A practical management of hypertension

THE PRACTICAL MANAGEMENT OF HYPERTENSION EDWARD D. FROHLICH

Editorial Board. Robert A. O’Rourke, J. Leonard.

EDITOR’S

Seated, W. Proctor Harvey, William C. Roberts, Frank

Antonio C. de Leon. Standing, I. Marcus. Not pictured, James

PREFACE

Hypertension unquestionably is one of the most important problems of cardiology today. Fortunately, it is probable that hypertension is controllable in most patients, and therefore complications may be prevented. As discussed in the July issue of CURRENT F'ROBLEMS IN CARDIOLOGY (Prevention of Cardiovascular Disease, by William B. Kannel), the message is clear that there is a great need for early diagnosis and treatment of hypertension. As pointed out by Doctor Frohlich in the present discussion, treatment of hypertension means, for many, a lifelong commitment on the part of the patient as well as the physician. The author has approached this subject in a very organized and logical fashion, stressing a careful evaluation of the patient by the history, physical examination, electrocardiogram, x-ray and laboratory studies; the pathophysiologic concepts of hypertension related to vascular and cardiac diseases are important in understanding the patient’s hypertension, which, in turn, have a direct relationship to selection of the proper management. His discussion provides the rationale for the use of various diagnostic procedures of the hypertensive work-up and the selection of specific drugs needed for effective treatment. This is in contrast to the frequent empirical use of drugs in treatment of hypertension without the understanding of the basic pathophysiology and

2

pharmacology of drugs used. When one thinks of the great advances in the effective drug treatment of hypertension in the past three decades, it has literally been miraculous, progressing from surgical sympathectomy, which formerly was in vogue as one of the most accepted methods of treatment. I well remember Ed Frohlich when he was a medical student; first, when he was a summer Fellow at Georgetown University Hospital and the National Heart Institute. At that time, he was privileged to be under the special tutelage of the late Dr. Robert Grant of the National Heart Institute. This was a “special treat” for Ed Frohlich, providing him with an initial stimulus for investigation and a career in cardiovascular diseases. Subsequently, he was a member of our house staff here at Georgetown University Hospital. It is always a pleasure to see physicians such as Ed perform so ably in their subsequent medical careers. W. PROCTORHARVEY

TABLE

OF CONTENTS

A NEW CONCEPT OF THE HYPERTENSIVE THE HYPERTENSION CLASSIFICATION

PROBLEM

AND DEFINITIONS

OF HYPERTENSIVE

MANIFESTATIONS

.

.

.

.

.

9

.

.

.

.

13

.

15

DISEASES .

CLINICAL AND PHYSIOLOGIC RATIONALE WORK-UP OF HYPERTENSION . CLINICAL

DISEASES

FOR THE DIAGNOSTIC . . .

OF HYPERTENSIVE

DISEASE .

DISEASES COMPLICATING SYSTEMIC HYPERTENSION ANTIHYPERTENSIVE THERAPY . . . . . SUMMARY

.

.

.

.

.

.

.

.

19 36

.

41 44

.

51

SELF-ASSESSMENT

QUESTIONS

1. A 34-year-old woman with 4 children presently receiving oral contraceptives is referred with an elevated arterial pressure. There is no family history of hypertension. She had urinary tract infections as a child and during pregnancy. Her only symptoms are severe headaches and apparently easy fatigability. Which of the following causes of hypertension would you consider possible in this patient? a. Essential hypertension. b. Renal parenchymal disease. c. Renal arterial disease. d. Oral contraceptives. e. All of the above. 2. A 38year-old woman presents with a history of hypertension of 5 years’ duration, muscle weakness and nocturia. Physical examination reveals a blood pressure of 184/112, heart rate 88, with occasional ectopic beats; mild arteriolar constriction of her optic fundi; and no other significant findings. CBC reveals a hematocrit of 39% and white count of 7000. Urinalysis reveals specific gravity of 1.012 and pH of 7.5. Plasma renin activity, obtained with upright posture and after an overnight fast, was of barely detectable levels. Which of the following other laboratory results would be consistent with this history? a. Abnormal carbohydrate tolerance. b. Increased serum aldosterone level. c. Expanded plasma volume. d. Hypokalemic alkalosis. e. All of the above. 3. Which of the following hemodynamic alterations results in a decrease in mean arterial blood pressure (other conditions remaining constant)? a. Elevated cardiac output with increased viscosity of the blood. b. Increased blood viscosity with decreased net length of blood vessels. c. Decreased arteriolar vessel radius with increased output of blood by the left ventricle. d. Peripheral vasoconstriction combined with decreased venous return. e. Diminished net vascular tone together with hemodilution. 4. The ideal antihypertensive agent should: a. Reduce arterial pressure coincident with a reduced cardiac output and total peripheral resistance. b. Reduce arterial pressure coincident with reduced total peripheral resistance and minimal cardiac stimulation. c. Reduce arterial pressure and total peripheral resistance but increase cardiac output. d. Reduce arterial pressure, cardiac output and total peripheral resistance. e. None of the above. 5. Of the following circulating substances, which serve(s) to increase vascular resistance? a. Norepinephrine. b. Ionized serum calcium. c. Vasopressin. d. Angiotensin II. e. All of the above. 6. Of the following, which constellation of laboratory findings is best consistent 5

with the diagnosis of primary aldosteronism in a patient receiving no medications? a. JNa, J K, JCO,, TurinepH. b. TNa, J K, t CO,, turine pH, $ PRA. c. Normal Na, J K, normal CO,, t urine pH, t PRA. d. Normal Na, J K, TCO,, turine pH, JPRA. e. None of the above. Serum potassium concentration is an important laboratory study for the initial evaluation of the patient with hypertension. Which of the following hypertensive diseases may be associated with hypokalemia? a. Essential hypertension treated with thiazides or furosemide. b. Malignant hypertension. c. Renal arterial disease. d. Pheochromocytoma. e. Renal parenchymal disease. When ordering a laboratory determination of peripheral plasma renin activity, which of the following factors should be considered? a. Time of day and posture of patient. b. Use of estrogen-containing pills. c. Use of antihypertensive drugs. d. Dietary restrictions. e. All of the above. A 54-year-old man has consulted you for evaluation and treatment of hypertension. He has had an elevated arterial pressure for many years, for which he has not been evaluated or treated. His mother, father and two brothers had hypertension. His father died at age 48 of a myocardial infarction; his mother had a stroke at age 56. Both brothers had severe coronary arterial disease; one died at age 51 of a stroke. On physical examination, blood pressure is 224/ 116 mm Hg and heart rate is 88 beats per minute. Funduscopic examination reveals grade 2 generalized and focal constriction, arteriovenous nicking, but no hemorrhages or exudates. Cardiac examination reveals a sinus rate and rhythm, left ventricular lift, a fourth heart sound and a grade 1 precordial ejection-type systolic murmur. There were no arterial bruits heard. The immediate office evaluation should include: a. Hemogram. b. Blood chemistries, including serum potassium, uric acid, sugar, creatinine and lipids. c. Chest x-ray. d. Electrocardiogram. e. Intravenous pyelogram. Outpatient treatment of the above patient might include: a. Hydrochlorothiazide 50 mg daily in the morning, with instructions to return in 1 month’s time. b. Reserpine 0.25 mg b.i.d., with instructions to return in 1 week. c. Hydrochlorothiazide 50 mg and methyldopa 250 mg, each taken twice daily, with instructions to return in 1 week. d. Diazoxide 300 mg rapidly by vein and methyldopa 250 mg q.i.d. by mouth, with instructions to return in 1 week. e. None of the above. In addition to the above historical features, the patient presents a history of decreased exercise tolerance. ankle edema at the end of the dav. an awareness of skipped heartbeats and recent appearance of nocturia. Physical examination, in addition to the above findings, includes four to five ectopic beats

7.

8.

9.

10.

11.

6

per minute, a third heart sound, a pulsus alternans, but clear lung fields. Which antihypertensive drugs are not indicated to reduce pressureat least immediately? a. Thiazide diuretic. b. Hydralazine. c. Diazoxide. d. Methyldopa. e. Propranolol. 12. Instead of the conditions described in the preceding question, this man presents to the emergency room with severe chest and back pain, some shortness of breath and a rapid heart rate (112 beats per minute) with frequent ectopic beats. Blood pressure is 224/126 mm Hg. ECG revealed ST-segment deviation, urinalysis microscopic hematuria and the chest x-ray has not been reported. Which drugs might be useful for immediate use under these circumstances? a. Propranolol, 5 mg (I.V.1. b. Methyldopa, 500 mg (p.0.). c. Reserpine, 1.0 mg KM.). d. Sodium nitroprusside (IV. infusion). e. Trimethaphan camsylate (IV. infusion) 13. Of the following clinical circumstances, which may precipitate angina pectoris? a. Persistent diastolic pressure >130 mm Hg without evidence (by arteriography) of occlusive coronary arterial disease. b. Rapid reduction of arterial pressure with intravenous therapy from levels of 140 mm Hg to 100 mm Hg in a 50-year-old man with only left ventricular hypertrophy on pretreatment electrocardiogram. c. Intravenous d&oxide (300 mg) in a patient with known symptomatic coronary arterial disease. d. Hydrochlorothiazide (50 mg twice daily) and hydralazine (50 mg three times daily) by mouth in a 50-year-old man with known symptomatic coronary arterial disease. e. All of the above. Answers on p. 56.

is Vice President, Education and Research at the Alton Ochsner Medical Foundation and Head, Division of Hypertensive Disease at the Ochsner Clinic. He is also Clinical Professor of Medicine and Adjunct Professor of Pharmacology at Tulane Universitv and Clinical Professor of Physiology and Medicine at Louisiana State University. Doctor Frohlich received his M.D. degree from the University of Maryland School of Medicine and later obtained an M.S. in physiology from Northwestern University. After serving at the U.S. Army Medical Research Laboratory at Fort Knox, he served on the faculty of Northwestern University Medical School and the Veterans Administration Research Hospital, Chicago, later joining the staff of the Cleveland Clinic and its research division. In 1969 he established a Division of Hvoertension in the Department of Medicine at the University of Oklahoma Health Sciences Center. Internationally recognized for his work in experimental and clinical forms of hypertension, Dr. Frohlich is a member of numerous professional organizations.

A NEW CONCEPT

OF THE HYPERTENSIVE

DISEASES

HYPERTENSION: PREVENTIVE CARDIOLOGY. -Over the past several decades the practice of medicine-and, more specifically, of cardiology-has evolved through several phases. First, our leading clinicians progressed through a phase of description and classification of disease. This era was associated with development of astute physical diagnostic methods, radiographic technics and ultimately the availability of the diagnostic tools of cardiac catheterization. Means were made available for the clinician to define rather precisely the site and extent of cardiovascular lesions. It therefore was of extreme necessity that the clinician have available to him improved therapeutic modalities; these permitted the movement from the initial diagnostic era of clinical medicine to a succeeding era of remarkable improvements in therapy. During these years we have seen the very dramatic technics of cardiac and vascular surgery come into their own-cardiopulmonary bypass, open heart surgery, artificial grafts; we passed into the therapeutic era. From a pharmacologic point of view, we have witnessed the introduction of new NOTE: This work was Heart and Lung Institute

supported (HL-16478).

in part

by a grant-in-aid

from

the

National 9

therapeutic agents such as anticoagulants, antibiotics, antiarrhythmics, diuretics and the antihypertensives. With the introduction of these compounds, it became possible to treat effectively heretofore untreatable cardiovascular problems such as thromboembolic disease, arrhythmias, endocarditis, congestive heart failure and hypertension (to name but a few). Eventually, a new concept of therapeutic prophylaxis of cardiovascular disease came into its own. We learned that it was possible to minimize the anticipated frequency of problems from pulmonary embolism, rheumatic and congenital heart diseases, fatal cardiac arrhythmias and the target organ effects of hypertension. This, then, has led to the present era of preventive cardiology. This current era of preventive cardiology perhaps is the most difficult of the three for the practicing physician to comprehend completely. In part, this is because during the previous two eras-indeed, for the many hundreds of years prior to this age of modern medicine-the active practitioner was constantly attuned to “crisis” medicine. With the large numbers of patients seen daily, he was forced to pay maximal attention to those patients whose problems could be attended to and resolved effectively and quickly; chronic illness and the prevention of insidious disease processes played but a minor role in this busy practice. Hence, attention was devoted to the patient with acute pulmonary edema, life-threatening treatable arrhythmias, myocardial infarction, acute stroke, emergent infectious processes and so forth. As hypertension became treatable, interest naturally was directed to the treatment of hypertensive emergencies and the “surgically curable” hypertensions. But despite the recent reports, including a study by the American College of Cardiology, indicating that 95% of all patients seen by the cardiologist had either hypertension and/or noninfarction coronary arterial disease, most patients with hypertension remain unattended to and untreated. Thus, the time has arrived for the cardiologist to take a new and enlightened view of the patient with an elevated systemic arterial pressure. He must consider that each patient in his twenties, thirties and forties with an elevated arterial pressure is the potential patient of the forties, fifties and sixties with target organ functional impairment from the prolonged elevation of arterial pressure of earlier years. This is the patient who will return years later with congestive heart failure, stroke, myocardial infarction and renal failure, and who is forced to retire from our economy prematurely because effective therapy was not made available years earlier. The challenge of preventive cardiology is here; the modern cardiologist has no recourse but to accept this challenge and to deal with it as effectively as he did with the challenges of the previous two eras of diagnostic and therapeutic advances! 10

