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Practical considerations in treating the elderly hypertensive patient
Practical Considerations Hypertensive Patient JAMES
in Treating the Elderly
F. BURRIS, M.D., Washington, LX
More than half of all older Americans die of cardiovascular diseases. Hypertension is a major risk factor for cardiovascular diseases, and its prevalence increases with age. Older patients are both at higher risk for end-organ complications and less likely than younger ones to survive such complications as myocardial infarction and stroke. Clinical studies have shown that reduction of elevated blood pressure is beneficial in many older persons. Optimal selection of antihypertensive therapy requires consideration of the special characteristics of the elderly, who differ from their younger counterparts in physiology, response to therapy and frequency of concomitant illnesses and medications. Calcium antagonists are particularly effective in these patients; other agents are useful in selected situations. Drugs that are likely to cause central nervous system side effects or orthostatic hypotension generally should be avoided in this patient population. Therapy should begin with a low dose and be titrated upward slowly, thus avoiding excessive reduction of blood pressure and the development of orthostatic hypotension. Treatment should be altered as necessary to minimize side effects that may impair quality of life or lead to poor compliance.
hould elderly hypertensive patients be treated? Hypertension is well known to be a major risk factor for cardiovascular diseases, which kill more than half of all Americans over age 65. Indeed, older patients have a higher risk of end-organ complications such as myocardial infarction (MI) and stroke and a lesser likelihood of surviving them than do younger patients with comparably severe hypertension. The prevalence and severity of hypertension tend to increase with age. Since the number of older people is projected to increase rapidly in coming decades, the question of whether and how to treat older hypertensive patients is of great importance to physicians. Although hypertension clearly poses a risk to older patients, many clinicians have been concerned that antihypertensive therapy might be less effective in reducing complications and that its adverse effects might be more frequent and severe in older patients than in younger ones. Evidence from clinical trials indicates these concerns are not justified. Several large-scale studies have shown that older patients benefit at least as much from therapy as younger ones (Figure 1) and have no higher incidence of adverse effects [l]. Few data are available on patients who are aged 80 years or older or who have isolated systolic hypertension; thus, the beneficial effects of therapy are not yet established for these groups. Patients in the 65- to 80-year-old range with established diastolic or combined systolic/diastolic hypertension definitely should be considered candidates for pharmacologic and nonpharmacologic antihypertensive therapy [Z].
S
PATHOPHYSIOLOGY OF HYPERTENSION IN THE ELDERLY
From the Georgetown University School of Medicine, Washington, D.C. Requests for reprints should be addressed to James F. Burris, M.D., Northeast 120 Med-Dent, Georgetown University School of Medicine, 3900 Reservoir Road, Northwest, Washington, DC. 20007.
48-28s
April 25, 1991
The American Journal of Medicine
Older patients, particularly when hypertensive, differ from younger patients in a number of ways that have practical relevance to their antihypertensive therapy: myocardial reserve, cardiac output, baroreceptor sensitivity, aortic elasticity, intravascular volume, and plasma renin activity tend to be reduced [3]. Total peripheral resistance is increased, and regional blood flow is correspondingly reduced. The elderly are susceptible to orthostatic hypotension and impaired perfusion of vital organs when blood pressure is reduced rapidly. Consequently, blood pressure should be measured in the
Volume 90 (suppl 46)
HYPERTENSION
IN AN AGING POPULATION I BURRIS
120-
70-
600 0600
”
VA
HDFP
Austr
EWPHE
Study gure 1. Relative reduction of cardiovascular morbidity and mortality (M &M) for participants younger than age 50 years ( pZ ) compared with those older than age 60 years ( ) in the Veterans Administration Cooperative Study (VA), the Hypertension Detection and Follow-up Program (HDFP), the Australian Trial on Mild Hypertension (Au&), and the European Working Party on Hypertension in the Elderly (EWPHE). From Applegate [1], with permission.
