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Use of Antihypertensive Agents with Particular Comorbid Problems
Hypertension
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Use of Antihypertensive Agents with Particular Comorbid Problems
Stephen Mascioli, MD, MPH,* and Nelly Mercedes Gonzalez, MDJ-
The combination of the progressive age-related rise in blood pressure in Western societies and the rapidly increasing number of elderly persons has resulted in hypertension in the elderly population being a common medical problem. As the life expectancy of adults has gradually increased, the proportion of elderly with comorbid medical conditions has likewise increased. These comorbid conditions may potentially affect the timing and type of treatment of the various types of hypertension, which has centered around pharmacologic agents. Several classes of antihypertensive agents are available for effective reduction of blood pressure. Choice of agent(s) often depends on coexisting diseases to minimize adverse effects and potentially enhance beneficial therapeutic interactions. This article will review common medical conditions in elderly persons which may influence the choice of antihypertensive drug. This review is based on a literature search that used many excellent studies but also some that had substantial limitations including small sample size, inadequate blinding, no randomization, and no control groups. When possible, the results of rigorous clinical trials are emphasized.
SPECIFIC COMORBIDITIES
A major risk factor for coronary artery disease (CAD) in the elderly ~ ~ often develops in patients with longpopulation is h y p e r t e n ~ i o n .CAD From the Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis, Minnesota *Assistant Professor +Research Assistant Clinics in Geriatric Medicine-Vol.
5, No. 4, November 1989
established mild or moderate hypertension who often have additional risk factors for atherosclerosis. People with myocardial infarction or angina pectoris who have elevated blood pressure should be treated. Recent trials have demonstrated that Pblocking agents will reduce recurrent infarction in patients after acute myocardial infar~tion.'~ 52 For the postmyocardial infarction hypertensive patient who also has congestive heart failure, drugs other than P-blockers should be used. Such patients are considered at high risk, however, and are liable to develop complications as a result of therapy. All drugs used in young hypertensive patients may be used in elderly hypertensive patients, but age-related changes in efficacy, pharmacokinetics, and safety should be considered when treating the elderly patient. If possible, half of the maximum dose recommended for the patient without complications should be used, and individual dose adjustments are indicated. "3
P-Adrenergic-Blocking Agents P-blockers have been used widely for the treatment of angina pectoris and hypertension in elderly patients. Theoretically, they are cardioprotective and exert a beneficial effect by decreasing systemic arterial pressure and heart rate, and mildly reducing contractility-thus reducing myocardial oxygen demand. Furthermore, it is possible that the prolongation of diastole following heart rate reduction facilitates blood flow through poorly perfused regions of the myocardium, p-blockers have intrinsic antiarrhythmic activity and may inhibit platelet aggregation. An increase in the prevalence of lowrenin hypertension occurs with advancing age.50Plasma renin activity and concentrations as well as plasma angiotensin I1 concentration decline with increasing age. In essential hypertension, these declines may be accelerated with progression of the disease. Because they reduce renin levels, Pblockers may be more effective in patients with high-renin hypertension, but studies have shown that p-blockers can be effective in elderly patients with low-renin levels.36.62 Coronary artery spasm can be aggravated by P-blockers by allowing unopposed a-stimulation. This is often not a problem, however, because the reduction in cardiac work is great enough to offset this imbalance.36 A diminished responsiveness of the P-adrenoceptor to both agonist and antagonist drugs occurs with advancing age.g Increased norepinephrine levels in the elderly population could compete for occupancy of the Preceptors in the heart, causing a reduction in affinity of both types of Despite these findings, increasing evidence exists that p-adrenoreceptor blockers such as pr~pranolol,~' t i m ~ l o l , ' and ~ metoproIo17'' may produce clinically significant benefit in postmyocardial infarction patients. A statistically significant reduction in morbidity has been demonstrated with these drugs, and the effect appears to be as great in older as in younger patients. 79 In a study of the use of metoprolol after myocardial infarction, patients aged 65 to 74 years showed a significant reduction in postmyocardial .~~ the placebo group, mortality was more than twice infarction m ~ r t a l i t y In as high in the age group 65 to 74 years than in the age group 40 to 64 years," showing the importance of treating the elderly. In the p-Blocker
Heart Attack (BHAT) Study, propranolol reduced postinfarction mortality in patients up to 69 years of age (the upper age limit for inclusion in the study). The placebo group mortality was considerably higher among the group of patients aged 60 to 69 years compared with those aged 30 to 59 years, and the proportionate effect of active treatment was greater in the older patients.'' In the Norwegian Timolol Study, patients 65 to 75 years old who received long-term treatment with timolol and who survived acute myocardial infarction experienced significant reductions in mortality, cardiac death, sudden death, and reinfarctiom4' Comparing a range of p-blockers, it has been found that for patients with stable exertional angina pectoris, p,-selective (metoprolol, proctolol, tolomolol) and nonselective (propranolol and oxprenolol) P-blockers were equally effective in reducing symptoms and improving exercise tolerance.' Metoprolol is recommended as a first-choice agent in the setting of hypertension and stable angina. It is also beneficial in postmyocardial infarction patients. In early acute myocardial infarction complicated by hypertension, Pblockers are contraindicated because of their myocardial depressive effects. Nitrates or calcium channel blockers are preferred in this setting, with use of p-blockers reserved for later in the clinical course.36 When prescribing p-blockers, the usual contraindications should be observed: obstructive airway disease, atrioventricular block, congestive heart failure, or insulin-dependent diabetes. Side effects, quality of life, and cost (especially for newer agents) should also be considered when using these drugs. Thiazides and Related Diuretics Thiazides are often preferred as initial therapy for patients with hypertension and coronary artery disease because of their low cost and the little dose-titration needed, but important concerns exist for elderly patients. The most worrisome of these is hypokalemia, which can initiate ventricular arrhythmias. This potential adverse effect is especially deleterious in patients with coronary artery disease and left ventricular hypertrophy. In addition, thiazides have been shown to have deleterious effects on serum lipids, which can potentially aggravate risk of a t h e r o s c l e r ~ s i s . ~ ~ The European Working Party on High Blood Pressure in the Elderly (EWPHE) assessed the effects of antihypertensive drugs in patients aged 60 to 97 years. One third of them had pre-existing cardiovascular complications. Treatment was hydrochlorothiazide plus triamterene and a-methyldopa, if needed, compared with placebo. Treatment yielded about 27 per cent reduction in cardiovascular mortality. The benefits of treatment observed in the trial seemed to be independent of the presence or absence of cardiovascular complications at entry. Little or no benefit from treatment was demonstrated in patients older than 80 years of age.2 The Systolic Hypertension in the Elderly Program (SHEP) Pilot Study showed that chlorthalidone in low doses of 15 to 30 mg per day was well tolerated, and serum lipid changes at 1 year were not ~ i g n i f i c a n t . ~ ~
Calcium Channel Blockers The calcium entry-blocking drugs have been used recently in the therapy of essential hypertension. Their ability to inhibit selectively the transmembrane flux of calcium ions in excitable tissues is presumed to account for their various actions, including peripheral and coronary artery vasodilation. The three major calcium channel blockers used in the United States are verapamil, nifedipine, and diltiazem. Studies evaluating the use of calcium-channel blockers in coexisting coronary artery disease and hypertension support the idea that calcium-channel blockers can protect potentially jeopardized myocardium when the therapy is initiated at the appropriate time. It seems that for those patients who survive their first infarct and who are maintained on calcium channel blockers, the risk of reinfarction is reduced if congestive heart failure can be a ~ o i d e d . ~It' has been shown that comparable antihypertensive activity exists among verapamil, nifedipine, diltiazem, and nitrendipine. The antihypertensive effect of verapamil and nitrendipine has been found to be greatest in older patients and in those with low-renin levels.47Long-acting nifedipine significantly reduced blood pressure in patients with angina, and side effects were few and not significant.l3. l4 Verapamil in a slow-release form and nitrendipine appear to achieve effective control of blood pressure comparable with the effect of a P-blocking agent.17 Calcium antagonists are excellent alternatives for the elderly population, especially in those whom P-blocking drugs are contraindicated.
ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITORS The ACE inhibitors' primary mechanism of action is a decrease in peripheral resistance, which is elevated in the elderly population. This is a physiologic advantage over P-blocking drugs (which can increase peripheral resistance) when treating hypertension in elderly persons. Whether ACE inhibitors have particular benefit in patients with coronary artery disease (except those with heart failure) is uncertain. It has been shown that captopril in relatively small doses, as monotherapy in some instances, or in combination with a second or third antihypertensive agent, provides welltolerated and effective therapy for the elderly hypertensive patient (65 years of age or older).34
Left ventricular hypertrophy is a common accompaniment of hypertension in the elderly population. Its presence carries an increased risk of subsequent cardiovascular disease events. Several classes of antihypertensives have been shown to reduce left ventricular mass, as measured by echocardiography, over the short term. Most drugs effective in this regard are adrenergic inhibitors of some type.40, Diuretics and direct vasodilators have not consistently shown reductions of left ventricular mass, at least in
the short term.3677 This is presumably because of reflex activation of the sympathetic nervous system when using these agents as monotherapy. Long-term change, however, in left ventricular mass with any agent is virtually unknown, as is a beneficial impact, if any, on subsequent cardiovascular risk. Long-term studies are necessary to answer these important questions.
Hypertension and congestive heart failure coexist in many elderly persons. The treatment of either condition should be chosen with the other in mind. Fortunately, several available drugs are effective for both conditions. Diuretics Diuretics have been the traditional drugs used in this setting. Loop diuretics such as furosemide are effective preload reducers, and such potent diuretics are often necessary in congestive heart failure.23Elderly patients treated long term with diuretics have been shown to have diminished serum potassium and magnesium levels.'s These can be increased with potassium supplementation and potassium-sparing diuretics. lg Occasionally, magnesium supplementation may be required. ACE Inhibitors Afterload reduction is also a goal and can be accomplished with various vasodilators. ACE inhibitors are favored in this setting because they reduce both preload and afterload, and enhance renal blood flow, glomerular filtration rate, sodium excretion, and cardiac output.= ACE inhibitors are effective in treating these two disorders through their expected mechanism 46 of preload and afterload reducti~n.'~. Calcium Channel Blockers Calcium channel blockers are effective treatment in patients with hypertension and congestive heart failure. A series of nine patients with refractory hypertension and congestive heart failure were treated with nifedipine. It was effective in reducing blood pressure and relieving symptoms of congestive heart failure.25.59 Verapamil tends to depress myocardial contractility and probably should be avoided in patients with heart failure. Atrial Natriuretic Peptides A novel treatment shown to be effective in both hypertension and heart failure is a-human atrial natriuretic peptides. The drug was administered intravenously to 16 patients, some elderly, and the hemodynamic changes noted were acute and transient. The changes, however, were all in a favorable direction: increased cardiac output, cardiac index, stroke volume, ejection fraction, ejection rate, urine volume, electrolyte excretion,
creatinine excretion, and decreased right-sided vascular pressures. Use of these drugs may increase in the future.=
@-Blockers should be used with caution in treating elderly hypertensives with chronic obstructive pulmonary disease (COPD, chronic bronchitis, and emphysema) or asthma. Smooth muscle in the bronchial tree has P,-receptors, which, when stimulated, cause smooth muscle relaxation and bronchodilatation. If these P,-receptors are blocked, bronchoconstriction is favored, which may aggravate obstructive airway disease. Nonselective Pblockers (both P, [cardiac] and P, [bronchial]) are of primary concern because of their pulmonary effects. Propranolol, a nonselective p-blocker, is contraindicated in hypertension treatment in patients with pulmonary disease. PI-selective-blockers, such as metoprolol or celiprolol, are often used in patients with COPD or asthma.30 In addition, P-blockers with intrinsic sympathomimetic activity can be tried c a ~ t i o u s l y Caution .~~ must be exercised because PI-selectivity is only relative and diminishes at higher doses. Labetolol, a combination nonselective p-blocker and al-peripheralblocker has been studied for use in hypertensive patients with pulmonary 41 These studies show that it appears to be safer than other Pblockers but should still be used with caution. Both authors recommend using other classes of antihypertensives in the presence of pulmonary disease, however. Other antihypertensives such as reserpine and a-methyldopa are reported to have aggravated existing pulmonary disease. 23 Other Drugs Other antihypertensives have been studied regarding their effects on bronchial smooth muscle. Calcium channel blockers, ACE inhibitors, and direct vasodilators have no effect on bronchial tone. These agents, along with diuretics, should be considered antihypertensive agents of first choice in patients with lung disease.'', 37. 58 Prazosin, an a,-blocker, has been shown to dilate the bronchial tree, and ACE inhibitors have been used successfully in patients with lung disease receiving corticosteroid therapy.23
Like many chronic diseases, the prevalence of diabetes increases with age, making it a common problem in elderly persons. Because some risk factors for type I1 diabetes mellitus are the same as those for hypertension, a sizable number of patients with both conditions exists. Hence, choice of antihypertensive drug must be made with knowledge of its potential effects on diabetes. Also, because patients with both disorders have a much-
increased risk of further morbidity and m ~ r t a l i t y the , ~ ~ goal of therapy is optimal control of both conditions. Diuretics Diuretics are safe, effective, and well-tolerated antihypertensive agents, and several different types are available. Thiazide diuretics have been shown to aggravate diabetic control in elderly person^,^. 32' 70 but generally the disturbances are not ~ e r i o u sThe . ~ mechanism of this problem probably is inhibition of insulin release.23 Therefore, these agents are safe to use in insulin-dependent diabetes mellitus but can be problematic in type I1 diabetes mellitus.= Blood sugars are raised, along with glycosylated hemoglobin, a marker of long-term blood sugar levels. Also, the addition of the p-blocker propranolol to diuretic treatment will further aggravate diabetic control. Hypokalemia, which can often accompany diuretic therapy, can worsen hyperglycemia. This may be because of decreased insulin effect or secretion.=. Maintaining normokalemia is therefore important for this as well as other reasons. Potassium-sparing diuretics, however, are generally contraindicated in diabetics because these patients have a high prevalence of renal insufficiency and hyporeninemic hypoaldosteronism; both conditions reduce renal secretion of potassium and may result in h y ~ e r k a l e m i a . ~ Chlorthalidone, a thiazide-like diuretic, may impair glucose tolerance in elderly hypertensives with diabetes.32.71 Studies of indapamide, a 2methylinsoline diuretic, show no effect on glucose t ~ l e r a n c e , '57. ~ ffi but some authors disagree.32 Loop diuretics generally cause increased blood This may be so because loop diuretics sugars but less so than thiazide~.~' cause less hypokalemia, thereby facilitating the conversion of proinsulin to insulin.
The effects of p-blockers on diabetes are mixed. They may be a good choice mechanistically because they do not aggravate postural hypotension, a complication often present in the elderly diabetic.23 Some reports show a deleterious effect on glucose h o m e o ~ t a s i s3,"~45 whereas others show little or no effect on blood glucose levels.16 P-Blockers may aggravate diabetes by interfering with P-adrenergic stimulation of pancreatic islet cells, which potentiates insulin release. Metoprolol, a cardioselective P-blocker, may be preferable in diabetics being treated with sulfonylureas compared with the nonselective P-blocker propranolol because less inhibition of insulin release occurs.45 P-blockers used in low dose, those with intrinsic sympathomimetic activity, cardioselective agents, or those with mixed p- and a-blocking effects are not prone to disturb diabetic control.32 Apart from their direct effects on glucose levels, p-blockers are relatively contraindicated in diabetics because of their tendency to mask hypoglycemic episodes. p-blockers attenuate the sympathetic reaction to hypoglycemia by reducing tachycardia and adrenalmediated glycemic response. For this reason, many clinicians are hesitant to treat hypertensive insulin-dependent diabetics with P - b l ~ c k e r s . ~ ~
ACE Inhibitors and Calcium Channel Blockers ACE inhibitors have been studied by several groups in diabetic
patient^.^" 43, 54 ACE inhibitors do not affect blood sugars in types I or I1 diabetes, making them a good choice for the treatment of hypertension in this group of patients. Calcium channel blockers are effective antihypertensive agents in patients with diabetes.13 In diabetics and nondiabetics, calcium channel blockers have no adverse effects on glucose tolerance, also making them a good choice in these patients. Other Drugs Clonidine appears to affect glucose tolerance in diabetics adversely as measured acutely by an increased glycemic response to an intravenous glucose load but did not appear to affect long-term contr01.'~ Several classes of antihypertensive drugs have not been studied extensively, but the available reports indicate that peripheral a, blockers, central adrenergic inhibitors, potassium-sparing diuretics, and direct vasodilators have little or no effect on glucose levels.3263. 74 A Scandinavian group studied 65 hypertensive men aged 61 to 65 years who also had impaired glucose tolerance. They were treated with a calcadol, an investigational synthetic analogue of active vitamin D, in a placebo-controlled, double-blind trial. Because calcium metabolism influences blood pressure regulation, supplementation with this agent could be beneficial for hypertensives. The treatment period lasted 12 weeks, and results showed that a-calcadol lowered blood pressure without affecting glucose tolerance.42
General Considerations Renal failure can either precede and cause hypertension or may be the end result of long-term, severe hypertension. Hypertensive renal disease is much less common now than in the past because severe hypertension is usually successfully treated. The elderly patient needs special considerations because the effects of aging on renal physiology involve both glomerular and tubular function. Glomerular filtration rate (GFR) may fall as much as 50 per cent, with an average decline of about 35 per cent between 20 and 90 years of age. Renal plasma flow, urine concentration (especially during water deprivation), and renal sodium conservation decline with age." Therapy should be individualized, particularly when hypertension and renal insufficiency are associated with other significant medical problems. Most of the drugs used in younger patients may be used in the elderly population, but the starting doses should be halved, maintenance dosages should be lower, and frequency of administration may also be reduced. For example, in renal insufficiency in which GFR is < 10 ml per minute, clonidine should be given at 50 to 75 per cent of the normal dose.8 For detailed prescribing guidelines, one should refer to information supplied by pharmaceutical manufacturers.