HYPERTENSION: A SIGN OF NONHOMOGENEOUS DISEASES. - During this dramatic increase in the sophistication of the practice of cardiology and medicine, we have come to understand that disease characterized by ,.elevated body temperature is not to be diagnosed as just “fever” and that disease characterized by hypotension is not to be diagnosed as just %hock.” We are well aware. that included among the febrile diseases are conditions associated with hypermetabolism (e.g., thyrotoxicosis), abnormal exposure to elevated environmental temperature (e.g., heat stroke) and the unlimited number of infectious agents. Each of these conditions is treated rather specifically. Indeed, even the infectious diseases are not considered homogeneously; the physician uses his diagnostic technics to select appropriate microbial agents rather specifically. Similarly, of the variety of conditions that comprise the life-threatening condition we call “shock,” we now realize that hypotension resulting from anaphylaxis, hemorrhage, myocardial infarctions, gram-negative sepsis, etc., is also approached therapeutically by rather specific means. The net result from these rather enlightened approaches is the improvement of yesterday’s very disappointing morbidity and mortality statistics to the more encouraging data of today and, hopefully, to still better prospects for the future. Just as the above rationale for the approach of febrile and hypotensive diseases seems justifiable for the modern-day practice of medicine, it is equally reasonable to consider the hypertensive diseases as a nonhomogeneous clinical grouping. Thus, we have found it most useful to consider, from a variety of physiologic pressor mechanisms (operative in all human beingsnormotensive or not), which mechanism seems to be participating most in the maintenance of the elevated arterial pressure in a particular patient. There are a variety of mechanisms (including mechanical obstruction to the forward flow of blood, adrenergic neural function, catecholamines, renopressor system, hormones, fluid volume and possibly even the absence of certain depressor mechanisms) that serve to regulate arterial pressure in man. In some of the hypertensive diseases having specific causes (i.e., aortic coarctation, renal arterial disease, renal parenchymal disease, pheochromocytoma, adrenal cortical tumors producing specific steroidal hormonal excess, etc.), these pressor mechanisms are readily identified. However, in the majority of patients with hypertension, the cause is not identifiable (patients with essential hypertension). Nevertheless, in these latter patients the mechanisms subserving their elevated arterial pressure can be identified clinically, and specific antihypertensive therapy thus can be “wedded” to that patient’s altered physiologic state. Indeed, as newer (and more specific) antihypertensive drugs become available, this will be the precise means that will be used to select therapy. Thus, not all patients 11

treated with beta-adrenergic blocking drugs will respond to these compounds alone -but some will; not all patients will respond to drugs that will inhibit the release of renin from the kidney and the subsequent generation of angiotensin II- but some will; not all patients will respond to vigorous contraction of the extracellular fluid volumes-but some will; not all patients will respond to drugs that inhibit adrenal steroidal biosynthesis - but some will; and so forth. To be sure, the practice of medicine today as it relates to the treatment of the patient with hypertension seems rather straightforward. It is most reasonable for the physician to realize that the severe morbidity and mortality statistics resulting from persistently elevated arterial pressures can be reduced dramatically with rather nonspecific and persistent reduction of arterial pressure. To satisfy this important public health need, the “stepped-care” or standard treatment protocol advocated for the treatment of hypertension has been most successful. Indeed, if the practicing physician is more comfortable with this therapeutic approach to hypertension, he should continue to use this approach; the important thing (about which there is no controversy) is that all patients with persistently elevated arterial pressure should be brought under effective antihypertensive treatment. And, most important, such patients should remain on a treatment program indefinitely so that arterial pressure remains under excellent control. Nevertheless, even if the physician follows this standard “stepped-care” approach to therapy, he should realize that the patients so treated are actually, in an empirical fashion, demonstrating suppression of the commonly participating pressor mechanisms of hypertensive diseases: volume control (e.g., diuretics), adrenergic suppression (e.g., reserpine) and vascular smooth muscle tone relaxation (e.g., vasodilator). As with most therapy prescribed today (which also may seem to be empirical), clinical investigators many years earlier had demonstrated safety, efficacy and rationale of suppressing the abnormally participating disease mechanisms (e.g., insulin in diabetes mellitus, antacids and antispasmodics in peptic ulcer, bronchodilators in asthma, thyroid replacement in hypothyroidism, etc.). Note that in most of these clinical problems the specific causes of these diseases are also unknown. The following discussion, therefore, will concern itself with the definition of the hypertension problem, its classification, magnitude and association with other diseases; the diagnostic evaluation of the patient with hypertension; the clinical manifestations and pathophysiologic alterations of hypertensive cardiovascular disease; and the clinical pharmacology and therapy of hypertension. 12

THE HYPERTENSION

PROBLEM

AND DEFINITIONS

The term hypertension, as used in this discussion, refers to an abnormally elevated systemic arterial pressure, and herein lies the first bit of controversy. At what level is arterial pressure abnormal? Life insurance actuarial data have shown that the higher the arterial pressure -systolic or diastolic - the greater will be the morbidity and mortality of the population.’ There is no specific level above which this mortality suddenly takes an abrupt upward swing; the relationship between pressure and death or morbid events is linear. This same relationship was demonstrated in prospective epidemiologic studies such as that carried out with the entire population of the city of Framingham, Massachusetts.2 Thus, those patients who had the greatest prevalence of sudden death, myocardial infarction, angina pectoris and stroke were the patients with the highest arterial pressure, and the higher the pressure the greater was the attack rate. These findings were confirmed for both the systolic and the diastolic pressure, and the applicability was the same for men as for women, although women seemed to have a later relationship with respect to age; perhaps they were able to withstand a specific level of arterial pressure somewhat better than could a man. However, a specific level of arterial pressure seems to be necessary for the definition of hypertension so that above that level clinical evaluation and treatment may be indicated for a specific patient. With this point of view, it is of some interest to consider a 35year-old man with no specific organ functional impairment other than an elevated arterial pressure. Should his arterial pressure be “normal,” life insurance actuarial tables would project that he would be expected to live until 711/2 years; however, should his pressure be 130/90 mm Hg, his life expectancy would be diminished by 4 years. Furthermore, should his pressure be 140/95 mm Hg, his projected life span would be reduced by 9 years, and if his pressure were 150/100 mm Hg (a pressure still lower than that recommended by the High Blood Pressure Education Program for treatment), he would lose l6V2 years from his expected 711/2 years of life. Thus, just these mildly elevated arterial pressures (even below levels presently not strongly recommended for antihypertensive treatment) are associated with a frightening reduction of life span. The life insurance companies assume a greater financial risk with individuals whose systolic arterial pressure levels are above 140 mm Hg and diastolic pressures of 90 mm Hg; it is for this reason that many authorities in the United States advocate antihypertensive therapy at pressures in excess of 140/90 mm Hg. Data from the Framingham study were tabulated within the frame of reference of the World Health Organization, which 13

defined the earliest stage of hypertension at 95 mm Hg (Stage I). These groups therefore defined hypertension at diastolic arterial pressure levels in excess of 95 mm Hg. However, even in the Framingham studies, patients whose arterial pressure fell between 140 and 160 mm Hg systolic and 90 and 95 mm Hg diastolic had significantly higher morbidity and mortality rates than subjects whose arterial pressure was less than 140/90 mm Hg. The patients with arterial pressure levels of 140 to 160/90 to 95 mm Hg were said to have “borderline” hypertension. This term is specifically used in this context, but the term “borderline hypertension” has been used by other investigators to mean “labile hypertension” (a term that generally is used to connote the finding of normal arterial pressures in a patient at some times and pressures in excess of 140190 mm Hg at other times). In recent years, “significant hypertension” has been defined as that level of arterial pressure above which antihypertensive therapy should be strongly recommended. This has received its greatest support from the United States High Blood Pressure Education program; and the level of arterial pressure above which therapy is recommended is 105 mm Hg.3 The explanation for this selection of pressure level is also of some interest. The immediate event (historically) that had the greatest impact in the establishment of this public health educational program was the publication of results from the Veterans Administration cooperative studies on hypertension.4-6 These studies, in brief, showed that patients whose arterial pressures were in excess of 90 mm Hg and who were treated with antihypertensive agents had a far better prognosis (with respect to cardiovascular morbidity and mortality) than a randomly selected, matched group of patients who were not treated with active antihypertensive therapy. However, because there were few patients included in this study who were in their third and fourth decades and who had initial diastolic pressures (prior to therapy) between 90 and 104 mm Hg, it was deemed advisable to base the broader public health recommendations for antihypertensive therapy at levels above 104 mm Hg-thus, the recommendation of 105 mm Hg.3 To help him appreciate the alarming magnitude of the hypertension problem, the physician should be aware of another astounding epidemiologic fact. Recent data demonstrate that 54% of all deaths in the United States are directly attributable to diseases of the cardiovascular system, and the two most prevalent cardiovascular diseases in this country are atherosclerosis (and coronary heart disease) and arterial hypertension.7 With this information in mind, and with the knowledge that systemic arterial hypertension is the most common and preventable major risk factor underlying coronary (atherosclerotic) arterial disease, it is not surprising that considerable emphasis has been directed to the problem of detection and treatment of patients 14

with arterial hypertension. Furthermore, public health statistics also have shown that approximately 20% of our population have pressures in excess of 140/90 mm Hg, and that there are in excess of 23 million Americans today with arterial hypertension.3p 8 Thus, we are dealing with a major health problem of epidemic proportions, and the problem is of no less importance in other nations. Indeed, hypertension has drawn the attention of the World Health Organization, and major clinical studies and nationwide education programs are being actively pursued in many nations in Western and Eastern Europe, Scandinavia and Latin America, as well as in Australia, Japan, New Zealand and the Middle East. Peoples of all races are severely affected, but data seem to indicate that the prevalence is greater in the black and possibly the yellow races. Studies in the United States seem to indicate that the prevalence may be several times greater in the black population than in the white. The explanation for these findings is not yet at hand, although some suggest that this may be on the basis of dietary sodium intake. Certainly this seems to offer some explanation in the Japanese population, in whom the northern population has a significantly higher sodium intake than the southern population, and the northern Japanese with higher sodium intake have a higher prevalence of hypertension. One remarkable finding is the very strong association of hypertension with other diseases. We already have alluded to the close association of hypertension with atherosclerosis, coronary heart disease and sudden death. The precise reasons for this remain unknown, but several theories have been suggested, including explanations on the bases of altered hemodynamics of the hypertensive circulation and the possibility of lipid infiltration of the vessel wall associated with the increased intraluminal pressure.‘O Many studies have shown the coexistence of diabetes mellitus, hyperuricemia, gout and hyperlipidemias with arterial hypertension,” and these clinical observations have great relevance in the evaluation of patients with hypertension and in the selection of antihypertensive therapy.

CLASSIFICATION

OF HYPERTENSIVE

DISEASES

Traditionally, the hypertensive diseases have been subdivided into two basic groups: the secondary hypertensions, included in which are all types of arterial hypertension in which specific causes can be identified, and primary hypertension, in which no cause can be demonstrated (Table 1). The key diagnosis in this classification is “essential” hypertension and two forms thereof, termed “benign” and “malignant” essential hypertension. These diagnoses by themselves require some explanation, because implicit in the terms are actual misrepresentations. First, there 15

TABLE

1. - ETIOLOGIC

CLASSIFICATION

OF

HYPERTENSION

A. Primary (hypertension of undetermined cause) 1. Labile (borderline) 2. “Benign” essential 3. Malignant essential 4. Systolic B. Secondary (related to a cause) 1. Aortic coarctation 2. Renal a. Parenchymal (pyelonephritis, glomerulonephritis, cystic disease, b. Renal arterial (1) Atherosclerotic (2) Nonatherosclerotic (fibrosing) (3) Other (embolic, perinephric, hematoma, etc. 1 c. Renoprival (with kidneys and anephric) 3. Endocrine a. Thyrotoxicosis b. Hyperparathyroidism c. Pheochromocytoma d. Acromegaly e. Adrenal cortical (Gushing’s syndrome and disease, primary aldosteronism, biosynthetic enzymatic defects) f. Oral contraceptives g. Licorice-induced 4. Neural (porphyria, poliomyelitis, increased intracranial pressure, diencephalic syndrome, lead encephalitis, cord transection)

etc.)

is nothing about any of the hypertensive diseases that should be construed as being “benign.” As indicated above, persistently elevated arterial pressure (systolic or diastolic) significantly reduces life span and increases cardiovascular morbidity. Patients with malignant hypertension are destined to die within 1 year if not treated vigorously with antihypertensive drugs. Those patients who have what is termed “benign” essential hypertension have a disease with a better long-term prognosis than malignant hypertension; nonetheless, it is responsible for a major proportion of disability and death in our population today. Second, the term “essential” is a misnomer, contributing nothing to our understanding of the disease. Thus, although physicians presently look on diseases termed “essential” as being idiopathic in origin, the term “essential” as initially introduced by the Germans at the turn of the century referred to the essentiality of the elevated arterial pressure. Nothing about this concept could be further from the truth. Although years ago it was held that the elevated arterial pressure was essential for the perfusion of tissue of the vital organs, this elevated pressure is, in fact, the perpetuating force of the hypertensive disease itself, and the effective reduction and control of this elevated pressure will provide the arresting factor for the unrelenting vascular disease.4-6 Hence, the practicing physician of the 1970s should not be distracted by the attractive-but nonetheless erroneous 16

concept that pressure reduction will only be followed by impairment of organ function. True, antihypertensive drug therapy may be associated with transient impairment of renal function, but this will be only temporary; and if therapy is not maintained, the progression of disease is a certain cause of progressive impairment and eventual failure of renal function. The same argument may be applied to brain and cardiac function. With respect to cardiac function, it is also true that certain antihypertensive drugs may reduce tissue perfusion and provide a negative myocardial inotropic action. However, on the positive side of the therapeutic balance the clinician must use to weigh all factors necessary to arrive at a clinical judgment is the beneficial effect of pressure reduction on the heart. Thus, reduction of arterial pressure, myocardial afterload and myocardial tissue oxygen requirements far outweigh the possible effects of myocardial depletion of catecholamine stores and negative inotropic effects. l2 In recent years we have suggested that an alternative means for classifying hypertensive diseases may be based on the pressor mechanisms involved in the maintenance of the elevated arterial pressure.13-15 As indicated above, many of these mechanisms may be attributed to specific secondary forms of hypertension. This is indicated in Table 2, which details the various known pressor mechanisms and an example of a secondary form of hypertension associated with that particular mechanism. However, it is important to note that associated with each pressor mechanism are other pressor mechanisms that also become secondarily involved in the regulation of arterial pressure. For example, the potent renin-angiotensin pressor system produces severe vasoconstriction; it also stimulates the release of aldosterone from the adrenal medulla and its subsequent physiologic effects on the kidney in producing sodium and water retention and potassium wastage. In addition, angiotensin II has a direct effect on the adrenal medulla to release catecholamines, a positive inotropic effect on the myocardium and a stimulating effect on certain areas in the brain (e.g., area postrema), which serves to increase the adrenergic outflow from the medulla and promote an increase in heart rate, cardiac output, myocardial contractility and vasoconstriction. l6 Another example concerns the circulating catecholamines, which may stimulate the release of renin from the kidney and produce severe arteriolar and venular constriction and a contraction of circulating intravascular volume.17 Still another example is the effect of the adrenal steroidal hormones on the kidney to produce sodium and water retention, expansion of the extracellular fluid volumes and the suppression of plasma renin activity. Each of these primary and secondary pressor mechanisms has direct clinical implications. With respect to the first example concerning the renopressor system, is it any 17

