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Managing hypertension in the elderly in light of the changes during aging

Managing hypertension in the elderly in light of the changes during aging The natural rise in systolic blood pressure with age is often complicated by other co-morbidities. Pharmacokinetics and pharmacodynamics of antihypertensive drugs are altered during aging, resulting in decrease in absorption and function of the kidney and liver, as well as interactions and adverse reactions of antihypertensives with the often large number of medications taken by the elderly. The problem of compliance in the elderly that may be disrupted by depression, loss of memory, vascular dementia and other conditions that compromise cognition is also of concern. Despite the many issues facing healthcare providers in managing hypertension in the elderly, the benefits are extensively documented and warrant overcoming therapeutic inertia, especially in view of current access to well documented therapeutic options. Key Words: Aging, altered metabolism, polypharmacy Introduction w140/w90 mmHg or were taking antihypertensive medication (5). This phenomenon is further com- As the population ages, health issues multiply, posing plicated by the prevalence of co-morbidities in enormous challenges to the medical community. It is elderly hypertensive patients. A retrospective review estimated that by the year 2030, there will be (6) of medical records turned up at least one co- approximately 70 million people in the United morbidity in 88% of the patients, the most common States over the age of 65 (1), representing 20% of being isolated systolic hypertension. Multiple co- the total population. The 85 and older age group will morbidities were present in 61% of cases. The grow to 7 million people (2). There is a high incidence increased risk of cardiovascular death, stroke and of common diseases and conditions in the aging myocardial infarction associated with high systolic population, which range from heart disease, renal pressure is well known and documented (4). disease and diabetes, osteoporosis, gastrointestinal When medical conditions such as dyslipidemia, problems, diminished humoral- and cell-mediated diabetes mellitus, congestive heart failure and immune responses, to sensory and musculoskeletal chronic renal disease are joined by hypertension, disturbances (3). there is a significant rise in the risk for cardiovascular When considering the natural rise in systolic blood events (7), predominantly in subjects with metabolic pressure with age, it is not surprising to find a syndrome (8,9). Such patients exhibit higher pulse prevalence of hypertension in excess of 70% after the pressure amplification, heart rate and pulse wave age of 70 (4). Indeed, a study conducted in North velocity compared with subjects without metabolic America, Europe, Japan and Australia showed that syndrome(s) of the same age, gender and mean 80% of people 70 and over had a blood pressure arterial pressure. Correspondence: Talma Rosenthal, Department of Physiology and Pharmacology, Hypertension Research Unit, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Tel: 972-3-6960210. Fax: 972-3-6968844. E-mail: [email protected] (Received 14 April 2008; accepted 26 June 2008) ISSN 0803-7051 print/ISSN 1651-1999 online # 2008 Informa UK Ltd. (Informa Healthcare, Taylor & Francis AS) DOI: 10.1080/08037050802305578 Managing hypertension in the elderly 187 The importance of blood pressure control in the (22). Also in the ASCOT study (23), there was a elderly is underscored by a number of studies. Large- preference for newer drugs over older ones: calcium scale clinical trials have demonstrated that treatment blocker agents and ACEIs versus diuretics and beta- of isolated systolic and systolic/diastolic hypertension blocking agents. In addition, ACEIs were found lowers total mortality rates, cardiovascular mortality superior to calcium-channel blockers for the preven- rates and stroke in older adults (10,11). tion of coronary heart disease, and calcium-channel SHEP (12), STOP (13) and MRC (14) were the blockers were superior for the prevention of stroke in first large hypertension trials that enrolled exclu- a meta-analysis of 28 trials (24). sively people over 65 years of age. All these trials In the ALLHAT Study, with 57% of the cohort compared diuretics and/or beta-blockers to placebo over 65 years of age at baseline, despite a less and reported 25–47% reductions in the relative risk favorable metabolic profile, thiazide-like diuretic of stroke and 19–27% reductions in coronary events. therapy for hypertension offers similar, and possibly The decrease in coronary events was significant in superior, cardiovascular disease outcomes in older only one of the trials, in SHEP, a study in which hypertensive adults with metabolic syndrome, as treatment reduced the risk of cardiovascular death compared with treatment with calcium-channel after 14 years of extended follow-up (15). STOP blockers and ACEIs (25). enrolled an older cohort of subjects – 70–84 years at The Hypertension in the Very Elderly Trial the beginning of the study – and reported a 43% (HYVET) Working Group (26) gathered data on reduction in total mortality. Subsequent trials the over 85-year age group, an important cohort enrolling people over 60 years of age evaluated the where little data was previously available. The main treatment of isolated systolic hypertension with the aim of this study was to resolve persistent areas of long-acting calcium-channel blocker nitrendipine uncertainty about the relative benefits and risks of with or without an angiotensin-converting enzyme antihypertensive in this very elderly group. This large (ACE) inhibitor (ACEI), with or without hydro- pilot study evaluated a diuretic-based or ACEI-based chlorothiazide (16–18). The greatest absolute ben- regimen versus placebo, with stroke the primary efit was seen in male patients 70 years and older, and endpoint and total mortality the second one. In the patients with previous cardiovascular complications results, published recently (27), there was clear or wider pulse pressure. documentation of a linear association between blood Combination therapy consisting of perindopril and pressure and stroke reduction, which was attenuated indapamide lowered the relative risk of stroke by 43% with age, and a significant reduction in the risk of in PROGRESS (Perindopril Protection against death from stroke under active treatment. In fact, the Recurrent Stroke Study) (19), a study that enrolled risk of death from any cause was found to be reduced 6105 subjects with a mean age of 64 years and baseline with active treatment in HYVET, highlighting the systolic blood pressure levels of ,147/86 mmHg. The benefits of blood pressure reduction on mortality. risk of stroke was lowered by this combination in both The significant reduction in the risk of death from hypertensive and non-hypertensive individuals with