Obat Inotropik dan Kronotropik

Inotropik adalah agen obat yang berperan dalam kontraksi otot jantung
(miokardium). Inotropik dibagi dalam dua agen yaitu :
1. Agen inotropik positif  : : agen yang meningkatkan kontraktilitas miokard, dan
digunakan untuk mendukung fungsi jantung dalam kondisi seperti gagal jan tung,
syok kardiogenik, syok septic, kardiomiopati.
Contoh agen inotropik positif meliputi  : Berberine, Omecamtiv, Dopamin,
Epinefrin (adrenalin), isoprenalin (isoproterenol), Digoxin, Digitalis, Amrinon,
Teofilin

2. Agen inotropik negative  : agen menurunkan kontraktilitas miokard, dan

digunakan untuk mengurangi beban kerja jantung.
Contoh agen inotropik negative meliputi  : Carvedilol, Bisoprolol, metoprolol,
Diltiazem, Verapamil, Clevidipine, Quinidin.

Kronotropik  adalah
 adalah agen obat yang berperan dalam denyut jantung. Kronotropik
dibagi dalam dua agen yaitu :
1. Agen kronotropik positif  : : agen yang meningkatkan denyut jantung dengan
mempengaruhi saraf mengendalikan hati, atau dengan mengubah irama yang
dihasilakan oleh node sinoatrial
Contoh agen kronotropik positif meliputi : sebagian Adrenergic agonic,
Antropin, Dopamin, Epinefrin, Isoproterenol.

2. Agen kronotropik negative  : agen yang menurunkan denyut jantung dengan cara
mempengaruhi saraf mengendalikan hati, atau dengan carah mengubah irama
yang dihasilakn oleh node sinoatrial.
Contoh agen kronotropik negative meliputi : Metoprolol. Asetilkolin, Digoxin,
Diltiazem dan Verapamil.
nhibitors of Na+/K+-ATPase: Cardiac glycosides - Effects
The inhibition of Na+/K+-ATPase by cardiac glycosides is res ponsible of their
cardiac, vascular and incidentally diuretic effects.

Cardiac effects

1. Positive inotropic effect: cardiac glycosides increase the force of contraction o f

the normal and failing myocardium. This reinforcement is accompanied by an
increase in the rate of contraction and by a shortening of the duration of the
systole with a relative lengthening of the diastole, independently of slowing
heart rythm.
2. Positive tonotropic effect: cardiac glycosides reduce the size of the heart in
diastole both in normal subjects and in patients with heart failure (heart dilated,
distended, with a blood residue in the ventricle at the end of the systole). The
reduction of the size of the heart in diastole increases cardiac output in heart
failure but not in normal heart, because the normal heart has the optimal size
and any decrease reduces its efficacy. This partly explains the different effects
obtained in normal subjects and in patients with heart failure.
3. Negative chronotropic effect: cardiac glycosides slow down the heart rhythm.
This bradycardiac effect results from their direct action on the heart and from
indirect action on autonomic nervous system:
o decrease of the sympathetic tone by reduction o f the catecholamine
release following the improvement of cardiac output. However cardiac
glycosides could, in certain circumstances, increase the catecholamine
release by inhibition of the Na+/K+-ATPase of the adrenergic
terminations.
o parasympathomimetic effect by increased acetylcholine release and
increase of the sensitivity of muscarinic receptors to its action. This
effect is inhibited by atropine.
4. Dromotropic effect (conduction) and bathmotropic effect (excitability):
generally cardiac glycosides reduce the rate of atrioventricular conduction, both
by direct effect and indirect effect via acetylcholine. They increase at low-dose
the excitability of the myocardium, which can cause ectopic beats.

Cardiac glycosides modify the electrocardiogram: they induce at therapeutic

doses, in patients with heart failure, a decrease or an inversion of T wave, a
lengthening of PR space, a shortening of QT interval. At toxic dose they induce
rhythm disorders.

In patients with heart failure, there is an excessive catecholamine release with a

decrease of the density of the cardiac beta-adrenergic receptors and a decrease of
the sensitivity of the heart to the beta effects of catecholamines. This adrenergic
overstimulation has long-term harmful effects
Vascular effect

Cardiac glycosides increase peripheral vascular resistance by acting directly on

arterial and venous smooth vascular muscles, in normal subject and in patients
with heart failure. The essential difference between normal subjects and patients
with heart failure is that there is no overactivity of the adrenergic system in
healthy subjects. The reduction of the adrenergic hyperactivity in patients wit h
heart failure induces an indirect vasodilation more important than the direct
vasoconstriction.

