Pharmacokinetics Of Digoxin Research Articles

The Clinical Pharmacokinetics of Levofloxacin

Levofloxacin is a fluoroquinolone antibiotic and is the optical S-(-) isomer of the racemic drug substance ofloxacin. It has a broad spectrum of in vitro activity against Gram-positive and Gram-negative bacteria, as well as certain other pathogens such as Mycoplasma, Chlamydia, Legionella and Mycobacteria spp. Levofloxacin is significantly more active against bacterial pathogens than R-(+)-ofloxacin. Levofloxacin hemihydrate, the commercially formulated product, is 97.6% levofloxacin by weight. Levofloxacin pharmacokinetics are described by a linear 2-compartment open model with first-order elimination. Plasma concentrations in healthy volunteers reach a mean peak drug plasma concentration (Cmax) of approximately 2.8 and 5.2 mg/L within 1 to 2 hours after oral administration of levofloxacin 250 and 500mg tablets, respectively. The bioavailability of oral levofloxacin approaches 100% and is little affected by the administration with food. Oral absorption is very rapid and complete, with little difference in the serum concentration-time profiles following 500mg oral or intravenous (infused over 60 minutes) doses. Single oral doses of levofloxacin 50 to 1000mg produce a mean Cmax and area under the concentration-time curve (AUC) ranging from approximately 0.6 to 9.4 mg/L and 4.7 to 108 mg.h/L, respectively, both increasing linearly in a dose-proportional fashion. The pharmacokinetics of levofloxacin are similar during multiple-dose regimens to those following single doses. Levofloxacin is widely distributed throughout the body, with a mean volume of distribution of 1.1 L/kg, and penetrates well into most body tissues and fluids. Drug concentrations in tissues and fluids are generally greater than those observed in plasma, but penetration into the cerebrospinal fluid is relatively poor (concentrations approximately 16% of simultaneous plasma values). Levofloxacin is approximately 24 to 38% bound to serum plasma proteins (primarily albumin); serum protein binding is independent of serum drug concentrations. The plasma elimination half-life (t1/2 beta) ranges from 6 to 8 hours in individuals with normal renal function. Approximately 80% of levofloxacin is eliminated as unchanged drug in the urine through glomerular filtration and tubular secretion; minimal metabolism occurs with the formation of no metabolites possessing relevant pharmacological activity. Renal clearance and total body clearance are highly correlated with creatinine clearance (CLCR), and dosage adjustments are required in patients with significant renal dysfunction. Levofloxacin pharmacokinetics are not appreciably affected by age, gender or race when differences in renal function, and body mass and composition are taken into account. Important drug interactions exist with aluminium- and magnesium-containing antacids and ferrous sulfate, as with other fluoroquinolones, resulting in significantly decreased levofloxacin absorption when administered concurrently. These agents should be administered at least 2 hours before or after levofloxacin administration. Cimetidine and probenecid decrease levofloxacin renal clearance and increase t1/2 beta; the magnitudes of these interactions are not clinically significant. Levofloxacin appears to have only minor potential for significantly altering the pharmacokinetics of theophylline, warfarin, zidovudine, ranitidine, digoxin or cyclosporin; however, patients receiving these drugs concurrently should be monitored closely for signs of enhanced pharmacological effect or toxicity. Levofloxacin pharmacokinetics are not significantly altered by sucralfate when administration of these drugs is separated by at least 2 hours.

Population Pharmacokinetics of Digoxin in Korean Clearance After The Multiple Intravenous Administrations

Population Pharmacokinetics of Digoxin in Korean Clearance After The Multiple Intravenous Administrations

Advances in the management of digoxin toxicity in the older patient.

Digoxin intoxication is a common problem in the elderly. In its mildest forms it may go undiagnosed, but in severe cases it is often fatal. Altered digoxin pharmacokinetics, attributable to the physiological changes associated with aging, underlying illness, and drug-drug interactions all contribute to the occurrence of digoxin toxicity. Advanced age, male gender, initial hyperkalaemia, underlying heart disease, and advanced atrioventricular block at the time of admission are poor prognostic factors. Supportive care alone is often insufficient. Digoxin-specific Fab therapy may result in dramatic recovery from digoxin intoxication, but it must be administered early and in a an adequate dosage if reductions in mortality are to be achieved.

