Digoxigenin, R'* OH Digitoxigeain, Ä'» H R - sugars
Digoxin (Lanoxin) Digitoxin (Crystodigin)
R ' tri-digitoxose R = tri-digitoxose
R " rhamnose-glucose
late eighteenth century that its real medicinal value was recognized in the treatment of CHF (actually, the accompanying edema, or dropsy) by W. Withering in England. After a decade of study and use he wrote a treatise in 1785 on the use of foxglove for dropsy and other diseases. For the next 150 years digitalis was used in the form of decoctions, infusions, tinctures, fluid extracts, and even as the powdered dried leaf.
Today, the active constituents have all been isolated and structurally identified as glycosides of a steroid nucleus with two unusual features: a hydroxyl function at C-14 and an unsaturated five-membered lactone called an a-^-unsaturated butenolide at C-17 (Fig. 10-18). Both features appear essential to cardiotonic activity. Enzymatic or chemical cleavage of the glycosidic bond at C-3 removes the various sugars attached, yielding the aglycone (e.g., digitoxin —» digitoxigenin). The sugars such as digitoxose and rhamnose, which are deoxyhexoses, have no biological activity, but they do increase and modify the action of the aglycones. The number of alcoholic functions they bring to the total molecule predictably affects solubility in body fluids, transport ability across membranes, binding tenacity to cardiac (and other) tissues, and ultimately the onset and duration of action. Thus, digoxin, carrying the additional OH at C-12, is slightly more water soluble than digitoxin. One result is a somewhat better oral absorption for digitoxin, where lipid solubility is slightly enhanced.
Active cardiac glycosides have also been obtained from species of Strophanthus and squill (a sea onion). The former is a source of glycoside ouabain, which has an intense but short action; the latter provides scillaren A and other glycosides that are not widely used anymore. The glycosides most frequently used today are digoxin (Lanoxin) and digitoxin (Crystodigin, Purodigin).
The geometry at the fusion points of the various rings of the steroidal aglycone are significant. For example, the A/B ring fusion of the active glycosides is cis (i.e., the CH3 at C-1019 and the H at C-5 are p, or above the general plane of the steroid ring system).20 The
" The CH3 carbon itself is No. 19; it is bonded to C-10.
20 In most other naturally occurring steroids such as sex hormones, the configuration is trans.
hydrogen atoms on the two carbons representing the B/C ring juncture (C-8 and C-9) are trans to each other, with the C-9 H being a, or below the ring system. This is characteristic of all bioactive steroids. The C/D ring juncture has cis stereochemistry, where the CH3 group at C-13 (itself the No. 18 carbon) and the C-14 OH are both (3. This C/D configuration is again unique to the cardiac glycosides. These geometric requirements are "strict." Thus removal of the C-14 OH or inversion to the a-configuration eliminates or greatly reduces the activity. Epimerizing the configuration of the C-17 cardenolide from p to a abolishes activity.
To better understand certain aspects of the mechanism of digitalis drugs, it would be useful to outline briefly their cardiovascular properties. The increased force of myocardial contraction produced by these glycosides is by far their most dramatic pharmacodynamic property. This positive inotropic (increased contractile force) action translates into increased cardiac output and effects on cardiac size and blood volume through diuresis (i.e., the relief of the edema that accompanies CHF). The rate of tension development is apparently affected, not the length of time during which contraction is maintained by the muscle fiber. Digitalis exerts its effect even in the presence of p-blockers or reserpine.
For many years it was thought that factors other than the increase in contractile power were responsible for the beneficial effects of these agents (Withering believed foxglove had a renal effect). One explanation was that since an enlarged heart was inefficient, digitalis' benefits were derived from its ability to reduce cardiac size by some "tonic" effect. The situation is actually the reverse—cardiac inefficiency causes the enlargement as a compensatory effect. The ultimate benefit of digitalis is the increased ability of the myocardium to do the work (that is, pump) at any given filling pressure.