1200
1800 Time of day
2400
0500
Figure 2. Long-acting antihypertensive efficacy of amlodipine therapy compare with placebo baseline as demonstrated with 24.hour ambulatory blood pressure (BP) monitoring. From Mroczek et a/ (61, with permission.
q
standing as well as the seated position, and drug therapy should be titrated slowly. Medications that characteristically potentiate orthostatic changes (e.g., guanethidine) should generally be avoided. Reduced renal and hepatic function in older patients may alter drug metabolism and excretion and impair fluid and electrolyte balance, potentially increasing risks of antihypertensive drug therapy.
OTHERPRACTICALCONSIDERATIONS Older patients frequently have concomitant medical conditions that significantly affect management of their hypertension. As will be discussed in more detail later, these concomitant conditions may constitute specific indications or contraindications for particular antihypertensive drugs. Beta-adrenergic antagonists, for example, may be useful in patients with hypertension and angina but generally should be avoided in those with bronchospasm, diabetes mellitus, or congestive heart failure (CHF). Medications taken for concomitant conditions may also affect antihypertensive therapy. For example, nonsteroidal anti-inflammatory agents taken for arthritis can promote sodium and fluid retention and antagonize antihypertensive therapy. Furthermore, antiarrhythmic agents and digoxin can potentiate the adverse effects of certain calcium antagonists (e.g., verapamil) on cardiac conduction. Compliance is recognized as a major problem in treating hypertension, and it is frequently assumed that older patients are less compliant than younger
ones. In fact, clinical trials have shown that older patients comply with therapy at least as well as do younger ones [41. Convenience, cost of therapy, and freedom from annoying side effects are important medication-related factors that influence patients’ adherence to prescribed treatment. The circadian surge in serum catecholamines, blood pressure, heart rate, and other physiologic parameters is now recognized to be associated with-and may cause-an increase in the incidence of myocardial ischemia, MI, sudden death, and strokes during the first few hours after patients arise [5]. Thus, the persistence of a medication’s full antihypertensive efficacy beyond the hour of awakening may be important to protect the patient during that most vulnerable part of the day. A longacting medication such as the calcium antagonist amlodipine may enhance patient compliance with its convenient once-daily dosing schedule while maintaining 24-hour antihypertensive efficacy (Figure 2) [6].
TREATMENTOF HYPERTENSIONIN THE ELDERLY Nonpharmacologic measures, including sodium restriction, weight reduction in the obese, and avoidance of excessive alcohol consumption, have documented antihypertensive effectiveness [2]. Although difficult for patients to sustain, nonpharmacologic measures should be instituted where appropriate. Thiazide diuretics are very effective and generally well tolerated in elderly hypertensive patients. The metabolic effects of thiazides have been controversial for years and continue to be hotly debated [7]. A favorable thiazide effect of considerable clini-
April 25, 1991
The American Journal of Medicine
Volume 90 (suppl 48)
4B-2%
HYPERTENSION IN AN AGINGPOPULATlONI BURRS
r=
-.36
A
PC .OOl
A
0
0
-60 1, 4b
$5
9'0
Age W)
cal importance in the elderly is a 33% reduction in the incidenceof hip fractures associatedwith their long-term use [8]. However, this advantagemust be weighed against the potential hazards of fluid depletionand hypokalemiaassociatedwith diuretic therapy. Small dosesof thiazides are less likely to cause significant metabolic disturbances and are often quite effective, particularly when used in combination therapy. Calcium channelantagonistsare the other class of antihypertensive agents unequivocally effective in a broad range of older hypertensive patients. Some studies have shown that calcium antagonists producea greater absolutereduction in bloodpressure in older than in younger patients (Figure 3) [9,10]. However, when results are adjusted for baselineblood pressurewith a multivariate analysis, amlodipine,nitrendipine, and diltiazem haveall been shown to work equally well in older and younger patients [ll-131. Calcium antagonists have a very favorablehemodynamicprofile in older patients, reducing peripheral vascular resistance without inducing reflex tachycardia or impairing renal blood flow. They may causea mild, sustained diuresis 1141.Generally, calcium antagonists have neutral effects on serum lipids, and in animal models they havebeenshownto reducearterial athero40-30s
April 25, 1991
The American Journal of Medicine
Figure 3. Relation between age and antihypertensive response to calcium antagonists in essential hypertension. From Kiowski efa/[9], with permission.
