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Hypertension: Recent Trends in Treatment
Hypertension: Recent Trends in Treatment ROBERT W. WILKINS, M.D. *
trends in medical treatment of essential hypertension are definitely towards the use of combinations of drugs. This is because, in the absence of a known etiology of the disease, all treatments must be regarded as nonspecific procedures of varying merit depending on: (1) their effectiveness in lowering blood pressure, (2) their safety and freedom from unpleasant side actions, and (3) their practicability for longterm use. Since no single medicinal agent has proved to be either uniformly effective, free of side actions or useful over long periods of time, various combinations of drugs have been tried in the hope that at least they might be additive in their good and not in their bad effects, or at best synergistic in their good effects and counteracting in their bad effects. It now seems fair to say that these hopes have been partially realized since it is generally agreed by workers in the field that combinations of drugs offer considerably more aid in controlling the blood pressure of hypertensive patients than anyone drug alone, and possibly more aid than anyone procedure alone including surgery or diet. This paper will describe the use of those combinations of drugs which in our clinic have proved to be safe and feasible for general use in ordinary practice. RECENT
THE DRUGS USED
Rauwolfia
Rauwolfia serpentinat is an old drug in India but new in this country for the treatment of essential hypertension. It has the following desirFrom the Robert Dawson Evans Memorial, Massachusetts Memorial Hospitals, and the Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.
* Associate Professor of Medicine, Boston University School of Medicine; Member, Robert Dawson Evans Memorial, Massachusetts Memorial Hospitals; Physician, Massachusetts Memorial H ospitaZs. t
"Serpina," manufactured by the Himalaya Drug Company, Bombay, India, 1303
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Robert W. W ilkins
ahie characteristics: 1. It is a mild, very slow-acting, relaxing, or sedative-like drug. 2. It is moderately hypotensive. 3. It slows the pulse rate. 4. Alone it is most effective as a rule in excitable, labile (neurotic) hypertensive patients with tachycardia. Rauwolfia has the following side effects: 1. It causes nasal stuffiness. 2. It causes a gain in weight. 3. It causes some increase in frequency of the bowel habit. 4. In too large a dose or after several weeks it may cause nightmares, or rarely a state of "depressed anxiety or jitteriness." Rauwolfia is certainly a valuable addition to our armamentarium against hypertension, not so much because it is a powerful or striking hypotensive agent (which it is not) as because it is our most effective symptom-reliever, and because it acts very well in combination with other more powerful drugs. Its side effects as a rule are so mild, and its action so slow to' appear (five days) that one can judge its effects better by asking patients placed on it to return only every week or two. Its pulse rate-slowing action seems particularly beneficial in patients to be given hydralazine which often causes distressing palpitation due to tachycardia. The dose of Rauwolfia is 100 to 125 mg. of crude root (or equivalent) one to three times a day, which may be continued indefinitely or reduced slightly if in time its effects (sleepiness) or side actions (nightmares or "jitteriness") become bothersome. Hydralazine Hydralazine* is a centrally acting adrenergic blocking agent which lowers blood pressure by causing peripheral (particularly renal) vasodilatation. It has the following side effects: 1. It may cause severe headaches. 2. It usually causes tachycardia (palpitation). 3. It causes nasal congestion. 4. It may cause dependent edema. 5. It may cause angina in patients presumed to have arteriosclerotic heart disease. If administered in gradually increasing doses its side effects may be minimized. The dose should be started at 10 mg. four times a day, and and obtained through the courtesy of E. R. Squibb & Sons, New York City; Raudixin, obtained from E. R. Squibb & Sons, New York City, or "Rauwiloid" (an extract) obtained from Riker Laboratories, Incorporated, Los Angeles, California.
* "Apresoline," available from Ciba Pharmaceutical Products, Incorporated, Summit, New Jersey.
Hypertension: Trends in Treatment
1305
slowly raised to 50 mg., and if necessary to no more than 200 mg. four times a day. Raising the dose above 800 mg. a day does not seem to add materially in lowering blood pressure of resistant patients. Hydralazine is more effective when given in combination with Rauwolfia, and particularly so when started after Rauwol5.a has been administered for some time. We now rarely use hydralazine alone. However, it may be continued indefinitely, and occasionally may be reduced in dosage with the passage of time. While its chemical structure suggests that it would have a bone marrow-depressing effect, we know of only one instance of this complication, a pancytopenia which disappeared on stopping the drug. One other complication possibly due to the action of this drug has been the occurrence of a massive gastro-intestinal hemorrhage (presumably from a peptic ulcer) which has occurred (without a defect in the clotting mechanism) in 3 out of several hundred patients taking the drug. Since peptic ulcer and hypertension are common diseases and frequently occur together these 3 cases may have been purely fortuitous. However, because it was felt that the drug might be responsible in some way, it was stopped in these cases. Other more frequent causes for stopping the drug have been intractable headache, dependent edema, or angina. Nasal stuffiness, however, is not an indication for stopping the drug since this symptom may be counteracted by an antihistamine (Chlor-Trimeton* 4 mg. three times a day) or a local nasal vasoconstrictor (drops or inhalant). Veratrum Derivatives Veratrum derivatives are powerful central reflex vasodilators, but have the unfortunate characteristic of causing nausea and vomiting at a dosage slightly if any above the hypotensive range. However, they slow the pulse rate and can be given effectively along with hydralazine or with Rauwolfia or both. The dosage (as Veriloid t) in such combinations is 1 to 3 mg. four times a day, which is smaller than the usual minimal effective dose of this drug alone. It has no other adverse side effect than the emetic one. It may be continued indefinitely, or it may be stopped when the blood pressure has come to normal under a com,bination of drugs (Case 11). In this connection it is interesting that even when veratrum has appeared clearly to have contributed to the return of blood pressure to normal it has then been omitted from a regimen without a rise in blood pressure. PLAN OF TREATMENT
Our usual plan of treatment of ordinary essential hypertension in ambulatory patients is to institute Rauwolfia 100 mg. (or equivalent),
* Available from t Available from
Schering Corporation, Bloomfield, New Jersey. Riker Laboratories, Incorporated, Los Angeles, California.
