Hyperlension: Pathophysiology, Diagnosis, and Management. Second Edition. edited by J.H. Laragh and B.M. Brenner, Raven Press, Ltd., New York 0 1995. CHAPTER 164 Historical Development of Antihypertensive Treatment Edward D. Freis Growth of Knowledge in the Nineteenth Century, 2742 The Measurement of Blood Pressure, 2743 Forerunners of Modern Treatment, 2743 Low-Salt Diets, 2743 Surgical Sympathectomy, 2744 The Beginnings of Drug Treatment, 2744 Ganglion-Blocking Drugs, 2745 Veratrum Viride, Hydrazaline, and Reserpine, 2746 The Modern Era of Antihypertensive Drugs, 2747 Thiazide Diuretics, 2747 Guanethidine and Alpha-Methyldopa, 2747 Beta-Adrenergic Blocking Drugs, 2748 Converting-Enzyme Inhibitors, 2748 Calcium Channel Blockers, 2748 Proving the Efficacy of Antihypertensive Drug Treatment, 2748 Summary and Conclusions, 2749 References, 2750 Arterial blood pressure (BP) was not measured clinically until this century. However, the hardness of the arterial pulse has been the subject of considerable medical atten- tion, including treatment, since ancient times. The early history related to hypertension has been collected by Ruskin in his important treatise, Classics in Arterial Hy- pertension (I), and I am indebted to him for much of the following discussion of that period. As early as 2600 B.C. the Yellow Emperor's Classic of Internal Medicine (2) stated, "Nothing surpasses the ex- amination of the pulse, for with it errors cannot be com- mitted. In order to examine whether Yin or Yang pre- dominates, one must distinguish a gentle pulse and one of low tension from a hard and bounding pulse. The heart influences the force and fills the pulse with blood." With remarkable insight the author states, "If too much salt is used in food, the pulse hardens." Also, he indicated the relationship between hypertension and congestive heart failure by stating that, "When the pulse is abundant but tense and hard like a cord there are dropsical swellings." E. D. Freis: Hypertensive Research Unit, Department of Veterans Affairs Medical Center, Washington, D.C. 20422. In the Pulse Classic of Wang, published in 280 A.D., some prognostic guidelines are given such as, "In cases of apoplexy, the pulse should be superficial and slow; if it is firm, rapid and large there is danger. Where there is pulmonary congestion a wiry and large pulse is favor- able; but few can recover quickly if it is small and thready" (1). A medical text from the Ashurbanipal Li- brary at Nineveh (669-626 B.C.) recommended venesec- tion (which reduces BP) and cupping for the treatment of apoplexy. Leeches were used for apoplexy throughout the ancient world. Some ancient Chinese texts advised acupuncture or venesection when the pulse hardens (1). The Romans also were much concerned with the pulse. The Roman patrician Cornelius Celsus (3) pointed out the increased rate and tenseness of the pulse with exercise, passion, and even the doctor's arrival! The latter is reminiscent of what we call today the "white- coat" phenomenon. Lack of temperance in eating, and in emotions were regarded as injurious by ancient Chinese. The Arabic text Al-Azkhora (The Therapy) (1) was even more ex- plicit in stating that "Nothing is more harmful to an aged person than to have a clever cook and a beautiful concu- bine." Hippocrates also said that sudden death is more common in the fat than in the lean (4). 2'741 2742 / CHAPTER 164 Galen (13 l-201 A.D.) was greatly revered until the eighteenth century. Yet he probably held back medical progress at least in some areas. For example, he claimed that the pulse in apoplexy was weak and denied that the plethoric pulse syndrome described by Erasistrates was associated with stroke (5). By failing to associate in- creased arterial tension with apoplexy, Galen may have delayed the understanding of their relationship for many years. On the other hand, Hippocrates (4) believed that pa- ralysis was caused by apoplexy, which in turn, resulted from plethora of the brain. From examining head wounds, he made the important observation that the pa- ralysis occurs on the side opposite the lesion. Venesec- tion, which could reduce the arterial blood pressure, was recommended by the Hippocratic school to relieve cere- bral plethora. This method continued as the major treat- ment for stroke into the eighteenth century. The ancient Greeks and Romans treated apoplexy as an independent disease entity and did not realize its fre- quent connection with high blood pressure, then known as hardening of the pulse. For the treatment of paralysis, Soravas of Ephesus ( 120 A.D.) recommended cupping of the spine to draw the animals spirits down and out (1). He also recommended bleeding and emetics. If the pa- tient was able to survive all this, he probably would make a good recovery. For many centuries there had been bans on doing au- topsies. These bans were lifted (at least in Basel, Switzer- land) in the seventeenth century, when J. J. Wepfer in 1658 reported four individuals who had died of apoplexy (6). In each case he found a cerebral hemorrhage on the side opposite to the paralysis. GROWTH OF KNOWLEDGE IN THE NINETEENTH CENTURY Thomas Young (7) is known for his 1808 Croonian Lecture on the functions ofthe heart and arteries. Young was a man of universal interests and accomplishments. He mastered seven languages; he developed theories of light (Young-Huygens wave theory) and accommo- dation (lens curvature, color vision, astigmatism), and even carried out a partial translation of the Rosetta stone! These were only a part of his many diverse accomplishments. In his studies of the circulation, he found "that the pressure of the blood at the beginning of the great trunk of the aorta is kept up without noticeable loss down to the branches of the lower order." The statement is essen- tially correct. He claimed to have measured the percent fall in systolic and diastolic blood pressure in dogs from the aorta to mesenteric arteries of 200-pm diameter. The decrement averaged 16 mm Hg. Approximately 150 years later, we remeasured the pressure drop using mod- ern dynamic equipment (8) and found an average pres- sure drop of 17% systolic and 12% diastolic from aorta to mesenteric arteries of 200~pm diameter-a remarkable agreement, considering the methods used in Young's time. Young also affirmed the dependence of the quality of the arterial pulsation upon the force of the heart. One of the best known contributors to the history of hypertension is