- Email: [email protected]
Hypertension in the elderly with coexisting benign prostatic hyperplasia
HYPERTENSION IN THE ELDERLY WITH COEXISTING BENIGN PROSTATIC HYPERPLASIA JAVIER MARUENDA, VINEESH BHATNAGAR,
AND
DAVID T. LOWENTHAL
ABSTRACT The treatment of hypertension in the elderly can be safely achieved with low-dose diuretic therapy. Men with prostatism may benefit from peripheral a-blocking drugs. However, drugs such as doxazosin or terazosin may further lower blood pressure and at times may be associated with orthostatic hypotension, especially if diuretics are given concomitantly. Tamsulosin achieves relaxation of the smooth muscle of the prostate, as do terazosin and doxazosin, but without provoking changes in blood pressure, especially orthostatic hypotension. There appears to be no adverse interaction with any other antihypertensive medication or with low-dose diuretics. To manage such patients with hypertension and prostatism, hydrochlorothiazide 6.25 to 12.5 mg/day and tamsulosin 0.4 mg/day would be an adequate combination. Low-dose diuretics have been shown to be effective in both isolated systolic hypertension as well as fixed diastolic hypertension in the elderly. If other antihypertensives need to be added, then a low dose of a long-acting calcium-entry blocker, a central a-agonist (a transdermal clonidine for better compliance), an angiotensin-converting enzyme inhibitor (if renal vascular disease has been ruled out), or an angiotensin II receptor blocker, e.g., losartan or valsartan, should be considered. UROLOGY 53 (Suppl 3A): 7–13, 1999. © 1999, Elsevier Science Inc. All rights reserved.
A
verage blood pressure tends to increase progressively with increasing age in almost every population,1 although in many persons, blood pressure does not increase with age. In the US population aged $60 years examined in the National Health and Nutrition Examination Survey (NHANES) III, elevated blood pressure was found in 60% of non-Hispanic whites, 71% of non-Hispanic African-Americans, and 61% of MexicanAmericans.2 The age-related rate of increase in blood pressure is consistently greater for systolic than for diastolic blood pressure: systolic blood pressure tends to increase until 70 or 80 years of age, whereas diastolic blood pressure tends to remain constant or decrease after the age of 40 years. As a consequence, isolated systolic hypertension is common From the University of Florida College of Medicine and Geriatric Research, Education and Clinical Center, Veterans Affairs Medical Center, Gainesville, Florida (JM, VB); Pharmacology and Exercise Science, University of Florida College of Medicine and Director, Geriatric Research, Education and Clinical Center, Veterans Affairs Medical Center, Gainesville, Florida (DTL) Reprint requests: David T. Lowenthal, MD, PhD, Geriatric Research, Education and Clinical Center (182), Veterans Affairs Medical Center, 1601 SW Archer Road, Gainesville, FL 326081197 © 1999, ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED
in the elderly, and systolic blood pressure is a better predictor of events (cardiovascular disease, heart failure, stroke, end-stage renal disease, and all-cause mortality) than diastolic blood pressure.3 Finally, primary hypertension is the most common form of hypertension in the elderly, with renovascular disease being the most frequent form of secondary or reversible hypertension. Benign prostatic hyperplasia (BPH) is the proliferation of epithelial and stromal prostate tissue; its prevalence also significantly increases with age, with pathologic evidence of BPH being found in nearly 80% of men by age 80 years.4 Data indicate that 28 –35% of older men have moderate or severe voiding symptoms.5,6 Therefore it is not uncommon in clinical practice to find an elderly patient with hypertension and coexisting BPH, and an estimated 25% of men .60 years have both BPH and hypertension.7 PATHOPHYSIOLOGY OF HYPERTENSION IN THE ELDERLY As is the case in younger individuals, the etiology of essential hypertension in older subjects is unknown. With age there is a gradual loss in the elasticity of the arteries, particularly of the larger arter0090-4295/99/$20.00 S0090-4295(99)00533-0 7
ies. Alterations in vessel structure that contribute to the decrease in distensibility are (1) an increase in smooth muscle cell size and number; (2) an increase in medial collagen deposition; and (3) a decrease in elastin content. The arterial tree becomes more like a system of rigid pipes in which the same cardiac output results in higher systolic and lower diastolic pressures. In addition to these changes, there are alterations in the regulation of vascular tone by the autonomic nervous system in the elderly. There is also a decrease in the sensitivity of the baroreflex with age, which contributes to the greater blood pressure variability in older individuals. Many studies have demonstrated an age-associated increase in the activity of the sympathetic nervous system, as measured by an increase in plasma norepinephrine levels and rates of norepinephrine release, which would result in increased cardiovascular adrenergic responses if it were not for an age-associated decrease in the b-adrenergic receptor chronotropic, inotropic, and vascular responses as well as a-adrenergic vasoconstrictor responses.8 As a result of the decrease in the arterial a-adrenergic receptor response, it appears that overall arterial a-adrenergic tone is similar in older and younger normotensive individuals. Another modulator of vascular tone is the vascular endothelium. Nitric oxide is a potent vasodilator synthesized by the endothelium, and studies have demonstrated an age-associated decrease in nitric oxide–mediated vasodilation. However, the extent to which impaired endothelial function contributes to an increase in blood pressure in aging remains to be defined.8 There is also evidence of an age-associated decline in plasma renin activity, and older patients with hypertension are characterized by low plasma renin activity. This impaired secretion of aldosterone in the elderly results in potassium retention and can increase the risk of hyperkalemia caused by b blockers or angiotensin-converting enzyme (ACE) inhibitors.9 Changes in renal function (decreased renal flow and glomerular filtration rate) result in an age-associated inability to excrete a sodium load rapidly, resulting in sodium retention and an increase in total body sodium.10 Due to the changes with aging described above, the elderly may display 2 clinical features. The first is pseudohypertension due to markedly sclerotic arteries that do not collapse under the cuff, giving much higher cuff pressures than are present within vessels. The second, seen in 20% of the elderly, is postural and postprandial hypotension, usually reflecting the progressive loss of baroreceptor responsiveness with age.11 8
PATHOPHYSIOLOGY OF BPH IN THE ELDERLY BPH, the age-related proliferation of epithelial and stromal prostate tissue, includes changes to the extracellular matrix of collagen and elastin. This involves downregulation of collagen types I and III (which constitute the interstitial collagen) and elastin and collagen type IV upregulation (found primarily in the basement membrane).11–13 Medical treatment of BPH is directed at the dynamic components involved and at the pathogenesis of the disease. Glandular epithelial tissue comprises approximately 20 –30% of BPH tissue and its growth is stimulated by dihydrotestosterone. Hyperplasia of these components produces a mechanical obstruction of the bladder neck and prostatic urethra, and is the static causative factor for BPH.14 Stromal or fibromuscular tissue comprises 70 – 80% of BPH tissue and is under a-adrenergic tone. Smooth muscle is one of the dominant cellular constituents of BPH15; the tension of this prostate smooth muscle is mediated by the a1 adrenoreceptor (primarily of the A1C class). When stimulated, this tissue contracts around the bladder neck, reducing the urethral lumen diameter and causing dynamic obstruction to urinary outflow.14 In patients with BPH, increased glandular tissue volume and/or excessive adrenergic tone may be present, thereby causing symptoms compatible with impaired voiding. Medical treatment is directed at these factors. Selective a1-adrenergic antagonists reduce sympathetic stimulation of BPH tissue, resulting in relaxation of smooth muscle around the bladder neck and the prostatic urethra. This improves urinary flow.14 NONPHARMACOLOGIC MANAGEMENT OF HYPERTENSION The approach to managing hypertension is bimodal, including nondrug and drug therapy. The nondrug considerations with proven efficacy include (1) low-salt diet; (2) an increase in foods containing potassium, e.g., fruits, including figs and dates, and calcium; (3) an intake of alcohol of #2 ounces per day; (4) cessation of tobacco smoking; (5) change from a sedentary to an active lifestyle emphasizing aerobic exercise (30 min of exercise per day, 3–5 days per week); and (6) weight reduction. Obese hypertensive men would benefit markedly by losing weight to counteract the insulin resistance that occurs in obesity and produces exaggerated sympathetic nervous system activity, sodium retention, hyperlipidemia, and hypertension. Weight loss can rectify these abnormalities; therefore considerable emphasis must be given to nonpharmacologic approaches in patients with hypertension, regardless of underlying comorbidity. UROLOGY 53 (Supplement 3A), March 1999
