Selection of antihypertensive therapy

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<ul><li><p>June 1990 1446 Letters to the Editor American Heart Journal </p><p>however, the anemia was the result of iron deficiency, and the el- evated ESR was thought to reflect exacerbation of the patient's Crohn's disease. At this time we cannot assess the prevalence of this cause of valvular heart disease; however, it is possible that such a cause may be responsible for a percentage of the "unknown causes" of valvular incompetence. </p><p>Steve Burdick, MD Donald D. Tresch, MD </p><p>Cardiology Division Medical College of Wisconsin </p><p>Milwaukee, WI 53226 </p><p>REFERENCE </p><p>1. Burdick S, Tresch D, Komokowski R. Cardiac valvular dys- function associated with Crohn's disease in the absence of ankylosing spondylitis. AM HEART J 1989;118:174-6. </p><p>SELECT ION OF ANT IHYPERTENSIVE THERAPY </p><p>To the Editor: Although Houston 1 has described a logical approach to the st- </p><p>lection of antihypertensive therapy in a recent review in the JOUR- NAL, he has unfortunately drawn inappropriate conclusions re- garding the properties of some agents. This is possibly the result of citing only a limited number of references. We wish to clarify several points based on the greater body of data that exist for la- betalol. </p><p>Houston groups labetalol with reserpine, guanethidine, and guanadrel, implying that these agents have similar antihyperten- sive mechanisms. He states that these agents reduce systemic vas- cular resistance and reduce cardiac output. For labetalol he sup- ports this statement with a review article, 2 which cites among three studies original research by the same individual. 3 In that study, by means of pretreatment controls, the cardiac index was signifi- cantly reduced at 1 year in the sitting position at rest and at three levels of exercise but not in the supine position. However, at 6 years there were no significant changes in the cardiac index under any of these conditions when compared to control values. This finding is acknowledged in the cited review article. Other studies, both single-dose and long-term, indicate that generally labetalol does not alter cardiac output to a significant degree. 47 In fact results from at least one recent study s indicate that despite its beta- blocking activity labetalol may improve left ventricular function in hypertensive patients with preexisting heart failure, possibly the result of an afterload-reducing effect. </p><p>In the review labetalol is noted to have a neutral or slightly ad- verse effect on serum lipids. Two references are cited; one is a re- view article 9 and the other is a study that demonstrated no change in total cholesterol and a slight, insignificant increase in serum triglycerides in eight subjects treated for 4 months. 1~ However, there was a significant decrease in the total cholesterol/triglycer- ide ratio of the very low-density lipoprotein fraction (p &lt; 0.02), suggesting the formation of triglyceride-rich particles. Yet the au- thor ignores the findings in the majority of studies that indicate labetalol has essentially no effect on total cholesterol, triglycerides, or lipoprotein fractions. 11-19 The author also states that labetalol causes slight increases in uric acid, but no reference is provided. We are not aware of any studies or published case reports that suggest a significant elevation in serum uric acid, whereas in fact there are studies that have demonstrated a lack of effect on serum uric acid by labetalol. 14,15, is, 20 </p><p>Throughout the article labetalol is inconsistently classified. Ta- ble XX indicates that labetalo! is simply a beta-adrenergic block- er, whereas interestingly the selective alpha-1 antagonists are not </p><p>classified as alpha-adrenergic blockers but as indirect vasodilators. Table XXI, which classifies labetalol as an "alpha and beta block- er," includes among its effects on coronary heart disease risk fac- tors unfavorable actions on serum lipids and uric acid. As noted previously these claims are inaccurate. </p><p>Finally, in Table XXIIIA labetalol is grouped with the beta blockers that have intrinsic sympathomimetic activity. (Although labetalol does indeed possess partial agonist activity, the clinical relevance of this property has not been fully established.) In this table labetalol is reported to cause increases in serum potassium and magnesium. No references are provided. Although labetalol or any adrenergic antagonist may influence serum electrolytes in st- lect cases, this should not be considered a routine problem with labetalol. In summary, we believe that to use those approaches advocated by Houston for treatment of essential hypertension, one must first have accurate and complete product information. The preceding clarifications are requisite for labetalol. </p><p>David A. Richards, MD 278 Hills Road </p><p>Cambridge CB2 2QE, UK Dan Mitchell, PharmD </p><p>Mark A. Sirgo, PharmD Glaxo Inc </p><p>Five Moore Drive PO Box 13438 </p><p>Research Triangle Park, NC 27709 </p><p>REFERENCES </p><p>1. Houston MC. New insights and new approaches for the treat- ment of essential hypertension: selection of therapy based on coronary heart disease risk factor analysis, hemodynamic pro- files, quality of life, and subsets of hypertension. AM HEART J 1989;117:911-51. </p><p>2. Lund-Johansen P. Exercise and antihypertensive therapy. Am J Cardiol 1987;59:98A-107A. </p><p>3. Lund-Johansen P. Short- and long-term (six-year) hemody- namic effects of labetalol in essential hypertension. Am J Med 1983;75:24-31. </p><p>4. Mehta J, Cohn JN. Hemodynamic effects of labetalol, an al- pha and beta adrenergic blocking agent, in hypertensive sub- jects. Circulation 1977;55:370-5. </p><p>5. Holtzman JL, Finley D, Johnson B, et al. The effects of sin- gle-dose atenolol, labetalol, and propranolol on cardiac and vascular function. Clin Pharmacol Ther 1986;40:268-73. </p><p>6. Koch G. Haemodynamic adaptation at rest and during exer- cise to long-term antihypertensive treatment with combined alpha- and beta-adrenoceptor blockade by labetalol. Br Heart J 1979;41:192-8. </p><p>7. Mehta J, Feldman RL, Marx JD, et al. Systemic, pulmonary, and coronary hemodynamic effects of labetalol in hyperten- sive subjects. Am J Med 1983;75:32-9. </p><p>8. Johnson LL, Cubbon J, Escala E, et al. Hemodynamic effects of labetalol in patients with combined hypertension and left ventricular failure. J Cardiovasc Pharmacol 1988;12:350-6~ </p><p>9. Rohlfing JJ, Brunzell JD. The effects of diuretics and adren- ergic-blocking agents on plasma lipids. West J Med 1986; 145:21-8. </p><p>10. Pagnan A, Pessina AC, Hlede M, et al. Effects of labetalol on lipid and carbohydrate metabolism. Pharmacol Res Commun 1979;11:227-36. </p><p>11. McGonigle RJS, Williams L, Murphy MJ, et al. Labetalol and lipids [Letter]. Lancet 1981;1:163. </p><p>12. Kochar MS, Barboriak JJ, Tyson J, et al. Effect of beta block- ers and converting enzyme inhibitors on serum lipids. Adv Ther 1984;1:370-5. </p><p>13. Hylander B, Eliasson K, Nilsson-Ehle P, et al. Effects of long- term therapy with labetalol on lipoprotein metabolism in pa- tients with mild hypertension. Acta Med Scand 1985;218: 51-4. </p></li><li><p>Vo lume 119 </p><p>Number 6 Letters to the Editor 1447 </p><p>14. Novo S, Giamporcaro A, Davi G, et al. Chronic administration of labetaloI in hypertensives With chronic heart disease (CHD) does not influence plasma lipid concentrations. Curr Ther Res 1984;36:532-6. </p><p>15. Ponti GB, Carnovali M, Banderali G, et al. Effects of labetalol on the lipid metabolism in hypertensive patients. Curr Ther Res 1983;33:466-71. </p><p>16. Frishman W, Michelson E, Johnson B, et al. Multiclinic comparison of Iabetalol to metoprolol in treatment of mild to moderate systemic hypertension. Am J Med 1983;75: 54-67. </p><p>17. Flamenbaum W, Weber MA, McMahon FG, et al. Monother- apy with labetalol compared with propranolol. Differential ef- fects by race. J Clin Hypertens 1985;1:56-69. </p><p>18. Weber MA, Drayer JIM, Kaufman CA. The combined alpha- and beta-adrenergic blocker labetalol and propranolol in the treatment of high blood pressure: similarities and differences. J Clin Pharmacol 1984;24:103-12. </p><p>19. Sommers DK, DeVilliers LS, Van Wyk M, et al. The effects of labetalol and oxprenolol on blood lipids. S Afr Med J 1981; 60:379-80. </p><p>20. B011i P, Waal-Manning H J, Wood A J, et al. Experience with labetalol in hypertension. Br J Clin Pharmacol 1976; (suppl 3):765-71. </p><p>REPLY </p><p>To the Editor: I appreciate the in-depth review of my recent article 1 by Rich- </p><p>ards et al. detailing their comments on labetalol. Only minor areas of disagreement exist, in my opinion, because of the selection of parts of the article that are interpreted by the "'eyes of the reader" or, as they point out, the limited number of studies that are cited because of the scope of the topic. The points of difference are as follows. </p><p>Hemodynamics. The relative effects of labetalol on blood pres- sure, heart rate. systemic vascular resistance, cardiac output, car- diac index, and stroke volume depend on the method of adminis- tration (intravenous or oral), dosage, relative effects of alpha or beta blockade, position of the patient, whether testing is done at rest or during exercise, preexisting cardiac status and left ventric- ular function, and duration of therapy. At rest in the supine po- sition, with acute intravenous administration, heart rate, cardiac output, cardiac index, and stroke volume are reduced. One study did show a 10% reduction in cardiac output; however, others showed no change. 