Of digitoxins

Because digitoxin is a nonpolar, lipophilic glycoside, absorption from the GI tract is complete. About 90% of the dmg in plasma is tightly bound to protein. It is metabolized in the Hver to many metaboHtes, including digoxin which is the only pharmacologically active metaboHte. The dmg is excreted via the bile into feces. The elimination half-life of digitoxin is seven to nine days (87). 

It is known that the presence of the 143-hydroxyl group and a sugar at the 3 position are absolute requirements for activity. A modified drug actodigin (100) demonstrates that reversal of the lactone 17 is consistent with activity. Reduction of digitoxigenin 91, the aglycone of digitoxin... 

Intestinal absorption of digoxin is less complete compared to digitoxin. In order to improve absorption, acetylated- and methylated-digoxin derivates were developed. Digitoxin is metabolised in hepatic microsomal enzymes and can be cleared independently from renal function. The therapeutical serum level of digoxin is 0.5-2.0 ng/ml and 10-35 ng/ml of digitoxin. Steady state plateau of therapeutic plasma concentrations is reached after 4-5 half-life-times using standard daily doses [5]. 

Application of this tandem conjugate addition-aldol cyclization methodology may lead to the concise synthesis of digitoxin (Scheme 67) and related cardiac steroids. 

L17. Lukas, D. S., and De Martino, A. G., Binding of digitoxin and some related cardenolides to human plasma proteins. J. Clin. Invest. 48, 1041-1053 (1969). 

Digitoxin Digitoxin, 3b,14b-dihydroxy-5b-card-20(22)enolide-3-tridigitoxide (17.1.1), is a glycoside isolated from leaves of various types of foxgloves. About 6 g of digitoxin are isolated from 10 kg of leaves [1-9]. 

Digitalis glycosides [NE] Decreased gastrointestinal absorption of digitoxin (possibly also digoxin). 

Rifampin [NE] Increased metabolism of digitoxin and elimination digoxin. 

Today foxglove is still the source of digitoxin, a widely used drug that increases the force of the heart s contraction. To produce it chemists separate and purify one compound from the plant s roughly thirty cardiac glycosides, each of which has different activity. Manufacturers of herbal supplements do not note such distinctions they merely try to justify their products by pointing out that many of our prescription pharmaceuticals derive from plant sources. 

In normal individuals, the effects of toxic doses of digitoxin are extreme slowing of the heart (bradycardia) and atrial fibrillation. In cardiac patients, however, the effects could be fatal with ventricular fibrillation, but certainly arrythmias and extra beats will occur. 

Figure 7.53 The mechanism of action of digitoxin in cardiac muscle cells.

Thus, in patients taking digitoxin, who then start therapy with phenobarbital, (CYP3A4 inducer), the blood level of digitoxin decreases by about half. The dose would then need to be raised to compensate, but if the phenobarbital was stopped, the induction would decline and toxicity would ensue if there was no readjustment of the dose. 

Coadministration of CYP3A4 inhibitors could cause a dangerous increase in the level of digitoxin also. Thus, quinidine increases the blood level and decreases clearance of digitoxin. 

Chemistry of the glycoside linkage. Exceptionally fast and efficient formation of glycosides by remote activation, Carbohydr. Res. 80 07 (1980). (e) K. Wiesner, T. Y. R. Tsai, and H. Jiu, On cardioactive steroids. XVI. Stereoselective P-glycosylation of digitoxose the synthesis of digitoxin, Helv. Chim. Acta 60 300 (1985). (f) R. B. Woodward (and 48 collaborators), Asymmetric total synthesis of erythromycin. 3. Total synthesis of erythromycin, J. Am Chem. Soc. 103 3215 (1981). (g) P. G. M. Wuts and S. S. Bigelow, Total synthesis of oleandrose and the avermecin disaccharide, benzyl ot-L-oleandrosyl-ot-L-4-acetOxyoleandroside, J. Org. Chem. 43 3489 (1983). 

Johansson S, Lindholm P, Gullbo J, Larsson R, Bohlin L, Claeson P. Cytotoxicity of digitoxin and related cardiac... 

The elderly are also prone to toxicity from numerous drugs, including cardiac glycosides. A dose of digitoxin, which may be totally therapeutic and innocuous at the age of 60, may produce severe toxicity and even death at the age of 70. The abilities of the liver to metabolize drugs and of the kidney to excrete drug metabolites decline with aging. 

B. Desta and K. M. McErlane, High-performance liquid chromatographic analysis of digitoxin formulations, J. Pharm. Sci., 77 1018(1982). 

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