

Characteristics of Hypertension in the Black Population

Essential hypertension in blacks differs greatly from essential hypertension in the nonblack population. Major differences in socioeconomic factors and pathophysiologic characteristics are believed to have resulted in a poorer response to traditional treatment in the black than in the nonblack population.3

Socioeconomic factors: A specific genetic basis for the differences between hypertension in black and nonblack patients has not been found to date. Other factors such as socioeconomic problems are thought to contribute to the severity and complications of black hypertension. The relatively low distribution of health-care professionals in the black community results in decreased access to care. This, together with the relatively high cost of treatment compared with income levels, is believed to contribute to the high rate of undetected, untreated and uncontrolled hypertension in this population.3*4

Several positive steps are now being taken to over- come the socioeconomic barrier to care. Assistance such as help with transportation, providing inexpen- sive or free medication, making clinic hours more convenient and addressing babysitting problems can have a positive impact on treatment.4

Another sociologic problem is believed to be a rela- tive lower educational level, leading to misconcep-

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tions about this asymptomatic disease in the general public.3 Patients who do not understand their disease and its medications cannot be expected to comply ade- quately with treatment. Better communication and educational programs coupled with medications that simplify compliance, such as once- or twice-daily for- mulations, may encourage patient cooperation.

Pathophysiologic characteristics: Hypertension in the black population is characterized by earlier onset, increased severity, and different hemodynamic and biochemical factors compared with the nonblack pop- ulation3 The following paragraphs will expand on these characteristics.

Onset of hypertension: The onset of hypertension occurs at an earlier age in the black population compared with the nonblack population.3 Even at first screening, blacks have higher levels of diastolic blood pressure than do nonblacks. This difference holds true for both men and women, and for both mild to moderate and severe hypertension.

Severity of hypertension: Hypertension not only begins earlier in life for the black patient but the disease also often takes an accelerated course.5 Black patients are at greater risk for hypertensive complications at a younger age. They are prone to have atherosclerosis, left ventricular hypertrophy leading to heart failure, vascular smooth muscle hypertrophy and nephrosclerosis resulting in kidney failure.5v6 Car- diac hypertrophy in black patients results from elevated cardiac work in the setting of expanded total blood volume, which is associated with a high-salt diet coupled with an increased peripheral vascular resistance due to hypertension, This hypertrophy can lead to increased ventricular ectopy and impaired coronary re- serve.7 As the hypertensive process progresses, elevation of intraglomerular pressure may occur, ultimately leading to nephrosclerosis and a decline in renal func- tions Until recently, it has not been appreciated that reduction in systemic blood pressure does not invari- ably result in glomerular capillary pressure reduction, and that reduction of intraglomerular pressures is nec- essary to provide protection of renal tissue from the glomerulosclerotic effects of hypertension.g

When black patients are treated with medications to retard or prevent the vascular destructive properties of hypertension, they often exhibit a decreased efficacy profile for various antihypertensive therapies compared with nonblack hypertensives. This decreased efficacy may be related to the special hemodynamic factors that characterize black patients.

Hemodynamic factors: The special hemodynamics of black hypertensive patients are summarized in Ta- ble I. Hypertension in black patients is characterized by salt sensitivity, a tendency toward expanded plasma volume [although this can vary], low-renin production, and low cardiac output with increased peripheral and renal vascular resistances.lOJ1 In the black patient these characteristics frequently occur even in the younger patient. This contrasts significantly with the younger nonblack hypertensive having high cardiac output, normal peripheral resistance, normal plasma volume and salt insensitivity, but is somewhat similar

TABLE I Pathophyslologlc Considerations In Black Patients

Lowered cardiac output Increased peripheral vascular resistance Renal vascular resistance higher Renal blood flow significantly decreased Low-renin levels Tendency toward expanded intravascular volume

to the older nonblack hypertensive with salt sensitivity, decreased cardiac output, high peripheral vascular resistance and contracted total blood volume.12

Biochemical factors: Certain biochemical abnormalities are seen in black hypertensives that would conceivably be of a genetic basis, yet no specific genetic factor has been definitely proven.