1306
Robert W. Wilkins
two to three times a day, and ask the patient to return in one to four weeks. This is often satisfactory alone, especially in only moderately severe cases and particularly if the patients also have tachycardia and anxiety. At a minimum we expect symptoms such as nervousness, anxiety, headache and palpitation to be relieved. Frequently in addition we find that this regimen will suffice to control the pressure at normal, or near normal, levels. The patient is asked to reduce the dose slightly if he becomes too sleepy or depressed. The dose is never raised above 400 mg. of crude root (or equivalent) a day. In more severe cases, or in patients in whom this treatment does not suffice, we may add hydralazine to the Rauwolfia regimen, starting with 10 mg. (or 12.5 mg.) four times a day (at meals and at bedtime) and increasing the dosage gradually to 25 mg., or even to 50 mg. four times a day. We warn the patient to reduce (not discontinue) the dosage if symptoms of headache and/or palpitation are distressing, but to resume in gradually increasing doses if possible. We prefer to see the patient again in one week, but if this is not feasible we ask him to return after two to four weeks, at which time, depending on the results, we may increase the dosage of hydralazine (gradually to 100 mg. four times a day). It is our impression that doses of hydralazine above 800 mg., and probably even 600 mg. a day, are unwarranted. If, for any reason, hydralazine therapy is interrupted for a period of days, it should be resumed only by gradual reinstitution of the drug in the same manner as on initial administration. As an alternative procedure, especially when the pulse rate is above 90 even though the patient is taking Rauwolfia, we may add veratrum to the Rauwolfia regimen. This may be done with any of the standardized extracts or the pure alkaloids. We have generally used Veriloid, starting with 2 mg. four times a day, warning the patient to reduce (not discontinue) the dosage slightly only if there is nausea, and to try to increase the breakfast and bedtime doses (to 3 mg.) if possible. We do not require the patient on this regimen to return in one week although if they are readily accessible to the office it is well to have them do so. Finally, we may try all three agents together in certain cases in which no combination of two is effective. This is almost never done as an initial regimen, however, in order to avoid, if possible, overloading the patient with pills. A common schedule is as follows: Rauwolfia, 100 mg. (or equivalent) at breakfast and bedtime; hydralazine, 50 mg. (after working up slowly) at breakfast, lunch, supper and bedtime; veratrum (Veriloid) 3 mg. at breakfast, 2 at lunch and supper, and 3 at bedtime. Illustrative Cases
Several case histories will illustrate this plan of treatment and the results that may be obtained.
Hypertension: Trends in Treatment
1307
Case I (Fig. 170). I. B., a business woman, aged 50, was sent to us by a prominent internist, who gave the following account: The patient had always been extremely nervous, even hysterical; she had blushed and flushed easily, and had run a constant tachycardia. In 1942 her blood pressure was found to be moderately elevated, but rapidly rose from 140/100 to 180/110. In 1943 it was 190/110, in 1944, 190/130. The fundi and electrocardiogram were normal at that time and pyelogram showed blunting of the calyces on the right suggesting healed pyelonephritis. In 1945 the pressure was 200/120, in 1947, 220/140, and there was an aortic systolic murmur. Urine showed 1 to 2+ albumin and a few red cells. She now complained of banging occipital headaches. She was placed on a salt-free diet and increased rest, without avail. She began to complain of vague lB. i,50
CONTROL
YERILOID. SERPINA a APRESOLINE
YERILOID
260 240 220
200 180
~~160
PRESSURE 140 " mm.Hg 120 100 PULSE RATE 80 IIeotI/mln. 60 VERILOIO
.... /oa,
SERPINA Toblets/Ooy
:.HtI_ _...
APRESOLINE MOo/Day
I 2 3 4 YEARS
_
:~~
5 6 7 8,: "------
Fig. 170 (Case I). Course of the blood pressure and pulse rate, showing responses to therapy as indicated.
