This parasympathomimetic action of digitalis reduces sinoatrial firing rate decreases heart rate; negative chronotropy and reduces conduction velocity of electrical impulses through the atrioventricular node negative dromotropy. The long half-life of digitalis compounds necessitates special considerations when dosing.
With a half-life of 40 hours, digoxin would require several days of constant dosing to reach steady-state, therapeutic plasma levels digitoxin with a half-life of hours, would require almost a month!
Therefore, when initiating treatment, a special dosing regimen involving "loading doses" is used to rapidly increase digoxin plasma levels. This process is termed "digitalization. It is very important that therapeutic plasma levels are not exceeded because digitalis compounds have a relatively narrow therapeutic safety window. Plasma concentrations above 2. If toxicity occurs with digoxin, it may take several days for the plasma concentrations to fall to safe levels because of the long half-life.
There is available for digoxin toxicity an immune Fab Digibind that can be used to rapidly reduce plasma digoxin levels. Potassium supplementation can also reverse the toxic effects of digoxin if the toxicity is related to hypokalemia see below. Many commonly used drugs interact with digitalis compounds. The Class IA antiarrhythmic, quinidine , competes with digoxin for binding sites and depresses renal clearance of digoxin.
These effects increase digoxin levels and can produce toxicity. Similar interactions occur with calcium-channel blockers and nonsteroidal anti-inflammatory drugs.
Other drugs that interact with digitalis compounds are amiodarone Class III antiarrhythmic and beta-blockers. Diuretics can indirectly interact with digoxin because of their potential for decreasing plasma potassium levels i.
Hypercalcemia enhances digitalis-induced increases in intracellular calcium, which can lead to calcium overload and increased susceptibility to digitalis-induced arrhythmias. Hypomagnesemia also sensitizes the heart to digitalis-induced arrhythmias.
Digitalis compounds have historically been used in the treatment of chronic heart failure owing to their cardiotonic effect. Although newer and more efficacious treatments for heart failure are available, digitalis compounds are still widely used. Clinical studies in heart failure patients have shown that digoxin, when used in conjunction with diuretics and vasodilators, improves cardiac output and ejection fraction, and reduces filling pressures and pulmonary capillary wedge pressure this reduces pulmonary congestion and edema ; heart rate changes very little.
These effects are to be expected for a drug that increases inotropy. Although the direct effect of digoxin on blood vessels is vasoconstriction, when given to patients in heart failure, the systemic vascular resistance falls. This most likely results from the improvement in cardiac output, which leads to withdrawal of compensatory vasoconstrictor mechanisms e. Digitalis compounds have a small direct diuretic effect on the kidneys, which is beneficial in heart failure patients.
Atrial fibrillation and flutter lead to a rapid ventricular rate that can impair ventricular filling due to decreased filling time and reduce cardiac output. Furthermore, chronic ventricular tachycardia can lead to heart failure.
Digitalis compounds, such as digoxin, are useful for reducing ventricular rate when it is being driven by a high atrial rate. The mechanism of this beneficial effect of digoxin is its ability to activate vagal efferent nerves to the heart parasympathomimetic effect. Vagal activation can reduce the conduction of electrical impulses within the atrioventricular node to the point where some of the impulses will be blocked.
When this occurs, fewer impulses reach the ventricles and ventricular rate falls. Digoxin also increases the effective refractory period within the atrioventricular node. Male patients with serum digoxin levels of 0. Hence current evidence suggest that the beneficial effects of digoxin appear to be limited to male patients having low 0.
Since then, digitalis glycosides have become, and have remained, one of the major classes of drugs used in the treatment of CHF. Digitalis glycosides are a group of chemically related compounds isolated primarily from plant sources , such as the purple and white foxglove plants Digitalis purpurea and Digitalis lanata. Digitoxin is another derivative still in clinical use in other countries such as Canada and Europe. The only structural difference between these two drugs is a single hydroxyl group, which is missing in Digitoxin see Figure 1.
This small structure difference nevertheless results in major differences in pharmacokinetic properties of the two drugs Table 2. Ouabain is another similar endogenous compound with the same mechanism of action that has been identified in the human circulation, and has been linked to changes in vascular function in hypertension Manunta et al. Figure 1. Chemical structures of two digitalis glycosides.
Each compound has 3 basic structural components: an unsaturated lactone ring, a steroid nucleus, and several sugar moieties which primarily influence the pharmacokinetic properties. Digoxin has an extra hydroxyl group compared to digitoxin. Digitalis glycosides have multiple direct and indirect effects on the heart that contribute to both its therapeutic and toxic effects.
At therapeutic doses, digoxin increases vagal tone to the heart. The increase in vagal tone results from several different mechanisms including:. Increased vagal tone has a number of potentially therapeutic effects, including increasing the ERP of the AVN , and decreasing automaticity.
Increasing the ERP of the AVN can have a beneficial effect to reduce ventricular rate in patients suffering from atrial fibrillation or flutter , and atrial tachyarrhythmias are common in patients with CHF who have heart failure with a dilated heart. High ventricular rates may also result in myocardial ischemia in patients having coronary artery disease and coronary insufficiency. Positive Inotropic Action. As illustrated in Figure 2, this effect can be therapeutic in that it can increase cardiac output sufficiently to allow adequate perfusion of vital organs, including the kidney.
This effect is typically accompanied by a significant diuresis following the improvement in kidney perfusion. Note that this effect is indirect, and results from improved cardiac output, and not from a direct diuretic effect on the kidney. Figure 2. Effect of heart failure and digoxin on the Frank-Starling relationship.
During heart failure, the relationship between cardiac output and venous pressure becomes shifted down and to the right patient moves from point A to B.
Sympathetic activation and increased fluid retention result in an increased venous pressure preload which acts to increase cardiac output by increasing the stretch of cardiac fibers patient moves from B to C. Digoxin can shift the curve upwards and to the left by a mechanism different from sympathetic stimulation so that the patient ideally moves from point C to D.
The resulting increase in blood flow to the kidney results in a diuresis patient moves from D to E with an associated reduction in venous pressure due to reduced venous volume. This larger Ca release from the SR results in a stronger force of contraction.
Figure 3. However, during systole, the net increase in SR Ca content results in a greater release of SR Ca into the cytoplasm with each action potential. Note that conditions that reduce Na influx into cardiac cells e. Na channel blockers would reduce intracellular [Na], and be negative inotropic.
These effects include:. Depolarization of the Resting Potential. This will in turn inactivate some Na channels. The combination of partial Na channel inactivation combined with a decreased Na concentration gradient will decrease the amplitude of the Na current during phase 0, leading to slow conduction. Delayed After-Depolarizations. DAD's may reach threshold, resulting in one or more ectopic beats , bigeminy or even a sustained tachycardia.
ST Segment Changes. Increases in intracellular [Ca] can also increase Ca-modulated potassium conductance. This may contribute to shortening of the action potential duration, repolarization rate, and resultant ST segment changes.
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