TABLE

2. -CLASSIFICATION

PRIMARY PRESSOR MECHANISMS

OF

CLINICAL

DIAGNOSIS

Mechanical Catecholamines

Coarctation of aorta Pheochromocytoma

Renopressor

Renal

Hormonal

Thyrotoxicosis Hyperparathyroidism

Volume

Neural

arterial

KNOWN PRESSOR

disease

Oral contraceptives Acromegaly, gigantism Cushing’s syndrome or disease Primary hyperaldosteronism Adrenal virilism Hydroxylase deficiencies DOC-tumors Renal parenchymal disease

?Essential hypertension; labile hypertension

Beta-adrenergic circulatory

hyperstate

Porphyria Diencephalic syndrome “‘Most of these pressor mechanisms have been in certain patients with essential hypertension.

wonder that these adrenergic inhibiting antihypertensive drugs are so effective in the treatment of renovascular hypertensioneither through the suppression of plasma renin activity, the inhibition of adrenergic cardiovascular outflow or a combination of these mechanisms? Similar relationships may be made with the other primary and secondary pressor mechanisms and the antihypertensive drugs that may be used to reverse the hypertensive disease process in those instances.ls This same concept, used to explain the maintenance of increased arterial pressure in the secondary forms of hypertension, may also be applied to our understanding of the primary hypertensions. Indeed, our clinical literature during recent years has become concerned with this approach to essential hy18

HYPERTENSIVE MECHANISMS*

IMPLICATED

DISEASES

OTHER PRESSOR

ACCORDING

MbHANISMS

Renopressor Volume, renopressor,

neural

Aldosterone,

neural

volume,

Thyroid, neural Calcium on vascular muscle Renopressor ?

smooth

SPECIFIC

TESTS

Chest x-ray, angiography Urine assay (VMA, catecholamines, metaand normetanephrines) Renal arteriography; immunoassay of plasma renin activity or angiotensin Thyroid function studies Serum calcium; parathormone level Renin; withdrawal HGH

Compounds Volume, Volume, Volume, Volume, Electrolytes,

D, F electrolytic electrolytic electrolytic electrolytic renopressor

17-OH steroids Aldosterone, renin Ketosteroids Corticosteroids 17-OH steroids IVP, urine culture, renal biopsy, renal function studies, measurement of body fluid volumes

Volume,

?renopressor

Hemodynamics; plasma activity; measurement of fluid volumes

?Adenylate

cyclase,

CAMP

?Renopressor shown

TO

to participate

in the

maintenance

Hemodynamics; infusion Porphobilinogen of the

elevated

renin

isoproterenol

arterial

pressure

pertension. We have come to think of the hyperkinetic circulatory states associated with hypertension,‘g the levels of plasma renin activity (high, low, or normal) in essential hypertension,20 the volume-dependent forms of essential hypertension,*l etc.

CLINICAL AND PHYSIOLOGIC RATIONALE DIAGNOSTIC WORK-UP OF HYPERTENSION

FOR THE

The foregoing discussion is an appropriate lead-in to a consideration of which laboratory studies might be appropriate for the diagnostic “work-up” of the patient with hypertension. In preface to this discussion, we do not believe that every study dis19

cussed below must be performed for the evaluation of every patient with hypertension. However, all are discussed for consideration and judgment of applicability for the individual patient. Presently, there seems to be too much dialogue and needless argument concerned with the relative merits of this or that laboratory test in the diagnostic evaluation of the hypertensive patient. What follows, then, is a rationale for the inclusion of each of the various procedures for particular patients; it is the role and duty of the practicing physician to make the choice himself of which tests should be ordered for his specific patient. In this day and age when a battery of automated tests is performed at very reasonable costs by modern laboratories, it seems pointless to argue back and forth as to whether this or that test should be done. Moreover, in this frame of reference, the practicing physician without hesitation orders an upper gastrointestinal and gallbladder radiographic study on any patient with suggestive history of a problem that might be either peptic ulceration or gallbladder disease. Such studies are clinically justified in patients with chronic gastrointestinal disease. There is no reason why the physician should consider less effort for a series of studies (costing no more) that may be applied as an important reference of clinical knowledge for patients having a longstanding clinical problem such as we find in systemic arterial hypertension. Furthermore, many of the studies that the generalist, internist or cardiologist would order for the patient with hypertension would provide ideal baseline knowledge of organ function for any patient to be followed over many years. PREPARATION OF THE PATIENT. -This is a very important point in discussing the laboratory evaluation of the studies obtained in the “work-up” of the hypertensive patient. First, the physician should be alerted to have the patient refrain from any medication (if at all possible) for at least 3 - 4 weeks prior to laboratory studies. Even a sodium-restricted diet will provide sufficient stimulation to the adrenal cortex to invalidate any consideration of those studies that might suggest primary aldosteronism. Note, also, that ingestion of the oral contraceptives may not only obscure the baseline arterial pressure readings but will also alter intravascular volume, hemodynamics and plasma renin activity, among other considerations.** Furthermore, diuretics, laxatives and even intercurrent viral infections (producing nausea, vomiting and diarrhea) may produce hypokalemia and varying degrees of hyperaldosteronism. Realize that many antihypertensive drugs may have effects lasting for as long as 4 weeks, thereby providing a false concept for your “baseline” arterial pressure levels. Even the thiazide diuretics may have persistent effects for as long as 2 weeks following their discontinuation. It is recognized that it is not always clinically practicable 20

to have the patient discontinue any or all of these factors, but the physician is reminded of their effects so that interpretations of laboratory studies are not invalid. COMPLETE BLOOD COUNT. -In addition to their value in evaluating the hematologic status of a newly evaluated patient, three fundamental clinical points are noteworthy from these studies. First, if the patient is anemic, the physician should ascertain whether the anemia is related to the hypertension or to another clinical problem. In this respect, since as many as 40% of black patients may have an elevated arterial pressure, and since 10% of this same population may have an inherited abnormality of hemoglobin, then 4% of all black hypertensive patients may have sickle cell anemia or another hemoglobinopathy. If an abnormal hemoglobin or anemia is not present, it is of importance to know the baseline state of red cell production, since certain antihypertensive drugs (e.g., methyldopa) may be used in treatment, and it would be of importance to know prior to initiation of therapy whether a hemolytic anemia process is incidental or related to the antihypertensive therapy. Finally, there is abundant information that indicates that an elevated hemoglobin concentration or hematocrit is not an infrequent finding in hypertension.23, 24 Refer, if you will, to a recent issue of any medical journal for an advertisement depicting patients waiting in the physician’s office and asking which patient has the elevated arterial pressure. Usually he is the healthy, obese, florid-appearing businessman. This preconception actually has some basis of scientific fact (although the physician needs to realize that the usual patient with hypertension may have no symptoms and appear to be quite healthy at first glance). Actually, more than 50 years ago, Gaisbijck described a group of patients having an elevated arterial pressure, “polycythemia,” but no splenomegaly, leukocytosis or thrombocytosisz5 The Gaisbijck syndrome, as it has been referred to, may be explained physiologically as a relative polycythemia; the red cell mass, erythropoietin levels and state of erythropoiesis are perfectly normal, and the defect is explained by a contracted plasma volurne.23,~ 26 Thus, in a recent series of studies, we have learned that in most patients with essential hypertension, the higher the diastolic and mean arterial pressure (and total peripheral resistance) the more contracted will be the plasma volume.26’ 27 These observations, also demonstrated with patients with renal arterial disease and with pheochromocytoma,27 indicate that those Starling forces that regulate the transcapillary migration of fluid are of major importance in the patient with hypertension. The higher the intravascular hydrostatic pressure the greater will be the contraction of intravascular volume.zx Not only does this observation have great diagnostic import; it 21

also has very practical therapeutic value. Thus, with effective antihypertensive drug therapy (except for diuretics and possibly beta-adrenergic blocking drug@), the kidney responds to the reduced arterial perfusion pressure by retaining sodium and water. Plasma volume may also expand on the basis of reversal of the above-described Starling hydrostatic factor: lower pressure permits intravascular migration of water from the extravascular compartments. The net result is an expansion of the intravascular compartment and a reduction in the effectiveness of the antihypertensive drugs (i.e., the antiadrenergic or vasodilator drugs).3U-32 This emphasizes the importance of diuretic therapy in an effective long-term antihypertensive treatment program. Therefore, expansion of intravascular volume when the patient is receiving a once-effective antihypertensive treatment program bespeaks insufficient use of diuretics. The prevention of this phenomenon, heretofore ascribed erroneously to antihypertensive drug tachyphylaxis (and more recently termed “pseudotolerance”) requires either the addition of diuretics or more optimal agents (and dosages). We shall discuss this phenomenon later when measurement of plasma volume is discussed. BLOOD CHEMISTRIES. -Several laboratory tests are of major interest in evaluating the patient with hypertension (Table 3). First, the fasting blood sugar not infrequently may be abnormal, and diabetes mellitus (as discussed above) is not infrequently coincidental with hypertension. However, the fasting blood sugar may be normal and a 2- or 4-hour glucose tolerance test may be abnormal. This is not to suggest that the high frequency of TABLE 3. -LABORATORY STUDIES THAT MAY BE OF VALUE IN THE DIAGNOSTIC EVALUATION OF THE PATIENT WITH HYPERTENSION. (PLEASE REFER TO THE TEXT FOR A JUSTIFICATION OF THE CLINICAL MERIT OF EACH STUDY) Complete Blood Count White blood cell count (and differential) Hemoglobin concentration Hematocrit Adequacy of platelets Blood Chemistries Sugar (fasting, 2 hours postprandial, or tolerance Uric acid Cholesterol and triglyceride concentration Renal function (blood urea and/or serum creatinine) Serum electrolytes (Na, K, Cl, COZ) concentrations Calcium and phosphate concentrations Total protein and albumin concentration Hepatic function (alkaline phosphatase, bilirubin, Urine Studies Urinalysis Urine culture 24-hour collection (protein, Na, K, creatinine) 22

test)

serum

enzymes)

carbohydrate intolerance (as high as 70% in some reports) bespeaks insulin-dependent diabetes mellitus in each of these patients with hypertension. However, this finding should put the clinician on the alert for other subclinical manifestations of diabetes; and, more important, it should suggest those patients who might develop hyperglycemia, glycosuria and diabetes mellitus while receiving one of the thiazide-related diuretics. Indeed, with the performance of these studies I have yet to find a patient with hypertension who later developed carbohydrate intolerance (or diabetes mellitus) de novo while receiving the thiazide diuretic. Similarly, the blood uric acid determination is also of great importance because of the ability of these same diuretics to produce hyperuricemia and precipitate clinical gout. Not only are clinicians advised to screen their patient population for hypertension; they are also advised to screen for hyperlipidemia. In this respect, we usually obtain a blood cholesterol and triglyceride level in all patients when first evaluated for hypertension. However, the physician is cautioned to know the criteria for preparation of these patients for these tests. Usually, most laboratories will insist that the patient remain fasting from after dinner the evening before until determination of plasma triglyceride concentrations the next morning before any diagnostic consideration be ascribed to this test. Some measurement of renal function always is of value in the baseline evaluation of the patient with hypertension. The kidney is a prime target organ of hypertensive vascular disease, and renal functional impairment is a major complication. To this end, it is of value to obtain measurement of the blood urea nitrogen and/or serum creatinine concentrations in all patients with hypertension. We usually obtain both tests with the first evaluation, using the BUN as the reference for the periodic (annual or semiannual) follow-up examinations - and the serum creatinine for the less frequent determination of creatinine clearance. Measurement of serum electrolytes (serum sodium, potassium, chloride and carbon dioxide concentrations), particularly of serum potassium concentration, is of great value for excluding those secondary forms of hypertension that are associated with aldosterone or other steroidal hormone excess. In this respect, the Na, Cl and CO, concentrations provide an excellent check for the interpretation of the potassium concentration. The physician should remember the many factors that may produce hypokalemia (Table 4) and that very few factors are responsible for hyperkalemia. Thus, if renal disease and drugs that actively retain potassium are excluded, the physician should consider technical problems with the procedure of blood collection (e.g., prolonged application of the tourniquet, prolonged “muscle pumping” or contraction) and hemolysis of the collected blood sample. In addition to the above-described electrolytes, I usually 23

