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1 Cardiac glycosides have been used for centuries as therapeutic agents for the treatment of heart diseases. In patients with heart failure, digoxin and the other glycosides exert their positive inotropic effect by inhibiting Na(+)-K(+)-ATPase, thereby increasing intracellular sodium, which, in turn, inhibits the Na(+)/Ca(2+) exchanger and increases intracellular calcium levels. As the therapeutic index of digitalis is narrow, arrhythmias are common problems in clinical practice. The mechanisms and mediators of these arrhythmias, however, are not completely understood. 2 The involvement of the sympathetic and parasympathetic nervous system in digitalis cardiac toxicity is reviewed. 3 Receptors, channels, exchange systems or other cellular components involved in digitalis-induced cardiotoxicity are also reviewed. 4 Possible mediators of digitalis-induced cardiac toxicity are discussed. 5 Management of digitalis toxicity in patients is summarized. 6 The determination of the possible mediators of digitalis-induced cardiac toxicity will enhance our knowledge and lead to the development of new therapeutic strategies to treat these lethal arrhythmias.
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Following the guide of the publications written by Weissler, Thomas, Ahmed, Perry, Buyukoztur, Rahimotola, the Authors have executed on 25 patients with results of the myocardic infarction a polygraphic examination, comparing the variations of the intervals of the systolic time (STI) with the modifications of the fraction of the ejection (Fe) and of the velocity of the circular fibres (Vcf), calculated with echocardiographic method. From the results obtained the Authors have concluded that there is a perfect correspondence among the alterated values of the isovolumetric contraction time (TCIV), preejection period (PEP), LVET/PEP, and the variations of the Fe and Vcf, and furthermore the amelioration obtained with the digitalis therapy are controlled justly with both the methods. In conclusion both the polygraphic examination and the echocardiographic examination consent a perfect control of the patients with results of the miocardic infarction if they are subject to a digitalis treatment or not, and furthermore they permit a functional valutation of the patient.
We evaluated a commercial (Clinical Assays, Inc.) 125I radioimmunoassay for digitoxin for use in measuring cardiac glycosides in serum, buffer, urine, and cerebrospinal-fluid samples. We also assessed interference of seven cardioactive metabolites of digitoxin, including digoxin, with the assay. The precision of the assay was adequate for all matrixes studied for glycoside concentrations less than 5 microgram/L. Reactivity in the assay was dependent on the nature of the matrix: buffer and serum samples containing digitoxin showed a stronger reactivity than did samples of urine and cerebrospinal fluid. Patients' samples must therefore be analyzed with a standard curve prepared by use of the same matrix. The digitoxosides of digitoxin showed a slightly higher reactivity in the assay than did digitoxin itself, but digitoxigenin showed a 50% lesser reactivity. Digoxin, its digitoxosides, and digoxigenin hardly react at all in the assay and so do not interfere with digitoxin determinations.
BACKGROUND: The vasodilatory response to local specific type III phosphodiesterase inhibition with amrinone was evaluated before and immediately after local administration of digoxin in 14 patients with severe congestive heart failure (CHF). METHODS AND RESULTS: A 3F polyethylene catheter was inserted into the common femoral artery for drug administration and pressure monitoring. Mean blood flow velocity (MBFV) was continuously determined in the superficial femoral artery by transcutaneous Doppler ultrasonography. After intra-arterial administration of 10 mg amrinone, group MBFV increased from 7.7 +/- 1.4 to 16.0 +/- 2.1 cm/sec (p less than 0.05, n = 10). Local administration of 20 micrograms digoxin, which was infused over 20 minutes, did not alter group MBFV (i.e., 8.2 +/- 1.6 versus 7.6 +/- 1.5 cm/sec; p = NS, n = 10). The second administration of 10 mg amrinone, which immediately followed completion of local digoxin infusion, increased group MBFV but to a lesser extent than that produced by the first amrinone administration (i.e., 11.9 +/- 1.9 versus 16.0 +/- 2.1 cm/sec; p less than 0.05, n = 10). When placebo was administered instead of digoxin, group MBFV was similar after the first and second administrations of amrinone (i.e., 15.3 +/- 3.3 versus 15.6 +/- 3.8 cm/sec; p = NS, n = 4). CONCLUSIONS: Although local administration of digoxin did not significantly alter baseline vascular tone in patients with CHF, it substantially decreased the direct vasodilatory effect induced by specific type III phosphodiesterase with amrinone.