sclerotic lesions [15]. Dihydropyridine derivatives such as amlodipine, nicardipine, and nifedipine are less likely than diltiazem (and especiallyverapamil) to causecardiacconductiondisturbances,bradycardia, and constipationor to interact adverselywith p blockers, antiarrhythmic drugs, and digoxin. Beta-adrenergicantagonists,on the other hand, must be used selectively in older patients and appear to be somewhatlesseffective in this agegroup than in younger patients. Older patients with angina, previous MI, certain arrhythmias, or migraine may specifically benefit from p-blocker therapy, but thesedrugs shouldgenerally be avoidedin those with CHF, bronchospasm,diabetesmellitus, and peripheral vascular disease. Peripheral a blockers must also be used selectively in older patients becausethey may induce or worsen orthostatic hypotension. Alpha blockers have been reported to have favorable effects on serum lipids [16] and on the symptoms of prostatic obstruction [17], so they may be especiallyuseful for patients with hyperlipidemia or prostatism. Angiotensin-convertingenzyme(ACE) inhibitors are effective in some older patients, although the elderly tend to have low-renin, salt-sensitive hypertension. Recent evidence indicates that ACE inhibitors improve survival in patients with CHF
Volume 90 (suppl 48)
HYPERTENSION
[18] and may retard the progression of renal disease in diabetic patients [19]. On the other hand, they have long been known to precipitate proteinuria and renal failure in patients with underlying renal insufficiency or renal artery stenosis and dehydration. Dysgeusia and especially cough are moderately frequent side effects that may discourage patient adherence to ACE-inhibitor therapy.
COMMENTS The future goals of antihypertensive therapy should include not only lowering blood pressure but also maintaining the quality of life of elderly patients and maximally reducing overall cardiovascular risk. To this end, the choice of antihypertensive therapy must consider alterations in patients’ physiology due to age, other medical illnesses, concomitant medications, and ease of administration, and thus must be individualized. As a result of a balanced consideration of many of these factors, calcium channel antagonists will often be the drugs of choice for older patients with hypertension.
REFERENCES 1. Applegate WE? Hypertensron in elderly patients. Ann Intern Med 1989; 110: 901915. 2. 1988 Joint National Committee: The 1988 report of the Joint National Commrttee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1988; 148: 1023-1038. 3. Chobanian AV: Treatment of the elderly hypertensive patient. Am J Med 1984; 77 (28): 22-27.
