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Use of Drugs in Cardiovascular Disease
Medical Clinics oj North America July, 1937. Philadelphia Number
CLINIC OF CHARLES L. BROWN TEMPLE UNIVERSITY SCHOOL OF MEDICINE AND TEMPLE UNIVERSITY HOSPITAL
USE OF DRUGS IN CARDIOVASCULAR DISEASE
THE significant clinical developments in the course of cardiovascular disease which are influenced by the use of drugs may be listed as of three types; namely, congestive myocardial failure, cardiac pain, and abnormal. heart action. Although some of these clinical features may be present more commonly in certain forms of heart disease, one or more of these conditions may occur in most any type of cardiovascular disease, and the treatment of them is essentially the same, irrespective of the etiology of the heart disease. The use of drugs, then, in patients presenting these features, may, be considered as treatment indicated by symptoms and signs. For the purpose of the subject under discussion cardiovascular disease is divided etiologically into five groups; namely, rheumatic heart disease, hypertensive heart disease and coronary arteriosclerosis, thyrogenic heart disease, syphilitic heart disease, and subacute bacterial endocarditis. Then, accordingly, the drugs used in the different types of heart disease should be referred to as treatment indicated by etiology. I. TREATMENT INDICATED BY SYMPTOMS AND SIGNS 1. CONGESTIVE MYOCARDIAL FAILURE
Digitalis.-Digitalis, the most useful drug in the treatment of congestive myocardial failure is especially efficacious in those cases in which auricular fibrillation with a high ventricular rate is also present. However, it has been demonstrated adequately that very satisfactory results can be obtained in cases of cardiac decompensation with regular VOL. 21-68
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rhythm. Hypertension in itself is no contraindication to digitalis therapy. The plan of digitalis administration should vary somewhat with the individual patient. First, one should determine whether the patient has had any digitalis within the past three weeks, and how much if possible, and if the patient has had digitalis during this time further digitalis should be given in smaller doses and more cautiously. If no digitalis has been given within three weeks, or the patient has never had any digitalis the decision rests between rapid digitalization in a few hours by massive doses and slower digitalization by smaller doses at less frequent intervals during the next three or four days or longer. A severe degree of decompensation in a patient who has had no digitalis is the prime indication for rapid digitalization, while slow digitalization may have some advantages in the milder form of decompensation or in the patient who has had a considerable or an unknown amount of digitalis. At a time when the massive dosage method was first coming into wide use, inadequate results from digitalis were attributed to insufficient digitalis and properly so. No doubt the potency of many digitalis preparations was less certain then than now. The common method of calculation of the digitalization dose was on the basis of body weight, using such formulae as 30 mg. of digitalis folia, or its equivalent, per kilogram of body weight, or 1 grain per 5 pounds of body weight. Accordingly, for a patient weighing 154 pounds the calculated dose would be 2 Gm. or 31 grains of digitalis folia, or its equivalent. The dosage might be expressed in terms of cat units, the "cat method" being commonly accepted for pharmacologic assay, and 1 cat unit representing 1% grains, the above total dosage being equivalent to approximately 20 cat units. Ordinarily, one quarter of the digitalization dose (in the above instance 7lh grains or 0.5 Gm.) was given -for 3 doses, about four to six hours apart, making three quarters of the calculated dose received by the patient within an eight- to twelve-hour period. By this time some effect would be noted probably as diuresis from digitalis usually does not occur in any marked degree until two thirds to three fourths of the digitalization dose is given, and by this time some effect upon the pulse rate or digestiVe tract might be looked for. If the optimum effect were
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not noted 1Y2 grains (0.1 Gm.) to 3 grains (0.2 Gm.) one to three times a day would be given until beneficial effect was obvious or early toxic effects resulted. A good therapist would get the desired effects but stop short of toxicity, fulfilling the directions of Withering: "Let the medicine be continued until it either acts upon the kidneys, the stomach, the pulse or the bowels; let it be stopped upon the first appearance of anyone of these effects." This method of administration is satisfactory for hospital practice or very carefully controlled house practice, but in cases where such close observation is not possible it has become common practice to count on the average optimum amount of digitalis for the averaged-sized adult (150 pounds) as about 20 grains of digitalis folia, or its equivalent in other preparations, given in divided doses as above stated, and to proceed to satisfactory digitalization from that point cautiously up to the maintenance dose. Two factors enter into this problem; first, it is almost impossible to gage the dosage accurately by the body weight as a considerable portion of the body weight may be edema fluid, and second, the maintenance dose may be greatly different in individual cases. Usually, however, the patient will know something about his weight before the edema appeared or some estimate of the weight representing edema may be attempted, and calculation can be made accordingly. In general, 1Y2 grains of digitalis folia (or its equivalent) has been found to be the average maintenance dose, but it should be known that some cases are well maintained on less (% grain) or more (2 grains) than this, and only close clinical observation will control this factor. Four methods of administration are available; namely, the oral, the subcutaneous, the intravenous, and the rectal. Only in very rare instances need any other than the oral route be employed. Digitalis folia and tincture of digitalis are entirely satisfactory for oral administration and, except in very unusual instances are there any obvious advantages of other preparations. An injectable form for intravenous and subcutaneous administration is necessary in cases demanding quick action and many proprietary preparations are now available in properly standardized forms, and the future promises more
