DIGITALIS

Among the dwindling number of galenicals there stand preparations of the foxglove—drugs which have proved of supreme value in the treatment of cardiac failure. Yet it is true to say that few drugs are in practice more deserving of the epithet " much abused ". It is unhappily true that the great potentialities of the drug are all too rarely realized as it is so often prescribed for the wrong indica¬tions, in inadequate or toxic doses, and with its actions insufficiently supervised.
Various factors are responsible for this lack of precision in its use including the complexity of its pharmacological actions, the multiplicity of preparations available, the difference in their equivalent doses and the variation in the response and sensitivity of patients to the drug. Admittedly, skill in its efficient adminis¬tration can only be acquired through knowledge and experience, but effort expended in mastering its use is amply rewarded by the results obtained. The indications for its use are simple; its toxic effects are easily recognized ; and by judicious administration of an appropriate preparation a desired effect is readily obtained. The variation in sensitivity from one patient to another can be met only by observation of the effects of a given dose in the individual concerned.
Indications for Digitalis.—The prime indication for the administration of digitalis is heart failure. This applies to both the congestive heart failure which is under discussion and the left heart failure with intense pulmonary. Digitalis can also be used to control the ventricular rate in patients with atrial fibrillation, when its action is so striking that for long it was considered that this was its principal indication. In heart failure with normal rhythm digitalis may also prove valuable, though the effect upon the heart rate is naturally less dramatic. It is also of use in the treatment of supra-ventricular paroxysmal tachycardia. On the other hand digitalis is of no value in the control of simple sinus tachycardia, whether this be due to infection, to metabolic disorders such as hyperthyroidism, or to anxiety.
Cardiac catheterization has shown that in patients with congestive cardiac failure of low-output type digitalis simultaneously raises the cardiac output and lowers the venous pressure; which effect is primary has been the subject of debate, but there is evidence that some preparations have a direct stimulant action on the heart muscle (e.g. ouabain). In patients with atrial fibrillation the effect of digitalis in slowing the ventricular rate can be abolished by atropine, and yet the increased cardiac output due to the drug persists despite a marked rise in ventricular rate. Other actions of digitalis include relief of oedema and pro¬duction of diuresis. The effect produced is independent of the preparation used, provided that equivalent doses are given.
Preparations of Digitalis and its Allies.—A wide variety of preparations of digitalis is available and their multiplicity has led to confusion. It is wise for the practitioner to make himself thoroughly familiar with a few of these and to confine his prescribing to them. The preparations differ widely in potency, toxicity, speed of action and duration of effect. The most commonly used are :
(I)—tablets of digoxin (B.P.), 0.25 mg., a pure glycoside prepared from the Hungarian foxglove (D. lanata); a preparation is also available for intravenous use when a speedy action is essential and (2)—tablets of digitalis (B.P.), 30, 6o and 90 mg. (1/2 , 1 and 1 1/2), which are prepared from the whole leaf of the English foxglove (D. purpurea). By contrast, other preparations of digitalis are much less frequently prescribed. These consist mainly of two groups : digi-toxin—the pure glycoside from the English foxglove, comparable in many ways to digoxin though considerably more potent and prescribed in smaller dosage. It is available in numerous proprietary forms, e.g. Nativelle's Digitaline, a well-known preparation of long standing and Crystodigin. The other group includes the strophanthins, which have digitalis-like actions and of which the most commonly used today is ouabain, prepared from S. gratus. This should be restricted to intravenous use, since when given by mouth absorption is erratic and its action unpredictable.
The equivalent dosage of these various preparations is set out in the following table:

Oral Route
Digoxin 0-25 mg.
Digitalis tablet (B.P.) 0.1 mg.
Digitoxin 0.1 mg.

Intravenously, digoxin is given in doses of 0.5 to 1 mg.; the corresponding dosage of ouabain is 0.25 to 0.5 mg.
