65: Cardioactive Steroids

65: Cardioactive Steroids Jason B. Hack HISTORY AND EPIDEMIOLOGY The Ebers Papyrus provides evidence that the Egyptians used plants containing cardioactive steroids (CASs) at least 3000 years ago. However, it was not until 1785, when William Withering wrote the first systemic account about the effects of the foxglove plant, that the use of CASs was more widely accepted into the Western apothecary. Foxglove, the most common source of plant CAS, was initially used as a diuretic and for the treatment of “dropsy” (edema), and Withering eloquently described its “power over the motion of the heart, to a degree yet unobserved in any other medicine.”124 Subsequently, CASs became the mainstay of treatment for congestive heart failure and to control the ventricular response rate in atrial tachydysrhythmias. Because of their narrow therapeutic index and widespread use, both acute and chronic toxicities remain important problems.84 According to the American Association of Poison Control Centers data, between the years 2006 and 2011, there were approximately 8000 exposures to CAS-containing plants with one attributable deaths and about 14,500 exposures to CAS-containing xenobiotics resulting in more than100 deaths (Chap. 136). Pharmaceutically induced CAS toxicity is typically encountered in the United States from digoxin; other internationally available but much less commonly used preparations are digitoxin, ouabain, lanatoside C, deslanoside, and gitalin. Digoxin toxicity most commonly occurs in patients at the extremes of age or those with chronic kidney disease (CKD). In children, most acute overdoses are unintentional by mistakenly ingesting an adult’s medication, or iatrogenic resulting from decimal point dosing errors (digoxin is prescribed in submilligrams, inviting 10-fold dosing calculation errors), or the elderly who are at risk for digoxin toxicity, most commonly from interactions with another medication in their chronic regimen or indirectly as a consequence of an alteration in the absorption or elimination kinetics. These include drug–drug interactions from an adult’s polypharmacy or from additional acute care xenobiotics that change CAS clearance in the liver or kidney, may alter protein binding and may result in increased bioavailability. CAS toxicity may also result from exposure to certain plants or animals, including oleander (Nerium oleander), yellow oleander (Thevetia peruviana), which has been implicated in the suicidal deaths of thousands of patients in Southeast Asia,26 foxglove (Digitalis spp), lily of the valley (Convallaria majalis), dogbane (Apocynum cannabinum), and red squill (Urginea maritima). CAS poisoning may result from teas containing seeds of these plants and water and herbal products contaminated with plant CASs (Chap. 45).16,19,52,79,90,97,116 Toxicity has resulted from ingestion, instead of the intended topical application, of a purported aphrodisiac derived from the dried secretion of toads from theBufo species, which contains a bufadienolide-class CAS.10,12,13 Although there have been no reported human exposures, fireflies of the Photinusspecies (P. ignitus, P. marginellus, and P. pyralis) contain the CAS lucibufagin that is structurally a bufadienolides (see Chemistry).30,65 CHEMISTRY Cardioactive steroids contain an aglycone or “genin” nucleus structure with a steroid core and an unsaturated lactone ring attached at C-17. Cardioactive glycosides contain additional sugar groups attached to C-3. The sugar residues confer increased water solubility and enhance the ability of the molecule to enter cells. Cardenolides are primarily plant-derived aglycons with a five-membered unsaturated lactone ring. The bufadienolide and lucibufagin groups of CAS molecules are mainly animal derived and contain a six-membered unsaturated lactone ring (a plant derived exception is scillaren from red squill). Thus when the aglycone digoxigenin is linked to one or more hydrophilic sugar (digitoxoses) moieties at C-3, it forms digoxin, a cardiac glycoside. The aglycone of digitoxin differs from that of digoxin by the absence of a hydroxyl group on C-12, and ouabain differs from digoxin by both the absence of a hydroxyl group on C-12 and the addition of hydroxyl groups on C-1, C-5, C-10, and C-11. The cardioactive components in toad secretions are genins and lack sugar moieties. PHARMACOKINETICS The correlation between clinical effects and serum concentrations is based on steady-state concentrations, which are dependent on absorption, distribution, and elimination (Table 65–1). Although not proven, other CASs likely follow the absorption and distribution pattern ofdigoxin or digitoxin such that obtaining a serum concentration before 6 hours after ingestion (the time at which tissue concentrations plateau) gives a misleadingly