Richard Bright (9) although there were others who preceded him in some aspects of his work. In the sixth century A.D., Aetios described sclerosis of the kidneys with possible manifestations of oliguria, hema- turia, and dropsy in the absence of pain. Albuminuria was first noted by Cotugo in 1770 (1). In 176 1, Morgagni found enlargement of the heart in autopsies exhibiting extensive hardening of the arteries (1). Bright's principal contribution was to bring these var- ious observations together, such as albuminuria, fullness and hardness of the pulse, and dropsy with inflammation or hardening of the kidneys. These were presented in well-described case histories illustrated by excellent color illustrations. In 1836 he expanded his observations to in- clude apoplexy, serositis, hypertrophy of the left ventri- cle, and diminution of the specific gravity and urea content of the urine with increase in blood urea. He listed scarlatina or some other acute disease as the cause of this condition. Because of these accurate observations, Bright's disease and glomerulonephritis became synony- mous. Bright also provided an accurate pathological description of glomerulonephritis and probably of nephrosclerosis as well. With respect to the latter, he noted the thickening of the arterioles not only in the kid- neys but also throughout the body. In 1872, Gull and Sutton ( 10) postulated that Bright's disease was in fact due to a primary generalized deposi- tion of "hyaline fibrinoid" in arterioles and capillaries. This arteriolar change, in turn, resulted in both hyper-' trophy of the left ventricle and contracted kidneys. In 1874, Mahomed (11) was the first to state that hyperten- sion could occur without primary renal disease, that ar- teriocapillary fibrosis began as generalized hypertensive (not nephrogenic) lesions. Although the ophthalmo- scope was developed by Helmholtz in 185 1, a clear description of the constricted retinal vessels as related to hypertension was not described until 1876, by Gowers ( 12). The physician principally responsible for popularizing the concept of hypertensive disease was Sir Clifford All- butt. In 1895 he presented his views on "senile plethora" and "hyperpiesia" as a generalized primary vascular dis- ease separate from glomerulonephritis ( 13). This was not original, since he was using the concepts previously de- veloped by Mahomed. Although he had little new to con- tribute, he wrote well and spoke well, which won him fame and a knighthood. Allbutt also separated hyperten- HISTORICAL DEVELOPMENTOFTREATMENT / 2'743 sive vascular disease from arteriosclerosis, stating that hypertension could occur without arteriosclerosis and vice versa. In Germany, Frank (14) used the terms white and red hypertension to distinguish the two forms of primary re- nal as compared to primary generalized arteriosclerotic disease. Also in Germany the latter was named hyper- tonie essential, which might be freely translated as "pri- mary hypertension." Unfortunately, many physicians interpreted the term to mean that hypertension was an essential adaptive reaction, a concept that discouraged any attempt to lower the blood pressure. This led to the confusing term essential hypertension. A more accurate term was given by Janeway ( 15), who, in 19 13, described the varied course of hypertension and called the disorder "hypertensive cardiovascular disease." THE MEASUREMENT OF BLOOD PRESSURE Real progress in understanding hypertension and its treatment came with the measurement of BP quantita- tively, beginning with the studies of a small-town parson in eighteenth-century England. Stephen Hales per- formed his now-famous BP experiments in his backyard using horses. The animals were tied down to a wooden gate without anesthesia (16). A brass pipe was inserted into the carotid artery connected to a vertical glass tube by a flexible connection made from the windpipe of a goose. While a servant stood on a chair to hold up the tube, the blood rose 9 feet 6 inches in height initially and then gradually fell. The animals died when the blood in the tube fell to approximately 2 feet. Fifty years after Hales measured BP directly, Poiseuille (17) introduced the mercury hydrodynometer, thereby greatly reducing the height of the column needed for measuring the blood pressure. In 1864, Carl Ludwig ( 18), the great German physiologist from Leipsig, added a float to Poiseuille's mercury manometer with a connect- ing arm, which inscribed the arterial pulse wave on a moving smoked drum, thereby making a permanent record. Essential hypertension as a clinical entity was clearly defined, however, only after the development of nonin- vasive methods for measuring BP in humans, which oc- curred at the beginning of this century. Since hyperten- sion is an asymptomatic disorder, its recognition in humans depended upon the development of a simple noninvasive instrument for recording the level of blood pressure in the doctor's office. The early indirect at- tempts proved to be impractical. They were mostly aimed at measuring the systolic BP only, by determining the force required to obliterate the pulse. For example, von Basch ( 19), in 1880, employed a mercury-filled ma- nometer with a rubber bulb resting on the radial artery. He recorded the systolic blood pressure as the force re- quired to obliterate the pulse. In 1889, von Helmholtz made important improvements in the von Basch instru- ment; this led him to find, for the first time, hypertension in the radial and temporal arteries but not in the dorsalis pedis artery in coarctation of the aorta, which he also correctly surmised caused the left ventricular hypertro- phy found in this disorder. The next important step was made by Riva-Rocci (20). In 1896, he developed a wraparound inflatable rub- ber cuff to occlude the artery in the upper arm. Subse- quently, von Recklinghausen (2 1) increased the width of the cuff from 5 to 14 cm to obtain better accuracy on the adult arm. Riva-Rocci recorded only the systolic blood pressure, which he determined by using the first pulse that he could palpate as the cuff was slowly deflated. The landmark breakthrough, which made blood pres- sure measurement a routine office procedure, came from Nikolai Sergeyevich Korotkoff (22). In 1905, he de- scribed the sounds that he heard with a stethoscope placed over the brachial artery below the Riva-Rocci- von Recklinghausen inflatable cuff during its slow defla- tion. Korotkoff was a