The treatment of primary hgpertension Twelfth of a series on drug therapy I Atherosclerosis, first, and hy- pertension, second, constitute the most common therapeutic prob- lems of our time, considerably outranking cancer in incidence. Whereas little progress has been made in reducing the mortality rate from atherosclerosis or can- cer, deaths from hypertension have fallen significantly over the past fifteen years, and the favor- able trend is continuing. Antihypertensive drugs were developed during the 1950s and it is tempting to ascribe these en- couraging trends in mortality to advances in specific therapy. How- ever, it must be recognized that mortality figures may change as a result of other factors, and it is, therefore, prudent to seek out ad- ditional supporting evidence. Prevention of organic complications Hypertensive complications. What effect does reduction of blood pressure have on prevent- ing the organic complications that are commonly associated with hy- pertension? In considering this question, it is convenient to sepa- rate those complications which are associated specifically with hypertension from those which are due primarily to atheroscle- rosis. The available evidence sug- gests that hypertensive complica- tions are the result of stresses placed on the heart and blood ves- sels by the elevated blood pres- sure. The predominant effect on the vascular system is sclerosis of the arterioles, and on the heart, EDWARD D. FREIS, M.D. Senior Medical Investigator, Veterans Administration Hospital, and Professor of Medicine, Georgetown University School of Medicine, Washingion, D. C. ' left ventricular hypertrophy and dilatation. There is convincing evidence that any form of treatment which lowers blood pressure is effective in improving and preventing hy- pertensive congestive heart fail- ure. Cardiac failure has fallen from a major to a minor cause of death in adequately treated hy- pertensive patients. Reduction of blood pressure al- so has been shown to be effective in the treatment of acute, severe, hypertensive states. Antihyper- tensive therapy will revert malig- nant hypertension to the benign phase. Hemorrhages, exudates, and papilledema in the optic fun- di gradually disappear when the blood pressure is effectively low- ered. If renal damage is not se- vere, patients may lead produc- tive lives for many years with continued treatment. Since antihypertensive treat- ment reverses the accelerated phase of hypertension, it follows that the transition from benign to malignant hypertension also should be prevented in adequately treated patients. This assumption is supported by the observation that the incidence of malignant hypertension appears to be very low in patients receiving contin- uous antihypertensive therapy. In addition to preventing ma- lignant hypertension, antihyper- tensive therapy has practically eliminated the occurrence of acute hypertensive encephalopathy. Al- so, clinical trials comparing treat- ed with nontreated patients have shown that cerebral hemorrhage is significantly less frequent in treated patients. Nephrosclerosis. Sclerosis of ar- terioles is the primary small ves- sel lesion related to hypertension, the principal target organ being the kidney. The fulminant type, characterized by arteriolonecrosis, is effectively prevented by antihy- pertensive therapy. Nephrosclero- sis without necrosis, however, oc- curs in patients with essential hypertension and progresses at a much slower pace. Because of this slow progression it has been dif- ficult to demonstrate a favorable effect of antihypertensive treat- I ment. There is, however, indirect evidence favoring the view that lowering blood pressure may re- tard the rate of development of nephrosclerosis. Atherosclerotic complications. The most important atheroscle- rotic complications are myocar- dial infarction and cerebrovascu- lar thrombosis, which have now risen to first and second place as the major causes of death in hy- pertension, replacing congestive heart failure, cerebral hemorrhage, and uremia. This change in inci- dence may be due in part to the fall in death rate from the latter complications. However, it also is probable that hypertensive pa- tients who are saved by drug Reprinted from MODERN MEDICINE, March 1 I, 1968, pp. 86-91 Copyright 1968, Modern Medicine Publications, Inc. PRINTEI) IN u. 5. A. treatment from the fulminant ef- fects of severe hypertension may now live long enough to develop the atherosclerotic complications. It is well established that hy- pertension is a significant risk factor in the genesis of athero- sclerosis. The available evidence suggests that the elevated arterial pressure per se predisposes the arterial walls in some unknown way to the deposition of athero- sclerotic plaques. Such consider- ations suggest that blood pressure should be lowered to ",.VW AL\, L 1 I Lll in the early stages of hypertension in order to prevent the future de- velopment of atherosclerosis. Estimating prognosis and need for treatment Lability in hypertension. Since many of the complications of hy- pertension appear to be related directly to the elevated blood pres- sure, it is reasonable to assume that the extent of the pathologi- cal changes will depend on both the height of the blood pressure and its duration. If