IN AN AGING POPULATION / BURRIS
4. Hulley SB. Furberg CD, Gurland 6, et al: Systolic Hypertension in the Elderly Program (SHEP): Antihypertensive efficacy of chlorthalidone. Am J Cardiol 1985; 56: 913-920. 5. Muller JE, Tofler G, Stone PH: Circadian variation and triggers of onset of acute cardiovascular drsease. Circulahon 1989; 80: 733-743. 6. Mroczek WJ, Burris JF, Allenby KS: A double-blind evaluation of the effect of amlodipine on ambulatory blood pressure in hypertensive patients. J Cardiovasc Pharmacol 1988; 12 (suppl 7): S79-S84. 7. Freis ED Critique of the clinrcal importance of diuretic.induced hypokalemia and elevated cholesterol level. Arch Intern Med 1989; 149: 2640-2648. 8. LaCroix AZ, Wienpahl J, Whrte LR, et al: Thiazide diuretic agents and the incidence of hip fracture. N Engl J Med 1990; 322: 286-290. 9. Kiowskr W, Buhler FR, Fadayomi, MO, et al: Age, race, blood pressure, and renin: Predictors for antihypertensive treatment with calcium antagonists. Am J Cardiol 1985; 56: 81H-85H. 10. Abernethy DR, Schwartz JB, Todd EL, et al: Verapamil pharmacodynamics and disposttion in young versus elderly hypertensrve patients. Ann Intern Med 1986; 105: 329-336. 11. Burns JF, Schwartz LA, Mroczek WJ: Effect of nitrendipine In relation to age and basekne blood pressure (abstr). Clin Pharmacol Ther 1989; 45: PII E-3. 12. Burrrs JF, Sheridan MJ, Mroczek WJ: Antihypertensive effect of amlodipine in relation to age and baseline blood pressure (abstr). J Clin Pharmacol 1989; 29: 853. 13. Burris JF, Weir WR, Oparil S, et a/: Antrhypertensive effect of slow-release diltiazem in relation to age and race (abstr). J Clin Pharmacol 1989; 29: 861. 14. MacGregor GA, Pevahouse JB, Cappuccio FP, et at Nifedipine, sodium intake, diuretics, and sodium balance. Am J Nephrol 1987; 7 (suppl 1): 44-48. 15. Fleckenstern A, Fleckenstern-Grun G, Frey M, et af Expenmental antiarteriosclerotic effects of calcium antagonists. J Clin Pharmacol 1990; 30: 151154. 16. Deger G: Effect of terazosin on serum lipids. Am J Med 1986; 80 (suppl 58): 82-85. 17. Lepor H: Role of alpha-adrenergrc blockers in the treatment of benign prostatic hyperplasia. Prostate 1990; 3 (suppl): 75-84. 18. The CONSENSUS Trial Study Group: Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987; 316: 1429-1435. 19. Wtlliams GH: Converhng-enzyme Inhibitors in the treatment of hypertension. N Engl J Med 1988; 319: 1517-1525.
April 25, 1991
The American Journal of Medicine
Volume 90 (suppl 46)
4B-31s
in Treating the Elderly
F. BURRIS, M.D., Washington, LX
More than half of all older Americans die of cardiovascular diseases. Hypertension is a major risk factor for cardiovascular diseases, and its prevalence increases with age. Older patients are both at higher risk for end-organ complications and less likely than younger ones to survive such complications as myocardial infarction and stroke. Clinical studies have shown that reduction of elevated blood pressure is beneficial in many older persons. Optimal selection of antihypertensive therapy requires consideration of the special characteristics of the elderly, who differ from their younger counterparts in physiology, response to therapy and frequency of concomitant illnesses and medications. Calcium antagonists are particularly effective in these patients; other agents are useful in selected situations. Drugs that are likely to cause central nervous system side effects or orthostatic hypotension generally should be avoided in this patient population. Therapy should begin with a low dose and be titrated upward slowly, thus avoiding excessive reduction of blood pressure and the development of orthostatic hypotension. Treatment should be altered as necessary to minimize side effects that may impair quality of life or lead to poor compliance.
hould elderly hypertensive patients be treated? Hypertension is well known to be a major risk factor for cardiovascular diseases, which kill more than half of all Americans over age 65. Indeed, older patients have a higher risk of end-organ complications such as myocardial infarction (MI) and stroke and a lesser likelihood of surviving them than do younger patients with comparably severe hypertension. The prevalence and severity of hypertension tend to increase with age. Since the number of older people is projected to increase rapidly in coming decades, the question of whether and how to treat older hypertensive patients is of great importance to physicians. Although hypertension clearly poses a risk to older patients, many clinicians have been concerned that antihypertensive therapy might be less effective in reducing complications and that its adverse effects might be more frequent and severe in older patients than in younger ones. Evidence from clinical trials indicates these concerns are not justified. Several large-scale studies have shown that older patients benefit at least as much from therapy as younger ones (Figure 1) and have no higher incidence of adverse effects [l]. Few data are available on patients who are aged 80 years or older or who have isolated systolic hypertension; thus, the beneficial effects of therapy are not yet established for these groups. Patients in the 65- to 80-year-old range with established diastolic or combined systolic/diastolic hypertension definitely should be considered candidates for pharmacologic and nonpharmacologic antihypertensive therapy [Z].