privatdocent at the Imperial Mili- tary Medical Academy of St. Petersburg when Pavlov was a professor of physiology. Unlike the lengthy report- ing style of his time, Korotkoffs communication was very succinct, covering less than two pages. In it he de- scribed the phases of the sounds and their probable ori- gins based on his animal experiments. He also clearly de- fined the sounds that indicated systolic and diastolic blood pressure. Clinical recording of blood pressure then spread rapidly throughout the world. FORERUNNERS OF MODERN TREATMENT Another highly important development at that time was the discovery of renin by Tigerstedt and Bergman (23) the Scandinavian researchers who, in 1897, dem- onstrated a pressor principle in kidney extracts. Their pi- oneering effort led to the later discoveries by Goldblatt et al. (24), Page et al. (25) and Braun-Menendez et al. (26). These fundamental advances led to the surgical correc- tion of renovascular hypertension. In addition, the dis- covery of the renin-angiotensin system led to the recent development of a series of important antihypertensive drugs, the converting-enzyme inhibitors. Low-Salt Diets The importance of salt in the diet was discovered in 1904 by Ambard and Beaujard (27), who were then med- ical students in Paris. Their emphasis was on chloride. However, in reducing dietary chloride they were also re- stricting sodium, which is probably more important in 2744 / CHAPTER 164 hypertension control. Their observations preceded the use of diets extremely low in salt, which became popular in the 1940s. The success of these diets stimulated the development of the thiazide diuretics. Several investigators, such as Watkin et al. (28) and Murphy (29) found that the rice diet of Kempner (30) depended on severe sodium restriction to levels as low as 20 to 30 mEq/day. Moderate salt restriction (as is often prescribed today) was ineffective in these patients, possi- bly because they all had severe hypertension. Whether moderate restriction (approximately 80 mEq/day) is effective in milder forms of hypertension remains a con- troversial question: some investigators claim that it is (31-33) whereas others claim that it is not (34-36). Several investigators of the rice and fruit diet found that the marked sodium restriction leads to a reduction in plasma and extracellular fluid volume, which, in turn, is associated with the fall of BP (28,29). Extracellular fluid volume was reduced about 1 to 2 L, and plasma volume was reduced by approximately 500 ml. Dustan et al. (37) and ourselves (38) independently found a similar reduction of plasma and extracellular fluid volumes dur- ing treatment with thiazide diuretics. This suggests that the antihypertensive mechanism in both of these inter- ventions is probably volume-dependent. It also suggests that sodium deprivation will probably not be very effective unless it is restrictive enough to cause some vol- ume depletion (28,29,38,39). Surgical Sympathectomy The vasoconstrictor and cardioaccelerator properties of the sympathetic nervous system had long been known, but it was Kraus who urged the surgeon Fritz Bruening (40) to perform the first sympathectomy operation for hypertension in 1923. More extensive operations were developed by American surgeons in subsequent years, including Peet (4 l), Smithwick (42) and others. The ex- perience with surgical sympathectomy led to the devel- opment of drugs producing chemical sympathectomy. These ganglion-blocking agents included tetraethylam- monium chloride (43), hexamethonium (44) penta- quine (45), bretylium (46), and others. THE BEGINNINGS OF DRUG TREATMENT Prior to World War II there were no effective antihy- pertensive drugs. Sodium thiocyanate was first used by Treupel and Edinger (47) in 1900 and sporadically there- after, including Hines (48) at the Mayo Clinic. Its effectiveness was not demonstrated by controlled trials, and it was potentially toxic. Blood level measurements were required in order to keep the dosage within a safe range; even then, side effects were not infrequent. For these reasons the drug never became popular. Drug treatment, however, was held back primarily by the prevailing attitude of therapeutic nihilism, popular- ized and given respectability by most leading medical au- thorities. Well into the 1960s some experts in the field believed that the arterial disease was the cause of the hy- pertension, rather than the result (49). The prevailing opinion scoffed at the use of drugs as "treatment of the manometer rather than of the patient." The frequent toxicity associated with the early drug treatment of hy- pertension only reinforced this opinion. To my knowledge, the first effective drug treatment of malignant hypertension was in 1947 with the use of the World War II antimalarial agent, pentaquine. At that time, the head of the Squibb Institute for Medical Re- search, which developed pentaquine, was James Shan- non, who later became the first director of the National Institutes of Health. During the preclinical testing phase, it had been found that large oral doses of pentaquine led to a reduction of BP with severe orthostatic hypotension. Shannon proposed that Squibb should initiate a program to develop drugs that would lower BP, of which penta- quine would be the first example. To carry out the clini- cal portion of the program he turned to Chester Keefer, chairman of the Department of Medicine at Boston Uni- versity, where I was a medical resident. Keefer asked me to test pentaquine and subsequent drugs, if any, in hy- pertensive patients. In 1946, I gave pentaquine to 17 patients with moder- ately severe to severe hypertension, including three with malignant hypertension (45). All patients were hospital- ized for the therapeutic trial. After several days of treat- ment, supine blood pressure fell 10% to 40% below the baseline level (Fig. 1). Orthostatic hypotension was often severe at first but was usually moderate with continued administration of the drug. Side effects, however, were especially troublesome, consisting of abdominal pain and tenderness, back and chest pains, facial pallor, anorexia, nausea and vomiting, and constipation or diarrhea. The three patients with malignant-phase hypertension showed reversal of their neuroretinitis, relief of head- ache, and clearing of congestive heart failure; however, there was no improvement in renal failure, which was already far advanced. Hemodynamic studies disclosed a reduction