Digitoxin Concentrations Research Articles

Correlation between pharmacokinetics and intropic and electrophysiologic responses to digitoxin in the intact dog.

We attempted to correlate inotropic and eletrophysilogic digitoxin effects with serum digitoxin concentrations during 8 hr after a single dose. Eight pentobarbital-anesthetized Labrador dogs were given 2.0 mg digitoxin intravenously. Left heart catheterization and His bundle registration were performed. acing and programed electrical stimulation were used to determine heart rate-independant changes in dP/dt, intra-atrial, atrioventricular (AV), His-Purkinje, and intraventricular conduction velocity. The effective (A-ERP) and functional (A-FRP) refractory periods of the atrium and the functional nodal refractory period (AV-FRP) were measured. Serum digitoxin concentrations were determined by radioimmunoassay. Median serum digitoxin half-time was 5.7 hr. The dP/dt increased after digitoxin, with maximum values after 2 hr. Digitoxin concentration correlated with the inotropic response after 4 hr. Heart rate fell significantly within 2 min and remained below control values for the 8 hr observation period concimitant with an increase in AV-nodal conduction time and AV-ERP increased significantly in the late elimination phase, while A-FRP increased slightly initially and remained high. No consistent correlation was found between the electrophysilogic variables and serum concentrations. We conclude that the two main effects of digitoxin, the inotropic and electrophysiologic, are dissociated in the elimination phase after a single dose.

Studies on digitalis. 23. Blood‐brain barrier of digitoxin in humans

AbstractData on the cerebrospinal fluid concentrations of digitoxin in man have been lacking. Aim of the present study was to investigate serum and cerebrospinal fluid concentrations of digitoxin. Eleven patients with normal cerebrospinal fluid composition, normal serum albumin values, normal renal and hepatic function and normal hematologic tests were given a single dose of 0.6 mg digitoxin. Serum and cerebrospinal fluid were collected 16 h after the dose, and assayed by radio‐immunoassay, serum digitoxin protein binding was measured with equilibrium dialysis.Mean serum digitoxin concentration was 12.4 ng/ml (SD 2.6) and mean CSF concentration 0.84 ng/ml (SD 0.22) giving a CSF/serum ratio of 0.07 (SD 0.03). Serum digitoxin protein binding was 97.4% (SD 0.4) and the calculated CSF/free serum digitoxin ratio was thus 2.94 (SD 1.43).Free serum digitoxin concentrations are more relevant for pharmacologic effect than total serum digitoxin concentrations and also for passage into the central nervous system. Using free drug concentrations the ratio between digitoxin in serum and CSF is lower than reported values for digoxin indicating a higher penetrance of digitoxin into the central nervous system. This corresponds well with the higher lipid solubility of digitoxin. Post mortem studies have shown that concentrations are higher in cerebral tissue than in CSF for digoxin. Determination of CSF concentrations thus probably underestimates the penetrance of digitalis glycosides into the central nervous system, but may serve as a useful indicator of variance among digitalis glycosides.

Effect of hemoperfusion on the pharmacokinetics of digitoxin in dogs.

Abstract To determine the pharmacokinetics of digitoxin, five dogs were given 0.15 mg/kg digitoxin intravenously. Serum digitoxin concentrations were measured by 125 l RIA. Pharmacokinetic analysis was performed with a three-compartment model. The mean Vd was 0.81 ± 0.27 (S.D.) L/kg, mean t12 was 6.60 ± 1.97 hr, and mean Clt was 27 ± 11 ml/min. Another five dogs received the same amount of digitoxin and were hemoperfused at a flow of 108 ml/min for 4 hr with a 300 gm Amberlite XAD-4 column. Vd, t12, and Clt values before perfusion were 0.66 ± 0.27 L/kg, 7.09 ± 3.52 hr, and 34 ± 20 ml/min, not significantly different from the values of the first five dogs. In two dogs, digitoxin concentrations became undetectable within 15 min of starting perfusion, and 58.5 μg of digitoxin were recovered from the columns. In the remaining three dogs, the plasma clearance of digitoxin by the columns was 25 ±7 ml/min, and 233 ± 55 μg of digitoxin were recovered. Mean hemoperfusion clearance calculated from the total amount recovered was 19.7 ± 3.9 ml/ min. After perfusion there was an increase in the serum digitoxin concentration. Once the new pseudo-steady state was reached, the serum digitoxin concentration was from 5 to 44 ng/ml less than if hemoperfusion had not been done. The increase in serum digitoxin concentration after hemoperfusion occurred because the central compartment, depleted of digitoxin during hemoperfusion, was refilled from peripheral compartments. In conclusion, 4 hr of resin hemoperfusion nearly doubled the rate of removal of digitoxin from dogs, and a multicompartmental pharmacokinetic model explains the postperfusion increase in serum digitoxin concentrations.