CONSIDERATIONS IN THE USE OF SPECIFIC CLASSES OF ANTIHYPERTENSIVE DRUGS IN THE ELDERLY Special considerations in the selection of initial antihypertensive medication in the elderly include demographic characteristics, comorbidity, quality of life, cost, and use of other drugs.16 Table I lists the most important considerations for individualizing therapy. CALCIUM CHANNEL BLOCKERS Calcium channel blockers (CCBs) are a heterogeneous group of drugs with different pharmacokinetic and pharmacodynamic properties that are used mainly to treat hypertension, angina pectoris, and cardiac arrhythmia.17 There is insufficient justification for their use in hypertension and relief of symptoms of BPH. They inhibit calcium influx into smooth muscle cells by blocking calcium channels; they also block mobilization of calcium from intracellular stores. This activity decreases arterial pressure by reducing total peripheral vascular resistance, and as a consequence, the CCBs evoke a baroreceptor-mediated sympathetic discharge, which in the case of the dihydropyridines causes a mild-to-moderate tachycardia. The CCBs also inhibit the entrance of calcium into myocardium and coronary artery smooth muscle cells. Despite their common mechanism of action, CCBs vary considerably in their effects on the myocardium, conduction system, and circulatory system.18 CCBs are well absorbed after oral administration and are extensively metabolized by microsomal oxidases in the liver, with a small amount of unchanged drug being excreted in the urine.17,19 Plasma concentrations tend to be higher in the elderly or in patients with liver disease; in these patients it is safer to start therapy with lower doses. Depending on their half-life and pharmaceutical formulation, CCBs can be short or long acting. Among the short-acting CCBs are the immediaterelease forms of isradipine (DynaCirc), nicardipine (Cardene), nifedipine (Adalat, Procardia), and nimodipine (Nimotop). In a recent study of older patients in an academic hospital-based geriatrics practice, CCBs were used more often than b blockers in patients with hypertension and previous myocardial infarction or coronary artery disease.20 DIURETICS When the decision has been made to begin antihypertensive medication and there are no indications for a specific type of drug, a diuretic or b blocker should be used because numerous studies have demonstrated reductions in morbidity and mortality with these agents.16 Thiazide diuretics in UROLOGY 53 (Supplement 3A), March 1999
TABLE I.
Considerations for specific classes of antihypertensive agent
Comorbidity
Drug
Indicated unless contraindicated Isolated systolic Diuretics, CCBs (longhypertension (elderly) acting dihydropyridine) Diabetes mellitus (type 1) ACE inhibitors with proteinuria Heart failure ACE inhibitors, diuretics Myocardial infarction b-Blockers (non-ISA), ACE inhibitors Potential favorable effects Angina b-Blockers, CCBs Atrial tachycardia and b-Blockers, CCBs fibrillation (nondihydropyridine) Diabetes (types 1 and 2) ACE inhibitors, CCBs with proteinuria Diabetes (type 2) Low-dose diuretics Dyslipidemia a-Blockers Essential tremor b-Blockers (noncardioselective) Heart failure Carvedilol, losartan potassium Myocardial infarction Diltiazem HCl, verapamil Osteoporosis Thiazides Preoperative hypertension b-Blockers Prostatism a-Blockers Renal insufficiency (with ACE inhibitors caution) Potential unfavorable effects Chronic obstructive b-Blockers* pulmonary disease Depression b-Blockers, central a-agonists, reserpine* Diabetes mellitus (types 1 b-Blockers, high-dose and 2) diuretics Dyslipidemia b-Blockers (non-ISA), high-dose diuretics Gout Diuretics High-degree b-Blockers,* CCBs atrioventricular block (nondihydropyridine)* Heart failure b-Blockers (except carvedilol) CCBs (except amlodipine and felodipine) Peripheral vascular b-Blockers disease Renal insufficiency Potassium-sparing agents Renovascular disease ACE inhibitors, angiotensin II receptor Blockers ACE 5 angiotensin-converting enzyme; CCBs 5 calcium channel blockers; ISA 5 intrinsic sympathomimetic activity. *Contraindicated. Adapted from Arch Intern Med.16
9
small doses (hydrochlorothiazide 6.25–25 mg/ day) are effective as monotherapy in the treatment of mild essential hypertension and of isolated systolic hypertension in the elderly.21 A diuretic is recommended as a second agent (if not already used) when the target blood pressure has not been achieved with monotherapy, i.e., a b blocker.16 Elderly men with BPH may be at risk for greater urgency, frequency, and overflow incontinence as the diuretic dose is increased. Thus it is critical to keep the dose low. In addition, diuretics can cause different types of metabolic abnormalities, including increases in cholesterol levels, glucose intolerance, hyperuricemia, hypokalemia, hyponatremia, and hypomagnesemia. These can be attenuated by not exceeding a dose of hydrochlorothiazide 25 mg/day, combining it with a potassium-sparing diuretic, and periodic monitoring of blood chemistry. In the Treatment of Mild Hypertension Study (TOMHS), diuretics produced a greater reduction in left ventricular mass than any other major class of antihypertensive drug.22 Loop diuretics on the other hand should be reserved for elderly patients with signs of heart or renal failure.23 BETA BLOCKERS All of the b blockers, except those with intrinsic sympathomimetic activity (ISA), reduce cardiac output and heart rate, have similar antihypertensive response rates, and reduce mortality and reinfarction in patients with a previous myocardial infarction.24 In patients with heart failure, the new a,b blocker carvedilol added to an ACE inhibitor has been shown to be beneficial.25 Beta blockers can produce bronchospasm, and are contraindicated in chronic obstructive pulmonary disease and asthma; other side effects include masking of insulin-induced hypoglycemia, worsening of heart failure, impaired peripheral arterial circulation, insomnia, fatigue, decreased exercise tolerance, and hypertriglyceridemia. These may occur less frequently with b1-selective blockers than with nonselective b blockers. The adverse central nervous system effects, i.e., sleep disturbances, depression, and nightmares, may be more common with lipophilic b blockers (like propranolol) due to their increased blood– brain barrier penetration.7 CENTRALLY ACTING ANTIHYPERTENSIVES The prototype postsynaptic a2-agonist is clonidine, which can be administered orally or transdermally. It is an effective antihypertensive agent, but it is highly lipid soluble and can produce sedation and dry mouth, problems that already exist in the elderly not taking clonidine. If absolutely necessary, the transdermal preparation provides a smoother blood pressure reduction response than 10