Black hypertensive patients tend to have increased sodium:potassium ratios in their urine,13J4 reduced natriuretic vasodilatory prostaglandins and kinins,15 different sodium-potassium and sodium-lithium counter- transport in red cells,16J7 and diminished sympathetic nervous system function l8 to possibly explain their tendency toward renal salt retention and plasma ex- pansion.lg Other investigators have suggested that abnormal cellular handling of calcium or magnesium may lead to excessive vascular hyperreactivity in black patientszOJ1

Ideal therapeutic characteristics of an antihypertensive agent in a black patient: The pathophysiologic factors that characterize the black hypertensive population signify that drugs that are effective for the young, salt-insensitive, higher-renin, nonblack patient will not always be effective for the salt-sensitive, low- renin, black patient. All hypertensives, but especially black patients with their markedly elevated vascular resistance and proclivity for deveIopment of cardiovascular disease, need antihypertensive agents that lower blood pressure and total peripheral resistance, yet maintain tissue perfusion. The ideal drugs would be afterload reducers, which would improve the already decreased cardiac output and expand myocardial reserves. The drugs should also produce a regression of left ventricular hypertrophy while they control pressure, so as to reduce the risk of cardiac death associated with left ventricular hypertrophy.2ZJ3 Further- more, in the ideally treated hypertensive patient, renal blood flow would be maintained or even increased; however, intraglomerular pressures would be reduced because of the marked predisposition for hypertensive renal damage to develop in black hypertensives.10~24~25 Blood pressure should be controlled at a local vascular level in the kidney, brain, heart and other vascular beds in a physiologic way so as to maintain function and perfusion (Table II).

Some major clinical factors that can influence the selection of drugs in the black hypertensive are listed in Table III.

The issue of age and race are of paramount impor- tance in addressing the hemodynamic aspects of the hypertensive process. A physician’s ability to tailor the pharmacologic agent to his patient’s underlying physiology will improve the likelihood of success with the

48H A SYMPOSIUM: THE SALT-SENSITIVE HYPERTENSIVE PATIENT

TABLE II Physiologic Considerations for Blood Pressure Reduction In the Black Hypertensive

Pathophysiologic Findings

Desired Pharmacologic Effects

Low cardiac output Tendency toward expanded

plasma volume High peripheral vascular

resistance Decreased renin activity,

salt sensitivity Decreased renal blood flow Tendency toward left

ventricular hypertrophy

Afterload reduction Natriuretic effect

Physiologic vasodllation

Natriuretic effect

Increased renal blood flow Regression of left

ventricular hypertrophy

TABLE Ill Cllnlcal Factors lnfluenclng Drug Selection

Age-hemodynamic physiology Race-hemodynamic physiology Sex Weight Level of pretreatment blood pressure Efficacy and safety Adverse-effects profile (clinical and laboratory) cost Compliance estimate Concomitant disease (Le., coronary artery disease, obesity, chronic

obstructive pulmonary disease, diabetes and renal) Concomitant medic&Ions (prescription and over-the-counter drugs) Convenience of dosing Exercise profile

agent as well as potentially minimize the risk of adverse effects. Exercise profile and compliance would therefore be improved.

Issues related to coexistent diseases and medications, cost and convenience of dosing are also important aspects of drug selections. Convenient formula- tions (once, or at most twice, daily] that have minimal side effects and yet maintain a good quality of life are especially important in the black hypertensive who tends to be younger and consequently more suscepti- ble to certain kinds of adverse effects.

The different drug classes and highlights of those drugs whose physiologic characteristics improve clinical response and side-effects profile in the black hy pertensive will be discussed.

Diuretics Black patients have been shown to be very respon-

sive to diuretic therapy.l Diuretics from a physiologic standpoint make sense in the black hypertensive who tends to be volume-expanded with increased vascular resistance. However, the degree of diuresis obtained with the diuretic, if great enough to cause volume contraction, could potentially increase peripheral vascular resistance through activation of the renin-angiotensin-aldosterone axis or sympathetic nervous systems, with a negative impact on organ perfusion in the black hypertensive who already has increased vascular resistance. Thus, judicious use of diuretics so as to avoid

the hazards of volume contraction is indicated not only from a physiologic standpoint but also to avoid increased adverse effects.

