The digitalis are cardiovascular medicines that are used for the treatment of patients with alteration in the systolic cardiac function and for treatment of patients with a high cardiac frequency especially in the cases in which exists the cardiac arrhythmia so called auricular fibrillation.

HISTORY

This type of medicines, in particular the digoxin and the digitoxin, have been used for centuries. In fact the digitalis plant: "Digitalis purpurea" was already mentioned in "Meddygon myddmai" that is one of the first well-known pharmacopoeia written in Scotland about the year 1200.

In the year 1785, William Withering published a book where he was gathering his 10 years experience using "Digitalis purpurea" for the treatment of the ascites, whichever was its origin. In other words, he was using the digoxin for its diuretic effects. And 14 years later, in 1794, William Ferrier published the effects of the digitalis in regard to the heart.

Since then, it has been a medicine full of controversy regarding its use, mechanisms of action and efficacy. In the XIX^th century it use was diminished inside the medical practice due to the toxicity that some patients were demonstrating to whom digoxin was administered.

At the beginning of the XX^th century the aptitude of this medicine to diminish the cardiac frequency was discovered. In 1920 and in the later years, its inotropic effects were even verified as positive and the efficacy of its use on patients who were presenting a sinusal cardiac rhythm. In 1953, the mechanism responsible for the inotropic positive effect was discovered.

They are the most studied cardiovascular medicines and still today, its use is controversial. In human medicine exists thousands of articles in which its utility is described and also its toxicity when they are used in sick patients with heart failure. In one of the most important studies done in 1997 with digoxin opposite to a placebo and where there were included more than 7000 patients with heart failure, it was observed that its administration did not affect the survival period of the patients who received this medicine, even one of the publishers after publishing these articles, wrote the following: "The incapability of the digoxin to influence in the morbidity and mortality, eliminates, ethically, any prescription for its use and this one remains relegated to the treatment of the persistent symptoms after the administration of medicines that diminish the risk of death and of hospitalization."

In veterinary medicine studies of this type have never been done, so that the controversy with regard to his use is even major. The clinical response to the administration of the digoxin in patients inside veterinary medicine is very variable and always the response is monitored even echocardiographically, for which some authors like Kittleson, still advise the administration of digoxin in patients with severe myocardic failure.

An information to bear in mind is that the presence of serum concentrations above 1 ngr/mL, is associated to a major mortality than serum concentrations below 1 ngr/mL. The effective serum concentration is between 1-2 ngr/mL, concentrations above 2,5 ngr/mL are considered to be poisonous.

CHEMICAL STRUCTURE

The digoxin is a steroid derivate, it presents a steroid nucleus combined with a lactone ring and a series of sugars joined to the third carbon of the nucleus.

CLINICAL ACtIONS

1. Positive inotropic effect

It increases the cardiac contraction so much in the normal myocyte as in the sick ones. Nevertheless, the increase in the contraction of the normal myocyte is just of 1/3 with regard to the increase in the contraction that develops with the administration of other sympathetic mimetic drugs as the dobutamine, the dopamine; or the bipyridine derivatives such as the amrinone and the milrinone. This indicates that it is a weak inotropic drug.

Besides, the aptitude to increase the contraction depends on the species and the age; so that to major age the inotropic response is less.

This medicine affects the sodium/potassium/ATPasa cellular bombs (Na/K/ATPasa) located in the myocyte membranes. They join in competitive form to the bonding places of the potassium so that the normal activity of the bomb is disable. In therapeutic doses, the digoxin affects 30 % of the Na/K/ATPasa bombs located in the myocardium.

When these bombs are inhibited, the myocardic cells lose the aptitude to eliminate sodium from the intracellular space during the cardiac diastole. When the intracellular sodium concentration increases, the own intracellular osmolarity increases.

In this moment, the cell answers exchanging the intracellular sodium for extracellular calcium across the sodium/calcium channels or well, diminishes the exchange of intracellular calcium to extracellular sodium. The clear result is an increase of calcium ions concentration inside the myocardium.

In a normal myocyte, the excess of calcium ions join the sarcoplasmic reticulum during the diastole and is liberated towards the contractile proteins during the systole, increasing hereby the cardiac contraction.

The same mechanism takes place in the sick myocyte when the sarcoplasmic reticulum is capable of joining the calcium that exists in excess. Nevertheless, in the course of heart failure because of myocardic failure, all the effects on the myocyte from all the positive inotropic medicines are diminished.

2. Diuretic effects

In the epithelial cells of the renal tubes also exist Na/K/ATPasa bombs which promote the renal retention of sodium.