the oral formulation. Methyldopa, guanfacine, and guanabenz are less frequently used oral centrally acting drugs, but possess lipid solubility similar to that of clonidine with central side effects of depression, sedation, and dry mouth. ACE INHIBITORS AND ANGIOTENSIN II RECEPTOR ANTAGONISTS Although plasma renin activity is often reduced in the elderly, ACE inhibitors have been shown to be effective in this population, particularly if hypertension is associated with chronic heart failure (studies have shown that ACE inhibitors reduce mortality in this situation).26 As monotherapy, these agents are as effective as any other antihypertensive agent. Studies have also demonstrated long-term beneficial effects on proteinuria and glomerular filtration rate for patients with diabetic and nondiabetic renal disease.27 Other beneficial effects include prevention of adverse remodeling and dilatation of the left ventricle after MI, and reduction of left ventricular mass. Major considerations in patients on ACE inhibitors are the development of hyperkalemia, and the potential for renal failure in patients with bilateral renal artery stenosis or stenosis to a solitary kidney.28 The ACE inhibitor dose needs to be adjusted if the glomerular filtration rate is ,30 mL/min,29 except with fosinopril, 50% of which is eliminated by hepatic metabolism and 50% by the kidney. Hypotension has been observed with initiation of therapy, which may be avoided by starting with the lowest dose; cough is a major side effect, but resolves on discontinuation of ACE inhibitor treatment. The angiotensin II receptor antagonist losartan effectively reduces blood pressure in patients with essential hypertension.30 This selective angiotensin II receptor antagonist has not been associated with cough and, at least in theory, should have the same beneficial effects as the ACE inhibitors. The same precautions mentioned for the use of ACE inhibitors also apply to this drug.31 ALPHA-ADRENOCEPTOR BLOCKERS The peripheral a-adrenoreceptor blockers inhibit postsynaptic vascular a-adrenergic receptors, causing vasodilation and decreasing peripheral vascular resistance; they prevent reflex tachycardia by inhibiting baroreflex activity.32 Prazosin, doxazosin, and terazosin have similar efficacy in the treatment of hypertension, but doxazosin and terazosin have longer durations of action.33 These drugs are not well suited for initial monotherapy because of their tendency to cause orthostatic hypotension.16 All of them may cause orthostatic hypotension with the first dose. The recommendation is to start with small doses and increase them as tolerated. UROLOGY 53 (Supplement 3A), March 1999
Patients with BPH may obtain symptomatic relief with a-blocker therapy due to blockade of the a receptors in the smooth muscle of the bladder outlet.14 Alpha-adrenergic agents have been used successfully in combination with b blockers, diuretics, CCBs, and ACE inhibitors in patients with hypertension that is uncontrolled with monotherapy,34 but there are concerns regarding excessive hypotension with combination therapy for hypertension that includes an a-adrenergic antagonist. Several studies suggest that the average decrease in diastolic blood pressure associated with a-adrenergic blockers in normotensive and hypertensive patients is 4 –5 mm Hg and 15–20 mm Hg, respectively.35,36 Careful titration of a-adrenergic antagonist dose or a decrease in dose of any other antihypertensive agent is indicated in patients receiving combination therapy for hypertension and BPH with an a-adrenergic antagonist. If intolerable dizziness and hypotension occur after initiation of an a-antagonist, discontinuation is recommended. More highly selective antagonists of the a1A-receptor have been developed. Alpha1A receptors comprise 70% of the a receptors in the prostate and bladder neck, and have not been identified at significant levels elsewhere in the body.37 Tamsulosin is the first subtype-selective (a1A) a1-adrenoreceptor antagonist with specificity for prostatic a1 adrenoreceptors.38 Some studies have shown that tamsulosin is well tolerated and suitable for use in both older (.65 years) and younger (#65 years) patients with lower urinary tract symptoms suggestive of BPH39; the optimal effects are achieved with tamsulosin 0.4 mg administered once daily. In some small studies, coadministration of tamsulosin had no clinically significant effects on the pharmacodynamic action of nifedipine, enalapril, or atenolol: it produced no clinically significant differences in pulse rate and blood pressure, did not alter electrocardiographic or Holter monitoring results, did not cause increased side effects, and the dose of the antihypertensives did not need to be adjusted, which may give tamsulosin an advantage over other a-blocking agents used to treat BPH.40 POTENTIAL AGE–DISEASE–DRUG INTERACTIONS IN BPH Diuretics produce volume contraction. The reduced muscle mass of elderly patients is a clinical indicator that intracellular and interstitial volumes are decreased. This occurs because skeletal muscle is 70% water and 30% protein. Excess doses of diuretics, e.g., .25 mg of hydrochlorothiazide, can produce orthostatic hypotension, especially in a deconditioned, sedentary person. In this setting of a reduced preload secondary to volume contracUROLOGY 53 (Supplement 3A), March 1999
tion, adding a dual-acting peripheral a blocker (doxazosin, terazosin) to the patient’s regimen to augment the antihypertensive action of the diuretic and to decrease urinary outflow obstruction adds insult to injury. Further lowering of blood pressure in the upright posture results in gait and balance problems, which can result in falls and hip fractures. Tamsulosin, a urospecific a blocker, does not produce any adverse blood pressure–lowering effects that could further compromise patient status. The advantage of tamsulosin is the avoidance of an a blocker that can produce orthostatic hypotension. Elderly men are often depressed, and tricyclic antidepressants can have anticholinergic activity and produce peripheral a blockade. The anticholinergic effect on the bladder of men with BPH can result in complete obstruction and/or overflow incontinence. The effect on peripheral a receptors can potentiate orthostatic hypotension. To avoid these problems, depressed, hypertensive men with prostatism who require multiple drug therapy are best initially treated with a lowdose (12.5 mg/day) hydrochlorothiazide diuretic, a selective serotonin reuptake inhibitor (paroxetine, sertraline, or fluoxetine) for depression (no anticholinergic activity), and a uroselective a1A antagonist, e.g., tamsulosin, which does not interact synergistically to lower blood pressure further and can be safely administered to hypertensive patients who are controlled with medication. CONCLUSIONS Hypertension and BPH are common in elderly men; their prevalence increases significantly with age and an estimated 25% of men aged .60 years have both conditions. Antihypertensive medication must be prescribed on an individual basis, but if there are no indications for a specific type of drug, e.g., an ACE inhibitor for chronic heart failure and proteinuria, a diuretic or b blocker is the initial drug of choice. Alpha-blockers are effective in the treatment of hypertension and may produce symptomatic relief of voiding symptoms in patients with coexisting BPH, but they are associated with postural hypotension, especially in the elderly. Therefore, careful titration of a-blocker doses and monitoring for excessive decreases in blood pressure are warranted. On achieving a BPH clinical response, the other antihypertensive medication, if any, can be modified. It is advisable to alter cardiovascular medications with the assistance of the primary care physician. The new, highly selective a1A-receptor antagonist tamsulosin may be an alternative in patients who develop intolerable side effects with nonselective a-blocker therapy. 11