The mechanism(s) for uptake of organic cations by renal cortical tubules was (were) examined further. Renal cortical tubules were purified from rat kidneys by a Percoll gradient centrifugation technique. Bicarbonate buffer (Krebs-Henseleit, KHS) conditions were altered, and chemical modulators were used which affect the activity of the basolateral Na+/K+-ATPase. Renal tubule uptake of the achiral organic cation amantadine was determined. The cardiac glycosides digoxin and acetylstrophanthidin and ouabagenin did not alter amantadine uptake by either proximal or distal tubule fragments in KHS. However, ouabain inhibited proximal tubule amantadine uptake in a dose-dependent manner with lower potency than distal tubule amantadine uptake in KHS. Ouabain did not inhibit amantadine tubule uptake in phosphate buffer. However, inhibition of amantadine uptake by ouabain returned in a time-dependent manner upon addition of bicarbonate to the phosphate buffer. Low extracellular sodium or potassium did not alter amantadine uptake by proximal tubules. Hypokalemic and hypokalemic/ hyponatremic conditions decreased the inhibitory potency of ouabain for amantadine uptake by proximal tubules. For distal tubules, both hyponatremic and hypokalemic conditions, alone and together, decreased the inhibitory potency of ouabain, but did not affect amantadine uptake in the absence of ouabain. Hypochloremic conditions decreased affinity for amantadine uptake by distal, but not proximal tubules. No change in maximal transport capacity for amantadine uptake was observed under hypochloremic conditions for either tubule fragment. These studies challenge the widely accepted concept of Na+/ K+-adenosine triphosphatase activity and maintenance of the basolateral membrane potential as rate-limiting steps for the energy-dependent renal tubule uptake of organic cations. Furthermore, these studies suggest a mechanism for ouabain inhibition of organic cation renal tubule uptake that may not involve the Na+/K+-adenosine triphosphatase and may be possibly bicarbonate-dependent.
The use of digitalis in severe disorders of intra-ventricular conduction is debatable, and some consider it contra-indicated. Once it had been shown that the latter attitude is at best based on contraversial theoretical arguments, two types of study were undertaken: 1. Nine patients with bilateral bundle branch block had intracavitary recordings made of the HV interval both before and for one hour after the administration of lanatoside C (0.8 to 1.6 mg). In no case was this interval found to be increased, indicating that there was no increase in the original conduction defect. 2. Thirty four patients with complete right bundle branch block and associated left antero-superior hemiblock were digitalised, and followed up for an average of 16 months; only 2 complete atrio-ventricular blocks occurred (5.9%). The risk of complete atrio-ventribular block occurring within a year (4.5% in our series) does not differ significantly from that in an identical control group of 38 patients with the same conduction defect, but who were not digitalised (6%). Three patients had a therapeutic overdose of digitalis with no observed increase in their atrio-ventricular block. The authors conclude that it is perfectly in order to digitalise a patient with a severe intra-ventricular conduction defect.
The relative toxicity of numerous cardiotonic steroids (viz. ouabain, digitoxin, digoxin, convallatoxin, SC4453, bufalin, gitaloxin, digoxigenin, actodigin, oleandrin, digitoxigenin, gitoxin, strophanthidin, gitoxigenin, lanatosides A, B and C, alpha- and beta-acetyl digoxin, alpha- and beta-methyl digoxin) and related compounds towards a number of independent cell lines established from human, monkey, mouse, Syrian hamster, and Chinese hamster have been determined. All cardiac glycosides and their genins, as well as the cardiotonic alkaloid cassaine, exhibited greater than 100-fold higher toxicity towards cultured human and monkey cells in comparison to the cell lines of mouse, Syrian hamster, and Chinese hamster origins. These differences are species-related as all cell lines (both normal as well as transformed) from any one species, as well as cells from the closely related species (e.g., man and monkey or mouse, Chinese hamster, and Syrian hamster), showed similar sensitivity towards these drugs. The failure to see any significant differences in cellular toxicity for a larger number of other compounds which either bear limited structural resemblance to cardiac glycosides (viz. estradiol 17-beta-acetate, testosterone propionate, 21-acetoxy pregnenolone, beta-estradiol, digitonin, tigogenin, and tomatine) or interact with the Na+/K+ ATPase in a different manner (viz. veratridine, sanguinarine nitrate, penicillic acid, vanadium pentoxide, harmaline-HCI,5,5'-diphenyl hydantoin, quindonium bromide, and methyl quinolizinum bromide) provides strong evidence that the observed species-related differences are highly specific for cardiotonic steroids. Studies on the binding of [3H]ouabain show that, in comparison to human and monkey cell lines, no significant binding of the drug is observed in cells derived from the resistant species (i.e., mouse and Chinese hamster). The Na+/K+ ATPase from cells of the resistant species is inhibited at much higher concentrations of ouabain and digitoxin in comparison to the enzyme from human cells, and a good correlation is observed between these concentrations and those reported for inhibition of the enzyme from isolated heart muscles of the same species. These results provide strong evidence that the species-related differences in sensitivity to digitalis have a cellular basis and that the cultured cells from various mammalian species provide a useful model system for investigating the mechanism of action of cardiac glycosides.