While the individual preparations of digitalis vary in rate of absorption, rate of destruction and persistence of effect, they all show a similarity of pharma¬cological action. In general, preparations of digitalis are slowly absorbed and the capacity of the body to destroy or excrete them is limited. This implies that if the daily dose is greater than the total destructive capacity of the body, cumula¬tion will occur. The drugs are rapidly bound by the tissues and particularly by the myocardium. Persistence of action for a considerable period after stopping administration is therefore inevitable, and in the case of preparations of digitalis leaf and of digitoxin the effect may last for many days ; the action of digoxin is less prolonged. Further, all exert their full activity only when a certain thera¬peutic level in the blood and tissues has been reached, and this unfortunately approximates to that at which toxic effects become prominent. It is a great disadvantage that therapeutic and toxic levels are so close together. In any discussion of the therapeutics of digitalis the great variation in individual response to these drugs must be taken into account. Some persons require only a half or a quarter of the average daily requirement to maintain an effective action, and at the opposite extreme there are others who may require three or a quarter of the average daily requirement to maintain an effective action, and at the opposite extreme there are others who may require three of four times the average dose. There is no way of foretelling which patient is sensitive and which resistant; this great individual variation in sensitive and which resistant; this great individual variation in sensitivity renders at once both hazardous and suspect any scheme of calculating massive dosage on the basis of units of activity of the drug multiplied by the body weight of the individual.
The administration of digitalis to a patient involves two separate processes :
(1) digitalization, i.e. administration over a short period in doses necessary to attain a therapeutic level in the blood and tissues, and (2) maintenance dosage, i.e. the long-term administration of an amount to balance that destroyed daily by the body and to maintain the therapeutic level attained by preliminary digitalization. The factor of individual variation in sensitivity referred to above operates in both phases.
Digitalization by Oral Route.—Digitalization by the oral route on the dosage schedules recommended below takes three or four days to accomplish. If the patient is judged in urgent need of digitalization, it is preferable to use an intravenous preparation rather than to adopt oral medication with massive doses as was popular twenty years ago. In practice, cases demanding urgent digitaliza¬tion are relatively infrequent and the majority of patients in failure respond well to gradual digitalization over a three-day period. Moreover, such cautious therapy avoids the risk of giving excessive amounts of the drug to an individual who may be highly sensitive to it. On an average the total dose required to digitalize a fully grown adult is of the order of i -5 to 2 g. (20 to 30 gr.) of digitalis powder over a period of several days. Using digoxin, a common practice is to give 4 tablets of 0-25 mg. followed by a single tablet of 0-25 mg. 6-hourly until the full effect is obtained. With digitalis a conventional dosage schedule is 0-3 g. (3 gr.) three times on the first day and 0-12 g. (2 gr.) three times on the second day, followed by 0-06 g. (1 gr.) three times daily on subsequent days. Alter¬natively 0.1 g. (1 gr.) can be given 6-hourly, i.e. four times daily, for the first three days, subsequent dosage being adjusted in accordance with the result achieved. It is essential that a patient on digitalis therapy should be kept under close observation for signs of toxicity or overdosage, and that the administration be interrupted or the dosage reduced on their first appearance.
Digitalization by Intravenous Route.—When an effect is required within half an hour, digitalization can be achieved by a single intravenous injection of digoxin. This is dispensed in ampoules containing 1 mg., the contents of which should be dissolved in 10 ml. of saline and injected slowly intravenously. More concentrated solutions tend to cause venous thrombosis. It is essential that every care should be taken to ensure that the patient has not already been digitalized and in fact has had no digitalis for a period of one to two weeks. It is not sufficient to inquire of the doctor whether he has prescribed digitalis, since many cardiac patients have a stock of " heart pills " among their possessions and, unknown to the doctor, the patient may have taken digitalis for several days before consulting him. The advocated dose of i mg. is an average one. In some individuals this may be increased to 1.5 mg. without danger, whereas in others of smaller stature, 0-75 mg. would be sufficient. The effect of injection is apparent within a quarter of an hour and is maximal within thirty to forty minutes. If any doubt exists it is always safer to err on the side of low dosage, giving initially say 0.5 mg. only, and a further 0.25 mg. after one hour if necessary. Under no circumstance should a total intravenous dosage of 1.5 mg. in six hours be exceeded. Another intravenous preparation is ouabain, given in smaller dosage, the digitalizing dose varying from 0-35 to 0-5 mg. Its action is rapid and maximal within fifteen minutes. Again every care must be taken to ensure that the patient is not already partially digitalized before such treatment is given.