the blood pressure is high for only brief pe- riods of time, significant vascular pathology might not be anticipat- ed. This precept is borne out by a number of studies indicating that morbidity and mortality rates are considerably higher in so-called fixed hypertension than in the labile form. Patients whose hy- pertension is initially labile may later develop fixed hypertension in middle age. Differentiation between the two groups is not possible on the basis of recordings of blood pressure in the physician's office. Individuals who remain labile may, in middle and old age, exhibit high pres- sures during a visit to a doctor's office and still be normotensive during normal daytime activities at home or work. Such individuals often exhibit little or no evidence of organic damage. Other hyper- tensive patients exhibit elevation of blood pressure throughout the day, even when they are at home or are hospitalized. The majority of these patients exhibit organic changes, the rate of progression varying in general with the height of the diastolic blood pressure. Thus, in evaluating hypertensive patients for treatment, it should be recognized that it is not only the height of the blood pressure which is important but also its persistence. When blood pressure is measured only in the office or clinic it is difficult, if not impos- sible, to differentiate between the fixed and labile forms of hyper- tension. Determination of lability. In determining the "basal" blood Dr. Edward D. Freis, Director, Cardiovascular Research Laboratory, Georgetown University pressul@ it is essential to repeat the recording procedure frequent- ly enough so that the alarm reac- tion wears off. This can be accom- plished by hospitalization for three or four days with recordings taken by the nursing staff four or five times daily. The patient is encouraged to be up and about the hospital ward during this pe- riod. For outpatients, the recording of blood pressure at home by the patient or a member of his family is the most practical method of estimating the basal blood pres- sure. The physician should have available a spare manometer which can be loaned to the pa- tient. The office nurse instructs the patient or, preferably, a mem- ber of his family in the proper technique of blood pressure re- cording. Twice-daily recordings for a period of two weeks are suf- ficient to provide an indication of the average blood pressure. The readings can be taken at the beginning and end of the day so as not to interfere with normal work schedules. A record is kept which is presented to the physi- cian at the next office visit. Some physicians fear that such emphasis on blood pressure levels and open disclosure of the read- ings may induce a "manometric neurosis." Experience has shown, however, that in the majority of patients the procedure soon loses its capacity for: promoting appre- hension when frequently and IOU- tinely repeated: Further, the pa- tient should be reassured that if the blood pressure remains ele- vated it can be effectively con- trolled by antihypertensive treat- ment. Extent of organic damage. In addition to the assessment of basal blood pressure, the extent of the organic damage present at the time of the initial evaluation of the patient also is of great value in estimating the prognosis and, hence, the need for treat- ment. The important organ systems that are affected in hyperten- sion are the central nervous sys- tem including the optic fundi, the heart plus aorta, and the kid- neys. In the optic fundi, vascular changes are characterized by arte- riolar tortuosity, widening of the light reflex, arteriovenous nicks, and irregularity of arteriolar cali- ber. Since the larger vessels close to the optic disk may exhibit some of these changes in normal individuals, inspection of the blood vessels two disk diameters or more peripheral to the nerve head provides more reliable cri- teria of vascular pathology. Be- cause of the wide range of normal variation, great emphasis should not be placed on minor vascular changes. Hemorrhages, soft exudates, or papilledema indicates that gen- eralized arteriolar damage is oc- curring at an accelerated rate. The hemorrhages are tlame- shaped or striate rather than round and occur near the disk. Other causes for hemorrhages such as diabetes and anemia should be ruled out. Soft fluffy exudates, generally occurring close to the main vessels within three diame- ters of the disk, are characteristi- cally seen in patients with severe hypertension. Smaller, sharply defined, hard exudates also occur and persist for longer periods fol- lowing treatment. The presence of hemorrhages, soft exudates, or papilledema indicates the need for immediate hospitalization and in- tensive treatment in order to ar- rest the rapid progression of vas- cular damage. In the central nervous system the most frequent complication is a stroke. Although patients who recover from a cerebral hemor- rhage or thrombosis may live for many years thereafter, especially if the blood pressure is well con- trolled, the prognosis is more guarded than if such complica- tions had not occurred. Similarly, patients with acute hypertensive encephalopathy may survive for long periods, providing renal func- tion is adequate and the blood pressure is vigorously controlled. On