Although diuretics have proved effective in reducing blood pressure in blacks and nonblack hypertensives, in recent years, knowledge of their adverse metabolic effects are limiting their usefulness. Effects of diuretics include hypokalemia due to urinary potassium loss, 26 hyperuricemia due to elevated uric acid renal reabsorption, carbohydrate intolerance and hyper- lipidemia.27*26

Diuretic-induced hypokalemia can worsen or pre- cipitate ventricular ectopy in patients with cardiac complications of hypertension such as left ventricular hypertrophy.2g-33 Diuretics have not been demonstrated to be helpful in causing regression of left ventricular hypertrophy (Messerli FH, unpublished observations). An increase in cardiac mortality with long-term diuretic treatment has been suspected in certain patient populations despite blood pressure control as a result of cardiac arrhythmias from diuretic-induced hypokalemia.35.36

Recent experimental findings have also raised questions about using diuretics for treatment of hypertension associated with renal disease.g Diuretics, because of volume contraction, stimulate the renin-angiotensin system, elevating intrarenal angiotensin II. This results in vasoconstriction of the efferent arteri- ole, maintaining high glomerular capillary pressures despite a reduction in systemic blood pressure.6*g In a study with hypertensive rats, diuretic therapy did not protect the kidney from intraglomerular hypertension despite reducing peripheral pressure. Other investigators have also shown that the elevation of intrarenal angiotensin II has the potential to increase urinary protein excretion, which is in itself a potential cause for nephrosclerosis.37J8

Antiadrenergic Agents Beta blockers: Beta-adrenergic receptor blocking

agents are believed to reduce blood pressure by blocking sympathetic effects on the heart and adrenergic nerve-mediated release of renin from the juxtaglo- merular cells.3g-42 Young black patients (younger than age 40 years] may be responsive to p-blocker therapy because their renin levels tend to be closer to normal rather than low. Most black patients, however, exhibit low levels of renin** and frequently are less responsive to P-blocker therapy.4 Another reason black patients may not be responsive to &blocker therapy is that /3 blockers primarily decrease blood pressure by reducing cardiac output, not by reducing peripheral resistance. This mechanism is most useful for hypertensive patients having increased cardiac sympathetic nerve activity. Black patients, however, have increased peripheral resistance and often lower cardiac output. In their case, further drug-induced reduction of cardiac output may not be effective in decreasing blood pressure and in fact may be counterproductive by causing symptoms related to low cardiac output.

However, because there is such a high risk of left ventricular hypertrophy and early cardiovascular dis-

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ease in blacks and because these agents can cause regression of left ventricular hypertrophy43 and offer cardioprotection after a myocardial infarction and reduce angina, their use in black hypertensive patients with ischemic heart disease may be indicated.44-46 La- betalol, a p blocker with more predominant a-blocking effects, has recently been demonstrated to be more effective than “true” p blockers in treating hypertensive blacks.47 Pindolol, a p blocker with intrinsic sym- pathomimetic activity, has also been shown to be more effective in black hypertensives as the dose is increased.48 The improved success of these drugs is probably due to their ability to reduce the elevated peripheral vascular resistance so often seen in the black hypertensive. Because labetalol does not appear to have natriuretic effects, which is important in the black patient who tends to be volume-expanded, the addition of a low dose of a thiazide diuretic will frequently improve the control rate of hypertension. In fact, all the ,8 blockers are more effective when used in conjunction with a low dose of a thiazide diuretic.

Beta blockers have several adverse effects, includ- ing bronchospasm, bradycardia, impotence, night- mares and hallucinations. In addition, concerns about metabolic abnormalities have also been raised about the cardioselective and nonselective p blockers.4g*50 Patients with left ventricular dysfunction, peripheral vascular disease or bronchospastic pulmonary disease can have their condition aggravated by /3-adrenergic blockade. Thus, although p blockers may be of use in some patients as monotherapy and are certainly important in patients with coronary artery disease, they may not be effective without diuretic support for many black patients; also, they are not always physiologic unless a hyperadrenergic component exists in the patient’s hypertension.