3, 4 At rest in the standing position, cardiac out- put and stroke volume are significantly reduced, a-6 At rest in the sitting position, cardiac index is reduced 10% to 14% at 1 year. 2 During exercise all hemodynamic variables ~blood pressure, heart rate, and cardiac output} are blunted. 3, 5, 7-1I Cardiac output is sig- nificantly reduced at work loads of 50 and 100 W both with short- term intravenous or oral therapy and chronic oral therapy com- pared with baseline values. 3 Cardiac index was reduced 10% to 14% with exercise at 1 year. 2 Although labetalol does not reduce cardiac output as much as nonintrinsic sympathetic activity (ISA) beta blockers, its standing and exercise hemodynamics remain abnormal for at least the first year of treatment or longer. This may have significance for patients who engage in vigorous aerobic ex- ercise if their exercise is blunted. In addition, the hemodynamic derangements present in essential hypertension are not com- pletely reversed with labetalol. </p><p>Receptor properties. Labetalol is primarily a beta blocker if its overall effects on receptor blockade are reviewed. It was classified this way merely for simplicity in Table XX but was also listed in other ways to note its special characteristics (see Tables XXI and XXIIIA [with alpha-blocking and mild ISA activity]). The beta- </p><p>to-alpha antagonist ratio is 3 to 1 when labetalol is administered orally and 7 to I when it is given intravenously. 12; 13 Clinically one must remember that adverse effects of beta blockade (such as bronchospasm and heart block) may occur with labetalol. </p><p>Lipids and other metabolic parameters. The discussion in the report on lipids is fair and balanced if it is read carefully: Page 929 reads "Labetalol has a neutral or slightly adverse effect on serum lipids and elevates triglycerides." The major effect noted may be a Slight elevation in serum triglycerides 14,15 which may not have reached clinical significance because of the small number of patients studied. 14 I agree with their comments (consistent with my statements) that the effects are neutral or slightly unfavorable. Unfortunately no long-term, prospective, double-blinded, place- bo-controlled studies exist that have an adequate number of pc- tients to properly determine the effects of labetalol on lipids. Se- rum uric acid 16 and glucose TM are increased with labetalol. Serum potassium and magnesium may be increased with nonselective beta blockers by inhibiting potassium influx into cells, 17 especially in patients with impaired renal function, those receiving nonste- roidal anti-infiammatory drugs, Or those who exercise. We have noted this occurrence with labetalol in a few patients and urge caution when this agent is used under these circumstances. </p><p>Mark C. Houston, MD Department of Medicine </p><p>Division of General Internal Medicine Vanderbilt University, Room 2553 TVC </p><p>23rd Avenue and Pierce Street Nashville, TN 37232 </p><p>REFERENCES </p><p>1. Houston MC. New insights and new approaches for the treat- ment of essential hypertension: selection of therapy based on coronary heart disease risk factor analysis, hemodynamic pro- files, quality of life, and subsets of hypertension. AM HEART J 1989:117:911-51. </p><p>2. Luns-Johansen P. Short- and long-term (six year) hemody- namic effects of labetalol in essential hypertension. Am J Med 1983;75:24-31. </p><p>3. Svendsen TL. Rasmussen S. Hartling OJ. Sequential haemo- dynamic effects of labetalol at rest and during exercise in es- sential hypertension. Postgrad Med J 1980:56(suppl 2): 21-6. </p><p>4. Trap-Jensen J, Clausen JP, Hartling OJ. Immediate effects of labetalol on central splanchnic-hepatic and forearm haemo- dynamics during pleasant emotional stress in hypertensive patients. Postgrad Med J 1980:56(suppl 2):37-42. </p><p>5. Koch G. Haemodynamic effects of combined alpha and beta adrenoceptor blockade after intravenous labetalol in hyper- tensive patients with reference to haemodynamic effects at rest and during exercise. Br J Clin Pharmacol 1976;3(suppl 3):725-8. </p><p>6. Koch G. Combined alpha and beta adrenoceptor blockade with oral labetalol in hypertensive patients with reference to haemodynamic effects at rest and during exercise. Br J Clin Pharmacol 1976:3{suppl 3):729-32. </p><p>7. Mehta J, Cohn JN. Hemodynamic effects of labetalol, an al- pha- and beta-adrenergic blocking agent in hypertensive sub- jects. Circulation 1977;55:370-5. </p><p>8. Lammintausta R. Koulu M. Allonen H. Alpha and beta adrenoceptor blocking properties of labetalol in renin release. Int J Clin Pharmacol Biopharm 1979;17:240-3. </p><p>9. Lund-Johansen P, Bakke OM. Haeodynamic effects and plasma concentrations of labetalol during long term treatment of essential hypertension. Br J Clin Pharmacol 1979:7:169-74. </p><p>10. Koch G. Haemodynamic adaptation at rest and during exer- cise to long term antihypertensive treatment with combined aipha and beta adrenoceptor blockade by labetalol. Br Heart J 1979:41:192-8. </p></li></ul>