Substantial excretion of digoxin via the intestinal mucosa and prevention of long-term digoxin accumulation in the brain by the mdr 1a P-glycoprotein.

1. We have used mice with a disrupted mdr 1a P-glycoprotein gene (mdr 1a (-/-) mice) to study the role of P-glycoprotein in the pharmacokinetics of digoxin, a model P-glycoprotein substrate. 2. [3H]-digoxin at a dose of 0.2 mg kg-1 was administered as a single i.v. or oral bolus injection. We focussed on intestinal mucosa and brain endothelial cells, two major pharmacological barriers, as the mdr 1a P-glycoprotein is the only P-glycoprotein normally present in these tissues. 3. Predominant faecal excretion of [3H]-digoxin in wild-type mice shifted towards predominantly urinary excretion in mdr 1a (-/-) mice. 4. After interruption of the biliary excretion into the intestine, we found a substantial excretion of [3H]-digoxin via the gut mucosa in wild-type mice (16% of administered dose over 90 min). This was only 2% in mdr 1a (-/-) mice. Biliary excretion of [3H]-digoxin was not dramatically decreased (24% in wild-type mice versus 16% in mdr 1a (-/-) mice). 5. After a single bolus injection, brain levels of [3H]-digoxin in wild-type mice remained very low, whereas in mdr 1a (-/-) mice these levels continuously increased over a period of 3 days, resulting in a approximately 200 fold higher concentration than in wild-type mice. 6. These data demonstrate the in vivo contribution of intestinal P-glycoprotein to direct elimination of [3H]-digoxin from the systemic circulation and to the pattern of [3H]-digoxin disposition, and they underline the importance of P-glycoprotein for the blood-brain barrier.

Digitalis in the treatment of heart failure in the elderly. The GIFA study results.

Digitalis glycosides have played an important role in the treatment of patients with heart failure (HF) for more than two centuries. Despite the introduction of new therapeutic strategies in the treatment of HF, and controversies regarding the role of digitalis in HF in sinus rhythm and its effect on mortality, digoxin is one of the most commonly prescribed drugs in the community and in hospital settings, particularly in the elderly. The Italian Group of Pharmacosurveillance in the Elderly (GIFA) monitored 20,047 hospitalized patients in 1988, 1991 and 1993, and found that digoxin was the most frequently prescribed drug in the management of HF. Inappropriate prescriptions of digitalis, defined with standardized criteria, were uncommon, and the mean daily dosage was low. Compared to earlier studies the incidence rate of adverse drug reactions (ADRs) to digoxin, was also low. The reduction in ADRs incidence was probably due to a better understanding of digoxin pharmacokinetics and to a lower daily dosage in the elderly. Nevertheless, digoxin toxicity was significantly more frequent in patients aged >or= 80 years than in those aged < 65 and and 65-79 years. In a multidrug approach to the treatment of chronic HF, digoxin exerts clinical benefits also in patients with sinus rhythm, it is not costly, it is easy to administer, and toxic effects are not common.

The Effects of Epoprostenol on Drug Disposition I: A Pilot Study of the Pharmacokinetics of Digoxin with and without Epoprostenol in Patients with Congestive Heart Failure

The influence of epoprostenol on the pharmacokinetics of drugs administered concurrently to patients with congestive heart failure (CHF) receiving epoprostenol was evaluated as a secondary objective of a Phase II pilot study. A total of 278 blood samples were collected from 30 patients with end-stage CHF receiving conventional therapy alone or conventional therapy plus epoprostenol. Estimates of oral clearance (Cl), volume of distribution, and absorption rate constant of digoxin were generated from plasma digoxin concentrations using nonlinear mixed effects modeling, and the effect of epoprostenol on Cl of digoxin was evaluated by univariate analysis. Additional factors that were evaluated by univariate analysis included age, obesity, time since study entry, cardiac output, concomitant use of angiotensin-converting enzyme (ACE) inhibitor, concomitant dobutamine, and estimated creatinine clearance. Backward elimination was used to arrive at a final model that included concomitant epoprostenol as a covariate. The final model revealed an approximate 15% decrease in Cl of digoxin in response to short-term administration of epoprostenol that was no longer apparent by the end of the 12-week treatment phase. Simulations revealed that this effect, although statistically significant, would not be clinically significant in most patients; however, the potential exists for short-term elevation of digoxin concentrations in response to concurrent administration of epoprostenol.