The heart rate is decreased by digitalis in the patient with CHF, but not significantly in the normal individual. The effect is only partially mediated through the vagus nerve to the heart. Improved work capacity is not dependent on a decreased rate; a decreased rate should really be viewed as a secondary therapeutic effect. It is of interest that in spite of centuries of use of digitalis against heart failure, it was not until recently that its long-term beneficial effects were demonstrated.
Digitalis can be shown to cause some increase in the electrical excitability of both atrial and ventricular fibers in low doses. In excessive doses, this effect may increase to dangerous levels, thus constituting one of the toxic effects of these drugs. Digitalis compounds are very toxic and have a very small therapeutic index. Clinical dosages are frequently within 60% of toxic levels. Digoxin dosages were revised downward in the middle 1970s. Age, renal failure, electrolyte imbalance (particularly K+), and cardiac ischemia all tend to increase greatly the risk of digitalis toxicity.
The rate of electrical impulse conduction through different cardiac tissues is variably affected. Thus low doses increase the velocity in the atrium and ventricle but toxic doses decrease velocity, sometimes even producing a block. Digitalis affects the refractory period by shortening it in the atrium, but markedly prolonging it for atrioventricular (AV) transmission.
Automaticity is the ability of cardiac tissue fibers to depolarize spontaneously. This enables them to contract again without external nerve stimulation. It is not surprising that digitalis affects this ability profoundly. When digitalis causes an increase in the rate of spontaneous depolarization during diastole of the ventricle, automaticity is increased at the pacemaker site. This may result in premature beats that increase as higher doses reduce excitability.
When the heart develops an arrhythmia because of defective electrical transmission from the atrium to the ventricle (AV transmission), an atrial fibrillation will occur. The cause is likely to be failure of the impulses to reach the AV node. Changes in the refractory period may aggravate the condition even further. By a very complex series of events, including prolongation of the refractory period, digitalis can restore the rhythm to almost normal. Coronary circulation does not appear to be significantly affected by digitalis in either normal patients or patients with congestive heart failure; nor is oxygen consumption by cardiac tissue increased.
Heart failure results in edema either because of increased hydrostatic pressure in capillaries or because of a compensatory renal mechanism. As the effective output of the heart decreases, renal flow, and therefore glomerular filtration, also decrease. Reabsorption of sodium and water is more complete, resulting in increased tissue retention of both substances. Digitalis has a diuretic effect to the extent that it relieves the underlying factors in the heart.
Although the various mechanisms by which digitalis glycosides exert these actions have been intensely studied for more than four decades, a total understanding is still not forthcoming. Certain aspects, however, have been established.
Cardiac glycosides are specific inhibitors of the pumping mechanism that transports Na+ and K+ across cell membranes against the electrochemical gradient (Chapter 8). The pivotal role in the active transport of these two ions across the membrane of the cardiac cell has been attributed to a membrane-bound enzyme, adenosine triphosphatase (ATPase, or more properly Na+-K+-ATPase), which is in a steric orientation that apparently allows for interaction with the digitalis steroid nucleus and the lactone at C-17. This interaction affects the enzyme's activation by causing variations in the concentrations of Na+ and K+. It is agreed that this inhibition occurs when digitalis is administered in toxic doses. It has not been well established that the same mechanism is also operative in producing increased cardiac contractility. Of course, it can be postulated that suppression of the pump would result in higher intracellular Na+ (and decreased K+) levels, resulting in a lower action potential. Impulse-sensitive cells (neuronal or myocardial) exchange these ions with a net loss (three Na+ for two K+) that obviously establishes the electrical potential between the internal and external membrane surfaces.
Extensive SAR studies, as well as a wealth of clinical experiences, have shown digitalis glycosides to be very potent, very selective, and very specific—facts that suggest that a receptor interaction is involved in producing the physiological results observed. Interactions of Na+-K+-ATPase with its various substrates are complex. Thus binding affinities with ATP, cofactor Mg2~, Na+, K+, and a digitalis glycoside are all important to the overall effect. The assumption can safely be made that binding will bring about conformational changes. It is now accepted that a digitalis receptor is one or more of the conformations of Na+-K+-ATPase that occur during the ion pump's operation, possibly during a state in which the drug helps to stabilize one of the intermediate states of the enzyme (for example, during phosphorylation).
