DIGITALIS has, fro the past 170 years, been the most popular and the most valuable single remedy for the treatment of heart disease. It is without a doubt one of the really great drugs in possession of the human race. Yet no one can state with certainly who discovered digitalis or when it was discovered. As a matter of fact, when it was first used as a remedy it was for other than it cardiotonic properties. Its use in medicine goes back to the Anglo-Saxon period when it was mentioned in the”Leechdoms” of the twelfth century.
In those days it was called foxglove, which is derived from the Anglo-Saxon foxesglew, i.e. for music, an allusion to the ancient musical instrument consisting of bells hung on an arched support. It was mentioned in the “Liber Medicinalis” of Apuleus, and in the “Vocabulary of the Names of Plants” of the eleventh century, as foxes glofa, while in a later vocabulary it was called foxesglove.
The ancient Welsh “physicians of Myddvai” made frequent use of foxglove. It appears as an external remedy in a treatise in the year 1250. Fuchius described it in his “Plantarium Omnium Nomenclaturae” in 1541, and gave it is present name of digitalis, in allusion to the German fingerhut (finger-stall). He also gave it its present botanical description. He described its flowers as ranging from white to purple and gave it the name of digitalis purpurea, which it still retains in spite of the fact that it is not a very accurate designation.
In the sixteenth century digitalis passed into the “Herbals” and was mentioned by Turner, and by Gerarde in 1597, who stated: “It doth cut and consume the thicke toughenesse of grosse and slimie flegme and naughty humours” in 1640, Parkinson observed its value in “extenuating tough flegme or viscous humours troubling the chest,” and remarked further that “there are few physicians who use it and it is in a manner wholly neglected.”
Ten years later, however, it was included in the London Pharmacopoeia, which shows it had found a place in the materia medica of the physicians of that period. Previous to its first inclusion Lobel mentioned that “the country people of Somersetshire employ a decoction for the cure of fever, but its operation is exceedingly violent”.
It was chiefly in the treatment of epilepsy and as an external application for scrofula or the Kings Evil, as well as for wounds and ulcers of the legs, that digitalis was employed in those days. In a manuscript book of medical recipes written in 1644 the following formula is given for “an Ointment for Kings Evil”: “Stamp a peck of Fox gloves in a stone mortar and add to it a pound of fresh butter and set them on a soft fire for four hours to make the ointment.”
Another: “Against ye falling sickness take purple foxgloves 2 handfuls of the leaves with 4 ounces of polipodium of the oak. Boil them in beer or ale and drink ye concoction. One that had the disease 26 years so that he fell with it 2 or 3 times in every month, was so cured by ye use of this decoction that he had not a fit for 16 months after”.
In the eighteenth century, the great Boerhaave considered foxglove to be of a “poisonous nature,” and Haller observed that “6 or 7 spoonfuls of the decoction produced nausea and vomiting”.
During the year 1775, in the county of Shropshire, England, an old woman was making a wonderful reputation with a mixture which was remarkably effective in curing dropsy. Her fame had spread far and wide, for her concoction had attracted acclaim over the country side. In the same year a practicing physician in the Midlands, William Withering by name, was impressed by the fact that this old woman “had sometimes made cures of cases of dropsy after the more regular practitioners had failed”.
Dr. Withering made a thorough investigation of the old womans potent herb brew and at length was successful in ascertaining that “The medicine was composed of twenty or more different herbs but it was not very difficult for one conversant in these subjects to perceive that the active herb could be no other than the Foxglove.” That very same year Withering began his study of this remarkable plant.
“I soon found,” he wrote, “the Foxglove to be a very powerful diuretic, and so in the Botanical Arrangements, published in the following spring (1776), I ventured to assert that the Digitalis purpurea merited more attention than modern practice bestowed upon it…..The more I saw of the great powers of this plant the more it seemed necessary to bring the doses of it to the greatest possible accuracy….In the spring of 1776 I ordered a quantity of the leaves to be dried and as it became possible to ascertain its does it was gradually adopted by the medical practitioners in the circle of my acquaintance.
“In February, 1779, my friend, Dr. Stokes, communicated to the Medical Society of Edinburgh the result of my experiments of the Foxglove. At length in the year 1783 it appeared in the new edition of the Edinburgh Pharmacopoeia, but from which, I am satisfied, it will again be very soon rejected if it should continue to be exhibited in the unrestrained manner in which it has hithertofore been used in Edinburgh and in the enormous doses in which it is now directed in London.”.
