Composition: digitalis (or cardiokinetic, or cardioactive glycosides) are
composed of two fundamental parts:
* Aglycone or genin, costed by a steroid group bound to an unsaturated lactone
ring;
* from 1 to 5 glycosidic molecules
They are determined by some aspects of the molecule, in particular by the number
of OH radicals of the aglycone, which act as hydrophilic poles. So for example:
* digioxin, which has only one OH radical:
- it is not polar;
- is liposoluble;
- has an almost complete enteric absorption;
- has a strong link with plasma albumin,
- is metabolized by the liver;
- has a slow start of action;
- has a long duration of action;Strophanthus, which has 5 OH radicals:
- it is polar;
- is water-soluble;
- is not absorbed intestinally (5%);
- does not have a strong link with plasma proteins;
- is excreted predominantly unmetabolized;
- has a rapid start of action;
- has a short duration of action.
Despite the different physico-chemical characteristics, which differentiate the
various cardioactive glycosides especially in terms of intestinal absorption and
the beginning and duration of the pharmacological action, this is essentially
the same for all the substances in this group.
Digitalis have two fundamental properties.
Identical both in the normal heart and in the heart in decompensation, it
manifests itself with an increase in the power and speed of cardiac contraction.
- The mechanism of action has not yet been fully clarified. However, it is shown
that digitalis determine a block of the Na / K ATPase dependent pump, at the
level of the cell membrane; this leads to an increase in Na + ions within the
myocell, and the subsequent exchange of these with Ca ++ ions, responsible for
the increase in the contraction force.
- In heart failure these drugs determine a series of positive effects, such as:
- increased systolic and cardiac output;
- decrease in ventricular pressures and volumes;
- reduction of the volume of the heart;
- decrease in venous pressure, O2 consumption, total blood volume;
- increased diuresis (by improved renal perfusion).
* Reduction of heart rate (by vagal stimulation) and slowing of atrioventricular
conduction (for lengthening of the refractory period of the conduction tissue at
this level).
Practically provided with the same activity, the cardioactive glucosides differ
in their route of administration, rapidity of action and delay in elimination.
Three categories can be distinguished: rapid (deslanoside C): they are used only
by ev (the absorption of lanatoside C orally is only 50%);
* glucosides having a semi-rapid action (digoxin, medigoxin, etc.) generally
prescribed by os, absorbed at 80%;
* slow-acting glucosides (digitoxin) with almost total gastric absorption.
Whatever the route of administration, after a variable interval, a maximum blood
concentration is observed which decreases at first rapidly (at the fixation of
tissues), then more slowly: this reduction corresponds to the rate of drug
elimination. The elimination of digitalis occurs essentially via the kidneys,
since only a modest amount is found in the faeces. It depends on the functional
capacity of the kidney, varies with the products (less affected are the
medinossin and digitoxin, mostly inactivated by the liver), but remains
relatively stable for each of them. The daily eliminated quota remains constant:
about 7% (inactive for 85%) for digitoxin, 30% (active for 90%) for digoxin.
The indications
There are two essential indications of digital or its derivatives: some rhythm
disorders and most heart failure.
Rhythm disorders
After the discovery of external electrical shock and the introduction of other
antiarrhythmics, the use of digitalis is limited to their bradycarding effect.
In flutter and atrial fibrillation, they are referred to if electrical
cardioversion has failed or is contraindicated.
- In the flutter, digital can decrease the ventricular rate (change from 2: 1 to
4: 1) or turn it into atrial fibrillation.
- In fibrillation, digital maintains and also increases the frequency of atrial
fibrillation waves, but slows the ventricular rate by increasing the actual
refractory period in the atrioventricular node. The posology of the digital
requires attack doses the greater the faster the ventricular rate, then a
maintenance dose to stabilize the ventricular rate around 70 / min. In
supraventricular tachycardias and paroxysmal atrial fibrillations it is
preferable to use the fast acting digitalis (digoxin, deslanoside C) and then to
prescribe a prophylaxis treatment:
- both with digitalis only,
- either by associating them with other antiarrhythmic substances.
In case of heart failure, digitalis can eliminate the ventricular extrasystoles
if these are secondary to the failure condition.
All or nearly heart failure can benefit from digital, especially when there
is atrial fibrillation. Today, however, other more manageable drugs are used:
cardioselective beta-blockers. Some characteristic elements of particular
etiological forms must however be underlined.
* Myocardial infarction in its acute phase is a safe indication but today not
very prescribed, if AV conduction is normal and in the absence of ventricular
extrasystoles.
* The chronic pulmonary heart requires a preliminary correction of electrolyte
abnormalities and blood pH and there must be atrial fibrillation with high
ventricular response.
* Cardiothyreosis is quite rebellious to digital, but this must be prescribed to
be able to use, without risk, a beta-blocker
* Aortic stenosis hinders the ejection of the left ventricle, so that the
digitalization can not find indications except in particular cases and with
moderate doses.