substernal pain. In 1949 the blood pressure was 240/150, in 1950, 250/150. The electrocardiogram now showed left ventricular strain. The doctor felt he was making no headway with the patient, although he thought this might be due to the resentment that she appeared to harbor for him. He said he feared that she was in line for a cerebral accident and that a pressure of 170/100 or less would be a highly significant achievement. We confirmed the doctor's physical examination and blood pressure readings which were as high as 300/150 when the patient discussed her husband whom «Ihe violently resented. The pulse rate was 104. She was placed on Veriloid, 2 mg. four times a day which was the only safe oral hypotensive agent we had available at that time. On veratrum treatment consisting of amounts up to 3 mg. of Veriloid four l~~imes a day her tachycardia and blood pressure subsided moderately to average ~80 and 200/100 respectively, but at the price of occasional attacks of nausea ;8,nd vomiting. Nevertheless she lost her headaches completely, and felt so much
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Robert W. Wilkins
better generally that she continued the therapy faithfully for the next year. She continued to work, and if anything was more active. At the end of the first year, Rauwolfia became available as "Serpina" and was prescribed for the patient, 1 tablet a day, while the veratrum was reduced to a non-nauseating dose (Veriloid 2 mg. four times a day). The pulse rate slowed to 72, and her blood pressure remained the same or averaged slightly lower. She visited her physician, who reported, "Her blood pressure is lower than I have seen it for a long time." After 6 months on this combination, hydralazine was instituted gradually. The patient resisted the idea of taking so many pills, but after 3 months was finally coaxed into taking 50, 25, 25 and 50 mg. respectively in a 4-dose schedule. Her pressure now averaged 170/100, pulse 72. After 2 months her physician called and said, "I am really impressed now, her pressure is lower than since 1942. Her urine shows no albumin, and the electrocardiogram has returned to normal." Hydralazine was then raised to 50 mg. four times a day and in one month the patient's blood pressure averaged 135/85. She was now on a four dose schedule: Veriloid, total 6 mg. a day; hydralazine, 200 mg. a day; and Rauwolfia, 1 tablet a day. Even after discussing her husband her blood pressure rose only to 160/100. The patient remarked frequently on her symptomatic improvement, and "change in personality." When quizzed about the latter she said, "I am not less ambitious, I'm not less agressive, I'm not less effective. I just don't seem to have to do the things I used to. Before, I felt I had no control over myself, I had to do things. Now I don't care, I don't even notice things. Dust doesn't annoy me now. Before, I knew it wasn't important, but I had to clean it up. Now I let it go for 2 weeks, and it doesn't bother me." Gradually during the next month (July) her pressure moderated to 120/70 sitting, 105/80 standing, and she felt lackadaisical. Therefore, it was decided to omit the veratrum. Blood pressure rose slightly to 135/80. Her doctor sent the following note: "Mrs. B. dropped in for a visit this afternoon, and you can imagine my surprise to find her blood pressure 140/90 without a preliminary rest period. She has done remarkably well, and I am most pleased with the results." During the hot summer months of 1952 the patient's pressure averaged 130/80, but she felt a little weak. The dosage of hydralazine was, therefore, reduced to 50, 25, 25 and 50 mg. in a four dose schedule. The pressure rose slightly to 140/90 and she felt fine. In October with the onset of cold weather, her pressure was found to be 170/95, and the dosage of hydralazine was raised again to 50 mg. four times a day. Thereafter and to the present her pressure has averaged 145/85, pulse 76 and she feels good. Case 11 (Fig. 171). E. B., a stock broker, aged 49, was sent by his company physician and his brother (a physician) for treatment of hypertension. In 1947 he had complained of fatigue, and also of occasional pain in the left arm. The only abnormal finding at that time was a blood pressure of 182/112. Urine and electrocardiogram were normal. In 1950 the pressure rose to 230/140 and in 1951 to 245/170. He developed severe headaches and cardiac enlargement by x-ray and electrocardiogram. The eyegrounds showed hemorrhages, exudates and mild papilledema. Conservative treatment by diet and rest was of no avail. The patient was admitted to the hospital for evaluation of his suitability for sympathectomy. Physical, x-ray and electrocardiographic examinations confirmed the findings reported by his physicians. The pulse rate was 72, and the blood pressure 240/140, but on bed rest subsided to 230/130 and on sedation test to 175/110. His response to the cold test was 235/145. Renal function tests
Hypertension: Trends in Treatment
1309
showed 1 + albuminuria, otherwise satisfactory. He was considered suitable for sympathectomy and agreed to have the operation in one month, but asked to be tried on drugs during the interim. He was started on Rauwolfia (Serpina) 1 tablet morning and night, and hydralazine 25 mg. three times a day. He returned in a week, and his pressure was 190/100, pulse 68. Hydralazine was gradually increased to 50 mg. three times a day and 1 month later he was readmitted to the hospital. Blood pressure was 180/100, pulse 60. Blood pressure on bed rest fell to 150/90 and during the cold test rose from 165/95 to 175/110. The renal function was good, and the urine albumin-free. The patient continued on this therapy of Rauwolfia 2 tablets a day, hydralazine 50 mg. four times a day, and later 75 mg. four times a day. Ambulatory
SERPINA a APRESOLINE
CONTROL '230 210 190 170
ARTERIAL 150
BLOOD
PRESSURE 130
mm. Hg
110
PULSE RATE beott/min.
70 50
90
• •_
SERPINA ~fl
Cl
Tablets I Day
APRESOLINE Mg./Day
2
345 TIME IN YEARS
IOOE_ ~'" . :~~~
6
7
Fig. 171 (Case 11). Course of the blood pressure and pulse rate, showing responses to therapy as indicated.
blood pressure remained about 170/95. After four months he was readmitted to the hospital for check-up. Admission blood pressure was 150/90, and during the sedation test 140/80. Electrocardiogram showed improvement toward normal and' the optic fundi revealed no papilledema, no hemorrhages, no new exudates, and a few old scars while the fundal arteries showed increased light reflex, but no spasms and only slight AV nicking. The patient continued on the same regimen of Rauwolfia 1 tablet twice a day, hydralazine 75 mg. four times a day for the ensuing 8 months with ambulatory blood pressure 170/95, pulse 56. He feels well, has resumed playing golf once a week, and does not tire as easily as formerly. Case III (Fig. 172). V. V., a white woman, aged 36, had been in good health until 15 years ago, when she developed toxemia with her initial pregnancy characterized by severe hypertension (systolic pressure, 240 mm. Hg), edema, and albuminuria. Ten years ago during a routine physical examination blood pres-
Robert W. W ilkl:ns
1310
sure was again found to be elevated. Four years ago the patient had had a subarachnoid hemorrhage (? rupture of intracranial aneurysm) with transient right hemiparesis. Three years ago (1950) she was referred to our hospital for treatment of 3rt.~rial hypertension. She stated that she had always been bothered with headaches) B,nd. during episodes of excitement or anger, with vasomotor disturbances such as diffuse blotchy eruption and sweating over face, neck and thorax. Fundoscopic examination showed a Grade 11 hypertensive retinopathy; heart size, chest film, and electrocardiogram were normal. Intravenous pyelogram and renal function studies were essentially normal. During the succeeding 1~~ years the patient was given a thorough trial of treatment with Veriloid, without any striking consistent effect on the blood pressure. A brief trial of hydralazine then indicated some reduction of pressure but not to normal. In October, 1951, lumbodorsal sympathectomy (Smithwick) was performed. However, the patient continued to have v.v. t
34,Wh.