S
PATHOPHYSIOLOGY OF HYPERTENSION IN THE ELDERLY
From the Georgetown University School of Medicine, Washington, D.C. Requests for reprints should be addressed to James F. Burris, M.D., Northeast 120 Med-Dent, Georgetown University School of Medicine, 3900 Reservoir Road, Northwest, Washington, DC. 20007.
48-28s
April 25, 1991
The American Journal of Medicine
Older patients, particularly when hypertensive, differ from younger patients in a number of ways that have practical relevance to their antihypertensive therapy: myocardial reserve, cardiac output, baroreceptor sensitivity, aortic elasticity, intravascular volume, and plasma renin activity tend to be reduced [3]. Total peripheral resistance is increased, and regional blood flow is correspondingly reduced. The elderly are susceptible to orthostatic hypotension and impaired perfusion of vital organs when blood pressure is reduced rapidly. Consequently, blood pressure should be measured in the
Volume 90 (suppl 46)
HYPERTENSION
IN AN AGING POPULATION I BURRIS
120-
70-
600 0600
”
VA
HDFP
Austr
EWPHE
Study gure 1. Relative reduction of cardiovascular morbidity and mortality (M &M) for participants younger than age 50 years ( pZ ) compared with those older than age 60 years ( ) in the Veterans Administration Cooperative Study (VA), the Hypertension Detection and Follow-up Program (HDFP), the Australian Trial on Mild Hypertension (Au&), and the European Working Party on Hypertension in the Elderly (EWPHE). From Applegate [1], with permission.
1200
1800 Time of day
2400
0500
Figure 2. Long-acting antihypertensive efficacy of amlodipine therapy compare with placebo baseline as demonstrated with 24.hour ambulatory blood pressure (BP) monitoring. From Mroczek et a/ (61, with permission.
q
standing as well as the seated position, and drug therapy should be titrated slowly. Medications that characteristically potentiate orthostatic changes (e.g., guanethidine) should generally be avoided. Reduced renal and hepatic function in older patients may alter drug metabolism and excretion and impair fluid and electrolyte balance, potentially increasing risks of antihypertensive drug therapy.
OTHERPRACTICALCONSIDERATIONS Older patients frequently have concomitant medical conditions that significantly affect management of their hypertension. As will be discussed in more detail later, these concomitant conditions may constitute specific indications or contraindications for particular antihypertensive drugs. Beta-adrenergic antagonists, for example, may be useful in patients with hypertension and angina but generally should be avoided in those with bronchospasm, diabetes mellitus, or congestive heart failure (CHF). Medications taken for concomitant conditions may also affect antihypertensive therapy. For example, nonsteroidal anti-inflammatory agents taken for arthritis can promote sodium and fluid retention and antagonize antihypertensive therapy. Furthermore, antiarrhythmic agents and digoxin can potentiate the adverse effects of certain calcium antagonists (e.g., verapamil) on cardiac conduction. Compliance is recognized as a major problem in treating hypertension, and it is frequently assumed that older patients are less compliant than younger
ones. In fact, clinical trials have shown that older patients comply with therapy at least as well as do younger ones [41. Convenience, cost of therapy, and freedom from annoying side effects are important medication-related factors that influence patients’ adherence to prescribed treatment. The circadian surge in serum catecholamines, blood pressure, heart rate, and other physiologic parameters is now recognized to be associated with-and may cause-an increase in the incidence of myocardial ischemia, MI, sudden death, and strokes during the first few hours after patients arise [5]. Thus, the persistence of a medication’s full antihypertensive efficacy beyond the hour of awakening may be important to protect the patient during that most vulnerable part of the day. A longacting medication such as the calcium antagonist amlodipine may enhance patient compliance with its convenient once-daily dosing schedule while maintaining 24-hour antihypertensive efficacy (Figure 2) [6].
