Subject(s)
Anti-Arrhythmia Agents/adverse effects , Digitalis Glycosides/adverse effects , Anti-Arrhythmia Agents/pharmacokinetics , Anti-Arrhythmia Agents/therapeutic use , Arrhythmias, Cardiac/complications , Arrhythmias, Cardiac/drug therapy , Digitalis Glycosides/pharmacokinetics , Digitalis Glycosides/therapeutic use , HumansABSTRACT
BACKGROUND: Although the value of digitalis glycosides in the treatment of heart failure is limited, approximately 255 million DDDs of digitalis glycosides (DGs) were prescribed in Germany in 2004. METHOD: The authors analyzed data from adverse drug reactions (ADRs) resulting in hospitalization in the four German Pharmacovigilance Centers (PVCs) associated with DGs between 2000 and 2004. All patients with an at least "probable" ADR were included. RESULTS: Out of 3,092 ADR patients, in 314 patients (10.2%, 244 women) admission was caused by a DG-related ADR. Patients with DG-related ADR had a significantly lower body weight and were significantly older than patients with other ADRs. Per 1,000 patients exposed to DGs the incidence [95% CI] was calculated to 1.9 [1.0; 3.3] ADRs per 3 months exposition. Oral digitoxin was involved in 296 patients (228 women). 70.6% of women but only 29.3% of men were overdosed (> 1 mug/kg body weight per day). Women received significantly higher body weight-related digitoxin doses and had significantly higher digitoxin plasma levels than men. ADRs in patients with nonelevated digitoxin serum level were mainly caused by pharmacodynamic drug-drug interactions (e.g., beta-blockers). Overall, 42.4% of the ADRs were supposed to be preventable. CONCLUSION: Body weight-adapted dosing of digitoxin is essential for preventing DG-ADRs, particularly in elderly women with low body weight. Beyond giving attention to pharmacodynamic and pharmakokinetic drug-drug interactions, regular measurements of digitoxin plasma concentrations are crucial accounting for the increased half-life of digitoxin in the very old.
Subject(s)
Arrhythmias, Cardiac/drug therapy , Cardiotonic Agents/toxicity , Digitalis Glycosides/toxicity , Heart Failure/drug therapy , Patient Admission/statistics & numerical data , Adverse Drug Reaction Reporting Systems , Aged , Aged, 80 and over , Arrhythmias, Cardiac/blood , Arrhythmias, Cardiac/epidemiology , Cardiotonic Agents/administration & dosage , Cardiotonic Agents/pharmacokinetics , Digitalis Glycosides/administration & dosage , Digitalis Glycosides/pharmacokinetics , Dose-Response Relationship, Drug , Drug Interactions , Drug Monitoring , Female , Germany , Heart Failure/blood , Heart Failure/epidemiology , Humans , Incidence , Male , Middle AgedABSTRACT
The lessons that the physician William Withering learned from his studies of digitalis are still relevant today. This paper highlights four of these lessons and updates them using the tools of clinical pharmacology and pharmacoepidemiology. First, Withering learned that failure to prepare digitalis from the foxglove in a standard manner resulted in a product with unpredictable clinical effects. Preparation of medicines from plants since then has not followed similar good practice and medicines have often not been granted marketing authorisation because of variability in their quality. Second, differences in the response to digitalis were noted by Withering, but he had little idea of their basis. Clinical pharmacology has shown that for drugs such as digitalis differences are caused by variability both in receptor sensitivity and in drug disposition. Third, the dose-response characteristics of digitalis were well known to Withering. Modern techniques of measuring response, such as the use of biomarkers, have made such studies easier, although clinical observations remain the gold standard. Fourth, Withering documented many of the adverse effects of digitalis. The use of various modern databases has facilitated the analysis of clinical toxicology and thus of risk-benefit profiles.
Subject(s)
Digitalis Glycosides/pharmacokinetics , Phytotherapy , Biological Availability , Digitalis , Digitalis Glycosides/adverse effects , Digitalis Glycosides/history , Dose-Response Relationship, Drug , England , History, 18th Century , Pharmacology, Clinical , Phytotherapy/history , Plant Leaves , Plant Preparations/adverse effects , Plant Preparations/history , Plant Preparations/pharmacokineticsABSTRACT
In patients with heart failure and atrial fibrillation cardiac glycosides, generally in combination with beta-blockers, are indicated to control ventricular rate. In systolic heart failure and sinus rhythm, however, the use of digitalis continues to be debated. There are special concerns that cardiac glycosides might lead to an increased mortality rate in women. Retrospective analyses, however, do not indicate any sex-based differences in the effectiveness of cardiac glycosides. Beneficial effects of cardiac glycosides in heart failure seem to be related to the attenuation of sympathetic activation and neurohumoral alterations, which is already obtained at low digoxin serum concentrations, while high serum levels are associated with increased mortality. Therefore, in patients with sinus rhythm who remain symptomatic under an optimized therapy with ACE inhibitors, beta-blockers and diuretics in addition to digitalis should be considered regardless of the gender. However, target serum digoxin concentrations should be low in a range of 0.5 to 0.8 ng/ml.