ARTERIAL 160
P:Ea.:~E 140 mmHg
.
120
PULSE RATE beats/min.
Fig. 172 (Case Ill). Course of the blood pressure and pulse rate, showing responses to therapy as indicated.
elevation of the arterial pressure (perhaps at less severe levels) and complained of nervousness and frequent facial flushing. A trial of combination drug therapy (Rauwolfia, veratrum, and hydralazine) was undertaken. On this regimen the blood pressure was maintained consistently at normotensive levels without disturbing side effects. In addition, the patient felt relaxed and experienced no more attacks of flushing. With interruption of the regimen the blood pressure returned to pretreatment levels and the nervousness and vasomotor symptoms reappeared. On reinstituting the same combination of drugs normotension was again achieved and when the drugs were interrupted a second time the hypertension again returned. She will now be ma~ntained on this combination of drugs. GENERAL RESULTS
On Rauwolfia alone, 13 of 39 patients had a return of blood pressure to within the normal range (150/90 or lower). However, these 13 patients were in general younger, milder and more neurotic than the average. In
Hypertension: Trends in Treatment
1311
addition they tended to have a more rapid heart rate. Therefore, this drug alone was considered to be wholly satisfactory only in this type of patient. Of 22 patients placed on a combination of Rauwolfia and veratrum (many of whom had failed to respond adequately to Rauwolfia alone) only 5 had a return of blood pressure to normal (although 4 others were within 5 mm. Hg of these values). Of 23 patients treated with a combination of Rauwolfia and hydralazine 6 had normal pressures (and 2 were within 5 mm. of normal). However, of 18 patients placed on a combination of all 3 drugs, 13 had a normal pressure, and the average of the group was normal. Thus it appeared that in patients who failed to respond adequately to one drug, the effects of any combination of two tried were, on the average, about the same. However, there were individual patients who responded to one combination of two drugs and not to another. Furthermore some patients responded to all three when they had failed to respond to any combination of two. Finally there were patients who failed to respond to all three drugs together, at least in the dosages so far employed. DISCUSSION
The results reported here, as well as in the recent literature, indicate that combinations of hypotensive drugs are offering ne,v and more effective means of lowering blood pressure in hypertensive patients. It should be emphasized, however, that the three drugs discussed here, either alone, or in various combinations, are not capable of producing beneficial effects in all patients. However, we have frequently observed beneficial results to occur merely on continuing a regimen of one of these drugs or a combination of them at the same dosages for longer periods of time. Similarly, on adding a new drug to a regimen already established, or on increasing the dosage of the drug or drugs in the regimen, we have observed a favorable effect to occur. Therefore, too early assessment of such combination drug therapy should not be attempted. On the other hand in occasional patients there have been disappointing results even after long and faithful trials of the drugs. This has occurred most often in patients with uremia, but rarely it has occurred for no obvious reason. When it appears urgent to lower the pressure in such patients, one may feel it necessary to turn to more drastic measures such as sympathectomy, or hexamethonium given parenterally. These measures, however, should not be undertaken except by experts under the most carefully controlled conditions. The particular drugs mentioned here are not unique or even unusual in their ability to lower blood pressure either alone or in combinations. Similar results have been obtained with other drugs and other combinations. However, of all the drugs tried in this clinic (and we believe
1312
Robert W. W ilkins
we have tried them all) these have appeared to be the safest, simplest, least symptom-producing and longest-lasting in their action. Until better agents or truly specific therapies based on a knowledge of etiology are available we will continue to use these drugs. However, even these drugs can produce untoward effects. Hydralazine unquestionably is the chief offender of the three. Not only may it cause troublesome headache, palpitation and breathlessness, but it may also result in dependent edema. Usually these side effects will disappear if the patient can persist in taking the drug. However, angina pectoris or status anginosus, with electrocardiographic changes suggesting myocardial ischemia, we regard as an indication for discontinuation of the drug. As already mentioned, unexplained gastrointestinal hemorrhage has occurred in 3 patients taking the drug, while a pancytopenia has occurred in 1 other patient to our knowledge. The other two drugs produce mild side effects; veratrum, nausea and vomiting, Rauwolfia, sleepiness and depression, all of which can be relieved by reducing the dosage of the drug causing the effect. Experience thus has taught us that these new drugs, like other new drugs in medicine, do not make the lot of the physician in charge any easier; on the contrary they increase the necessity for his constant vigilance. But some of the newer hyp~tensive drugs do increase his satisfaction in dealing with hypertensive patients because he can relieve not only many of the symptoms but also some of the signs of their disease, in addition to the blood pressure itself. SUMMARY AND CONCLUSIONS
Hypertension can be relieved for long periods of time in a nUillger of patients by Rauwolfia, hydralazine and veratrum, either singly or in various combinations. The methods of using these drugs are described. They are worth continuing until better methods appear.
trends in medical treatment of essential hypertension are definitely towards the use of combinations of drugs. This is because, in the absence of a known etiology of the disease, all treatments must be regarded as nonspecific procedures of varying merit depending on: (1) their effectiveness in lowering blood pressure, (2) their safety and freedom from unpleasant side actions, and (3) their practicability for longterm use. Since no single medicinal agent has proved to be either uniformly effective, free of side actions or useful over long periods of time, various combinations of drugs have been tried in the hope that at least they might be additive in their good and not in their bad effects, or at best synergistic in their good effects and counteracting in their bad effects. It now seems fair to say that these hopes have been partially realized since it is generally agreed by workers in the field that combinations of drugs offer considerably more aid in controlling the blood pressure of hypertensive patients than anyone drug alone, and possibly more aid than anyone procedure alone including surgery or diet. This paper will describe the use of those combinations of drugs which in our clinic have proved to be safe and feasible for general use in ordinary practice. RECENT
THE DRUGS USED
Rauwolfia
Rauwolfia serpentinat is an old drug in India but new in this country for the treatment of essential hypertension. It has the following desirFrom the Robert Dawson Evans Memorial, Massachusetts Memorial Hospitals, and the Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.
* Associate Professor of Medicine, Boston University School of Medicine; Member, Robert Dawson Evans Memorial, Massachusetts Memorial Hospitals; Physician, Massachusetts Memorial H ospitaZs. t
"Serpina," manufactured by the Himalaya Drug Company, Bombay, India, 1303
1304
Robert W. W ilkins
ahie characteristics: 1. It is a mild, very slow-acting, relaxing, or sedative-like drug. 2. It is moderately hypotensive. 3. It slows the pulse rate. 4. Alone it is most effective as a rule in excitable, labile (neurotic) hypertensive patients with tachycardia. Rauwolfia has the following side effects: 1. It causes nasal stuffiness. 2. It causes a gain in weight. 3. It causes some increase in frequency of the bowel habit. 4. In too large a dose or after several weeks it may cause nightmares, or rarely a state of "depressed anxiety or jitteriness." Rauwolfia is certainly a valuable addition to our armamentarium against hypertension, not so much because it is a powerful or striking hypotensive agent (which it is not) as because it is our most effective symptom-reliever, and because it acts very well in combination with other more powerful drugs. Its side effects as a rule are so mild, and its action so slow to' appear (five days) that one can judge its effects better by asking patients placed on it to return only every week or two. Its pulse rate-slowing action seems particularly beneficial in patients to be given hydralazine which often causes distressing palpitation due to tachycardia. The dose of Rauwolfia is 100 to 125 mg. of crude root (or equivalent) one to three times a day, which may be continued indefinitely or reduced slightly if in time its effects (sleepiness) or side actions (nightmares or "jitteriness") become bothersome. Hydralazine Hydralazine* is a centrally acting adrenergic blocking agent which lowers blood pressure by causing peripheral (particularly renal) vasodilatation. It has the following side effects: 1. It may cause severe headaches. 2. It usually causes tachycardia (palpitation). 3. It causes nasal congestion. 4. It may cause dependent edema. 5. It may cause angina in patients presumed to have arteriosclerotic heart disease. If administered in gradually increasing doses its side effects may be minimized. The dose should be started at 10 mg. four times a day, and and obtained through the courtesy of E. R. Squibb & Sons, New York City; Raudixin, obtained from E. R. Squibb & Sons, New York City, or "Rauwiloid" (an extract) obtained from Riker Laboratories, Incorporated, Los Angeles, California.
* "Apresoline," available from Ciba Pharmaceutical Products, Incorporated, Summit, New Jersey.
Hypertension: Trends in Treatment
1305
slowly raised to 50 mg., and if necessary to no more than 200 mg. four times a day. Raising the dose above 800 mg. a day does not seem to add materially in lowering blood pressure of resistant patients. Hydralazine is more effective when given in combination with Rauwolfia, and particularly so when started after Rauwol5.a has been administered for some time. We now rarely use hydralazine alone. However, it may be continued indefinitely, and occasionally may be reduced in dosage with the passage of time. While its chemical structure suggests that it would have a bone marrow-depressing effect, we know of only one instance of this complication, a pancytopenia which disappeared on stopping the drug. One other complication possibly due to the action of this drug has been the occurrence of a massive gastro-intestinal hemorrhage (presumably from a peptic ulcer) which has occurred (without a defect in the clotting mechanism) in 3 out of several hundred patients taking the drug. Since peptic ulcer and hypertension are common diseases and frequently occur together these 3 cases may have been purely fortuitous. However, because it was felt that the drug might be responsible in some way, it was stopped in these cases. Other more frequent causes for stopping the drug have been intractable headache, dependent edema, or angina. Nasal stuffiness, however, is not an indication for stopping the drug since this symptom may be counteracted by an antihistamine (Chlor-Trimeton* 4 mg. three times a day) or a local nasal vasoconstrictor (drops or inhalant). Veratrum Derivatives Veratrum derivatives are powerful central reflex vasodilators, but have the unfortunate characteristic of causing nausea and vomiting at a dosage slightly if any above the hypotensive range. However, they slow the pulse rate and can be given effectively along with hydralazine or with Rauwolfia or both. The dosage (as Veriloid t) in such combinations is 1 to 3 mg. four times a day, which is smaller than the usual minimal effective dose of this drug alone. It has no other adverse side effect than the emetic one. It may be continued indefinitely, or it may be stopped when the blood pressure has come to normal under a com,bination of drugs (Case 11). In this connection it is interesting that even when veratrum has appeared clearly to have contributed to the return of blood pressure to normal it has then been omitted from a regimen without a rise in blood pressure. PLAN OF TREATMENT
Our usual plan of treatment of ordinary essential hypertension in ambulatory patients is to institute Rauwolfia 100 mg. (or equivalent),
* Available from t Available from
Schering Corporation, Bloomfield, New Jersey. Riker Laboratories, Incorporated, Los Angeles, California.