Blood pressure control can partially reverse renal insufficiency by restoring to function that part of renal tissue in which blood flow is reduced in a pressure-dependent manner. Progression of renal failure can be significantly retarded by effective blood pressure control.12 Usually more than one drug is needed to achieve good results. One must be cautious in reducing blood pressure too rapidly in this setting because renal blood flow can fall, especially in the presence of high renovascular resistance or bilateral renal artery stenosis. Because the kidneys autoregulate blood flow through changes in vascular tone secondary to the juxtaglomerular apparatus and angiotensin 11, a rapid decrease in arterial blood pressure can result in a fall in glomerular filtration rate. Diuretics Loow diuretics such as furosemide or bumetamide are the agents of choice in patients with a z ~ t e m i a Compared .~~ with other diuretics, they have less hypokalemia, less lipid disturbance, and possibly less orthostatic hypotension. They should be used in patients with poor compliance to a low-salt diet. If the patient is refractory to a loop diuretic alone, a thiazide diuretic such as metolazone can be added. Excessive diuresis is a votential problem with metolazone and must be guarded against. Also, hyponatremia secondary to thiazide-induced decreased free water clearance is a problem seen in the elderly population. Thiazides, however, are often ineffective if the serum creatinine is above 2.5 to 3.0 mg per dl (GFR 5 30 ml per minute). Indapamide can be useful in lowering blood pressure in this situation. The response can be assessed by monitoring body weight in addition to blood pressure. 23 A series of small studies looking at atenolol, nadolol, and labetolol showed that they were effective in lowering blood pressure, with no significant effect on serum creatinine, urea, and GFR.53Thus, their use in elderly patients has been recommended. These agents, however, tend to reduce cardiac output and increase peripheral vascular resistance, two changes present in many elderly hypertensives. Also, the elderly have decreased numbers of @-receptors or a decreased P-receptor sensitivity, making these agents less effective compared with younger patients. In patients with reduced G F R of between 0.3 and 3.3 1 per hour, the elimination half-life and total body clearance of metropolol were not significantly different from those in healthy subjects.? Some studies indicate a reduction in G F R of about 25 per cent in elderly persons treated with Pblocking agents. This may potentially lower renal sodium excretion, an unwanted effect in patients with decreased renal function and volume expansion. Antiadrenergic Agents In one study, sixteen elderly patients with early renal insufficiency and hypertension were compared with age-matched controls.39They had abnormalities in the sympathetic nervous system that contributed to hypertension, such as elevated plasma renin activity, norepinephrine, and aldoste-
rone. Clonidine was used successfully in these patient^.^' This drug must be used with caution in elderly patients because of the frequent side effect of postural hypotension. With appropriate dose reduction, however, tolerance is good.8 a-Adrenergic Blocker Prazosin, by virtue of postsynaptic a,-blockade, lowers left ventricular preload and afterload and may effectively lower blood pressure in elderly patients with renal failure." A risk of orthostatic hypotension and syncope on the first dose as well as an association with diabetes mellitus and autonomic neuropathy exists. Because of these adverse effects, these agents should be used cautiously in the elderly population. Trimazosin has been used in patients with impaired renal function and hypertension. In those cases, the addition of trimazosin to a diuretic as first-step therapy significantly lowered blood pressure without alteration of renal function.68 ACE Inhibitors ACE inhibitors available in the United States are captopril, enalapril, and lisinopril. These drugs lower blood pressure by decreasing peripheral resistance and dilating capacitance vessels without affecting cardiac ACE inhibitors have a potentially favorable effect on renal hemodynamics, because they lower glomerular capillary pressure independent of blood pressure reduction. If ACE inhibitors are used in the setting of significant bilateral renovascular disease, worsening renal function can result because GFR is highly dependent on angiotensin I1 in this state. ACE inhibitors have been recommended in treating elderly persons with hypertension.I5, In patients with renal insufficiency, however, renal elimination of captopril and enalapril is decreased. This could lead to excessively high blood levels of these agents, thereby increasing the risk of toxic reactions. It has been shown, however, that captopril may be safely used and is well tolerated in the setting of severe renal failure. Captopril alone or with additional drugs significantly improves blood pressure control and can be a useful drug for the elderly hypertensive with renal insufficiency. 34 Lisinopril is the lysine analogue of enalaprilic acid, the active metabolite of enalapril, and has a longer duration of action. Lisinopril effectively lowered blood pressure in patients with moderate and severe renal failure. This drug may accumulate when given to patients with severe renal disease, however. To avoid this problem, especially in the elderly population, reduction of dose or frequency to accommodate the degree of renal failure is re~ornmended.~' Calcium Channel Blockers Nifedipine and verapamil effectively lower blood pressure in patients with renal insufficiency. Though effective as monotherapy, they are usually added to an existing regimen to control blood pressure.' In general, they are well-tolerated, but edema, gastric intolerance, headaches, and a mild tachycardia can be problematic. The edema seems secondary to dilatation
of precapillary sphincters, not to fluid retention. No adverse effects on kidney function or renal hemodynamics have been reported. 13. 20 The acute antihypertensive efficacy of nifedipine has been investigated in small studies of hypertensive patients with renal failure, particularly those requiring hemodialysis. In these studies, nifedipine administered orally or sublingually rapidly reduced blood pressure, with maximal blood pressure reduction observed within 30 to 60 minutes. This characteristic makes nifedipine extremely effective in treating hypertensive emergencies ~~ with advanced renal disease during or following h e m ~ d i a l y s i s .Patients who had received verapamil showed a significant decrease in apparent volume of distribution, elimination half-life, and total body clearance. Thus, in elderly patients with renal impairment, dosages of verapamil should be lowered.55 Regarding other calcium channel blockers, nifedipine has an enhanced effect in the setting of renal failure, but for diltiazem no dosage adjustment is needed. Hernodialysis For patients with end-stage renal disease, hemodialysis can be dramatically effective in controlling blood pressure, because of adequate volume control. In addition, chronic ambulatory peritoneal dialysis and kidney transplantation can also be useful in this regard. Often posttransplant immunosuppressive therapy (such as cyclosporine) can raise blood pressure, however. 36
Treatment of hypertension reduces the incidence of stroke.=. 36 This result is clear-cut and strong, unlike antihypertensive treatment's equivocal impact on coronary events. In the setting of an acute stroke, care must be taken in lowering elevated blood pressure. If the blood pressure is high, intravenous nitroprusside is preferred, enabling effective titration of dose as blood pressure fluctuates. Rapid reductions of blood pressure can significantly reduce cerebral blood flow, because the cerebral blood flow autoregulation curve is shifted to the right in chronic hypertensives. One can cause diminished mental function with overly aggressive treatment. With time and gradual lowering of blood pressure, the curve is shifted to the left, toward its normal position, and normal cerebral blood flow is then maintained at lower pressure^.^^ Agents to be avoided in the setting of acute stroke include the centrally acting agents a-methyldopa, reserpine, and clonidine because they cause sedation, making serial assessments of neurologic change difficult. 23
Depression occurs as frequently among elderly as in younger persons." Its causes are legion, but drug treatment is frequently a factor.76 In fact,
clinicians are frequently faced with the quandary of whether the patient's antihypertensive medications are causing or contributing to depression. In certain cases, hospital admission is the outcome of antihypertensive drugrelated depression. An interesting medical record survey was performed in almost 150,000 Medicaid recipient^.^ A much higher use of tricyclic antidepressants (TCA) was found in patients taking P-blockers. The rate of TCA use was 23 per cent in P-blocker users compared with between 10 to 15 per cent in patients using hydralazine, a-methyldopa, reserpine, or various oral hypoglycemic agents. This comparison indicates reserpine may not cause depression as frequently as was formerly thought while underscoring the high prevalence of depression in P-blocker users. These prevalence estimates of depression in the elderly population are undoubtedly low because they represent only those treated with TCAs, and the total prevalence is probably much higher. Diuretics Although p-blockers are recognized most often as culprits in druginduced depre~sion,'~ diuretics are frequent offenders as well.'l Thiazide diuretics have been singled out, possibly because of their common use. Care must be taken in elucidating the cause of probable iatrogenic depression in today's elderly patients. Because of polypharmacy, the cause may be found among a long list of possibilities, and thiazides may be erroneously overlooked. Other drugs that can cause depression include reserpine, amethyldopa, and clonidine.23 Many manic-depressive and unipolar depressive patients are treated with lithium salts. Because diuretics induce a salt-depleted state and lithium is transported in the tubules in the same carriers as sodium, blood lithium levels can b e high in patients being treated with diuretics. Because of this potentially harmful interaction, this drug combination is generally contrainauthor states that the combination of lithium salts and the d i ~ a t e d . 'One ~ diuretic furosemide, however, was safe to use in this disorder.@'
CONCLUSION Choice of drug in the elderly hypertensive patient with comorbid problems is based on an understanding of the pathophysiology of both hypertension and the comorbid condition. In coronary artery disease, Pblockers are generally recommended, but several other classes of drugs are also efficacious. Long-term treatment with its possible benefits in the setting of left ventricular hypertrophy is uncertain, but presumably the various adrenergic inhibitors hold the most promise. In congestive heart failure, diuretics, ACE inhibitors, and some calcium channel blockers are useful. In COPD, P-blockers should be avoided, but most other drugs are well tolerated and effective. Diabetics can be treated with diuretics and Pblockers, but caution should be used because of their effects on diabetic control. Patients with renal failure may need the dose of drug reduced because of reduced clearance, but many classes of antihypertensive drugs can be used. In treating hypertension in stroke patients, care must be
taken to lower blood pressure gradually to avoid compromising cerebral blood flow. Depressed hypertensive elderly patients should avoid Pblockers in particular, but other antihypertensive drugs can also cause depression.
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vasopressin in plasma during treatment with captopril in hypertension and heart failure. Acta Med Scand 677(suppl):110-114, 1983 Gavras G, Gavras I: Management of specific problems associated with hypertension. In Gavras G, Gavaras I (eds): Hypertension in the Elderly. Boston, John Wright PSG, 1983 George RB, Light RW, Hudson LD, et al: Comparison of the effects of labetolol and hydrochlorothiazide on the ventilatory function of hypertensive patients with asthma and propranolol sensitivity. Chest 88:815-818, 1985 Given BD, Lee TH, Stone PH, et al: Nifedipine in severely hypertensive patients with congestive heart failure and preserved ventricular systolic function. Arch Intern Med 145:281-285, 1985 Gunderson T, Abraham AM, Kjekhaus J, et al, for the Norwegian Multicenter Study Group: Timolol-related reduction in mortality and reinfarction in patients aged 65-75 years surviving acute myocardial infarction. Circulation 66:1179-1184, 1982 Guthrie GP Jr, Miller RE, Kotchen TA, et al: Clonidine in patients with diabetes and mild hypertension. Clin Pharmacol Ther 34713-717, 1983 Harrower AD, McFarlane G, Donnelly T, et al: Blood pressure and diabetic control. Results of indapamide treatment. Practitioner 228602-603, 1984 Hawkins CM, Richardson DW, Vokonas PS, for the Beta Blocker Attack Trial Research Group: Effect of propranolol in reducing mortality in older myocardial infarction patients: The Beta-Blocker Heart Attack Trial Experience. Circulation 67(suppl):94-97, 1983 Hitzenberger G: Celiprolol, clinical dosage, efficacy and safety in asthmatic and elderly patients. Br J Clin Pract (symp suppl) 40:25-32, 1985 Hjalmarson A, Herlitz J, Malek I, et al: Effect on mortality of metoprolol in acute myocardial infarction. Lancet 2:823-827, 1981 Houston MC: The effects of antihypertensive drugs on glucose intolerance in hypertensive non-diabetics and diabetics. Am Heart J 115:640-656, 1988 Hulley SB, Furberg CD, Gurland B, et al, for the SHEP Research Group: Systolic hypertension in the elderly program (SHEP): Antihypertensive efficacy of chlorthalidone. Am J Cardiol 56:913-920, 1985 Jenkins AC, Knill JR, Dreslinski GR: Captopril in the treatment of elderly hypertensive patients. Arch Intern Med 145:2029-2031, 1985 Kannell WB, Brand FN: Cardiovascular risk factors in the elderly. In Anders R, Bierman EL, Heggard WR (eds): Principles of Geriatric Medicine. New York, McGraw-Hill, 1985, pp 104-119 Kaplan NM: Management of Hypertension, ed 1. Durant, OK, Creative Infomatics, 1986, pp 138-153 Krane NK, Wallin JD: Managing the elderly patient with both hypertension and pulmonary disease. Geriatrics 42:45-49, 52, 1987 Lardinois CK, Neuman SL: The effects of antihypertensive agents on serum lipids and lipoproteins. Arch Intern Med 148:1280-1288, 1988 Levitan D, Massry SG, Romoff M, et al: Plasma catecholamines and autonomic nervous system function in patients with early renal insufficiency and hypertension: Effect of clonidine. Nephron 36:24-29, 1984 Liebson PR, Savage DD: Echocardiography and hypertension: A review: 11. Echocardiographic studies of the effects of antihypertensive agents on left ventricular wall mass and function. Echocardiography 4:215-251, 1987 Light RW, Chetty KG, Stansbury DW: Comparison of the effects of labetalol and hydrochlorothiazide on the ventilatory function of hypertensive patients with mild chronic obstructive pulmonary disease. Am J Med 75:109-114, 1983 Lind L, Lithell H, Skarfors E, et al: Reduction of blood pressure by treatment with alphacalcidol: A double-blind, placebo-controlled study in subjects with impaired glucose tolerance. Acta Med Scand 223211-217, 1988 Matthews DM, Wathen CG, Bell D, et al: The effect of captopril on blood pressure and glucose tolerance in hypertensive non-insulin dependent diabetics. Postgrad Med J 62(suppl 1):73-75, 1986 Messerli FH: The age factor in hypertension. Hosp Prac 21:103-112, 1986 Micossi P, Pollavini G, Raggi U, et al: Effects of metoprolol and propranolol on glucose tolerance and insulin secretion in diabetes mellitus. Horm Metab Res 16:59-63, 1984