Subject(s)
Atrial Fibrillation/drug therapy , Digitalis Glycosides/therapeutic use , Heart Failure/drug therapy , Adrenergic beta-Antagonists/adverse effects , Adrenergic beta-Antagonists/pharmacokinetics , Adrenergic beta-Antagonists/therapeutic use , Atrial Fibrillation/blood , Atrial Fibrillation/mortality , Digitalis Glycosides/adverse effects , Digitalis Glycosides/pharmacokinetics , Digoxin/adverse effects , Digoxin/pharmacokinetics , Digoxin/therapeutic use , Dose-Response Relationship, Drug , Heart Failure/blood , Heart Failure/mortality , Humans , Risk Factors , Sex Factors , Survival Analysis , Sympathetic Nervous System/drug effects , Treatment OutcomeSubject(s)
Aged , Cardiovascular Diseases/physiopathology , Cardiovascular Diseases/mortality , Pharmacology/trends , Digitalis Glycosides/administration & dosage , Diuretics/administration & dosage , Diuretics/pharmacokinetics , Diuretics/pharmacology , Diuretics/metabolism , Diuretics/therapeutic use , Pharmacokinetics , Digitalis Glycosides/pharmacokineticsABSTRACT
Three cases of patients with symptoms of digitalis overdosage were presented. The principal manifestations included complex supraventricular dysrhythmias and atrio-ventricular conduction disturbances. In the discussion a special attention was paid to digitalis dosage. Multiple factors influencing plasma concentration of digitalis including pharmacokinetics, bioavailability and drug interactions with glycosides were described. Short review of toxic manifestations of digitalis was made and the treatment of digitalis intoxication was outlined.
Subject(s)
Arrhythmias, Cardiac/chemically induced , Atrioventricular Node/drug effects , Digitalis Glycosides/poisoning , Digitalis/poisoning , Plants, Medicinal , Plants, Toxic , Aged , Aged, 80 and over , Captopril/pharmacology , Digitalis Glycosides/administration & dosage , Digitalis Glycosides/pharmacokinetics , Drug Interactions , Drug Overdose , Drug Therapy, Combination , Female , Heart Conduction System/drug effects , Humans , Male , Medigoxin/pharmacology , Middle Aged , Pentoxifylline/pharmacology , Tachycardia, Supraventricular/chemically inducedSubject(s)
Cardiotonic Agents/therapeutic use , Digitalis Glycosides/therapeutic use , Heart Failure/drug therapy , Animals , Cardiotonic Agents/pharmacokinetics , Cardiotonic Agents/pharmacology , Digitalis Glycosides/pharmacokinetics , Digitalis Glycosides/pharmacology , Female , Heart Failure/physiopathology , Hemodynamics/drug effects , Humans , Male , Myocardial Infarction/drug therapy , PregnancySubject(s)
Humans , Cardiotonic Agents/pharmacokinetics , Cyclic AMP/biosynthesis , Amrinone/pharmacokinetics , Calcium Channels/pharmacokinetics , Digitalis Glycosides/pharmacokinetics , Ventricular Dysfunction/drug therapy , Dobutamine/pharmacokinetics , Enoximone/pharmacokinetics , Cardiotonic Agents/classification , Dopamine/pharmacokinetics , Cyclic GMP/biosynthesis , Intraoperative CareABSTRACT
The experimental and clinical evidence on the decreased efficacy of digitalis on old age are reviewed. The trials on the efficacy of digitalis on elderly in heart failure and sinus rythm, are analysed and we try to characterize the sub-group of responders. So we try to explain the criteria to choose the therapeutic dose, to avoid intoxication and to interpret the seric concentrations. We describe the pharmacocynetics of digitalis on old people on heart failure which can explain the susceptibility to intoxication. We reviewed the incidence of digitalis intoxication on old age and the difficulties on its recognition.
Subject(s)
Arrhythmias, Cardiac/drug therapy , Cardiac Output, Low/drug therapy , Digitalis Glycosides/therapeutic use , Digitalis , Plants, Medicinal , Plants, Toxic , Aged , Digitalis Glycosides/blood , Digitalis Glycosides/pharmacokinetics , HumansABSTRACT
The role of digitalis therapy in patients with sinus rhythm and mild to moderate heart failure has been a subject of controversy. This review critically examines the relevant literature and specifically evaluates trials in this patient population. The pharmacokinetics and the pharmacodynamics of the most commonly prescribed agents are briefly discussed. The available evidence supports the use of this agent in patients with sinus rhythm and clinical signs of systolic dysfunction. Digitalis is not recommended as a routine when the primary cause of heart failure is diastolic dysfunction. The use of digitalis therapy in combination with diuretics and vasodilator therapy deserves further attention.
