INOTROPES

Inotropes
 * Background:** The inotropes, all of which share the ultimate hemodynamic and pharmacodynamic goal of increasing the force of myocardial contraction, can be classified into one of three basic pharmacologic mechanisms. For the purposes of this overview, the inotropes will be divided into the following categories: 1) digitalis glycosides; 2) receptor agonists; and 3) inodilators or inotropic phosphodiesterase inhibitors. Although epinephrine, isoproterenol, and norepinephrine possess beta-agonist activity that results in a positive inotropic action, these catecholamines will be excluded because they are not routinely used as inotropes; proarrhythmic actions, renal artery vasoconstriction, and myocardial ischemia complicate their use as inotropes. In general, catecholamine inotropes are intended for short-term use because tachyphylaxis and/or receptor-density changes can develop.


 * History:** Traditionally, the discussion of inotropes initiates with digitalis glycosides (e.g., digoxin, digitoxin, and deslanoside). Their history dates back to the 13th century and perhaps earlier. Although digitalis, or foxglove, was described in medical writings of a Welch physician in 1250, it is believed that digitalis was referred to as squill by the ancient Egyptians, who recognized its medicinal potential. The Roman civilization also used the plant extract for many purposes including as a heart tonic and rat poison. In the mid-16th century, Fuchsius assigned the botanical name //digitalis purpurea// to the foxglove plant, whose dried leaves are the official source of digitalis. //Digitalis lanata// is another botanical source of cardiac glycosides.

Digitalis was recognized as a significant medicinal agent in 1785 when William Withering described its usefulness in dropsy (edema). It wasn't until 1799 when John Ferriar identified the cardiac effects (primary effect) and diuretic activity (secondary effect) of digitalis. The drug initially was, and still is, used as a specific treatment for atrial fibrillation, but establishment of the drug's effectiveness as an inotrope has taken decades, despite having undergone over 200 years of use and countless challenges to its effectiveness.[309]

Dopamine and dobutamine are the primary receptor agonists used as inotropes. Dopamine, the immediate endogenous precursor of norepinephrine and epinephrine, was released in 1974 for use as an inotrope. Because it is an endogenous multi-receptor agonist, dopamine shares many common pharmacodynamic activities with these neurotransmitters. The biosynthetic pathway for dopamine begins with tyrosine as the basic substrate that is sequentially metabolized into: DOPA, dopamine, norepinephrine, and epinephrine. This process was first described by Blaschko in 1939 and requires many enzymes and cofactors.[307] Dopamine is one of the most complex and often misunderstood inotropic agents. It has different pharmacodynamic and hemodynamic effects based on the dose administered and, consequently, the type of receptor being stimulated (e.g., dopaminergic, beta-adrenergic, or alpha-adrenergic.)[295] [312] Today, dopamine is more commonly used in low doses to enhance perfusion of vital organs and in higher doses as a vasopressor.

Dobutamine, released in 1978, is a synthetic analog of dopamine. Dobutamine possesses unique properties, despite its being chemically related to dopamine. Dobutamine was designed to be a selective inotropic agent devoid of peripheral vascular activity. Based on Ahlmquist's theories of adrenergic stimulation, a beta1-selective agent should result in a potent inotropic response, with minimal chronotropic (i.e., beta2 effects) or vascular (i.e., dopaminergic or alpha effects) properties. Initially, it was believed that dobutamine was a pure beta1-agonist, but the drug also stimulates, to a lesser degree, beta2- and alpha1-receptors.[313] Despite the difference in mechanism of action and pharmacodynamics between dopamine and dobutamine, both share the ability to produce positive inotropic effects as well as peripheral vasodilation.

The third group of inotropes are referred to as phosphodiesterase III (PDE III) inhibitors (i.e., inotrope/vasodilator agents or inodilators). Amrinone was released in 1984 and milrinone in 1987, and both are unlike any of the previous inotropes. (NOTE: In 2000, amrinone's generic name was changed to "inamrinone" in due to confusion with the drug amiodarone.) These drugs possess both direct cardiac-stimulant properties and vasodilatory activity. Although oral formulations of these drugs were considered a potential replacement/adjunct for digoxin in the management of congestive heart failure, efficacy and safety could not be established. Studies of oral amrinone were equivocal in demonstrating efficacy. Long-term use of the drug was associated with tachyphylaxis or intolerable side effects (thrombocytopenia). Although many patients demonstrated early hemodynamic improvements, the oral formulation was removed from the market.[314] Similar results were found with oral milrinone. Following hemodynamic improvement, deterioration occurred. The PROMISE study demonstrated a 27% increase in mortality compared to placebo with long-term use. These and other studies prompted the removal of oral milrinone; however, compared to oral amrinone, oral milrinone appeared to be better tolerated by patients and thrombocytopenia was less severe. Nonetheless, the intravenous formulations of both products proved to be safe and efficacious for short-term (i.e., 24 hours or less) support of decompensated heart failure.