TREATMENTOF HYPERTENSIONIN THE ELDERLY Nonpharmacologic measures, including sodium restriction, weight reduction in the obese, and avoidance of excessive alcohol consumption, have documented antihypertensive effectiveness [2]. Although difficult for patients to sustain, nonpharmacologic measures should be instituted where appropriate. Thiazide diuretics are very effective and generally well tolerated in elderly hypertensive patients. The metabolic effects of thiazides have been controversial for years and continue to be hotly debated [7]. A favorable thiazide effect of considerable clini-
April 25, 1991
The American Journal of Medicine
Volume 90 (suppl 48)
4B-2%
HYPERTENSION IN AN AGINGPOPULATlONI BURRS
r=
-.36
A
PC .OOl
A
0
0
-60 1, 4b
$5
9'0
Age W)
cal importance in the elderly is a 33% reduction in the incidenceof hip fractures associatedwith their long-term use [8]. However, this advantagemust be weighed against the potential hazards of fluid depletionand hypokalemiaassociatedwith diuretic therapy. Small dosesof thiazides are less likely to cause significant metabolic disturbances and are often quite effective, particularly when used in combination therapy. Calcium channelantagonistsare the other class of antihypertensive agents unequivocally effective in a broad range of older hypertensive patients. Some studies have shown that calcium antagonists producea greater absolutereduction in bloodpressure in older than in younger patients (Figure 3) [9,10]. However, when results are adjusted for baselineblood pressurewith a multivariate analysis, amlodipine,nitrendipine, and diltiazem haveall been shown to work equally well in older and younger patients [ll-131. Calcium antagonists have a very favorablehemodynamicprofile in older patients, reducing peripheral vascular resistance without inducing reflex tachycardia or impairing renal blood flow. They may causea mild, sustained diuresis 1141.Generally, calcium antagonists have neutral effects on serum lipids, and in animal models they havebeenshownto reducearterial athero40-30s
April 25, 1991
The American Journal of Medicine
Figure 3. Relation between age and antihypertensive response to calcium antagonists in essential hypertension. From Kiowski efa/[9], with permission.
sclerotic lesions [15]. Dihydropyridine derivatives such as amlodipine, nicardipine, and nifedipine are less likely than diltiazem (and especiallyverapamil) to causecardiacconductiondisturbances,bradycardia, and constipationor to interact adverselywith p blockers, antiarrhythmic drugs, and digoxin. Beta-adrenergicantagonists,on the other hand, must be used selectively in older patients and appear to be somewhatlesseffective in this agegroup than in younger patients. Older patients with angina, previous MI, certain arrhythmias, or migraine may specifically benefit from p-blocker therapy, but thesedrugs shouldgenerally be avoidedin those with CHF, bronchospasm,diabetesmellitus, and peripheral vascular disease. Peripheral a blockers must also be used selectively in older patients becausethey may induce or worsen orthostatic hypotension. Alpha blockers have been reported to have favorable effects on serum lipids [16] and on the symptoms of prostatic obstruction [17], so they may be especiallyuseful for patients with hyperlipidemia or prostatism. Angiotensin-convertingenzyme(ACE) inhibitors are effective in some older patients, although the elderly tend to have low-renin, salt-sensitive hypertension. Recent evidence indicates that ACE inhibitors improve survival in patients with CHF
Volume 90 (suppl 48)
HYPERTENSION
[18] and may retard the progression of renal disease in diabetic patients [19]. On the other hand, they have long been known to precipitate proteinuria and renal failure in patients with underlying renal insufficiency or renal artery stenosis and dehydration. Dysgeusia and especially cough are moderately frequent side effects that may discourage patient adherence to ACE-inhibitor therapy.