Ｄｉｇｏｘｉｎの体内動態に及ぼすＤｉｈｙｄｒｏｐｙｒｉｄｉｎｅ系Ｃａきっ抗剤の影響

Ｄｉｇｏｘｉｎの体内動態に及ぼすＤｉｈｙｄｒｏｐｙｒｉｄｉｎｅ系Ｃａきっ抗剤の影響

Effect of multiple doses of losartan on the pharmacokinetics of single doses of digoxin in healthy volunteers.

1. Losartan (DuP 753, MK-954) is a novel, potent and highly selective AT1 angiotensin II receptor antagonist. The effect of multiple oral doses of losartan on digoxin pharmacokinetics was evaluated in healthy male subjects. 2. In a double-blind and randomized fashion, subjects received 50 mg losartan or placebo once daily for 15 days in each period. At least 7 days elapsed between the two treatment periods. On days 4 and 11 of each period, subjects also received a single 0.5 mg dose of digoxin intravenously and orally respectively. 3. Eleven of 13 subjects completed the study. Side effects were mild and transient (12 out of 13 subjects reported at least one adverse experience). During the study, no laboratory abnormalities were noted. 4. Multiple oral doses of losartan (50 mg daily) did not affect the pharmacokinetic parameters of 0.5 mg of digoxin i.v. AUC(0.48h) of immunoreactive digoxin during losartan 28.8 +/- 2.9 vs 28.5 +/- 3.9 ng ml-1 h during placebo; not significant, and 96 h urinary excretion [% dose] during losartan 54.0 +/- 7.2 vs 51.9 +/- 6.5% during placebo; not significant). Geometric mean ratios (90% confidence interval) for AUC and urinary excretion were respectively, 1.03 (0.98, 1.08) and 1.09 (0.98, 1.21). 5. Multiple oral doses of losartan did not affect the pharmacokinetic parameters of oral digoxin AUC(0.48 h) during losartan 23.6 +/- 3.7 ng ml-1 h vs 22.4 +/- 2.6 ng ml-1 h during placebo; not significant, Cmax 3.5 +/- 0.7 ng ml-1 with vs 3.1 +/- 0.5 ng ml-1 without losartan; not significant and tmax 0.6 +/- 0.2 h with vs 0.9 +/- 0.7 h without losartan; not significant, and 96 h urinary excretion [% dose] during losartan 51.2 +/- 6.3 vs 46.3 +/- 2.4% during placebo; not significant). Geometric mean ratios (90% confidence interval) for AUC and urinary excretion were respectively, 1.06 (0.98, 1.14) and 1.12 (0.97, 1.28). 6. We conclude that multiple oral doses of losartan (50 mg daily) do not alter the pharmacokinetics of immunoreactive digoxin, following either intravenous or oral digoxin. Furthermore, the co-administration of digoxin with losartan is well tolerated by healthy male volunteers.

The effect of meloxicam on the pharmacokinetics of beta‐acetyl‐digoxin.

The influence of multiple-dose administration of meloxicam on the pharmacokinetics of oral beta-acetyl-digoxin was studied in 12 healthy male volunteers in a randomized double-blind two-way crossover study. The primary endpoint, Cminss, was within the accepted range for bioequivalence, as were Cmaxss and AUCss. The 90% confidence interval and the point estimator of 98.7 for Cminss were within the equivalence range of 0.8-1.25. MRT and tmax were also unchanged, while the elimination rate constant was decreased slightly by 12%, which is of no therapeutic relevance. It is concluded that co-treatment with meloxicam has no effect on the pharmacokinetics of oral digoxin.