Effect of cardiopulmonary bypass with heparin administration on digitoxin pharmacokinetics, serum electrolytes, free fatty acids, and renal function.

In 14 patients investigated before, during, and after extracorporeal circulation, serum digitoxin concentration fell significantly during bypass but returned to preoperative values within 24 hr. Both changes occurred in parallel with changes in hematocrit. Serum magnesium concentration fell markedly just before and during bypass and returned to preoperative values on the third and fourth postoperative days. Urine digitoxin concentration fell on the day of operation and remained low in the postoperative period, with a concomitant reduction in the renal excretion of digitoxin. Creatinine and digitoxin clearances decreased on the day of operation and returned slowly to control values during the postoperative period. In 5 other patients, serum digitoxin protein binding decreased significantly during bypass due to heparinization and was normalized by administration of protamine sulfate. Free fatty acids increased significantly immediately before bypass and returned to normal toward its end. The marked changes in digitoxin serum levels during cardiopulmonary bypass can be explained by hemodilution. Acute deterioration of renal function does not lead to accumulation of digitoxin. Heparin administration causes major changes in free fatty acids and serum digitoxin protein binding without important changes in the free digitoxin concentration. Digitoxin can thus be safely administered to patients undergoing cardiac surgery with extracorporeal circulation.

Some Observations on Serum Concentrations of Digitoxin and Digoxin

Serum concentrations of digitoxin and digoxin were measured in 145 cases with various heart diseases receiving maintenance doses of digitalis. Digitalis toxicity was seen in only 2 cases (1.4%). Day-to-day variation of serum concentration while taking the same daily dose was small in digitoxin therapy (13.8%), but a considerable variation was seen in digoxin therapy (24.4%). Serum concentrations of both digitoxin and digoxin were measured in the patients receiving digitoxin, and there was a positive correlation between the two (r = 0.66, p less than 0.001). This fact suggested that the effect of digitoxin was the sum of the effects of digitoxin and its metabolite, digoxin. In the patients taking digoxin, digitoxin was not detected in the serum. Serum digitoxin level had a significantly positive correlation to serum albumin level, presumably because digitoxin was retained in serum in the bound form to albumin. Minimal effective level, 10 ng/ml, was however obtained with higher daily dose of digitoxin in patients with lower serum albumin.

Reversal of advanced digitoxin toxicity and modification of pharmacokinetics by specific antibodies and Fab fragments.

