INOTROPIC DRUGS

Inotropic drugs are used to increase the force of ventricular contraction when myocardial systolic function is impaired. The pharmacologic agents in this category include the cardiac glycosides, sympathomimetic amines, and phosphodiesterase-3 inhibitors. Although they work through different mechanisms, they are all thought to enhance cardiac contraction by increasing the intracellular calcium concentration, thus augmenting actin and myosin interactions. The hemodynamic effect is to shift a depressed ventricular performance curve (Frank–Starling curve) in an upward direction, so that for a given ventricular filling pressure, stroke volume and cardiac output are increased.

Cardiac Glycosides (Digitalis).
The cardiac glycosides are called “digitalis” because the drugs of this class are based on extracts of the foxglove plant, Digitalis purpurea. The most commonly used member of this group is digoxin.

Mechanism of Action
The two desired effects of digoxin are (1) to improve contractility of the failing heart (mechanical
effect) and (2) to prolong the refractory period of the atrioventricular (AV) node in patients with supraventricular arrhythmias (electrical effect).

Mechanical Effect
The action by which digoxin improves contractility appears to be inhibition of the sarcolemmal Na+     K +-ATPase “pump,” normally responsible for maintaining transmembrane Na+ and K+ gradients. By binding to and inhibiting this pump, digitalis causes the intracellular [Na+ ] to rise. As shown in Figure 17.2, an increase in intracellular sodium content reduces Ca++ extrusion from the cell by the Na +   –Ca ++ exchanger. Consequently, more Ca++ is pumped into the sarcoplasmic reticulum, and when subsequent action potentials excite the cell, a greaterthan- normal amount of Ca++ is released to the myofi laments, thereby enhancing the force of contraction. The magnitude of the positive inotropic effect correlates with the degree of Na +K+ -ATPase inhibition.

Electrical Effect
     The major therapeutic electrical effect of digoxin occurs at the AV node, where it slows conduction velocity and increases refractoriness. Digoxin has modest direct effects on the electrical properties of cardiac tissue directly, but more importantly, it modifi es autonomic nervous system output by enhancing vagal tone and reducing sympathetic activity. As a result, digitalis decreases the frequency of transmission of atrial impulses through the AV node to the ventricles. This is benefi cial in reducing the rate of ventricular stimulation in patients with rapid supraventricular tachycardias such as
atrial fi brillation or atrial fl utter. In addition, by enhancing the refractoriness of the AV node, digoxin may convert supraventricular reentrant arrhythmias to normal rhythm. However, if digoxin  concentrations rise into the toxic range, further enhancement of vagal tone and more extreme inhibition of the Na+ K+ -ATPase pump can result in adverse electrophysiologic effects. For example, in atrial and ventricular Purkinje fi bers, a high digoxin concentration has three important actions that may lead to dangerous arrhythmias:
1. Less negative resting potential. Inhibition of the Na +K+ -ATPase causes the resting potential to become less negative. Since the Na +K+ -ATPase normally removes three Na+ ions from the cell in exchange for two inwardly moving K+ ions, inhibition of the pump results in a decrease of this outward current and a resulting depolarization of the cell. Consequently, there is a voltagedependent partial inactivation of the fast Na+ channels, which leads to a slower rise of phase 0 depolarization and reduction in conduction velocity. The slowed conduction, if present heterogeneously among neighboring cells, enhances the possibility of reentrant arrhythmias.

2. Decreased action potential duration. At high digitalis concentrations, the cardiac action potential shortens. This relates in part to the digitalis-induced elevated intracellular [Ca++ ], which increases the activity of a Ca ++-dependent K+ channel. The opening of this channel promotes K+ efflux and more rapid repolarization. In addition, high intracellular [Ca ++] inactivates the Ca++ channels, decreasing the inward depolarizing Ca++ current. The decrease in action potential duration and the associated shortened refractory period increase the time during which cardiac fi bers are responsive to external stimulation, allowing greater opportunity for propagation of arrhythmic impulses.

3. Enhanced automaticity. Digoxin enhances cellular automaticity and may generate ectopic rhythms by two mechanisms:
a. The less negative membrane resting potential may induce phase 4 gradual depolarization, even in nonpacemaker cells, and an action potential is triggered each time the threshold voltage is reached.
b. The digoxin-induced increase in intracellular [Ca ++] may trigger delayed afterdepolarizations. If an afterdepolarization reaches the threshold voltage, an action potential (ectopic beat) is generated. Ectopic beats may lead to additional afterdepolarizations and self-sustaining arrhythmias such as ventricular tachycardia.

In addition, the augmented direct and indirect vagal effects of toxic doses of digitalis slow conduction through the AV node, such that high degrees of AV block, including complete heart block, can occur. Thus, digoxin in toxic concentrations may lead to several types of rhythm disorders.