REFERENCES 1. He J, and Whelton PK: Epidemiology and prevention of hypertension. Med Clin N Am 81: 1077–1097, 1997. 2. Burt VL, Whelthon P, Rocella EJ, et al: Prevalence of hypertension in the US adult population: results from the third National Health and Nutrition Examination Survey, 1988 –1991. Hypertension 25: 305–313, 1995. 3. Madhavan S, Ooi WL, Cohen H, et al: Relation of pulse pressure and blood pressure reduction to the incidence of myocardial infarction. Hypertension 23: 395– 401, 1994. 4. Chute CG, Panser LA, Girman CJ, et al: The prevalence of prostatism: a population based survey of urinary symptoms. J Urol 150: 85– 89, 1993. 5. Diokno AC, Brown MB, Goldstein N, et al: Epidemiology of bladder emptying symptoms in elderly men. J Urol 148: 1817–1821, 1992. 6. Guthrie R: Doxazosin for benign hyperplasia in primary care. Clin Ther 19:1269 –1277, 1997. 7. Supiano AM: Hypertension. Pathophysiology, in Cassel CK, Cohen HJ, Larsoon EB, et al (Eds): Geriatric Medicine, 3rd edn. New York, Spring-Verlag, 1997, pp 375–377. 8. Messerli FH, Sundgaard-Rise K, Ventura HO, et al: Essential hypertension in the elderly: haemodynamics, intravascular volume, plasma renin activity, and circulating catecholamine levels. Lancet ii: 983–986, 1983. 9. Meyer BR: Renal function in aging. J Am Geriatr Soc 37: 791– 800, 1989. 10. Amery A, Wasir H, and Bulpitt C: Aging and the cardiovascular system. Acta Cardiol (Brux) 6: 443, 1978. 11. Nakada T, and Kubota Y: Connective tissue protein in the prostate gland. Int Urol Nephrol 26: 183–187, 1994. 12. Suzuki H, and Nakada T: Alteration of collagen biosynthesis and analysis of type I and type III collagens of prostate in young rats following sex hormone treatments. Arch Androl 36: 205–216, 1996. 13. Marks LS, Treiger B, Dorey FJ, et al: Morphometry of the prostate: I. Distribution of tissue components in hyperplastic glands. Urology 44: 486 – 492, 1994. 14. Lee M, and Sharifi R: Benign prostatic hyperplasia: diagnosis and treatment guideline. Ann Pharmacother 31:481– 486, 1997. 15. Shapiro E, and Lepor H: Pathophysiology of clinical BPH. Urol Clin North Am 22: 285–290, 1995. 16. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 157: 2413–2446, 1997. 17. Borst SE, and Lowenthal DT: Cardiovascular drugs in the elderly, in Brest A (Ed): Cardiovascular Clinics: Geriatric Pharmacology. Philadelphia, F.A. Davis Co., 1991, pp 161– 173. 18. Frohlich ED: Calcium antagonists. Their physiological differences. Am J Hypertens 4: 430S, 1991. 19. Kochar MS, and Qurashi MI: Calcium channel blockers. Postgrad Med 102: 127–128, 1997. 20. Fishkind D, Paris BEC, and Aronow WS: Use of digoxin, beta blockers, ACE I, and calcium channel blockers in older patients in an academic hospital-based geriatrics practice. J Am Geriatr Soc 45: 809 – 812, 1997. 21. Weir MR, Flack JM, and Applegate WB: Tolerability, safety, and quality of life and hypertensive therapy: the case for low dose diuretics. Am J Med 101: 83S–92S. 22. Liegson PR, Grandtis GA, Dianzumba S, et al: Comparison of five antihypertensive monotherapies and placebo for change in left ventricular mass in patients receiving nutritional-hygienic therapy in the Treatment of Mild Hypertension Study (TOMHS). Circulation 91: 698 –706, 1991. 23. Grodzicki T, and Messerli F: Cardiovascular drug ther12
apy in the elderly, in Messerli FH (Ed): Cardiovascular Drug Therapy, 2nd edn. Philadelphia, W.B. Saunders, 1997, pp 225– 234. 24. Norweigan Multicenter Study Group: Timolol induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction. N Engl J Med 304: 801– 807, 1981. 25. Australia/New Zeland Heart Failure Research Collaborative Group: Randomised, placebo-controlled trial of carvedilol in patients with congestive heart failure due to ischaemic heart disease. Lancet 349: 375–380, 1997. 26. Garg R, and Yusuf S, for the Collaborative Group on ACE Inhibitor Trials: Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. JAMA 273: 1450 –1456, 1995. 27. Maki DD, Ma JZ, Louis TA, et al: Long term effects of antihypertensive agents on proteinuria and renal function. Arch Intern Med 155: 1073, 1995. 28. Toto RD, Mitchell HC, Lee HC, et al: Reversible renal insufficiency due to ACE inhibitors in hypertensive nephrosclerosis. Ann Intern Med 115: 513, 1991. 29. Burnier M, and Biollaz J: Pharmacokinetic optimisation of ACE inhibitor therapy. Clin Pharmacokinet 22: 375, 1992. 30. Messerli FHG, Weber MA, and Brunner HR. Angiotensin II receptor inhibition—a new therapeutic principle. Arch Int Med 156: 1957, 1996. 31. Kang PM, Landau AJ, Eberhardt RT, et al: Angiotensin II antagonists: a new approach to blockade of the renin-angiotensin system. Am Heart J 127: 1388, 1994. 32. Huchet AM, Velly J, and Schmidt H: Role of alpha-1 and alpha-2 adrenoceptors in the modulation of the baroreflex vagal bradycardia. Eur J Pharmacol 71: 455– 461, 1981. 33. Freis ED: Current status of diuretics, beta blockers, and alpha-blockers in the treatment of hypertension. Med Clin N Am 81: 1305–1317, 1997. 34. Fulton B, Wagstaff AJ, and Sorkin EM: Doxazosin: an update of its clinical pharmacology and therapeutic applications in hypertension and BPH. Drugs 49: 295–320, 1995. 35. Lepor H, for the Terazosin Research Group: Long term efficacy and safety of terazosin in patients with BPH. Urology 45: 406 – 413, 1995. 36. Gillenwater JY, and Mobley DL: A sixteen week, double blind, placebo-controlled, dose-titration study using doxazosin tablets for the treatment of BPH. Lancet 337: 1457–1461, 1991. 37. Chapple CR, Burt RP, Andersson PO, et al: Alpha 1-adrenoreceptor subtypes in the human prostate. Br J Urol 74: 585–589, 1994. 38. Wilde MI, and McTavish D: Tamsulosin. A review of its pharmacological properties and therapeutic potential in the management of symptomatic BPH. Drugs 52: 883– 898, 1996. 39. Chapple CR, Baert L, Thind P, et al: Tamsulosin 0.4 mg once daily: tolerability in older and younger patients with lower urinary tract symptoms suggestive of BPH (symptomatic BPH). The European Tamsulosin Study Group. Eur Urol 132: 462– 470, 1997. 40. Lowe FC: Coadministration of tamsulosin and three antihypertensive agents in patients with BPH: pharmacodynamic effect. Clin Ther 19: 730 –742, 1997.
QUESTIONS AND ANSWERS: DAVID T. LOWENTHAL, MD, PhD E. David Crawford, MD: Hypertension is more serious than I thought, which has an important impact on my thinking about BPH. I would like to UROLOGY 53 (Supplement 3A), March 1999
ask what the normal blood pressure for a 70-yearold man should be. Dr. Lowenthal: Assuming that he is not apprehensive the normal blood pressure for a 70 –75year-old man would be ,140/90 mm Hg. Dr. Crawford: We routinely take vital signs in my clinical practice. If I see a 65-year-old man with BPH whom I want to treat with an a blocker, but his blood pressure is 160/96 mm Hg, what should I do? Should he be referred to an internist? Dr. Lowenthal: Assuming that this is a seated blood pressure, it is critical to take the patient’s blood pressure when supine. An increase in the systolic blood pressure to 230 –240 mm Hg indicates that the patient may fall on standing due to a marked orthostatic decrease in systolic and/or diastolic blood pressure. Looking at 1 blood pressure reading is insufficient; one really needs to take blood pressure readings with the patient standing, sitting, and supine, especially if he is taking doxazosin or terazosin. The clue to an existing problem is a marked increase in blood pressure when the patient is supine because this indicates a dysregulation or inability to regulate blood pressure with positional changes. If the systolic blood pressure in the standing position shows a marked decrease, an underlying problem is indicated. In summary, taking 1 blood pressure reading does not provide the optimum amount of information. Dr. Crawford: I see many elderly men with hypertension who are already being treated with angiotensin-converting enzyme (ACE) inhibitors or b blockers. These patients are often well controlled
UROLOGY 53 (Supplement 3A), March 1999
on this medication, but I often want to introduce an a blocker to treat BPH. What should I do? Dr. Lowenthal: If the patient is taking an ACE inhibitor or a b blocker, the first question one should ask is why. Is he taking it for heart failure or angina? If the answer is yes and you need to give the patient a peripheral a blocker, as an internist I would want you to give consideration to not perturbing the blood pressure and certainly not reducing it, especially in the upright position. In that case, I would look for a drug that does not affect blood pressure in the upright position. I think that tamsulosin is an option for inclusion in that patient’s treatment regimen. Adding doxazosin or terazosin may be safe, but there is always potential for a significant reduction in blood pressure in the upright position and thus for falls. Dr. Crawford: To me, that is an advantage of tamsulosin: I do not have to consult an internist before treating hypertensive patients with BPH with an a blocker. Question from audience: When we started prescribing terazosin, we were told to ensure that patients took the drug at night before going to bed to ensure that any hypotension would occur while the patient was in bed. Is there any evidence that the timing of administration of tamsulosin is important? Dr. Lowenthal: I am not sure that I have any data on the best timing, but it should always be given after food. I am not aware that it should be given at any particular time of day to prevent side effects.