In 1785, Withering publishing his thesis “An Account of the Foxglove and Some of Its Medical Uses, with Practical Remarks on Dropsy, and Other Diseases,” which ranks with the classics of medical literature. It gave the clinical histories of 163 of his own cases and many “communications from Correspondents.” Complete directions were given for the gathering stripping, drying, and powdering of the leaves. Regarding dosage he had this to say: “I give to adults one to three grains of the powder twice a day.
Sometimes I give the powder alone, sometimes unite it with aromatics and sometimes form it into pills; if a liquid is preferred, I make an infusion…Patients were sometimes ordered to persist until the nausea came on and then to stop. But it soon appeared in the bottom of it. We shall assume for the same of argument that the hole permits one ounce of fluid to leak day. This corresponds to the physician who gives his patient five drops of the tincture of digitalis three times a day. pt the encysted. That it may be made subservient to the cure of diseases unconnected with dropsy. That it has a power over the motion of the heart, to a degree yet unobserved in any other medicine, and that this power may be converted to salutary ends”.
When physicians became fairly well acquainted with the clinical efficacy of digitalis the chemists evinced an interest in its chemical composition. Among the first to attempt to unravel the chemical mystery of this drug was Thompson on his “London Dispensatory,” 1811, who alluded to the fact that Destouches established inorganic compound of calcium and potassium, while Radig found potassium acetate in the plant. Thompson himself made a personal examination, establishing “a deep green resinous matter, in which its narcotic power resides.” Leroyer, of Geneva, after wards gave the named digitaline and digitalis to a material made by a circuitous chemical process, in which it is questionable whether the final products had any place in the original drug. Thompson sums it up as “an extractive mixture,” adding that “the active principle of Digitalis is unknown”.
Then followed more chemical investigation, notable by Walz, Kosmann, Momelle and Quevenne, Nativelle and Schmideberg. It was the last named chemist who first studied the active principles in digitalis and found that at least three active glucosides could be obtained. These he called digitoxin, digitalin and digitalein. These glucosides were decomposed by heating with acids and broke up into glucose and a complex molecule.
In spite of brilliant chemical research the nature of digitalis is still not explained satisfactorily. At any rate, its clinical efficacy cannot be determined from chemical tests. This has led to the introduction of pharmacologic estimation based not he reactions of animals. The following are the most common methods of standardizing digitalis:.
U.S.P. Frog Method.- Frogs (20 to 30 grams in weight) are kept at 20C. and the digitalis to be essayed is injected into the ventral lymph sac, the volume being about 0.015 cc. per gram, and the alcohol content being about 20 per cent. The smallest dose causing systolic standstill of the heart at the end of one hour is the minimum lethal dose. The frogs should be standardized by injections of ouabaine which should kill in a dose of 0.00054 mgm. per gram body weight. If the dose for any lot differs from this, a corresponding correction should be made in the result of the assay. Digitalis tincture must cause systolic stoppage in a dose between 0.0055 and 0.00065 cc. per gram.
Famulener and Lyons One-hour Method.- The digitalis is injected into several forty-gram frogs in varying hour, leaving it sensitive to stimulation, is the quantity on which standardization is based. Each lot of frogs must be standardized before use by testing them with ouabaine. The result of the test is then compared with this standard, and expressed in units.
Fockes Frog Heart Method.- The heart of a normal frog is exposed, the digitalis injected, and the time required for the heart to stop in systole is observed. If this is not between seven and twenty minutes a larger or smaller dose must be given. Four such frogs are weighed after the heart stops, and the averages are taken. The weight divided by the minutes multiplied by the dose in cubic centimeters is the standard, and should be about 10 (e.g., weight, 0.30 gram, dose 0.3 cc.; time, ten minutes for a 10 per cent infusion).
Reed and Vanderkleeds Guinea-pig Method.- Guinea pigs of any size are used, a dose based on that for a 250-gram pig, and adjusted to the weight, being injected subcutaneously into the abdomen. The smallest amount of the preparation which will kill 250 grams of guinea pig in twenty-four hours is the unit.