In addition, cardiac glycosides can in patients with heart failure reduce the
requirements of oxygen for the heart because, although reinforcing the force of
contraction of the myocardium, which increases the requirements for oxygen, they
reduce the size of the heart, slow down its rhythm, decrease peripheral resistances.

Cardiac glycosides have little effect on the blood pressure.

Diuretic effect

Cardiac glycosides increase diuresis in patients with heart failure, less because of
the renal inhibition of Na+/K+-ATPase than because they decrease the
sympathetic tone and the stimulation of the renin-angiotensin-aldosterone s ystem.

In addition cardiac glycosides can induce contractions of intest inal muscles by

direct effect and indirect effect by bulbar stimulation.
Diagram of the mechanism of action of digoxin

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Inhibitors of Na+/K+-ATPase: Cardiac glycosides - Chemical

structure and pharmacokinetics
Digoxin and digitoxin are the two principal cardiac glycosides.

Digoxin is made up of a molecule of digoxigenin and three molecules of

digitoxose. Digitoxin is made up of a molecule of digitoxigenin and three
molecules of digitoxose.

Chemical structure of digoxin and digitoxin differ only by one OH group: digoxin
has one OH group more than digitoxin but their pharmacokinetic characteristi cs
are very different.
The bioavailability by oral route of digitalin reaches nearly 100% that of the
digoxin is approximately 75%.

Binding to plasma proteins is of 95% for digitoxin, and 25% for digoxin.

Digitoxin is more metabolized by the liver than digoxin which is eliminated

 primarily by the kidney without biotransformation. The dosage of digoxin must be
reduced in patients with renal insufficiency.

The plasma half-life of digitoxin is from 4 to 6 days, that of digoxin

approximately 40 hours. With constant dosage, i.e . without giving a loadind dose
in the initial stage of therapy, it takes a long time to reach the steady-state
concentration.

Digitalin and digoxin cross blood-brain barrier, which explains the possibility of
neuropsychiatric adverse effects, particularly in case of overdose.

They cross the placental barrier and are sometimes given to the mother for
treating disorders of the cardiac rhythm of the fetus in utero. A low fraction is
eliminated in breast milk.

In adults, the effective therapeutic concentration of digoxin is about 1 microgram

 per liter, that of digitoxin between 13 and 25 micrograms per liter, sampling being
made 8 to 24 hours after the last intake.

 Notice

Ouabain could be synthesized by the adrenocortical gland and be found in low

concentration in the blood of non treated persons. Its role remains t o be specified.

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Cardiac glycosides - Therapeutic use, adverse effects and

interactions

Therapeutic uses

The essential therapeutic use of digoxin which is more used than digitoxin is the
treatment of cardiac failure. Digoxin improves the cardiac function and decreases
the frequency of hospitalizations without delaying mortality. The second
therapeutic use of digoxin is the treatment of supra-ventricular arrhythmias,
 particularly atrial fibrillation.

The initial dosage, generally high and called loading dosage, is followed by a
lower dosage, called maintenance dosage. It is advised to control the plasma level
of digoxin to reach the best dosage.

 Adverse effects

The majority of adverse effects of digoxin and other cardiac glycosides are dose-
related. It is thus essential, when an undesirable effect is suspected, to control
 blood concentrations. Moreover its adverse effects in women seem more marked
(increased mortality) than in men, which does not encourage to prescribe digoxin
to women with congestive heart failure.

See Sex-Based Differences in the Effect off Digoxin for the Treatment of Heart
Failure.

One observes:

 digestive disorders: frequently, anorexia, nausea, vomiting, salivation; more

rarely, diarrhea or constipation and stomach pains.
 neurosensory disorders: frequently, headache, insomnia, sometimes confusions,
depression, dizziness, visual disturbances of colors, micropsy or macropsy,
amblyopia, pain (neuralgia of the trigeminal nerve), seizures, paresthesias,
delirium.
 cardiac manifestations, generally linked to an overdose and beginning generally
by bradycardia, then extrasystoles, tachycardia or fibrillation.
 endocrine adverse effects, such as gynecomastia in men, related to the steroid
structure of cardiac glycosides which can have metabolites with an estrogen
effect.