13
AND
DAVID T. LOWENTHAL
ABSTRACT The treatment of hypertension in the elderly can be safely achieved with low-dose diuretic therapy. Men with prostatism may benefit from peripheral a-blocking drugs. However, drugs such as doxazosin or terazosin may further lower blood pressure and at times may be associated with orthostatic hypotension, especially if diuretics are given concomitantly. Tamsulosin achieves relaxation of the smooth muscle of the prostate, as do terazosin and doxazosin, but without provoking changes in blood pressure, especially orthostatic hypotension. There appears to be no adverse interaction with any other antihypertensive medication or with low-dose diuretics. To manage such patients with hypertension and prostatism, hydrochlorothiazide 6.25 to 12.5 mg/day and tamsulosin 0.4 mg/day would be an adequate combination. Low-dose diuretics have been shown to be effective in both isolated systolic hypertension as well as fixed diastolic hypertension in the elderly. If other antihypertensives need to be added, then a low dose of a long-acting calcium-entry blocker, a central a-agonist (a transdermal clonidine for better compliance), an angiotensin-converting enzyme inhibitor (if renal vascular disease has been ruled out), or an angiotensin II receptor blocker, e.g., losartan or valsartan, should be considered. UROLOGY 53 (Suppl 3A): 7–13, 1999. © 1999, Elsevier Science Inc. All rights reserved.
A
verage blood pressure tends to increase progressively with increasing age in almost every population,1 although in many persons, blood pressure does not increase with age. In the US population aged $60 years examined in the National Health and Nutrition Examination Survey (NHANES) III, elevated blood pressure was found in 60% of non-Hispanic whites, 71% of non-Hispanic African-Americans, and 61% of MexicanAmericans.2 The age-related rate of increase in blood pressure is consistently greater for systolic than for diastolic blood pressure: systolic blood pressure tends to increase until 70 or 80 years of age, whereas diastolic blood pressure tends to remain constant or decrease after the age of 40 years. As a consequence, isolated systolic hypertension is common From the University of Florida College of Medicine and Geriatric Research, Education and Clinical Center, Veterans Affairs Medical Center, Gainesville, Florida (JM, VB); Pharmacology and Exercise Science, University of Florida College of Medicine and Director, Geriatric Research, Education and Clinical Center, Veterans Affairs Medical Center, Gainesville, Florida (DTL) Reprint requests: David T. Lowenthal, MD, PhD, Geriatric Research, Education and Clinical Center (182), Veterans Affairs Medical Center, 1601 SW Archer Road, Gainesville, FL 326081197 © 1999, ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED
in the elderly, and systolic blood pressure is a better predictor of events (cardiovascular disease, heart failure, stroke, end-stage renal disease, and all-cause mortality) than diastolic blood pressure.3 Finally, primary hypertension is the most common form of hypertension in the elderly, with renovascular disease being the most frequent form of secondary or reversible hypertension. Benign prostatic hyperplasia (BPH) is the proliferation of epithelial and stromal prostate tissue; its prevalence also significantly increases with age, with pathologic evidence of BPH being found in nearly 80% of men by age 80 years.4 Data indicate that 28 –35% of older men have moderate or severe voiding symptoms.5,6 Therefore it is not uncommon in clinical practice to find an elderly patient with hypertension and coexisting BPH, and an estimated 25% of men .60 years have both BPH and hypertension.7 PATHOPHYSIOLOGY OF HYPERTENSION IN THE ELDERLY As is the case in younger individuals, the etiology of essential hypertension in older subjects is unknown. With age there is a gradual loss in the elasticity of the arteries, particularly of the larger arter0090-4295/99/$20.00 S0090-4295(99)00533-0 7
ies. Alterations in vessel structure that contribute to the decrease in distensibility are (1) an increase in smooth muscle cell size and number; (2) an increase in medial collagen deposition; and (3) a decrease in elastin content. The arterial tree becomes more like a system of rigid pipes in which the same cardiac output results in higher systolic and lower diastolic pressures. In addition to these changes, there are alterations in the regulation of vascular tone by the autonomic nervous system in the elderly. There is also a decrease in the sensitivity of the baroreflex with age, which contributes to the greater blood pressure variability in older individuals. Many studies have demonstrated an age-associated increase in the activity of the sympathetic nervous system, as measured by an increase in plasma norepinephrine levels and rates of norepinephrine release, which would result in increased cardiovascular adrenergic responses if it were not for an age-associated decrease in the b-adrenergic receptor chronotropic, inotropic, and vascular responses as well as a-adrenergic vasoconstrictor responses.8 As a result of the decrease in the arterial a-adrenergic receptor response, it appears that overall arterial a-adrenergic tone is similar in older and younger normotensive individuals. Another modulator of vascular tone is the vascular endothelium. Nitric oxide is a potent vasodilator synthesized by the endothelium, and studies have demonstrated an age-associated decrease in nitric oxide–mediated vasodilation. However, the extent to which impaired endothelial function contributes to an increase in blood pressure in aging remains to be defined.8 There is also evidence of an age-associated decline in plasma renin activity, and older patients with hypertension are characterized by low plasma renin activity. This impaired secretion of aldosterone in the elderly results in potassium retention and can increase the risk of hyperkalemia caused by b blockers or angiotensin-converting enzyme (ACE) inhibitors.9 Changes in renal function (decreased renal flow and glomerular filtration rate) result in an age-associated inability to excrete a sodium load rapidly, resulting in sodium retention and an increase in total body sodium.10 Due to the changes with aging described above, the elderly may display 2 clinical features. The first is pseudohypertension due to markedly sclerotic arteries that do not collapse under the cuff, giving much higher cuff pressures than are present within vessels. The second, seen in 20% of the elderly, is postural and postprandial hypotension, usually reflecting the progressive loss of baroreceptor responsiveness with age.11 8
PATHOPHYSIOLOGY OF BPH IN THE ELDERLY BPH, the age-related proliferation of epithelial and stromal prostate tissue, includes changes to the extracellular matrix of collagen and elastin. This involves downregulation of collagen types I and III (which constitute the interstitial collagen) and elastin and collagen type IV upregulation (found primarily in the basement membrane).11–13 Medical treatment of BPH is directed at the dynamic components involved and at the pathogenesis of the disease. Glandular epithelial tissue comprises approximately 20 –30% of BPH tissue and its growth is stimulated by dihydrotestosterone. Hyperplasia of these components produces a mechanical obstruction of the bladder neck and prostatic urethra, and is the static causative factor for BPH.14 Stromal or fibromuscular tissue comprises 70 – 80% of BPH tissue and is under a-adrenergic tone. Smooth muscle is one of the dominant cellular constituents of BPH15; the tension of this prostate smooth muscle is mediated by the a1 adrenoreceptor (primarily of the A1C class). When stimulated, this tissue contracts around the bladder neck, reducing the urethral lumen diameter and causing dynamic obstruction to urinary outflow.14 In patients with BPH, increased glandular tissue volume and/or excessive adrenergic tone may be present, thereby causing symptoms compatible with impaired voiding. Medical treatment is directed at these factors. Selective a1-adrenergic antagonists reduce sympathetic stimulation of BPH tissue, resulting in relaxation of smooth muscle around the bladder neck and the prostatic urethra. This improves urinary flow.14 NONPHARMACOLOGIC MANAGEMENT OF HYPERTENSION The approach to managing hypertension is bimodal, including nondrug and drug therapy. The nondrug considerations with proven efficacy include (1) low-salt diet; (2) an increase in foods containing potassium, e.g., fruits, including figs and dates, and calcium; (3) an intake of alcohol of #2 ounces per day; (4) cessation of tobacco smoking; (5) change from a sedentary to an active lifestyle emphasizing aerobic exercise (30 min of exercise per day, 3–5 days per week); and (6) weight reduction. Obese hypertensive men would benefit markedly by losing weight to counteract the insulin resistance that occurs in obesity and produces exaggerated sympathetic nervous system activity, sodium retention, hyperlipidemia, and hypertension. Weight loss can rectify these abnormalities; therefore considerable emphasis must be given to nonpharmacologic approaches in patients with hypertension, regardless of underlying comorbidity. UROLOGY 53 (Supplement 3A), March 1999