Electrophysiologic Effects of Digitalis

Region                           Mechanism of Action                        Effect 
Therapeutic effects
AV node                         Vagal effect                                     • ↓ Rate of transmission of atrial
                                    ↓ Conduction velocity                          impulses to the ventricles in
                                    ↑ Effective refractory period                supraventricular tachyarrhythmias
                                                                                          • ↓ Conduction velocity and ↑
                                                                                             refractory period may interrupt
                                                                                             reentrant circuits passing through
                                                                                             the AV node
Toxic effects
Sinoatrial node                ↑ Vagal effect and direct                   • Sinus bradycardia
                                        suppression                                 • Sinoatrial block (impulse not
                                                                                            transmitted from SA node to atrium)
                                      
Atrium                           Delayed afterdepolarizations             • Atrial premature beats
                                       (triggered activity), ↑ slope            • Nonreentrant SVT (ectopic rhythm)
                                       of phase 4 depolarization
                                       (↑ automaticity)
                                     Variable effects on conduction          • Reentrant PSVT
                                       velocity and ↑ refractory period
                                       (can fragment conduction
                                       and lead to reentry)

AV node                         Direct and vagal-mediated                • AV block (fi rst, second, or
                                       conduction block                              third degree)
                                    
AV junction                    Delayed afterdepolarizations             • Accelerated junctional rhythm
  (between AV node          (triggered activity), ↑ slope
    and His bundle)            of phase 4 depolarization
                                      (↑ automaticity)

Purkinje fibers and         Delayed afterdepolarizations              • Ventricular premature beats
ventricular muscle           (triggered activity), ↓ conduction
                                     velocity and ↑ refractory period
                                     (can lead to reentry)
                                   ↑ Slope of phase 4 depolarization        • Ventricular tachycardia
                                      (↑ automaticity)


Clinical Uses
     The most common use of digoxin historically has been as an inotropic agent to treat heart failure caused by decreased ventricular contractility. Digoxin increases the force of contraction and augments cardiac output, thereby improving left ventricular emptying, reducing left ventricular size, and decreasing the elevated ventricular filling pressures typical of patients with systolic dysfunction. It is not benefi cial in forms of heart failure associated with normal ventricular contractility (i.e., heart failure with preserved ejection fraction).
     Once the mainstay of therapy in congestive heart failure (CHF), the use of digitalis has waned in the face of newer. Nonetheless, digitalis continues to be useful in treating patients with CHF complicated by atrial fibrillation (it has the added benefit of slowing the ventricular heart rate), or when symptoms do not respond adequately to angiotensin-converting enzyme (ACE) inhibitors, B -blockers, and diuretics. Unlike ACE inhibitors and B-blockers, digoxin does not prolong the life expectancy of patients with chronic heart failure, though it may improve their quality of life.

     The second most common use of digoxin is as an antiarrhythmic agent in the treatment of atrial fibrillation, atrial flutter, and paroxysmal supraventricular tachycardia (PSVT). In atrial fibrillation and flutter, digitalis reduces the number of impulses transmitted across the AV node, thereby slowing the ventricular rate. Digitalis may terminate reentrant supraventricular tachycardias, likely through enhancement of vagal tone, which slows impulse conduction, prolongs the effective refractory period,
and can therefore interrupt reentrant circuits that pass through the AV node.
     The use of digoxin as an antiarrhythmic has become less common because other agents such as B-blockers, calcium channel blockers (CCBs), and amiodarone are often more effective.

Pharmacokinetics and Toxicity
     Digoxin is excreted unchanged by the kidney. A series of loading doses is necessary to raise the drug’s concentration into the therapeutic range. If a loading dose is not given, the steady-state concentration is established in approximately 7 days. The maintenance dosage depends on the patient’s ability to excrete the drug (i.e., renal function).
     The potential for digitalis toxicity is significant because of a low toxic-to-therapeutic drug concentration ratio. Although many side effects are minor, life-threatening arrhythmias may result. Extracardiac signs of acute digitalis toxicity are often gastrointestinal (e.g., nausea, vomiting, anorexia), thought to be mediated by the action of digoxin on the area postrema of the brain stem. Cardiac toxicity includes several types of arrhythmias that may precede extracardiac warning symptoms. The most frequently encountered rhythm disturbance is the development of ventricular extrasystoles. As described above, various degrees of AV block may occur because of the
direct and vagal effects on AV nodal conduction. Digitalis toxicity is also a cause of nonreentrant
types of supraventricular tachycardia (i.e., those caused by enhanced automaticity or delayed afterdepolarizations).
     Many factors contribute to digitalis intoxication, the most common of which is hypokalemia, often caused by the concurrent administration of diuretics. Hypokalemia exacerbates digitalis toxicity because it further inhibits the Na+ K+ -ATPase pump. Other conditions that promote digitalis toxicity include hypomagnesemia and hypercalcemia. In addition, the concurrent administration of other
drugs (e.g., amiodarone) may raise the serum digoxin concentration by altering its clearance
or volume of distribution.
     The treatment of digitalis-induced tachyarrhythmias includes administration of potassium
(if hypokalemia is present) and often intravenous lidocaine (discussed later in the chapter). High-grade AV block may require temporary pacemaker therapy. In patients with severe intoxication, administration of digoxinspecific antibodies may be life saving.