CHARLES L. BROWN
stable solutions of this type. General principles of assay and dosage expressed above are sufficient in guiding treatment if dependable and in-date preparations are used. It is well to remember that tincture of digitalis, or other solutions of digitalis are almost as efficacious if given by rectum as by mouth, usually some dilution with normal saline being desirable. If slower digitalization is employed a satisfactory method is to use 112 grains or 3 grains, depending on rapidity desired, of digitalis folia three times a day until the therapeutic effect is obtained and then giving a daily maintenance dose. In using digitalis in the presence of thyrotoxicosis or pneumonia or any other toxic state it is advisable to give only about half of the calculated dose for digitalization and then proceed cautiously, as it may be difficult to differentiate any increased toxicity as due to the digitalis or change in the preexistent toxic condition. Clinically it seems to make no difference in the average case whether digitalis folia or the tincture is used providing potent and well standardized fresh preparations are employed and given in sufficient doses. There is a fallacy in the suggestion that the dosage can be more accurately gaged with tincture as the individual dose may be varied by as little as 1 drop. Usually it is not possible to determine the optimum amount by such small margin and there is no practical advantage in attempting to do so. It should be remembered that a drop of tincture of digitalis from the average dropper is less than a minim (usually about 2 drops to the minim) and the only dependable way is to ~easure the dose in minims. Other drugs in the digitalis series still in use are strophanthus, ouabain, squills, and apocynum. These drugs seem to present no clinical advantage over digitalis, and since digitalis preparations now are so dependable it seems much wiser in average practice to know how t6 give digitalis and use it. Perhaps on rare occasions strophanthin or ouabain should be used when the digitalis effect must be obtained very promptly as a life-saving measure, but these drugs need no consideration in the ordinary management of congestive failure. Except in very rare instances there seems to be no good reason to pr~fer some of the glucosides of digitalis, although advantages are claimed by some. Verodigen, a gitalin- or digitalein-
USE OF DRUGS IN CARDIOVASCULAR DISEASE
IOn
like fraction of digitalis is an example, said to be more readily absorbed than digitalis, and claimed to be better tolerated by the gastro-intestinal tract, but its potency, Y240 grain of verodigen being equivalent to 1Y2 grains of digitalis folia, indicates the advisability of its use in specially selected cases and under facilities for very careful observation. Diuretics.-Diuretics are valuable adjuncts to digitalis therapy and three general groups are available: the xanthine derivatives, certain mercury compounds, and several salts. One of these diuretics may be helpful when another has failed, or a combination may act favorably when no appreciable effect has been obtained by one or the other alone. The presence of gastro-intestinal symptoms; the necessity for prompt diuresis, the definite accompaniment of nephritis, and the physician's personal preference are factors that influence the choice of one or other of these diuretics in the beginning. Failure of this choice leads to trial of others or combinations. Theophylline (theocin), theobromine sodium salicylate (diuretin), and theobromine calcium salicylate (theocalcin) are the commonly used representatives of the xanthine derivatives. These three often produce excellent diuresis, and all are better given in fairly large doses for a short period of time and repeated, than in small doses over a long period of time. These drugs, especially theophylline, may produce gastric irritation or mental aberration, but not commonly, and such occasion need cause no alarm as discontinuance of the drug is accompanied by fairly prompt clearing of these symptoms. Theophylline in doses of 5 to 7Y2 grains (0.3 to 0.5 Gm.), or theobromine sodium salicylate, 7Y2 to 10 grains (0.5 to 0.6 Gm.), or theobromine calcium salicylate, 15 grains (0.1 Gm.) three times a day for two days or 6 doses, usually proves a satisfactory way to give these drugs. If diuresis is to occur from the drug it will do so likely by this time. Although these three drugs all belong to the same group, occasionally one will produce a diuresis in the same patient who has had no appreciable effect from one of the other two. The mercurial diuretics are very important in the treatment of congestive failure and properly have enjoyed widespread clinical use. Merbaphen (novasurol, a mercury urea compound), mersalyl (salyrgan, a mercury salicylate com-