Human pharmacokinetics of tiludronate

Tiludronate is a bisphosphonate evaluated extensively as an osteoregulator in the treatment of metabolic bone disorders. It is highly polar and has a low and variable oral absorption similar to its related compounds. An absolute bioavailability of approximately 6% has been reported with large inter- and intra-subject variability. The extent of absorption is increased at doses above 400 mg and may be reduced by a factor of 5 when tiludronate is administered with, or within 2 h after, food or dairy products. Approximately 90% of tiludronate is bound to serum albumin, and the binding is linear in the concentration range 1-10 mg/L. Preliminary in vitro studies using human hepatocytes failed to show any evidence of biotransformation of tiludronate. The elimination half-life in patients with normal renal function is approximately 40-60 h, but is significantly increased in subjects with severe renal impairment. The renal clearance (0.7 L/h) is independent of dose and suggests that glomerular filtration is the mechanism responsible for elimination. Approximately 50% of the absorbed dose is bound to bone and the rate of release of the drug from this site is limited by bone turnover. In vitro experiments indicate that tiludronate is not an enzyme inducer or inhibitor. Drug interaction studies with the nonsteroidal agents acetylsalicylic acid, indomethacin, and diclofenac indicate that only with indomethacin was there any change in the pharmacokinetic parameters, and that these changes were minimal and unlikely to be of clinical significance. Tiludronate does not influence the pharmacokinetics of digoxin at steady state. Tiludronate appears to exhibit similar pharmacokinetic behavior to other bisphosphonates with the exception that its absolute bioavailability is significantly higher than that previously reported for clodronate and pamidronate. The impact of its pharmacokinetic properties on clinical outcome has yet to be determined.

Absence of the mdr1a P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A.

We have previously shown that absence of the mouse mdr1a (also called mdr3) P-glycoprotein in mdr1a (-/-) "knockout" mice has a profound effect on the tissue distribution and elimination of vinblastine and ivermectin, and hence on the toxicity of these compounds. We show here that the mouse mdr1a and the human MDR1 P-glycoprotein actively transport ivermectin, dexamethasone, digoxin, and cyclosporin A and, to a lesser extent, morphine across a polarized kidney epithelial cell layer in vitro. Injection of these radio-labeled drugs in mdr1a (-/-) and wild-type mice resulted in markedly (20- to 50-fold) higher levels of radioactivity in mdr1a (-/-) brain for digoxin and cyclosporin A, with more moderate effects for dexamethasone (2- to 3-fold) and morphine (1.7-fold). Digoxin and cyclosporin A were also more slowly eliminated from mdr1a (-/-) mice. Our findings show that P-glycoprotein can be a major determinant for the pharmacology of several medically important drugs other than anti-cancer agents, especially in the blood-brain barrier. These results may explain a range of pharmacological interactions observed between various drugs in patients.

The Influence of Reduced Dietary Fat Absorption Induced by Orlistat on the Pharmacokinetics of Digoxin in Healthy Volunteers

To assess the influence of an orlistat-induced reduction in dietary fat absorption on the pharmacokinetics of digoxin, an open-label, placebo-controlled, randomized, two-way crossover study was performed in 12 healthy volunteers. Each subject received single 0.4-mg doses of digoxin (soft gelatin capsules) administered orally on the fourth day of orlistat (120 mg three times daily for 6 days) and placebo (three times daily for 6 days) treatment, separated by at least an 11-day washout period. Serial blood samples were collected before and at appropriate intervals after each digoxin dose to determine plasma concentrations of unchanged digoxin. The 90% confidence intervals for the ratio of geometric least-squares means (for Cmax, AUC0-48, AUC0-t, and AUC) and for the difference of arithmetic least-squares means (for tmax and lambda z) indicate that the pharmacokinetics of digoxin was not altered by treatment with orlistat. This results suggests that a approximately 30% reduction in dietary fat absorption will not change the efficacy of digoxin in cardiac patients.

Pharmacokinetic changes in patients with oedema.

