View metadata, citation and similar papers at core.ac.uk brought to you by CORE JACCVol. 5, No.5 provided by Elsevier - Publisher43A Connector May 1985:43A-50A Pharmacokinetics, Bioavailability and Serum Levels of Cardiac Glycosides THOMAS W. SMITH, MD, FACC Boston. Massachusetts Digoxin, the cardiac glycoside most frequently used in bioavailability of digoxin is appreciably less than that of clinical practice in the United States, can be givenorally digitoxin, averaging about two-thirds to three-fourths of or intravenously and has an excretory half-life of 36 to the equivalent dose given intravenously in the case of 48 hours in patients with serum creatinine and blood currently available tablet formulations. Recent studies urea nitrogen values in the normal range. Sincethe drug have shown that gut ftora of about 10% of patients re­ is excreted predominantly by the kidney, the half-life is duce digoxin to a less bioactive dihydro derivative. This prolonged progressivelywithdiminishingrenal function, process is sensitiveto antibiotic administration, creating reaching about 5 days on average in patients who are the potential for important interactions among drugs. essentially anephric. Serum protein binding of digoxin Serum or plasma concentrations of digitalis glycosides is only about 20%, and differs markedly in this regard can be measured by radioimmunoassay methods that are from that of digitoxin, which is 97% bound by serum nowwidelyavailable, but knowledgeofserum levelsdoes albumin at usual therapeutic levels. Digitoxin is nearly not substitute for a sound working knowledge of the completely absorbed from the normal gastrointestinal clinical pharmacology of the preparation used and care­ tract and has a half-lifeaveraging 5 to 6 days in patients ful patient follow-up. receiving usual doses irrespective of renal function. The (J Am Coil Cordial 1985;S:43A-SOA) Pharmacokinetics Digoxin Preparations ofcardiac glycosides used clinically are de­ Routes of administration. Digoxin is the form of dig­ rived from the leaves and seeds of plants from the genera italis most frequently used in the United States, both in Digitalis and Strophanthus. Other flora contain cardiac gly­ hospital and office practice. This is probably due in large cosides that may be of importance with regard to toxicity, part to its flexible routes of administration, its intermediate but are not used clinically. These include Convallaria ma­ duration of action and the availability of convenient methods jalis (lily of the valley) and Thevetia neriifolia (yellow for assaying serum digoxin concentrations. Although dig­ oleander) . oxin may be administered orally , intravenously or intra­ All of the cardiac glycosides consist of combinations of muscularly , the intramuscular route is not recommended an aglycone, or genin , with one to four attached sugar res­ because it is painful and produces localized muscle damage idues. The characteristic pharmacologic properties reside in reflected in increased serum creatine kinase levels . The clas­ the genin, while factors influencing pharmacokinetic prop­ sic studies of the pharmacokinetics of digoxin carried out erties , including water solubility, are influenced by the na­ by Doherty et al. (2) established the patterns observed after ture of the sugars (glycosides) attached to the genin. use of these three routes of administration in volunteers with Figure I outlines the derivation of the cardiac glycosides normal renal function (Fig. 2). As expected, the serum currently in clinical use in the United States. Leaves from concentration rises most rapidly after intravenous admin­ the Digitalis lanata plant contain precursor glycosides that istration , followed by oral and, still later, by intramuscular yield digitoxin and digoxin after minor chemical derivation administration . (1) . The seeds of Strophanthus gratus contain ouabain . Excretion. Excretion of digoxin occurs at a rate inde­ pendent of the route of administration. Digoxin is excreted From the Cardiovascular Division, Brigham and Women 's Hospital in an exponential manner, with an average half-life of 36 and the Departments of Medicine, Brigham and Women 's Hospital and hours in healthy individual s with normal renal function (3). Harvard Medical School, Boston, Massachusetts. Approximately 37% of total body stores of digoxin are ex­ Address for reprints: Thomas W. Smith , MD, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts creted daily under these circumstances. Older patients usu­ 02115. ally have a reduced glomerular filtration rate even if the ©1985 by the American College of Cardiology 0735-1097/85/$3.30 44A SMITH JACC Vol. 5, No.5 CARDIAC GLYCOSIDES May 198H3A-50A ~Duocerrldi9iI0"id A 0_ purpurlo DIGITALIS ( leal) Lanatoside A - --ACltrldIQitolin -IOIGITO Xl!il Figure 1, Derivation of clinically relevant digitalis .