1306
Robert W. Wilkins
two to three times a day, and ask the patient to return in one to four weeks. This is often satisfactory alone, especially in only moderately severe cases and particularly if the patients also have tachycardia and anxiety. At a minimum we expect symptoms such as nervousness, anxiety, headache and palpitation to be relieved. Frequently in addition we find that this regimen will suffice to control the pressure at normal, or near normal, levels. The patient is asked to reduce the dose slightly if he becomes too sleepy or depressed. The dose is never raised above 400 mg. of crude root (or equivalent) a day. In more severe cases, or in patients in whom this treatment does not suffice, we may add hydralazine to the Rauwolfia regimen, starting with 10 mg. (or 12.5 mg.) four times a day (at meals and at bedtime) and increasing the dosage gradually to 25 mg., or even to 50 mg. four times a day. We warn the patient to reduce (not discontinue) the dosage if symptoms of headache and/or palpitation are distressing, but to resume in gradually increasing doses if possible. We prefer to see the patient again in one week, but if this is not feasible we ask him to return after two to four weeks, at which time, depending on the results, we may increase the dosage of hydralazine (gradually to 100 mg. four times a day). It is our impression that doses of hydralazine above 800 mg., and probably even 600 mg. a day, are unwarranted. If, for any reason, hydralazine therapy is interrupted for a period of days, it should be resumed only by gradual reinstitution of the drug in the same manner as on initial administration. As an alternative procedure, especially when the pulse rate is above 90 even though the patient is taking Rauwolfia, we may add veratrum to the Rauwolfia regimen. This may be done with any of the standardized extracts or the pure alkaloids. We have generally used Veriloid, starting with 2 mg. four times a day, warning the patient to reduce (not discontinue) the dosage slightly only if there is nausea, and to try to increase the breakfast and bedtime doses (to 3 mg.) if possible. We do not require the patient on this regimen to return in one week although if they are readily accessible to the office it is well to have them do so. Finally, we may try all three agents together in certain cases in which no combination of two is effective. This is almost never done as an initial regimen, however, in order to avoid, if possible, overloading the patient with pills. A common schedule is as follows: Rauwolfia, 100 mg. (or equivalent) at breakfast and bedtime; hydralazine, 50 mg. (after working up slowly) at breakfast, lunch, supper and bedtime; veratrum (Veriloid) 3 mg. at breakfast, 2 at lunch and supper, and 3 at bedtime. Illustrative Cases
Several case histories will illustrate this plan of treatment and the results that may be obtained.
Hypertension: Trends in Treatment
1307
Case I (Fig. 170). I. B., a business woman, aged 50, was sent to us by a prominent internist, who gave the following account: The patient had always been extremely nervous, even hysterical; she had blushed and flushed easily, and had run a constant tachycardia. In 1942 her blood pressure was found to be moderately elevated, but rapidly rose from 140/100 to 180/110. In 1943 it was 190/110, in 1944, 190/130. The fundi and electrocardiogram were normal at that time and pyelogram showed blunting of the calyces on the right suggesting healed pyelonephritis. In 1945 the pressure was 200/120, in 1947, 220/140, and there was an aortic systolic murmur. Urine showed 1 to 2+ albumin and a few red cells. She now complained of banging occipital headaches. She was placed on a salt-free diet and increased rest, without avail. She began to complain of vague lB. i,50
CONTROL
YERILOID. SERPINA a APRESOLINE
YERILOID
260 240 220
200 180
~~160
PRESSURE 140 " mm.Hg 120 100 PULSE RATE 80 IIeotI/mln. 60 VERILOIO
.... /oa,
SERPINA Toblets/Ooy
:.HtI_ _...
APRESOLINE MOo/Day
I 2 3 4 YEARS
_
:~~
5 6 7 8,: "------
Fig. 170 (Case I). Course of the blood pressure and pulse rate, showing responses to therapy as indicated.
