Therapeutic Use and Rationale
Therapeutic Use of
- Heart failure
Cardiostimulatory drugs (also called "cardiotonic drugs") enhance cardiac function by increasing heart rate (chronotropy) and myocardial contractility (inotropy), which increases cardiac output and arterial pressure. Many of these drugs also increase electrical conduction (dromotropy) within the heart and augment relaxation (lusitropy). Some drugs produce systemic vasodilation, whereas others produce vasoconstriction by mechanisms that differ from their cardiac mechanisms.
The cardiac effects of these drugs make them suitable for heart failure, cardiogenic shock, and hypotension.
Heart failure and cardiogenic shock
The most common cause of cardiogenic shock is a loss of cardiac contractile function. This leads to reduced organ perfusion and hypotension. Because the primary problem is cardiac, therapeutic interventions that improve cardiac function should benefit the patient because improving cardiac output increases organ perfusion and by normalizing arterial pressure. Cardiac function can be improved by reducing afterload, increasing preload by increasing fluid volume (seldom appropriate except for hypovolemic and circulatory shock), and enhancing contractility of the heart. Cardiostimulatory drugs work by this latter mechanism (some cardiostimulatory drugs also can reduce afterload by separate mechanisms). Cardiostimulatory drugs that are sympathomimetics or phosphodiesterase inhibitors are only useful, however, for short-term therapy because of long-term deleterious effects. Digoxin, in contrast, is safe and effective for long-term therapy of heart failure.
This form of hypotensive shock can be caused by an inadequate blood volume (e.g., hypovolemia caused by hemorrhage) or because of a loss of vascular tone caused by infection and inflammation (e.g., septic shock). Cardiostimulatory drugs (especially sympathomimetics such as beta-agonists) are frequently used in these conditions to improve arterial pressure. They are often used with resuscitation fluids and vasoconstrictor drugs.
Drug Classes and General Mechanisms of Action
- Digitalis compounds
- Calcium sensitizers
Cardiostimulatory drugs used in clinical practice can be divided into four mechanistic classes: beta-adrenoceptor agonists (β-agonists), digitalis compounds, phosphodiesterase inhibitors, and calcium sensitizers.
Beta-agonists are sympathomimetic drugs that bind to beta-adrenoceptors in cardiac nodal tissue, the conducting system, and contracting myocytes. The heart has both beta1 ( β1) and beta2 ( β2) adrenoceptors, although the predominant receptor type in number and function is β1. These receptors normally bind norepinephrine that is released from sympathetic adrenergic nerves. They also bind norepinephrine and epinephrine that circulate in the blood. β1 and β2 adrenoceptor activation increases heart rate and contractility, which increases cardiac output. The activation of these receptors also increases conduction velocity within the heart and the rate of mechanical relaxation (lusitropy). These drugs are used to treat acute and refractory heart failure, as well as circulatory shock.
Digitalis compounds have been used for over two hundred years to treat heart failure. These drugs inhibit the cardiac sarcolemmal Na+/K+-ATPase, which leads to an increase in intracellular calcium through the Na+-Ca++-exchanger. Increased intracellular calcium stimulates increased release of calcium by the sarcoplasmic reticulum and makes more calcium available to bind to troponin-C, which increases contractility.
Phosphodiesterase inhibitors are drugs that inhibit the enzyme (cAMP-dependent phosphodiesterase) responsible for breaking down cAMP. This leads to an increase in cAMP. In the heart, this produces positive inotropic and chronotropic responses, like beta-agonists. These drugs are used to treat acute and refractory heart failure, not chronic heart failure.
Calcium sensitizing drugs
Calcium sensitizing drugs represent the newest class of cardiostimulatory drugs. These drugs increase the binding sensitivity of troponin-C for calcium so that more calcium becomes bound to troponin-C, which enhances contractility. At present, these drugs are under clinical investigation for heart failure, and therefore not yet approved in the U.S., although they are approved in some other countries. Most of these drugs also inhibit phosphodiesterase.
Click below on a drug class for more details: