POSITIVE INOTROPIC DRUGS

Positive inotropic drugs are substances that increase the contraction force of the
myocardium, useful in the treatment of acute and chronic heart failure.
Heart failure means a systolic ventricular dysfunction because of a pressure/volume
overload or a direct negative effect upon the myocardial fibers. The consequence is a
dilation and compensatory hypertrophy of the ventricle, to maintain a systolic pressure. The
final effects will be a decreased cardiac output and venous stasis, with symptoms of fatigue,
dyspnea, signs of pulmonary (stasis crackles) and systemic (hepatomegaly, jugular vein
distension, edema) congestion.
Secondary, some neuroendocrine compensatory mechanisms of feedback will be
activated: the adrenergic and RAAS, with vasoconstriction, sodium and water retention and
heart stimulation.
The four main elements in heart failure: contraction deficiency, tachycardia,
increased pre- and afterload, are influenced by:
● Inotropic positive drugs, increase the contraction force.
● Diuretics, eliminate the sodium and water excess and reduce the preload.
● Vasodilators decrease the pre- and afterload, making it easier for the heart.
Classification
1. Digitalis (cardiac glycosides)
DIGOXIN
DIGITOXIN
STROPHANTIN
2. Phosphodiesterase inhibitors
THEOPHYLLINE MILRINONE
AMINOPHYLLINE ENOXIMONE
AMRINONE
3. Sympathomimetics (adrenergic and dopaminergic drugs)
ADRENALINE ISOPRENALINE
DOPAMINE PRENALTEROL
DOBUTAMINE PIRBUTEROL
Mechanism of action
 Fig. – Positive inottropic drugs - mechanism of action
CARDIAC GLYCOSIDES

They are used for over 200 years, as extracts of vegetal origin. Digoxin is extracted
from Digitalis lanata leaves, Digitoxin from Digitalis purpurea leaves and Strophantin from
Strophantus gratus seeds. There are also some semisynthetic derivatives, like Beta-methyl
digoxin.
Cardiac glycosides possess an aglycone steroid nucleus, responsible for the
pharmacological activity, an unsaturated lactone ring, responsible for the cardiotonic activity
and a sugar residue component, responsible for the pharmacokinetic behaviour (see figure).

Fig. - Structure of the cardiac glycosides

Pharmacokinetics
The pharmacokinetic features of any drug are influenced by its hydro- or
liposolubility. Digitoxin is very liposoluble, Digoxin has a medium liposolubility and
Strophantin is hydrosoluble. Digoxin is preferred because it has a good digestive absorption,
a short T1/2 and a lower overdosage risk (see table). Digitoxin is administered in patients with
heart failure and chronic renal failure, because it is mostly metabolised through the liver. It
needs special precautions in pregnant women, because it crosses the placenta. Strophantin
has limited usage, in emergencies.

Table - Pharmacokinetic parameters of the cardiac glycosides

Cardiac glycoside Absorption (%) Binding on T½ Elimination
(oral administration) plasma proteins (%) (hours)
DIGITOXIN >90 >90 168 90% hepatic
metabolise
d
DIGOXIN 55-75 25 38-40 80% renal
STROPHANTIN 1-3 0.5 21 100% renal

Factors that may influence cardiac glycosides pharmacokinetics are:

 ● The age of the patient. Because of the decreased muscle mass in elderly, digitalis form
a stronger bond in the myocardium, with an increased risk of myocardial toxicity. As a
consequence, the dose will be reduced by half in patients over 65 years.
● Renal insufficiency. The effect will be of an increase in the Digoxin’s T 1/2 and
digoxinemia. The Digoxin dose will be decreased according to the renal clearance or it
will be replaced by Digitoxin.
● Hepatic insufficiency. Because of the decreased Digitoxin metabolisation, the dose
will be reduced by half or replaced by Digoxin.
● Hypokalemia (a result of diuretic treatment) increases the myocardial binding of
digitalis, with a higher cardiac toxicity. It will be corrected by oral or IV potassium
chloride administration.
● Hypomagnesemia, frequently associated with hypokalemia, worsens the arrhythmias
in digitalis intoxication.
● Hyperthyroidism causes resistance to digitalis treatment, with the necessity of
increasing the digitalis dose.
● Hypothyroidism decreases the tolerance to digitalis, with the necessity of decreasing
the digitalis dose.
● Alcalosis is more arrhythmogenic in the presence of digitalis.
Pharmacodynamics
● The cardiac effects are:
o Positive inotropic action, with an increase in the contraction force and velocity
of the normal and insufficient myocardium, especially upon the left ventricle.
This will decrease the ventricular ejection duration and increase the ventricular
ejection volume, diastolic filling time and telediastolic volume. As a
consequence, the heart is emptied better and more efficient. The positive
inotropic effect is more significant upon the insuffficient heart, compared to
the normal myocardium. The efficacy of the positive inotropic action is
proportional to the administered dose and digitalis serum levels. The prolonged
administration of digitalis does not cause tolerance. The positiv inotropic
action is the main pharmacodynamic effect of digitalis. Because of the
increased contraction force and the duration of diastolic filling time, the
cardiac output and heart pumping efficacy are significantly increased.
o Negative chronotropic action, with a decrease in the heart rate, because of the
reduced sinus node discharge. It is a result of the direct vagal centre
stimulation (vagal hyertonia) and baroreceptors, in the carotid sinus and aortic
arch, activation. These are not stimulated in heart failure because the cardiac
output and the arterial pressure are lower, compared to normal. The
baroreceptors stimulation will result in a depressing effect, with vasodilation
and bradycardia.
o Negative dromotropic action, slowing down the atrio-ventricular conductance.
This is done because of an increased refractory period at the atrio-ventricular
node and the bundle of His, with an antiarrhythmic effect in rapid atrial
fibrillation rhythm, by blocking the atrial impulses.
o Negative batmotropic action is proarrhythmic. After therapeutic doses or upon
a normal myocardium, this effect is inessential, but in case of an excessive
dose, or on an unhealthy myocardium, digitalis might have a proarrhythmic
effect, by increasing the effective refractory period, increasing the atrio-
ventricular excitability. That is why, in patients under chronic digitalis
treatment, arrhythmias may occur.
 The EKG effects of digitalis glycosides are: a decrease in the heart rate, prolonged PR
(may be a sign of toxicity), shortening of QT interval, ST segment depression with upward
concavity and decreased amplitude or T wave inversion.