The effects of Fab fragments of high-affinity specific antibodies have been studied in a canine experimental model of lethal digitoxin toxicity. Selected antiserum from sheep immunized and boosted with a digoxin-serum albumin conjugate contained antibodies that cross-reacted with digitoxin with an average intrinsic association constant of 1.4 x 10(10) M(-1) as determined by equilibrium dialysis. Rapid second-order association kinetics (k(f) = 3.7 x 10(6) M(-1) per s) and slow dissociation kinetics (k(r) = 1.9 x 10(-4) per s) were documented for the antibody-digitoxin complex. Eight dogs given 0.5 mg/kg digitoxin intravenously developed ventricular tachycardia after 23+/-4 (SEM) min. Control nonspecific Fab fragments were then given. All animals died an average of 101+/-36 min after digitoxin administration. Another eight dogs given the same digitoxin dose similarly developed ventricular tachycardia after 28+/-3 min. This group then received a molar equivalent dose of specific Fab fragments intravenously over 3 min, followed by a 30-min infusion of one-third of the initial dose. All dogs survived. Conducted sinus beats reappeared 18+/-4 min after initial Fab infusion, and stable normal sinus rhythm was present at 54+/-16 min. Plasma total digitoxin concentrations increased threefold during the hour after initial Fab infusion, while plasma free digitoxin concentration decreased to less than 0.1 ng/ml. Effects on digitoxin pharmacokinetics of these Fab fragments and the antibody population from which they were derived were further investigated in a primate species. Unlike common laboratory animals previously studied, the rhesus monkey was found to have a prolonged elimination half-life, estimated at 135 and 118 h by radioimmunoassay and [(3)H]digitoxin measurements, respectively, similar to man and thus providing a clinically relevant experimental model. Intravenous administration of 2 mol of specific Fab fragments per mole of digitoxin 6 h after 0.2 mg of digitoxin produced a rapid 4.3-fold increase in plasma total digitoxin concentration followed by a rapid fall (t((1/2)) 4 h) accompanied by a 14-fold enhancement of urinary digitoxin excretion over control values during the 6-h period after Fab was given. Analytical studies were consistent with increased excretion of native digitoxin rather than metabolites, and the glycoside was found in equilibrium dialysis studies to be excreted in the urine in Fab-bound form. Administration of 2 mol of specific antibody binding sites per mole of digitoxin as intact IgG caused a greater and more prolonged increase in plasma total digitoxin concentration, peaking 13-fold above control levels. In contrast to the effects of Fab, however, specific IgG reduced the rate of urinary digitoxin excretion substantially below control values. We conclude that Fab fragments of antibodies with high affinity for digitoxin are capable of rapid reversal of advanced, otherwise lethal digitoxin toxicity, and are capable of reducing the plasma half-life and accelerating urinary excretion of digitoxin.

Studies on digitalis. X. Digitoxin metabolites in human myocardium and relationship between myocardial and serum concentrations of digitoxin in patients on maintenance treatment.

The levels of digitoxin and cardioactive metabolites were measured in 42 atrial biopsies with a 86Rb method modified for analysis of myocardial samples. The mean value was 91.0 ng/gm wet weight (SD 54.4). Myocardial and serum concentrations were compared in 23 patients; there was no significant correlation. The ratio of total drug concentration in myocardium and serum ranged from 1 to 38 with a mean value of 5.4. Calculated from the free drug concentrations, the mean myocardial serum ratio was 200, which reflects the high affinity of digitoxin and cardioactive metabolites to the myocardium. The metabolic pattern of cardioactive and inactive metabolites (conjugates with glucuronic and sulfuric acid) was studied in autopsy samples from left ventricular myocardium from 7 patients. Significant differences between the myocardial and serum patterns of cardioactive and inactive metabolites were demonstrated. The myocardium contained less unchanged digitoxin (25.7%) and more hydrolyzed (55.4%) and conjugated (54.1%) metabolites than serum (57.6%, 31.0%, and 33.1%, respectively). Hydroxylated metabolites in myocardium (15.8%) were not significantly changed compared to serum (10.0%).

Studies on Digitalis

In a prospective study on digitalis intoxication, low serum magnesium was found in 90 patients, while 388 patients had values above 1.5 mEq/l. Hypomagnesemia was more frequent in women than in men, in those with low body weight and in those with advanced heart failure. More patients with hypomagnesemia than those without had nausea, anorexia, fatigue, flickering of vision and atrial tachycardia with block. Patients with hypomagnesemia also had lower serum potassium than normomagnesemic patients. There was, however, no significant difference in the prevalence of digitalis intoxication or in serum digitoxin concentration. Nor was there any correlation between serum digitoxin and serum magnesium levels.

