The Evolution of Antihypertensive Therapy: Current Theoretical Conditions and Individualized Treatment Options MICHAEL A. WEBER, M.D., Long Beach, Ca/tomia

D uring the past two decades, there has been a radical shift in our concepts of hypertension

therapy. As Hollenberg notes in “Evolution of the Treatment of Hypertension: What Really Matters in the 199Os?” we have progressed from a highly structured stepped-care approach to a more indi- vidualized approach to treatment. In the 1970s the Joint National Committee on Detection, Evalua- tion, and Treatment of High Blood Pressure recom- mended a distinct stepped-care approach to treat- ment. At the time, treatment options were limited to a few available drugs, with thiazide-type diuret- ics as the drug of choice [l-3].

As the number of drug choices expanded, how- ever, physicians began to adjust the treatment to the individual patient’s needs [4,5]. Additionally, demographic data such as age, race, and gender proved less helpful, and concurrent medical prob- lems-such as coronary artery disease, diabetes mellitus, renal dysfunction, chronic obstructive pul- monary disease (COPD), asthma, or anxiety- became significant factors in selecting an individu- alized treatment for hypertension [6].

The actual intent of antihypertensive treatment, however, is reduction of morbidity and mortality. Thus, we have begun to consider left ventricular hypertrophy (LVH), obesity, hyperlipidemia, and insulin resistance as additional risk factors in hy- pertension [6]. Indeed, it may be appropriate to start viewing hypertension as an inherited syn- drome rather than a chance gathering of metabolic and cardiovascular abnormalities [7].

There is also an interesting relationship between hypertension and kidney disease: the kidney is af- fected by hypertension and may also cause hyper- tensive disease [8]. Further, traditional antihyper- tensive therapy has been effective in controlling hypertension, but has not satisfactorily reduced mortality from renal disease, which may be a result

From the Department of Medicine, California College of Medicine, Unwersity of California, Irvme, Caltfornla, and the Veterans Admrnistratlon Medical Center,

Requests for reprints should be addressed to Michael A. Weber, M.D., Sec- tion of Clinical Pharmacology and Hypertenston, VA Medical Center (W-130) 5901 East 7th Street, Long Beach, California 90822

of nonphysiologic methods of blood pressure control [g-11]. As Weir discusses, renal blood flow and glo- merular filtration rate both decrease with age [ll]. The decline may be even more aggravated in cer- tain groups such as diabetics, black patients, the elderly, or those with preexisting renal disease.

The kidneys, therefore, may require more spe- cific methods of blood pressure control that also reduce the risk of renal damage [ll]. Short-term studies show that both angiotensin-converting en- zyme (ACE) inhibitors and calcium channel block- ers have some efficacy in slowing the progression of renal disease in hypertensives with concomitant renal disease or diabetes mellitus, but there are conflicting data in this regard with calcium channel blockers [12-181. ACE inhibitors may also reduce urinary protein excretion in hypertensive patients with concomitant diabetes [19]. The nondihydro- pyridine calcium channel blockers (diltiazem and verapamil) also reduce proteinuria 120,211, but the dihydropyridine nifedipine increases proteinuria in hypertensive patients with concomitant renal dis- ease and diabetes [22]. On the other hand, nicar- dipine, another dihydropyridine calcium channel blocker, tends to reduce both proteinuria and blood pressure [23]. Clearly, further research is required to resolve these apparent inconsistencies.

Similarly, LVH is a risk factor for cardiovascular morbidity and mortality that is independent of hy- pertension [24,25]. As Messerli and Soria discuss, LVH can be reduced by antihypertensive therapy, although not all drugs will act with equal effective- ness 1261. ACE inhibitors, methyldopa, and calcium channel blockers, in general, appear to be effective in causing regression of LVH [27,28]. There tends to be a lesser effect with other drug classes. It is not clear, however, whether this action of antihy- pertensive drugs on the left ventricle produces clin- ical benefits.

Resnick has investigated the cellular basis that links hypertension, LVH, obesity, and noninsulin- dependent diabetes mellitus (NIDDM), specifically studying levels of cytosolic free calcium and free magnesium in these conditions [29]. He has noted the association between increased intracellular cal- cium, decreased intracellular magnesium, and such

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characteristics of hypertension as insulin resistance reduction of cardiovascular risk. Thus, considera- and altered cardiac structure. Resnick’s data sug- tion of concomitant medical conditions in addition to gest an ionic hypothesis of cardiovascular and meta- other risk factors now makes it possible to individu- bolic disease: the separate clinical syndromes of alize therapy for essential hypertension and pro- hypertension, obesity, and NIDDM may only be vide the hypertensive patient with a better toler- different pathophysiological manifestations of the ated and more effective therapy, with potential same underlying cellular defect [291. benefits beyond reduction of blood pressure.

