The aglycones in cardiac glycosides fall into one of two categories, both derived from a steroidal base. They can be the more common cardenolides, with a five-member ring attached to the steroidal base, or the much less common bufadienolides, with a six-member ring attached.
Regardless of their structure, all cardiac glycosides inhibit Na+/K+-ATPase pumps throughout the body. Because these pumps are most concentrated and critical in cardiac myocytes, they have their greatest effect on this tissue. When an action potential passes through a cardiac myocyte, the cardiac glycoside limits sodium outflow and potassium inflow from the cell. The linked Na+/Ca2+ pump thus does not have sufficient sodium available to move calcium out of the cell. The higher than normal intracellular calcium concentration means that during the next action, potential contractility is increased. This is described as a positive inotropic action. Another consequence of this activity is a reduction in heart rate, described as negative chronotropic action. The glycosides also limit conduction velocity in the atrioventricular node, an action described as negative dromotropic.
All of these effects, combined with a mild tendency to reduce tubular resorption of sodium in the kidneys and a moderate vasoconstrictive effect, make cardiac glycosides best suited for relieving symptoms due to congestive heart failure (CHF). They can also reduce some atrial arrhythmias. However, these agents do not address the cause of CHF and do not appear to reduce CHF-induced mortality; they do, however, reduce the need for hospitalization, at least in humans.
The number of sugars or uronic acids attached to the aglycone affects the water solubility of the overall glycoside and can alter its bioavailability. A lesser degree of hydroxylation correlates with rapid oral absorption and rapid renal excretion; greater hydroxylation slows oral absorption and is associated with biliary excretion, significant enterohepatic recirculation, and long half-lives.
Cardiac glycosides with long half-lives (4 to 6 days in the case of digitoxin) accumulate in the body. This greatly increases the danger of toxicity. Those glycosides that are rapidly cleared, such as those found in Convallaria majalis (lily of the valley), do not accumulate and are of mild potency. Those that accumulate, such as those found in Digitalis purpurea (foxglove), are of strong potency and must be used cautiously. Major common adverse effects caused by overdose include anorexia, nausea, vomiting, arrhythmia, confusion, headache, depression, green or yellow tinting of the vision, blurred vision, and worsening CHF. The toxic and therapeutic doses of Digitalis and potent, isolated cardiac glycosides can be very close, and sometimes toxicity is noted before therapeutic benefit. These problems are rarely noted with milder herbs (Major Cardiac Glycoside-Containing Herbs). Because even mild potassium depletion can greatly increase the toxicity of all cardiac glycosides, it is critical for the practitioner to avoid combining these agents or herbs that contain them with potassium-depleting medications. Of particular concern are non-potassium-sparing diuretics, corticosteroids, and Glycyrrhiza glabra (licorice). Antibiotics may also unpredictably alter the effects of cardiac glycosides by changing the gut flora, thus altering enterohepatic recirculation. Any change in metabolism, such as fever, kidney failure, or intervening hyperthyroidism, can also dramatically alter the pharmacokinetics and thus the pharmacodynamics of these compounds.
|Major Cardiac Glycoside-Containing Herbs*|
|• Digitalis purpurea (foxglove), D. lanata (woolly foxglove)|
|• Strophanthus kombe (stropanthus)|
|• Adonis vernalis (pheasant’s eye)|
|• Nerium oleander (oleander)|
|• Apocynum spp (dogbane, Indian hemp)|
|• Asclepias asperula (inmortal)|
|• Asclepias tuberosa (pleurisy root)|
|• Urginea maritima (squill)|
|• Convallaria majalis (lily of the valley)|
|*Note: Arranged approximately from most toxic to least.|