Hatcher and Brody Cat Method.- A cat is anesthetized and an amount of digitalis less than enough to cause death is injected into a vein. Injection is then discontinued and a standard solution of ouabaine, the value of which is known, is injected until death occurs. The amount less 0.1 mgm. per gram required represents the value of digitals previously given. The amount which would have been required without the ouabaine is calculated by a simple proportion. The test may be modified by giving 0.075 mgm. of ouabaine per kilo, and continuing with the unknown solution until death supervenes, which must take place in one to two hours after beginning the injection. The quantity which represents the activity corresponding to the additional 0.025 mgm. of ouabaine is multiplied by four to give the fatal dose per kilo, which is termed cat unit. The cat method of Hatcher and Brody is considered the best. The cat being a warm-blooded animal, its heart more closely resembles that of man.
It has been proven that investigators working independently in different parts of the country get results that vary less than 10 per cent when assaying samples from the same lot of digitalis by the cat method.
To insure more accurate observations through the use of digitalis of a known and constant behavior a plan was adopted by the Adult Clinic of Bellevue Hospital and the Department of Pharmacology of Cornell University Medical College. This consists in obtaining a quantity of digitalis leaf sufficient to last for a period of two to three years. It is first standardized by the cat unit method and a sample is tested on several patients to determine its clinical effectiveness.
This lot of digitalis leaf is placed in a suitable container sufficient to hold the entire amount. Withdrawals for manufacturing purposes do not exceed a maximum of 10 per cent of the whole amount of the drug. Immediately on withdrawal of a portion of the lot for manufacturing, an equal amount of biologically and clinically standardized digitalis leaf is added to replace the amount withdrawn. After each addition of a new lot the old and the new are intimately mixed. By following this procedure the essential potency of the powdered digitalis leaf remains practically unchanged. At no time can the variation, if any, be more than 10 per cent.
The chief use of digitalis is in the relief of congestive heart failure. In this condition the most striking results are obtained, and benefit is derived regardless of the rhythm of the heart. Clinical and experimental data have brought out the fact that in the presence of heart failure digitalis causes an increase in the cardiac output, in this way creating a more efficient circulation. Digitalis should be given in cases of congestive heart failure, no matter what the cause of the failure is. Relief can be obtained in the presence of active rheumatic carditis, even when the carditis is obviously the cause of the failure. This has been demonstrated by Sutton and Wyckoff. Even in the congestive heat failure which occurs after coronary thrombosis digitalis may be give with benefit to the patient.
Although the most striking results with digitalis therapy are obtained in congestive heart failure, the uses of this drug are by no means limited to this condition. When the ventricular rate in patients having auricular fibrillation is high and it is evident that the high rate may cause symptoms of cardiac insufficiency, digitalis may then be given to keep the ventricular rate down to within normal limits. This from of treatment is more prophylactic than curative, for it is essentially aimed at preventing heart failure. It is also known that digitalis will as times change auricular flutter to auricular fibrillation, in which condition the treatment of the patient can be handled more effectively, and possibly with quinidine.
Gold and Otto have shown that digitalis is capable of diminishing the number of ventricular premature contractions and occasionally cause them to disappear completely. Before digitalis is employed in such conditions, the toxic factor responsible must first be eliminated, and the toxic agent have may be tobacco, alcohol, coffee, etc. If the premature contractions persist, then digitalis may be given.
Digitalis is also of value in preventing the occurrence of attacks of paroxysmal auricular or nodal tachycardia. This, however, should be postponed until quinidine has been thought of and ruled out as contra- indicated. Quinidine, of course, is the specific in these conditions, but quite often, due to certain circumstances, cannot be used without too great danger to the patient.
In the past, and even today, some clinicians give digitalis to support the heart in pneumonia and other infections disease. Recent clinical and laboratory reports have come out which caution against this practice. Digitalis in pneumonia is of no value. In fact, it is harmful in quite a few cases. Increased body temperature increases also the bodys susceptibility to the toxic effects of digitalis. It is best not given at all.
Digitalis is indicated in aortic insufficiency of whatever type. In the stage of decompensation, of mitral involvement, digitalis should be given in its fullest doses. Once the stage of compensation has set in the usefulness of digitalis is diminished. It may be continued for a short time in small doses for its vasodilator effect.
In mitral disturbances, such as mitral insufficiency, digitalis gives very effective relief. In mitral stenosis where there is but a slight closing of the mitral valves and with no tendency to heart block, digitalis may be given with benefit. In those cases where the stenosis is marked and where there is a tendency to heart block, digitalis should not be administered.