Alpha blockers/centrally acting agents: Alpha blockers, in contrast to /3 blockers, decrease blood pressure by ‘reducing total peripheral resistance.51 There is no effect on cardiac output and there are no known adverse effects on electrolytes or glucose metabolism. The (Y blocker, prazosin, may also reduce total cholesterol and increase high-density lipoprotein cholesterol levels.52*53 Although CK blockers are effective in dealing with the problem of increased vascular resistance in the black hypertensive, they do not deal with the problem of expanded plasma volume because they lack natriuretic effects. Thus, their use as monotherapy in black hypertensives, although beneficial, is not as effective unless used in combination with a diuretic.54 Alpha-blocking therapy can be limited by adverse effects such as orthostatic hypotension, tachycardia, and occasionally salt and water retention.

Centrally acting agents primarily act through de- pressing central nervous system outflow.55 Like the (Y blockers, they tend to maintain peripheral and organ perfusion but lack significant natriuretic effects, which limit their use as monotherapy in the black hypertensive. Although these agents lack metabolic problems, they do have adverse effects related to the depression of the sympathetic nervous system, which may limit their use in selected patients.

Vasodilators Nonspecific vasodilators such as hydralazine and

minoxidil reduce blood pressure by reducing arterial resistance.56 Unfortunately, the effect on peripheral resistance is partly negated by reflex increases in sympathetic discharges that increase heart rate, cardiac output, plasma norepinephrine concentrations and plasma renin activity. 56 Additionally, abnormalities in the lipid profile may occur from sympathetic nerve stimulation.57

Recent studies suggest that vasodilators may be det- rimental in treating hypertension associated with renal disease.8 Vasodilators stimulate the renin-angiotensin system and thus intraglomerular pressures may be increased despite a reduction in systemic blood pressure. In black hypertensives with increased risk for hypertensive renal damage, this poses hypothetical risks. During long-term treatment with vasodilators, fluid and salt retention is also a complication owing to a reduction in effective arterial blood flow to the kidney.56 The black patient who already has expanded intravascular volume is thus at further risk for worsen- ing of their hypertension.

With the use of diuretics, vasodilators are more effective as antihypertensives, but adverse effects and frequent dosing limit their use in the younger black hypertensive.

Angiotensin-Converting Enzyme Inhibitors ACE inhibitors decrease systemic blood pressure

by inhibiting the formation of angiotensin.11 not only in the peripheral circulation but also at the tissue leve1.58~5g

ACE inhibitors, in addition to decreasing systemic blood pressure, can reduce intraglomerular pressures and cause regression of left ventricular hypertrophy, ventricular ectopy, and potentially reduce the risk of coronary artery disease as well as congestive heart failure.**60-63 Thus, ACE inhibitors have excellent potential to reduce some of the major cardiovascular complications of hypertension64 which is important in the black hypertensive predisposed to early and accelerated cardiovascular disease. ACE inhibitors appear to have limited adverse effects and a good quality of life compared with other traditional antihypertensive agents.65 The only major concern with their use occurs in patients with reduced effective arterial blood volume to the kidney where functional insufficiency may occur if excessive diuresis takes place. Adverse effects are unusual, but can occur if captopril is used excessively in.patients with renal dysfunction or enalapril is used excessively in patients with hepatic im- pairment.66

Although ACE inhibitors are most effective as monotherapy in patients with middle- to high-renin profiles (salt-insensitive), black patients appear less responsive to monotherapy than nonblacks because of their low-renin, salt-sensitive profile.64 Thus, ACE inhibitors are most effective in the black hypertensive if combined with thiazide diuretics. They are also partic- ularly suited to patients who have symptoms of conges-

SOH A SYMPOSIUM: THE SALT-SENSITIVE HYPERTENSIVE PATIENT

tive heart failure or conduction system disease in which other agents such as fi blockers or calcium antagonists would be relatively contraindicated.