The advent of vasodilator therapy and new cardiotonic agents has modified the medical treatment of heart failure. First-line treatment is no longer standard; its choice must take into account a number of individual factors such as patient's age, causative cardiopathy, severity of the disease, response to treatment, contra-indications and side-effects of drugs. The aim is to obtain an improvement not only in the patient's comfort but also in long-term prognosis. The prescription of digitalis compounds to heart failure patients with sinus rhythm has been questioned. Alternatives to the conventional therapeutic approach based on cardiac glycosides and diuretics are now available. They include the use at an early stage of vasodilator therapy, and notably angiotensin-converting enzyme inhibitors, in the hope of avoiding gradual reduction of cardiac performance.
In a group of 29 patients treated with digoxin for cardiac failure, only 16 showed increased calcium and potassium concentrations in saliva. There was no correlation in the 29 patients between serum digoxin levels and concentrations of salivary electrolytes. On the other hand, in 4 normal subjects treated with digoxin no change in salivary electrolytes was noted. It is concluded that modifications in salivary electrolytes seen in patients with cardiac failure treated with digitalis are not due to this drug. However, a retrospective clinical study showed a good correlation between clinical signs of cardiac failure and increased levels of salivary calcium, potassium and CaX Kproduct. It is suggested that this phenomenon is due to the well-known adrenergic stimulation in patients with cardiac failure.
HISTORY AND CLINICAL FINDINGS: A 61-year-old man suffering from histologically confirmed amyloidosis associated with coagulation disturbances presented with exercise induced shortness of breath and symptoms of cardiac asthma after four cycles of chemotherapy with melphalan and prednisolone. As a result, treatment with digitoxin was initiated. In addition furosemide and an oral nitrate were administered. INVESTIGATIONS: Disparity between electrocardiogram and echocardiographic findings was observed in that, while the electrocardiogram showed loss of 'R wave in precordial leads V(2 - 4), excessive thickening of both left and right ventricular wall was shown in the echocardiogram. Doppler-echocardiography revealed a left ventricular outflow tract obstruction at rest with a peak pressure gradient of 64 mm Hg which rose to 145 mm Hg during Valsalva manoeuvre. Colour Doppler presented a moderate mitral insufficiency and the transmitral Doppler flow studies detected a restrictive left ventricular filling pattern. DIAGNOSIS, TREATMENT AND COURSE: Digitalis therapy was stopped because of the outflow tract obstruction complicating cardiac amyloidosis. Cardiac symptoms abated over the following weeks. This improvement was reflected in a significant reduction of the outflow tract gradient, the gradients now being 16 mm Hg under resting conditions and a maximum of 36 mm Hg during the Valsalva manoeuvre. The transmitral Doppler flow pattern showed a pseudonormalisation and the mitral regurgitation regressed nearly completely. The patient was free from cardiac complaints until his sudden death 21 months after the diagnosis of cardiac amyloidosis. CONCLUSION: Cardiac amyloidosis can present with left ventricular outflow tract obstruction mimicking hypertrophic obstructive cardiomyopathy. This fact must be borne in mind to avoid therapy with preload-reducing or positive inotropic drugs and especially glycosides.
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