obtain the measurement of serum calcium and phosphate concentrations on at least one occasion during the evaluation of a patient with hypertension. The physician should realize that any disease that produces hypercalcemia is associated with a high incidence of hypertension, and with correction of the hypercalcemia, arterial pressure returns to normotensive levels. This serendipitous procedure has been responsible for the diagnosis of many patients with hyperparathyroidism who otherwise would not have been detected. Usually the routine measurement of serum proteins and hepatic function is part of the automated serum chemistry determinations. On first thought, these tests may seem to be of little consequence to the patient evaluated for hypertension; however, on a number of occasions I have found them to be of great value. Already mentioned was the finding of hemoconcentration as the result of plasma volume contraction in the patient with hypertension; measurement of plasma protein concentrations confirms this observation. Not infrequently the patient with hypertension may be hospitalized following myocardial infarction or hepatic disease; the baseline hepatic function data (which earlier seemed of no practical value) could be of great value in evaluating the serum enzymes under these circumstances. Similarly, the occasional intercurrent and incidental problem of hepatitis, drug hepatotoxicity or the possible low-grade elevation of serum bilirubin in a patient with Gilbert’s disease has made these data of retrospective value to me on several occasions. URINE STUDIES. -Of prime importance in the initial (and ongoing) evaluation of any patient with hypertension is the routine urinalysis. Once again, one is reminded of the urinary loss of sugar in diabetes mellitus, the progressive impairment of renal function with advancing nephrosclerosis (loss of overnight urine concentratability), the alkaline urine of the patient with primary hyperaldosteronism and the abnormal urinary sediment in the patient with renal parenchymal disease. I have found fewer problems in obtaining a 24-hour collection of urine in an outpatient than with in-hospital patient care. Thus, I have found it very valuable to instruct the newly referred patient with hypertension in the procedure of collecting the 24-hour urine. The untreated hypertensive patient is instructed that he should eat whatever he desires over a weekend period, and from 7:00 A.M. Sunday morning to 7:00 A.M. Monday morning he is to collect all urine. Then, on Monday morning he comes fasting to the laboratory with the urine collection for withdrawal of blood; from the blood and urine measurements it is possible to determine the creatinine clearance. If the serum potassium concentration is less than 3.8 mEq per liter, the laboratory is instructed to measure the sodium and potassium concentrations in the 24-hour urine collection. Thus, we know that if the urinary sodium excre24

tion is greater than 100 mEq in 24 hours (demonstrating adequacy of sodium intake and the effect of diet on inordinately stimulating aldosterone production), and if the urinary excretion of potassium is less than 40 mEq (per 24 hours), the measured hypokalemia most likely is not on the basis of excessive adrenal cortical hormone excretion. On the other hand, if the 24hour potassium excretion is excessive (i.e., greater than 50 mEq) in the presence of adequate sodium intake and no other obvious explanation for the hypokalemia (Table 4), the laboratory is instructed to determine the urinary excretion of aldosterone. Should aldosterone excretion be abnormally increased, the patient then should be evaluated further for hyperaldosteronism. Normally, no more than 200- 300 mg protein should be excreted by the kidney; any amount in excess bespeaks either renal parenchymal disease (including nephrosclerosis) or the effect of high arterial pressure itself. Note, however, that nephrosclerosis per se will not be associated with protein excretion in excess of 400-500 mg daily. Also note that severely elevated arterial pressure may be associated with massive proteinuria, which will promptly remit with reduction of arterial pressure to normotensive levels. Therefore, if urinary protein excretion persists or remains in excess of 400-500 mg in 24 hours, the physician should consider the differential diagnoses of renal parenchymal diseases (e.g., chronic pyelonephritis, glomerulonephritis, etc.). TABLE

4. -FACTORS RESPONSIBLE HYPOKALEMIA

FOR

Chronic

gastrointestinal potassium losses Gomco suction Vomiting Diarrhea Villous adenoma Malabsorption syndrome Laxative abuse Pyloric obstruction Ureterosigmoidoscopy Adrenocortical excess Primary aldosteronism (adenoma or hyperplasia) Cushing’s syndrome and disease Other adrenal steroidal hormone excess Drug therapy and foods Salicylate intoxication Diuretics Licorice Outdated tetracycline Adrenal steroids Renal disease (chronic) Potassium-wasting nephropathy Nephrotic syndrome Renal tubular acidosis Secondary hyperaldosteronism Renal arterial disease Cirrhosis Congestive heart failure Diabetes mellitus (acidosis) Primary periodic paralysis (hypokalemic type) 25

83 KS 85 8R 90 92 94 95 97 99 101 103 105 106 108 110 112 114 116 118 120 122 124 126 128 130 132 134 136 139

Heart

100 mm 101 ’

103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129

” ” ” ” ” ” u u ” ” ” ” ” ” ”

” ” ” ” ” ” ’

102 ”

5’0”

TD of

85 86 88 90 92 93 95 97 99 101 102 104 106 108 110 112 114 116 118 120 122 124 126 128 130 132 134 137 139 141

1’

86 88 90 92 93 95 97 99 100 1oa 104 106 108 110 112 114 116 118 120 122 124 126 128 130 132 134 137 139 141 143

y

87 89 91 93 95 96 98 100 102 104 106 108 110 112 114 116 118 120 122 124 126 128 130 132 134 137 139 141 143 146

3’

KS 91 92 94 96 98 100 102 104 106 108 109 111 113 115 117 120 122 124 126 128 130 132 134 137 139 141 143 146 148

4

90 92 94 96 98 99 101 103 105 107 109 111 113 115 117 119 121 124 126 128 130 132 134 136 139 141 143 146 148 150

5”

92 93 95 97 99 101 103 105 107 109 111 113 115 117 119 121 123 125 128 130 132 134 136 139 141 143 145 148 150 152

fi’

95 97 99 101 103 104 106 108 110 113 115 117 119 121 123 125 127 129 132 134 136 138 141 143 145 148 150 152 155

7’

100 101 104 106 108 110 112 114 116 118 121 123 125 127 129 131 134 136 138 140 143 145 147 150 152 155 157 106 108 110 112 114 116 118 120 123 125 127 129 131 133 136 138 140 143 145 147 150 152 154 157 159 111 113 115 118 120 122 124 126 129 131 133 135 138 140 142 145 147 149 152 154 157 159 162

HEIGHT 8 Y 10-

117 119 121 124 126 128 130 133 135 137 140 142 144 147 149 152 154 156 159 161 164

11”

1”

2”

3”

5.

4”

Y

fi”

Refer to paper entitled “A Study of the Transverse Diameter of the Heart Silhouette with Prediction Table Based on the Teleoroentgenagram” presented to the Assoaation of Life Insurance Medical Directors of America by Dr. Harry E. Ungerleider of the Equitable Life Assurance Society, and Dr Charles P. Clark, of the Mutual Benefit Life Insurance Cumpany (1938) 121 123 125 125 127 129 128 129 131 133 130 132 133 135 137 132 134 136 138 140 141 134 136 138 140 142 144 146 137 139 141 143 144 146 148 139 141 143 145 147 149 151 142 143 145 147 149 151 153 144 146 148 150 152 154 156 146 148 150 152 154 156 159 149 151 153 155 157 159 161 151 153 155 157 160 162 164 154 156 158 160 162 164 166 156 158 160 163 165 167 169 159 161 163 165 167 170 172 161 163 166 168 170 172 175 164 166 168 171 173 175 177 166 169 I71 173 176 178 180

6’V

TABLE

Yi

75 76 77 77 78 79 80 80 81 X2 83 Y3 84 85 Y6 86 Ri 88 89 89 90 91 ‘92 92 93 S4 9.5 95 96

25% 80 81 82 82 83 84 85 86 86 87 88 89 90 90 91 92 93 94 94 95 96 97 98 98 99 100 101 102 102 103

20% 85 86 87 88 88 89 90 91 92 93 94 94 95 96 97 98 99 99 100 101 102 103 104 105 105 106 107 108 109 110

15%

Minus

90 91 92 93 94 95 95 96 97 98 99 100 101 102 103 104 104 105 106 107 108 109 110 111 112 113 113 114 115 116

10% 95 96 97 98 99 100 101 102 103 104 105 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123

5% 100 101 102 103 104 105 106 107 108 109 110 111 112 113 IL4 115 116 117 118 11Y 120 121 122 123 124 125 126 127 128 129

o/r

Av’ge 5%

105 106 107 108 109 110 111 112 113 114 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135

110 111 112 113 114 116 117 118 119 120 121 132 123 124 125 127 128 129 130 131 132 133 134 135 136 138 139 140 141 142

10%

115 116 117 118 120 121 122 123 124 125 127 128 129 130 131 132 133 135 136 137 138 139 140 141 143 144 145 146 147 148

15%

PIUS

120 121 122 124 125 126 127 128 130 131 132 133 134 136 137 138 139 140 142 143 144 145 146 148 149 150 151 152 154 155

20%

125 126 128 129 130 131 133 134 135 136 138 139 140 141 143 144 145 146 148 149 150 151 153 154 155 156 158 159 160 161

25%

130 131 132 133 134 135 136 13i 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 15i 158 159 160 161 162 163 164

’ ” ’ ” ” I’ ’ ” ’ ” ” ” ” ” ” ’ ’ ” ” ” ” ” ” ” ” ” II ” n ”

’ ’

141 143 145 14i 150 15s 154 156 159 161 163 166 166 170 173 175 178 180 189 185 18i 190 192 195 198 200

143 145 148 150 152 154 157 159 161 164 166 168 171 173 176 178 180 183 185 188 191 193 196 198 201 203 206

145 148 150 152 155 157 159 162 164 166 169 171 174 Ii6 178 181 183 186 188 191 194 196 199 201 204 207 210

148 150 152 155 157 159 162 164 167 169 171 174 176 179 181 184 186 189 192 194 197 199 202 205 207 210 213 216

150 152 155 157 160 162 164 167 169 172 174 177 179 182 184 167 189 192 195 197 200 203 205 208 211 213 216 219

152 155 157 160 162 164 167 169 172 174 177 179 182 184 187 190 192 195 198 200 203 206 208 211 214 217 220 222 225

1.55 157 160 162 164 167 169 172 174 177 180 182 185 187 190 193 195 198 201 203 206 209 212 214 217 220 773 -.. ‘I’)6 __ ‘7’19 d*

157 160 162 165 167 169 172 175 177 180 182 185 188 190 193 196 198 201 204 206 209 212 215 218 221 224 227 229 232 235

160 162 164 167 169 172 175 177 180 182 185 188 190 193 196 198 201 204 207 210 212 215 218 221 224 227 230 233 236 239

162 164 167 169 li2 175 Iii 180 182 185 188 190 193 196 199 201 204 207 210 213 215 218 221 224 227 230 233 236 239 242 245

164 167 169 172 174 177 180 182 185 188 190 193 196 199 201 204 207 210 213 216 219 222 224 227 230 233 236 239 243 246 249

167 169 172 174 177 180 182 185 188 190 193 196 199 202 204 2Oi 210 213 216 219 922 225 228 231 234 237 240 243 246 249 252 255 259

169 172 174 177 179 182 185 188 190 193 196 199 202 204 207 210 213 216 219 222 225 226 231 234 237 240 243 246 “49 253 256 259 252

171 174 1:: 179 182 185 187 190 193 196 199 201 204 207 210 213 216 219 222 225 228 231 234 237 240 243 247 250 253 256 259 263 266 269 273

174 176 179 182 184 187 190 193 196 198 201 204 207 210 213 216 219 222 225 228 231 234 237 240 244 247 250 253 256 260 263 266 270 273 276

176 179 181 184 187 190 193 195 198 201 204 207 210 213 216 219 222 225 228 231 234 237 241 244 247 250 254 25: 260 263 266 270 273 277 280

178 181 184 187 189 1% 195 198 201 204 207 210 213 216 219 222 225 228 231 234 237 241 244 247 250 253 257 260 263 267 270 273 277 280 284

181 183 186 189 192 195 198 201 204 206 209 212 216 219 222 225 228 231 234 237 240 244 247 250 253 257 260 263 26: 270 274 277 280 284 287

183 186 189 192 194 197 200 203 206 209 212 215 218 221 224 248 231 234 237 240 243 247 250 253 257 260 264 267 270 274 277 281 284 288 291

104 105 106 106 107 108 109 110 110 111 112 113 114 114 115 116 I17

111 11X 112 119 113 120 113 191 114 122 115 122 116 123 116 124 117 125 I18 126 11Y 126 119 127 120 128 121 129 1’12 i 130 122 130 123 131

110 iia

Y8 98 99 100 101 101 102 103 104 104 105 106 107 107 108 109 110

III 111 112 113 114 115 116 116 117 118 119 120 121 122 122 123 124 125 126 127 128 128 129 130 131 132 133 133 134 135 136 137 138 139 139

117 118 119 120 121 1’12 &. 122 123 124 125 126 1’7 128 129 130 131 131 132 133 134 1s 136 13i 138 1.19 140 140 141 142 143 144 145 146 14i 148

124 124 125 126 127 12x 129 130 131 132 133 134 135 136 137 13x 139 140 141 142 143 143 144 145 146 147 148 14Y 150 151 152 153 154 1% 156

130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 14; 148 149 130 151 132 153 li4 155 156 15i 158 159 160 161 162 163 164

137 138 139 140 141 142 143 144 145 146 147 148 149 1PI 151 152 153 154 155 156 1% 159 160 161 162 163 164 165 166 167 168 169 170 171 172

143 144 145 146 147 149 150 151 152 153 154 155 156 157 156 lti0 161 162 163 164 165 166 167 168 lti9 lil 172 173 li4 175 176 177 178 179 180

150 151 152 153 154 155 156 158 159 160 161 162 163 164 166 167 168 169 170 171 173 174 175 176 177 17X 179 181 182 183 184 185 186 187 189

156 157 158 160 161 162 163 164 166 167 168 169 170 172 173 174 175 176 178 179 180 181 182 184 185 186 la7 188 190 191 192 193 194 196 197

163 164 165 166 168 169 170 171 173 174 175 176 178 179 180 181 183 184 185 186 188 189 190 191 193 194 195 196 198 199 200 201 203 204 205