Resnick indicates that the accumulation of excess free calcium (with a corresponding deficit of free magnesium) may be reversed with ion-specific agents, such as calcium channel blockers [301. These drugs may ameliorate the other aspects of the hypertensive state in addition to the elevated blood pressure of hypertension.

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REFERENCES

Prisant, Bottini, DiPiro, and Carr discuss novel controlled-release drug-delivery systems [31]. The authors state that these systems (which have been utilized with diltiazem, propranolol, clonidine, ni- fedipine, verapamil, felodipine, and metoprolol suc- cinate) will become more commonplace and have a potential benefit in improving compliance with anti- hypertensive therapeutic regimens.

Graney’s article specifically reviews the pub- lished clinical experience with a new, extended- release formulation of diltiazem HCl,* a calcium channel blocker [32]. Data from these studies indi- cate that administration of this once-daily formula- tion of diltiazem effectively lowers systolic and dia- stolic blood pressure in patients with mild-to- moderate essential hypertension. The side-effect profile of this product, Graney noted, was compara- ble to that of placebo in these clinical trials.

1. National High Blood Pressure Education Program. Report to the Hypertension Information and Education Advisory Committee. Task Force I. Data Base. Recom- mendations for a national blood pressure program data base for effective antihyper- tensive therapy. Washington, DC.: U.S. Department of Health, Education and Wel- fare publication NIH 75-593; 1973. 2. Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. JAMA 19n; 237: 255-65.

3. The 1980 Report of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure. Arch Intern Med 1980; 140: 1280-5. 4. The 1988 report of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure. Arch Intern Med 1988; 148: 1023-38. 5. Final report of the 1984 Joint National Committee on Detection, Evaluation and

Treatment of High Blood Pressure. Arch Intern Med 1986; 8: 444-67. 6. Hollenberg NK. Evolution of the treatment of hypertension: What really matters in the 199Os! Am J Med 1992:93(Suppl 2A):4-10. 7. Weber MA. Cardiovascular and metabolic characteristics of hypertension. Am J Med 1991;91 (Suppl 1A): 4S-10s. 8. Klahr S. The kidney in hypertension-villain and vrctim. N Engl J Med 1989; 320: 731-3.

As is noted throughout this supplement, the new direction in treatment options is the emphasis on the need for individualized therapy. As Murphy states, the challenge for the physician is to select the most appropriate first-line agent for a particu- lar patient [33]. Among other factors to be consid- ered are demographic data, concomitant illness, presence of hypertensive target-organ damage, life-style, occupation, and economic status. With regard to concomitant illness, for instance, patients with angina might be given a p blocker or calcium channel blocker as a first-line agent; those with renal impairment might be best treated with a diu- retic; those with heart failure might be prescribed an ACE inhibitor [333. Physicians must also be aware of the metabolic effects of different antihy- pertensive agents, e.g., the detrimental effects of diuretics on glucose, lipid, and electrolyte homeo- stasis [34]. Or as Hollenberg points out, both the elderly and blacks may be most responsive to cal- cium channel blockers and diuretics, although this remains controversial 161.

9. Kannel WB, Sorlie P. Hypertension in Framingham. In: Paul 0, ed. Epidemiology and control of hypertension. Miami: Symptosis Specialist, 1975; 553-92. 10. Multiple Risk Factor Intervention Trial Research Group. Risk factor changes and mortality results. JAMA 1982; 248: 1465-77. 11. Weir MR. Hypertensive nephropathy: Is a more physiologic approach to blood pressure control an important concern for the preservation of renal function? Am J Med 1992;93 (Suppl 2A):27-37. 12. Ruilope LM, Miranda B, Morales JM, Rodicio JL, Romero JC, Raij L. Converting