The pharmacokinetics of furosemide (frusemide) in patients with oedema have been relatively well studied, but in many studies it is unclear whether the disease or the oedema per se has the major effect. The rate of absorption of oral furosemide in patients with oedema was decreased, but total bioavailability was almost unchanged. The peak serum concentration (Cmax) and time taken to achieve Cmax were either decreased or unchanged. Binding of furosemide to plasma proteins is lower in patients with congestive heart failure (CHF), decompensated liver cirrhosis (DLC) and nephrotic syndrome, probably as a result of hypoalbuminaemia. The elimination half-life (t1/2) can be unchanged (CHF, DLC) or prolonged (chronic renal failure: CRF). Plasma and renal clearance are reduced in patients with CRF and nephrotic syndrome, but are almost unchanged in CHF and DLC. Disease-induced disorders are mainly responsible for the alterations of furosemide pharmacokinetics in oedematous conditions, while the influence of oedema per se is probably not clinically relevant. The pharmacokinetics of digoxin have been studied in a small number of studies only. In patients with CHF, considerable interindividual differences have been found. Because digoxin has a narrow therapeutic window, this drug should be administered cautiously to oedematous patients. Theophylline has higher bioavailability in patients with oedema, with a significantly higher Cmax in patients with hepatic cirrhosis and CHF than in healthy volunteers (29 and 22%, respectively). Furthermore, clearance decreases and t1/2 increases in these patients. Angiotensin converting enzyme (ACE) inhibitors are often administered as prodrugs, and their pharmacokinetic profile could be influenced by the diseases that accompany oedematous states. However, the effect of oedema is difficult to discriminate from that of the disease. Individual ACE inhibitors are affected differently, but importantly the dosage of perindopril should be reduced in patients with CHF, while for most other ACE inhibitors the changes in pharmacokinetic parameters are clinically irrelevant. In conclusion, studies on pharmacokinetic changes in oedema are limited. Besides affecting absorption (after oral administration) and conversion of the prodrug to the active form, probably as a result of the associated disease, oedema has not been proven to cause any clinically relevant changes in pharmacokinetic parameters for individual drugs. However, further studies of this aspect of pharmacokinetics are needed.

Pharmacokinetics of cardiovascular drugs in children. Inotropes and vasopressors.

Infants and children with congenital or acquired heart disease and children with systemic disease often require pharmacological support of their failing circulation. Catecholamines may serve as inotropic (enhance myocardial contractility) or vasopressor (elevate systemic vascular resistance) agents. Noncatecholamine inotropic agents, such as the cardiac glycosides or the bipyridines, may be used in place of, or in addition to, catecholamines. Developmental changes in neonates, infants and children will affect the response to inotropic or pressor therapy. Maturation of the gastrointestinal tract, liver and kidneys alters absorption, metabolism and elimination of drugs, although there are few clear examples of this among the vasoactive drugs considered in this review. Changes in body composition affect the volume of distribution (Vd) and clearance (CL) of drugs. Developmentally based pharmacodynamic differences also affect the responses to both therapeutic and toxic effects of inotropes. These pharmacodynamic differences are based in part upon developmental changes in myocardial structure, cardiac innervation and adrenergic receptor function. For example, the immature myocardium has fewer contractile elements and therefore a decreased ability to increase contractility; it also responds poorly to standard techniques of manipulating preload. Available data suggest that dopamine and dobutamine pharmacokinetics are similar to those in adults. Wide interindividual variability has been noted. A consistent relationship between CL and age has not been demonstrated, although one investigator demonstrated an almost 2-fold increase in the CL of dopamine in children under the age of 2 years. The CL of dopamine appears to be reduced in children with renal and hepatic failure. Fewer data are available regarding the pharmacokinetics of epinephrine (adrenaline), norepinephrine (noradrenaline) and isoprenaline (isoproterenol). Digoxin pharmacokinetics have been extensively evaluated in infants and children. The Vd for digoxin is increased in infants and children. Children beyond the neonatal period display increased CL of digoxin, approaching adult values during puberty. Although it was previously thought that children both needed and tolerated higher serum concentrations of digoxin than adults, more recent studies indicate that adequate clinical response can be achieved with serum concentrations similar to those aimed for in adults, with decreased toxicity. Evaluation of studies of digoxin pharmacokinetics is complicated by the presence of an endogenous substance with digoxin-like activity on radioimmunoassay. Limited studies of amrinone pharmacokinetics in infants and children indicate a dramatically larger Vd, and a decreased elimination half-life in older infants and children, compared with values observed in adults.