* Digitalis is contraindicated in hypertrophic cardiomyopathy.
* Among the congenital heart disease, digitalis treatment, above all those with
left-right shunts, benefit.
* When heart failure complicates high-heart disease, such as beriberi,
arterio-venous fistulas, severe anemia, etc., digitalis are not very effective.
* During tampon-induced heart failure or constrictive pericarditis, mechanical
extracardiac disturbance can not be resolved with the cardiac kinetics. Each
grade: complete AV block, II degree, I degree with PQ higher than 0.24 sec; in
the presence of permanent electrical stimulation (pacemakers) of patients with
AV block, the use of digitalis does not present any particular problem.
* Intraventricular conduction disorders (complete or incomplete branch block):
these do not represent an obstacle to digitalis treatment, except in the case of
a bifascular block (anterior or posterior left hemiblock + right bundle branch
block), which will be a cause for special attention. In obstructive hypertrophic
cardiomyopathies, the positive inotropic action of glucosides accentuates
intraventricular functional stenosis and aggravates the symptomatology.
► When deciding to reconvert an atrial fibrillation with electric shock, digital
treatment must be suspended a few days earlier; the amount of this advance
depends on the speed of elimination of the digitalis (from 2 to 6 days depending
on whether it is digoxin or digitoxin).
► Digitization can trigger ventricular fibrillation in ventricular tachycardias.
They depend on the evolutionary stage of heart disease and the severity of heart
failure (for the treatment modalities of arrhythmias, see the individual entries).
- Cardiopathies on the other hand: digitization is mostly not useful, while it
can result in ventricular disturbance disorders that hinder electrocardiographic
control.
- Decompensated cardiopathies: they require digital treatment that generally
goes on indefinitely.
The attack treatment
The choice of medicament is based on therapeutic urgency.
* Fast-acting products (Lanoxin) are used venously in case of immediate danger
(acute pulmonary edema); administration can be repeated several times a day.
* The products with protracted absorbed action by gastric route (Lanoxin,
Lanitop, etc.) substitute the previous ones or, more often, they are prescribed
from the beginning, since the common heart failure is not a real urgency and
that these drugs cause some improvement already after the first or second dose.
The total dose corresponds to the quantity necessary to obtain, in view of its
elimination, a sufficient accumulation of the digitalis, and it is within the
therapeutic limits, quite distinct from the toxic ones; the safety margins,
however, are not very large.
* The duration of the attack treatment must be short. In principle it is 5-6
days. but, if the heart failure is modest or discreet and, even more so, if the
frequent check of the patient is difficult, this treatment can be diluted in
10-15 days.
Maintenance treatment
It is based on the principle of replacing the dose eliminated daily, so as to
always remain in the therapeutic area and to maintain the benefit obtained
during the attack phase.
* The definitive posology is usually represented by 1 cpr. per day of Lanoxin
and from 1-2 tablets of Lanitop, but it can undergo extensive changes; sometimes
a certain observation period may be necessary before establishing the optimal
dose.
* This treatment should be followed indefinitely, unless you notice the
disappearance of the initial cause (eg surgical treatment of a valvular lesion,
reduction of atrial fibrillation).
* In more advanced stages, myocardial impairment is such that heart failure
becomes refractory. In this type of patients, the daily dosage of digitalis must
be accurately determined, so that it does not exceed 1-2 cpr. of Lanoxin. The
therapy must be strictly controlled with ECG and with plasma dosages of
electrolytes (in particular potassium) and digital.
* It is possible that signs of digitalis intoxication, appear quickly, since the
safety margin between the therapeutic area and the toxic area progressively
decreases. In the child, treatment of heart failure is similar to * that of the
adult, with a dosage appropriate to age and body weight.
The therapeutic range of digoxin is between 0.8 and 2.2 ng / ml. However, the
DIG trial (the main digoxin study) that documented digoxin values between 0.8
and 1.2 ng / ml was correlated with a lower incidence of adverse cardiovascular
events. Therefore it is currently recommended to maintain a digoxinemia value of
around 1.5 ng / ml. Digoxin toxicity can start with blood concentrations above
2.2 ng / ml. The therapeutic range of digitoxin is between 14 and 16 ng / ml and
a toxicity greater than 30 ng / ml. It should always be considered that
digitalis action is not immediate, and that their half-life is 33/36 h for
digoxin and 5/7 days for digitoxin: there are numerous therapy protocols.
Lanoxin: 0.06-0.08 mg / kg under 2 years, 0.04-0.06 mg / kg over 2 years (useful
for this purpose the administration of the drug in syrup); both Digitaline: 0.04-0.05 mg / kg up to 2 years, 0.02-0.04 mg / kg after 2 years,
the severity of the cardiac situation imposes it, Lanoxin and Cedilanid are
administered via venous, by the % of the dosage necessary for os.
The doses must be divided into 24 h.
► In the elderly the doses are usually slightly reduced, due to the decrease in
muscle mass and to the generally pre-existing reduction of renal function.