a stroke and death from any cause was observed when previous history of stroke or transient ischemic attack. treated with sustained release indapamide, with or Cardiovascular events were similarly reduced in without perindopril. The interesting finding of fewer 70–84-year-old hypertensive patients in each of the deaths from any cause on treatment is consistent with three treatment arms of STOP-2 (20), a trial the results of the INDIANA meta-analysis of 1670 comparing a diuretic/beta-blocker, the calcium patients 80 and over that included treatment regi- antagonist amiloride, or an ACEI. According to mens based on high doses of diuretics other than Hansson et al. (20), the ‘‘older’’ and ‘‘newer’’ indapamide or on beta-blockers (28). antihypertensive drugs exhibited similar ability to Seto et al. (29) reported that people 60 years and prevent cardiovascular mortality or major events. In even much older, up to 80, with isolated systolic contrast, in the Second Australian National Blood hypertension have good prognoses in terms of Pressure Study in 65–84-year-olds (21), beginning longevity, but many develop late-onset cardiovascu- antihypertensive treatment with ACEIs improved lar complications, suggesting the importance of cardiovascular outcome in older subjects, even blood pressure control. though the comparative diuretic-based regimen produced similar reductions in blood pressure. This coincides with the findings of the LIFE study Polypharmacy that showed a difference in terms of the endpoints of risk reduction in favor of the newer drug losartan The subspecialty of geriatric pharmacology has an over the older beta-blocker-based drug regimen important focus on the high incidence and prevalence 188 T. Rosenthal & N. Nussinovitch of drugs such as anticoagulants, cardiovascular and of systemic diseases among older adults, especially psychotropic drugs (37) (Figure 1). Most drugs are chronic diseases, and the resultant rise in medication absorbed from the gastrointestinal tract, where use (3), often referred to as polypharmacy. Studies hydrochloric acid and pepsin are secreted, and then show that one-quarter of hospitalized patients over pass through the liver. Since liver volume and liver the age of 65 are taking six or more drugs daily, older blood flow decrease progressively with age in parallel adults average 13 prescriptions per year, and some to an altered body composition, there may be an 90% of patients 75 years and older take drugs increased volume of distribution of lipid-soluble regularly, more than one-third of them three or more drugs, and reduced clearance of lipid-soluble and drugs a day (3). According to a national survey of the water-soluble drugs with advancing age. Thus, first- non-institutionalized US population, the highest pass metabolism of some drugs may be reduced in prevalence of medication use was among women the elderly, which means that the bioavailability of aged at least 65, of whom 23% used five medications, drugs that undergo extensive first-pass metabolism, and 12% used 10 or more different medications every like propranolol and labetalol, can be significantly day (30,31). Other studies have reported that the increased. On the other hand, the majority of ACEI elderly have three times more prescriptions for pro-drugs (enalapril and perindopril) that undergo psychotropic drugs than do younger people, despite activation in the liver may have an impaired their susceptibility to the untoward effects of these biotransformation in patients with severe heart drugs and the twice-longer period needed to recover failure and hepatic dysfunction, conditions often from them than seen in young patients (3). found in the elderly (3). Not only are the elderly taking more drugs, but they Advancing age may also impair kidney function and also run the risk of mistakes in selecting drugs and excretion, resulting in diminished renal blood flow, doses provided by multiple health providers, or they glomerular filtration rate, tubular secretion (3,34) and take medicine prescribed for someone else (32). In renal mass due to the reduction in nephrons (34,37). addition to that, age-related changes in pharmacoki- Diminished blood flow also occurs in the afferent netics and pharmacodynamics render them more arterioles in the cortex due to intra-renal vascular susceptible to drug-related problems (33,34). Based changes. Ambulatory, community-dwelling volun- on a mean of 8.7 prescriptions per patient in the 65 teers of the Baltimore Longitudinal Study on Aging and over age group, a study in the Netherlands (38) exhibited about a one-third reduction in creati- identified 3.9 potential drug-related problems per nine clearance between 20 and 90 years of age. Since elderly person (35). More than prescribing the wrong most drugs are removed via the kidney, this reduction medications, the pitfalls of medical care of older in renal function in elderly subjects, particularly patients also include a considerable risk of toxicity of glomerular filtration rate, impacts on the clearance drugs in this age group, and failures by healthcare of many drugs such as e.g. diuretics, water-soluble personnel to prescribe the indicated medications, beta-adrenoceptor blockers and non-steroidal anti- perform adequate follow-up, document the manage- inflammatory drugs (37). The age-related changes in ment of care, educate patients and maintain con- glomerular filtration and tubular secretion are parti- tinuity (35). Proper management requires that the cularly detrimental to the excretion of several ACEIs, general practitioner balance incomplete information resulting in an increase in plasma concentration (37). about the efficacy of drugs in compromised elderly Some ACEIs such as benazepril, fosinopril and people against the potential adverse drug reactions ramipril are also eliminated by the biliary route. while at the same time providing the requisite Homeostatic regulatory mechanisms decline in pharmacotherapy (36). the elderly, which may explain the greater incidence of postural hypotension, slower thermoregulation and slower capacity to compensate for the hypoten- Altered drug metabolism due to sive effects of an antihypertensive drug (3). Elderly pharmacokinetic and pharmacodynamic hypertensives with orthostatic hypotension may be changes in the elderly over-represented among those who develop Drug metabolism in the elderly is a complicated advanced silent cerebrovascular disease (39). area. Aging is accompanied by pharmacokinetic Taken together, in elderly hypertensives, there changes such as reduced renal and hepatic clearance, may be a need to adjust drug dosages in patients and increased volume of distribution of lipid-soluble with renal insufficiency, especially in those with drugs that prolongs elimination half-life as well as creatinine clearance below 30 ml/min (37). Serum pharmacodynamic changes (34) such as altered creatinine may not be a correct estimate of renal (generally heightened) sensitivity to