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pound), and mercupurin (a mercury theophylline compound), are the three representatives of this group. These drugs are prepared for clinical usage as a solution in glass ampules, to give 1 cc. to 2 cc., preferably intravenously, or intramuscularly, but never subcutaneously. Subcutaneous injection or leakage about the point of injection into the vein causes necrosis of tissue, so extreme care about injection is necessary. The use of a small caliber needle and dilution of the drug before intravenous injection are helpful in avoiding such accidents. A great deal has been written about the relative toxicity especially of the first two of these mercurials mentioned; the approximate percentage of mercury in the three compounds is: novasurol, 33.9 per cent, salyrgan, 39.6 per cent, and mercupurin, 41 per cent. One gathers the impression from the literature that salyrgan is less toxic than novasurol, and that mercupurin is no more toxic than salyrgan, and possibly less so. The two main factors thought to influence this apparent paradox are individual sensitivity to mercury, or greater tolerance by some patients, and the possibility that the toxicity de- . pends on the chemical linkage of the mercury to the rest of the molecule rather than to the actual percentage of mercury present. While there is no clear preference of one of these drugs over the other, on the whole, clinical reports have seemed more favorable to the use of salyrgan or mercupurin. Clinical doses of these mercurials may be accompanied by some increase in the casts in the urine, and because of the effect of mercury on the kidney, their use in patients with nephritis is cautioned. However, in ordinary cases of congestive failure their use need pot be curtailed, as the kidney irritation as determined by the urinary cast count quickly subsides, and the gravity of the situation justifies their use. Salyrgan and the mercurial salt of mercupurin (mercurin) are now available in suppository form and these preparations produce diuresis comparatively favorable with the intravenous administration. If these diuretics are effective the diuresis will occur within a few hours, so it is advisable to give the drug early in the morning, so as to least disturb the patient at night. The dose of any of these ordinarily used is 1 cc. to 2 cc.; it may be repeated in one week, or if occasion demands as often as twice
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a week. In some instances the mercurials have been efficacious, when they have not been before, after three or four days taking 60 to 90 grains (4 to 6 Gm.) of ammonium chloride daily. Certain Salts.-The acid-producing salts, calcium chloride, ammonium chloride, and ammonium nitrate, may serve as excellent diuretics when given in large doses, ranging from 90 to 180 grains (6 to 12 Gm.) daily. Ammonium chloride or ammonium nitrate is more commonly used, and is- best given in enteric-coated pills in an effort to avoid gastric irritation. These drugs may be given in capsules with the meals. If they are to be given ill liquid form a vehicle containing yerba santa makes the preparation more tolerable. At times a better diuretic effect is noted by giving these salts in the above doses for a few days then discontinue them for a few days. A neutral diet aids in decreasing the amount of the salt necessary, but this is difficult to follow out for longer than a few days unless dietetic service is available. . Potassium nitrate or potassium chloride in large doses, 120 to 180 grains (8 to 12 Gm.) daily have been found to produce satisfactory diuresis in many cases, caution being given in cases with severe renal insufficiency. Morphine and Sedatives.-These drugs are very useful in the cardiac patient, to give them mental and physical rest, and morphine sulfate is especially effective in the acute distress of congestive failure, when used in moderate doses. Cathartics.-In some instances cathartics, especially the salines, are very useful, but generally the extra effort of increased bowel movements is undesirable if other measures are effective. In the foregoing discussion no distinction has been made between so-called "right ventricular failure" and "left ventricular failure," although the general picture of congestive failure represents essentially the result finally or predominantly of "right ventricular failure." Attention should be called to the acute paroxysmal dyspnea with or without "cardiac asthma" due to acute failure of the left ventricle. Morphine sulfate is indicated in such an attack; aminophyllin, intravenously, may be helpful; and in those cases tending to have associated "cardiac asthma" with pulmonary edema the mercurials may be of some value.
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CHARLES L. BROWN
Aminophyllin, 0.24 Gm. (4 grains) given slowly intravenously, is very effective in relieving the acute distress of Cheyne-Stokes respiration, and an O!::ll dose in the evening may prevent occurrence at night, or steady dosage of 1Yz grains three or four times a day may offer freedom from this symptom. 2. CARDIAC PAIN
The most significant cardiac pain is that of angina pectoris and coronary thrombosis. Although of similar character in onset, location and distribution the treatment of the two is different in the use of the vasodilators. The vasodilators are contraindicated in coronary thrombosis, as shock is a part of the picture. The blood pressure as a guide will help to avoid giving the nitrites when the diagnosis may not at first be apparent. The nitrites, theobromine sodium salicylate, and aminophyllin are the drugs of choice for angina pectoris. Of the nitrites, nitroglycerin and amyl nitrite are the quickest and shortest in action and therefore useful in the acute attack. Sodium nitrite and erythrol tetranitrate are more useful in an attempt to decrease the frequency and severity of the attacks. The same may be said of aminophyllin and theobromine sodium salicylate; aminophyllin is given in doses of 1Yz to 3 grains (0.1 to 0.2 Gm.) three times a day or sometimes 1Yz grains five or six times a day is more effective. Theobromine sodium salicylate is given much the same way, the dose being 7Yz grains (0.5 Gm.). For coronary thrombosis morphine sulfate and aminophyllin are more effective. Morphine sulfate may and should be given in large doses, in the severe case Yz grain hypodermically being justified. Aminophyllin, 4 grains (0.24 Gm.) intravenously, is frequently attended by more prompt and greater relief than is morphine sulfate. It should be given slowly; if the pain recurs after a few hours it is permissible to repeat the dosage. Aminophyllin, 1Yz grains (0.1 Gm.) by mouth three or more times a day, is recommended routinely in coronary thrombosis for an indefinite time. Of the drugs, sedatives play an important part in the relief of painful discomfort over the heart, due to other forms of heart disease; or treatment of the primary conditions is indicated ifother than cardiac in origin.