In chronic myocarditis small doses of digitalis may be used over long periods of time (not more than twenty days at a time, however) with intervening pauses of five days if of benefit to the patient.
When digitalis is given to a patient with cardiac insufficiency it has a variable action on the systolic pressure; it may lower, raise, or have a no effect on it whatsoever. But it always lowers the diastolic pressure. The diuretic action of digitalis is one of its most valuable properties. It is at once a direct diuretic through heart tonic action and an indirect diuretic through renal vasodilator action. Diuresis produced by digitalis is relatively slow when compared to other diuretic drugs. It begins, on the average, twenty-four to thirty-six hours after administering the drug, and usually continues for several days.
The patient under digitalis medication should be watched at all times for signs of toxicity. These are:.
(1) Persistent nausea or vomiting coming after appreciable amounts of digitalis, and not appearing immediately after the administration of the drug.
(2) The appearance of frequent ventricular premature contractions or bigeminal rhythm in a heart which had not shown these irregularities previously.
(3) Disturbances of vision, usually of color vision, accompanied frequently by a band-like headache.
(4) In auricular fibrillation the slowing of the ventricular rate to below 50 per minute.
(5) The appearance of auricular fibrillation or signs of tachycardia in a heart which had not previously shown them.
Digitalis is perhaps the only drug in the materia medica concerning the dosage of which there seems to be a great deal of mystery. This is more apparent then real, for digitalis can be given for varying degrees of heart damage, which naturally requires different doses. Thus, in cases where digitalis is to the given for its tonic effect and where digitalization is not an immediate problem it may be given in the form of powder or tablets in 12 grain doses, or as the tincture in sixteen minimum cases, three to four times a day.
In cases where digitalization is required there are three methods available:.
(1) The slow method in which digitalization is obtained in from four to six days.
(2) The rapid method in which digitalization is obtained in from one to two days.
(3) The intensive Eggleston body-weight method for use in urgent conditions in which digitalization is obtained in a few hours.
The slow method is used in cases where the heart is decompensated, but in which no urgency exists. In these cases four doses of digitalis, every four hours during the day, are given. This is done as follows: In form of the tablets or powder one and a half grains of digitalis are administered from one to three tablets every four hours In the form of the tincture the dose is from sixteen to forty minims every four hours. By this method digitalization is obtained in from four to six days.
The rapid method is used in cases which are more urgent and in which digitalization is required in from one to three days. Here the following regime is used: First day, give four tablets (each one and a half grains) of digitalis every six hours for the first twenty-four hours. This would be equivalent to 64 minims of the tincture at each dose. On the second day the dosage is reduced as follows: Two tablets (three grains) or 32 minims of the tincture are given every four hours only during the daytime. From the third day and thereafter until complete digitalization is secured continue with the dosage of the second day schedule.
In urgent cases where intensive digitalization is required and in which the heart must be completely under the influence of the drug in from twelve to twenty-four hours, mathematical exactitude is required. The total requirements of digitalis for each patient are calculated by one of the following formulas:.
Grams of powdered digitalis leaf: C.U. X 0.15 X W.
Cc. of tincture of digitalis: C.U. X 0.15 X W.
Cc. of infusion of digitalis: C.U. X W.
C.U. represent the milligrams of digitalis in a cat unit. Thus one and a half grains of the tablet of 16 minims of the tincture will have this equivalence. W represents the weight of the patient in pounds.
For sake of convenience three tables of the dosages in use with this method are herewith given. Table one represents the dosages for patients who have had no digitalis within ten days. Table two is for patients who have had digitalis within ten days, but in whom there is no evidence of digitalis action. Table three is for patients who have had digitalis within ten days and who at presents show evidence of digitalis action.
After the patient has been fully digitalized by any of the above methods, the equilibrium which has been thus established may be maintained by the administration of digitalis in sufficient amounts to replace that eliminated by exertion. The average rate of disappearance of the drug form the body is 12 minims of the tincture per day. There are, of course, wide variations from the normal. It is therefore suggested that in order to avoid danger of accumulation, the daily dose should not exceed 16 minims of the tincture.
Digitalis may be introduced into the body by any one of four different ways: (1) by mouth; (2) by rectum; (3) intravenously, and (4) intramuscularly. The greatest quantity of digitalis under ordinary conditions is given orally. However, special occasions may arise which demand other routes for administrated.
Body Weight of Patient.
100 115 130 145 160 175 190.