( 46%) preparations. D. lonola .• Lanatoside 8 ( 17%) • Lanoloside C ~ACI'rld iQo'in --IDIGOXIN I (37%1 / <( Cedilonid I CUilonid 0 ( Dulonoside ) •I DiQilonid • composite 01 lonotosidee A, 8, C ) blood urea nitrogen and creatinine levels remain in the nor­ daily losses of digoxin through renal and other pathways mal range, and a half-life of 48 hours represents a more match the daily intake of the drug. reasonable estimate. Renal excretion of digoxin tends to be Absorptioh. A useful clinical principle is that when daily independent of the rate of urinary flow in patients with maintenance therapy is begun in patients not previously reasonably normal renal function (4,5). There is, however, receivingdigoxin, steady state plateau concentrations exist some dependence of renal tubular reabsorption of digoxin after four to five half-livesor about 7 days in patients with on the urinary flow rate, and hence digoxin reabsorption normal renal function (9). In the presence of renal impair­ ruay increase at very low rates of urinary flow and con­ mentresulting in prolongation of the half-lifeof elimination, versely may be decreased by acute vasodilator therapy in the time required to reach steady state on a daily mainte­ patients with congestive heart failure (6,7). Digoxinexcre­ nance regimen is correspondingly prolonged. When rapid tion by way of the kidney is predominantly in an unchanged onset of digoxin effect is needed, a loading dose is admin­ to.rn, but a subset of about 10% of patients excrete appre­ istered. followed by daily maintenance therapy. In obese ciablequantitiesof relativelyinactivemetabolites (8). Equi­ subjects, digoxin pharmacokinetics change little after the librium or steady state conditions occur at the point when loss of large amounts of adipose tissue, indicating that lean body mass should be used when dosages are calculated (10,11). Figure 2. Comparison of pharmacokinetics of digoxin given by the intravenous (IV), oral and intramuscular (1M) routes. As ex­ Nomograms for calculationof the total oral loadingdose pected, serum concentration rises most rapidly by the intravenous anddaily maintenance doseof digoxinbasedon bodyweight form of administration. T'I2 = half-life of elimination. (Repro­ and renal function are available (12). Such nomograms are duced from Doherty et al. [2] withpermission of the authors and helpful for the initial estimation of digoxin dosage, but do Progress in Cardiovascular Diseases.) not change the need for careful follow-up by the clinician. 1 AT Ea CR[ToG \0 "". Gastrointestinal absorption ofdigitalis glycosides is pas­ ' 00 0 ~( R "T, _ , tOOl sive . The rate and completeness of absorption are greatest ,n ... ,s IV 92 - with the least polar molecules and decrease with increasing cardiac glycoside polarity (13). Patients with normal gas­ '8"' " -,". • 63"- trointestinal function shouldabsorbdigoxinadministered by l 00 J .a Pu ," o A. 62' the oral routeat about85%of the administered dose in elixir ~ • ., form and 60 to 75% in tablet formulations that meet current <.." Food and Drug Administration and United States Pharma­ '" ~ copeia guidelines (14) (see subsequent comments on ... ' 0 bioavailability). -.... _-- - - -::-: '"' -..... -- ... Protein binding of digoxin averages 20 to 25% under usualcircumstances (15,16). Only the free fraction is phar­ macologically active. In the caseof digoxin, proteinbinding is a minor factor in determining the pharmacokinetics be­ 0 ' cause glomerularfiltration of the drug should be about 80% o ,'2 of the serum concentration. JACC Vol. 5. No.5 SMITH 45A May 1985:43A-50A CARDIACGLYCOSIDES Time course of digoxin distribution in the body. The binds avidly to serum proteins. This results in very limited time course is well characterized by a two compartment renal excretion, and the half-life of elimination of digitoxin model (2). Distribution from the central (vascular) com­ accordingly varies littie from the average of 4 to 6 days, partment to peripheral sites occurs with a half-time of about irrespective of renal status (15). Because of the longer half­ 30 minutes. Although the concentration of digoxin in skel­ life, initiation of daily maintenance doses of digitoxin will etal muscle is relatively low compared with that in the kid­ not produce steady state levels until about 3 to 4 weeks. ney or heart, the total digoxin content of skeletal muscle The bioavailability of digitoxin when administered orally represents the largest single pool in the body because of the approaches 100% (25). large mass of this component of body composition. As stated, digitoxin binds avidly to human serum albumin Available studies (17)