General Anesthetic Management of a Patient With Hypertrophic Cardiomyopathy for Oral Surgery: Did Digitalis Contribute to Bradycardia?

Stabilization of circulatory dynamics is a critical issue in the anesthetic management of patients with hypertrophic cardiomyopathy (HCM). In this report, we managed general anesthesia for a 74-year-old male patient with nonobstructive HCM who developed circulatory instability intraoperatively. Severe bradycardia measuring 35 beats/min and hypotension measuring 78 mm Hg systolic were observed during surgery. Using stroke volume variation and stroke volume from the FloTrac as indices, successful circulatory management was performed with dopamine. The hypotension and bradycardia were thought to be the result of methyldigoxin and possibly associated with our perioperative management. Cardiology consult should have been obtained. We demonstrated that the FloTrac can be beneficial in diagnosing and managing cardiovascular instability and administration of dopamine in the anesthetic management of nonobstructive HCM patients.

Impact of ABCB1 (MDR1) gene polymorphism and P-glycoprotein inhibitors on digoxin serum concentration in congestive heart failure patients.

Digoxin, a drug of narrow therapeutic index, is a substrate for common transmembrane transporter, P-glycoprotein, encoded by ABCB1 ( MDR1 ) gene. It has been suggested that ABCB1 polymorphism, as well as co-administration of P-glycoprotein inhibitors, may influence digoxin bioavailability. The aim of the present study was to evaluate the effects of ABCB1 gene polymorphism and P-gp inhibitor co-administration on steady-state digoxin serum concentration in congestive heart failure patients. Digoxin concentrations as well as 3435C > T and 2677G > A,T ABCB1 single nucleotide polymorphisms, were determined in 77 patients administered digoxin (0.25 mg daily) and methyldigoxin (0.50 mg daily), some of them co-medicated with known P-glycoprotein (Pgp) inhibitors. Significant differences were noted in digoxin serum concentrations (C(min,ss)) between patients co-administered and not co-administered P-gp inhibitors: 0.868 +/- 0.348 and 0.524 +/- 0.281 for digoxin (p < 0.002), as well as 1.280 +/- 0.524 and 0.908 +/- 0.358 for methyldigoxin (p < 0.02), respectively. No influence of ABCB1 2677G > A,T and C3435C > T polymorphisms on digoxin concentration was noted. Although some of the previous studies have shown that digoxin pharmacokinetics might be affected by ABCB1 genetic polymorphism, those modest changes are probably clinically irrelevant, and digoxin dose adjustment should include P-gp inhibitor co-administration rather than ABCB1 genotyping.

Influence of food on the absorption of beta-methyldigoxin.

Nine healthy subjects received 0.2 mg of beta-methyldigoxin (beta-MD) orally in the fasting state, 30 minutes after and before a standard breakfast. The time-to-peak serum glycoside concentration was delayed and the peak concentration was lower in the postprandial state compared with the other regimens (P less than .01). The absorption rate constant was significantly reduced when beta-MD was given after a meal (1.55 +/- 1.75 hr-1) than before a meal (5.54 +/- 2.16 hr-1) and in the fasting state (5.22 +/- 3.06 hr-1)(P less than .01). Although the area under the serum glycoside concentration-time curve and the cumulative urinary excretion (CUE) of beta-MD, digoxin, and total drug (beta-MD plus digoxin) was not significantly different between three regimens, the CUE infinity tended to be smaller in the postprandial state compared with before a meal. The results indicate that the timing of drug administration in relation to a meal is an important factor leading to the fluctuations of serum glycoside concentration after oral beta-MD, which might be of some clinical importance.

New and simple method for estimating metildigoxin dosing regimens by multiple trough screen analysis.

The pharmacokinetics of digitalis glycosides were studied using routine therapeutic drug monitoring data to evaluate the role of patient characteristics for estimating metildigoxin dosing regimens. The 232 serum glycoside concentration data at steady-state after repetitive oral administration in 144 hospitalized patients was analyzed using NONMEM, a computer program designed for population pharmacokinetic analysis that allows pooling of data. Pharmacokinetic analysis of digitalis glycosides was described using a simple steady-state pharmacokinetic model. The effect of a variety of developmental and demographic factors on glycoside clearance was investigated. NONMEM estimates indicated that this digitalis glycoside clearance was influenced by the demographic variables of age, total body weight, serum creatinine, gender, daily dose and the coadministration of spironolactone. An elderly patient was expected to have a lower rate of clearance than a young patient of equal body weight and serum creatinine. The interindividual variability in glycoside clearance was modelled with proportional error with an estimated coefficient of variation of 19.7% and the residual variability was 21.8% The dosing method based on glycoside clearance value obtained by NONMEM analysis allowed the prediction of the minimum steady-state glycoside concentration as a function of metildigoxin maintenance dose with acceptable error for therapeutic drug monitoring.

Asterixis associated with carbamazepine.