It is thought that these bombs are regulated by prostaglandins since the indomethacin diminishes the synthesis of prostaglandins, increasing the activity of the Na/K/ATPasa bombs, hereby, increasing the renal retention of sodium.

Nevertheless, the administration of prostaglandins favors the natriuresis. The administration of digitalis increases the elimination of sodium in a similar way to what happens after the administration of prostaglandins.

If digitalis are administered directly on the renal artery it diminishes the renin liberation.

3. Effects on the baroreceptors

In the patients with heart failure, the baroreceptors function is diminished so that a scarce vagal tone exists and a predominance of the sympathetic activity. This supposes a compensating mechanism inside the physiopathogeny of the own heart failure but it presents negative effects.

The digitalis increases the activity of the baroreceptors as it has been verified in dogs, cats and healthy human beings. This increase in the activity of the baroreceptors is because of three facts:

 They diminish the concentration of plasmatic catecholamines

 They diminish the activity of the sympathetic nerves

 They diminish the activity of the renin.

This is why the increase in the vagal tone observed after the administration of digoxin owes partly to these described effects.

4. Antiarrhythmic effects

The digitalis prove to be effective for the control of the supraventricular arrhythmias. In therapeutic doses, they increase the parasympathetic activity on the sinusal node, the auricles and the auricular-ventricular node.

This way, they diminish the frequency of the sinusal node and are capable of controlling the premature depolarizations that could take place in the auricles, like in the auricular tachycardia.

On the other hand, the digitalis prolong the conduction time and the refractory period of the auricular-ventricular node interrupting, this way, the arrhythmias by reentry and controlling the ventricular response in front to the auricular fibrillation.

During the auricular fibrillation the auricular frequency is 500-700 bpm, in the course of the heart failure there exist a major concentration of circulating catecholamines that they shorten the refractory period of the auricular-ventricular node and approximately a third of the auricular depolarizations go on to the ventricles giving place to a dangerously high ventricular frequency concerning 200-240 bpm.

After the administration of digitalis, the refractory period of the auricular-ventricular node extends, that will leak the majority of these depolarizations in order that they do not reach the ventricles. The global result is a descend in the ventricular frequency.

When they are administered to patients with ventricular arrhythmias, some of them improve but many others deteriorate and it cannot be known which is going to be the final score, that is why, in these cases its use is not advised.

5. Effects on the diaphragmatic muscle

The administration of digitalis gives place to a better function of the diaphragmatic muscle both in human patients as in dogs. This effect is beneficial to patients with chronic respiratory insufficiency or acute respiratory insufficiency with muscular fatigue and hypercapnia.

The effects are similar to the ones observed after the administration of theophylline or dopamine, in the cases in which this effect is chased as basic, the administration of theophylline constitutes a minor option than the digoxin.

Indications

1. Myocardial failure

Are indicated for the treatment of the myocardial systolic function insufficiency caused by an expanded cardiomyopathy, moderate persistent arterial conduit supported for more than five years, severe aortic insufficiency and serious mitral insufficiency (it is not habitual but it can appear with the time).

Nevertheless, not all the dogs with expanded cardiomyopathy answer to a treatment with digoxin, hereby it has been seen in a study realized in 1985 that 5 dogs of a whole of 22, answered to the digoxin and survived during a longer period of time.

On their part, some authors like Kittleson, administer it to all the patients with myocardial failure but they do not hesitate to suspend the treatment if negative effects appear or positive effects are not observed.

Besides, they are counterindicated in the treatment of hypertrophic cardiomyopathy, since the increase in the contraction worsens the movement of the previous valve or septum giving place to a major obstruction in the left tract of ventricular exit. Also they are counterindicated in the treatment of pericardiac blockage.

2. Supraventricular tachycardia

The efficacy for the control of the supraventricular tachycardia is moderated and if a descend in the ventricular frequency is not obtained correctly (minor to 160 bpm) it can be administer along with beta-blocking or calcium channels blocking medicines.

Pharmacokinetics

The pharmacokinetic differs between the digoxin and the digitoxin; because of the bigger clinical importance of the first one regarding the second one, we will refer exclusively to the digoxin.

The absorption differs between 60% for the presentations in pill form and 75% for the presentations in the elixir form.

It joins the albumin in a 27%. The plasmatic half-life is 20-40 hours (very variable between the different patients). Hereby, they are needed between 2 to 4 days to reach the therapeutic serum dose.

The excretion is exclusively by renal route, so that when there exists renal failure, the plasmatic concentration increases. The 15% of whole dose suffers an hepatic metabolism.