Maintenance Therapy.—Efficient maintenance therapy implies recognition of two fundamental factors : first, that the daily dose of digitalis administered should balance that destroyed by the body ; and secondly, that the therapeutic and the toxic doses of digitalis lie uncomfortably close to one another. The average patient destroys or excretes between 0-5 and 0-75 mg. of digoxin or 0.1 to 0.2 g. (1 ½ to 3 gr.) of digitalis powder daily and the maintenance dosage will lie as a rule within this range. The exact dose required for each individual patient must be found bv trial and error, by close observation of the effects produced by a given dose in that patient, and the adjustment of his dosage schedule in the light of this experience. There is a wide scatter in the daily requirements and some patients are kept in full therapeutic control with as little as 0-25 mg. digoxin a day five days a week; others require i mg. a day con¬tinuously over long periods. The position has been further complicated in recent years by the introduction of diuretics causing profound potassium loss, which in turn sensitizes the body to digitalis and potentiates its action. It is implicit that every patient receiving a maintenance dose of digitalis should be seen at frequent intervals, questioned regarding toxic symptoms and examined for signs of toxicity. The patient who takes a given dose of digitalis continuously seven days a week over long periods without toxic effects is probably having a daily ration which is less than the body's excretory capacity, so that his tissue level is steadily falling—it may be too far below the effective level. It is because Of this difficulty in keeping the tissue level at a therapeutic optimum just short of the toxic level that the writer prefers to administer digitalis for maintenance purposes on a five-day week schedule. The patient is instructed to take his daily ration each day from Monday to Friday inclusive, and to stop the drug on Saturdays and Sundays. The daily dose is adjusted in such a way that during a period of five days the patient is taking a total quantity of the drug which is just short of the amount known to produce toxic symptoms. He is warned that should he develop anorexia, headache or nausea toward the end of the week he should stop the drug and inform his doctor.
It will be noted that no mention has been made of the tincture of digitalis, a time-honoured remedy which has now largely fallen into disuse. It is cumber¬some to handle, difficult to standardize and to measure accurately and hence is inferior to tablets of digoxin or of powdered digitalis leaf.
Toxic Effects.—Every doctor should be familiar with the toxic effects of digitalis and should be constantly on the lookout for their appearance. The commonest toxic effects are gastrointestinal on the one hand, and cardiac arrhythmias on the other. The earliest toxic symptom is anorexia, progressing in the course of hours to malaise with headache and nausea ; if further doses are given, vomiting is induced, and once this occurs it is apt to persist for twenty-four or thirty-six hours after discontinuing the drug. Every patient should be taught to recognize that loss of appetite and the slightest sensation of nausea may be due to digitalis, and should be instructed to stop taking the drug at once when such symptoms arise. The other common effects of digitalis are seldom apparent to the patient but are detected by the doctor on examination: these are prin¬cipally disorders of cardiac rhythm. Marked cardiac slowing occurs with high dosage. This is most readily detected in patients with atrial fibrillation, in whom a ventricular rate falling below 60/minute is the signal for stopping the administration of digitalis. Slowing, however, can occur in patients with normal rhuthm if toxic levels are reached and a sinus bradycardia of 50/minute or less may be produced. More commonly extrasystoles appear, at first scattered and later following each normal sinus beat, the condition of pulsus bigemimis or coupled rhythm. The extrasystoles may be too weak to reach the pulse at the wrist and may therefore escape detection unless the heart is auscultated, when the characteristic extrasystolic sounds following the normal beat are easily detected. This is a most important sign and it should be the signal for stopping the administration of the drug at once, since if digitalis is continued the patient may develop ventricular paroxysmal tachycardia—a very serious condition. If this too is overlooked, then the patient is in peril from a fatal ventricular fibrilla¬tion. Another arrhythmia which may occur is partial or complete heart block as indicated by the electrocardiogram or by the classical clinical features. It is important to remember that the ventricular rate in complete AV dissociation due to digitalis is commonly 40 to 50/minute, much faster than when the arrhythmia is due to structural changes in the contractile tissues, and hence it may be overlooked. For the practitioner who is without an electrocardiograph it should be a golden rule that when a pulse falls below 55 or when an extra¬systolic rhythm is found on auscultation the administration of digitalis should be discontinued at once. These abnormal rhythms may persist for many days after the drug has been stopped.