several classes function, especially in the elderly (40,41). Managing hypertension in the elderly 189 Brain Permeability Mouth and Esophagous Fatty Tissues Chewing and Swallowing Skeletal Muscle Sense of Taste and Smell Oesophageal Peristalsis Skeletal Body Mass Stomach Total Body Fat Changes in Gastric pH Slow Gastric Emptying Immunologic System Liver Small Intestine Kidney Circulation Gut Motility Impaired Immune Response Constipation Transit Time From Gut Clearance and Gastrointestinal and Elimination Splanchnic Blood Flow Albumin Concentration or Drug and Food Interaction and Bioavailability Figure 1. Increases or decreases in drug metabolism due to pharmacokinetic and pharmacodynamic changes in the elderly. In: Akamine D, Filho MK, Peres CM. Drug nutrient interactions in elderly people. Curr Opin Clin Nutr Metab Care. 2007;10:304–310, by permission to the author by Lippincott Williams and Wilkins. Adverse drug reactions problematic in the elderly, being associated with impaired renal function, GI toxicity or hypertension Drug adverse reactions and interactions are also (3,45,46). Masoudi & Krumholz (41) recommend common phenomena in the elderly (34,42). Ideally, use of these drugs with caution in this population patients with chronic kidney disease or diabetes and because they counter the effects of ACEIs and those on an ACEI or angiotensin receptor blocker exacerbate hypertension. (ARB) run an increased risk of hyperkalemia when Despite the many obstacles to safe antihyperten- aldosterone antagonists are given concomitantly (43). sive drug therapy in the elderly, there is strong Captopril was the most frequently prescribed drug in evidence of benefits of such treatment in reducing Passarelli and coworkers’s study (44) and produced morbidity and mortality. As already noted, compel- adverse drug reactions in a large percentage of their ling data from clinical trials demonstrate the benefits patients. Indeed, it was noted that inappropriate drug of treating hypertension in the elderly. Randomized prescription is a major cause of adverse drug reactions antihypertensive trials on people over 60 years of age in the elderly hospitalized population. On the other have often had as a primary objective to control hand, hypokalemia due to diuretics was the most systolic blood pressure. They all concluded that once prevalent adverse drug reaction in 186 elderly the systolic blood pressure goal is achieved, most patients admitted to the internal medicine service in elderly hypertensives also reach their diastolic blood Brazil (44). Some 10% of men exhibited breast pressure goal (47). However, since elderly patients tenderness even while taking low-dose spironolactone may be more vulnerable to an acute fall in blood in a study by Calhoun (43), and caution must be pressure, drug treatment should be initiated care- exercised when adding spironolactone to a regimen fully, with a low dose of a drug that has a safe profile that includes potassium supplements, or amiodarone of adverse events. to a regimen that includes coumadin (41). Non- Extensive studies have been conducted on the steroidal anti-inflammatory drugs (NSAIDs) are also efficacy and relative benefits of various classes of 190 T. Rosenthal & N. Nussinovitch antihypertensive agents in the elderly, taking into uncomplicated hypertension, but withhold judgment consideration the special problems of this popula- pending results of the outcome trials. tion. To cite a few among the many studies, ACEIs Indeed, despite the tendency of many doctors to and ARBs were found to have a significant benefit in avoid beta-blockers (57) in the elderly, their benefits elderly patients with arterial fibrillation in two large have been documented in a number of trials. randomized trials (48). In addition to blood pressure Nebivolol lowered the risk of death and cardiovas- reduction, significant neuroprotection seems to cular hospitalization in elderly patients with heart occur with calcium-channel blockers, ACEIs and failure in the SENIORS trial (58). In ICARUS, a ARBs (49). Nifedipine, atenolol and valsartan are all sub-study of LIFE, after 3 years of antihypertensive effective as monotherapy to control ABP and restore treatment with a beta-blocker regimen or an ARB cerebral blood flow (50). Valsartan normalizes the regimen in patients with left ventricular hypertrophy, changes in cerebral vasomotor reserve to a level both groups exhibited equivalent and significant similar to that in age-matched healthy subjects (50). reduction in blood pressure and no significant Evidence is emerging that the use of ARBs as first- differences in carotid plaque index (59). line therapy for hypertension and cognitive protec- tion in the elderly should be strongly considered Psychotrophic drugs (51). A recent observational study (52) suggests that the use of ACEI in Alzheimer’s disease patients is Psychotrophic drugs can be especially problematic in associated with slower rate of progression of the the elderly, since dosages must take into account the disease. This observation, however, requires con- diminished function of the kidneys and liver where firmation by a randomized clinical trial (52). most of these drugs are cleared from the body. Also, While the effect of verapamil on heart conduction the neuroleptic effects of psychotrophic drugs must is reduced as compared to younger subjects, the also be looked for in the treatment regimen. These drug tends to have a greater effect on blood pressure include apathy, flattened affect, drowsiness, extra- and heart rate in older patients. This might be pyramidal symptoms, arrhythmias, postural hypo- explained by enhanced sensitivity to the negative tension and delirium (37). Most of these affect inotropic and vasodilator effect of verapamil as well cognition and therefore compliance. Physicians need as diminished baroreceptor sensitivity. Induction to be alert to the reversible effect some drugs may problems can be avoided by refraining from giving have on cognition in the elderly, including memory verapamil to patients with sick sinus syndrome, loss (60). Compliance may also be affected by the second- or third-degree AV block, or congestive altered moods and behavior that accompany vascu- heart failure (53). Age also brings reduced beta- lar dementia, common among the elderly (61), by adrenoceptor function, mainly related to reflex insomnia (62) and by the deleterious effects of cardiovascular effects on heart rate. Indeed, beta- hypnotics used to treat insomnia, which may lead to blockers were found to be less beneficial than other non-compliance (62). Such sequelae of hypnotics antihypertensive drugs in elderly hypertensives with- have prompted recommendations that treatment for out co-morbidities in a retrospective population- insomnia should be based on cognitive–behavioral based cohort study (54) that enrolled all elderly therapy or a combination of such approaches and patients in Ontario, Canada. suitable drug therapy (62). Beta-blockade (atenolol) as first-line therapy in The potential interaction between psychotrophic elderly hypertensives performed poorly in reducing drugs and antihypertensives remains to be deter- cardiovascular risk also according to Cruickshank mined since it may influence the types and dosages of (55). However, both he and Panteleimon et al. (56) such drugs in the elderly. Elderly show heightened consider beta-blockade suitable for hypertensives sensitivity to the central nervous system effects of with ischemia of all ages, such as those with co- benzodiazepines (36), which may explain the involve- existing angina, post-myocardial infarction or heart ment of such drugs in drug-associated hospital failure. Cruickshank (55) also noted that vascular admissions. Some evidence suggests that benzodia- compliance can be improved without causing meta- zepines, especially those with long half-lives, may bolic disturbance with certain beta-blockers, like account for the falling accidents in people of old age bisoprolol, which is highly beta-1 selective, and (63). A study on changes in correlates of cognitive nebivolol, which has beta-2/3 intrinsic sympathomi- function over a 2-year period among 70–84-year-old metic activity. Panteleimon et al. (56) also specu- urban Japanese (64) showed that successful treatment late that the unique mechanisms of action and of hypertension was associated with reduced risk of fewer untoward effects of the newer beta-blockers progression of white matter hyperintensities and may make them effective first-line therapy for possibly brain atrophy (65). Despite the many Managing hypertension in the elderly 191 benefits of lowering blood pressure in the elderly, it conditions in elderly patients (31). For example, must be borne in mind that lowering it below a critical underuse of guideline-indicated drugs was found in level in those with long-standing hypertension may elderly patients with suspected acute myocardial actually increase the risk of cerebral hypoperfusion infarction admitted to US hospitals in 1992 and and cognitive decline, especially when additional 1993 (74). vascular risk factors are present (66). Lifestyle modifications The benefits of combination therapy Lifestyle changes for hypertension have been recom- mended for decades (75), and evidence is accumu- Combination and fixed-combination therapies, which lating attesting to their benefit. High systolic and decrease the risk of medication non-compliance (67), high pulse pressure, lack of physical activity and type are becoming increasingly used in hypertension 2 diabetes may reduce the probability of surviving to management. According to Nash (10), the combina- an advanced age (76). Adherence to healthy diets tion of a calcium-channel blocker and an ACEI brings reduces the risks of developing hypercholesterole- together two classes of metabolically neutral agents, mia, hypertension, diabetes and obesity (77). The offering the advantages of better tolerability and better prevention of cardiovascular diseases afforded by protection of cognitive function. Puig et al. (68) found increased physical activity is well documented (78), additive antihypertensive effects on both ambulatory but exercise regimens must be prescribed with and office blood pressure, and good tolerance to a caution in light of the significant elevation in blood combination of lercanidipine and enalapril in hyper- pressure from regular swimming in previously tensive patients aged 60–85 years. Smith et al. (69) sedentary, normotensive, older women (79). reported a good tolerance to a combination regimen of amlodipine and valsartan in people 65 years and older. The addition of a statin to antihypertensive Conclusions regimens in fixed combinations is currently being Modern well documented antihypertensive drugs have evaluated. A single-pill amlodipine/atorvastatin com- made it possible to tailor to patients a drug regimen bination facilitated reaching blood pressure and that is both effective and tolerable (80). Treatment cholesterol targets in African Americans approach- inertia in the elderly, however, has to be overcome by ing 60 years of age (70). better understanding the pharmacodynamics and Diminished understanding and memory, impaired pharmacokinetics of antihypertensive agents, as well eyesight and hearing, financial restrictions, a general as patient compliance (81). Optimizing secondary decline in the ability to cope, depression, poor prevention in elderly patients requires a multidisci- nutrition, simply being unable to remove pills from plinary approach that brings together the cardiologist, the bottle and living far from family may all general practitioner, geriatrician and nursing personnel contribute to non-compliance (3). Simon & (82). One of the major factors that remains to be Gurwitz (31) found that the medications patients overcome is the phenomenon of ‘therapeutic inertia’ decide not to take were those used for primary (83) in the elderly, especially when systolic blood prevention, such as hypertension and dyslipidemia. pressure levels are only moderately elevated (83). In a study on 40,492 elderly hypertensive patients taking at least one antihypertensive drug class (71), the adherence rates ranged from 78.3% for thiazide Acknowledgment diuretics to 83.6% for ARBs. Cooke & Fatodu (72) Neither of the authors has any financial or proprie- also reported that older people adhered more to their tary interest in the subject matter or materials ACEI or angiotensin II antagonist therapy. discussed in the manuscript. Many doctors prescribe inappropriate medications to the elderly. When Beers’ criteria (73) for determin- ing inappropriate medication use in the institutiona- References lized elderly patient population was applied to data 1. Duncker A, Greenberg S. A profile of older Americans. from the 1987 National Medical Expenditure Survey, Washington, (DC): Administration on aging. US Department almost 25% of all community-dwelling elderly were of Health and Human Services. Public Health Service; 2000. 2. US Bureau of the consensus. Population projections of the prescribed potentially inappropriate medications, a United States by age sex race and Hispanic origin: 1993 to figure that declined substantially in a 1996 study (31). 2050. 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Secondary prevention in the elderly or very Hypertens. 2005;23:1803–1808. elderly patient: Indications, limitations and perspectives. Arch 77. Panagiotakos DB, Polystipioti A, Papairakleous N, Mal Coeur Vaiss. 2006;99 Spec No 4: 45–9. French. Polychronopoulos E. Long-term adoption of a Mediterranean 83. Andrade SE, Gurwitz JH, Field TS, Kelleher M, diet is associated with a better health status in elderly people; a Majumdar SR, Reed G, et al. Hypertension management: cross-sectional survey in Cyprus. Asia Pac J Clin Nutr. The care gap between clinical guidelines and clinical practice. 2007;16:331–337. Am J Manag Care. 2004;10(7 Pt 2):481–486. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Blood Pressure Taylor & Francis