 * Mechanism of Action:** The digitalis glycosides exert their inotropic properties via inhibition of the sodium/potassium ATPase pump of the cell membrane. Inhibition of this pump allows for extracellular sodium to enter the cardiac cell. Intracellular sodium is then exchanged for extracellular calcium, resulting in a net increase in intracellular calcium. Increased intracellular calcium is believed to be the principal therapeutic mechanism of digitalis. The increase in intracellular calcium creates a relative acidotic state, which further augments sodium/calcium ion exchange. Besides its inotropic actions, digitalis also depresses conduction, increases the refractory period, and enhances vagal tone, all of which reduce ventricular rates and therefore explain the utility of digitalis as an "antiarrhythmic" agent.[310]

Dopamine, a metabolic precursor of norepinephrine and epinephrine, causes the release of norepinephrine from nerve terminals. Its clinical effects are related to the rate of infusion. In the cardiovascular system, dopamine receptors are subdivided into D1 and D2, and exogenous dopamine stimulates both. At low doses (0.5—2 mcg/kg/min), dopamine acts principally on specific dopaminergic receptors in the renal, mesenteric, coronary, and intracerebral vasculature, resulting in vasodilation. The most clinically significant effect of this vasodilatory response is increased renal blood flow. At moderate therapeutic doses (2—10 mcg/kg/min), dopamine also stimulates beta1-adrenergic receptors, resulting in increased cardiac output while maintaining the dopaminergic-induced vasodilatory effects. At high doses (>10 mcg/kg/min), alpha-adrenergic agonism predominates, and increased peripheral vascular resistance and renal vasoconstriction result. Interestingly, fenoldopam and bromocriptine, selective agonists at D1- and D2-receptors, respectively, both lower blood pressure in hypertensive patients.[142]

Although dobutamine is considered primarily a beta1-adrenergic agonist, it also possesses both beta2- and alpha1-stimulatory effects. The net pharmacology of the drug is a reflection of the combination of the beta-agonism by the (+) isomer and the less potent alpha-agonism by the (-) isomer of the racemic parent compound. The stimulation of beta1-adrenergic receptors predominates and increases myocardial contractility and stroke volume with modest chronotropic effects, resulting in increased cardiac output. Secondary hemodynamic effects of dobutamine include decreases in systemic vascular resistance (afterload) and ventricular filling pressure (preload). Unlike dopamine, dobutamine does not affect dopaminergic receptors, nor does it cause release of norepinephrine from sympathetic nerve endings.[313]

The inodilators (i.e., PDE III inhibitors) amrinone (i.e., inamrinone) and milrinone simultaneously increase (secondary to inotropic actions) and decrease (secondary to vasodilatory actions) filling pressures, preload, and afterload. Although not entirely understood, it is believed that inodilators inhibit the isoenzyme responsible for the degradation of cyclic AMP (cAMP). Inhibition of isoenzyme PDE III results in increased intracellular concentrations of cAMP. Interestingly, PDE III is highly concentrated in the myocardium and vascular smooth muscle. As with other inotropes, increased cAMP increases myocardial contractility, cardiac index, diastolic compliance, and stroke volume, all with minimal increases in heart rate. The inodilators also may alter release and/or uptake of calcium by the sarcoplasmic reticulum, increase sensitivity of contractile proteins to calcium, or activate a calcium-dependent sodium channel, although further study is needed.[312] This biochemical cascade ultimately decreases myocardial oxygen demand, systemic vascular resistance, afterload, and preload.[312]'[315] Clearly, a pharmacologic agent that can produce such a hemodynamic profile, particularly without adverse effects during prolonged use, is a promising agent in the management of CHF or selected low-output states. At this time, however, only short-term use of either inodilator is recommended to prevent the development of tachyphylaxis and/or adverse events.


 * Distinguishing Features:** Although the digitalis glycosides share the same mechanism of action, they differ in pharmacokinetics. Digitoxin is primarily metabolized, is highly protein-bound, and undergoes enterohepatic circulation. The therapeutic range for serum digitoxin concentrations is 10—35 ng/ml. It is important to note that digoxin assays do not accurately quantify digitoxin concentrations, and a misinterpretation could result in a potentially serious clinical condition. Digoxin, on the other hand, is primarily cleared renally, is minimally protein-bound, possesses a much shorter elimination half-life, and has a therapeutic serum concentration range of only 0.5—2 ng/ml. Although bioavailability is virtually complete with digitoxin, the bioavailability of digoxin varies with the dosage formulation administered.