46. Moncloa F, Sromovsky JA, Walker JF, et al: Enalapril in hypertension and congestive heart failure: Overall review of efficacy and safety. Drugs 30(suppl 1):82-89, 1985 47. Muller FB, Bolli P, Erne P, et al: Calcium antagonism-a new concept for treating essential hypertension. Am J Cardiol 57:SOD-53D, 1986 48. Nayler WG, Sturrock WJ, Panagiotopoulos S: Calcium channel blockers and ischemia: A review: Long-term management of patients after myocardial infarction. Dev Cardiovasc Med 84:209-221, 1988 49. The Norwegian Multicenter Study Group: Timolol-induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction. N Engl J Med 304:801807, 1981 50. Noth RH, Lassman MN, Tan SY, et al: Age and the renin-aldosterone system. Arch Intern Med 137:1414-1417, 1977 51. Okada F: Depression after treatment with thiazide diuretics for hypertension. Am J Psychiatry 142:1101-1102, 1985 52. Olsson G, Rehnquist N, Sjogren A, et al: Long-term treatment with metoprolol after myocardial infarction: Effect on 3 year mortality and morbidity. J Am Coll Cardiol 5:1428-1437, 1985 53. O'Malley K, O'Brien E: Renal effects of antihypertensive drugs in elderly hypertensives. Acta Med Scand 676(suppl):110-117, 1983 54. Passa P, LeBlanc H, Marre M: Effects of enalapril in insulin-dependent diabetic subjects with mild to moderate uncomplicated hypertension. Diabetes Care 10:200-204, 1987 55. Piepho RW: Individualization of calcium entry-blocker dosage for systemic hypertension. Am J Cardiol56:105H-lllH, 1985 56. Pollack MH, Rosenbaum JF, Cassem NH: Propranolol and depression revisited: Three cases and a review. J Nerv Ment Dis 173:118-119, 1985 57. Raggi U, Palumbo P, Moro B, et al: Indapamide in the treatment of hypertension in noninsulin dependent diabetics. Hypertension 7(suppl2):157-160, 1985 58. Riska H, Stenius-Aarniala B, Sovijarvi AR: Comparison of the efficacy of an ACE-inhibitor and a calcium channel blocker in hypertensive asthmatics: A preliminary report. Postgrad Med 62(suppl):52-53, 1986 59. Ryman KS, Kuho SH, Shaknovich A, et al: Influence of baseline hemodynamic status and sympathetic activity on the response to nicardipine, a new dihydropyridine, in patients with hvvertension or chronic congestive heart failure. Clin Pharmacol Ther 41:483489, 19g7 60. Saffer D, Coppen A: Frusemide: A safe diuretic during lithium therapy? J Affective Disord 5:289-292, 1983 61. Schlant RC, Felner JM, Blumenstein BA, et al: Echocardiographic documentation of regression of left ventricular hypertrophy in patients treated for essential hypertension. Euro Heart J 3(suppl A):171, 1982 62. Scott P, Giese J: Age and the renin-angiotensin system. Acta Med Scand 676(suppl):4551, 1983 63. Sood VP, Stannard M, Beastall G, et al: Indoramin in the hypertensive diabetic patient. J Cardiovasc Pharmacol 8(suppl 2):80-83, 1986 64. Sorkin EM, Clissold SP, Brogden RN: Nifedipine: A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy, in ischaemic heart disease, hypertension and related cardiovascular disorders. Drugs 30:182-274, 1985 65. Tang J, Xie CW, Xu CB, et al: Therapeutic actions of alpha-human atrial natriuretic polypeptide in 16 clinical cases. Life Sci 40:2077-2086, 1987 66. Thomas JR: A review of 10 years of experience with indapamide as an antihypertensive agent. Hypertension 7(suppl 2):152-156, 1985 67. Thygesen K, Strate M, Hansen L, et al: Survival of diabetic hypertensive patients. Hypertension 7(suppl 2):14-17, 1985 68. Van Kalken CK, Van der Meulen J, Oe PL, et al: Pharmacokinetics of trimazosin and its effects on blood pressure, renal function and proteinuria during short-term therapy of patients with impaired renal function and hypertension. Eur J Clin Pharmacol 316368, 1986 69. Van Schaik BA, Geyskes GG, Boer P: Lisinopril in hypertensive patients with and without renal failure. Eur J Clin Pharmacol 32:ll-16, 1987 70. Vardan S, Mookherjee S, Warner R, et al: Systolic hypertension in the elderly: Hemo-
71. 72. 73. 74. 75. 76. 77. 78. 79.
dynamic response to long-term thiazide diuretic therapy and its side effects. JAMA 250:2807-2813, 1983 Vestal RE (ed): Drug Treatment in the Elderly. Sydney, Australia, ADIS Health Science Press, World Health Organization, 1984, p 40 Vestal RE, Peto R, Lewis J, et al: Drug use in the elderly: A review of problems and special consideration. Drugs 16:358-382, 1978 Vestal RE, Wood AJ, Shand DG: Reduced beta-adrenoceptor sensitivity in the elderly. Clin Pharmacol Ther 26:181-186, 1979 Weber MA, Drayer JI, Deitch MW: Hypertension in patients with diabetes mellitus: Treatment with a dentrally acting agent J ~ardiovascPharmacol 6(suppl 5):823-829, 1984 Wilhelmsen L: Trials in coronary heart disease and hypertension with special reference to the elderly. Eur Heart J 9:207-214, 1988 Williamson J, Chopin JM: Adverse reactions to prescribed drugs in the elderly, a multicenter investigation. Age Ageing 9:73-80, 1980 Wollim GL, Hall WD, Porter VD, et al: Time course of regression of left ventricular hypertrophy in treated hypertensive patients. Am J Med 75(suppl 3A):lOO-110, 1983 Woo J, Woo KS, Valiance-Owen J: Captopril vs hydrochlorothiazide/triamterene in mild to moderate hypertension in the elderly. Lancet 2:924, 1986 Yusuf R: Beta blockade during and after myocardial infarction: An overview of the randomized trials. Prog Cardiovasc Dis 27:335-371, 1985
Division of Epidemiology School of Public Health University of Minnesota Stadium Gate 27 611 Beacon Street SE Minneapolis, MN 55455
0749-0690189 $0.00
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Use of Antihypertensive Agents with Particular Comorbid Problems
Stephen Mascioli, MD, MPH,* and Nelly Mercedes Gonzalez, MDJ-
The combination of the progressive age-related rise in blood pressure in Western societies and the rapidly increasing number of elderly persons has resulted in hypertension in the elderly population being a common medical problem. As the life expectancy of adults has gradually increased, the proportion of elderly with comorbid medical conditions has likewise increased. These comorbid conditions may potentially affect the timing and type of treatment of the various types of hypertension, which has centered around pharmacologic agents. Several classes of antihypertensive agents are available for effective reduction of blood pressure. Choice of agent(s) often depends on coexisting diseases to minimize adverse effects and potentially enhance beneficial therapeutic interactions. This article will review common medical conditions in elderly persons which may influence the choice of antihypertensive drug. This review is based on a literature search that used many excellent studies but also some that had substantial limitations including small sample size, inadequate blinding, no randomization, and no control groups. When possible, the results of rigorous clinical trials are emphasized.
SPECIFIC COMORBIDITIES
A major risk factor for coronary artery disease (CAD) in the elderly ~ ~ often develops in patients with longpopulation is h y p e r t e n ~ i o n .CAD From the Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis, Minnesota *Assistant Professor +Research Assistant Clinics in Geriatric Medicine-Vol.