Subject(s)
Arrhythmia, Sinus/drug therapy , Digitalis Glycosides/therapeutic use , Heart Failure/drug therapy , Arrhythmia, Sinus/complications , Digitalis Glycosides/pharmacokinetics , Heart Failure/complications , Heart Failure/physiopathology , HumansABSTRACT
Digibind is a purified antigen binding fragment (Fab) of immunoglobulin G antibodies raised to bind digoxin. Studies in animals suggest renal excretion accounts for a substantial portion of Fab's elimination. Thus it is expected that elimination of antidigoxin Fab fragments would be prolonged in patients with renal impairment; it remains unclear whether digoxin might be released with possible recurrence of toxicity. To shed light on this potential for recrudescent digitalis toxicity following release of bound digoxin, the author scrutinized the records of patients with impaired renal function who were treated with Digibind. Data are available from three sources: the original multicenter investigation of Digibind in 150 patients with life-threatening digoxin or digitoxin toxicity, a postmarketing surveillance study of 745 patients treated with Digibind, and all other reports in the literature or to Burroughs Wellcome Co of physician experience with any antidigoxin Fab. Sixty percent of patients in the multicenter trial and 80% of patients in the postmarketing surveillance trial had some degree of renal impairment. Patients with poor renal function had no evidence of decreased effectiveness or safety either in terms of percent of patients responding, onset of effect or evidence of recrudescence. From all sources the authors identified 28 patients treated with Fab who were functionally anephric. Twenty-seven of these patients had no evidence of recrudescent toxicity. One patient was reported to have complete resolution of digoxin-induced third-degree atrioventricular (AV) block, but AV block recurred 10 days after Fab treatment and persisted for 10 days thereafter. Although this case offers the only clinical evidence suggesting recrudescence can occur, there were no likely alternative explanations for the clinical findings.(ABSTRACT TRUNCATED AT 250 WORDS)
Subject(s)
Digitalis Glycosides/poisoning , Immunoglobulin Fab Fragments/therapeutic use , Kidney Diseases/complications , Poisoning/drug therapy , Creatinine/blood , Digitalis Glycosides/pharmacokinetics , Female , Humans , Immunoglobulin Fab Fragments/administration & dosage , Immunoglobulin Fab Fragments/pharmacokinetics , Kidney Diseases/blood , Male , Poisoning/complications , Poisoning/physiopathology , Product Surveillance, Postmarketing , RecurrenceABSTRACT
The intestinal epithelial cell layer is the first major barrier to absorption encountered by xenobiotics. An understanding of the mechanism and sites of drug absorption and metabolism is thus a critical first step in developing orally active compounds. In this context human brush-border membrane vesicles obtained from multi-organ donor intestines have been purified. This model has been validated and used to investigate the duodenal absorption of drugs "in vitro", namely digitalis. It is well established that digitalis compounds present great variability in their respective "in vivo" bioavailability in human (60-90% for digoxin, 0% for ouabain). These particular characteristics prompted us to determine whether this membrane model constitutes a suitable tool in predicting the bioavailability or intestinal transport processes of these molecules. The uptake of [3H] digoxin and [3H] ouabain by membrane vesicles incubated in media of increasing osmolarities demonstrated that: i/two factors are involved in the uptake processes of digoxin: membrane binding and intravesicular transport (osmotic sensitive), ii/ for ouabain, no osmotic sensitivity was observed, indicating that no transport process occurred, but only membrane binding processes. These results are in complete agreement with the absolute bioavailability data reported for man "in vivo". This human brush-border model constitutes an interesting approach to the intestinal absorption phenomena which are known to be among the factors influencing the bioavailability of orally administered drugs.
Subject(s)
Digitalis Glycosides/pharmacokinetics , Duodenum/metabolism , Intestinal Absorption/physiology , Biological Availability , Biological Transport, Active/physiology , Biomarkers , Cell Membrane/metabolism , Digoxin/pharmacokinetics , Duodenum/enzymology , Humans , In Vitro Techniques , Membranes/metabolism , Microscopy, Electron , Microvilli/enzymology , Microvilli/metabolism , Ouabain/pharmacokinetics , Taurocholic Acid/metabolism , TemperatureSubject(s)
Digitalis Glycosides/therapeutic use , Heart Failure/drug therapy , Delayed-Action Preparations , Digitalis Glycosides/adverse effects , Digitalis Glycosides/pharmacokinetics , Drug Interactions , Drug Tolerance , Heart Failure/metabolism , Humans , Magnesium/metabolism , Sodium/metabolismABSTRACT
Many studies and cases of digitalis intoxication have been reported since the time of William Withering's first publication in 1785. Recognition and management of digitalis toxicity is challenging. Before digoxin immune Fab was commercially available, treatment consisted of managing the signs and symptoms of toxicity until the digitalis was eliminated. Digoxin immune Fab offers a safe, effective, and specific method of quickly reversing digitalis toxicity. Factors that must be considered with the clinical use of this agent include the dosage calculation, administration technique, postdose monitoring, pharmacokinetics, mechanism of action, interference with commercially available digoxin assays, partial neutralizing dosing, rebound of free digoxin, and indications for use. For severe, life-threatening toxicity, digoxin immune Fab is the treatment of choice.