Evidence suggests that the entire glycoside molecule participates in the proposed drug-receptor interaction. The steric relationship of the lactone ring (P) to the steroid nucleus is absolute. The double bond is also critical since saturation results in an almost total loss of activity. The required stereochemical positioning of rings C and D in relation to each other (cis) and of A and B (also cis), and the configuration of the OH at C-14 have all been established. Figure 10-19 represents a highly simplified version of a proposed interaction of the C-17 lactone side chain with such a digitalis receptor.
If we "view" the butenolide as being perpendicular to this page with the double bond at eye level lying within an imaginary cavity formed by the enzyme's surface, a two-point binding can be visualized: (1) the polarized carbonyl group, with its electron-rich oxygen, hydrogen bonds to a hydroxyl group on the enzyme's surface (a serine residue?) and (2) the carbon atom bonded to the steroid nucleus is attracted to an anionic (or at least electron-dense) site at a secondary location. The electron deficiency (8+) on that carbon can be easily justified by the resonance concept, which requires an overall shift of electrons toward the oxygen in a conjugated system as exists in this case.
The cyclic C-17 a-p-unsaturated butenolide (lactone) could be replaced with a small group of what can be considered noncyclic bioisosteres. The requirements seem to be at least an a-P-unsaturated system that also permits a partial positive charge on the P-carbon, as long as the system is not extended (as in D) or bulky (as in C, when R = C2H5).
-CH=CH-Cfe=K -CH=CH—C—O, -Ot=CH-CH=CH-C=0 P a (R=ch3 0rC2Hs)
The centrality of this mechanism has by now been established. Na+-K+-ATPase is the glycoside receptor. This receptor—two catalytic enzymes plus glycoprotein and phospholipid—maintains the Na+ and K+ gradient.
It is tempting to rationalize this Na+-K+-ATPase digitalis-receptor complex as the biochemical explanation for drug-induced myocardial contractility. Much of the experimental evidence looks promising. However, some of it may be circumstantial. One disturbing fact is that substances exist that can inhibit the enzyme, yet do not affect myocardial contractility. In the final analysis we do not yet have a fully satisfactory explanation for the actions of digitalis glycosides. The fact remains that after two centuries this botanical drug is still absolutely essential for the treatment of the cardiac patient.
Other inotropic drugs are necessary not to replace digitalis as much as to supplement in cases of severe heart failure refractory to the glycosides, and in situations where their efficacy is insufficient and the therapeutic index is too low. The clinical goal is to improve the symptoms of cardiac failure by improving left ventricular function or by reducing resistance to the heart's output against the peripheral circulation—or even better—to achieve both.
An approach to improved inotropic drugs was to re-examine p-adrenergic agonists. The problem with most P-agonists was a duality of action: inotropic activity on the myocardium, which is desirable in CHF, and chronotropic activity (i.e., increased rate or tachycardia and the high associated risk of arrhythmias). In addition, of course, any significant pressor activity would also be detrimental. Isoproterenol is not a pressor; it has inotropic activity and because of strong peripheral p2 agonism would, by its skeletal muscle effects there, lower resistance (reduce diastolic pressure) to the point of diminishing myocardial perfusion. A synthetic SAR study was therefore undertaken systematically to modify IPR to reduce its chronotropic, arrhythmogenic, and vascular effects while retaining, primarily and selectively, increased cardiac contractility. The compound sought was one with maximum cardiac Pi agonist activity and minimal peripheral p2 and a agonism. The result was dobutamine (Dobutrex, Tables 9-1 and 10-12). The drug acts mostly on cardiac Pi-adrenoceptors, much less so on peripheral p2- and a-receptors, and not at all on renal and mesenteric dopamine receptors (the compound is a dopamine derivative, having no P-OH; see structure). Its chronotropic effect is only 25% that of IPR. Dobutamine is thus a beginning, having been useful for short-term therapy to improve cardiac output in severe, chronic cardiac failure. It should be pointed out that DA itself, within a narrow dosage range, has also been useful, especially in cases of cardiac failure accompanied by
Table 10-12. Dobutamine and Experimental Analogs as Inotropes"
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