substernal pain. In 1949 the blood pressure was 240/150, in 1950, 250/150. The electrocardiogram now showed left ventricular strain. The doctor felt he was making no headway with the patient, although he thought this might be due to the resentment that she appeared to harbor for him. He said he feared that she was in line for a cerebral accident and that a pressure of 170/100 or less would be a highly significant achievement. We confirmed the doctor's physical examination and blood pressure readings which were as high as 300/150 when the patient discussed her husband whom «Ihe violently resented. The pulse rate was 104. She was placed on Veriloid, 2 mg. four times a day which was the only safe oral hypotensive agent we had available at that time. On veratrum treatment consisting of amounts up to 3 mg. of Veriloid four l~~imes a day her tachycardia and blood pressure subsided moderately to average ~80 and 200/100 respectively, but at the price of occasional attacks of nausea ;8,nd vomiting. Nevertheless she lost her headaches completely, and felt so much
1308
Robert W. Wilkins
better generally that she continued the therapy faithfully for the next year. She continued to work, and if anything was more active. At the end of the first year, Rauwolfia became available as "Serpina" and was prescribed for the patient, 1 tablet a day, while the veratrum was reduced to a non-nauseating dose (Veriloid 2 mg. four times a day). The pulse rate slowed to 72, and her blood pressure remained the same or averaged slightly lower. She visited her physician, who reported, "Her blood pressure is lower than I have seen it for a long time." After 6 months on this combination, hydralazine was instituted gradually. The patient resisted the idea of taking so many pills, but after 3 months was finally coaxed into taking 50, 25, 25 and 50 mg. respectively in a 4-dose schedule. Her pressure now averaged 170/100, pulse 72. After 2 months her physician called and said, "I am really impressed now, her pressure is lower than since 1942. Her urine shows no albumin, and the electrocardiogram has returned to normal." Hydralazine was then raised to 50 mg. four times a day and in one month the patient's blood pressure averaged 135/85. She was now on a four dose schedule: Veriloid, total 6 mg. a day; hydralazine, 200 mg. a day; and Rauwolfia, 1 tablet a day. Even after discussing her husband her blood pressure rose only to 160/100. The patient remarked frequently on her symptomatic improvement, and "change in personality." When quizzed about the latter she said, "I am not less ambitious, I'm not less agressive, I'm not less effective. I just don't seem to have to do the things I used to. Before, I felt I had no control over myself, I had to do things. Now I don't care, I don't even notice things. Dust doesn't annoy me now. Before, I knew it wasn't important, but I had to clean it up. Now I let it go for 2 weeks, and it doesn't bother me." Gradually during the next month (July) her pressure moderated to 120/70 sitting, 105/80 standing, and she felt lackadaisical. Therefore, it was decided to omit the veratrum. Blood pressure rose slightly to 135/80. Her doctor sent the following note: "Mrs. B. dropped in for a visit this afternoon, and you can imagine my surprise to find her blood pressure 140/90 without a preliminary rest period. She has done remarkably well, and I am most pleased with the results." During the hot summer months of 1952 the patient's pressure averaged 130/80, but she felt a little weak. The dosage of hydralazine was, therefore, reduced to 50, 25, 25 and 50 mg. in a four dose schedule. The pressure rose slightly to 140/90 and she felt fine. In October with the onset of cold weather, her pressure was found to be 170/95, and the dosage of hydralazine was raised again to 50 mg. four times a day. Thereafter and to the present her pressure has averaged 145/85, pulse 76 and she feels good. Case 11 (Fig. 171). E. B., a stock broker, aged 49, was sent by his company physician and his brother (a physician) for treatment of hypertension. In 1947 he had complained of fatigue, and also of occasional pain in the left arm. The only abnormal finding at that time was a blood pressure of 182/112. Urine and electrocardiogram were normal. In 1950 the pressure rose to 230/140 and in 1951 to 245/170. He developed severe headaches and cardiac enlargement by x-ray and electrocardiogram. The eyegrounds showed hemorrhages, exudates and mild papilledema. Conservative treatment by diet and rest was of no avail. The patient was admitted to the hospital for evaluation of his suitability for sympathectomy. Physical, x-ray and electrocardiographic examinations confirmed the findings reported by his physicians. The pulse rate was 72, and the blood pressure 240/140, but on bed rest subsided to 230/130 and on sedation test to 175/110. His response to the cold test was 235/145. Renal function tests
Hypertension: Trends in Treatment
1309
showed 1 + albuminuria, otherwise satisfactory. He was considered suitable for sympathectomy and agreed to have the operation in one month, but asked to be tried on drugs during the interim. He was started on Rauwolfia (Serpina) 1 tablet morning and night, and hydralazine 25 mg. three times a day. He returned in a week, and his pressure was 190/100, pulse 68. Hydralazine was gradually increased to 50 mg. three times a day and 1 month later he was readmitted to the hospital. Blood pressure was 180/100, pulse 60. Blood pressure on bed rest fell to 150/90 and during the cold test rose from 165/95 to 175/110. The renal function was good, and the urine albumin-free. The patient continued on this therapy of Rauwolfia 2 tablets a day, hydralazine 50 mg. four times a day, and later 75 mg. four times a day. Ambulatory
SERPINA a APRESOLINE
CONTROL '230 210 190 170
ARTERIAL 150
BLOOD
PRESSURE 130
mm. Hg
110
PULSE RATE beott/min.
70 50
90
• •_
SERPINA ~fl
Cl
Tablets I Day
APRESOLINE Mg./Day
2
345 TIME IN YEARS
IOOE_ ~'" . :~~~
6
7
Fig. 171 (Case 11). Course of the blood pressure and pulse rate, showing responses to therapy as indicated.
blood pressure remained about 170/95. After four months he was readmitted to the hospital for check-up. Admission blood pressure was 150/90, and during the sedation test 140/80. Electrocardiogram showed improvement toward normal and' the optic fundi revealed no papilledema, no hemorrhages, no new exudates, and a few old scars while the fundal arteries showed increased light reflex, but no spasms and only slight AV nicking. The patient continued on the same regimen of Rauwolfia 1 tablet twice a day, hydralazine 75 mg. four times a day for the ensuing 8 months with ambulatory blood pressure 170/95, pulse 56. He feels well, has resumed playing golf once a week, and does not tire as easily as formerly. Case III (Fig. 172). V. V., a white woman, aged 36, had been in good health until 15 years ago, when she developed toxemia with her initial pregnancy characterized by severe hypertension (systolic pressure, 240 mm. Hg), edema, and albuminuria. Ten years ago during a routine physical examination blood pres-
Robert W. W ilkl:ns
1310
sure was again found to be elevated. Four years ago the patient had had a subarachnoid hemorrhage (? rupture of intracranial aneurysm) with transient right hemiparesis. Three years ago (1950) she was referred to our hospital for treatment of 3rt.~rial hypertension. She stated that she had always been bothered with headaches) B,nd. during episodes of excitement or anger, with vasomotor disturbances such as diffuse blotchy eruption and sweating over face, neck and thorax. Fundoscopic examination showed a Grade 11 hypertensive retinopathy; heart size, chest film, and electrocardiogram were normal. Intravenous pyelogram and renal function studies were essentially normal. During the succeeding 1~~ years the patient was given a thorough trial of treatment with Veriloid, without any striking consistent effect on the blood pressure. A brief trial of hydralazine then indicated some reduction of pressure but not to normal. In October, 1951, lumbodorsal sympathectomy (Smithwick) was performed. However, the patient continued to have v.v. t
34,Wh.