of sympathetic vasopressor reflexes such as or- thostatic hypotension, inhibition of the Valsalva over- shoot following a forced expiration, and abolition of skin temperature gradients from foot to abdomen. Two years later, Page and Taylor (50) reported on reversal of malig- nant hypertension using pyrogen therapy. However, side effects also limited its use. Pentaquine represented an important step toward effective treatment, because it demonstrated for the first time that some of the pathological manifestations of ma- lignant hypertension were reversed by reducing BP with drug treatment and that amelioration of less severe forms HISTORICALDEVELOPMENTOFTREATMENT / 2745 ARTERIAL PRESSURE MM `46 PULSE FIG. 1. Response to pentaquine in a patient with severe hy- pertension. The drug was increased, by daily increments, to a dose of 200 mg/day, at which point supine BP fell from ap- proximately 230/l 30 to 170/l 05 mm Hg. The dotted vertical lines represent BP in the orthostatic position. Following dis- continuation of pentaquine the BP gradually rose over a pe- riod of 2 weeks, to pretreatment levels. (From ref. 45, with permission.) of hypertension might occur with the same approach. Our results with pentaquine, therefore, were contrary to the prevailing opinion that reduction of BP, per se, was not beneficial and they also encouraged the development of new drugs with fewer side effects for the treatment of hypertension. Ganglion-Blocking Drugs Interest in the ganglion-blocking drugs began with the observations of Acheson and Moe (51), who demon- strated in animals that tetraethylammonium blocks transmission of autonomic nerve impulses. In 1947, Ly- ons et al. (43) reported on studies in patients. Because of the need for parenteral administration and especially because of its brief duration of action, it was not a prac- tical drug for treating hypertension; Lyons et al. recom- mended the drug primarily for evaluation of sympathetic activity in selecting patients for surgical sympathectomy and for the treatment of causalgic states. Hoobler et al. (52) described the hemodynamic effects of tetraethylammonium. Following intravenous admin- istration of the drug, they found a marked increase in blood flow to the extremities, particularly to the foot. Digital skin temperature rose to equal that of the thigh. Vasodilatation was not found in the sympathectomized extremity, proving that the effect of the drug on limb blood flow was due to sympathetic blockade. More potent and longer-acting ganglion-blocking agents such as hexamethonium soon were developed that completely blocked the sympathetic nerves as judged by increases in foot blood flow (53). Hexametho- nium was introduced by Paton and Zaimis (54), who de- scribed its pharmacological properties in 1948. Arnold and Rosenheim (55) used the drug in hypertensive pa- tients only for brief periods of time and for studies on the peripheral circulation, not as a therapeutic agent in hypertension. Finnerty and Freis (56) also used the drug in patients with peripheral vascular disease. Our main objections to hexamethonium for long-term use in treat- ing hypertension were the need for parenteral injections at least twice per day and the many side effects of both sympathetic and parasympathetic blockade. The first published report on the short-term effects of hexamethonium in hypertension was by Burt and Gra- ham (57) in 1950. Horace Smirk first saw the possibilities of prolonged treatment of hypertension with hexame- thonium despite its side effects. In 1950, Restall and Smirk (58) described the treatment of 15 patients with severe hypertension. BP was controlled by subcutaneous injections two to three times per day. Effective dosage varied widely, from 5 to 500 mg per dose. Despite or- thostatic hypotension and many other side effects that result from both sympathetic and parasympathetic blockade, Restall and Smirk reported regression of the funduscopic signs of malignant hypertension, reduction in heart size, and dramatic clearing of the signs and symptoms of heart failure. This is the response we had seen previously with pentaquine-induced reduction of BP. Our group found that in hypertensive patients without heart disease hexamethonium reduced BP primarily by a fall in cardiac output (59). Pressures fell not only on the arterial side but also on the venous side of the circulation; that is, there was venodilatation as well as arteriolar dila- tation. By contrast, in patients with congestive heart fail- ure the cardiac output increased (59). The marked im- provement in cardiac failure was not limited to hypertensive patients but also included those with other forms of heart disease (60). We interpreted our results (60) as follows: Hexamethonium may interrupt the congestive failure cycle at two points: (1) By decreasing the total peripheral resistance the work demand on the left ventricle is les- sened [previously the entire emphasis was on reducing the overloaded right side of the heart with phlebotomy, venous tourniquets, and the like]. (2) Also, by reducing the filling pressure ofthe right heart the overloaded right ventricle is able to contract more effectively. These data supply evidence that the degree of constriction of the pe- ripheral vessels both arterioles and veins may have an important influence on the function of the failing heart. [Fig. 21 Our data suggested that decreased BP and afterload were important in treating heart failure. This concept passed unnoticed by the medical community until 20 years later, when it was rediscovered by Cohn (6 1) and others (62)-although similar findings and conclusions had 2746 / CHAPTER 164 \ REFLEX ARTERIAL & FOST -ARTERlOLAR CONSTRICTION SHIFT TO LARGE VEINS FIG. 2. Chart illustrating concept of combined effects of arteriolar resistance (increased af- terload) and postarteriolar constriction (increased preload) in establishing a "vicious cycle" in the fail- ing heart, which was reversed by blocking the alpha-sympathetic system to both arterioles and veins with hexamethonium. (From ref. 60, with permission.) also been made simultaneously with our report by Brod and Fejfar (63). Hexamethonium also provided us with a vivid picture of the critical importance of the sympathetic nervous sys- tem in stabilizing the BP in the face of minor degrees of blood loss. In supine subjects following hexamethonium blockade, we removed blood by venesection into a blood transfusion bottle. With each 50 ml of blood taken