CONSIDERATIONS IN THE USE OF SPECIFIC CLASSES OF ANTIHYPERTENSIVE DRUGS IN THE ELDERLY Special considerations in the selection of initial antihypertensive medication in the elderly include demographic characteristics, comorbidity, quality of life, cost, and use of other drugs.16 Table I lists the most important considerations for individualizing therapy. CALCIUM CHANNEL BLOCKERS Calcium channel blockers (CCBs) are a heterogeneous group of drugs with different pharmacokinetic and pharmacodynamic properties that are used mainly to treat hypertension, angina pectoris, and cardiac arrhythmia.17 There is insufficient justification for their use in hypertension and relief of symptoms of BPH. They inhibit calcium influx into smooth muscle cells by blocking calcium channels; they also block mobilization of calcium from intracellular stores. This activity decreases arterial pressure by reducing total peripheral vascular resistance, and as a consequence, the CCBs evoke a baroreceptor-mediated sympathetic discharge, which in the case of the dihydropyridines causes a mild-to-moderate tachycardia. The CCBs also inhibit the entrance of calcium into myocardium and coronary artery smooth muscle cells. Despite their common mechanism of action, CCBs vary considerably in their effects on the myocardium, conduction system, and circulatory system.18 CCBs are well absorbed after oral administration and are extensively metabolized by microsomal oxidases in the liver, with a small amount of unchanged drug being excreted in the urine.17,19 Plasma concentrations tend to be higher in the elderly or in patients with liver disease; in these patients it is safer to start therapy with lower doses. Depending on their half-life and pharmaceutical formulation, CCBs can be short or long acting. Among the short-acting CCBs are the immediaterelease forms of isradipine (DynaCirc), nicardipine (Cardene), nifedipine (Adalat, Procardia), and nimodipine (Nimotop). In a recent study of older patients in an academic hospital-based geriatrics practice, CCBs were used more often than b blockers in patients with hypertension and previous myocardial infarction or coronary artery disease.20 DIURETICS When the decision has been made to begin antihypertensive medication and there are no indications for a specific type of drug, a diuretic or b blocker should be used because numerous studies have demonstrated reductions in morbidity and mortality with these agents.16 Thiazide diuretics in UROLOGY 53 (Supplement 3A), March 1999
TABLE I.
Considerations for specific classes of antihypertensive agent
Comorbidity
Drug
Indicated unless contraindicated Isolated systolic Diuretics, CCBs (longhypertension (elderly) acting dihydropyridine) Diabetes mellitus (type 1) ACE inhibitors with proteinuria Heart failure ACE inhibitors, diuretics Myocardial infarction b-Blockers (non-ISA), ACE inhibitors Potential favorable effects Angina b-Blockers, CCBs Atrial tachycardia and b-Blockers, CCBs fibrillation (nondihydropyridine) Diabetes (types 1 and 2) ACE inhibitors, CCBs with proteinuria Diabetes (type 2) Low-dose diuretics Dyslipidemia a-Blockers Essential tremor b-Blockers (noncardioselective) Heart failure Carvedilol, losartan potassium Myocardial infarction Diltiazem HCl, verapamil Osteoporosis Thiazides Preoperative hypertension b-Blockers Prostatism a-Blockers Renal insufficiency (with ACE inhibitors caution) Potential unfavorable effects Chronic obstructive b-Blockers* pulmonary disease Depression b-Blockers, central a-agonists, reserpine* Diabetes mellitus (types 1 b-Blockers, high-dose and 2) diuretics Dyslipidemia b-Blockers (non-ISA), high-dose diuretics Gout Diuretics High-degree b-Blockers,* CCBs atrioventricular block (nondihydropyridine)* Heart failure b-Blockers (except carvedilol) CCBs (except amlodipine and felodipine) Peripheral vascular b-Blockers disease Renal insufficiency Potassium-sparing agents Renovascular disease ACE inhibitors, angiotensin II receptor Blockers ACE 5 angiotensin-converting enzyme; CCBs 5 calcium channel blockers; ISA 5 intrinsic sympathomimetic activity. *Contraindicated. Adapted from Arch Intern Med.16
9
small doses (hydrochlorothiazide 6.25–25 mg/ day) are effective as monotherapy in the treatment of mild essential hypertension and of isolated systolic hypertension in the elderly.21 A diuretic is recommended as a second agent (if not already used) when the target blood pressure has not been achieved with monotherapy, i.e., a b blocker.16 Elderly men with BPH may be at risk for greater urgency, frequency, and overflow incontinence as the diuretic dose is increased. Thus it is critical to keep the dose low. In addition, diuretics can cause different types of metabolic abnormalities, including increases in cholesterol levels, glucose intolerance, hyperuricemia, hypokalemia, hyponatremia, and hypomagnesemia. These can be attenuated by not exceeding a dose of hydrochlorothiazide 25 mg/day, combining it with a potassium-sparing diuretic, and periodic monitoring of blood chemistry. In the Treatment of Mild Hypertension Study (TOMHS), diuretics produced a greater reduction in left ventricular mass than any other major class of antihypertensive drug.22 Loop diuretics on the other hand should be reserved for elderly patients with signs of heart or renal failure.23 BETA BLOCKERS All of the b blockers, except those with intrinsic sympathomimetic activity (ISA), reduce cardiac output and heart rate, have similar antihypertensive response rates, and reduce mortality and reinfarction in patients with a previous myocardial infarction.24 In patients with heart failure, the new a,b blocker carvedilol added to an ACE inhibitor has been shown to be beneficial.25 Beta blockers can produce bronchospasm, and are contraindicated in chronic obstructive pulmonary disease and asthma; other side effects include masking of insulin-induced hypoglycemia, worsening of heart failure, impaired peripheral arterial circulation, insomnia, fatigue, decreased exercise tolerance, and hypertriglyceridemia. These may occur less frequently with b1-selective blockers than with nonselective b blockers. The adverse central nervous system effects, i.e., sleep disturbances, depression, and nightmares, may be more common with lipophilic b blockers (like propranolol) due to their increased blood– brain barrier penetration.7 CENTRALLY ACTING ANTIHYPERTENSIVES The prototype postsynaptic a2-agonist is clonidine, which can be administered orally or transdermally. It is an effective antihypertensive agent, but it is highly lipid soluble and can produce sedation and dry mouth, problems that already exist in the elderly not taking clonidine. If absolutely necessary, the transdermal preparation provides a smoother blood pressure reduction response than 10