high (predistribution) serum concentration. After therapeutic dosing, the intravascular distribution and elimination ofdigoxin from the plasma are best described using a two-compartment model that is achieved over approximately 36 to 48 hours in patients with normal kidney function. The distribution or α-phase represents the decrease in intravascular drug concentration and is dependent on whether the route of exposure was intravenous (IV) or oral (PO). Blood concentrations decline exponentially with a distribution half-life of 30 minutes as the drug moves from the blood to the peripheral tissues. Most of the intravascular CAS leaves the blood and distributes to the tissues, resulting in a large volume of distribution (Vd) (eg, the Vd ofdigoxin is 5–7 L/kg with therapeutic use). The β or elimination phase fordigoxin has a half-life of approximately 36 hours and represents the total-body clearance of the drug, which is achieved primarily by the kidneys (70% of its clearance in a person with normal kidney function).17,46 TABLE 65–1. Pharmacology of Selected Cardioactive Steroids View Large | Favorite Table After a massive acute digoxin overdose, the apparent half-life may be shortened to as little as 13 to 15 hours because elevated serum concentrations result in greater renal clearance before distribution to the tissues.51,111 Even with therapeutic administration of CAS, adjustments to the dosing regimen must be made to avert toxicity caused by the physiologic changes associated with aging, including hypothyroidism, chronic hypoxemia with alkalosis, and decreased glomerular filtration rate (GFR). Physiologic changes in CAS kinetics occur with functional decline of the liver, kidney, and heart and dynamics with electrolyte abnormalities, including hypomagnesemia, hypercalcemia, hypernatremia, and commonly hypokalemia. Therefore, serum concentrations should be monitored to avoid inadvertent toxicity. Hypokalemia resulting from a variety of mechanisms, such as the use of loop diuretics, poor dietary intake, diarrhea, and the administration of potassium-binding resins, enhances the effects of CASs on the myocardium and is associated with toxicity at lower serum CAS concentrations. Chronic hypokalemia reduces the number of Na+-K+-adenosine triphosphatase (ATPase) units in skeletal muscle, which may also alter drug effects.63 Drug interactions between digoxin and quinidine, verapamil, diltiazem, carvedilol, amiodarone, and spironolactone are common.20,23,45,68,93These interactions occur because of a reduction in the protein binding of the CAS, increasing availability to the tissues; a reduction in excretion as a consequence of a decrease in renal perfusion; or, as a result of interference with secretion by the kidneys and intestines, because of inactivation of P-glycoproteins. Also, in approximately 10% to 15% of patients receiving digoxin, a significant amount of digoxin is inactivated in the gastrointestinal (GI) tract by enteric bacterium, primarilyEubacterium lentum. Inhibition of this inactivation by the alteration of the GI flora by many antibiotics, particularly macrolides, results in increased bioavailability73 and increased serum CAS concentrations.92 MECHANISMS OF ACTION AND PATHOPHYSIOLOGY Electrophysiologic Effects on Inotropy It is currently believed that CASs increases the force of contraction of the heart (positive inotropic effect) by increasing cytosolic Ca2+ during systole. Both Na+ and Ca2+ ions enter and exit cardiac muscle cells during each cycle of depolarization and contraction–repolarization and relaxation. Sodium entry heralds the start of the action potential (phase 0) and carries the inward, depolarizing positive charge. Calcium subsequently enters the cardiac myocyte through L-type calcium channels during late phase 0 and the plateau phase of the action potential, and this Ca2+ entry triggers the release of Ca2+ into the cytosol from the sarcoplasmic reticulum. During repolarization and relaxation (diastole), Ca2+ is both pumped back into the sarcoplasmic reticulum by a local Ca2+-ATPase and is moved extracellularly by an Na+-Ca2+antiporter (Fig. 65–1; Chap. 17).78 FIGURE 65–1. Pharmacology and toxicology of the cardioactive steroids (CASs). (A) Normal depolarization. Depolarization occurs after the opening of fast Na+channels; the increase in intracellular potential opens voltage-dependent Ca2+ channels, and the influx of Ca2+ induces the massive release of Ca2+from the sarcoplasmic reticulum, producing contraction. (B) Normal repolarization. Repolarization begins with active expulsion of 3Na+ ions in exchange for 2K+ ions using an ATPase. This electrogenic (3Na+ for 2K+) pump creates a Na+ gradient used to expel Ca2+ via an antiporter (NCX). The sarcoplasmic reticulum resequesters

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