enzyme inhibition in chronic renal failure. Am J Kidney Dis 1989; 13: 120-6. 13. Marre M, LeBlanc H, Suarez L, et al. Converting enzyme inhibition and kidney function in normotensive diabetic patients with persistent microalbuminuria. Br Med J 1987; 294: 1443-52. 14. Parving HH, Hommel E, Smidt UM. Protection of krdney function and decrease in albuminuria by captopril in insulin-dependent diabetics with nephropathy. Br Med J 1988; 297: 1086-91. 15. Bjork S, Nyberg G, Mulec H, Granerus G, Herlitz H, Aurell M. Benefictal effects of angiotensin-converting enzyme Inhibition on renal function in patients with diabetic nephropathy. Br Med J 1986; 293: 471-4. 16. Eliahou HE, Cohen D, Helberg B, et al. Effect of the calcium channel blocker nisoldipine on the progression of chronic renal failure in man. Am J Nephrol 1988; 8: 285-90.

The real goal of antihypertensive therapy is the

17. Herlitz H, Nyberg G, Granerus G, et a/. Effects of felodipine in patients wrth refractory hypertensron and progressive renal disease. Stand J Urol Nephrol 1988; 108 (Suppl): 31-4. 18. Ambroso GC, Como G, Scalamogna A, et al. Treatment of arterial hypertension with nifedipine inpatients with chronic renal insufficiency. Clin Nephrol 1985; 23: 41-3. 19. Keane WF, Anderson S. Aurell M, eta/. Angiotensin converting enzyme inhibitors and progressive renal insufficiency. Ann Intern Med 1989; 111: 503-16. 20. Bakris GL. Effects of diltiazem or lksrnopril on massive proteinuria associated with diabetes mellitus. Ann Intern Med 1990; 112: 707-8. 21. Barnhrll N, Bakris GL. The combined effects of verapamil and lisinopril on urinary protein excretion in diabetic nephropathy. (Abstr.) J Am Sot Nephrol 1990; 1: 304. 22. DeMane ET, Bakris GL. Effects of different classes of calcium antagonrsts on proteinuria in diabetic subjects. Ann Intern Med 1990; 113: 987-8. 23. Baba T, Murabayshi S, Taskebe K. Comparison of the renal effects of angiotensin

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converting enzyme inhrbitor and calcium antagonist In hypertensive type 2 (non- insulin-dependent) diabehc patients with microalbummuna: a randomized controlled trial. Diabetologra 1989; 32: 40-4. 24. Kannel WB. Prevalence and natural hrstory of electrocardrographic left ventricu- lar hypertrophy. Am J Med 1983; 75 (Suppl 3A): 4-11. 25. Kannel WB, Gordon T, Castelli WP, Margolis JR. Electrocardiographic left ventric- ular hypertrophy and risk of coronary heart drsease. Ann Intern Med 1970; 72: 813-Z. 26. Messerli FH, Soria F. Hypertension, left ventricular hypertrophy, ventricular ec. topy, and sudden death. Am J Med 1992;93 (Suppl 2A): 21-6. 27. Cruickshank J, Messerli FH. Reverstbrlity of left ventricular hypertrophy. Clan Sci 1992. Submitted for publicatron.

28. Crurckshank JM, Lewis J, Moore V, Dodd C. Reversibility of left ventricular hyper- trophy (LVH) by different types of antihypertensive therapy. Lancet 1992. Submitted for publication.

29. Resnick LM. Cellular calcium and magnesium metabolism in the pathophysiol- ogy and treatment of hypertension and related metabolic disorders. Am J Med 1992; 93 (Suppl 2A): 11-20. 30. Resnick L, Nicholson J, Laragh J. Calcium, the renin-angiotensin system, and the hypotensive response to nifedipine. Hypertension 1987; 10: 254-8. 31. Prisant LM, Bottini PB, DrPrro JT, Carr AA. Novel drug delivery systems for hypertension. Am J Med 1992; 93 (Suppl 2A): 45-55. 32. Graney WF. Clinical experience with a once-daily, extended-release formulation of dilttazem in the treatment of hypertension. Am J Med 1992; 93 (Suppl 2A): 56-64. 33. Murphy MB. Selecting optimum antihypertensive therapy: indications for choos- ing a calcium channel blocker. Am J Med 1992; 93 (Suppl 2A): 38-44. 34. Murphy MB, Lewis PJ. Kohner E. Schumer B, Dollery CTG. Glucose intolerance in hypertensive patients treated wrth diuretics: a fourteen year follow-up. Lancet 1982; ii: 1293-5.

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