Pharmacokinetic effects of fluvastatin in patients chronically receiving digoxin

A double-blind, randomized, crossover study assessed the effects of a single 40-mg dose of fluvastatin on the steady-state pharmacokinetics of digoxin in chronically treated patients. After demonstrating consistent digoxin serum concentrations as part of the inclusion criteria, 18 patients received a single dose of either fluvastatin or placebo, with a 1-week washout period between crossover to the other treatment. For each patient, 14 serum samples were drawn and urine collected over 24 hours; all samples were assayed for digoxin using a fluorescence polarization immunoassay. The following pharmacokinetic parameters were determined using noncompartmental techniques: area under the curve for 24 hours (AUC 24); time to maximum concentration after digoxin (t max); maximum concentration after digoxin dosing (C max); concentration at 24 hours after fluvastatin or placebo (C min); total amount excreted in the urine over 24 hours (U 24); and urinary clearance (Cl ren). The pharmacokinetic data were analyzed for sequence, patient nested with sequence, and period and treatment differences using ANOVA, Schuirmann's two one-sided testing approach, confidence intervals, and power analysis. The AUC 24, C max, and t max for digoxin were considered bioequivalent with the two treatments. The differences in C max, U 24, and Cl ren were statistically significant but were not considered to be clinically relevant due to the low magnitude of the difference (<20%). There were no clinically significant adverse reactions attributable to either digoxin or fluvastatin.

Pharmacokinetics of digoxin administered to horses with congestive heart failure

Summary Nine horses with (naturally acquired) congestive heart failure were treated with 2.2 μg of digoxin/kg of body weight by the Iv route, followed by 11 μg/kg administered orally every 12 hours thereafter. Furosemide was administered IV concurrently with IV administered digoxin every 12 hours. Serum concentration of digoxin was measured after the first (Iv) and seventh (orally administered) dose. After Iv administration, digoxin disposition was described by a 2-compartment model, with a rapid distribution phase (t1/2α = 0.17 hour), followed by a slower elimination phase (β = 0.096 ± 0.055 h−1, t1/2β = 7.2 hours, where β is the exponential term from the elimination phase of the concentration vs time curve). Bioavailability after oral administration was 21.2 ± 10.8%. After the seventh orally administered dose, serum concentration of digoxin peaked 1 to 2 hours later, and was 1.9 ± 0.7 ng/ml (mean ± sd). In 4 horses, a second increase in serum digoxin concentration was observed 4 to 8 hours after the initial peak, which possibly was evidence of enterohepatic recycling of the drug. Response to treatment included reduction in heart rate, peripheral edema, and pulmonary edema, but these could not be attributed to the digoxin alone because the horses were treated concurrently with furosemide.

Clinical pharmacokinetics of alprazolam. Therapeutic implications.

Alprazolam is a triazolobenzodiazepine that is extensively prescribed in the Western world for the treatment of anxiety and panic disorders. Its benzodiazepine receptor binding characteristics are qualitatively similar to those of other benzodiazepines. The drug is metabolised primarily by hepatic microsomal oxidation, yielding alpha-hydroxy- and 4-hydroxy-alprazolam as principal initial metabolites. Both have lower intrinsic benzodiazepine receptor affinity than alprazolam and appear in human plasma at less than 10% of the concentrations of the parent drug. Plasma concentrations of the 4-hydroxy metabolite exceed those of the alpha-hydroxy derivative, but urinary recovery of alpha-hydroxy-alprazolam greatly exceeds that of 4-hydroxy-alprazolam. This may be explained by chemical instability of 4-hydroxy-alprazolam in vitro. After single 1 mg oral doses in humans, typical pharmacokinetic variables for alprazolam are: a peak plasma concentration 12 to 22 micrograms/L occurring 0.7 to 1.8h postdose, a volume of distribution of 0.8 to 1.3 L/kg, elimination half-life of 9 to 16h and clearance of 0.7 to 1.5 ml/min/kg. Absolute bioavailability of oral alprazolam averages 80 to 100%. Pharmacokinetics are dose-independent and are unchanged during multiple-dose treatment. On average, mean steady-state plasma alprazolam concentrations change by 10 to 12 micrograms/L for each daily dosage change of 1 mg/day. Most studies show that alprazolam pharmacokinetics are not significantly influenced by gender. Clearance of alprazolam is reduced in many elderly individuals, even those who are apparently healthy. Clearance is significantly reduced in patients with cirrhosis. Renal disease causes reduced plasma protein binding of alprazolam (increased free fraction) and some data suggest reduced free clearance of alprazolam in such patients. Pharmacokinetics of alprazolam are not significantly altered in abstinent alcoholics or patients with panic disorder, and are not influenced by the phase of the menstrual cycle in women. Coadministration of cimetidine, fluoxetine, fluvoxamine or propoxyphene significantly impairs alprazolam clearance. However, alprazolam clearance is not altered by coadministration of propranolol, metronidazole, disulfiram, oral contraceptives or ethanol. Imipramine clearance may be impaired if alprazolam is coadministered. Alprazolam does not alter the pharmacokinetics of digoxin. Although a therapeutic concentration range is not clearly established, some studies indicate that optimal reduction of anxiety associated with panic disorder occurs at steady-state plasma alprazolam concentrations of 20 to 40 micrograms/L. Concentrations higher than this may be needed for suppression of the actual panic attacks. Side effects associated with alprazolam (drowsiness, sedation, etc.) are consistent with its primary benzodiazepine agonist action and increase in frequency with higher steady-state plasma concentrations.(ABSTRACT TRUNCATED AT 400 WORDS)