5, No. 4, November 1989
established mild or moderate hypertension who often have additional risk factors for atherosclerosis. People with myocardial infarction or angina pectoris who have elevated blood pressure should be treated. Recent trials have demonstrated that Pblocking agents will reduce recurrent infarction in patients after acute myocardial infar~tion.'~ 52 For the postmyocardial infarction hypertensive patient who also has congestive heart failure, drugs other than P-blockers should be used. Such patients are considered at high risk, however, and are liable to develop complications as a result of therapy. All drugs used in young hypertensive patients may be used in elderly hypertensive patients, but age-related changes in efficacy, pharmacokinetics, and safety should be considered when treating the elderly patient. If possible, half of the maximum dose recommended for the patient without complications should be used, and individual dose adjustments are indicated. "3
P-Adrenergic-Blocking Agents P-blockers have been used widely for the treatment of angina pectoris and hypertension in elderly patients. Theoretically, they are cardioprotective and exert a beneficial effect by decreasing systemic arterial pressure and heart rate, and mildly reducing contractility-thus reducing myocardial oxygen demand. Furthermore, it is possible that the prolongation of diastole following heart rate reduction facilitates blood flow through poorly perfused regions of the myocardium, p-blockers have intrinsic antiarrhythmic activity and may inhibit platelet aggregation. An increase in the prevalence of lowrenin hypertension occurs with advancing age.50Plasma renin activity and concentrations as well as plasma angiotensin I1 concentration decline with increasing age. In essential hypertension, these declines may be accelerated with progression of the disease. Because they reduce renin levels, Pblockers may be more effective in patients with high-renin hypertension, but studies have shown that p-blockers can be effective in elderly patients with low-renin levels.36.62 Coronary artery spasm can be aggravated by P-blockers by allowing unopposed a-stimulation. This is often not a problem, however, because the reduction in cardiac work is great enough to offset this imbalance.36 A diminished responsiveness of the P-adrenoceptor to both agonist and antagonist drugs occurs with advancing age.g Increased norepinephrine levels in the elderly population could compete for occupancy of the Preceptors in the heart, causing a reduction in affinity of both types of Despite these findings, increasing evidence exists that p-adrenoreceptor blockers such as pr~pranolol,~' t i m ~ l o l , ' and ~ metoproIo17'' may produce clinically significant benefit in postmyocardial infarction patients. A statistically significant reduction in morbidity has been demonstrated with these drugs, and the effect appears to be as great in older as in younger patients. 79 In a study of the use of metoprolol after myocardial infarction, patients aged 65 to 74 years showed a significant reduction in postmyocardial .~~ the placebo group, mortality was more than twice infarction m ~ r t a l i t y In as high in the age group 65 to 74 years than in the age group 40 to 64 years," showing the importance of treating the elderly. In the p-Blocker
Heart Attack (BHAT) Study, propranolol reduced postinfarction mortality in patients up to 69 years of age (the upper age limit for inclusion in the study). The placebo group mortality was considerably higher among the group of patients aged 60 to 69 years compared with those aged 30 to 59 years, and the proportionate effect of active treatment was greater in the older patients.'' In the Norwegian Timolol Study, patients 65 to 75 years old who received long-term treatment with timolol and who survived acute myocardial infarction experienced significant reductions in mortality, cardiac death, sudden death, and reinfarctiom4' Comparing a range of p-blockers, it has been found that for patients with stable exertional angina pectoris, p,-selective (metoprolol, proctolol, tolomolol) and nonselective (propranolol and oxprenolol) P-blockers were equally effective in reducing symptoms and improving exercise tolerance.' Metoprolol is recommended as a first-choice agent in the setting of hypertension and stable angina. It is also beneficial in postmyocardial infarction patients. In early acute myocardial infarction complicated by hypertension, Pblockers are contraindicated because of their myocardial depressive effects. Nitrates or calcium channel blockers are preferred in this setting, with use of p-blockers reserved for later in the clinical course.36 When prescribing p-blockers, the usual contraindications should be observed: obstructive airway disease, atrioventricular block, congestive heart failure, or insulin-dependent diabetes. Side effects, quality of life, and cost (especially for newer agents) should also be considered when using these drugs. Thiazides and Related Diuretics Thiazides are often preferred as initial therapy for patients with hypertension and coronary artery disease because of their low cost and the little dose-titration needed, but important concerns exist for elderly patients. The most worrisome of these is hypokalemia, which can initiate ventricular arrhythmias. This potential adverse effect is especially deleterious in patients with coronary artery disease and left ventricular hypertrophy. In addition, thiazides have been shown to have deleterious effects on serum lipids, which can potentially aggravate risk of a t h e r o s c l e r ~ s i s . ~ ~ The European Working Party on High Blood Pressure in the Elderly (EWPHE) assessed the effects of antihypertensive drugs in patients aged 60 to 97 years. One third of them had pre-existing cardiovascular complications. Treatment was hydrochlorothiazide plus triamterene and a-methyldopa, if needed, compared with placebo. Treatment yielded about 27 per cent reduction in cardiovascular mortality. The benefits of treatment observed in the trial seemed to be independent of the presence or absence of cardiovascular complications at entry. Little or no benefit from treatment was demonstrated in patients older than 80 years of age.2 The Systolic Hypertension in the Elderly Program (SHEP) Pilot Study showed that chlorthalidone in low doses of 15 to 30 mg per day was well tolerated, and serum lipid changes at 1 year were not ~ i g n i f i c a n t . ~ ~
Calcium Channel Blockers The calcium entry-blocking drugs have been used recently in the therapy of essential hypertension. Their ability to inhibit selectively the transmembrane flux of calcium ions in excitable tissues is presumed to account for their various actions, including peripheral and coronary artery vasodilation. The three major calcium channel blockers used in the United States are verapamil, nifedipine, and diltiazem. Studies evaluating the use of calcium-channel blockers in coexisting coronary artery disease and hypertension support the idea that calcium-channel blockers can protect potentially jeopardized myocardium when the therapy is initiated at the appropriate time. It seems that for those patients who survive their first infarct and who are maintained on calcium channel blockers, the risk of reinfarction is reduced if congestive heart failure can be a ~ o i d e d . ~It' has been shown that comparable antihypertensive activity exists among verapamil, nifedipine, diltiazem, and nitrendipine. The antihypertensive effect of verapamil and nitrendipine has been found to be greatest in older patients and in those with low-renin levels.47Long-acting nifedipine significantly reduced blood pressure in patients with angina, and side effects were few and not significant.l3. l4 Verapamil in a slow-release form and nitrendipine appear to achieve effective control of blood pressure comparable with the effect of a P-blocking agent.17 Calcium antagonists are excellent alternatives for the elderly population, especially in those whom P-blocking drugs are contraindicated.
ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITORS The ACE inhibitors' primary mechanism of action is a decrease in peripheral resistance, which is elevated in the elderly population. This is a physiologic advantage over P-blocking drugs (which can increase peripheral resistance) when treating hypertension in elderly persons. Whether ACE inhibitors have particular benefit in patients with coronary artery disease (except those with heart failure) is uncertain. It has been shown that captopril in relatively small doses, as monotherapy in some instances, or in combination with a second or third antihypertensive agent, provides welltolerated and effective therapy for the elderly hypertensive patient (65 years of age or older).34
Left ventricular hypertrophy is a common accompaniment of hypertension in the elderly population. Its presence carries an increased risk of subsequent cardiovascular disease events. Several classes of antihypertensives have been shown to reduce left ventricular mass, as measured by echocardiography, over the short term. Most drugs effective in this regard are adrenergic inhibitors of some type.40, Diuretics and direct vasodilators have not consistently shown reductions of left ventricular mass, at least in
the short term.3677 This is presumably because of reflex activation of the sympathetic nervous system when using these agents as monotherapy. Long-term change, however, in left ventricular mass with any agent is virtually unknown, as is a beneficial impact, if any, on subsequent cardiovascular risk. Long-term studies are necessary to answer these important questions.