One arrhythmia of importance, noteworthy for the difficulty attending its .diagnosis, has been described: in recent years. In a proportion of patients receiving digitalis the heart rate may increase slightly as the full therapeutic level is reached .and this may mislead the doctor to increase the dose. With the increased dosage the rate remains unchanged or may increase further, and it it is only when an electrocardiogram has been taken that the true cause may be apparent—the development of supraventricular paroxysmal tachycardia with 2 : i heart block. In these circumstances an atrial rate of say 160 implies a regular ventricular rate of So/minute, one neither so slow nor so fast as to arouse suspicion of digitalis toxicitv. The recognition of this arrhythmia is very important, since stopping digitalis therapy leads to the return of normal rhythm, while persistence with the drug may prove fatal. This arrhythmia is much commoner than was formerly suspected.
There are other toxic actions of digitalis, some common, some rare, and of less importance than those already discussed. Some patients for example, develop neurological signs, particularly confusion or delirium; in others the initial diuresis may be succeeded by oliguria ; disturbances of colour vision and bizarre complications such as gyneecomastia may occur.
The commonest symptom of intolerance to digitalis is the development of nausea and sickness which may be so readily induced and of such intensity that an occasional patient cannot tolerate the drug. Digoxin, the glycoside of Digitalis lanata is less prone to provoke sickness than digitalis powder, but even so is not well tolerated by some patients. For the latter, the pure glycosides of Digitalis purpurea are the drugs of choice and Nativelle's Digitaline has for many years proved of value in these cases. It is supplied in pills of respectively 0.1 and 0.25 mg. and the average maintenance dose is from 0.1 to 0-25 mg. per day. Similarly, other preparations of digitoxin may be used, supplied as pills of 0.1 mg., of which 1 or a pills daily will generally suffice to maintain digitalization. It is important that in all patients receiving digitoxin preparations a close watch should be kept on the cardiac rhythm, and if possible serial ECGs should be taken. The usual symptoms which are the guide to toxic levels when digitalis leaf or digoxin is given may be absent and an abnormal rhythm or the development of electrocardiographic changes may be the only index that a safe dosage has been exceeded. In general, such preparations are required only in a minority of patients.
Treatment of Digitalis Intoxication.—Administration of the drug must of course be stopped. The only other measure of real value is the administration of potassium salts (chlordie or citrate in ½ tablets), which in a dosage of 2 g. daily by mouth are effective in a proportion of cases in cutting short the duration of toxic rhythms. Their action may well be related to the lowered blood and tissue potassium often present in cardiac failure, particularly when the patient is treated with potassium-losing diuretics; hypopotassaemia is known to potentiate the toxic effects of digitalis.
The frequency with which cases of heart block, pulsus bigeminus, paroxysmal tachycardia with block and other arrhythmias are now encountered in patients receiving digitalis, in comparison to their rarity in previous years, is impressive; the reason appears to be the increased use of diuretics causing potassium loss.