Managing hypertension in the elderly in light of the changes during aging

Rosenthal, Talma; Nussinovitch, Naomi
Blood Pressure , Volume 17 (4): 9 – Jan 1, 2008
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Taylor & Francis
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© 2008 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted
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1651-1999
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0803-7051
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10.1080/08037050802305578
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Abstract

The natural rise in systolic blood pressure with age is often complicated by other co-morbidities. Pharmacokinetics and pharmacodynamics of antihypertensive drugs are altered during aging, resulting in decrease in absorption and function of the kidney and liver, as well as interactions and adverse reactions of antihypertensives with the often large number of medications taken by the elderly. The problem of compliance in the elderly that may be disrupted by depression, loss of memory, vascular dementia and other conditions that compromise cognition is also of concern. Despite the many issues facing healthcare providers in managing hypertension in the elderly, the benefits are extensively documented and warrant overcoming therapeutic inertia, especially in view of current access to well documented therapeutic options. Key Words: Aging, altered metabolism, polypharmacy Introduction w140/w90 mmHg or were taking antihypertensive medication (5). This phenomenon is further com- As the population ages, health issues multiply, posing plicated by the prevalence of co-morbidities in enormous challenges to the medical community. It is elderly hypertensive patients. A retrospective review estimated that by the year 2030, there will be (6) of medical records turned up at least one co- approximately 70 million people in the United morbidity in 88% of the patients, the most common States over the age of 65 (1), representing 20% of being isolated systolic hypertension. Multiple co- the total population. The 85 and older age group will morbidities were present in 61% of cases. The grow to 7 million people (2). There is a high incidence increased risk of cardiovascular death, stroke and of common diseases and conditions in the aging myocardial infarction associated with high systolic population, which range from heart disease, renal pressure is well known and documented (4). disease and diabetes, osteoporosis, gastrointestinal When medical conditions such as dyslipidemia, problems, diminished humoral- and cell-mediated diabetes mellitus, congestive heart failure and immune responses, to sensory and musculoskeletal chronic renal disease are joined by hypertension, disturbances (3). there is a significant rise in the risk for cardiovascular When considering the natural rise in systolic blood events (7), predominantly in subjects with metabolic pressure with age, it is not surprising to find a syndrome (8,9). Such patients exhibit higher pulse prevalence of hypertension in excess of 70% after the pressure amplification, heart rate and pulse wave age of 70 (4). Indeed, a study conducted in North velocity compared with subjects without metabolic America, Europe, Japan and Australia showed that syndrome(s) of the same age, gender and mean 80% of people 70 and over had a blood pressure arterial pressure. Correspondence: Talma Rosenthal, Department of Physiology and Pharmacology, Hypertension Research Unit, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Tel: 972-3-6960210. Fax: 972-3-6968844. E-mail: [email protected] (Received 14 April 2008; accepted 26 June 2008) ISSN 0803-7051 print/ISSN 1651-1999 online # 2008 Informa UK Ltd. (Informa Healthcare, Taylor & Francis AS) DOI: 10.1080/08037050802305578 Managing hypertension in the elderly 187 The importance of blood pressure control in the (22). Also in the ASCOT study (23), there was a elderly is underscored by a number of studies. Large- preference for newer drugs over older ones: calcium scale clinical trials have demonstrated that treatment blocker agents and ACEIs versus diuretics and beta- of isolated systolic and systolic/diastolic hypertension blocking agents. In addition, ACEIs were found lowers total mortality rates, cardiovascular mortality superior to calcium-channel blockers for the preven- rates and stroke in older adults (10,11). tion of coronary heart disease, and calcium-channel SHEP (12), STOP (13) and MRC (14) were the blockers were superior for the prevention of stroke in first large hypertension trials that enrolled exclu- a meta-analysis of 28 trials (24). sively people over 65 years of age. All these trials In the ALLHAT Study, with 57% of the cohort compared diuretics and/or beta-blockers to placebo over 65 years of age at baseline, despite a less and reported 25–47% reductions in the relative risk favorable metabolic profile, thiazide-like diuretic of stroke and 19–27% reductions in coronary events. therapy for hypertension offers similar, and possibly The decrease in coronary events was significant in superior, cardiovascular disease outcomes in older only one of the trials, in SHEP, a study in which hypertensive adults with metabolic syndrome, as treatment reduced the risk of cardiovascular death compared with treatment with calcium-channel after 14 years of extended follow-up (15). STOP blockers and ACEIs (25). enrolled an older cohort of subjects – 70–84 years at The Hypertension in the Very Elderly Trial the beginning of the study – and reported a 43% (HYVET) Working Group (26) gathered data on reduction in total mortality. Subsequent trials the over 85-year age group, an important cohort enrolling people over 60 years of age evaluated the where little data was previously available. The main treatment of isolated systolic hypertension with the aim of this study was to resolve persistent areas of long-acting calcium-channel blocker nitrendipine uncertainty about the relative benefits and risks of with or without an angiotensin-converting enzyme antihypertensive in this very elderly group. This large (ACE) inhibitor (ACEI), with or without hydro- pilot study evaluated a diuretic-based or ACEI-based chlorothiazide (16–18). The greatest absolute ben- regimen versus placebo, with stroke the primary efit was seen in male patients 70 years and older, and endpoint and total mortality the second one. In the patients with previous cardiovascular complications results, published recently (27), there was clear or wider pulse pressure. documentation of a linear association between blood Combination therapy consisting of perindopril and pressure and stroke reduction, which was attenuated indapamide lowered the relative risk of stroke by 43% with age, and a significant reduction in the risk of in PROGRESS (Perindopril Protection against death from stroke under active