from the patient there was a definite fall in BP, and when only approximately 350 ml was removed the BP had fallen to collapse levels (Fig. 3). We then rapidly reinfused the blood, and with each increment returned there was a cor- responding rise of BP. When all the blood had been re- turned the BP was restored to the baseline level (64). Therefore, in the presence of sympathetic blockade, blood pressure rises or falls in direct proportion to even minor degrees of blood loss that would have no effect when the sympathetic nervous system is able to respond. Veratrum Viride, Hydralazine, and Reserpine Veratrum viride is a shrub found in the foothills of the Allegheny mountains and elsewhere. In the nineteenth century, tincture of Veratrum viride was used by some American physicians to soften and slow the pulse (the former being due to a large fall in BP) in patients with febrile illnesses (65). Veratrum produced an initial decrease in BP, heart rate, and regional blood flow followed within a few min- ARTERIAL PRESSURE-MM HG 160 T BLOOD REMOVED BY VENESECTION AND RETRANSFUSED-CC. FIG. 3. Chart of arterial pressure and of the amount of blood removed by venesection and retransfused following administration of hexa- methonium (50 mg, IV). With the sympathetic nervous system blocked, there was a step- wise decrease of BP, beginning with the first 50 ml removed. With reinfusion of blood, BP paralleled the volume of blood reinfused. 5 There was no evidence of "compensation" as 0 IO 15 20 25 30 occurs with an unblocked sympathetic ner- MINUTES vous system. (From ref. 64, with permission.) HISTORICALDEVELOPMENTOFTREATMENT / 274'7 utes by a further decrease in arterial pressure and heart rate and a return of hepatic, renal, and muscle blood flows to essentially normal values. Unlike hexametho- nium, cardiac output remained unchanged after Vera- trum while total peripheral resistance fell (67). Side effects limited its clinical use. Hydralazine was developed soon after the introduc- tion of the ganglion-blocking agents. It was first studied by Reubi (68), who found that it was a vasodilator that increased renal blood flow. Hemodynamic studies indi- cated that as blood pressure fell, cardiac output increased while central venous and right heart pressure rose (69). These findings suggested that hydralazine dilates only the arterial side of the circulation and not the veins. In fact, the latter probably constrict through activation of the sympathetic nerves via the baroreceptors. This re- sults in the unusual combination of (a) arteriolar dilata- tion due to direct drug action and (b) venoconstriction due to reflex action-resulting in a rise of venous pres- sure and, therefore, an increase in the preload of the heart. Whereas some physicians abandoned hydralazine be- cause of the toxicity observed with high doses, we and others found that severe toxicity need not occur if doses are restricted to less than 200 mg/day. Hydralazine is only occasionally used today, usually for specific condi- tions such as toxemia of pregnancy. Reserpine appears to be a much underrated drug. Al- though it can produce side effects such as stuffy nose, de- pression, and impotence, these appear to be uncommon with low doses (70). In combination with a diuretic, it is one of our most effective antihypertensive regimens. The effectiveness of this combination has been demonstrated in several Veterans Administration cooperative studies (70,7 1). Furthermore, its effectiveness remains un- changed if the dose is reduced from the usual 0.25 mg/ day to a dose of 0.1 mg/day (70) thereby further mini- mizing side effects. One thiazide-reserpine combination tablet daily containing 0.1 mg reserpine and 25 or 50 mg hydrochlorothiazide should be an ideal treatment in Third-World countries because it is not only effective in a high percentage of patients, it is simply administered, being given in a fixed dose once daily, and it is also by far the least expensive of all effective antihypertensive regimens. THE MODERN ERA OF ANTIHYPERTENSIVE DRUGS Thiazide Diuretics The most important breakthrough in the history of the drug treatment of hypertension came with the discovery of the orally effective diuretic, chlorothiazide. The thia- zide diuretics were discovered by Beyer and Sprague (72). In hypertensive patients chlorothiazide was effective in reducing BP and produced the same volume changes (37,38) as the strict low-salt diet (28,29). Fur- thermore, the drug was much more acceptable to the pa- tients than a strict diet (73). Chlorothiazide was not only effective when used alone but it also enhanced the antihypertensive activity of other drugs. This permitted smaller and less toxic doses of the latter drugs, thereby allowing effective BP control in most patients with greatly reduced side effects. Be- cause of these properties, the drug treatment of hyper- tension came of age. Despite a number of excellent drugs, that have been developed in subsequent years, the thiazides remain among the most effective. The current fear of hypokalemic effects of thiazides on the heart or of long-term elevation of cholesterol appears to be un- founded (74). The diuretics are the only drugs that re- duce extracellular volume. This appears to be a most im- portant mechanism for controlling BP over the long term. An interesting feature of the hemodynamic effects of thiazide diuretics is that although the early reduction of BP is associated with a fall in cardiac output, this be- comes converted after approximately 1 month to a fall in total peripheral resistance and a rise in cardiac output, back to pretreatment levels (75). Ledingham and Cohen (76), Borst and Borst (77) and Guyton et al. (78) demonstrated the opposite effect dur- ing the development of salt-loading hypertension; cardiac output rose resulting in a high-output, normal resistance type of hypertension. After 1 to 2 months, however, total peripheral vascular resistance increased and cardiac output fell, returning to normal, resulting in the high resistance type of chronic hypertension seen clinically. The mechanism of these late changes is un- known. It has been called "delayed autoregulation" in the case of salt-loading hypertension (78) and "reverse autoregulation" (83) in the response to diuretics. Guanethidine and Alpha-Methyldopa Guanethidine is a selective blocker of the peripheral sympathetic nervous system (80). This drug was never well accepted because of difficulty in adjusting dosage to avoid orthostatic hypotension. Guanethidine also had some unusual side effects, including (a) retrograde ejacu- lation into the urinary bladder and (b) urgency of defe- cation due apparently to unopposed parasympathetic activity. Alpha-methyldopa represented the first centrally act- ing sympathetic inhibiting drug (8 1). It is less frequently prescribed today because of the development of more effective drugs. 