Some antiepileptic drugs, when administered at toxic plasma levels or more rarely at levels within the therapeutic range, induce asterixis. We report the case of a patient with painful syndrome of central origin being treated with carbamazepine, in which asterixis appeared with toxic serum levels. A pharmacologic interference was also observed between carbamazepine and beta-methyldigoxin, which in our patient was being used to treat disease. The blood digoxin levels were inversely proportional to those of carbamazepine. The therapeutic effectiveness of digoxin being sharply reduced when carbamazepine reached toxic levels.

[Maintenance therapy with beta-methyldigoxin in the elderly. A study of 40 patients]. / Terapia di mantenimento con beta metildigossina nell'anziano. Studio su 40 pazienti.

The efficacy of beta methyldigoxin was examined in a group of 40 elderly patients who had been hospitalised due to congested heart decompensation. A good clinical response was obtained in 95.5% of cases with the presence of slight toxic phenomena in 2 cases only (4.5%). The paper underlines the excellent pharmacokinetic pattern of the substance used in the steady state. Steady state digitalemic values were within the acceptable range in 83.76% of cases, whereas underdosage and overdosage phenomena were observed in 6.87% and 9.37% of patients respectively.

[Successful intrauterine digoxin therapy for fetal complete atrioventricular block with endocardial cushion defect: a case report].

We report herein a case of fetal complete atrioventricular block accompanied with endocardial cushion defect, successfully diagnosed and treated, in utero, with transplacental digitalization. A 23-year-old Japanese woman, at 20 weeks of gestation, was referred to the Maternity and Perinatal Care Unit of Kyushu University Hospital because of fetal continuous bradycardia. B-mode scanning and dual M-mode echocardiography revealed that the fetus had complete atrioventricular block with endocardial cushion defect with a ventricular rate of 60 beats per minute. At 23 weeks of gestation, it was found that the fractional shortenings (FSs) in both ventricles and the ventricular rate had decreased, with an increase in pericardial effusion. Thus, we diagnosed the fetus as having cardiac failure. Transplacental digoxin treatment was started and continued for 10 weeks, after which fetal pericardial effusion, as well as FSs ameliorated. The pregnancy was interrupted by cesarean section at 33 weeks of gestation due to a decrease in FSs with an accumulation of fetal ascites. A 1780g female infant was delivered and a pacemaker was implanted surgically, immediately after birth. She is alive and well at the time of writing.

[Possibility of using saliva for therapeutic monitoring of digoxin]. / Mozliwosc zastosowania sliny do terapii monitorowanej digoksyny.

Digoxin in salvia and blood serum of 24 patients obtained Bemecor was determined by the method of FPIA (IMx-ABBOT). Mixed saliva was collected by three different types of Salivette (Sarstedt) given in order: normal Salivette with cotton wool swab, Slivette with polyester wool and Salivette with citric acid as a stimulator. It was found, that the correletio between the digoxin concentrations in saliva and serum and saliva/serum rations depended on the type of Salivette. The highest correlation was obtained with the Salivette with polyester wool (r = 0.892), but low concentrations of this drug in serum were good reflected in all samples of saliva, independent on kind of Salivette.

Unintentional lethal overdose with metildigoxin in a 36-week-old infant--post mortem tissue distribution of metildigoxin and its metabolites by liquid chromatography tandem mass spectrometry.

A massive lethal overdose with beta-metildigoxin in a 36-week-old infant is presented. Determination of beta-metildigoxin and its metabolites digoxin, digoxigenin and digoxigenin-monodigitoxosid is achieved by a liquid chromatographic mass spectrometric (LC-MS/MS) method. Measured concentrations for beta-metildigoxin and digoxin in peripheral blood were 40.2 ng/ml and 25.6 ng/ml, respectively. Tissue distribution showed highest concentrations in kidney tissue and gastric content. The metabolite digoxigenin-monodigitoxosid could be detected in heart blood, duodenal content, gastric content and fat tissue while the metabolite digoxigenin could only be detected in gastric content since the drug was given by a stomach tube.

[Digitalization without saturation dose using methyldigoxin. Experiences with 29 patients]. / Digitalisierung ohne Sättigungsdosis mit Methyldigoxin. Erfahrungen an 29 Patienten.

The indications and performance of oral digitalization without saturation dose are evaluated on the basis of clinical parameters and plasma digitalis levels. A group of patients with evident cardiac insufficiency received a daily maintenance dosage of digitalis (2 tablets of 0.1 mg methyldigoxin) from the outset. After 7, 15 and 30 days the plasma concentration of methyldigoxin was measured. Objective and subjective signs of cardiac insufficiency were noted. In 28 of 29 patients the therapeutic plasma level (0.8-2.0 ng/ml) was achieved with a mean plasma digitalis concentration of 1.47 +/- 0.4 ng/ml. A clinical improvement was observed in 18 patients. On the 15th and 30th day of treatment the mean plasma level of methyldigoxin showed no significant difference: X15 = 1.51 +/- 0.57 ng/ml and X30 = 1.40 +/- 0.46 ng/ml. The measured plasma values were not influenced by the patient's weight or age. In 6 patients with renal insufficiency a clear correlation between the plasma level of methyldigoxin and the creatinine level was observed. The evaluation of ECG signs showed only minimal alterations of conduction and repolarisation. On the basis of these results conclusions are drawn with regard to the clinical value and use of this therapy.