treatment. In fact, the Recurrent Stroke Study) (19), a study that enrolled risk of death from any cause was found to be reduced 6105 subjects with a mean age of 64 years and baseline with active treatment in HYVET, highlighting the systolic blood pressure levels of ,147/86 mmHg. The benefits of blood pressure reduction on mortality. risk of stroke was lowered by this combination in both The significant reduction in the risk of death from hypertensive and non-hypertensive individuals with a stroke and death from any cause was observed when previous history of stroke or transient ischemic attack. treated with sustained release indapamide, with or Cardiovascular events were similarly reduced in without perindopril. The interesting finding of fewer 70–84-year-old hypertensive patients in each of the deaths from any cause on treatment is consistent with three treatment arms of STOP-2 (20), a trial the results of the INDIANA meta-analysis of 1670 comparing a diuretic/beta-blocker, the calcium patients 80 and over that included treatment regi- antagonist amiloride, or an ACEI. According to mens based on high doses of diuretics other than Hansson et al. (20), the ‘‘older’’ and ‘‘newer’’ indapamide or on beta-blockers (28). antihypertensive drugs exhibited similar ability to Seto et al. (29) reported that people 60 years and prevent cardiovascular mortality or major events. In even much older, up to 80, with isolated systolic contrast, in the Second Australian National Blood hypertension have good prognoses in terms of Pressure Study in 65–84-year-olds (21), beginning longevity, but many develop late-onset cardiovascu- antihypertensive treatment with ACEIs improved lar complications, suggesting the importance of cardiovascular outcome in older subjects, even blood pressure control. though the comparative diuretic-based regimen produced similar reductions in blood pressure. This coincides with the findings of the LIFE study Polypharmacy that showed a difference in terms of the endpoints of risk reduction in favor of the newer drug losartan The subspecialty of geriatric pharmacology has an over the older beta-blocker-based drug regimen important focus on the high incidence and prevalence 188 T. Rosenthal & N. Nussinovitch of drugs such as anticoagulants, cardiovascular and of systemic diseases among older adults, especially psychotropic drugs (37) (Figure 1). Most drugs are chronic diseases, and the resultant rise in medication absorbed from the gastrointestinal tract, where use (3), often referred to as polypharmacy. Studies hydrochloric acid and pepsin are secreted, and then show that one-quarter of hospitalized patients over pass through the liver. Since liver volume and liver the age of 65 are taking six or more drugs daily, older blood flow decrease progressively with age in parallel adults average 13 prescriptions per year, and some to an altered body composition, there may be an 90% of patients 75 years and older take drugs increased volume of distribution of lipid-soluble regularly, more than one-third of them three or more drugs, and reduced clearance of lipid-soluble and drugs a day (3). According to a national survey of the water-soluble drugs with advancing age. Thus, first- non-institutionalized US population, the highest pass metabolism of some drugs may be reduced in prevalence of medication use was among women the elderly, which means that the bioavailability of aged at least 65, of whom 23% used five medications, drugs that undergo extensive first-pass metabolism, and 12% used 10 or more different medications every like propranolol and labetalol, can be significantly day (30,31). Other studies have reported that the increased. On the other hand, the majority of ACEI elderly have three times more prescriptions for pro-drugs (enalapril and perindopril) that undergo psychotropic drugs than do younger people, despite activation in the liver may have an impaired their susceptibility to the untoward effects of these biotransformation in patients with severe heart drugs and the twice-longer period needed to recover failure and hepatic dysfunction, conditions often from them than seen in young patients (3). found in the elderly (3). Not only are the elderly taking more drugs, but they Advancing age may also impair kidney function and also run the risk of mistakes in selecting drugs and excretion, resulting in diminished renal blood flow, doses provided by multiple health providers, or they glomerular filtration rate, tubular secretion (3,34) and take medicine prescribed for someone else (32). In renal mass due to the reduction in nephrons (34,37). addition to that, age-related changes in pharmacoki- Diminished blood flow also occurs in the afferent netics and pharmacodynamics render them more arterioles in the cortex due to intra-renal vascular susceptible to drug-related problems (33,34). Based changes. Ambulatory, community-dwelling volun- on a mean of 8.7 prescriptions per patient in the 65 teers of the Baltimore Longitudinal Study on Aging and over age group, a study in the Netherlands (38) exhibited about a one-third reduction in creati- identified 3.9 potential drug-related problems per nine clearance between 20 and 90 years of age. Since elderly person (35). More than prescribing the wrong most drugs are removed via the kidney, this reduction medications, the pitfalls of medical care of older in renal function in elderly subjects, particularly patients also include a considerable risk of toxicity of glomerular filtration rate, impacts on the clearance drugs in this age group, and failures by healthcare of many drugs such as e.g. diuretics, water-soluble personnel to prescribe the indicated medications, beta-adrenoceptor blockers and non-steroidal anti- perform adequate follow-up, document the manage- inflammatory drugs (37). The age-related changes in ment of care, educate patients and maintain con- glomerular filtration and tubular secretion are parti- tinuity (35). Proper management requires that the cularly detrimental to the excretion of several ACEIs, general practitioner balance incomplete information resulting in an increase in plasma concentration (37). about the efficacy of drugs in compromised elderly Some ACEIs such as benazepril, fosinopril and people against the potential adverse drug reactions ramipril are also eliminated by the biliary route. while at the same time providing the requisite Homeostatic regulatory mechanisms decline in pharmacotherapy (36). the elderly, which may explain the greater incidence of postural hypotension, slower thermoregulation and slower capacity to compensate for the hypoten- Altered drug metabolism due to sive effects of an antihypertensive drug (3). Elderly pharmacokinetic and pharmacodynamic hypertensives with orthostatic hypotension may be changes in the elderly over-represented among those who develop Drug metabolism in the elderly is a complicated advanced silent cerebrovascular disease (39). area. Aging is accompanied by pharmacokinetic