The treatment of poisoning by cardiac glycoside involves first the ces sation of the
glycoside, possibly the use of a drug able to reduce digitalis effects: potassium in
case of hypokalemia, atropine in case of bradycardia, lidocaine, chelating agent of
calcium, or electric stimulation.
 In severe overdose, digoxin-specific antibody fragments can be used to neutralize
circulating free digoxin by binding to it. This neutralization induces a
displacement of digoxin from tissues towards plasma where it is neutralized. The
 beneficial effects of the antibody administration appear quickly, in less than one
hour, but can last less long than the effects of digoxin with reappearance of the
signs of poisoning. These relapses are seen in cas e of administration of an
insufficient antibody dose. The administration of digoxin-specific antibody
fragments can elicit allergic reactions.

Drug interactions

A certain number of interactions between cardiac glycosides and other drugs were
described:

 Reinforcement of their efficacy and their toxicity by combined calcium

administration.
 Decrease in their toxicity by potassium administration. Conversely hypokalemia,
as observed with certain diuretics, increases digitalis toxicity.
 Increase in the concentration of digoxin by quinidine probably by inhibition of P-
glycoprotein with increases the bioavailability of digitalis and itraconazole which
slows down the metabolism of digoxin.
 Decrease of the concentration of digoxin by acceleration of its catabolism by
enzyme inducers. But the interaction with rifampicin seems more related to the
induction of the P-glycoprotein with reduction of the digestive absorption.

 Note:

Among other drugs having a positive inotropic effect by mechanisms of action

different from that of digoxin there are milrinone, inhibitor of phosphodiesterases,
and sympathomimetics such as dobutamine and dopexamine.

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NA+/K+-ATPase and inhibitors (Digoxin)

The beneficial properties of digital extracts, recognized for several centuries, have
 been confirmed in 1785 by the English physician Whitering. One of their active
compounds, digitalin, was obtained by the French pharmacist Nativelle one
century later. The cardiac inotropic and bradycardiac effects of digitalin were
recognized but their mechanism of action, the inhibition of Na + /K + -ATPase
 pump, was discovered only recently. The most frequently cardiac glycoside used
today is digoxin.
 Na+/K+-ATPase ATPase pump, like H+/K+-ATPase and Ca+/K+-ATPase, is an
enzyme which plays the role of pump. It ensures the transmembrane t ransfer of
the cations Na+ and K+. Na+/K+-ATPase is located in the cytoplasmic
membranes. It consists of two alpha catalytic subunits and of two beta subunits.
 Na+/K+-ATPase uses the energy released by the hydrolysis of the ATP in the
 presence of magnesium to ensure the transport of three Na+ ions outside the cell
and of two K+ ions inside.

 Na+/K+-ATPase has three main functions:

 To maintain inside the cell a low concentration of sodium and a high

concentration of potassium. It is an electrogenic pump which creates a potential
difference between both sides of the c ytoplasmic membrane.
 To ensure the polarization of excitable and contractile tissues: depolarization
and repolarization correspond respectively to a sodium influx and a potassium
exit. Na+/K+-ATPase restores the equilibrium.
 To create a potential energy, related to the ion gradient on both sides of the
plasma membrane. This energy is used in particular for the secondary active
transport, generally coupled to that of sodium.

Cardiac glycosides, digoxin, digitoxin also called digitalin, and ouabain, are the
 principal inhibitors of Na+/K+-ATPase. They bind to the extracellular part of
enzyme i.e. that binds potassium, when it is in a phosphorylated state, to transfer
 potassium inside the cell. Extracellular potassium which induces the
dephosphorylation of the alpha subunit reduces the effects of cardiac glycosides.

Cardiac glycosides inhibit Na+/K+-ATPase of the myocardium, cardiac

conducting tissue, smooth vascular muscles and some other tiss ues like
erythrocytes. They have little effect on the Na + /K + -ATPase of skeletal
muscles.

Consequences of the inhibition of Na+/K+-ATPase by digoxin: increase of intracellular

sodium which is exchanged for calcium
The inhibition of Na+/K+-ATPase induces a rise in sodium concentration inside
cells. This sodium increase induces in its turn an increase in the intracellular
calcium concentration, via the sodium-calcium exchanger. The sodium-calcium
exchanger is particularly active in myocardium and in smooth vascular muscles.

The rise in intracellular calcium increases the force of contraction of the heart and
the contracture of smooth vascular muscles.

The inhibition of Na+/K+-ATPase reduces cellular polarization (depolarizing

effect).

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