● The extracardiac effects are:

o Upon kidneys: increased diuresis due to improved renal blood flow and
increased glomerular filtration.
o Upon vessels, through a direct effect on α-adrenoceptors: arteriolar
vasoconstriction, with increased peripheral resistance, and increased venous
tone, increasing the preload. This digitalis effects appear only after higher
doses than the usual used for the positive inotropic effect.
o Upon CNS: vagal tone activation after therapeutic doses.
Mechanism of action
● Cardiac glycosides act by inhibiting the membrane sodium/potassium-ATPase pump
(see figure above). This increases intracellular sodium concentration, thus reducing
the sodium gradient across the membrane and decreasing the amount of calcium
pumped out of the cell by the sodium/calcium exchanger during diastole.
Consequently, the intracellular calcium concentration rises, thus increasing the force
of cardiac contraction and maintaining normal blood pressure.
Indications
● Supraventricular arrhythmias: atrial fibrillation and atrial flutter with rapid ventricular
response.
● Congestive heart failure (not the first choice drug).
The treatment with cardiac glycosides is called digitalization which may be slow or
rapid with the objective of attaining a steady state of plasma concentration of drug in cardiac
patient. It depends on the degree of emergency, the presence of renal or hepatic failure, the
serum creatinine or creatinine clearance, the previous digitalization, the product’s
pharmacokinetic and the route of administration.
The treatment starts with a loading dose: the first dose is 1/3 of the loading dose and
the rest can be administered in:
▪ 24 hours - rapid digitalization
▪ 2-3 days - medium digitalization
▪ 6-7 days - slow digitalization
The signs of the loading dose efficiency are: a decrease heart rate, the reduction of
edema and hepatomegaly, the disappearance of jugular turgescence, the improvement of
dyspnea and an increased diuresis.
The treatment continues with a maintenance dose (0.25 mg/day; 0.125 mg/day in
elderly), the dose that is given to maintain the concentration of drug in blood.
Adverse effects
● Digitalis intoxication, can occur in 2-20% of the patients, because of the low
therapeutic index, of 2-3.
o Predisposing factors: high doses, old age, renal insufficiency, hypokalemia,
hypomagnesemia, active cardiac ischemia, myocarditis, cardiomyopathy and
cardiac amyloidosis;
 o Diagnosis: bradycardia, A-V block, bigeminal extrasystoles, delirium,
nightmares, fatigue, disturbance of colour vision (xanthopsia), anorexia,
nausea, vomiting, abdominal pain;
o Treatment:
▪ Stop the administration of cardiac glycosides;
▪ Activated charcoal (adsorbs digitalis) or Cholestiramine;
▪ Furosemide;
▪ Correct hypokalemia and hypomagnesemia;
▪ Treat bradyarrhythmias (Atropine), supra-ventricular tachycardias
(β-blockers or Verapamil) and ventricular arrhythmias (Lidocaine,
Phenytoin, cardioversion);
▪ Digibind (specific Digoxin antibody Fab fragments).
Contraindications
● Bradycardia, heart block.
● Hypokalemia associated with the use of diuretics.
● Severe ventricular arrhythmias: ventricular tachycardia or extrasystoles.
● Heart failure due to diastolic dysfunction.
Drug interactions
● Increase Digoxin absorption: antacids, Kaolin/Pectin.
● Increase Digoxin toxicity: diuretics, Amphotericin B, corticosteroids.
● Increase Digoxin levels: Verapamil, Diltiazem, Quinidine, Amiodarone.
● Increase bradycardia: β-blockers, antiarrhythmics.
● Increase the risk of arrhythmias: sympathomimetics.

PHOSPHODIESTERASE INHIBITORS

Mechanism of action
● By inhibiting the phosphodiesterase they raise the concentration of cAMP, resulting
in positive inotropic effects and modest diuretic effects. Cardiac output is increased,
and pulmonary wedge pressure and total peripheral resistance are reduced, without
much change in heart rate or blood pressure.
Indications
● Acute heart failure, resistant to other drugs, administered IV.
Adverse effects
● Nausea, vomiting, abdominal pain;
● Arrhythmias;
● Liver dysfunction;
● Hypersensitivity.

BETA-ADRENOCEPTOR AGONISTS

Indications
● In the short-term use of acutely decompensated heart failure, administered IV.