the other hand, subarachnoid hemorrhage carries an uncertain prognosis unless the cause of the subarachnoid bleeding can be identified and repaired surgically. Morning occipital headache often is a symptom of severe hyperten- sion, but headache in other loca- tions or dizzy spells have no prog- nostic value. The heart responds to sustained hypertension with hypertrophy or dilatation which often can be de- tected by X-ray and electrocar- diography. In the physical exami- nation, a forceful and prolonged apical impulse and a presystolic gallop may be detected. The fre- quent superimposition of coronary atherosclerosis may lead to an- gina or to increased susceptibility to develop congestive heart fail- ure. An additional useful sign is the degree of aortic dilatation and un- folding visualized in the chest X- ray. In the physical examination, tortuous and dilated peripheral arteries, such as the subclavian or the brachial, indicate that severe, sustained hypertension has been present for some time. The status of the kidneys has great prognostic importance. Mi- nor degrees of renal damage, how- ever, cannot be detected by rou- tine clinical methods. Lack of concentrating ability and reten- tion of phenolsulfonphthalein in- dicate significant impairment, while nitrogen retention reflects far-advanced renal deterioration. In the presence of a moderate degree of azotemia, antihyperten- sive therapy may still be of value, if effectively and judiciously ap- plied. However, ,the prognosis is much more guarded than if ef- fective measures had been taken at an earlier date. In th,e terminal stage of renal failure with,eleva- tion of BUN above 100 mg..per- cent, antihypertensive therapy usually is of little value. When, the uremia is accompanied by severe congestive heart failure, moderate reduction of blood pressure may be helpful in controlling symp- toms. Age and sex. Other aids in esti- mating the prognosis and, hence, the need for treatment include the age and sex of the patient. Young patients are more apt to develop accelerated hypertension. Athero- sclerotic complications also tend to occur at a relatively early age. The untreated patient who ex- hibits an elevation of basal blood pressure before age 35 has a great- ly increased risk of dying before age 55 as compared to a normal individual. In addition, numerous studies have shown that the mor- tality rate is higher in hyperten- sive men than in women. Other conditions being equal, a young man with hypertension should be more aggressively treated than other patients. In summary, the purpose of the prognostic evaluation is to decide on the need for and type of medical treatment. The work- up should include an estimate of basal blood pressure and an as- sessment of the degree of organic damage. The history and physical examination should be directed , especially toward the principal target organs in hypertension, namely, the optic fundi, central nervous system, heart, and kid- neys. Laboratory tests should include a chest X-ray and electrocardio- gram, urinalysis, phenolsulfon- phthalein excretion, and BUN or serum creatinine. If thiazide diu- retics are to be used in treatment, the fasting blood sugar, serum potassium, and serum uric acid should be included. Additional important tests which are helpful in screening patients for curable forms of hypertension are the in- travenous pyelogram and, when available, radioisotope renogram and renal scan for renovascular hypertension; the twenty-four- hour urinary excretion of vanyl- mandelic acid (VMA) for pheo- chromocytoma; and the serum potassium level for primary al- dosteronism. Choice of drug treatment Although there are several hun- dred preparations that are mar- keted for the treatment of hyper- tension, the useful drugs of proved value make up only a relatively small number. These are [l] the natriuretic agents, [2] rauwolfia alkaloids, [3] hydralazine, [4] methyldopa, and [5] the sympa- thetic blocking drugs such as guanethidine and pargyline. Natriuretic agents. Chlorothia- zide (DiuriP) and related agents are useful in all forms of hyper- tension. In patients with mild hy- pertension, they may effectively control blood pressure without additional therapy. In patients with more resistant disease, the natriuretic agents enhance the activity of the other antihyper- tensive drugs. While the mechanism of the antihypertensive activity of the thiazides is still in some dispute, it is most likely associated with sodium depletion. The various compounds differ primarily with regard to dose and duration of action, no one agent being supe- rior in antihypertensive effective- ness or in toxicity. Effective antihypertensive dos- es of representative natriuretic agents are as follows: chlorothia- zide, 250 to 500 mg. twice daily; hydrochlorothiazide (Hydro-Diu- ril@, Esidrexm), 25 to 50 mg. twice daily; and chlorthalidone (Hygrotonn), 50 to 100 mg. once daily. Except in severe hyperten- sion, treatment generally is initi- ated at the lower dose level and is increased to the higher level if the blood pressure is not con- trolled. Among the side effects of these drugs, the most frequent are hy- pokalemia and hyperuricemia. Hypokalemia seldom is trouble- some except in patients who are losing potassium from other causes or who are taking