Pharmacokinetics of digitoxin in chronic renal failure (author's transl)

Digitoxin concentration, measured by radio-immunoassay, was significantly lower in 51 patients in chronic renal failure (23.2 +/- 7.8 mug/l) than in 29 patients in heart failure (26.5 +/- 7.3 mug/l), although both groups were on the same maintenance dose of 0.1 mg daily. Despite a normal serum albumin concentration, digitoxin protein binding was less in uraemic patients than in those with normal renal function. Renal failure did not affect intestinal digitoxin absorption. In patients in chronic renal failure elimination half-time was significantly shorter (5.7 +/- 0.9 days) than in healthy controls (7.6 +/- 1.6 days). There was no significant difference in the excretion of water-soluble ("cardioinactive") digitoxin metabolites in urine between patients in chronic renal and those in heart failure. In patients with normal renal function, of dichloromethane-soluble (cardioactive) metabolites only digitoxin could be demonstrated by thin-layer chromatography. The results indicate that patients in chronic renal failure can safely be given the same dose as those with normal renal function, without danger of over- or underdosage.

Accumulation of radioactive cardiac glycosides by various brain regions in relation to the dysrhythmogenic effect.

Ouabain was administered at a loading dose of 3 mug/kg followed by an infusion at a rate of 1 mug/kg-1 min-1 in order to produce severe dysrhythmia in dogs within 60 minutes. Similarly, digitoxin at a loading dose of 9 mug/kg followed by an infusion at a rate of 3 mug kg-1 min-1 was administered to compare its effect with that of ouabain. 2 During the 60 min experimental period, the plasma concentrations gradually rose with the continuous infusion of these drugs. However, in comparison to the 60 min plasma value of 119+/-20 pmol/ml for ouabain and 177+/-68 pmol/ml for digitoxin, the cerebrospinal fluid (CSF) concentrations for these drugs at this time were less than 5 pmol/ml. 3 Upon termination of the experiment at 60 min it was found that kidney, liver, heart, adrenal, and the non-neural tissue in the brain such as pituitary and choroid plexus concentrated ouabain and digitoxin to give high tissue to plasma ratios. However, various neural areas of the brain (cerebellum, mesencephalon, hypothalamus, pons, and medulla) showed no preferential localization or uptake of these two glycosides. 4 Concentration of ouabain and digitoxin by the choroid plexus does not seem to affect the ionic composition of the CSF. 5 It was concluded that sampling the large areas of neural tissue above could provide no evidence for local accumulation of digitalis glycosides that might account for a central nervous system origin of digitalis-induced cardiac arrhythmias.

Binding of Digitoxin and Digoxin to Normal Human β‐Lipoproteins

Abstract The binding of digitoxin and digoxin to purified β‐lipoprotein, obtained from pooled normal human serum, was studied under equilibrium conditions. Even with as high concentrations of unbound digitoxin or digoxin as 4 μmol/1 the preparations of β‐lipoproteins, containing cholesterol 1.98–3.95 mmol/1, did not show any signs of saturation. The binding affinity of digitoxin was about ten times as high as that of digoxin. Gel filtration chromatography, performed on native serum after addition of 3H‐digitoxin or 3H‐digoxin, showed a minor fraction of the cardiac glycosides to be associated with the protein fraction of highest molecular weight. This phenomenon disappeared after precipitation of the β‐lipoproteins. In clinical relations the contribution of protein bound digitoxin caused by the lipoprotein interaction is immaterial, in relation to that caused by the albumin interaction.

Correlation between myocardial and plasma concentration of digitoxin and its metabolites with special reference to digitoxin radio-immunoassay.

According to our prevous study, the metabolites of digitoxin show nearly dentical affinity with digitoxin antibody. The present study reveals relatively constant ratio of heart to plasma in total 3H-counts, and the concentration of metabolites are ver similar between the two throughout the time investigated which indicates digitoxin concentration of plasma as determined by radioimmunoassay reflects well that of myocardium, although it may contain metabolites.