ARTERIAL 160
P:Ea.:~E 140 mmHg
.
120
PULSE RATE beats/min.
Fig. 172 (Case Ill). Course of the blood pressure and pulse rate, showing responses to therapy as indicated.
elevation of the arterial pressure (perhaps at less severe levels) and complained of nervousness and frequent facial flushing. A trial of combination drug therapy (Rauwolfia, veratrum, and hydralazine) was undertaken. On this regimen the blood pressure was maintained consistently at normotensive levels without disturbing side effects. In addition, the patient felt relaxed and experienced no more attacks of flushing. With interruption of the regimen the blood pressure returned to pretreatment levels and the nervousness and vasomotor symptoms reappeared. On reinstituting the same combination of drugs normotension was again achieved and when the drugs were interrupted a second time the hypertension again returned. She will now be ma~ntained on this combination of drugs. GENERAL RESULTS
On Rauwolfia alone, 13 of 39 patients had a return of blood pressure to within the normal range (150/90 or lower). However, these 13 patients were in general younger, milder and more neurotic than the average. In
Hypertension: Trends in Treatment
1311
addition they tended to have a more rapid heart rate. Therefore, this drug alone was considered to be wholly satisfactory only in this type of patient. Of 22 patients placed on a combination of Rauwolfia and veratrum (many of whom had failed to respond adequately to Rauwolfia alone) only 5 had a return of blood pressure to normal (although 4 others were within 5 mm. Hg of these values). Of 23 patients treated with a combination of Rauwolfia and hydralazine 6 had normal pressures (and 2 were within 5 mm. of normal). However, of 18 patients placed on a combination of all 3 drugs, 13 had a normal pressure, and the average of the group was normal. Thus it appeared that in patients who failed to respond adequately to one drug, the effects of any combination of two tried were, on the average, about the same. However, there were individual patients who responded to one combination of two drugs and not to another. Furthermore some patients responded to all three when they had failed to respond to any combination of two. Finally there were patients who failed to respond to all three drugs together, at least in the dosages so far employed. DISCUSSION
The results reported here, as well as in the recent literature, indicate that combinations of hypotensive drugs are offering ne,v and more effective means of lowering blood pressure in hypertensive patients. It should be emphasized, however, that the three drugs discussed here, either alone, or in various combinations, are not capable of producing beneficial effects in all patients. However, we have frequently observed beneficial results to occur merely on continuing a regimen of one of these drugs or a combination of them at the same dosages for longer periods of time. Similarly, on adding a new drug to a regimen already established, or on increasing the dosage of the drug or drugs in the regimen, we have observed a favorable effect to occur. Therefore, too early assessment of such combination drug therapy should not be attempted. On the other hand in occasional patients there have been disappointing results even after long and faithful trials of the drugs. This has occurred most often in patients with uremia, but rarely it has occurred for no obvious reason. When it appears urgent to lower the pressure in such patients, one may feel it necessary to turn to more drastic measures such as sympathectomy, or hexamethonium given parenterally. These measures, however, should not be undertaken except by experts under the most carefully controlled conditions. The particular drugs mentioned here are not unique or even unusual in their ability to lower blood pressure either alone or in combinations. Similar results have been obtained with other drugs and other combinations. However, of all the drugs tried in this clinic (and we believe
1312
Robert W. W ilkins
we have tried them all) these have appeared to be the safest, simplest, least symptom-producing and longest-lasting in their action. Until better agents or truly specific therapies based on a knowledge of etiology are available we will continue to use these drugs. However, even these drugs can produce untoward effects. Hydralazine unquestionably is the chief offender of the three. Not only may it cause troublesome headache, palpitation and breathlessness, but it may also result in dependent edema. Usually these side effects will disappear if the patient can persist in taking the drug. However, angina pectoris or status anginosus, with electrocardiographic changes suggesting myocardial ischemia, we regard as an indication for discontinuation of the drug. As already mentioned, unexplained gastrointestinal hemorrhage has occurred in 3 patients taking the drug, while a pancytopenia has occurred in 1 other patient to our knowledge. The other two drugs produce mild side effects; veratrum, nausea and vomiting, Rauwolfia, sleepiness and depression, all of which can be relieved by reducing the dosage of the drug causing the effect. Experience thus has taught us that these new drugs, like other new drugs in medicine, do not make the lot of the physician in charge any easier; on the contrary they increase the necessity for his constant vigilance. But some of the newer hyp~tensive drugs do increase his satisfaction in dealing with hypertensive patients because he can relieve not only many of the symptoms but also some of the signs of their disease, in addition to the blood pressure itself. SUMMARY AND CONCLUSIONS
Hypertension can be relieved for long periods of time in a nUillger of patients by Rauwolfia, hydralazine and veratrum, either singly or in various combinations. The methods of using these drugs are described. They are worth continuing until better methods appear.