COMMENTS The future goals of antihypertensive therapy should include not only lowering blood pressure but also maintaining the quality of life of elderly patients and maximally reducing overall cardiovascular risk. To this end, the choice of antihypertensive therapy must consider alterations in patients’ physiology due to age, other medical illnesses, concomitant medications, and ease of administration, and thus must be individualized. As a result of a balanced consideration of many of these factors, calcium channel antagonists will often be the drugs of choice for older patients with hypertension.
REFERENCES 1. Applegate WE? Hypertensron in elderly patients. Ann Intern Med 1989; 110: 901915. 2. 1988 Joint National Committee: The 1988 report of the Joint National Commrttee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1988; 148: 1023-1038. 3. Chobanian AV: Treatment of the elderly hypertensive patient. Am J Med 1984; 77 (28): 22-27.
IN AN AGING POPULATION / BURRIS
4. Hulley SB. Furberg CD, Gurland 6, et al: Systolic Hypertension in the Elderly Program (SHEP): Antihypertensive efficacy of chlorthalidone. Am J Cardiol 1985; 56: 913-920. 5. Muller JE, Tofler G, Stone PH: Circadian variation and triggers of onset of acute cardiovascular drsease. Circulahon 1989; 80: 733-743. 6. Mroczek WJ, Burris JF, Allenby KS: A double-blind evaluation of the effect of amlodipine on ambulatory blood pressure in hypertensive patients. J Cardiovasc Pharmacol 1988; 12 (suppl 7): S79-S84. 7. Freis ED Critique of the clinrcal importance of diuretic.induced hypokalemia and elevated cholesterol level. Arch Intern Med 1989; 149: 2640-2648. 8. LaCroix AZ, Wienpahl J, Whrte LR, et al: Thiazide diuretic agents and the incidence of hip fracture. N Engl J Med 1990; 322: 286-290. 9. Kiowskr W, Buhler FR, Fadayomi, MO, et al: Age, race, blood pressure, and renin: Predictors for antihypertensive treatment with calcium antagonists. Am J Cardiol 1985; 56: 81H-85H. 10. Abernethy DR, Schwartz JB, Todd EL, et al: Verapamil pharmacodynamics and disposttion in young versus elderly hypertensrve patients. Ann Intern Med 1986; 105: 329-336. 11. Burns JF, Schwartz LA, Mroczek WJ: Effect of nitrendipine In relation to age and basekne blood pressure (abstr). Clin Pharmacol Ther 1989; 45: PII E-3. 12. Burrrs JF, Sheridan MJ, Mroczek WJ: Antihypertensive effect of amlodipine in relation to age and baseline blood pressure (abstr). J Clin Pharmacol 1989; 29: 853. 13. Burris JF, Weir WR, Oparil S, et a/: Antrhypertensive effect of slow-release diltiazem in relation to age and race (abstr). J Clin Pharmacol 1989; 29: 861. 14. MacGregor GA, Pevahouse JB, Cappuccio FP, et at Nifedipine, sodium intake, diuretics, and sodium balance. Am J Nephrol 1987; 7 (suppl 1): 44-48. 15. Fleckenstern A, Fleckenstern-Grun G, Frey M, et af Expenmental antiarteriosclerotic effects of calcium antagonists. J Clin Pharmacol 1990; 30: 151154. 16. Deger G: Effect of terazosin on serum lipids. Am J Med 1986; 80 (suppl 58): 82-85. 17. Lepor H: Role of alpha-adrenergrc blockers in the treatment of benign prostatic hyperplasia. Prostate 1990; 3 (suppl): 75-84. 18. The CONSENSUS Trial Study Group: Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987; 316: 1429-1435. 19. Wtlliams GH: Converhng-enzyme Inhibitors in the treatment of hypertension. N Engl J Med 1988; 319: 1517-1525.
April 25, 1991
The American Journal of Medicine
Volume 90 (suppl 46)
4B-31s