If daily protein excretion exceeds 2 or 3 gm, the physician should conclude that chronic pyelonephritis alone is unlikely; a more rational diagnosis will include consideration of the various causes of the nephrotic syndrome. Urine culture (and sensitivity) always is a wise consideration in a patient with hypertension if a child or young woman, if the patient is pregnant or if an older man with symptoms of prostatic hypertrophy. CHEST X-RAY. -Routine chest x-ray examination is worthwhile in any initial examination, and it may be of great value in the patient with hypertension. It may be of particular value not only in recognizing left ventricular hypertrophy and the stigmata of aortic coarctation but also in serving as a baseline study for present and future evaluation of pulmonary pathology and the later complications of hypertension (e.g., pulmonary congestion, aortic widening, etc.). In any event, this routine chest x-ray examination should include both the posteroanterior and left lateral film projections. Substernal thyroid, thymoma and intrapulmonary lesions are among the variety of abnormal findings that would not have been detected in my initial evaluation had these studies not been performed. The physician is reminded of a very useful way of quantifying the degree of cardiac enlargement in the patient with hypertensiorr ?? .’ 34 (Table 5). By determining the Ungerleider index initially and later with periodic follow-up examinations, we have been able to document changes in left ventricular size.35T36 (Note: this technic will provide still more valid information if the films are exposed by the coincident timing with the R-wave of the electrocardiogram.) ELECTROCARDIOGRAM. -In my personal experience I have found this routine study to be of prime value in determining the degree of cardiac involvement from hypertensive vascular disease. Indeed, left atria1 abnormality is the first sign by either chest x-ray or electrocardiography of cardiac involvement from systemic arterial hypertension. This finding provides the first evidence that the left ventricle already is actively compensating to its increased afterload by hypertrophy (see below for further discussion) and is highly concordant with the presence (or absence) of the fourth heart sound (atria1 diastolic gallop rhythm3”-:~” ). As hypertensive heart disease progresses further, left ventricular hypertrophy can be detected by other roentgenographic and electrocardiographic criteria (Table 6). The electrocardiographic literature is replete with criteria for the diagnosis of left ventricular hypertrophy; each criterion has its own false negative and false positive results. However, the McPhie criterion (the tallest R-wave and deepest S-wave in any of the precordial leads achieving a total voltage of 4.5 mv) is the one with the lowest incidence of false positivity (1.5%).44 Other criteria we have chosen for left ventricular hypertrophy are the presence of 28

TABLE

6. -ABNORMAL

DIAGNOSTIC

CARDIAC

1. Left atria1 abnormality (ECG) -two of four a. P wave in Lead II 2 0.3 mv and 2 0.12 set”” b. Bipeak interval in notched P wave > 0.04 set”’ c. Ratio of P wave duration to PR segment 2 1.6 d. Terminal atria1 forces (in V,) 2 0.04 set”” 2. Left ventricular hypertrophy a. Ungerleider index 2 + 15% (chest x-ray alone)“” b. Ungerleider index ? + 10% (chest x-ray + two criteriaY (1) Sum of tallest R and deepest S waves 2 4.5 (2) LV “strain”i.e., QRS and T wave vectors (3) QRS frontal axis < d” c. All three ECG criteria (above)

CRITERIA

(Lead

II)“’

of the

following

ECG

mv (precordial)“’ 180” apart4’

left ventricular hypertrophy and strain by spatial vector methods45 and a negative frontal axis.4fi Using a combination of chest x-ray and electrocardiographic criteria for left ventricular hypertrophy, we believe that the stages for classification of hypertensive heart disease we have suggested are reasonable and were conservatively selected. Thus, we suggest that Stage I hypertensive heart disease is present when there is no evidence at all by chest x-ray or electrocardiograph of heart disease. Stage II is present if the only findings present are those of left atria1 enlargement, and Stage III occurs with the development of overt left ventricular hypertrophy (Table 6). Thus, if the chest x-ray Ungerleider index is 15% or more, this would be sufficient evidence of ventricular hypertrophy; postmortem studies indicate that at this degree of x-ray enlargement all autopsied hearts revealed left ventricular hypertrophy.33, 34 Furthermore, if all three of the above-described electrocardiographic criteria were present, left ventricular hypertrophy also would be most likely. In reality, in our experience, when either of the two foregoing criteria were established, the additional chest x-ray or electrocardiographic findings were also present. We also indicated that if a 10% Ungerleider index by chest x-ray were present (the upper limit of norma133, 34), it should also be necessary to demonstrate two electrocardiographic abnormalities to satisfy left ventricular hypertrophy. With these rather rigid criteria proposed, we met general agreement that in all probability the patients diagnosed as having Stage III hypertensive heart disease (obvious left ventricular hypertrophy) did, in fact, have the ventricular abnormality. We also reasoned that the chances were great that many of the patients with only left atria1 hypertrophy also had significant ventricular hypertrophy. However, if we could demonstrate physiologic and clinical differences between these two groups, they would be all the more significant. This we did in our initial hemodynamic studies,35 and they were confirmed recently using 29

noninvasive technics of echocardiography. The final (Stage IV) degree of advancing hypertensive heart disease that we proposed is the development of congestive heart failure.36 Thus, using both chest x-ray and the electrocardiogram, it is possible to describe functional progression of hypertensive heart disease; a physiologic explanation will be discussed below. The reader should note, however, that practically every patient studied who had left ventricular hypertrophy also demonstrated the atria1 abnormality, thereby providing further credence to the concept of the progression of hypertensive heart disease from no findings at all (Stage I) to left atria1 abnormality (Stage II) to left ventricular hypertrophy (Stage III) and then to congestive heart failure (Stage IV). INTRAVENOUS UROGRAPHY. -There has been much discussion and controversy generated in recent years as to whether or not the IVP should be performed routinely in the evaluation of the hypertensive patient (Table 7). The present discussion does not propose to resolve this argument but to present one point of view. In general, I believe that if: (1) the patient with hypertension is a child, a young woman, a patient hypertensive during pregnancy and has remained so postpartum; (2) the patient has no family history of hypertension; (3) the patient has had a sudden worsening of known chronic hypertension; (4) the individual has had evidence of renal parenchymal disease; (5) or the patient previously has had the diagnosis of established renal disease and is being followed for progression of disease;

who

was

arterial

then there is sufficient justification for ordering the intravenous urogram. If, however, renal arterial disease is strongly suggested by history, physical examination and other criteria, I do not regularly order the intravenous pyelogram but I will proceed TABLE 7. -OTHER LABORATORY STUDIES THAT MAY BE OF VALUE IN THE DIAGNOSTIC EVALUATION OF THE PATIENT WITH HYPER’tENSION. NOT ALL OF THESE STUDIES ARE DEEMED NECESSARY; THOSE WITH STRONG NECESSITY ARE MARKED WITH AN ASTERISK (*) “Chest x-ray (PA and lateral projections) “Electrocardiogram (12 lead, conventional) Intravenous urogram (“hypertensive IVP”) Renal arteriography Bilateral renal venous renin determinations Isotope renography and renal scans Blood volume determination (plasma volume, Radioimmunoassay studies Plasma renin activity Plasma aldosterone level Urinary hormone excretion studies (24-hour Catecholamines, VMA, metanephrines Aldosterone Corticosteroids and ketosteroids 30

RBC

collection)

mass)

directly to the selective renal arteriogram and differential renal venous renin determinations. It is also helpful to request that the radiologist obtain a postarteriographic flat plate of the abdomen to determine the renal excretory urographic findings as the arteriographic radio&ontrast material is being excreted. It is important to measure the renal sizes and tabulate the data in the patient’s clinical record. The renal sizes recorded represent the average of several film measurements of the length and widths of both kidneys. In general, the right kidney may be from 0.5 to 1.0 cm shorter than the left; therefore, a left kidney that is 0.5- 1.0 cm shorter than the right may be more significant than a right kidney that is 1.5 cm shorter than the left.47 Furthermore, if there is any evidence of delay in the appearance of contrast material in one kidney, if there is hyperconcentration of the contrast material in one kidney, if there is a significant disparity in renal lengths (as indicated) and if there is any evidence of lack of segmental renal function, there is evidence to proceed with selective renal arteriography. The reader should remember that performance of the intravenous urographic study is not exclusively indicated for the diagnosis of renal arterial disease; a more common indication is to determine whether there is evidence of renal parenchymal disease -and that includes the early and subtle findings of early chronic pyelonephritis. Thus, the physician must remember that prior to development of chronic renal failure (e.g., of chronic pyelonephritis) there must be earlier evidence of disease. If we are ever to control arterial pressure and prevent further renal functional impairment, we must be prepared to look for these early findings. RENAL ARTERIOGRAPHY. -Several years ago I was told that if renal arterial disease is to be diagnosed at all, one must be prepared to visualize the renal arteries. This very obvious truth frequently is not realized by physicians who seem more committed to establishing the presence of renal arterial disease by other less specific methods. Thus, for many years definition of significant renal arterial disease was based on findings of impaired renal excretory function. It may be more reasonable to relate “significance” in terms of its pressor implications; then one should find a means to quantify the renal pressor alterations of the arterial lesion. This has been made feasible in recent years with the availability of renal venous renin determinations; and the suggestion has been made that if the ratio of plasma renin activity of the affected to the unaffected kidney in renal venous blood is 2.0 or more, there is further evidence to ascribe true significance to the renal arterial lesion.4x An additional consideration must be the pathologic nature of the renal arterial lesion. In this regard, the physician must real31

ize that considerable information is available to suggest not only the significance but also the natural history of the disease from the arteriographic findings. 4y, 5o For example, if the renal mass is severely contracted, the implication is that the lesion must be “significant.” There are basically two types of renal arterial lesions: the atherosclerotic and the nonatherosclerotic (or fibrosing). With respect to the former, hypertension may have preceded the development of the lesion (e.g., hypertension may facilitate the progression of atherosclerosis) or it may be the result of the arterial lesion (e.g., renovascular hypertension). With respect to the probable response to corrective surgery in these patients with atherosclerotic plaques (and in patients with segmental lesions), much assistance may be anticipated from the renal venous renin studies.“‘* 52 Thus, if there is no evidence of increased production of renin by the “affected” kidney-especially if the affected kidney is not contracted in size-it might be wiser to treat the patient pharmacologically and to follow him with periodic radiographic studies (e.g., intravenous urography, renal scans or isotope renograms). If, on the other hand, renal parenchymal function seems to be worsening (as evidenced by further diminution of renal size or if the pressure becomes increasingly more difficult to control), surgical measures might be indicated. In any event, the physician should realize that atherosclerotic renal arterial disease is part of a systemic vascular disease, and prior to any surgical procedure the patient should be evaluated for atherosclerotic vascular disease involving the coronary, cerebral, mesenteric and great vessels.53 There are several types of the other form of renal arterial disease (i.e., fibrosing disease). Not infrequently, these patients present no family history of hypertension, but a renal arterial bruit may be audible over the abdomen or flanks. In these patients there is a higher probability that surgical correction of these lesions might be expected to be associated with a normalization of arterial pressures. 54 In some of these patients, involvement of both renal arteries may be present; this is found most often with the “string of beads” type of lesion, also termed perimedial fibroplasia. 5o Fortunately, this type of lesion progresses relatively slowly, is one of the most common of the fibrosing lesions and may be treated pharmacologically while the patient is periodically observed for evidence of progression of the arterial disease.j” There are several other types of fibrosing renal arterial disease, and these seem to be more likely to progress in severity.55, s6These types of renal arterial disease may be complicated by aneurysm formation, dissection and thrombosis of the renal artery.s7 For these reasons, surgical treatment may be considered more urgent; but, in any event, the general physical condition of the patient should be considered. (For a more detailed 32

discussion concerning the diagnosis, treatment and varieties renal arterial disease and hypertension, the reader is referred other more specific sources.x7, xx)

of to

RENAL VENOUS RENIN DETERMINATIONS. -We already have alluded to the importabce of these findings in interpreting the significance of renal arterial disease, particularly in the patient with atherosclerotic and unilateral renal arterial disease. However, I am not yet convinced from the literature that inability to demonstrate a specific ratio of renal venous renin activity means that surgical treatment will be unsuccessful. A sufficient number of patients with “normal” ratios have not been subjected to surgery to determine whether the elevated arterial pressure might have been corrected had surgery been performed. With respect to another caution, physicians have pursued the collection of their renin data differently. Some insist that their patient not have any pharmacologic therapy prior to renal venous renin collections and others insist that their patients be treated with a stimulating dose of a diuretic of one type or another. With respect to this latter consideration, some use a thiazide, some use a low-sodium diet and diuretic, others use furosemide. To confuse this problem further, many physicians obtain renal venous renins while their patients receive a variety of antihypertensive (and other) drugs. As an interested bystander to this area of developing knowledge, it seems valid to ask the questions: First, how does premeditation (for arteriography) affect the results? Second, how does prior introduction of radiocontrast material into the renal artery (it affects intrarenal hemodynamits) affect renin release? Third, if a patient is receiving antihypertensive therapy, how does this affect the release of renin by the affected and unaffected kidneys? Fourth, do the affected and unaffected kidneys respond similarly to the same doses of antihypertensive drugs? Fifth, if these kidneys respond differently, what is the significance of the stimulation tests using low-sodium diet and diuretics of varying types? The answers to these questions are not yet completely available; we must await this information, but we must also realize that our understanding of the problem has improved vastly in recent years. ISOTOPE RENOGRAPHY AND RENAL SCANS.-Reference to these studies already has been made, and I do not think that these isotopic procedures have a major role in the initial evaluation of the hypertensive patient. Their greatest value, however, may be related to the follow-up care of a patient with renal arterial disease once diagnosis has been made. Thus, if a renal arterial lesion has been demonstrated and the physician and patient elect to pursue pharmacologic treatment and to observe for progression of the disease, these noninvasive isotopic studies might provide evidence of further contraction of the renal mass and 33