digitalis. Hypokalemia increases the inci- dence of toxic arrhythmias pro- duced by the digitalis alkaloids. In patients who require digi- talis, mixtures of spironolactone and hydrochlorothiazide (Aldac- tazide@) or of triameterene and hydrochlorothiazide (Dyazidem) are indicated. Hyperuricemia occurs in ap- proximately 40 70 of thiazide- treated patients. In susceptible individuals, persistent hyperurice- mia can lead eventually to gout. It is not surprising, therefore, that the incidence of acute gouty arthritis has increased significant- ly in patients receiving thiazides. Since thiazide-induced hyperuri- cemia can be controlled with 0.25 to 0.5 gm. of probenecid (Bene- mid@) twice daily, treatment with the latter drugs may be indicated in patients who develop elevated levels of serum uric acid. Although thiazides lower car- bohydrate tolerance and on rare occasions precipitate acute hyper- glycemic attacks, there is little evidence to support the view that they produce permanent diabetes. The incidence of diabetes seems to be no higher in thiazide-treated patients than in control groups of similar age. In addition, the presence of diabetes is not an ab- solute contraindication to treat- ment with thiazide diuretics. Rauwolfia alkaloids. Reserpine is the alkaloid usually employed, there being no convincing evi- dence that other rauwolfia alka- loids are superior. The antihyper- tensive effect is mediated through partial depletion of catechola- mines. The usual dose is 0.5 to 1 mg. daily for two weeks followed by a maintenance dose of 0.1 to 0.5 mg. Higher maintenance doses are not advisable because of a considerable increase in the in- cidence of toxicity. The most important side reac- tion is the development of a se- vere and even suicidal mental de- pression. It is advisable to warn the patient or a member of the family of this possibility. The symptoms are early morning in- somnia, anxiety, despondency, and anorexia. True depression should be distinguished from mild lethargy and loss of drive which occurs fairly frequently with re- serpine. Other common side ef- fects are nasal stuffiness, slight diarrhea, increased appetite, and nightmares. Because of the limitation on dosage imposed by the risk of side effects, the antihypertensive effectiveness of reserpine used alone is somewhat limited. How- ever, the drug is often quite effec- tive when added to a regimen con- taining thiazides. The latter drugs enhance the mild antihyperten- sive activity of reserpine even when it is maintained at rather low-maintenance dose levels, such as 0.25 mg. daily. Hydralazine. Hydralazine (Apresolineo) is useful only as an adjunct to either thiazides or re- serpine or both. The initial dose is 10 to 25 mg. two to three times daily, which can be increased to 50 mg. three times daily if neces- sary. Doses above 150 mg. daily are not advisable because of the risk of developing the lupus ery- thematosus syndrome at higher doses. The syndrome resembles disseminated lupus with arthritis, dermatitis, and renal lesions. In the recommended lower dose range the principal side effects are headache and palpitation. Methyldopa. Although often well tolerated, methyldopa (Al- dome@) is more likely to produce orthostatic hypotension than the agents described above. The or- thostatic hypotension is less se- vere, however, than with guaneth- idine or pargyline. The effective dose range of methyldopa varies between 250 and 750 mg. three to four times daily. An important toxic effect of methyldopa is hepatitis. This re- action usually occurs within the first six weeks of treatment and generally is mild. Fever or malaise are the leading symptoms and elevation of SGOT is the most frequent laboratory abnormality. Recovery is rapid after discon- tinuation of the drug. The development of a positive Coombs test and hemolytic ane- mia have recently been ascribed to methyldopa. In addition to or- thostatic hypotension, other com- mon side effects include sleepi- ness, which often is transient, and dry mouth. Guanethidine and pargyline. Guanethidine (Ismelin@) general- ly is reserved for patients whose hypertension is severe and resis- tant to other antihypertensive drugs. Guanethidine induces a peripheral block of the sympathe- tic nervous system, thereby pro- ducing a decrease in blood pres- sure and heart rate. The duration of action is long and doses are cumulative over a period of sev- eral days. The effective dose varies widely in different patients from as little as 10 mg. to as much as 200 mg. daily. In most patients, however, the effective dose with adjunctive thiazide is in the neighborhood of 20 to 60 mg. per day. Because of the risk of syncope due to orthostatic hy- potension, the drug should be started at 10 mg. once daily, pref- erably with thiazides, and in- creased gradually by 10 mg. in- crements until the optimal reduc- tion of blood pressure is achieved within the limits imposed by or- thostatic symptoms. More rapid titration can be carried out in the hospital where the blood pres- sure can be checked frequently in both the supine and upright positions. Other common side effects of guanethidine are diarrhea, which may be controlled with atropine- like drugs but usually necessitates reduction in dosage, and retro- grade ejaculation. Pargyline (Eutonyl@), a mo- noamine-oxidase inhibitor, also blocks sympathetic nervous sys- tem activity, producing a reduc- tion of blood pressure with ortho- static hypotension. Because of the incompatibilities between mo- noamine-oxidase inhibitors and certain other drugs, as well as the severe hypertensive reac- tions that follow the ingestion of processed cheese, guanethidine appears to be the safer of the two drugs for use in resistant hy- pertension. Methods of treatment Hypertension should be regard- ed as an essentially controllable disease. Severe restrictions 011 normal patterns of living seldom need be imposed. The aim of treatment is not only to control blood pressure but also to inter- fere as little as possible with the patient's usual working and rec- reational habits. The patient should not be made to feel that he is an invalid. Hypertensive patients vary considerably in their response to ' individual drugs, with regard to both antihypertensive effective- ness and incidence of side effects. It often is necessary, therefore, to try a variety of drug schedules before settling on a regimen that provides the most effective blood , pressure control with the least number of side effects. In mild and moderate hyper- tension, treatment usually is be- gun with a natriuretic agent. If this is not effective, reserpine may be added, followed by hydralazine if necessary. By noting the effect of each antihypertensive agent as it is separately added, an in- formed judgment as to its relative efficacy in the individual patient can be made. From this experi- ence one may arrive at the regi- men best suited to the particular patient. Thus, patient A may need only a natriuretic agent, patient B will be best controlled on re- serpine alone, while patient C re- quires a combination of drugs. Once this decision has been made on the basis of the therapeutic trial, it often is possible to use preparations containing a desired combination in a single tablet. 1 Combination tablets should not be used initially, however, since it is not possible to determine which of the ingredients is pro- ducing the desired effect. Ob- viously, it is not desirable to ex- pose the patient for long periods of time to more medications than he actually needs. Most patients with essential hypertension will respond to thia- zide alone or to various combina- tions of thiazide, reserpine, and hydralazine. A few may not, and others may have side effects, ne- cessitating a change in regimen. In such instances, methyldopa, particularly when combined with a natriuretic agent, frequently is sfiective and usually is well toler- ated. Methyldopa also may be effec- tive in severe forms of hyperten- sion particularly when renal fail- ure is present. When the drug does not control blood pressure in severe hypertension, guanethidine should be used. Thiazides are use- ful adjuncts with either drug. In fact, in the presence of severe or malignant hypertension, it often is necessary to add several anti- hypertensive agents including thiazides, guanethidine, and me- thyldopa in order to achieve satis- factory blood pressure reduction. In such cases, after the blood pressure has remained under ade- quate control for several months, it frequently is possible to with- draw or reduce the doses of the drugs causing the most disturbing side effects. Fortunately, severe hypertension frequently tends to moderate after a period of inten- sive treatment so that less med- ication is required for adequate control. As in diabetes, the physician's role is to guide the patient in a lifelong program of controlling his disease. The patient will be more cooperative if he is given some understanding of the purpose of 1 the treatment and if the thera- peutic regimen is flexible. Home blood pressure record- ings can be an important motivat- ing influence. The procedure is particularly effective in convinc- ing the patient that regularly taken medications and toleration of occasional real or imagined side effects are essential for adequate blood pressure control. Home re- cordings also are a valuable guide to the effectiveness of treatment, ~ particularly when doses need to be carefully titrated, such as is the case with guanethidine. Tran- sient escape from the effects of antihypertensive drugs often oc- curs during the apprehension as- ' sociated with the office visit. A record of blood pressures taken in the home will prevent the physi- cian from being misled and, hence, overdosing on the basis of the 1 transiently elevated levels record- ed in his office. Since hypertensive patients de- velop atherosclerosis at an accel- erated rate, additional practical measures that may delay the latter process can go hand in hand with the program of blood pres- sure control. Such measures may include weight reduction if in- dicated, partial substitution of unsaturated for saturated fats, and a program of daily moderate exercise. Never before has the medical profession been in such an ad- vantageous position for construc- tive accomplishment in the treat- ment of hypertension. To the physician who applies this newer knowledge wisely, the satisfac- tions fully justify the effort ex- pended. The key to successful treatment is individualization of therapeutic schedules as judged by the response of each patient to treatment. B