2748 / CHAPTER 164 Beta-Adrenergic Blocking Drugs Prichard and Gillam (82) were the first to demonstrate the effectiveness of the beta-blocking drugs in hyperten- sion. Some physicians preferred them to diuretics as primary therapy. Some beta blockers are more cardio- selective than others, some have sympathomimetic effects, and others (such as labetolol) have additional a- adrenergic blocking effects. Converting-Enzyme Inhibitors The development of the converting-enzyme inhibitor captopril represents a major advance in antihypertensive drug treatment. Ondetti and his colleagues (84) in 1977 reported the synthesis of an inhibitor that blocks the en- zyme that converts inactive angiotension I to active an- giotension II. This class of compounds has since gained wide application in controlling hypotension and in treat- ing congestive heart failure. A Veterans Administration study demonstrated that captopril was as effective in small doses as in large doses (85). The study also demonstrated that when hydrochlo- rothiazide was added to captopril the fall in BP was sig- nificantly greater than with captopril alone and was with- out side effects of faintness, weakness, or impotence. Calcium Channel Blockers Calcium ions play an important role in many biologi- cal processes, including vascular smooth muscle contrac- tion. A number of calcium channel blockers are effective vasodilator antihypertensive agents such as nifedipine, verapamil, and diltiazem. They are also effective in treat- ing angina pectoris, and verapamil, in particular, slows atrioventricular conduction. Other favorable features in the hypertensive heart include coronary vasodilatation, accelerated ventricular relaxation, and improvement in subendocardial perfusion. PROVING THE EFFICACY OF ANTIHYPERTENSIVE DRUG TREATMENT The effectiveness of antihypertensive drug treatment in preventing cardiovascular complications is based on the theory that the elevated blood pressure, per se, pro- duces reactive hyperplastic and hyaline fibrotic changes in the arteries and arterioles as well hypertrophy of the left ventricle. During the predrug era it was believed that the vascular structural alterations were the initial change causing increased peripheral resistance, which in turn produced hypertension. The general acceptance of this concept of a secondary role for the hypertension became the basis for denying the value of reducing the blood pressure. Others believed that hypertension began as a func- tional, not structural constriction of the arterioles. The structural changes followed later as a reaction to the in- creased blood pressure. By lowering BP the vascular dis- ease could be arrested or, perhaps, reversed. Although drugs for lowering blood pressure were available in the 1950s and 1960s it had not been deter- mined whether they could reduce morbidity and mortal- ity in hypertensive patients (86). Except for the malig- nant phase of hypertension most physicians were reluctant to treat patients with less severe degrees of the disorder. This opinion was reversed, however, by the re- sults of the Veterans Administration (VA) Cooperative Study reported in 1967 (87) and 1970 (88). This con- trolled trial established beyond any reasonable doubt that the complications of moderate to severe essential hypertension were preventable by lowering the blood pressure with antihypertensive drugs. The VA studies were widely publicized by the National High Blood Pres- sure Education Program, an agency established by the then Secretary of Health, Education, and Welfare, Elliot Richardson. The Veterans Administration trial demonstrated that in patients with initial diastolic BP between 90 and 114 mm Hg the risk of developing a major cardiovascular complication over a j-year period was significantly re- duced with treatment as compared with placebo (Fig. 4). However, the results were favorable but not significant in the subgroup patients with mild hypertension between 90 and 104 mm Hg diastolic. Results in the mild group were indecisive probably because of the fewer complica- tions occurring in mild hypertension, which required a larger sample size than was available in the VA trial. This opened the way for larger trials focusing on mild hypertension. The Australian trial (89) found that treatment was sig- nificantly effective in preventing stroke and was margin- ally effective in reducing coronary heart disease (CHD) at all levels of entry diastolic BP from 95 to 109 mm Hg. The less well-controlled Hypertension Detection and Follow-up Program (HDFP) reported that treatment was effective in reducing cardiovascular mortality including CHD at diastolic BP levels of 90 to 104 mm Hg (90). The largest study, the well-controlled Medical Research Council (MRC) trial (9 l), concluded that although treat- ment of patients with entry diastolic BP of 90 to 109 mm Hg was effective, the benefit was small in mild hyperten- sion. There was a significant reduction in stroke in the treated group but not in CHD. Considering these and other trials it seems probable that treatment is effective in mild diastolic hypertension. More recent trials have demonstrated equally if not more effective reduction of complications in elderly pa- tients with hypertension. The MRC trial in over 4,000 patients ages 65 to 74 years showed significant reduction in both strokes and CHD in patients receiving thiazide HISTORICALDEVELOPMENTOFTREATMENT / 2749 1 2 3 4 5 Ywrc of Obmrmtion FIG. 4. Estimated cumulative incidence of major cardiovascular morbidity over a 5year period as calcu- lated by the life-table method. There is an increasing difference in morbidity-mortality over 5 years (55% versus 18%) between the control and treated oroups, representing a 67% effectiveness of treatment (37/55). (From ref. 87, with permission.) - plus amiloride but not in those treated with the beta blocker atenolol (92). In the STOP (Swedish trial in old patients)-Hypertension trial in the elderly the reduction in complications with treatment was seen at all age groups including those 80 to 84 