delay in appearance of the isotope to the kidney. In addition, these studies may be useful if surgical correction of the arterial lesion is elected. Then it might be wise to obtain preoperative studies in order to measure changes in appearance of isotope and change in renal mass during the immediate postoperative period. Thus, if vascular surgery is performed and the physician is interested in learning whether patency of the artery or graft is maintained in the early postoperative period (when arterial pressure either has not fallen or has increased further), and if renal arteriography is considered too hazardous, the isotopic renogram or scan may be of extreme value. BLOOD VOLUME STUDIES. -As indicated earlier, because of the Starling relationships of transcapillary fluid migration,58 one might expect that patients with arterial hypertension would be expected to demonstrate a contracted intravascular (plasma) volume solely on the basis of increased hydrostatic pressure. Further, renal physiologic studies have indicated that with increasing perfusion pressures, the kidney will excrete greater amounts of salt and water .5g, 6o Indeed, in some forms of hypertension such a relationship exists.26, 27 Thus, most men with essential hypertension, patients with renal arterial disease and patients with pheochromocytoma demonstrate an inverse relationship between arterial pressure and plasma volume: the higher the arterial pressure the more contracted the intravascular volume. These findings have important therapeutic implications; for example, in the patient with pheochromocytoma. Thus, these patients should have arterial pressure reduced (and intravascular volume expanded) prior to extirpation of the tumor; and, with removal of the tumor (and the exogenously produced norepinephrine), the intravascular compartment must be reexpanded. With application of these concepts in recent years, intra- and postoperative hypotensive episodes have been minimized (and surgical morbidity and mortality improved). Some forms of hypertension, however, fail to demonstrate this inverse relationship between arterial pressure and plasma volume. Thus, in patients with renal parenchymal disease or primary hyperaldosteronism and in some patients with essential hypertension, the magnitude of arterial pressure is directly related to the plasma volume. These patients, therefore, have a volume-dependent form of hypertension. The clinical relevance is apparent; these patients should respond best to volume deprivation, diuretics and low-sodium dietotherapy. Indeed, this is precisely why patients with primary aldosteronism respond to these therapeutic modalities.61 PLASMA RENIN ACTIVITY. -Without entering into the dialogue of the current controversy of the role of plasma renin in current medical practice, a few words seem indicated to permit interpre34

tation of these tests. First, the physician must have confidence in the laboratory he uses for measurement of PRA (the common term for the test). Second, he must be aware of the pitfalls in collection; and, third, he must be aware of the physiologic implications of the results. The physician must be aware of the many drugs and physiologic conditions that alter plasma renin activity.fi2 For example, upright posture, exercise, time of day, diuretic therapy, vasodilators, recent blood donation, oral contraceptives and anesthetic agents all will increase plasma renin activity. Moreover, permitting the withdrawn blood sample to stand at room temperature, failure to centrifuge the blood immediately in a cold centrifuge (thereby permitting plasma angiotensinases to act on the blood) and adrenolytic therapy (including betaadrenergic blocking drugs) all reduce plasma renin activity. And, since plasma renin activity increases with contraction of intravascular volume, this factor also is important in interpretation of the results. Therefore, it is not surprising that the patient with high arterial pressure and severely contracted intravascular volume (e.g., malignant hypertension) will have a high plasma renin activity and that the patient with volume-dependent hypertension (e.g., primary aldosteronism) will exhibit low plasma renin activity. It therefore follows (with respect to the concept of specificity of antihypertensive therapy) that the patient with low renin essential hypertension (or volume-dependent essential hypertension) will also respond to volume contraction (i.e., diuretic therapy) and the patient with high plasma renin essential hypertension will respond to adrenergic suppression.63 Indeed, these concepts provide the basis for the presently debated therapeutic and pathogenetic concepts. HORMONAL STUDIES. -With the introduction of radioimmunoassay technics, the means for the diagnosis of a variety of hormonal types of hypertension are available.64 Already we see the impact of the measurement of plasma renin activity and aldosterone in plasma. Means for the measurement of blood samples for catecholamines are on the threshold. Preliminary studies already have indicated that in patients with essential hypertension the higher the arterial pressure the greater will be the plasma concentration of circulating norepinephrine65; understanding of the full practical clinical significance of this finding is not far off. However, at present, we must be satisfied with determination of urinary excretion of catecholamines (and their metabolites) only for the suspected diagnosis of pheochromocytoma-an exaggerated example of a defect in catecholamine metabolism. (I have no doubt that with greater sophistication in our measurements of catecholamines, the entire significance of altered metabolism in essential hypertension will be forthcoming.) Most of the other known hormones necessary for quan35

titative measurement are measured in plasma and urine, and a discussion of these rarer forms of hypertension is found in more specific articles.66 CLINICAL DISEASE

MANIFESTATIONS

OF HYPERTENSIVE

SYMPTOMS. -The initial statement concerning the clinical recognition of hypertension always should include the oft-repeated statement that in most patients with systemic arterial hypertension there are no clinical manifestations other than the demonstrated elevated arterial pressure. Therefore, unless the physician measures blood pressure in all patients, the initial manifestation of hypertension will go unrecognized. Not infrequently one reads that the most common manifestations of hypertension are fatigue, headache and epistaxis. However, these three symptoms are the most common complaints encountered by most physicians, and I therefore see no real basis of scientific truth for that observation. Of course, patients with hypertension may display Wassic” headaches occurring on awakening in the morning and band-like in nature. The most important headache complaint, however, is the sudden onset of vertical head pain associated with high arterial pressure. This complaint should suggest subarachnoid hemorrhage, and vigorous pursuit of this diagnosis is indicated. A recent study concerning the frequency of hypertension among patients with epistaxis seems to question the time-perpetuated story that this is a frequent sign of hypertension. 67However, it is most important to follow these patients with epistaxis if one is to know whether the elevated arterial pressure, observed when the patient was being treated in the emergency room, has persisted. In my experience, the earliest findings in the patient with prolonged arterial hypertension (in addition to the family history of hypertension, premature death and elevated arterial pressure earlier in life) is decreased exercise tolerance and fatigue early in the course of hypertensive heart disease, and that of nocturia as an early evidence of renal involvement in hypertension and nephrosclerosis. The patient with early hypertension may describe symptoms of cardiac awareness (e.g., palpitations and tachycardia); indeed, these feelings may persist inordinately long after exertion or stress. Chest pain may be present later in hypertensive heart disease, and this may be a manifestation of coexistent coronary arterial (atherosclerotic) heart disease or no occlusive disease at all of the coronary vessels. This is because the chest discomfort may be brought about by an increased myocardial demand for oxygen, and this is produced by the increased arterial pressure and the increased heart size (both major determinants of ventricular wall tension and oxygen need). 36

OPTIC FUNDI. -If there is one vasculature that is accessible for routine clinical examination, it is the small vessels of the optic fundus. The retinal arterioles have been shown to provide an excellent assessment of the degree of systemic vasoconstriction; indeed, this forms the basis of classification of hypertensive vascular disease. The earliest form of classification was described by Keith, Wagener and Barker. 6x With this system, the earliest stage (Group I) of hypertensive vascular disease is recognized on the basis of increased tortuosity and mild arteriolar constriction. Group II changes reflect the complication of a coexisting vascular disease (i.e., atherosclerosis) and are manifested by “AV nicking,” which represents the disappearance of the continuity of the retinal vasculature at the points of arteriovenous crossing. Group III changes include the appearance of retinal exudates and hemorrhages, and in accelerated and malignant hypertension one usually observes the flame-shaped and punctate hemorrhages throughout the fields. With development of Group IV hypertensive changes there is the appearance of papilledema of the nerve head, it is this finding that is necessary to establish the diagnosis of malignant hypertension. This latter finding usually coexists with the development of hemorrhages and exudates and marked constriction of the retinal vessels.@ Unfortunately, this classification brings together the coexistence of two, and possibly three, diseases: hypertension (including both the “benign” essential and malignant forms) and atherosclerosis. It is for this reason that the American Ophthalmological Society recommended classification of retinal vasoconstriction separately from the other changes.70 Inherent in this classification (Table 8) is a progressive increase in focal and generalized vasoconstriction. The degree of hemorrhages and exudates is also classified from grades 1 to 4 (as with constriction changes), depending on the number of optic funduscopic quadrants (divided by twofor the two eyes) involved. Papilledema may also be classified arbitrarily on a 1 to 4 severity degree basis. It is important to recommend to the practicing physician that clinical observation can be made more scientific by utilizing more precise objective observations as recommended by Feinstein in his most provocative book, Clinical Judgment. ‘* This use of quantitative criteria permits more accurate comparison from one time to another in the same individual. Nevertheless, the most important point to be made from this brief discussion of the retinal vascular changes in hypertensive diseases is the necessity for routine use of the ophthalmoscope by all practicing physicians-including the cardiologist. PERIPHERAL VESSELS. -When discussing the examination of the peripheral vessels in patients with hypertensive diseases, the first thought that usually comes to mind is the necessity to pal37

TABLE A.

B.

8. -CLASSIFICATION

OF HYPERTENSIVE

RETINOPATHY

Keith-Wagener-Barker Classification Group I-tortuosity, minimal constriction Group II- above + arteriovenous nicking Group III - above + hemorrhages and exudates Group IV - papilledema American Ophthalmological Society Committee Classification (WagenerClay-Gipner) 1. Generalized arteriolar constriction Grade 1 -arterioles 3/4 of normal caliber; A/V ratio of 1:2 Grade 2 -arterioles l/2 of normal caliber; A/V ratio of 1:3 Grade 3 - arterioles l/3 of normal caliber; A/V ratio of ~1:4 Grade 4-arterioles thread-like or invisible 2. Focal arteriolar constriction or sclerosis Grade 1 -localized arteriolar narrowing to 2/3 caliber of proximal segment Grade 2 - localized arteriolar narrowing to l/2 caliber of proximal segment Grade 3 -localized arteriolar narrowing to l/3 caliber of proximal segment Grade 4-arterioles invisible beyond focal constriction 3. Generalized sclerosis Grade 1 -increased light-striping; mild AV nicking Grade 2-coppery arteriolar color; moderate AV nicking; veins almost completely invisible below arteriolar crossing Grade 3 - silver arteriolar color: severe AV nicking Grade 4 -arterioles visible only as fibrous cords without bloodstreams 4. Hemorrhage and exudates-grades 1 to 4 (based on number of affected quadrants divided by 2) 5. Papilledemagrades 1 to 4 (based on diopters of elevation)

pate bilaterally for the femoral arterial pulsations. One should also compare the pulsations with those of the brachial arteries to determine delay in the propagation of the aortic pulse wave in coarctution of the aorta. If this consideration has come to the reader’s mind, then enough has been said; but examination of peripheral pulsations in young patients with hypertension to exclude the possibility of aortic coarctation is not the sole purpose. Because of the coexistence of UtheFosc~eFosis, and the more rapid acceleration of the atherosclerotic processes in hypertension,72 checking for inequality of peripheral arterial pulsations in the extremities is also very important. Furthermore, examination of the carotid arterial pulsations and their auscultation for bruits may provide the first clinical signs of preventable cerebrovascular disease, transient ischemic attacks and strokes. Indeed, the initial manifestation of carotid arterial disease may be provided by examination of the optic fundi and the demonstration of cholesterol emboli to the retinal arterioles. Much has been written about the examination of the abdomen, flanks and back for the presence of Fend arterial bruits (which may be both systolic and diastolic in timing). 53 Indeed, any patient (old or young) with the development of these bruits should be suspected of having renal arterial disease, although it is acknowledged that the bruit may emanate from the splenic or other intra-abdominal vessels. 38

CARDIAC EXAMINATION. -Examination of the heart of a hypertensive patient will provide an index of the extent of cardiac involvement by the hypertensive vascular disease. Early in hypertension, before the heart is secondarily involved, palpation will reveal a hyperkinetic impulse and a faster rate, which is depicted by apex cardiography by a rapid upsweep and dissipation of the impulse. As the heart adapts to the increasing afterload imposed on it by the unrelenting increase in total peripheral resistance, the left ventricle hypertrophies. As indicated earlier, this increase in left ventricular mass and the hyperfunctioning myocardium may not be detectable initially by the chest x-ray and electrocardiogram by the conventional indices of left ventricular hypertrophy. However, the earliest index of cardiac involvement from hypertension is shown by the presence of left atria1 abnormality by electrocardiography. This finding, indicated by at least two of four conventional criteria of left atria1 abnormality,37 is highly concordant with the auscultatory evidence of left atria1 ejection of blood into a less compliant left ventricle - and the presence of the atria1 (fourth) heart sound.38 Hemodynamic studies have indicated that when these findings are present (without showing evidence otherwise of left ventricular hypertrophy) there is physiologic evidence of impaired left ventricular function.35, 36 The ventricle already demonstrates an impaired left ventricular ejection rate, and the tension time index and pressure time per beat is significantly greater than in the hypertensive patient without any evidence of cardiac involvement.35 Furthermore, these patients with left atria1 abnormality have higher arterial pressures, increased total peripheral resistance, a greater prevalence of atria1 and ventricular arrhythmias and, by echocardiography, a thicker intraventricular septum and left ventricular wall and a reduced left ventricular ejection fraction. 3s As ventricular hypertrophy becomes more evident by conventional chest roentgenographic and electrocardiographic technics, a louder aortic component of the second heart sound is evident, the fourth heart sound is almost universally heard and there is palpatory evidence of a left ventricular lift that now is more sustained.” These clinical findings are associated with the physiologic findings of a significantly reduced resting cardiac output, a further reduction in left ventricular ejection rate and increased left ventricular work, tension time index and pressure time per beaP5 (Fig. 1). These findings are confirmed by echocardiographic changes demonstrating a further increase in left ventricular wall and intraventricular septal thicknesses and reduction in ejection fraction and rate of fiber shortening.3s Hence, evidence is available, from invasive and noninvasive clinical hemodynamic and physiologic means, that progressively increasing arterial pressures are associated with a rising peripheral resistance and more severe impairment of car39

