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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 jantung, 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 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 responsible of their cardiac, vascular and incidentally diuretic effects.

Cardiac effects
1. Positive inotropic effect: cardiac glycosides increase the force of contraction of 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 of 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 with 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 system. In addition cardiac glycosides can induce contractions of intestinal muscles by direct effect and indirect effect by bulbar stimulation.

Diagram of the mechanism of action of digoxin

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 characteristics 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 to be specified.

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 doserelated. 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 cessation 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 case 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 Pglycoprotein 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.

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 transfer 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 cytoplasmic 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 tissues 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).