Serum digitoxin levels in the aged

radioimmunoassay により digitoxin 維持量投与中の患者118人 (男81人, 女37人) の血清 digitoxin 濃度を測定 (のべ262回) し, その臨床的意義につき検討した. さらに従来老齢者にジギタリス中毒が多いといわれているのでこの点に注目して血清濃度の面より検討を加えた. その結果,1) 中毒群の血清濃度は平均35.5ng/ml, 非中毒群のそれは平均18.4ng/mlであり両群間で明らかな有意差 を示した (P<0.0001).2) 中毒群と非中毒群の臨床所見, 検査所見を検討し, 両群間で心胸廓比, GOT, GPTに有意差が認められた.3) 血清濃度は維持量の増加に比例して dose-dependent に増加し, 回帰直線を求めると, y(濃度)=194x(投与量)+4.87であった. 血清濃度35.0ng/ml以上は全例中毒症状を示し, 24.5ng/ml未満では中毒例は認められず, 24.5～35.0ng/mlのレベルで中毒と非中毒例が overlap していた.4) 老齢者群 (60歳以上) と若年者群 (59歳以下) の2群に分けて同一維持量で比較すると老齢者群の血清濃度は統計学上有意に高く (P<0.001) 回帰直線を計算するとそれぞれ, y=231x+3.91, y=148x+5.39であった. なお中毒症状を示した症例は若年者群53人中3人 (5.6%), 老齢者群62人中21人 (34.0%) と圧倒的に老齢者に多かった.5) 両群間の検査所見を比較すると血清総蛋白は老齢者で有意に低く, また24時間内因性クレアチニン・クリアランスが低下すると中毒例が増加する傾向が認められた.老齢者で血清 digitoxin 濃度が高くなる理由の一つの因子として加齢に伴う腎機能低下が示唆された. その他薬物代謝系活性の低下など種々の因子を列挙して考察を加えた.老齢者では維持量0.1mg投与では過剰となる場合も少くなく, 投与量の慎重な配慮と注意深い経過観察が必要である. また臨床的所見, 心電図記録は当然のことであるが, さらに血清濃度を経過中頻回に測定することは臨床上ジギタリス中毒の早期発見に極めて有用である.

Concentration of digoxin, methyldigoxin, digitoxin and ouabain in the myocardium of the dog following coronary occulsion.

26 mongrel dogs were given a single dose of 0.03mg/kg tritium-labelled digoxin, beta-methyldigoxin, digitoxin or ouabain 2 hrs or 95 hrs following experimental coronary occlusion. Examination of the epicardial ECG was performed by moving from intact to ischemic or necrotic zones. 60 min after glycoside administration the animals were sacrificed and tissue samples from the marked heart muscles areas and from the skeletal muscle were analysed for glycoside content. The early glycoside uptake in acute ischemic or necrotic myocardium was diminished independently of the physicochemical properties of the glycoside. Significantly higher glycoside concentrations (ng/g wet weight) were measured in the injured myocardium 3 hrs after coronary occlusion than 96 hrs afterward (p less than 0.005). The values in acute ischemic myocardium varied considerably. This nonhomogeneity of glycoside uptake in the acute ischemic heart muscle may partly explain the increased sensitivity to glycosides in myocardial infarction. The decline of glycoside concentration correlates with the alterations in the epicardial ECG. The cardiac effects of cardenolides 60 min after intravenous administration was caused by the unchanged glycoside. In contrast to the myocardium, glycoside accumulation could not be found in the skeletal muscle. The concentrations of digoxin, beta-methyldigoxin and digitoxin in the skeletal muscle were significantly higher than the concentration of ouabain, which was rapidly eliminated via the urine.

A study of serum and myocardial digitoxin concentrations in man during cardiac arrest.