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3. ABNORMAL RHYTHM OR RATE
From the standpoint of general practice the following arrhythmias are the most important as they can usually be recognized at the bedside and often are amenable to treatment; ventricular extrasystoles, auricular fibrillation, auricular flutter, paroxysmal auricular tachycardia, ventricular tachycardia and complete heart block. Extrasystoles unless frequent and accompanied by palpitation or precordial discomfort rarely call for treatment, but if so, sedatives should be first of the drugs used. Very rarely it may be necessary to use quinidine sulfate or digitalis in trying to stop them. The principles in giving these two drugs is the same here as on other occasions of their use, except usually smaller and less frequent doses are necessary. If the extrasystoles first appear while the patient is under digitalization they probably signify digitalis effect. Auricular fibrillation and auricular flutter may be discussed together because two drugs are useful in both instances; namely, digitalis and quinidine sulfate. Digitalis is indicated in auricular fibrillation, unless perhaps in the case of "slow" fibrillation without congestive failure. Digitalis does not stop fibrillation but decreases the pulse deficit and the ventricular rate. All patients with auricular fibrillation should not be given quinidine sulfate, especially those with fibrillation of long standing. Quinidine sulfate is best indicated in the case of short duration, without congestive heart failure, and with a ventricular rate under 110. The auricular fibrillation of thyrogenic origin is especially suitable for quinidine sulfate therapy. Special caution is urged in the long-standing fibrillation with congestive failure of some duration, and quinidine sulfate will probably do no good anyway. Frequently it is advisable, especially in rapid fibrillation, to digitalize the patient before giving the quinidine sulfate. Digitalization and quinidine sulfate are advisable in auricular flutter and return to normal rhythm may be expected. Quinidine sulfate should be given first in a test dose of 3 grains to note any untoward effects of susceptibility. If any serious toxic effect occurs it is likely to be one of respiratory failure and caffeine sodium benzoate, 15 grains, should be given intravenously immediately, and artificial respiration if neces-
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CHARLES L. BROWN
sary. When the patient is known not to be susceptible, the quinidine sulfate may be given in 6-grain doses every four hours until rhythm is restored. Larger doses more frequently may be used if close observation and electrocardiographic control are available. Another often satisfactory clinical method is to give 3 doses a day, increasing the dose for each succeeding day by 1}2 grains, as for example, 3 grains three times a day, then 4}2 grains three times a day the next day, and so on. D sually it is not wise or necessary to give higher doses than 1O}2 or 12 grains three times a day. If vagal or ocular pressure has not stopped an attack of paroxysmal tachycardia, three drugs may be considered: quinidine sulfate, digitalis, and acetyl-,B-methylcholine chloride (mecholin or mecholyl). The dosage of the acetyl-,B-methylcholine is 15 to 20 mg. subcutaneously. Atropine sulfate will counteract any untoward effect of the acetyl-,B-methylcholine. If attacks are frequent quinidine sulfate, 3 grains one to three times daily, may be useful in preventing recurrence. Sedatives are suggested also to relieve anxiety and promote rest. Ventricular tachycardia is a dangerous arrhythmia and often responds satisfactorily to quinidine sulfate therapy, large doses and even intravenous use of quinidine sulfate being justified in some instances. The drugs of use in complete heart block are epinephrine hydrochloride, ephedrine sulfate, barium chloride, and possibly atropine sulfate. Epinephrine hydrochloride, 5 to 15 minims of 1: 1000 solution'hypodermically or intracardiac, is used for the attack of Adams-Stokes syndrome, while ephedrine sulfate, % grain by mouth one to three times daily, may help in preventing severe and frequent attacks. Barium chloride, ~ grain by mouth, three or four times a day, is sometimes effective in preventing attacks. 11. TREATMENT INDICATED BY ETIOLOGY
In rheumatic fever the salicylates still remain the therapeutic stand-by as far as drugs are concerned. The newly used drug, sulfanilamide (para-amino-benzene-sulfonamide, prontylin) , offers some, promise, but its effectiveness in rheumatic fever must await further observation. In hypertensive heart disease and coronary arteriosclerosis any drug therapy at
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present is entirely for symptomatic relief. Thyrogenic heart disease is of two varieties, the so-called "myxedema heart" and thyrotoxic cardiac disturbances. When congestive failure appears, its management is the same as in other instances. Desiccated thyroid gland in sufficient quantity to correct the myxedema improves the heart condition providing arteriosclerosis and resultant myocardial changes are not too great, and these very features may in a way influence the amount of thyroid the patient can take without producing angina pectoris or other symptoms of too great cardiac activity in a heart long unaccustomed to it. In the thyrotoxic case iodine in some form is a part of the program for preoperative preparation. When syphilis is the etiology of cardiovascular disease, alone or with associated arteriosclerosis, arst;nic, mercury, bismuth and the iodides in their various forms must be considered. More often the problem is one of syphilitic aortitis with or without aortic valvular disease rather than actual syphilis of the heart. By the time these cases have a predominant cardiac phase the matter of treatment is not so much specifically against the spirochete as against the damage it has caused. In such cases the arsenicals are used only after careful consideration of the individual case, then with caution. No effective drug treatment of subacute bacterial endocarditis (Streptococcus viridans) is known.