Digitalis also appers to have a place in therapy as an effective inotrope for many patients with normal sinus rhythm and moderate to severe congestive heart failure, particularly patients with an S3 gallop. Its inotropic activity is additive to angiotensin-converting enzymes, diuretics, and other inotropes.[310] Use of digitalis in cardiogenic shock is best reserved for patients with concomitant atrial fibrillation/flutter with accelerated ventricular response, but without acute ischemic heart disease, because those patients appear to have an increased mortality risk, especially with concomitant ventricular arrhythmias.[311]

The primary and most striking difference among the receptor agonists is the dose-dependent receptor pharmacology of dopamine that is unique to all inotropes. Some dose-dependent responses have been observed with the inodilators, although the mechanism of action does not change. Inotropes, as a rule, should be used only for the short-term management of cardiogenic shock or decompensated congestive heart failure, whereas dopamine may be used for longer periods for oliguric states or, occasionally, hypotension. Before initiating inotropic or vasoactive pharmacotherapy, it is critical to ensure the patient is euvolemic in order to achieve optimum pharmacodynamic response.

In general, amrinone (inamrinone) and milrinone are relatively similar. To date, newer agents have provided poor results with respect to chronic CHF therapy, so FDA approval for chronic use of this category of inotropes is unlikely.[316] As data demonstrating no benefit from inodilator therapy continue to appear, enthusiasm surrounding this group of inotropes continues to decrease. The lack of efficacy of these drugs appears to be due to an as yet unexplained acceleration of pathophysiology or possibly induction/progression of ventricular arrhythmias.[317]


 * Adverse Reactions:** Adverse effects related to digitalis toxicity can be classified as cardiac or extracardiac. Cardiac effects include: variable degrees of AV block, PR prolongation, unifocal or multifocal ventricular premature contractions, atrial tachycardia, atrioventricular (AV) dissociation, and an accelerated junctional rhythm. ST-segment depression can occur during digitalis administration, which may or may not indicate digitalis toxicity.

The extracardiac effects of cardiac glycoside intoxication include GI disturbances, ocular problems, CNS disturbances, and potassium-level alterations. Anorexia, nausea, vomiting, and diarrhea are early signs of intoxication, and these effects can precede or follow cardiotoxicity. Such symptoms, however, also may be associated with uncontrolled heart failure. Digitoxin therapy can increase plasma estrogen and can cause gynecomastia in men. Similar effects can be seen in women.

The symptoms of digitalis overdose or toxicity, in order of occurrence, are: stimulation of medullary centers, resulting in GI disturbances such as anorexia, nausea/vomiting, and diarrhea; electrolyte imbalance(s); slow or irregular heartbeat; visual disturbances; drowsiness; confusion; headache; and fainting. Early manifestations of overdose in children are usually arrhythmias. Visual disturbances, such as blurred vision, transient retrobulbar neuritis, photophobia, light flashes, and yellow-green halos surrounding visual images, are most likely the result of cardiac glycoside-induced functional changes in the retina and are generally reversible following discontinuance of the drug.

Ectopic heartbeats, tachycardia, and palpitations are well-understood adverse effects of dopamine and dobutamine secondary to beta-stimulation of the myocardium and cardiac conduction system. Angina and dyspnea can result from the increased workload and subsequent oxygen demands of the adrenergically stimulated heart. Peripheral vasoconstriction and subsequent hypertension result from the alpha-stimulation seen especially with high-dose dopamine. Hypotension, although more common with dopamine at low doses, can occur with either dopamine or dobutamine. Nausea/vomiting and/or headache could result from increased blood flow to these areas.

Ventricular arrhythmias are the most frequently occurring adverse reactions reported in patients receiving inodilators. Specifically, nonsustained ventricular tachycardia, sustained ventricular tachycardia, and ventricular fibrillation have been observed. Potentially fatal arrhythmias have been reported infrequently and are associated primarily with other precipitating factors such as preexisting arrhythmias; metabolic abnormalities such as hypokalemia, which can be induced by inodilators in the absence of diuretic therapy; and enhanced atrioventricular conduction. Improved cardiac function following administration of milrinone can induce diuresis, further predisposing the patient to hypokalemia and arrhythmias. Supraventricular arrhythmias also have been observed in some patients. Neither the precipitation of supraventricular arrhythmias nor ventricular arrhythmias appears to be dose-related. Cardiovascular effects that have been reported less frequently include hypotension and angina.