In 22 digitalized (of a total of 39) patients studied at random by radioimmunoassay during cardiac arrest, the mean serum digoxin concentration was 2.6 (+/- 1.86, range 0.6-8.2) ng/ml, significantly higher (P less than 0.001) than the "eudigitalized" concentration (1.3 +/- 0.52, range 0.5-2.3 ng/ml) determined under carefully standardized conditions in a non-toxic population. Half of the arrest patients had serum digoxin levels in the toxic range (2.4 ng/ml or above), mainly due to significant renal failure (mean serum creatinine concentration 2.9 +/- 2.66 v. 1 +/- 0.26 mg/dl for non-toxic subjects, P less than 0.001), partly due to a higher mean daily digoxin dose (0.40 v 0.31 mg/day, P less than 0.05) and frequently associated with potent diuretic therapy (73 v 54%). A smaller fraction of digitalized patients survived, both short- (27%) and long-term (14%), than did non-digitalized subjects (35% and 26%, respectively). The mean myocardial digoxin concentration was 150 (+/- 63.3, range 52-252) ng/g with an average myocardial/serum ratio of 62.5 (range 38-91). There were significant positive correlations between the serum digoxin and left-ventricular myocardial digoxin concentration (r=0.8107, P less than 0.01) or serum creatinine concentration (r=0.4637, P less than 0.001).

Serum digitoxin concentrations in infants and children.

Serum digitoxin levels were measured in 18 infants (under two years) and in 23 children (aged 2-13 years) receiving maintenance therapy. Digitalization was carried out because of heart failure in 17 infants and 13 children and for control of dysrhythmia in one infant and 10 children. Mean maintenance dosage for infants was 0.0042 plus or minus 0.0008 (sd) mg/kg/day and for children was 0.0031 plus or minus 0.0012 mg/kg/day. The mean serum digitoxin level was not significantly different in infants (30 plus or minus 10 ng/ml, range 14-58) from that found for children (34 plus or minus 11 ng/ml, range 19-61). Both values were significantly different (P smaller than 0.001) from those determined in this laboratory for adults (mean 24 plus or minus 7 ng/ml, range 5-39). In four infants with electrocardiographic or other evidence of toxicity, the mean serum level was 71 plus or minus 2 ng/ml (range 68-72), and in four children with electrocardiographic or other evidence of toxicity, the mean serum level for digitoxin was 72 plus or minus 14 ng/ml (range 53-84). The data suggest that infants and children tolerate a higher serum digitoxin concentration without any evidence of toxicity and may require more digitoxin (mg/kg) for therapeutic effect than do adults. Serum digitoxin levels may serve as an important guide in determining the adequacy of digitalization and in the recognition and management of digitalis toxicity.

Binding of Digitoxin to Human Serum Proteins: Influence of pH on the Binding of Digitoxin to Human Albumin

Abstract: The binding of digitoxin to albumin was studied under various conditions with regard to electrolytes and pH. Considerable variations of Na, K, Ca and Mg within the range of clinical relevance did not influence the binding of digitoxin to albumin. Under the influence of excessive concentrations of digitoxin this binding followed the simple law of mass action with an average number of binding sites of about 0.5 independent of pH. The intrinsic association constants were about twice the apparent association constants, calculated in another way and with the assumption of one binding site per molecule of albumin. The binding of digitoxin to albumin was shown to depend on the pH of the medium with a maximum association constant at pH = 4.8 (intrinsic association constant, K = 5 x 105 l/mol). The binding of digitoxin to human serum proteins was shown to be equal to that of the binding to albumin. Under conditions relevant for clinical interpretations the binding of digitoxin to other proteins was insignificant.

Radioimmunoassay of Digoxin—Interference by Digitoxin

Abstract Digitoxin interference with radioimmunoassay of digoxin may present a problem in determining digoxin concentrations in the serum of patients treated with digitoxin less than four weeks before digoxin was administered. Digoxin and digitoxin values were determined in the sera of 54 patients who were receiving only digitoxin. Additionally, digoxin was added to aliquots of sera from a patient receiving digitoxin, and digoxin concentrations were determined by radioimmunoassay. Digitoxin interfered with radioimmunoassay of digoxin in that 9% of the digitoxin present was counted as digoxin. The resulting spuriously high value for measured digoxin in patients receiving digoxin, but treated with digitoxin previously, can be corrected by applying the following equation (units: µg/liter): Digoxin (corrected) = digoxin (measured) — [0.09 x digitoxin (measured)]. This correction, which may differ somewhat with batch of antiserum, is applicable for digitoxin concentrations up to about 50 ng/ml. Digoxin does not interfere with the digitoxin assay.