CLINIC OF CHARLES L. BROWN TEMPLE UNIVERSITY SCHOOL OF MEDICINE AND TEMPLE UNIVERSITY HOSPITAL
USE OF DRUGS IN CARDIOVASCULAR DISEASE
THE significant clinical developments in the course of cardiovascular disease which are influenced by the use of drugs may be listed as of three types; namely, congestive myocardial failure, cardiac pain, and abnormal. heart action. Although some of these clinical features may be present more commonly in certain forms of heart disease, one or more of these conditions may occur in most any type of cardiovascular disease, and the treatment of them is essentially the same, irrespective of the etiology of the heart disease. The use of drugs, then, in patients presenting these features, may, be considered as treatment indicated by symptoms and signs. For the purpose of the subject under discussion cardiovascular disease is divided etiologically into five groups; namely, rheumatic heart disease, hypertensive heart disease and coronary arteriosclerosis, thyrogenic heart disease, syphilitic heart disease, and subacute bacterial endocarditis. Then, accordingly, the drugs used in the different types of heart disease should be referred to as treatment indicated by etiology. I. TREATMENT INDICATED BY SYMPTOMS AND SIGNS 1. CONGESTIVE MYOCARDIAL FAILURE
Digitalis.-Digitalis, the most useful drug in the treatment of congestive myocardial failure is especially efficacious in those cases in which auricular fibrillation with a high ventricular rate is also present. However, it has been demonstrated adequately that very satisfactory results can be obtained in cases of cardiac decompensation with regular VOL. 21-68
1073
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CHARLES L. BROWN
rhythm. Hypertension in itself is no contraindication to digitalis therapy. The plan of digitalis administration should vary somewhat with the individual patient. First, one should determine whether the patient has had any digitalis within the past three weeks, and how much if possible, and if the patient has had digitalis during this time further digitalis should be given in smaller doses and more cautiously. If no digitalis has been given within three weeks, or the patient has never had any digitalis the decision rests between rapid digitalization in a few hours by massive doses and slower digitalization by smaller doses at less frequent intervals during the next three or four days or longer. A severe degree of decompensation in a patient who has had no digitalis is the prime indication for rapid digitalization, while slow digitalization may have some advantages in the milder form of decompensation or in the patient who has had a considerable or an unknown amount of digitalis. At a time when the massive dosage method was first coming into wide use, inadequate results from digitalis were attributed to insufficient digitalis and properly so. No doubt the potency of many digitalis preparations was less certain then than now. The common method of calculation of the digitalization dose was on the basis of body weight, using such formulae as 30 mg. of digitalis folia, or its equivalent, per kilogram of body weight, or 1 grain per 5 pounds of body weight. Accordingly, for a patient weighing 154 pounds the calculated dose would be 2 Gm. or 31 grains of digitalis folia, or its equivalent. The dosage might be expressed in terms of cat units, the "cat method" being commonly accepted for pharmacologic assay, and 1 cat unit representing 1% grains, the above total dosage being equivalent to approximately 20 cat units. Ordinarily, one quarter of the digitalization dose (in the above instance 7lh grains or 0.5 Gm.) was given -for 3 doses, about four to six hours apart, making three quarters of the calculated dose received by the patient within an eight- to twelve-hour period. By this time some effect would be noted probably as diuresis from digitalis usually does not occur in any marked degree until two thirds to three fourths of the digitalization dose is given, and by this time some effect upon the pulse rate or digestiVe tract might be looked for. If the optimum effect were
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not noted 1Y2 grains (0.1 Gm.) to 3 grains (0.2 Gm.) one to three times a day would be given until beneficial effect was obvious or early toxic effects resulted. A good therapist would get the desired effects but stop short of toxicity, fulfilling the directions of Withering: "Let the medicine be continued until it either acts upon the kidneys, the stomach, the pulse or the bowels; let it be stopped upon the first appearance of anyone of these effects." This method of administration is satisfactory for hospital practice or very carefully controlled house practice, but in cases where such close observation is not possible it has become common practice to count on the average optimum amount of digitalis for the averaged-sized adult (150 pounds) as about 20 grains of digitalis folia, or its equivalent in other preparations, given in divided doses as above stated, and to proceed to satisfactory digitalization from that point cautiously up to the maintenance dose. Two factors enter into this problem; first, it is almost impossible to gage the dosage accurately by the body weight as a considerable portion of the body weight may be edema fluid, and second, the maintenance dose may be greatly different in individual cases. Usually, however, the patient will know something about his weight before the edema appeared or some estimate of the weight representing edema may be attempted, and calculation can be made accordingly. In general, 1Y2 grains of digitalis folia (or its equivalent) has been found to be the average maintenance dose, but it should be known that some cases are well maintained on less (% grain) or more (2 grains) than this, and only close clinical observation will control this factor. Four methods of administration are available; namely, the oral, the subcutaneous, the intravenous, and the rectal. Only in very rare instances need any other than the oral route be employed. Digitalis folia and tincture of digitalis are entirely satisfactory for oral administration and, except in very unusual instances are there any obvious advantages of other preparations. An injectable form for intravenous and subcutaneous administration is necessary in cases demanding quick action and many proprietary preparations are now available in properly standardized forms, and the future promises more