Taken together, in elderly hypertensives, there changes such as reduced renal and hepatic clearance, may be a need to adjust drug dosages in patients and increased volume of distribution of lipid-soluble with renal insufficiency, especially in those with drugs that prolongs elimination half-life as well as creatinine clearance below 30 ml/min (37). Serum pharmacodynamic changes (34) such as altered creatinine may not be a correct estimate of renal (generally heightened) sensitivity to several classes function, especially in the elderly (40,41). Managing hypertension in the elderly 189 Brain Permeability Mouth and Esophagous Fatty Tissues Chewing and Swallowing Skeletal Muscle Sense of Taste and Smell Oesophageal Peristalsis Skeletal Body Mass Stomach Total Body Fat Changes in Gastric pH Slow Gastric Emptying Immunologic System Liver Small Intestine Kidney Circulation Gut Motility Impaired Immune Response Constipation Transit Time From Gut Clearance and Gastrointestinal and Elimination Splanchnic Blood Flow Albumin Concentration or Drug and Food Interaction and Bioavailability Figure 1. Increases or decreases in drug metabolism due to pharmacokinetic and pharmacodynamic changes in the elderly. In: Akamine D, Filho MK, Peres CM. Drug nutrient interactions in elderly people. Curr Opin Clin Nutr Metab Care. 2007;10:304–310, by permission to the author by Lippincott Williams and Wilkins. Adverse drug reactions problematic in the elderly, being associated with impaired renal function, GI toxicity or hypertension Drug adverse reactions and interactions are also (3,45,46). Masoudi & Krumholz (41) recommend common phenomena in the elderly (34,42). Ideally, use of these drugs with caution in this population patients with chronic kidney disease or diabetes and because they counter the effects of ACEIs and those on an ACEI or angiotensin receptor blocker exacerbate hypertension. (ARB) run an increased risk of hyperkalemia when Despite the many obstacles to safe antihyperten- aldosterone antagonists are given concomitantly (43). sive drug therapy in the elderly, there is strong Captopril was the most frequently prescribed drug in evidence of benefits of such treatment in reducing Passarelli and coworkers’s study (44) and produced morbidity and mortality. As already noted, compel- adverse drug reactions in a large percentage of their ling data from clinical trials demonstrate the benefits patients. Indeed, it was noted that inappropriate drug of treating hypertension in the elderly. Randomized prescription is a major cause of adverse drug reactions antihypertensive trials on people over 60 years of age in the elderly hospitalized population. On the other have often had as a primary objective to control hand, hypokalemia due to diuretics was the most systolic blood pressure. They all concluded that once prevalent adverse drug reaction in 186 elderly the systolic blood pressure goal is achieved, most patients admitted to the internal medicine service in elderly hypertensives also reach their diastolic blood Brazil (44). Some 10% of men exhibited breast pressure goal (47). However, since elderly patients tenderness even while taking low-dose spironolactone may be more vulnerable to an acute fall in blood in a study by Calhoun (43), and caution must be pressure, drug treatment should be initiated care- exercised when adding spironolactone to a regimen fully, with a low dose of a drug that has a safe profile that includes potassium supplements, or amiodarone of adverse events. to a regimen that includes coumadin (41). Non- Extensive studies have been conducted on the steroidal anti-inflammatory drugs (NSAIDs) are also efficacy and relative benefits of various classes of 190 T. Rosenthal & N. Nussinovitch antihypertensive agents in the elderly, taking into uncomplicated hypertension, but withhold judgment consideration the special problems of this popula- pending results of the outcome trials. tion. To cite a few among the many studies, ACEIs Indeed, despite the tendency of many doctors to and ARBs were found to have a significant benefit in avoid beta-blockers (57) in the elderly, their benefits elderly patients with arterial fibrillation in two large have been documented in a number of trials. randomized trials (48). In addition to blood pressure Nebivolol lowered the risk of death and cardiovas- reduction, significant neuroprotection seems to cular hospitalization in elderly patients with heart occur with calcium-channel blockers, ACEIs and failure in the SENIORS trial (58). In ICARUS, a ARBs (49). Nifedipine, atenolol and valsartan are all sub-study of LIFE, after 3 years of antihypertensive effective as monotherapy to control ABP and restore treatment with a beta-blocker regimen or an ARB cerebral blood flow (50). Valsartan normalizes the regimen in patients with left ventricular hypertrophy, changes in cerebral vasomotor reserve to a level both groups exhibited equivalent and significant similar to that in age-matched healthy subjects (50). reduction in blood pressure and no significant Evidence is emerging that the use of ARBs as first- differences in carotid plaque index (59). line therapy for hypertension and cognitive protec- tion in the elderly should be strongly considered Psychotrophic drugs (51). A recent observational study (52) suggests that the use of ACEI in Alzheimer’s disease patients is Psychotrophic drugs can be especially problematic in associated with slower rate of progression of the the elderly, since dosages must take into account the disease. This observation, however, requires con- diminished function of the kidneys and liver where firmation by a randomized clinical trial (52). most of these drugs are cleared from the body. Also, While the effect of verapamil on heart conduction the neuroleptic effects of psychotrophic drugs must is reduced as compared to younger subjects, the also be looked for in the treatment regimen. These drug tends to have a greater effect on blood pressure include apathy, flattened affect, drowsiness, extra- and heart rate in older patients. This might be pyramidal symptoms, arrhythmias, postural hypo- explained by enhanced sensitivity to the negative tension and delirium (37). Most of these affect inotropic and vasodilator effect of verapamil as well cognition and therefore compliance. Physicians need as diminished baroreceptor sensitivity. Induction to be alert to the reversible effect some drugs may problems can be avoided by refraining from giving have on cognition in the elderly, including memory verapamil to patients with sick sinus syndrome, loss (60). Compliance may also be affected by the second- or third-degree AV block, or congestive altered moods and behavior that accompany vascu- heart failure (53). Age also brings reduced beta- lar dementia, common among the elderly (61), by adrenoceptor function, mainly related to reflex insomnia (62) and by the deleterious effects of cardiovascular effects on heart rate. Indeed, beta- hypnotics used to treat