Studies on digitalis. II. The influence of impaired renal function on the renal excretion of digitoxin and its cardioactive metabolites.

Simultaneous serum and urine measurements of digitoxin and its cardioactive metabolites were performed in patients with impaired renal function, after a single dose and during maintenance therapy. A modified 86Rb method was used. Comparison of serum levels after intravenous and peroral dosage of digitoxin in 5 patients with severe uremia showed that absorption was complete. After an intravenous dose, the serum‐tissue eqUilibration T/2 in renal failure had a mean value of 150 minutes, while it was 71 minutes in the control subjects. Mean T/2 of serum elimination was 3.9 days and 8.1 days in 5 control subjects (p &lt; 0.01). The urine digitoxin concentration T/2 with a mean value of 8.0 days did not differ significantly from the control subjects (7.2 days). The urine levels were, however, lower in uremics with lower cumulative excretion during an 8 day period. Eleven patients with slightly impaired renal function (creatinine clearance 50 to 80 ml per minute) on maintenance dosage did not differ Significantly from a control group of 22 patients. Twelve patients with uremia (mean serum creatinine 12.2 mg per 100 ml) had serum levels in the same range as the control subjects, but significantly lower urine levels, renal excretion, and digitoxin clearance. They excreted 13.6% of the daily dose compared to the 32.9% of the controls. The results indicate that compensatory mechanisms are operative in uremia as increased excretion through other pathways or as changes in hepatic metabolism of digitoxin.

Contribution of quantitative assay technics to the understanding of the clinical pharmacology of digitalis.

Despite recent advances in understanding of the pharmacokinetics and electrophysiologic effects of cardiac glycosides, digitalis toxicity remains distressingly common in clinical practice. Another substantial group of patients is markedly underdigitalized, failing to gain the full therapeutic benefits of optimal use of these drugs. Since cardiac digitalis toxicity is a dose-related phenomenon, and serum or plasma digoxin and digitoxin concentrations rise with increasing doses, at least a statistical correlation between circulating levels and clinical state might be expected. Increasing availability of serum or plasma digitalis concentration measurements thus offers the clinician a potential means of improving the patient's chances of benefiting from treatment with cardiac glycosides. Assay methods in current use include a double-isotope dilution derivative method (digitoxin), red cell 86 Rb-uptake inhibition (digitoxin and digoxin), Na + -K + ATPase inhibition (digitoxin), ATPase enzymatic displacement (digitoxin and digoxin), gas chromatography (digoxin), and radioimmunoassay (digitoxin, digoxin, and ouabain). The rapidly expanding literature reporting clinical experience with these technics reflects general agreement that mean serum or plasma digoxini and digitoxin levels are significantly higher in patients with clinical evidence of toxicity compared with nontoxic patients. Nevertheless, multiple factors influence individual responses, and blood level data must be interpreted in the overall clinical context. Hypokalemia, hypercalcemia, hypomagnesemia, acid-base disturbances, hypoxemia, and hypothyroidism all tend to decrease tolerance to any given digitalis dose or blood level. Autonomic nervous system tone and other drugs concurrently received must also be considered. Advanced heart disease in general, and coronary artery disease in particular, appear to predispose patients to apparent digitalis toxicity at relatively lower serum or plasma levels. Cardiac glycoside assay technics have also proven useful in various studies of the clinical pharmacology of digoxin, digitoxin, and ouabain. Handling of digoxin by patients on cardiopulmonary bypass has been assessed, and gastrointestinal absorption has been evaluated in normal subjects; poor and erratic absorption of the drug has been documented in patients with malabsorption syndromes. Potentially important drug-drug interactions of agents such as phenobarbital and phenylbutazone with digitoxin have been studied, as well as the effects of steroid-binding resins on digoxin and digitoxin metabolism. Studies of ouabain pharmacokineties by radioimmunoassay have demonstrated a plasma half-life of 21 hours, indicating that, as in the case of digoxin and digitoxin, half-life of serum or plasma concentration after establishment of blood-tissue equilibrium bears a close relationship to duration of clinical effect.