years old (93). The SHEP (systolic hypertension in the elderly program) trial inves- tigated the effectiveness of treatment in elderly patients with isolated systolic hypertension (94). Stroke was re- duced by 30 events per 1,000 patients. Thus, drug treat- ment has been shown to be effective in aged as well as younger patients. Furthermore, the treatments were well tolerated despite the patients' age. It is important to point out an additional benefit of treatment. Prior to the development of effective antihy- pertensive therapy many patients, especially the young and middle-aged, developed rapid progression of their hypertension. This often culminated in malignant hy- pertension or some other severe complication such as re- nal failure, congestive heart failure, or aortic dissection. Death usually occurred within a matter of months after the diastolic BP reached 140 mm Hg or more. Such pa- tients were formerly often seen on the hospital wards but are rarely encountered today. The effectiveness of pre- venting this problem has not been studied in the various clinical trials because untreated control patients exhibit- ing progressive elevations of BP have been promptly re- moved from the trial and treated openly with antihyper- tensive drugs, thus preventing further progression of the hypertension to severe levels. This successful prevention of progression to severe hypertension is one of the most important benefits of antihypertensive treatment. The various control trials have demonstrated that an- tihypertensive drug treatment is effective in reducing the cardiovascular complications of hypertension. This demonstration provides strong evidence that morbidity and mortality are the result of the elevated BP per se, and not to primary cardiovascular changes independent of the BP. Although the fundamental pathogenetic factor or factors that initiate hypertension are still unknown the cause of the complications has been clarified. It is the hypertension itself. SUMMARY AND CONCLUSIONS A method for measuring BP clinically was discovered less than 100 years ago. Prior to this, the disorder that we now call hypertension could be suspected only by the quality of the pulse. In ancient times a hard pulse-that is, one that was difficult to compress-was often treated with bleeding and leeches, which resulted in at least a 2750 / CHAPI`ER 164 temporary reduction of BP. In 1827, Bright (9) recog- in hypertensive patients. Reduction of BP generally has nized an inflammatory disorder of the kidney that been less successful in preventing myocardial infarction caused a generalized cardiovascular disease leading to than in preventing stroke. It seems probable that with dropsy, apoplexy, and uremia. Later, Mahomed (11) and simultaneous reduction of other risk factors for coronary Allbutt (13) described a primary, generalized, fibrosis of heart disease we may look forward to greater effective- the arterioles that did not originate in the kidney-a con- ness in treating this most important cause of death in dition that we now recognize as essential hypertension. hypertension. In 1905, Korotkoff (22) developed a clinically applica- ble method for measuring BP. This landmark discovery permitted epidemiological studies of BP in relation to cardiovascular mortality. It was primarily the Society of Actuaries (95) who, in the 1920s recognized the great prevalence and high risk of the disorder. Although it was clear to the insurance companies that a diastolic BP of 95 mm Hg or higher shortened life because of cardiovas- cular complications, their data relative to mild and mod- erate hypertension were dismissed by most physicians of the time. However, definitive proof was eventually pro- vided by Kannel and coworkers (96) in the classic Fra- mingham Study, which demonstrated beyond any doubt the importance of hypertension as a cardiovascular risk factor. REFERENCES 1. Ruskin A. Classics in arterial hypertension. Springfield IL: Charles C Thomas, 1956. 2. Nei Ching. Yellow emperor's classicof internal medicine. Books 2- 9, published between 2698 and 2598 B.C. 3. Ceisus AAC De Re Medicina, 3 vols, transl. W Spencer. London: Heinemann, 1935-1938. 4. Hippocrates. Genuine works ofHippocrates, 2 vols, transl. F Ad- ams. London: Sydenham Society, 1849. 5. Galen C. Introduction in Pulsus ad Teuthram. interpreted by M Gregory. London: Guliel Rovillius, 1959. 6. Except for rest and sedatives (which had no real anti- hypertensive effect), hypertension remained an un- treated disease until the 1940s when sympathectomy and the rice diet were advised for patients with severe hypertension. The first successful use of antihypertensive drugs in causing remission of malignant hypertension occurred in the late 1940s-initially with pentaquine and a few years later with hexamethonium. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. The early drugs had many side effects and it was not until the 1950s that the first breakthrough occurred with the development of chlorothiazide. This drug was highly effective orally, it was well tolerated, and it enhanced the antihypertensive effectiveness of other drugs when given in combination with them. The beta blockers repre- sented the leading advance of the 1960s followed in re- cent years by the converting-enzyme blockers and the calcium-channel blockers as major therapeutic agents. 17. 18. 19. 20. 21. 22. 23. 24. As recently as 25 years ago the effectiveness of antihy- pertensive drug treatment of moderate essential hyper- tension was still disputed. The issue was finally settled by a controlled clinical trial, the Veterans Administration Cooperative Study, which demonstrated beyond any reasonable doubt that drug treatment was effective in preventing the complications of moderate hypertension (diastolic BP of 105 mm Hg and above). Large-scale tri- als followed, which determined that treatment was also effective in mild asymptomatic hypertension (diastolic BP of 90-104 mm Hg). Other trials demonstrated the effectiveness of treatment in elderly patients, including those with isolated systolic hypertension. 25. 26. 27. 28. 29. 30. 31. 32. It is remarkable that it has taken less than 90 years from the time high blood pressure was first recognized clinically to the present period of effective control. Coro- nary heart disease is the most common cause of death 33. 34. 35. 36. 37. 