CHARLES L. BROWN
stable solutions of this type. General principles of assay and dosage expressed above are sufficient in guiding treatment if dependable and in-date preparations are used. It is well to remember that tincture of digitalis, or other solutions of digitalis are almost as efficacious if given by rectum as by mouth, usually some dilution with normal saline being desirable. If slower digitalization is employed a satisfactory method is to use 112 grains or 3 grains, depending on rapidity desired, of digitalis folia three times a day until the therapeutic effect is obtained and then giving a daily maintenance dose. In using digitalis in the presence of thyrotoxicosis or pneumonia or any other toxic state it is advisable to give only about half of the calculated dose for digitalization and then proceed cautiously, as it may be difficult to differentiate any increased toxicity as due to the digitalis or change in the preexistent toxic condition. Clinically it seems to make no difference in the average case whether digitalis folia or the tincture is used providing potent and well standardized fresh preparations are employed and given in sufficient doses. There is a fallacy in the suggestion that the dosage can be more accurately gaged with tincture as the individual dose may be varied by as little as 1 drop. Usually it is not possible to determine the optimum amount by such small margin and there is no practical advantage in attempting to do so. It should be remembered that a drop of tincture of digitalis from the average dropper is less than a minim (usually about 2 drops to the minim) and the only dependable way is to ~easure the dose in minims. Other drugs in the digitalis series still in use are strophanthus, ouabain, squills, and apocynum. These drugs seem to present no clinical advantage over digitalis, and since digitalis preparations now are so dependable it seems much wiser in average practice to know how t6 give digitalis and use it. Perhaps on rare occasions strophanthin or ouabain should be used when the digitalis effect must be obtained very promptly as a life-saving measure, but these drugs need no consideration in the ordinary management of congestive failure. Except in very rare instances there seems to be no good reason to pr~fer some of the glucosides of digitalis, although advantages are claimed by some. Verodigen, a gitalin- or digitalein-
USE OF DRUGS IN CARDIOVASCULAR DISEASE
IOn
like fraction of digitalis is an example, said to be more readily absorbed than digitalis, and claimed to be better tolerated by the gastro-intestinal tract, but its potency, Y240 grain of verodigen being equivalent to 1Y2 grains of digitalis folia, indicates the advisability of its use in specially selected cases and under facilities for very careful observation. Diuretics.-Diuretics are valuable adjuncts to digitalis therapy and three general groups are available: the xanthine derivatives, certain mercury compounds, and several salts. One of these diuretics may be helpful when another has failed, or a combination may act favorably when no appreciable effect has been obtained by one or the other alone. The presence of gastro-intestinal symptoms; the necessity for prompt diuresis, the definite accompaniment of nephritis, and the physician's personal preference are factors that influence the choice of one or other of these diuretics in the beginning. Failure of this choice leads to trial of others or combinations. Theophylline (theocin), theobromine sodium salicylate (diuretin), and theobromine calcium salicylate (theocalcin) are the commonly used representatives of the xanthine derivatives. These three often produce excellent diuresis, and all are better given in fairly large doses for a short period of time and repeated, than in small doses over a long period of time. These drugs, especially theophylline, may produce gastric irritation or mental aberration, but not commonly, and such occasion need cause no alarm as discontinuance of the drug is accompanied by fairly prompt clearing of these symptoms. Theophylline in doses of 5 to 7Y2 grains (0.3 to 0.5 Gm.), or theobromine sodium salicylate, 7Y2 to 10 grains (0.5 to 0.6 Gm.), or theobromine calcium salicylate, 15 grains (0.1 Gm.) three times a day for two days or 6 doses, usually proves a satisfactory way to give these drugs. If diuresis is to occur from the drug it will do so likely by this time. Although these three drugs all belong to the same group, occasionally one will produce a diuresis in the same patient who has had no appreciable effect from one of the other two. The mercurial diuretics are very important in the treatment of congestive failure and properly have enjoyed widespread clinical use. Merbaphen (novasurol, a mercury urea compound), mersalyl (salyrgan, a mercury salicylate com-
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CHARLES L. BROWN