Digoxin pharmacokinetics and perindopril in heart failure patients.

The influence of chronic perindopril treatment on digoxin pharmacokinetics was investigated in 10 patients with mild chronic heart failure under stable diuretic and digitalis treatment and normal renal function. Digoxin was administered at a dose of 0.125 mg/day (n = 2) or 0.250 mg/day (n = 8). The 24-hour steady-state digoxin profile was assessed before and after concomitant administration of perindopril for 1 month at doses of 2 mg once a day for the first 8 days and 4 mg once a day for the remaining 21 days. Chronic treatment with perindopril produced no significant effect on mean (+/- standard deviation) digoxin serum area under the curve for 24 hours (17.9 +/- 7.4 versus 16.3 +/- 4.4 ng/mL.h), peak digoxin concentration (1.3 +/- 0.54 versus 1.2 +/- 0.36 ng/mL), time to peak concentration (3 versus 4 hours), and apparent oral clearance of digoxin (237.7 +/- 109.6 versus 237.4 +/- 79.5 mL/min). Clinical and biologic tolerance of perindopril was good throughout the study. Chronic administration of perindopril did not alter steady-state digoxin kinetics in patients with mild chronic heart failure and normal renal function, indicating that no adaptation of the digoxin dose is required during co-prescription with perindopril in such patients.

The effect of digoxin on the serum potassium concentration.

In recent studies on the influence of muscular and symphatoadrenergic activity on digoxin pharmacokinetics, the serum potassium concentration was found to increase during 2 h of supine rest in digitalized healthy subjects and out-patients. The present study was made in order to find out whether this change in serum potassium concentration is dependent on inhibition of the Na-K-ATPase activity by digitalis treatment. Ten healthy subjects were investigated on two separate occasions: before and after digitalization with digoxin 0.37-0.50 mg daily for 10 days. Serum potassium and digoxin concentrations were analysed before and after 2 h of rest in the sitting position. Without digoxin treatment, no change in serum potassium concentration was seen. During digoxin treatment, the serum potassium concentration increased by 0.19 +/- 0.23 mmol(l)-1 (p < 0.05) during the period of rest. Thus, a digitalis-induced depression of Na-K-ATPase activity seems to be a prerequisite for the described change in serum potassium concentration.

Clinical use of serum digoxin concentrations

The development of the radioimmunoassay for digoxin by Smith and coworkers in 1969 was a landmark in digitalis therapy. Since then, the complex pharmacokinetics of digoxin have been defined. As a result, the incidence of digitalis toxicity has markedly decreased. To use the digoxin assay properly, however, the relation of this pharmacokinetic parameter to digoxin pharmacodynamics must be known and the limitations of the assay itself understood. Systolic time intervals (STI) are uniquely useful to quantitate the inotropic effect of digitalis preparations. This technique can demonstrate the onset and magnitude of the inotropic effect for both oral and intravenous digitalis administration. By defining the mathematical relation between STI and simultaneous serum digoxin concentrations following intravenous administration of 1 mg digoxin, computer simulations can be made of the effect of dosing changes on blood and tissue concentrations. The serum digoxin assay has technical problems relating to quality control, interference by metabolites, and cross-reactions with endogenous digitalis-like substances. Further, a standard time for measurement following dosing has not been established. Physical activity can significantly alter the serum digoxin concentrations by increasing skeletal muscle binding. Numerous drugs can interfere with digoxin absorption or elimination. Using the serum digoxin assay is the only way to assess these interactions. Computer surveillance (ideally with physician or pharmacist interaction) has been used to monitor digitalis but has not yet gained widespread acceptance. This is clearly a method in need of further testing.