CARDIAC

INDEX

TOTAL PERIPME RAL RESISTANCE

3.2

2.6 CT t 0 2.4 : 2 20 /

Ij II

I

nm

STROKE

r

WORK

L “i 1

60 x)

I B G

50

I

urn

STROKE

POWER

67 s\ 400 e350

90 60

f

N

: a 1 300 250 I 6 200 N

I

IIII

TENSION TIME INDEX

N

I

IH

PRESSURE TIME SCAT

Fig. l.-Hemodynamic indices in 25 normotensive volunteer subjects (N) and three groups of patients with essential hypertension: group I, 54 patients having normal-sized hearts; group 11, 20 patients having left atrial abnormality; group III, 23 patients having left ventricular hypertrophy. A, heart rate, mean arterial pressure, cardiac index and total peripheral resistance. 6, left ventricular ejection rate (index), ejection time and stroke index. C, four derived left ventricular functions. All bars represent the mean for the group (2 1 standard error of the mean).

disc function. Therefore, in summary, cardiac involvement is shown initially only by hyperkinetic cardiac function, later by more sustained and forceful contractions associated with clinical signs of atria1 involvement (the “left atria1 kick”74) and still later by overt clinical and laboratory evidence of ventricular hy40

TABLE

9. -CLASSIFICATION

Stage

I

Stage

II

Stage

III

Stage

IV

OF

HYPERTENSIVE

HEART

DISEASE”’

Normal-sized heart without evidence of cardiac involv ment (EGG or chest x-ray) Early le Pt ventricular hypertrophy as detected by left atria1 abnormality (ECG) and fourth heart sound Clinically evident left ventricular hypertrophy (by chest x-ray and ECG) Left ventricular failure

pertrophy. Finally, evidence of left (and right) ventricular failure becomes obvious. These findings have suggested a classification of hypertensive heart disease based on clinical and physiologic indice$” (Table 9). OTHER PHYSICAL FINDINGS. -It goes without saying that part of any good examination of a hypertensive patient should be the comprehensive neurologic examination and careful inspection for evidence of fluid retention and impairment of peripheral blood flow.

DISEASES

COMPLICATING

SYSTEMIC

HYPERTENSION

CORONARY ARTERIAL DISEASE.-As indicated above, atherosclerotic coronary arterial disease frequently coexists with hypertension. Indeed, the increased myocardial oxygen demand by the enlarged heart of a hypertensive patient that is performing increased “pressure work” will aggravate coexistent occlusive disease of the coronary arteries. Not infrequently, this increased oxygen demand may be of sufficient magnitude to produce angina pectoris - even without radiographically demonstrable occlusive coronary arterial lesions. In a series of 21 patients studied with Dr. Mason Sones and his colleagues at the Cleveland Clinic, we were unable to demonstrate significant coronary arterial lesions, and their hemodynamic data were similar to that described above for similarly classified patients with hypertensive heart disease”“; and with effective antihypertensive therapy, sufficient to control arterial pressure at normotensive levels, this angina pectoris disappeared. Thus, having documented that angina pectoris can be precipitated by increased arterial pressure in the absence of occlusive coronary arterial disease, it follows that in the presence of significant occlusive arterial disease, symptomatic coronary insufficiency will not only be aggravated by elevated arterial pressure but it also may be facilitated. The lessons from the observations are twofold: one, chest pain in the presence of elevated arterial pressures need not bespeak significant occlusive atherosclerotic coronary arterial disease; two, vigorous, effective and persistent antihypertensive drug therapy in the patient with hypertension and 41

symptomatic coronary control chest pain.

arterial

insufficiency

may be sufficient

to

AORTIC ANEURYSM. -Hypertension is the frequent complicating problem, if not the prime causative factor, of dissecting aortic aneurysm. This concept is important for understanding treatment of aortic dissection, since the mainstay of current therapy is effective and vigorous hypotensive therapy.75 Indeed, this approach is advocated not only for patients with aortic dissection and significantly elevated arterial pressure but also for patients who are normotensive. Not infrequently, reduction of arterial pressure in these patients is associated with an immediate disappearance of chest pain. However, it is important to realize that selection of the proper antihypertensive agent is of paramount importance. The physician must not choose an agent that, by virtue of its antihypertensive action, will stimulate reflexively certain cardiovascular actions-heart rate, cardiac output, ventricular ejection rate, myocardial contractility and the shear rate to aortic blood flow. Unless these reflexive cardiac effects are inhibited by appropriate agents (e.g., reserpine, beta-adrenergic receptor blocking drugs), potent vasodilating agents (e.g., d&oxide, hydralazine) may only serve to aggravate the dissection process. OTHER HYPERTENSIVE EMERGENCIES. -In addition to cardiac failure, acute myocardial infarction with high arterial pressures and aortic dissection, there are several other acute hypertensive problems that might be termed “hypertensive emergencies.” These problems may be treated immediately (i.e., within minutes) with selection of appropriate antihypertensive agents or they may be treated promptly (i.e., within hours) -depending on the emergent condition. Table 10 details the type of hypertensive emergency, defines the problem and suggests an appropriate course of hypertensive therapy. The reader is referred to other sources for a more detailed discussion of the problem.16, ~9 76 However, two important points always should be considered regarding treatment of a hypertensive emergency: first, coexistent with the introduction of emergency-type medications should be the introduction of a plan for the long-term therapy of that patient’s hypertensive problem; second, any agent that reduces arterial pressure will be associated with sodium and water retention by the kidney and will permit the re-entry of fluid from the extravascular compartments-these are the physiologic consequences of any effective antiadrenergic or vasodilator compound. Therefore, the physician should remember that potent antihypertensive drugs always should be accompanied by the intelligent use of diuretic agents. And if congestive heart failure is present and digitalis and cardiac arrhythmias are to be a factor 42

TABLE

10. -HYPERTENSIVE

EMERGENCY Hypertensive encephalopathy Malignant (and accelerated) hypertension Intracranial hemorrhage

Dissecting aortic EiIE”rySIll

EMERGENCIES-

Severely elevated arterial pressure; headache, nausea, vomiting, somnolence or coma, neurologic signs Severely elevated arterial pressure; exudative retinopathy and papilledema Elevated arterial pressure; severe headache, increased intracranial pressure; evidence of intracranial bleeding Elevated arterial pressure; chest pain; radiographic evidence of aortic widening and dissection

Acute left ventricular failure

Elevated arterial left ventricular and pulmonary

Myocardial infarction and pressor crisis

Elevated arterial pressure, evidence of acute myocardial infarction

Pheochromocytoma crisis

Evidence of catecholamineproducing tumor; elevated arterial pressure

Tyramine ingestion plus MAO inhibitor

Severely elevated arterml pressure; evidence of ingestion of a monoamine oxidase inhibiting drug and tyramine-containing foods Pressor crisis associated with ingestion of both types of drugs

Guanethidine plus tricyclic-acid antidepressant therapy

Sudden cessation of clonidme

Cardiac cathetenzatlon messor crisis Eclampsla

DEFINITION

AND

DEFINITION

pressure, failure edema

High arterial pressure (and possibly symptoms similar to pheochromocytoma crisis) following abrupt dlscontinuance of clonidme therapy Abrupt sudden elevation of arterial pressure during cardiac catheternation High arterial convulsions

pressure; during labor

TREATMENT

TREATMENT Nitroprusside (infusion) or d&oxide 1300 mg, IV) or trimethaphan (infusion) Guanethidine, bethanidine, OF methyldopa Diuretics Potassium repletion Diazoxide or nitroprusside

Nitroprusside

or trimethaphan

Dizoxide or hydralazine pltis beta-adrenergic blockade or reserpine Digitalis Diuretic(s) with careful potassium control Methyldopa Diuretics Methyldopa Careful observation and control of abnormal rhythm and ventricular function Alpha-adrenergic receptor blockade (phentolamine, IV, or phenoxybenzamine, p.o.1 Beta-adrenergic receptor blockade (for abnormal cardiac rhythm) Alpha- (or beta-, if arrhythmia) adrenergic receptor blockade, IV

Discontinuance of tricyclic antidepressant, or Selection of another antihypertensive whose action does not require entrance into postgangliomc nerve ending Alpha- (and possibly beta-) adrenergic receptor blockade Initiation of effective long-term antihypertensive therapy Phentolamine injection Then, if no response, nitroprusside Evaluation Magnesium Hydralazine Cryptenamine

sulfate or or la11 IV)

43

in therapeutic considerations, the state of potassium should be kept in mind continually.

balance

GOUT AND DIABETES MELLITUS. -These two metabolic diseases frequently coexist in a patient with systemic arterial hypertension.“* 77,‘I8 It is for this reason that I make every attempt in my evaluation of these patients to learn of the possibility of these problems complicating management of the patients’ problems. With this knowledge in mind, however, I am not dissuaded from using thiazide diuretics. Most physicians keep the possibility in mind that, later, treatment of thiazide-induced hyperuricemia or diabetes mellitus may be necessary. Usually, with the former problem, allopurinol in doses sufficient to maintain a reduced blood uric acid level is all that is necessary. If drug intolerance (e.g., skin rash) contraindicates its further use, one should consider its replacement with probenecid (with or without colchicine). With respect to diabetes mellitus, frequently careful control of the patient’s weight and periodic follow-up of carbohydrate tolerance and/or fasting blood and urinary sugars may be sufficient treatment without resorting to specific hypoglycemic therapy (either with insulin or oral hypoglycemic agents). HYPERLIPIDEMIAS. -Not infrequently, hyperlipidemia is diagnosed in the patient with arterial hypertension. It is important in these patients to determine the type of the hyperlipidemia, since some are more sensitive to specific dietotherapy, others to oral hypolipidemia therapy, others to both. The reader is referred to a variety of current discussions of this problem,7g-s1 but it is suggested that the most productive population group for screening, detection and treatment of hyperlipidemias (other than the immediate families of known patients with hyperlipidemia) are the large numbers of people with systemic arterial hypertension who are also undetected today.

ANTIHYPERTENSIVE

THERAPY

The important concepts in considering the introduction of antihypertensive therapy today are: first, all patients with elevated arterial pressure must have their pressures controlled; second, no matter which course of therapy is followed, treatment must be maintained or arterial pressure once again will become elevated; third, the important point is to maintain arterial pressure at effectively reduced levels. With these concepts in mind, the reader (as already discussed) can consider two means of pursuing effective therapy: first, with the standard, stepped-care approach; or, second, the use of a specific approach to the treatment of hypertension. In reality, there are no major differences in therapeutic goals of the proponents of either course; the only 44

variation is in the commitment with the same antihypertensive

to initiate all therapeutic efforts drug (i.e., thiazide diuretics).

GENERAL MEASURES+- AS part of any long-term treatment program for a patient with a chronic illness, the physician must consider the total approach of therapy for his patient. This is no different with the patient having systemic arterial hypertension. First, he must fully understand the nature of the hypertension problem, the need for the patient to remain on antihypertensive drug therapy indefinitely, the feasibility of adjusting and readjusting drug therapy in the eventuality of unwanted side-effects and the purpose of therapy in preventing, if possible, the consequences of hypertensive vascular and cardiac disease and other target organ involvement. Second, the physician should explain to the patient the advisability of weight reduction (if he is overweight), relaxation and a routine exercise program as part of a general program for good health. In this respect, there is little evidence to indicate that weight reduction, per se, in an obese patient actually will reduce arterial pressure. It is true that associated with weight reduction there may be a fall in arterial pressure, but this may be on the basis of more valid sphygmomanometric readings with a more suitably fitting “cuff” following the loss of weight (and arm girth) and because of a reduced dietary intake of sodium merely because the patient who is reducing caloric intake is simultaneously reducing sodium intake. In any event, this pursuit is a worthwhile health-care measure. With respect to relaxation, it is unfortunate that the first five letters and the last seven letters of the word hypertension convey to the medical and lay public concepts that the medical problem is on a basis of emotionality. At this point in our knowledge there is no conclusive evidence available to substantiate this preconception-despite the very appealing and popular trade publications on relaxation, meditation and biofeedback suggesting the contrary. Moreover, the present vogue of exercise and training programs also seems to suggest that these pursuits are beneficial in the treatment of hypertension. At present, no data are available to confirm these similarly popular beliefs. Nevertheless, relaxation, good diet, weight control and a daily exercise program should be encouraged as part of a broad and sensible program leading to good health. CONCOMITANT MEDICATIONS. -The physician and patient alike should be well aware of the many drugs commonly used that may be of conflicting value in the treatment of the patient with hypertension. For example, nose drops and antihistamines may elevate arterial pressure, and although their use may not be contraindicated in a patient with hypertension on medication, the physician should be aware of their potential effect of elevat45

ing arterial pressure. Furthermore, on the average, any population of women using the oral contraceptive means for birth control will display some elevation of arterial pressure, and some of these women may display rather dramatic elevations in arterial pressure. In general, I do not withhold these compounds from any woman desiring this form of birth control but explain the possible consequences, carefully follow her arterial pressure at regular intervals and, if pressure control becomes a real problem, re-evaluate. the use of the “pill” with the patient. Similarly, one should remember that concomitant use of any steroid compound will promote fluid retention and elevate arterial pressure. Thus, if this form of therapy is a necessity, the physician should be certain that effective arterial pressure control is ensured with adequate doses of diuretics and careful observation of potassium balance, since both of these exogenously administered drugs (steroid and diuretic) have kaliopenic properties. Among other drugs that may antagonize antihypertensive drugs are the tricyclic antidepressant compounds (imipramine and desimipramine derivatives), which prevent certain postganglionic sympatholytic compounds from gaining entrance to the nerve ending. PHARMACOLOGY OF ANTIHYPERTENSIVE DRUGS. -It is outside the scope of this monograph to discuss in great detail the pharmacologic and physiologic effects of the broad number of antihypertensive drugs available today. Several recent and well-referenced articles and symposia are available and they are recommended to the reader for reference.18, 66,82,83 In brief, however, antihypertensive drugs may be classified into three major groups: diuretics, antiadrenergic (or sympatholytic) compounds and vasodilators (Table 11). The diuretics act primarily by their natriuretic effect in contracting intravascular and extracellular fluid volumes and by attenuating the responsiveness of the circulation to pressor substances and enhancing responsiveness to depressor and antihypertensive agentss2 Hemodynamically, they initially reduce cardiac output and, with prolonged treatment, probably also total peripheral resistance. Associated with the prolonged reduction in pressure is a maintained reduction in plasma volume and a sustained increase in plasma renin activity.s4 Antiadrenergic agents presently are available to inhibit adrenergic function at virtually every level of sympathetic neuronal function, and agents can be used to actually dissect the autonomic nervous system at any anatomic site. Methyldopa and clonidine stimulate specific alpha-adrenotropic receptor sites in the brain and thereby reduce tierent sympathetic cardiovascular outflow and thus arterial pressure (an effect opposite from alpha-receptor site stimulation of vascular smooth muscle). The veratrum alkaloids also act centrally, but at other brainstem 46