Hypertension and congestive heart failure coexist in many elderly persons. The treatment of either condition should be chosen with the other in mind. Fortunately, several available drugs are effective for both conditions. Diuretics Diuretics have been the traditional drugs used in this setting. Loop diuretics such as furosemide are effective preload reducers, and such potent diuretics are often necessary in congestive heart failure.23Elderly patients treated long term with diuretics have been shown to have diminished serum potassium and magnesium levels.'s These can be increased with potassium supplementation and potassium-sparing diuretics. lg Occasionally, magnesium supplementation may be required. ACE Inhibitors Afterload reduction is also a goal and can be accomplished with various vasodilators. ACE inhibitors are favored in this setting because they reduce both preload and afterload, and enhance renal blood flow, glomerular filtration rate, sodium excretion, and cardiac output.= ACE inhibitors are effective in treating these two disorders through their expected mechanism 46 of preload and afterload reducti~n.'~. Calcium Channel Blockers Calcium channel blockers are effective treatment in patients with hypertension and congestive heart failure. A series of nine patients with refractory hypertension and congestive heart failure were treated with nifedipine. It was effective in reducing blood pressure and relieving symptoms of congestive heart failure.25.59 Verapamil tends to depress myocardial contractility and probably should be avoided in patients with heart failure. Atrial Natriuretic Peptides A novel treatment shown to be effective in both hypertension and heart failure is a-human atrial natriuretic peptides. The drug was administered intravenously to 16 patients, some elderly, and the hemodynamic changes noted were acute and transient. The changes, however, were all in a favorable direction: increased cardiac output, cardiac index, stroke volume, ejection fraction, ejection rate, urine volume, electrolyte excretion,
creatinine excretion, and decreased right-sided vascular pressures. Use of these drugs may increase in the future.=
@-Blockers should be used with caution in treating elderly hypertensives with chronic obstructive pulmonary disease (COPD, chronic bronchitis, and emphysema) or asthma. Smooth muscle in the bronchial tree has P,-receptors, which, when stimulated, cause smooth muscle relaxation and bronchodilatation. If these P,-receptors are blocked, bronchoconstriction is favored, which may aggravate obstructive airway disease. Nonselective Pblockers (both P, [cardiac] and P, [bronchial]) are of primary concern because of their pulmonary effects. Propranolol, a nonselective p-blocker, is contraindicated in hypertension treatment in patients with pulmonary disease. PI-selective-blockers, such as metoprolol or celiprolol, are often used in patients with COPD or asthma.30 In addition, P-blockers with intrinsic sympathomimetic activity can be tried c a ~ t i o u s l y Caution .~~ must be exercised because PI-selectivity is only relative and diminishes at higher doses. Labetolol, a combination nonselective p-blocker and al-peripheralblocker has been studied for use in hypertensive patients with pulmonary 41 These studies show that it appears to be safer than other Pblockers but should still be used with caution. Both authors recommend using other classes of antihypertensives in the presence of pulmonary disease, however. Other antihypertensives such as reserpine and a-methyldopa are reported to have aggravated existing pulmonary disease. 23 Other Drugs Other antihypertensives have been studied regarding their effects on bronchial smooth muscle. Calcium channel blockers, ACE inhibitors, and direct vasodilators have no effect on bronchial tone. These agents, along with diuretics, should be considered antihypertensive agents of first choice in patients with lung disease.'', 37. 58 Prazosin, an a,-blocker, has been shown to dilate the bronchial tree, and ACE inhibitors have been used successfully in patients with lung disease receiving corticosteroid therapy.23
Like many chronic diseases, the prevalence of diabetes increases with age, making it a common problem in elderly persons. Because some risk factors for type I1 diabetes mellitus are the same as those for hypertension, a sizable number of patients with both conditions exists. Hence, choice of antihypertensive drug must be made with knowledge of its potential effects on diabetes. Also, because patients with both disorders have a much-
increased risk of further morbidity and m ~ r t a l i t y the , ~ ~ goal of therapy is optimal control of both conditions. Diuretics Diuretics are safe, effective, and well-tolerated antihypertensive agents, and several different types are available. Thiazide diuretics have been shown to aggravate diabetic control in elderly person^,^. 32' 70 but generally the disturbances are not ~ e r i o u sThe . ~ mechanism of this problem probably is inhibition of insulin release.23 Therefore, these agents are safe to use in insulin-dependent diabetes mellitus but can be problematic in type I1 diabetes mellitus.= Blood sugars are raised, along with glycosylated hemoglobin, a marker of long-term blood sugar levels. Also, the addition of the p-blocker propranolol to diuretic treatment will further aggravate diabetic control. Hypokalemia, which can often accompany diuretic therapy, can worsen hyperglycemia. This may be because of decreased insulin effect or secretion.=. Maintaining normokalemia is therefore important for this as well as other reasons. Potassium-sparing diuretics, however, are generally contraindicated in diabetics because these patients have a high prevalence of renal insufficiency and hyporeninemic hypoaldosteronism; both conditions reduce renal secretion of potassium and may result in h y ~ e r k a l e m i a . ~ Chlorthalidone, a thiazide-like diuretic, may impair glucose tolerance in elderly hypertensives with diabetes.32.71 Studies of indapamide, a 2methylinsoline diuretic, show no effect on glucose t ~ l e r a n c e , '57. ~ ffi but some authors disagree.32 Loop diuretics generally cause increased blood This may be so because loop diuretics sugars but less so than thiazide~.~' cause less hypokalemia, thereby facilitating the conversion of proinsulin to insulin.
The effects of p-blockers on diabetes are mixed. They may be a good choice mechanistically because they do not aggravate postural hypotension, a complication often present in the elderly diabetic.23 Some reports show a deleterious effect on glucose h o m e o ~ t a s i s3,"~45 whereas others show little or no effect on blood glucose levels.16 P-Blockers may aggravate diabetes by interfering with P-adrenergic stimulation of pancreatic islet cells, which potentiates insulin release. Metoprolol, a cardioselective P-blocker, may be preferable in diabetics being treated with sulfonylureas compared with the nonselective P-blocker propranolol because less inhibition of insulin release occurs.45 P-blockers used in low dose, those with intrinsic sympathomimetic activity, cardioselective agents, or those with mixed p- and a-blocking effects are not prone to disturb diabetic control.32 Apart from their direct effects on glucose levels, p-blockers are relatively contraindicated in diabetics because of their tendency to mask hypoglycemic episodes. p-blockers attenuate the sympathetic reaction to hypoglycemia by reducing tachycardia and adrenalmediated glycemic response. For this reason, many clinicians are hesitant to treat hypertensive insulin-dependent diabetics with P - b l ~ c k e r s . ~ ~
ACE Inhibitors and Calcium Channel Blockers ACE inhibitors have been studied by several groups in diabetic
patient^.^" 43, 54 ACE inhibitors do not affect blood sugars in types I or I1 diabetes, making them a good choice for the treatment of hypertension in this group of patients. Calcium channel blockers are effective antihypertensive agents in patients with diabetes.13 In diabetics and nondiabetics, calcium channel blockers have no adverse effects on glucose tolerance, also making them a good choice in these patients. Other Drugs Clonidine appears to affect glucose tolerance in diabetics adversely as measured acutely by an increased glycemic response to an intravenous glucose load but did not appear to affect long-term contr01.'~ Several classes of antihypertensive drugs have not been studied extensively, but the available reports indicate that peripheral a, blockers, central adrenergic inhibitors, potassium-sparing diuretics, and direct vasodilators have little or no effect on glucose levels.3263. 74 A Scandinavian group studied 65 hypertensive men aged 61 to 65 years who also had impaired glucose tolerance. They were treated with a calcadol, an investigational synthetic analogue of active vitamin D, in a placebo-controlled, double-blind trial. Because calcium metabolism influences blood pressure regulation, supplementation with this agent could be beneficial for hypertensives. The treatment period lasted 12 weeks, and results showed that a-calcadol lowered blood pressure without affecting glucose tolerance.42
General Considerations Renal failure can either precede and cause hypertension or may be the end result of long-term, severe hypertension. Hypertensive renal disease is much less common now than in the past because severe hypertension is usually successfully treated. The elderly patient needs special considerations because the effects of aging on renal physiology involve both glomerular and tubular function. Glomerular filtration rate (GFR) may fall as much as 50 per cent, with an average decline of about 35 per cent between 20 and 90 years of age. Renal plasma flow, urine concentration (especially during water deprivation), and renal sodium conservation decline with age." Therapy should be individualized, particularly when hypertension and renal insufficiency are associated with other significant medical problems. Most of the drugs used in younger patients may be used in the elderly population, but the starting doses should be halved, maintenance dosages should be lower, and frequency of administration may also be reduced. For example, in renal insufficiency in which GFR is < 10 ml per minute, clonidine should be given at 50 to 75 per cent of the normal dose.8 For detailed prescribing guidelines, one should refer to information supplied by pharmaceutical manufacturers.