Pharmacokinetic study of beta-methyldigoxin by enzyme immunoassay using a novel specific antiserum in rats.

We previously showed that enzyme immunoassay (EIA) of beta-methyldigoxin (MDx3) using anti-MDx3 3'-hemisuccinate-bovine serum albumin antiserum (Antiserum-I) was superior to that using commercial anti-digoxin antiserum (Antiserum-II) in terms of specificity and that pretreatment of human serum with phenyl boric acid (PBA) column was effective. In the present study, we examined the precision of EIA using Antiserum-I and the recovery of MDx3 after PBA column treatment in rat serum, and also investigated pharmacokinetic changes of MDx3 in rats. The intra- and inter-assay variations and recovery tests using Antiserum-I were good. The PBA column was effective in selectively separating MDx3 from rat serum containing MDx3 and its metabolites. The recovery tests using Antiserum-I with PBA column showed about 110% and the interference of metabolites of MDx3 was negligible. Serum concentration-time courses of MDx3 by EIA using Antiserum-I with PBA column and Antiserum-I were lower than that using Antiserum-II. The distribution volume at steady state and total body clearance values of MDx3 in these conditions were significantly higher than those using Antiserum-II. The usefulness of PBA column was ascertained, while effects of PBA column on these parameters were not significant. In addition, rapid absorption of MDx3 was observed by EIA using Antiserum-I with PBA column. These results suggest that EIA using Antiserum-I with PBA column for the pretreatment of serum samples should be a more useful and valuable system in therapeutic drug monitoring and pharmacokinetic studies of the unchanged type of MDx3 than Antiserum-II.

Tissue distribution and elimination of digoxin and methyldigoxin after single and multiple doses in dogs.

Glycoside concentrations in plasma and various tissues of dogs were determined after a single and repeated intravenous administration of tritium-labeled digoxin and beta-methyldigoxin. Twenty-four hours after single dosing, the highest concentrations were measured in the kidney. This was followed by the heart, adrenal gland, liver, pancreas, lung, spleen, diaphragm, and skeletal muscle. The glycoside concentration in the brain was low after a single administration of dogoxin. A higher concentration was found after a single dose of the more lipophilic methyldigoxin. After repeated daily administration, the glycoside concentration in plasma and tissues increased continuously and, except for the brain, reached a plateau level after 6 to 8 days. The accumulation factor for both digoxin and methyldigoxin was 2.6. During daily administration for 10 days, the glycoside cconcentration in the brain increased continuously. The mean accumulation factor in all brain areas amounted to 12.4 for methyldigoxin. The concentration of digoxin and methyldigoxin in the tissues decreased, with mean half-lives of 33 and 28 hr, respectively. Glycoside elimination from the brain was clearly slower. A mean half-life of 73 hr was measured for digoxin and of 154 hr for methyldigoxin. The elimination of digoxin was largely renal, while that of methyldigoxin was largely fecal.

Evaluation of medigoxin in outpatients.

We compared our ability to predict the dose of medigoxin and of digoxin required to achieve a fixed serum concentration (the dose requirement) in 33 outpatients. Preliminary work supported the assumptions that the steady state glycoside concentration achieved was proportional to the daily dose given to an individual, and that the bioavailability of the different tablet presentations was similar for either glycoside. We were not able to predict the dose requirement from patient characteristics with any more certainty for medigoxin than for digoxin. Not only the between-patient variability in dose requirement, but also the within-patient variability, was similar for the two glycosides. However the digoxin used had a dissolution rate of over 90% in 1 h. When comparing medigoxin with digoxin of lower, or more variable dissolution rate, medigoxin may be preferable.

[Course of chronic life-threatening digitalis poisoning in infancy with immunopharmacologic treatment using antidigoxin Fab of sheep]. / Verlauf einer chronischen lebensbedrohlichen Digitalis-Intoxikation im Säuglingsalter unter immunpharmakologischer Behandlung mit Antidigoxin Fab vom Schaf.

A 2 months old girl was given a tenfold increased dosage of Beta-Methyldigoxin for 2 weeks and subsequently developed severe symptoms of glycoside intoxication. In hospital she was treated by digoxin-specific Fab antibody fragments. 18 hours later the symptoms had totally disappeared. However, 48 hours from the beginning of the treatment free digoxin levels rose again to toxic ranges. In chronic intoxications the rediffusion of glycosides from tissues and interstitial space seems to be much more pronounced than in acute intoxications, and there is a higher risk of reintoxication.