pound), and mercupurin (a mercury theophylline compound), are the three representatives of this group. These drugs are prepared for clinical usage as a solution in glass ampules, to give 1 cc. to 2 cc., preferably intravenously, or intramuscularly, but never subcutaneously. Subcutaneous injection or leakage about the point of injection into the vein causes necrosis of tissue, so extreme care about injection is necessary. The use of a small caliber needle and dilution of the drug before intravenous injection are helpful in avoiding such accidents. A great deal has been written about the relative toxicity especially of the first two of these mercurials mentioned; the approximate percentage of mercury in the three compounds is: novasurol, 33.9 per cent, salyrgan, 39.6 per cent, and mercupurin, 41 per cent. One gathers the impression from the literature that salyrgan is less toxic than novasurol, and that mercupurin is no more toxic than salyrgan, and possibly less so. The two main factors thought to influence this apparent paradox are individual sensitivity to mercury, or greater tolerance by some patients, and the possibility that the toxicity de- . pends on the chemical linkage of the mercury to the rest of the molecule rather than to the actual percentage of mercury present. While there is no clear preference of one of these drugs over the other, on the whole, clinical reports have seemed more favorable to the use of salyrgan or mercupurin. Clinical doses of these mercurials may be accompanied by some increase in the casts in the urine, and because of the effect of mercury on the kidney, their use in patients with nephritis is cautioned. However, in ordinary cases of congestive failure their use need pot be curtailed, as the kidney irritation as determined by the urinary cast count quickly subsides, and the gravity of the situation justifies their use. Salyrgan and the mercurial salt of mercupurin (mercurin) are now available in suppository form and these preparations produce diuresis comparatively favorable with the intravenous administration. If these diuretics are effective the diuresis will occur within a few hours, so it is advisable to give the drug early in the morning, so as to least disturb the patient at night. The dose of any of these ordinarily used is 1 cc. to 2 cc.; it may be repeated in one week, or if occasion demands as often as twice
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a week. In some instances the mercurials have been efficacious, when they have not been before, after three or four days taking 60 to 90 grains (4 to 6 Gm.) of ammonium chloride daily. Certain Salts.-The acid-producing salts, calcium chloride, ammonium chloride, and ammonium nitrate, may serve as excellent diuretics when given in large doses, ranging from 90 to 180 grains (6 to 12 Gm.) daily. Ammonium chloride or ammonium nitrate is more commonly used, and is- best given in enteric-coated pills in an effort to avoid gastric irritation. These drugs may be given in capsules with the meals. If they are to be given ill liquid form a vehicle containing yerba santa makes the preparation more tolerable. At times a better diuretic effect is noted by giving these salts in the above doses for a few days then discontinue them for a few days. A neutral diet aids in decreasing the amount of the salt necessary, but this is difficult to follow out for longer than a few days unless dietetic service is available. . Potassium nitrate or potassium chloride in large doses, 120 to 180 grains (8 to 12 Gm.) daily have been found to produce satisfactory diuresis in many cases, caution being given in cases with severe renal insufficiency. Morphine and Sedatives.-These drugs are very useful in the cardiac patient, to give them mental and physical rest, and morphine sulfate is especially effective in the acute distress of congestive failure, when used in moderate doses. Cathartics.-In some instances cathartics, especially the salines, are very useful, but generally the extra effort of increased bowel movements is undesirable if other measures are effective. In the foregoing discussion no distinction has been made between so-called "right ventricular failure" and "left ventricular failure," although the general picture of congestive failure represents essentially the result finally or predominantly of "right ventricular failure." Attention should be called to the acute paroxysmal dyspnea with or without "cardiac asthma" due to acute failure of the left ventricle. Morphine sulfate is indicated in such an attack; aminophyllin, intravenously, may be helpful; and in those cases tending to have associated "cardiac asthma" with pulmonary edema the mercurials may be of some value.
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CHARLES L. BROWN
Aminophyllin, 0.24 Gm. (4 grains) given slowly intravenously, is very effective in relieving the acute distress of Cheyne-Stokes respiration, and an O!::ll dose in the evening may prevent occurrence at night, or steady dosage of 1Yz grains three or four times a day may offer freedom from this symptom. 2. CARDIAC PAIN
The most significant cardiac pain is that of angina pectoris and coronary thrombosis. Although of similar character in onset, location and distribution the treatment of the two is different in the use of the vasodilators. The vasodilators are contraindicated in coronary thrombosis, as shock is a part of the picture. The blood pressure as a guide will help to avoid giving the nitrites when the diagnosis may not at first be apparent. The nitrites, theobromine sodium salicylate, and aminophyllin are the drugs of choice for angina pectoris. Of the nitrites, nitroglycerin and amyl nitrite are the quickest and shortest in action and therefore useful in the acute attack. Sodium nitrite and erythrol tetranitrate are more useful in an attempt to decrease the frequency and severity of the attacks. The same may be said of aminophyllin and theobromine sodium salicylate; aminophyllin is given in doses of 1Yz to 3 grains (0.1 to 0.2 Gm.) three times a day or sometimes 1Yz grains five or six times a day is more effective. Theobromine sodium salicylate is given much the same way, the dose being 7Yz grains (0.5 Gm.). For coronary thrombosis morphine sulfate and aminophyllin are more effective. Morphine sulfate may and should be given in large doses, in the severe case Yz grain hypodermically being justified. Aminophyllin, 4 grains (0.24 Gm.) intravenously, is frequently attended by more prompt and greater relief than is morphine sulfate. It should be given slowly; if the pain recurs after a few hours it is permissible to repeat the dosage. Aminophyllin, 1Yz grains (0.1 Gm.) by mouth three or more times a day, is recommended routinely in coronary thrombosis for an indefinite time. Of the drugs, sedatives play an important part in the relief of painful discomfort over the heart, due to other forms of heart disease; or treatment of the primary conditions is indicated ifother than cardiac in origin.