TABLE

11.-COMMONLY DRUGS

ACENT

Diuretics (agents are corn&d Chlorothiazide Hydrochlorothiazide Furosemide Spironolactone Adrenergic inhibitors Rauwolfia derivatives Reserpine (typical of this group) Reserpine (parenteral) Methyldopa Guanethidine Clonidine Trimethaphan Alpha-adrenergic receptor antagonists Phentolamine Phenoxybenzamine Beta-adrenergic receptor antagonists Propranolol Vasodilators Hydralazine Nitroprusside

USED ANTIHYPERTENSIVE AND DOSES

USUAL INITIATING

DOSE

in equivalent 500 mg b.i.d. 50 mg b.i.d. 40 mg b.i.d. 25 mg q.i.d.

dosage -

0.25

(oral)

mg q.d.

MAXIMAL

DAILY DOSE

forms) 1000 mg 100 mg As high as 2.0 gm 100 mg

0.25

mg

0.5 mg (to see if unusual response) 250 mg t.i.d. or q.i.d. 10 mg q.d. 0.1 mg b.i.d. 1 mg/ml, IV

2.5-5.0 mg q. 6 hr 4.0 gm 150- 250 mg 2.4 mg

5 mg, IV 5 mg b.i.d.

10 mg or by infusion As necessary

10 mg q.i.d.

160 mg q.i.d.

10 mg q.i.d. 60 pgm/ml,

200 mg IV

centers, to alter baroreceptor input. Reserpine also has a central action but, in addition, depletes the postganglionic nerve ending of the neurohumoral transmitter norepinephrine. This latter effect is similar to the action of guanethidine and bethanidine; however, these agents reduce norepinephrine stores in the postganglionic neuron by first actively depleting the nerve ending and later by replacement for norepinephrine. Methyldopa also acts peripherally by affixing itself (or, more precisely, its metabolite alpha-methylnorepinephrine) to alpha-adrenergic receptor sites of vascular smooth muscle as a false neurotransmitter. Ganglionic blocking drugs (e.g., trimethaphan) inhibit parasympathetic in addition to adrenergic function, producing additional effects, including inhibition of gastrointestinal and genitourinary smooth muscle and thereby accounting for constipation, paralytic ileus, urinary retention and impotence. In general, these adrenergic inhibiting drugs reduce arterial pressure primarily through a fall in total peripheral resistance, although ganglionic and postganglionic agents also decrease vascular smooth muscle tone in venules. Through this reduction in venous tone, blood pools in the dependent parts on assumption of upright posture, resulting in a fall in arterial pressure through 47

a reduction in venous return and, hence, cardiac output; this explains the postural hypotension observed with most agents that inhibit the sympathetic nervous system. As a further generality, most agents that inhibit renal adrenergic input decrease plasma renin activity. This-has been offered as the mechanism of antihypertensive action for the beta-adrenergic receptor blocking drugs, but inhibition of renin release is also a feature of methyldopa, clonidine and guanethidine. Alternative explanations for the antihypertensive effects of beta-adrenergic blocking drugs also include reduction of cardiac output, resetting of baroreceptors, adaptation of the peripheral circulation to the reduced output and, more recently, inhibition of beta-adrenergic receptor sites in the brain (producing a net effect similar to stimulation of central alpha receptors). To date, however, no precise mechanism of antihypertensive. action of beta blocking drugs is available. Finally, the peripheral vasodilating drugs act nonspecifically to relax vascular smooth muscular tone. Some produce this effect primarily on arteriolar smooth muscle (e.g., hydralazine, diazoxide), thereby reducing only total peripheral resistance; others also act on venular smooth muscle (e.g., nitroprusside), thereby attenuating the reflexively induced increase in cardiac output. This concept of reflexive stimulation in cardiac function (i.e., increased heart rate, cardiac output, myocardial contractility and shear rate of blood flow) is a very important clinical consideration, since if it is not prevented by an adrenergic inhibiting drug (e.g., reserpine, methyldopa, beta-adrenergic receptor blocking drugs), angina pectoris, congestive heart failure and aortic dissection may be provoked or aggravated. As already indicated, all antihypertensive drugs (except for diuretics and possibly the beta-adrenergic receptor blockers) will produce sodium and water retention, not a side-effect of these drugs but the normal physiologic response of the kidney, adrenal gland and blood vessels to reduced arterial pressure. As a result, the physician always should consider addition of a diuretic to an adrenergic inhibiting drug or vasodilating compound if the antihypertensive effect of these agents seems to wane. Furthermore, if a diuretic already is being used, the physician might consider increasing the dose, switching to a more potent diuretic or adding a second diuretic having a different mode of action (e.g., addition of spironolactone to thiazide). STANDARD ("STEPPED-CARE") APPROACH TO ANTIHYPERTENSIVE THERAPY. -Implicit with use of this approach to the treatment of

hypertension is the possible eventual use of all three types of antihypertensive agents, depending on the response to therapy with these drugs used in sequence (Table 12). Thus, with this approach (endorsed by the High Blood Pressure Education Program), a thiazide diuretic (e.g., hydrochlorothiazide) is pre48

TABLE 12. -STANDARD “STEPPED-CARE” The physician adds additional antihypertensive therapy previous level of therapy when arterial pressure fails control (<140/90 mm Hg). THERAPY

STAGE

I

One

DRUG

congeners hydrochlorothiazide) plus Rauwolfia derivatives reserpine) or Methyldopa or Propranolol plus Hydralszine or/plus Methyldopa or Guanethidine or Clonidine

DAILY

Thiazide (e.g.,

Two

Three Four

TREATMENT to the maximal to come under

dose of effective

DGSE RANGE

50-

100 mg

0.25-

0.50

mg

500-

3000

mg

(e.g.,

60-320

mg

75-200

mg

500- 3000 mg lo-200 mg 0.4-3.6 mg

scribed first-initially perhaps 25 mg once daily, then twice daily and eventually to 50 mg twice daily. Note particularly that these recommendations specifically use the thiazide diuretics as first selection and not any diuretic. These agents have a more prolonged action and are as effective (if not more so) as the socalled loop diuretics (i.e., furosemide or ethacrynic acid). These latter potent diuretics are extremely useful in treating certain types of hypertension but should not be the first choice in antihypertensive therapy for the patient with uncomplicated hypertension. They may have their best application in the hypertensive patient with impaired renal function, since the thiazide congeners will achieve maximal effectiveness with normal or slightly impaired renal function whereas the “loop diuretics” are effective in renal failure by a progressive increase in the dosage. If diuretic therapy is inadequate alone, the physician may add reserpine (0.25-0.50 mg daily), methyldopa (to as high as 2.0-3.0 gm daily) or clonidine (0.2 to as high as 3.6 mg daily), depending on the response of the patient to lower doses, severity of the hypertensive vascular disease and cardiac involvement and, of course, height of arterial pressure. Although propranolol still must receive Food and Drug Administration approval for use in hypertension* (currently there are as many as 25 beta-adrenergic blocking compounds in use around the world), betaadrenergic blocking drugs may be added to this second selection level of drugs in this “stepped-care” approach. Of course, the beta blocking drugs are contraindicated in patients with history of asthma, obstructive bronchial disease, congestive heart fail“Propranolol

has

now

received

FDA

approval

for use

in hypertension. 49

ure and vasospastic peripheral arterial disease (e.g., Raynaud’s phenomenon, severe atherosclerosis, etc.). The average daily dose of propranolol (the only beta-adrenergic receptor blocking drug commercially available in the United States) varies from 60 to 320 mg. Should these agents (a thiazide diuretic and either methyldopa, reserpine, clonidine or propranolol) be inadequate to provide optimal control of arterial pressure, an oral vasodilating drug (e.g., hydralazine, in daily dosages as high as 200 mg) may be added. In the next stage of stepped care, one of the already considered adrenergic inhibitors may be added to another already used, or the physician may add guanethidine and withdraw one or more of the other drugs (or reduce their dosages). MECHANISTIC (“SPECIFIC”) APPROACH TO ANTIHYPERTENSIVE THERAPY.-As indicated earlier, there really is little practical difference with this approach to antihypertensive therapy except that the physician is not obliged to follow a special prescribed therapeutic “algorhythm.” Indeed, in our experience, it has not been necessary to initiate therapy with a diuretic in every hypertensive patient. Inherent, then, in this therapeutic decisionmaking process is an understanding of the pressor mechanisms involved in hypertensive diseases and an insight into which mechanism seems most operative in a particular patient whose treatment program is under consideration. As indicated in our earlier discussion of the various pressor mechanisms involved in hypertension, it now is possible from the initial evaluation of the hypertensive patient to sort out which mechanism seems to be playing the most important role. Thus, for some patients with mild essential hypertension (in whom a hyperkinetic circulation or cardiac awareness may be present), beta-adrenergic blocking drugs may be indicated. In our experience with propranolol over the past 10 years, many of these patients have responded to this agent alone (average daily dosages of 60- 160 mg) without need for additional diuretic therapy and without developing evidence of “refractoriness” or “pseudotolerance.” In contrast, some patients with rather marked elevations of arterial pressure demonstrate evidence of hemodilution and expansion of intravascular volume associated with low plasma renin activity. These patients do not have hyperaldosteronism or provide other evidence of mineralocorticoid excess but respond dramatically to diuretic therapy. Some patients with mild hypokalemia prior to therapy or who develop hypokalemia with thiazide therapy may respond to spironolactone alone (100 mg daily) or to spironolactone and thiazide in combination. Others with more severe essential hypertension with evidence of vasoconstriction (direct determination of increased vascular resistance, left ventricular hypertrophy and contracted plasma volume with high plasma renin activity) may respond to either the addition of a diuretic and vaso50

dilator to propranolol or to methyldopa either alone or in combination with a thiazide diuretic. In other more severe hypertensive patients, guanethidine may be used; but in this situation, a diuretic should be used concomitantly to minimize the high doses of this potent sym’patholytic agent (and its associated additional effects). New antihypertensive agents may be expected over the next several years. Many of these compounds will be highly specific in their action and use. For example, we have witnessed the withdrawal from the marketplace of an antiepileptic agent, aminoglutethimide. This agent was withdrawn because it produced Addison’s disease; however, it has been used recently in patients with low renin essential hypertension who have been thought to have a steroidal basis of the elevated arterial pressure.86 Although the nature of this steroid still is under active clinical investigation (suggested are 1%OH-desoxycorticosterone and 16-beta-OHdehydroepiandrosterone), aminoglutethimide was able to normalize arterial pressure in these patients, suggesting that the concept behind its use is not only highly intriguing but valid. Therefore, clinicians should anticipate that within the next several years a variety of antihypertensive agents that interrupt adrenal steroidal biosynthesis at a variety of levels will be introduced for investigation in a pharmacologic effort to reduce arterial pressure more specifically. Another group of agents under active, current clinical investigation are compounds that antagonize the renopressor system. We already have discussed the usefulness of the beta-adrenergic receptor inhibitors in decreasing the renal release of renin. Other agents are being studied that compete with angiotensin II for vascular receptor response (e.g., saralsin) or prevent the intrapulmonary conversion of the decapeptide angiotensin I to the octapeptide angiotensin II. These agents not only may be useful in the diagnosis of the secondary high renin hypertensions (e.g., renal arterial disease) but also for the treatment of hypertensive emergencies associated with hyperreninemia (e.g., malignant hypertension). It is therefore anticipated that this wedding of specific antihypertensive drugs with specific operating pressor mechanisms in patients with hypertension will result in better control of arterial pressure with fewer side-effects. SUMMARY Presented in this monograph is a dynamic concept of hypertensive diseases. We all are aware that the appallingly high morbidity and mortality from the consequences of hypertensive diseases can be drastically reduced with antihypertensive therapy, provided that the patients with hypertension are recognized and that they continue to remain on effective therapeutic pro51

grams following their evaluation. Inherent in this concept of “preventive cardiology” is the acknowledgment that evaluation of the hypertensive patient provides a baseline for a lifelong program for the management of a chronic disease. Therefore, discussed herein is the rationale for the evaluation of the findings obtained from the patient’s history, physical examination, laboratory studies and the pathophysiologic concepts of the vascular disease and the cardiac involvement. These considerations should permit judicious selection of an effective treatment program.

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77.

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SELF-ASSESSMENT 1. 2. 3. 4.

e e e b

56

ANSWERS 5. 6. 7. 8.

e d a, b, c e

9. 10. 11. 12. 13.

a, c b, d, a,

b, c, d c, e e c