insomnia, which may lead to blockers were found to be less beneficial than other non-compliance (62). Such sequelae of hypnotics antihypertensive drugs in elderly hypertensives with- have prompted recommendations that treatment for out co-morbidities in a retrospective population- insomnia should be based on cognitive–behavioral based cohort study (54) that enrolled all elderly therapy or a combination of such approaches and patients in Ontario, Canada. suitable drug therapy (62). Beta-blockade (atenolol) as first-line therapy in The potential interaction between psychotrophic elderly hypertensives performed poorly in reducing drugs and antihypertensives remains to be deter- cardiovascular risk also according to Cruickshank mined since it may influence the types and dosages of (55). However, both he and Panteleimon et al. (56) such drugs in the elderly. Elderly show heightened consider beta-blockade suitable for hypertensives sensitivity to the central nervous system effects of with ischemia of all ages, such as those with co- benzodiazepines (36), which may explain the involve- existing angina, post-myocardial infarction or heart ment of such drugs in drug-associated hospital failure. Cruickshank (55) also noted that vascular admissions. Some evidence suggests that benzodia- compliance can be improved without causing meta- zepines, especially those with long half-lives, may bolic disturbance with certain beta-blockers, like account for the falling accidents in people of old age bisoprolol, which is highly beta-1 selective, and (63). A study on changes in correlates of cognitive nebivolol, which has beta-2/3 intrinsic sympathomi- function over a 2-year period among 70–84-year-old metic activity. Panteleimon et al. (56) also specu- urban Japanese (64) showed that successful treatment late that the unique mechanisms of action and of hypertension was associated with reduced risk of fewer untoward effects of the newer beta-blockers progression of white matter hyperintensities and may make them effective first-line therapy for possibly brain atrophy (65). Despite the many Managing hypertension in the elderly 191 benefits of lowering blood pressure in the elderly, it conditions in elderly patients (31). For example, must be borne in mind that lowering it below a critical underuse of guideline-indicated drugs was found in level in those with long-standing hypertension may elderly patients with suspected acute myocardial actually increase the risk of cerebral hypoperfusion infarction admitted to US hospitals in 1992 and and cognitive decline, especially when additional 1993 (74). vascular risk factors are present (66). Lifestyle modifications The benefits of combination therapy Lifestyle changes for hypertension have been recom- mended for decades (75), and evidence is accumu- Combination and fixed-combination therapies, which lating attesting to their benefit. High systolic and decrease the risk of medication non-compliance (67), high pulse pressure, lack of physical activity and type are becoming increasingly used in hypertension 2 diabetes may reduce the probability of surviving to management. According to Nash (10), the combina- an advanced age (76). Adherence to healthy diets tion of a calcium-channel blocker and an ACEI brings reduces the risks of developing hypercholesterole- together two classes of metabolically neutral agents, mia, hypertension, diabetes and obesity (77). The offering the advantages of better tolerability and better prevention of cardiovascular diseases afforded by protection of cognitive function. Puig et al. (68) found increased physical activity is well documented (78), additive antihypertensive effects on both ambulatory but exercise regimens must be prescribed with and office blood pressure, and good tolerance to a caution in light of the significant elevation in blood combination of lercanidipine and enalapril in hyper- pressure from regular swimming in previously tensive patients aged 60–85 years. Smith et al. (69) sedentary, normotensive, older women (79). reported a good tolerance to a combination regimen of amlodipine and valsartan in people 65 years and older. The addition of a statin to antihypertensive Conclusions regimens in fixed combinations is currently being Modern well documented antihypertensive drugs have evaluated. A single-pill amlodipine/atorvastatin com- made it possible to tailor to patients a drug regimen bination facilitated reaching blood pressure and that is both effective and tolerable (80). Treatment cholesterol targets in African Americans approach- inertia in the elderly, however, has to be overcome by ing 60 years of age (70). better understanding the pharmacodynamics and Diminished understanding and memory, impaired pharmacokinetics of antihypertensive agents, as well eyesight and hearing, financial restrictions, a general as patient compliance (81). Optimizing secondary decline in the ability to cope, depression, poor prevention in elderly patients requires a multidisci- nutrition, simply being unable to remove pills from plinary approach that brings together the cardiologist, the bottle and living far from family may all general practitioner, geriatrician and nursing personnel contribute to non-compliance (3). Simon & (82). One of the major factors that remains to be Gurwitz (31) found that the medications patients overcome is the phenomenon of ‘therapeutic inertia’ decide not to take were those used for primary (83) in the elderly, especially when systolic blood prevention, such as hypertension and dyslipidemia. pressure levels are only moderately elevated (83). In a study on 40,492 elderly hypertensive patients taking at least one antihypertensive drug class (71), the adherence rates ranged from 78.3% for thiazide Acknowledgment diuretics to 83.6% for ARBs. Cooke & Fatodu (72) Neither of the authors has any financial or proprie- also reported that older people adhered more to their tary interest in the subject matter or materials ACEI or angiotensin II antagonist therapy. discussed in the manuscript. Many doctors prescribe inappropriate medications to the elderly. When Beers’ criteria (73) for determin- ing inappropriate medication use in the institutiona- References lized elderly patient population was applied to data 1. Duncker A, Greenberg S. A profile of older Americans. from the 1987 National Medical Expenditure Survey, Washington, (DC): Administration on aging. US Department almost 25% of all community-dwelling elderly were of Health and Human Services. Public Health Service; 2000. 2. US Bureau of the consensus. Population projections of the prescribed potentially inappropriate medications, a United States by age sex race and Hispanic origin: 1993 to figure that declined substantially in a 1996 study (31). 2050. 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Journal

Blood Pressure – Taylor & Francis

Published: Jan 1, 2008

Keywords: Aging; altered metabolism; polypharmacy

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