Blood pressure control can partially reverse renal insufficiency by restoring to function that part of renal tissue in which blood flow is reduced in a pressure-dependent manner. Progression of renal failure can be significantly retarded by effective blood pressure control.12 Usually more than one drug is needed to achieve good results. One must be cautious in reducing blood pressure too rapidly in this setting because renal blood flow can fall, especially in the presence of high renovascular resistance or bilateral renal artery stenosis. Because the kidneys autoregulate blood flow through changes in vascular tone secondary to the juxtaglomerular apparatus and angiotensin 11, a rapid decrease in arterial blood pressure can result in a fall in glomerular filtration rate. Diuretics Loow diuretics such as furosemide or bumetamide are the agents of choice in patients with a z ~ t e m i a Compared .~~ with other diuretics, they have less hypokalemia, less lipid disturbance, and possibly less orthostatic hypotension. They should be used in patients with poor compliance to a low-salt diet. If the patient is refractory to a loop diuretic alone, a thiazide diuretic such as metolazone can be added. Excessive diuresis is a votential problem with metolazone and must be guarded against. Also, hyponatremia secondary to thiazide-induced decreased free water clearance is a problem seen in the elderly population. Thiazides, however, are often ineffective if the serum creatinine is above 2.5 to 3.0 mg per dl (GFR 5 30 ml per minute). Indapamide can be useful in lowering blood pressure in this situation. The response can be assessed by monitoring body weight in addition to blood pressure. 23 A series of small studies looking at atenolol, nadolol, and labetolol showed that they were effective in lowering blood pressure, with no significant effect on serum creatinine, urea, and GFR.53Thus, their use in elderly patients has been recommended. These agents, however, tend to reduce cardiac output and increase peripheral vascular resistance, two changes present in many elderly hypertensives. Also, the elderly have decreased numbers of @-receptors or a decreased P-receptor sensitivity, making these agents less effective compared with younger patients. In patients with reduced G F R of between 0.3 and 3.3 1 per hour, the elimination half-life and total body clearance of metropolol were not significantly different from those in healthy subjects.? Some studies indicate a reduction in G F R of about 25 per cent in elderly persons treated with Pblocking agents. This may potentially lower renal sodium excretion, an unwanted effect in patients with decreased renal function and volume expansion. Antiadrenergic Agents In one study, sixteen elderly patients with early renal insufficiency and hypertension were compared with age-matched controls.39They had abnormalities in the sympathetic nervous system that contributed to hypertension, such as elevated plasma renin activity, norepinephrine, and aldoste-
rone. Clonidine was used successfully in these patient^.^' This drug must be used with caution in elderly patients because of the frequent side effect of postural hypotension. With appropriate dose reduction, however, tolerance is good.8 a-Adrenergic Blocker Prazosin, by virtue of postsynaptic a,-blockade, lowers left ventricular preload and afterload and may effectively lower blood pressure in elderly patients with renal failure." A risk of orthostatic hypotension and syncope on the first dose as well as an association with diabetes mellitus and autonomic neuropathy exists. Because of these adverse effects, these agents should be used cautiously in the elderly population. Trimazosin has been used in patients with impaired renal function and hypertension. In those cases, the addition of trimazosin to a diuretic as first-step therapy significantly lowered blood pressure without alteration of renal function.68 ACE Inhibitors ACE inhibitors available in the United States are captopril, enalapril, and lisinopril. These drugs lower blood pressure by decreasing peripheral resistance and dilating capacitance vessels without affecting cardiac ACE inhibitors have a potentially favorable effect on renal hemodynamics, because they lower glomerular capillary pressure independent of blood pressure reduction. If ACE inhibitors are used in the setting of significant bilateral renovascular disease, worsening renal function can result because GFR is highly dependent on angiotensin I1 in this state. ACE inhibitors have been recommended in treating elderly persons with hypertension.I5, In patients with renal insufficiency, however, renal elimination of captopril and enalapril is decreased. This could lead to excessively high blood levels of these agents, thereby increasing the risk of toxic reactions. It has been shown, however, that captopril may be safely used and is well tolerated in the setting of severe renal failure. Captopril alone or with additional drugs significantly improves blood pressure control and can be a useful drug for the elderly hypertensive with renal insufficiency. 34 Lisinopril is the lysine analogue of enalaprilic acid, the active metabolite of enalapril, and has a longer duration of action. Lisinopril effectively lowered blood pressure in patients with moderate and severe renal failure. This drug may accumulate when given to patients with severe renal disease, however. To avoid this problem, especially in the elderly population, reduction of dose or frequency to accommodate the degree of renal failure is re~ornmended.~' Calcium Channel Blockers Nifedipine and verapamil effectively lower blood pressure in patients with renal insufficiency. Though effective as monotherapy, they are usually added to an existing regimen to control blood pressure.' In general, they are well-tolerated, but edema, gastric intolerance, headaches, and a mild tachycardia can be problematic. The edema seems secondary to dilatation
of precapillary sphincters, not to fluid retention. No adverse effects on kidney function or renal hemodynamics have been reported. 13. 20 The acute antihypertensive efficacy of nifedipine has been investigated in small studies of hypertensive patients with renal failure, particularly those requiring hemodialysis. In these studies, nifedipine administered orally or sublingually rapidly reduced blood pressure, with maximal blood pressure reduction observed within 30 to 60 minutes. This characteristic makes nifedipine extremely effective in treating hypertensive emergencies ~~ with advanced renal disease during or following h e m ~ d i a l y s i s .Patients who had received verapamil showed a significant decrease in apparent volume of distribution, elimination half-life, and total body clearance. Thus, in elderly patients with renal impairment, dosages of verapamil should be lowered.55 Regarding other calcium channel blockers, nifedipine has an enhanced effect in the setting of renal failure, but for diltiazem no dosage adjustment is needed. Hernodialysis For patients with end-stage renal disease, hemodialysis can be dramatically effective in controlling blood pressure, because of adequate volume control. In addition, chronic ambulatory peritoneal dialysis and kidney transplantation can also be useful in this regard. Often posttransplant immunosuppressive therapy (such as cyclosporine) can raise blood pressure, however. 36
Treatment of hypertension reduces the incidence of stroke.=. 36 This result is clear-cut and strong, unlike antihypertensive treatment's equivocal impact on coronary events. In the setting of an acute stroke, care must be taken in lowering elevated blood pressure. If the blood pressure is high, intravenous nitroprusside is preferred, enabling effective titration of dose as blood pressure fluctuates. Rapid reductions of blood pressure can significantly reduce cerebral blood flow, because the cerebral blood flow autoregulation curve is shifted to the right in chronic hypertensives. One can cause diminished mental function with overly aggressive treatment. With time and gradual lowering of blood pressure, the curve is shifted to the left, toward its normal position, and normal cerebral blood flow is then maintained at lower pressure^.^^ Agents to be avoided in the setting of acute stroke include the centrally acting agents a-methyldopa, reserpine, and clonidine because they cause sedation, making serial assessments of neurologic change difficult. 23
Depression occurs as frequently among elderly as in younger persons." Its causes are legion, but drug treatment is frequently a factor.76 In fact,
clinicians are frequently faced with the quandary of whether the patient's antihypertensive medications are causing or contributing to depression. In certain cases, hospital admission is the outcome of antihypertensive drugrelated depression. An interesting medical record survey was performed in almost 150,000 Medicaid recipient^.^ A much higher use of tricyclic antidepressants (TCA) was found in patients taking P-blockers. The rate of TCA use was 23 per cent in P-blocker users compared with between 10 to 15 per cent in patients using hydralazine, a-methyldopa, reserpine, or various oral hypoglycemic agents. This comparison indicates reserpine may not cause depression as frequently as was formerly thought while underscoring the high prevalence of depression in P-blocker users. These prevalence estimates of depression in the elderly population are undoubtedly low because they represent only those treated with TCAs, and the total prevalence is probably much higher. Diuretics Although p-blockers are recognized most often as culprits in druginduced depre~sion,'~ diuretics are frequent offenders as well.'l Thiazide diuretics have been singled out, possibly because of their common use. Care must be taken in elucidating the cause of probable iatrogenic depression in today's elderly patients. Because of polypharmacy, the cause may be found among a long list of possibilities, and thiazides may be erroneously overlooked. Other drugs that can cause depression include reserpine, amethyldopa, and clonidine.23 Many manic-depressive and unipolar depressive patients are treated with lithium salts. Because diuretics induce a salt-depleted state and lithium is transported in the tubules in the same carriers as sodium, blood lithium levels can b e high in patients being treated with diuretics. Because of this potentially harmful interaction, this drug combination is generally contrainauthor states that the combination of lithium salts and the d i ~ a t e d . 'One ~ diuretic furosemide, however, was safe to use in this disorder.@'
CONCLUSION Choice of drug in the elderly hypertensive patient with comorbid problems is based on an understanding of the pathophysiology of both hypertension and the comorbid condition. In coronary artery disease, Pblockers are generally recommended, but several other classes of drugs are also efficacious. Long-term treatment with its possible benefits in the setting of left ventricular hypertrophy is uncertain, but presumably the various adrenergic inhibitors hold the most promise. In congestive heart failure, diuretics, ACE inhibitors, and some calcium channel blockers are useful. In COPD, P-blockers should be avoided, but most other drugs are well tolerated and effective. Diabetics can be treated with diuretics and Pblockers, but caution should be used because of their effects on diabetic control. Patients with renal failure may need the dose of drug reduced because of reduced clearance, but many classes of antihypertensive drugs can be used. In treating hypertension in stroke patients, care must be
taken to lower blood pressure gradually to avoid compromising cerebral blood flow. Depressed hypertensive elderly patients should avoid Pblockers in particular, but other antihypertensive drugs can also cause depression.
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