It is administered to a dose of 0.005-0.01 mg/kg/12 hours PO route or 0.22mg/m2/12 hours by PO route in dogs of more than 20 kg. The administration of higher doses is related to a major risk of poisoning.

It is necessary to control the plasmatic dose after 3-5 days after initiating the treatment with digoxin and after 6-8 hours of the last administration.

If it is administered by intravenous route it must be done in approximately 15 minutes because if it is done quickly, a vasoconstriction and an increase of the heart postcharge of negative clinical importance appears.

FACTORS THAT INCREASE THE PRESENCE OF TOXICITY

The digoxin joins the muscle so that with less muscle, it will exist a major free concentration and a major risk of reaching poisonous doses. Thus, the dose must be based on the muscle content and not in the entire weight (it is a very slightly soluble medicine in lipids).

Before the presence of ascites, the dose must be diminished between a 10% and a 30 % according to the grade of ascites.

It is necessary to avoid the administration with quinidine because this medicine diminishes the renal elimination of digoxin and displeases it from its places of action so that a minor effectiveness and a major toxicity will be obtained.

The presence of hypokalemia predisposes to the toxicity of the digoxin on the myocardium. The digoxin and the potassium compete for the same union place in the Na/K/ATPasa bombs of the cellular membranes. When a minor quantity of potassium exists, there will be a major number of free places for the union of the digoxin.

On its part, the existence of hyperkalemia gives place to a displacement of the digoxin from its action places.

The presence of hypercalcemia and hypernatremia promotes the positive inotropic effects as well as the poisonous effects. In the opposite case, these effects will turn out to be limited.

The hyperthyroidism increases the myocardial effects of the digoxin so that in these cases, it is necessary to reduce the dose. In the cases of hypothyroidism adjustments of the dose are not needed.

When it exist myocardial failure the sensibility of the myocytes to the poisonous effects of the digoxin increases. It is thought that the sick myocytes are overloaded of calcium and the digitalis increases the intracellular calcium so that they are electrically unstable cells that can give place to the development of tachyarrhythmias.

The states of hypoxia also increase the sensibility of the myocytes to the poisonous effects of the digoxin, though in this case the mechanism has not been managed to be explained.

DIGOXIN Toxicity

An important information to bear in mind, is that when it already exist gastrointestinal signs of toxicity because of digoxin, a myocardial toxicity already exists and it can be fatal.

1. Clinical signs

At the nervous central system level it is observed depression, discomfort, drowsiness and headache (described in human beings)

In the gastrointestinal system, vomiting and anorexia are observed because of the direct effects of the digoxin on the marrow. Also it is possible to detect a descend in the corporal temperature.

2. Autonomous system

An increase in the vagal tone is observed, which can cause a descend in the cardiac frequency and auricular-ventricular blockades, nevertheless, the sympathetic compensating response can offset this vagal effect.

3. Myocardium

The presence of poisonous concentrations gives place to an alteration in the normal electrical activity of the heart by several mechanisms:

 Affects the chemoreceptor zone in the marrow which causes a sympathetic stimulus.

 Due to the surcharge of intracellular calcium, the membrane potential ranges and eventually can reach the threshold of depolarization giving place to a premature beat.

Before a poisoning by digoxin, 60-80% of the Na/K/ATPasa bombs are inhibited by the digoxin.

In the electrocardiogram it is possible to find any cardiac arrhythmia from ventricular tachycardia to bradyarrhythmias.

Finally, they can give place to alterations in the sarcolemme with necrosis and degeneration of the myocytes that gives place to an increase in the CPK and to systolic and diastolic alterations.

4. Renal alterations

They can cause hydropic alterations and epithelial necrosis in the proximal tube and in the medullar collecting duct which is demonstrated with elevations of the plasmatic urea and creatinine.

5. Electrolytic alterations

The digoxin poisoning causes increases in the potassium and sodium due to the massive inhibition of the Na/K/ATPasa bombs in the whole body.

Intoxication treatment

The first thing is to interrupt the digoxin treatment. The plasmatic half-life is 24-36 hours so that it takes between one day and one day and a half so that the plasmatic concentration descends to the half.

The electrolytic imbalances must be corrected, fundamentally the potassium and fluids.

In case they exist serious ventricular arrhythmias they must be treated as an urgency with lidocaine, phenytoin or propranolol, though it has been seen that 2/3 of human patients with ventricular tachycardia secondary to poisoning by digoxin does not answer to any treatment and dies even with the treatment.

In the cases in which it exists a massive and accidental ingestion of digoxin, it can be treated with activated coal, cholestyramine or specific antibodies opposite to the cardiac glucosides. The latter treatment is the most effective though it is very expensive and is not available for veterinary use.