38. Wepfer JJ. Observationes dnatomicae e.x Cadaveribus eorum quos sustilit Apoplexia. Cum Exercitatione de ejus Loco Affecto. Shaff- hausen: Johann Casper Suterus, 1958. Young TJ. Philos Tram R Sot Lond 1809; 1: l-3 I Sugiura T, Freis ED. Circ Res 1962; 11:838-843. Bright R. Guy's Hosp Rep 1836; 1:338-379. Gull WW, Sutton HG. Med Chir Tram Lond 1872;65:273-326. Mahomed FA. Guy's Hasp Rep 1881;25:295-416. Gowers W. Br Med J 1876;2:743-745. Allbutt TC. Transaction of the Hunter Society I 895- 1896, 77th session, 1986;38-57. Frank 0. Z Biol 1925;82:49-57. Janeway TC. Guide to the use of the sphygmomanometer. New York: D Appleton, 1904. Hales S. Statistical Essays: containing Hemostaiics London: In- nys and Manby, 1933. Poiseuille JLM. Arch Gen Med 1828;550-554. Ludwig C. Arch Anat Physiol U `issen Med (Mullrr'.s Arch) 1847;242-302. von Basch S. 2 Klin Med 1880:2:79-96. Riva-Rocci S. Ga:a Med Torino 1896;47:98 I-1001. von Recklinghausen H. Arch Exp Pathol Pharmacol 190 1:46. KorotkoffNS. Izvestiya Imperatorskoi Voenno-MeditsinskoyAka- demii (Rep ImperMil-Med Acca St Petersburg). 1905: 1 11365-367. Tigerstedt R, Bergman PG. Stand Arch Physiol 1897-1898;7-8: 223-271. Goldblatt H, Lynch T, Hanzal RF, Summerville WW. J Exp Med 1934;59:347-379. Page IH, Helmer OM. JExpMed 1940;71:495-520. Braun-Menendez EJ, Fasciolo C, Le Loir F, Munoz M. J Physiol (Land) 1940;98:283-298. Ambard L. Beauiard E. Arch Gen Med 1904: 1:520-523. Watkin DM, Fiaeb HF, Hatch FI, Gutman AB. Am J Med 1950;9:441-448. Murphy RJF. JClin Invest 1950;29:912-920. Kempner W. N Carolina h4ed J 1944; 5: 125,273. MacGregor GA, Best FE, Cam JM, et al. Lancet 1982; 1:351-355. Parijis J, Joosens JV, Van der Linden L, Verstrecken G, Amery AKPC. Am Heart J 1973;85:22-34. Morgan T, Gillies A, Morgan G. Adam W, Wilson M, Carney S. Lancer 1978; I:227-230. Richards AM, Espiner EA, Maslowski AH. et al. Lancet 1984; I: 757-761. Watt GCM, Edward C, Hart JT, Walton P, Fay CJW. Br Med J 1983;286:432-435, Silman AJ, Mitchell P, Locke C, Humpherson P. Lancet 1983; I: 1170-1182. Dustan HP, Cumming GR. Corcoran AC, Page IH. Circulation 1959; 19:360. Wilson IM, Freis ED. Circulation 1959;20: 1028. HISTORICALDEVELOPMENT OF TREATMENT / 2751 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. IO. Beard T, Gray WR, Cooke HM, Barge R. Lancet 1982;2:455-458. Bruening F. Klin Wochenschr 1947;236:270-276. Peet MM. N Engl JMed 1947;236:270-276. Smithwick RH, Thompson JE. JAMA 1953; 152: 1501-1504. Lyons RH, Moe GK, Neligh RM, Hoobler SW, Campbell KN, Berry RL, Rennick BR. Am JMedSci 1947;213:315-323. Smirk FH. NZ Med J 1950;49:637-643. Freis ED, Wilkins RW. Proc Sot Exp BiolMed 1947;64:73 l-736. Freis ED. Heart Bull 1960;9:88. Treupel G, Edinger A. Munch Med Wochenschr 1900;47:7 17-720. Hines EA. Med Clin North Am 1946: 30:869-877. Goldring W, Chasis H. In: Ingelfinger FJ, eds. Controversies in in- ternal medicine. Philadelphia: WB Saunders, 1966; 83-9 1. Page IH, Taylor RD. Mod Concepts Cardiovasc Dis 1949; 185 l- 52. Acheson GH, Moe GK. J Pharmacol Exp Ther 1946; 87:220-226. Hoobler SW. Malton SD, Ballantine TH Jr, Cohen SW, Nehgh RB, Peet MM, Lyons RH. JClin Invest 1949;28:638-647. Schnaper HW, Johnson RL, Touhy EB, Freis ED. J Clin Invest 1951;30:786-791. Paton WDM, Zaimis EJ. Nature 1948; 162:810. Arnold P, Rosenheim ML. Lancet 1949;2:321-323. Finnertv FA Jr. Freis ED. Circulation 1950:2:828-836. Burt CC, Graham AJP. BrMedJ 1950; 1:455-460. Restall PA, Smirk FH. NZ MED J 1950;49:206-209. Freis ED, Rose JC, Partenope A, Higgins TF, Kelley RT, Schnaper HW, Johnson RL. JClin Invest 1953;32:1285-1298. Kelley RT, Freis ED, HigginsTF. Circulation 1953:7: 169-174. Cohn JN. Circulation 1973;48:5-8. Miller RR, Vismara LA, Williams DO, Amsterdam EA, Mason DT. Circ Res 1976; 39: 127. BrodJ,FejfarZ,SoudLek1951;53:154-163. Freis ED, Stanton JR, Finnerty FA Jr, Schnaper HW, Johnson RL, Rath CE, Wilkins RW. JClin Invest 1952;30:435-442. Krayer 0, Acheson GH. Physiol Rev 1946;26:383-446. Freis ED, Stanton JR. Am Heart J 1948;28:723-738. Freis ED, Stanton JR, Culbertson JW, Litter J, Halperin MH, Bur- nett CH, Wilkins RW. J C/in Invest 1949;28:353-368. Reubi F. HelvMedActa 1949; 16:297. Freis ED, Rose JC, Higgins TF, Finnerty FA Jr, Kelley RT, Par- tenope EA. Circulation 1953;8: 199-203. Veterans Administration Cooperative Study Group on Antihyper- tensive Agents. JAMA 1982;248:247 l-2477. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. Veterans Administration Cooperative Study on Antihypertensive Agents. Arch Intern Med 1960; 106:96- 10 1. Beyer KH. Ann NYAcadSci 1958;71:363-371. Freis ED, Wilson IM, Parrish AE. 19th annual meeting of the American Heart Association, Chicago, Illinois, Ott 28, 1957. Freis ED. Clin Pharmacol Exp Ther 1986: 391224-239. Shah S, Khatri I. Freis ED. Am Heart J 1978;95:61 L-618. Ledingham JM, Cohen RD. Lancet 1963;2:979-98 I. Borst JGG, Borst De G. Lancer 1963; 1x577-682. Guyton AC, Coleman TG, Cawley AW, Manning RD Jr, Norman RA, Ferguson JD. CircRes 1974;35:159-164. Tobian L. Arch Intern Med 1974; 133:959-967. Cohn JN, Liptak TE, Fries ED. Circ Res 1963; 12:298-307. Oates JA, Gillespie L Jr, Udenfiiend S, Sjoerdsma A. Science 1960;131:1890-1891. Prichard BNC, Gillam PMS. Br Med J 1964;2:725-732. Veterans Administration Cooperative Study Group on Antihyper- tensive Agents. JAMA 1982;248: 1996-2003. Ondetti MA, Rubin B, Cushman DW. Science 1977; l96:44 l-447. Veterans Administration Cooperative Study Group on Antihyper- tensive Agents. Clin Sci 1982;63 (suppl 8):4435-4455. Ingelfinger FJ, Relman AS, Finland M. Controversy in internal medicine. Philadelphia: WB Saunders, 1966. Veterans Administration Cooperative Study Group on Antihyper- tensive Agents. JAMA 1967;202:1028-1034. Veterans Administration Cooperative Study Group on Antihyper- tensive Agents. JAMA 1970;213:143-152, Report of the Management Committee. Lancer 1980; 1: 126 l- 1267. Hypertension Detection and Follow-up Program. Five-year find- ings of the Hypertension Detection and Follow-up Program. JAMA 1979;242:2562-2570. Medical Research Council Working Party. BrMedJ 1985;291:97- 104. MRC Working Party. Br Med J 1992; 304:405-412. Dahlof B, Lindholm LH, Hansson L, Schersten B, Ekbom I, Web- sterP0. Lancet 1991;338:1281-1285. SHEP Cooperative Research Group. JAMA 199 1;265:3255-3262. Actuarial Society of American, Blood pressure study of 1925. New York: Actuarial Society of America and Association of Life Insur- ance Medical Directors, 1925. Kannel WB, Sorlie P. Hypertension in Framingham. In: Paul 0. ed. Epidemiology control of hypertension. International Medical Book, 1975;553-592.