Calcium Channel blocking Agents Calcium antagonists effectively decrease blood

pressure in a specific way through a physiologic relax- ation of resistance vessels due to inhibition of intra- cellular calcium accumulation.67 The physiologic re- laxation does not cause reflex stimulation of the sympathetic nervous system and renin-angiotensin system. Although there are slight variations within the group of calcium antagonists, there generally is no /3 receptor-mediated tachycardia and increased myocardial contractility, and no reflex a! receptor-mediated vasoconstriction or sodium and fluid retention.68

Recent experimental and human studies also suggest that the decrease in cytosol ionized calcium results in decreased sensitivity of the vasculature to angiotensin II and norepinephrine.Gg Investigators have demonstrated that calcium antagonists appear to protect the renal vasculature from the smooth muscle mito- genie effects of angiotensin II and norepinephrine, and may limit intraglomerular hypertension and minimize the chances for hypertensive nephrosclerosis to develop.70*71

Calcium channel blockers have been demonstrated to reduce left ventricular mass concomitantly with the decrease in arterial pressure (Messerli FH, unpublished observations). Recent studies have found a dra- matic reduction of premature ventricular contractions achieved by calcium antagonist therapy in conjunction with a regression of left ventricular hypertrophy (Mes- serli FH, unpublished observations).

As the antihypertensive effect of the calcium antagonists does not depend on the activity of the renin- angiotensin system, these agents are very useful in the black population which tends to have lower renin levels. They specifically reduce vascular resistance, improve left ventricular function through afterload reduction and improve renal blood flow, which may explain their natriuretic effect.72s73 The calcium entry blockers as well as the ACE inhibitors also have the theoretical advantage of improving cerebral perfusion through a selective action on vasoconstricted vascular beds.74 Calcium entry blockers thus appear well suited from a physiologic standpoint to treat the high vascular resistance, reduced renal blood flow, mildly reduced cardiac output, and expanded plasma volume seen in the black hypertensive.

Three calcium antagonists are currently marketed for cardiovascular disease: verapamil, nifedipine and diltiazem. Only verapamil is currently approved for hypertension, and approval is pending for diltiazem, nifedipine and others. All 3 have been demonstrated to be highly effective and safe antihypertensive agents.75-77

Limited side effects with calcium antagonists exist, but appear to be significantly fewer compared with other traditional agents. 77.78 Some differences exist among the 3 drugs in their side-effect profiles. The

mild cardiodepressant effects of verapamil and diltiazem limit their use in patients with advanced left ventricular or atrioventricular nodal dysfunction, but are frequently offset by their ability to reduce afterload and improve diastolic compliance, which improves left ventricular function overa11.72 Nifedipine tends to have more problems with its vasodilatory effects than the other 2, leading to associated tachycardia, dizzi- ness, headache, edema and flushing.

Efficacy of calcium antagonists in black hypertensives has recently been demonstrated in a multicenter trial that compared verapamil and propranolol for monotherapy of hypertension. This study found that verapamil was equally effective in blacks and whites, whereas propranolol was more effective in whites than in blacks.74

Thus, calcium antagonists appear to be effective as monotherapy in treating black hypertensive patients. Moreover, calcium antagonists appear to be well suited from a physiologic standpoint to the black hypertensive with low-renin production, salt sensitivity, high peripheral and renal vasculature resistance, and low cardiac output. Calcium antagonists are able to decrease systemic blood pressure while maintaining organ perfusion because of their ability to decrease afterload reduction in a physiologic way without acti- vating counterproductive neurohormonal systems. In addition, their natriuretic capabilities and ability to work in low-renin, salt-sensitive hypertensives makes their use more efficient in the black hypertensive who tends to be volume overloaded.

Conclusion Physicians are becoming increasingly aware of the

socioeconomic and pathophysiologic differences of hypertension in the black compared with the nonblack population. Drugs effective in 1 group of patients may not necessarily be effective in another. Black patients previously thought to be poor responders (either from a physiologic or side-effect standpoint) to the traditional stepped-care approach of diuretics, ,6 blockers and vasodilators may show improvement with the “indi- vidualized approach” based on the patient’s underlying hypertensive hemodynamic physiology and clinical profile.

Antihypertensive agents that are specifically di- rected toward the black patient’s abnormal pathophysiology will allow a more appropriate blood pressure correction, with a minimization of adverse effects and maximal preservation of quality of life and improved compliance.

Acknowledgment: We are grateful to Vivian Dul- lien, PhD, for editorial assistance, and Teresa Chiap- parelli for secretarial assistance.

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pharmacologic management of systemic hypertension in blacks

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