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3. ABNORMAL RHYTHM OR RATE
From the standpoint of general practice the following arrhythmias are the most important as they can usually be recognized at the bedside and often are amenable to treatment; ventricular extrasystoles, auricular fibrillation, auricular flutter, paroxysmal auricular tachycardia, ventricular tachycardia and complete heart block. Extrasystoles unless frequent and accompanied by palpitation or precordial discomfort rarely call for treatment, but if so, sedatives should be first of the drugs used. Very rarely it may be necessary to use quinidine sulfate or digitalis in trying to stop them. The principles in giving these two drugs is the same here as on other occasions of their use, except usually smaller and less frequent doses are necessary. If the extrasystoles first appear while the patient is under digitalization they probably signify digitalis effect. Auricular fibrillation and auricular flutter may be discussed together because two drugs are useful in both instances; namely, digitalis and quinidine sulfate. Digitalis is indicated in auricular fibrillation, unless perhaps in the case of "slow" fibrillation without congestive failure. Digitalis does not stop fibrillation but decreases the pulse deficit and the ventricular rate. All patients with auricular fibrillation should not be given quinidine sulfate, especially those with fibrillation of long standing. Quinidine sulfate is best indicated in the case of short duration, without congestive heart failure, and with a ventricular rate under 110. The auricular fibrillation of thyrogenic origin is especially suitable for quinidine sulfate therapy. Special caution is urged in the long-standing fibrillation with congestive failure of some duration, and quinidine sulfate will probably do no good anyway. Frequently it is advisable, especially in rapid fibrillation, to digitalize the patient before giving the quinidine sulfate. Digitalization and quinidine sulfate are advisable in auricular flutter and return to normal rhythm may be expected. Quinidine sulfate should be given first in a test dose of 3 grains to note any untoward effects of susceptibility. If any serious toxic effect occurs it is likely to be one of respiratory failure and caffeine sodium benzoate, 15 grains, should be given intravenously immediately, and artificial respiration if neces-
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CHARLES L. BROWN
sary. When the patient is known not to be susceptible, the quinidine sulfate may be given in 6-grain doses every four hours until rhythm is restored. Larger doses more frequently may be used if close observation and electrocardiographic control are available. Another often satisfactory clinical method is to give 3 doses a day, increasing the dose for each succeeding day by 1}2 grains, as for example, 3 grains three times a day, then 4}2 grains three times a day the next day, and so on. D sually it is not wise or necessary to give higher doses than 1O}2 or 12 grains three times a day. If vagal or ocular pressure has not stopped an attack of paroxysmal tachycardia, three drugs may be considered: quinidine sulfate, digitalis, and acetyl-,B-methylcholine chloride (mecholin or mecholyl). The dosage of the acetyl-,B-methylcholine is 15 to 20 mg. subcutaneously. Atropine sulfate will counteract any untoward effect of the acetyl-,B-methylcholine. If attacks are frequent quinidine sulfate, 3 grains one to three times daily, may be useful in preventing recurrence. Sedatives are suggested also to relieve anxiety and promote rest. Ventricular tachycardia is a dangerous arrhythmia and often responds satisfactorily to quinidine sulfate therapy, large doses and even intravenous use of quinidine sulfate being justified in some instances. The drugs of use in complete heart block are epinephrine hydrochloride, ephedrine sulfate, barium chloride, and possibly atropine sulfate. Epinephrine hydrochloride, 5 to 15 minims of 1: 1000 solution'hypodermically or intracardiac, is used for the attack of Adams-Stokes syndrome, while ephedrine sulfate, % grain by mouth one to three times daily, may help in preventing severe and frequent attacks. Barium chloride, ~ grain by mouth, three or four times a day, is sometimes effective in preventing attacks. 11. TREATMENT INDICATED BY ETIOLOGY
In rheumatic fever the salicylates still remain the therapeutic stand-by as far as drugs are concerned. The newly used drug, sulfanilamide (para-amino-benzene-sulfonamide, prontylin) , offers some, promise, but its effectiveness in rheumatic fever must await further observation. In hypertensive heart disease and coronary arteriosclerosis any drug therapy at
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present is entirely for symptomatic relief. Thyrogenic heart disease is of two varieties, the so-called "myxedema heart" and thyrotoxic cardiac disturbances. When congestive failure appears, its management is the same as in other instances. Desiccated thyroid gland in sufficient quantity to correct the myxedema improves the heart condition providing arteriosclerosis and resultant myocardial changes are not too great, and these very features may in a way influence the amount of thyroid the patient can take without producing angina pectoris or other symptoms of too great cardiac activity in a heart long unaccustomed to it. In the thyrotoxic case iodine in some form is a part of the program for preoperative preparation. When syphilis is the etiology of cardiovascular disease, alone or with associated arteriosclerosis, arst;nic, mercury, bismuth and the iodides in their various forms must be considered. More often the problem is one of syphilitic aortitis with or without aortic valvular disease rather than actual syphilis of the heart. By the time these cases have a predominant cardiac phase the matter of treatment is not so much specifically against the spirochete as against the damage it has caused. In such cases the arsenicals are used only after careful consideration of the individual case, then with caution. No effective drug treatment of subacute bacterial endocarditis (Streptococcus viridans) is known.