Treatment monitoring Numerous precautions are indispensable.
► Before each treatment it is necessary:
- register an ECG: it will be used as a comparison of the following;
dosing plasma electrolytes especially potassium, especially if diuretics have
been previously prescribed;
- make sure that no other digital preparations have been prescribed, otherwise
specify the type and dosage.
► The effects should be monitored regularly during treatment. During the attack
therapy, this clinical and electrocardiographic check will be daily, during the
maintenance one, on the other hand, weekly and gradually more sparse.
- In the case of complete tachyarrhythmia, the therapeutic effects are quickly
evident with a regulated dosage so that the heart rate, at rest, oscillates
around 70 / min.
- In heart failure in sinus rhythm, digitalis is less clear, so the posology is
uncertain.
* It is necessary to know the dangerous INCOMPATIBILITIES:
- in particular the simultaneous administration of other digital products such
as venous strophalos;
- calcium, if injected into the vein, reserpine and catecholamines.
* Particularly close control should be performed in case of association with
drugs that can interfere with digital effects:
- diuretics, which can cause hypokalemia;
- quinidine, which increases digitalemia;
- beta-blockers and verapamyl, which enhance the effects on AV conduction;
- cholestyramine and neomycin, which reduce intestinal absorption of digitalis.
* In patients with renal insufficiency it is necessary to reduce the doses of
Lanoxin due to the decreased renal excretion of this (the elimination of
digitoxin, as we have already said, occurs instead mainly via the
bilio-digestive pathway). As a guideline data, the daily dose of Lanoxin can be
calculated:
- it must not be reduced until creatinine clearance remains above 50 ml / min;
- must be reduced to 1/2 if this clearance is between 50 and 25 ml / min;
- must be reduced to 1/4 if this clearance falls between 25 and 10 ml / min.
- In a young person, in an initial stage of heart failure, anorexia with nausea,
vomiting, and sometimes abdominal pain are the first alarming manifestations,
for which the dosage must be reduced; visual disturbances, allergies, and a
gynecomastia are more exceptional.
- In an elderly person, in a debilitated subject or in the case of multi-treated
refractory heart failure, digital toxicity is often difficult to detect.
- In any case, the appearance or aggravation of anorexia and nausea recommend
the immediate suspension of the drug.
- But you can also have an aggravation of the general conditions, a feeling of
malaise, insomnia, contraction of diuresis. These premonitory signs, if
misinterpreted, can lead to a toxicity confirmed by severe and different rhythm
disorders: incomplete or complete AV block, sinoatrial block, atrial
tachisistolia, bigeminal ventricular extrasystoles, ventricular fibrillation.
- Their appearance should be seized promptly by systematic electrocardiographic
checks.
* The plasma dosage of digoxin or digitoxin according to the preparation used (pre-dilution
performed at least 6 hours after the last administration) may be useful in the
diagnosis of digitalis intoxication. We remember that:
- for the digoxinemia the therapeutic values are comprised between 1 and 2 ng
/ ml and that beyond these begin the toxic values;
- for digitoxinemia the therapeutic values are between 15 and 25 ng / ml and
the toxic levels are over 35 ng / ml.
It should however be noted that, at the same values of digitalemia, other
factors influence the determination of the appearance of toxic phenomena (see
above).
The treatment of digitalis intoxication
► It is essentially preventive:
* respecting the contraindications of the drug, which we briefly summarize:
- hypokalemia;
- hypercalcemia;
- A V block of II and III degree;
- mixedema ;.
* implementing PARTICULARLY ATTENTIVE CHECKS in case of:
- old age;
- kidney failure;
- chronic pulmonary heart;
- acute myocardial lesions;
- particular pharmacological associations (in particular quinidine, verapamil,
amiodarine, potassium-sparing diuretics increase its effects, cholestyramine,
neomycin, rifampicin reduce its absorption);
* avoiding overdoses;
* ensuring a sufficient supply of potassium during diuretic treatment;
* By identifying any disturbing gastric and / or arrhythmic signs over time.
► There are no specific antidotes on the healing plan.
* We therefore need to suspend digitalization on the first suspect, which is
usually sufficient to quickly control the consequences of a mild overdose.
* Potassium chloride is the best treatment:
- orally or at high doses: 20-80 mEq / day;
- both by venous route, in very slow infusion: 10-40 mEq / h.
It will be completed:
* in case of myocardial hyperexcitability (ventricular extrasystoles,
ventricular tachycardia, etc.):
- both with 2% Xylocaine, in very slow IV injections of 50 mg every 1-2 hours,
- either with diphenylhydantoin, 50 mg iv slowly, possibly repeated,
- either with beta-blockers, e.g. Inderal 1 -3 f. ev very slowly;
* in case of conduction disturbances
- both with Atropine 0.5-1 mg ev,
- either with transient endocavitary electrical stimulation.
* Recently, good results have been obtained with the administration of specific
antibodies to digital or FAB fragments of anti-digital antibodies, which are
still not available and at a high cost.
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