the oral formulation. Methyldopa, guanfacine, and guanabenz are less frequently used oral centrally acting drugs, but possess lipid solubility similar to that of clonidine with central side effects of depression, sedation, and dry mouth. ACE INHIBITORS AND ANGIOTENSIN II RECEPTOR ANTAGONISTS Although plasma renin activity is often reduced in the elderly, ACE inhibitors have been shown to be effective in this population, particularly if hypertension is associated with chronic heart failure (studies have shown that ACE inhibitors reduce mortality in this situation).26 As monotherapy, these agents are as effective as any other antihypertensive agent. Studies have also demonstrated long-term beneficial effects on proteinuria and glomerular filtration rate for patients with diabetic and nondiabetic renal disease.27 Other beneficial effects include prevention of adverse remodeling and dilatation of the left ventricle after MI, and reduction of left ventricular mass. Major considerations in patients on ACE inhibitors are the development of hyperkalemia, and the potential for renal failure in patients with bilateral renal artery stenosis or stenosis to a solitary kidney.28 The ACE inhibitor dose needs to be adjusted if the glomerular filtration rate is ,30 mL/min,29 except with fosinopril, 50% of which is eliminated by hepatic metabolism and 50% by the kidney. Hypotension has been observed with initiation of therapy, which may be avoided by starting with the lowest dose; cough is a major side effect, but resolves on discontinuation of ACE inhibitor treatment. The angiotensin II receptor antagonist losartan effectively reduces blood pressure in patients with essential hypertension.30 This selective angiotensin II receptor antagonist has not been associated with cough and, at least in theory, should have the same beneficial effects as the ACE inhibitors. The same precautions mentioned for the use of ACE inhibitors also apply to this drug.31 ALPHA-ADRENOCEPTOR BLOCKERS The peripheral a-adrenoreceptor blockers inhibit postsynaptic vascular a-adrenergic receptors, causing vasodilation and decreasing peripheral vascular resistance; they prevent reflex tachycardia by inhibiting baroreflex activity.32 Prazosin, doxazosin, and terazosin have similar efficacy in the treatment of hypertension, but doxazosin and terazosin have longer durations of action.33 These drugs are not well suited for initial monotherapy because of their tendency to cause orthostatic hypotension.16 All of them may cause orthostatic hypotension with the first dose. The recommendation is to start with small doses and increase them as tolerated. UROLOGY 53 (Supplement 3A), March 1999
Patients with BPH may obtain symptomatic relief with a-blocker therapy due to blockade of the a receptors in the smooth muscle of the bladder outlet.14 Alpha-adrenergic agents have been used successfully in combination with b blockers, diuretics, CCBs, and ACE inhibitors in patients with hypertension that is uncontrolled with monotherapy,34 but there are concerns regarding excessive hypotension with combination therapy for hypertension that includes an a-adrenergic antagonist. Several studies suggest that the average decrease in diastolic blood pressure associated with a-adrenergic blockers in normotensive and hypertensive patients is 4 –5 mm Hg and 15–20 mm Hg, respectively.35,36 Careful titration of a-adrenergic antagonist dose or a decrease in dose of any other antihypertensive agent is indicated in patients receiving combination therapy for hypertension and BPH with an a-adrenergic antagonist. If intolerable dizziness and hypotension occur after initiation of an a-antagonist, discontinuation is recommended. More highly selective antagonists of the a1A-receptor have been developed. Alpha1A receptors comprise 70% of the a receptors in the prostate and bladder neck, and have not been identified at significant levels elsewhere in the body.37 Tamsulosin is the first subtype-selective (a1A) a1-adrenoreceptor antagonist with specificity for prostatic a1 adrenoreceptors.38 Some studies have shown that tamsulosin is well tolerated and suitable for use in both older (.65 years) and younger (#65 years) patients with lower urinary tract symptoms suggestive of BPH39; the optimal effects are achieved with tamsulosin 0.4 mg administered once daily. In some small studies, coadministration of tamsulosin had no clinically significant effects on the pharmacodynamic action of nifedipine, enalapril, or atenolol: it produced no clinically significant differences in pulse rate and blood pressure, did not alter electrocardiographic or Holter monitoring results, did not cause increased side effects, and the dose of the antihypertensives did not need to be adjusted, which may give tamsulosin an advantage over other a-blocking agents used to treat BPH.40 POTENTIAL AGE–DISEASE–DRUG INTERACTIONS IN BPH Diuretics produce volume contraction. The reduced muscle mass of elderly patients is a clinical indicator that intracellular and interstitial volumes are decreased. This occurs because skeletal muscle is 70% water and 30% protein. Excess doses of diuretics, e.g., .25 mg of hydrochlorothiazide, can produce orthostatic hypotension, especially in a deconditioned, sedentary person. In this setting of a reduced preload secondary to volume contracUROLOGY 53 (Supplement 3A), March 1999
tion, adding a dual-acting peripheral a blocker (doxazosin, terazosin) to the patient’s regimen to augment the antihypertensive action of the diuretic and to decrease urinary outflow obstruction adds insult to injury. Further lowering of blood pressure in the upright posture results in gait and balance problems, which can result in falls and hip fractures. Tamsulosin, a urospecific a blocker, does not produce any adverse blood pressure–lowering effects that could further compromise patient status. The advantage of tamsulosin is the avoidance of an a blocker that can produce orthostatic hypotension. Elderly men are often depressed, and tricyclic antidepressants can have anticholinergic activity and produce peripheral a blockade. The anticholinergic effect on the bladder of men with BPH can result in complete obstruction and/or overflow incontinence. The effect on peripheral a receptors can potentiate orthostatic hypotension. To avoid these problems, depressed, hypertensive men with prostatism who require multiple drug therapy are best initially treated with a lowdose (12.5 mg/day) hydrochlorothiazide diuretic, a selective serotonin reuptake inhibitor (paroxetine, sertraline, or fluoxetine) for depression (no anticholinergic activity), and a uroselective a1A antagonist, e.g., tamsulosin, which does not interact synergistically to lower blood pressure further and can be safely administered to hypertensive patients who are controlled with medication. CONCLUSIONS Hypertension and BPH are common in elderly men; their prevalence increases significantly with age and an estimated 25% of men aged .60 years have both conditions. Antihypertensive medication must be prescribed on an individual basis, but if there are no indications for a specific type of drug, e.g., an ACE inhibitor for chronic heart failure and proteinuria, a diuretic or b blocker is the initial drug of choice. Alpha-blockers are effective in the treatment of hypertension and may produce symptomatic relief of voiding symptoms in patients with coexisting BPH, but they are associated with postural hypotension, especially in the elderly. Therefore, careful titration of a-blocker doses and monitoring for excessive decreases in blood pressure are warranted. On achieving a BPH clinical response, the other antihypertensive medication, if any, can be modified. It is advisable to alter cardiovascular medications with the assistance of the primary care physician. The new, highly selective a1A-receptor antagonist tamsulosin may be an alternative in patients who develop intolerable side effects with nonselective a-blocker therapy. 11
REFERENCES 1. He J, and Whelton PK: Epidemiology and prevention of hypertension. Med Clin N Am 81: 1077–1097, 1997. 2. Burt VL, Whelthon P, Rocella EJ, et al: Prevalence of hypertension in the US adult population: results from the third National Health and Nutrition Examination Survey, 1988 –1991. Hypertension 25: 305–313, 1995. 3. Madhavan S, Ooi WL, Cohen H, et al: Relation of pulse pressure and blood pressure reduction to the incidence of myocardial infarction. Hypertension 23: 395– 401, 1994. 4. Chute CG, Panser LA, Girman CJ, et al: The prevalence of prostatism: a population based survey of urinary symptoms. J Urol 150: 85– 89, 1993. 5. Diokno AC, Brown MB, Goldstein N, et al: Epidemiology of bladder emptying symptoms in elderly men. J Urol 148: 1817–1821, 1992. 6. Guthrie R: Doxazosin for benign hyperplasia in primary care. Clin Ther 19:1269 –1277, 1997. 7. Supiano AM: Hypertension. Pathophysiology, in Cassel CK, Cohen HJ, Larsoon EB, et al (Eds): Geriatric Medicine, 3rd edn. New York, Spring-Verlag, 1997, pp 375–377. 8. Messerli FH, Sundgaard-Rise K, Ventura HO, et al: Essential hypertension in the elderly: haemodynamics, intravascular volume, plasma renin activity, and circulating catecholamine levels. Lancet ii: 983–986, 1983. 9. Meyer BR: Renal function in aging. J Am Geriatr Soc 37: 791– 800, 1989. 10. Amery A, Wasir H, and Bulpitt C: Aging and the cardiovascular system. Acta Cardiol (Brux) 6: 443, 1978. 11. Nakada T, and Kubota Y: Connective tissue protein in the prostate gland. Int Urol Nephrol 26: 183–187, 1994. 12. Suzuki H, and Nakada T: Alteration of collagen biosynthesis and analysis of type I and type III collagens of prostate in young rats following sex hormone treatments. Arch Androl 36: 205–216, 1996. 13. Marks LS, Treiger B, Dorey FJ, et al: Morphometry of the prostate: I. Distribution of tissue components in hyperplastic glands. Urology 44: 486 – 492, 1994. 14. Lee M, and Sharifi R: Benign prostatic hyperplasia: diagnosis and treatment guideline. Ann Pharmacother 31:481– 486, 1997. 15. Shapiro E, and Lepor H: Pathophysiology of clinical BPH. Urol Clin North Am 22: 285–290, 1995. 16. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 157: 2413–2446, 1997. 17. Borst SE, and Lowenthal DT: Cardiovascular drugs in the elderly, in Brest A (Ed): Cardiovascular Clinics: Geriatric Pharmacology. Philadelphia, F.A. Davis Co., 1991, pp 161– 173. 18. Frohlich ED: Calcium antagonists. Their physiological differences. Am J Hypertens 4: 430S, 1991. 19. Kochar MS, and Qurashi MI: Calcium channel blockers. Postgrad Med 102: 127–128, 1997. 20. Fishkind D, Paris BEC, and Aronow WS: Use of digoxin, beta blockers, ACE I, and calcium channel blockers in older patients in an academic hospital-based geriatrics practice. J Am Geriatr Soc 45: 809 – 812, 1997. 21. Weir MR, Flack JM, and Applegate WB: Tolerability, safety, and quality of life and hypertensive therapy: the case for low dose diuretics. Am J Med 101: 83S–92S. 22. Liegson PR, Grandtis GA, Dianzumba S, et al: Comparison of five antihypertensive monotherapies and placebo for change in left ventricular mass in patients receiving nutritional-hygienic therapy in the Treatment of Mild Hypertension Study (TOMHS). Circulation 91: 698 –706, 1991. 23. Grodzicki T, and Messerli F: Cardiovascular drug ther12
apy in the elderly, in Messerli FH (Ed): Cardiovascular Drug Therapy, 2nd edn. Philadelphia, W.B. Saunders, 1997, pp 225– 234. 24. Norweigan Multicenter Study Group: Timolol induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction. N Engl J Med 304: 801– 807, 1981. 25. Australia/New Zeland Heart Failure Research Collaborative Group: Randomised, placebo-controlled trial of carvedilol in patients with congestive heart failure due to ischaemic heart disease. Lancet 349: 375–380, 1997. 26. Garg R, and Yusuf S, for the Collaborative Group on ACE Inhibitor Trials: Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. JAMA 273: 1450 –1456, 1995. 27. Maki DD, Ma JZ, Louis TA, et al: Long term effects of antihypertensive agents on proteinuria and renal function. Arch Intern Med 155: 1073, 1995. 28. Toto RD, Mitchell HC, Lee HC, et al: Reversible renal insufficiency due to ACE inhibitors in hypertensive nephrosclerosis. Ann Intern Med 115: 513, 1991. 29. Burnier M, and Biollaz J: Pharmacokinetic optimisation of ACE inhibitor therapy. Clin Pharmacokinet 22: 375, 1992. 30. Messerli FHG, Weber MA, and Brunner HR. Angiotensin II receptor inhibition—a new therapeutic principle. Arch Int Med 156: 1957, 1996. 31. Kang PM, Landau AJ, Eberhardt RT, et al: Angiotensin II antagonists: a new approach to blockade of the renin-angiotensin system. Am Heart J 127: 1388, 1994. 32. Huchet AM, Velly J, and Schmidt H: Role of alpha-1 and alpha-2 adrenoceptors in the modulation of the baroreflex vagal bradycardia. Eur J Pharmacol 71: 455– 461, 1981. 33. Freis ED: Current status of diuretics, beta blockers, and alpha-blockers in the treatment of hypertension. Med Clin N Am 81: 1305–1317, 1997. 34. Fulton B, Wagstaff AJ, and Sorkin EM: Doxazosin: an update of its clinical pharmacology and therapeutic applications in hypertension and BPH. Drugs 49: 295–320, 1995. 35. Lepor H, for the Terazosin Research Group: Long term efficacy and safety of terazosin in patients with BPH. Urology 45: 406 – 413, 1995. 36. Gillenwater JY, and Mobley DL: A sixteen week, double blind, placebo-controlled, dose-titration study using doxazosin tablets for the treatment of BPH. Lancet 337: 1457–1461, 1991. 37. Chapple CR, Burt RP, Andersson PO, et al: Alpha 1-adrenoreceptor subtypes in the human prostate. Br J Urol 74: 585–589, 1994. 38. Wilde MI, and McTavish D: Tamsulosin. A review of its pharmacological properties and therapeutic potential in the management of symptomatic BPH. Drugs 52: 883– 898, 1996. 39. Chapple CR, Baert L, Thind P, et al: Tamsulosin 0.4 mg once daily: tolerability in older and younger patients with lower urinary tract symptoms suggestive of BPH (symptomatic BPH). The European Tamsulosin Study Group. Eur Urol 132: 462– 470, 1997. 40. Lowe FC: Coadministration of tamsulosin and three antihypertensive agents in patients with BPH: pharmacodynamic effect. Clin Ther 19: 730 –742, 1997.
QUESTIONS AND ANSWERS: DAVID T. LOWENTHAL, MD, PhD E. David Crawford, MD: Hypertension is more serious than I thought, which has an important impact on my thinking about BPH. I would like to UROLOGY 53 (Supplement 3A), March 1999
ask what the normal blood pressure for a 70-yearold man should be. Dr. Lowenthal: Assuming that he is not apprehensive the normal blood pressure for a 70 –75year-old man would be ,140/90 mm Hg. Dr. Crawford: We routinely take vital signs in my clinical practice. If I see a 65-year-old man with BPH whom I want to treat with an a blocker, but his blood pressure is 160/96 mm Hg, what should I do? Should he be referred to an internist? Dr. Lowenthal: Assuming that this is a seated blood pressure, it is critical to take the patient’s blood pressure when supine. An increase in the systolic blood pressure to 230 –240 mm Hg indicates that the patient may fall on standing due to a marked orthostatic decrease in systolic and/or diastolic blood pressure. Looking at 1 blood pressure reading is insufficient; one really needs to take blood pressure readings with the patient standing, sitting, and supine, especially if he is taking doxazosin or terazosin. The clue to an existing problem is a marked increase in blood pressure when the patient is supine because this indicates a dysregulation or inability to regulate blood pressure with positional changes. If the systolic blood pressure in the standing position shows a marked decrease, an underlying problem is indicated. In summary, taking 1 blood pressure reading does not provide the optimum amount of information. Dr. Crawford: I see many elderly men with hypertension who are already being treated with angiotensin-converting enzyme (ACE) inhibitors or b blockers. These patients are often well controlled
UROLOGY 53 (Supplement 3A), March 1999
on this medication, but I often want to introduce an a blocker to treat BPH. What should I do? Dr. Lowenthal: If the patient is taking an ACE inhibitor or a b blocker, the first question one should ask is why. Is he taking it for heart failure or angina? If the answer is yes and you need to give the patient a peripheral a blocker, as an internist I would want you to give consideration to not perturbing the blood pressure and certainly not reducing it, especially in the upright position. In that case, I would look for a drug that does not affect blood pressure in the upright position. I think that tamsulosin is an option for inclusion in that patient’s treatment regimen. Adding doxazosin or terazosin may be safe, but there is always potential for a significant reduction in blood pressure in the upright position and thus for falls. Dr. Crawford: To me, that is an advantage of tamsulosin: I do not have to consult an internist before treating hypertensive patients with BPH with an a blocker. Question from audience: When we started prescribing terazosin, we were told to ensure that patients took the drug at night before going to bed to ensure that any hypotension would occur while the patient was in bed. Is there any evidence that the timing of administration of tamsulosin is important? Dr. Lowenthal: I am not sure that I have any data on the best timing, but it should always be given after food. I am not aware that it should be given at any particular time of day to prevent side effects.
13