Essay: Drug interactions with digoxin

Abstract :
Drug interactions with digoxin are important because of this agent’s narrow therapeutic index. Among the drugs that can diminish digoxin bioavailability are cholestyramine, antacid gels, kaolin-peetate, certain antimicrobial drugs and cancer chemotherapeutic agents. Also rifampin, an antibiotic utilized as a part of the treatment of tuberculosis, may lower steady state serum digoxin levels in patients with severe renal disease. Antiarrhythmic drugs, such as quinidine and amiodarone, can markedly increase steady state serum digoxin levels. Physicians must maintain constant vigilance whenever medications are added to or withdrawn from a therapeutic regimen that includes digoxin
 
Introduction :
The aim of this article, is to focus on the pharmacokinetic interactions of digoxin. The focus on drug interactions with digoxin is appropriate for this agent since it not only is one of the most commonly prescribed drugs, but also has a narrow therapeutic index. There is a high incidence of toxicity during the therapeutic use of different class of drugs. We will mentioned later on other agnets and how it will interact in pharmacokinetic way. however, Interactions of cardiac glycosides with other drugs contribute significantly to the high prevalence of digitalis toxicity.
Uses of Digoxin: Treating an irregular heartbeat can decrease the risk for blood clots, an effect that may reduce your risk for a heart attack or stroke. Treating heart failure may help maintain your ability to walk and exercise and may improve the strength of your heart. This reduces strain on the heart and helps it maintain a normal, steady, and strong heartbeat.
 
Results and Discussion:
 
Drugs That Affect Bioavailability of Digoxin
 
– Cholestyramine: Administration of digoxin 8 hours before cholestyramine prevents the interference with absorption of the glycoside .The Lanoxicap preparation also produces less variability in digoxin absorption when cholestyramine is given with the capsules as compared with the tablets. at the point when 4 to 8 g of cholestyramine are given in the meantime as digoxin, there is a 25% decrease in steady state serum digoxin levels.The mechanism of this interference appears to be related to physical binding of digoxin to the resin. This interaction can also be minimized by prescribing digoxin in a solution contained in a gelatin capsule (Lanoxicap).
 
 
– Antacids : Antacid gels , however not the tablets , seem to diminish the absorption of a single dose of digoxin by approximately 25%. The mechanism of this reduction of digoxin absorption by antacids is unclear. Since only magnesium trisilicate has been found to adsorb digoxin in vitro while other antacids also lowered plasma levels in human beings, the decreased absorption of digoxin may be because of elements other than adsorption.
– Kaolin-pectateand bran: The decrease in digoxin absorption can be abolished by giving digoxin 2 hours before administration of the antidiarrheal agent or may be minimized by administration of the capsule formulation of digoxin When digoxin was given at the beginning of a meal containing a high content of fiber, there was a 20% decrease in cumulative 6 day urinary digoxin excretion . The decreased bioavailability of digoxin as a result of the coadministration of an antidiarrheal suspension containing 18% kaolin and 0.4% pectin (Kaopectate) was first reported by Binnion after observing ineffective blood levels of digoxin in a patient who had taken the antidiarrheal at the same time as digoxin.Others were not able to document a decrease in digoxin absorption when digoxin was given 15 to 30 minutes before a meal containing high fiber content.
– Antimicrobial drugs. : In a recent study, a 5 day course of erythromycin or tetracycline was found to raise the serum digoxin concentrations by 43 to 116% in three volunteers who produced large amounts of digoxin reduction products (> 35 to 40% of total urinary digoxin and its metabolites). Administration of digoxin in capsule form decreases the percent of digoxin reduction products formed, presumably by more complete absorption of digoxin in the small intestine . The reduced metabolites virtually disappear from the stool and urine after therapy with certain antibiotics, and this can lead to an increase in bioavailability of digoxin . Certain antimicrobial drugs such as neomycin, sulfasalazineand paraaminosalicylic acid (PAS), often used for their effect on intestinal function and flora, appear to depress digoxin absorption. This interaction results in an 18 to 28% decrease in the bioavailability of digoxin and is not minimized by temporal separation of the time of administration of digoxin and the concurrently administered antimicrobial agent. Since only 10% of subjects produce large amounts of these reduced derivatives, this increase in digoxin levels due to antibioticsshould occur in only a minority of patients . Thus, the increase in bioavailability during administration of these antibiotics should be minimized with the use of the capsule forms of digoxin. Drugs that alter gut motility. Digoxin absorption is not affected by medications that alter gut motility, such as propantheline (Probanthine) or metoclopramide Cancer chemotherapeutic agents: Digoxin absorption and steady state levels may be markedly decreased by cancer chemotherapy
 
 
 
– Interaction of Digoxin With Antiarrhythmic Drugs
Quinidine It is clear that the elevation of digoxin levels by concurrent quinidine administration results in enhanced electro physiologic effects demon started on the surface electrocardiogram as a prolongation of the PR interval , by central nervous system manifestation s of toxicity such as anorexia , nausea and vomiting also by enhanced ventricular ectopic activity . The elevated serum digoxin levels induced by concurrent administration of digoxin and quinidine have been reported not to show an enhanced inotropic effect as measured by systolic time intervals . Clinical evidence indicates that there are increased electro physiologic and inotropic effects associated with the elevation of serum digoxin as a result of concurrent quinidine administration . In 1978, Ejvinsson reported that the concurrent administration of quinidine to 12 patients increased average serum digoxin concentrations from 0.9 to 1.6 ng/ml. Decisive evidence for a decrease in the nonretail excretion of digoxin under the influence of quinidine was established by comparing the kinetics of digoxin in anuric patients on chronic hemodialysis when given digoxin alone and concomitantly with quinidine . However, in patients with a glomerular filtration rate of less than 50 ml/rnin , the time required for digoxin to reach a new steady state with the addition of quinidine may be considerably longer. , however, measured inotropic effects of digoxin at steady state during digoxin administration alone and during digoxin and quinidine administration . Since glornerular filtration rate is unchanged during concurrent digoxin quinidine administration, it is clear that the decreased renal elimination of digoxin in human beings results from a quinidine- induced decrease in tubular secretion of digoxin . If the dose of quinidine is increased, one can anticipate a further increase in serum digoxin levels. They then gave sufficient digoxin to achieve a serum digoxin concentration similar to that obtained when digoxin and quinidine were given concomitantly.
 
Amiodarone. There is suggestive evidence that the increase in digoxin levels may in part be directly related to the dose of amiodarone since a linear correlation was observed between plasma amiodarone levels and digoxin serum levels . observed a mean increase in plasma digoxin concentration of 70% in seven patients when amoidarone, 600 mg/day, was administered concurrently with digoxin. a daily amiodarone dose of 400 mg is sufficient to reduce clearance of a digoxin concentration by 26%
Other antiarrhythmic drugs: There are several antiarrhythmic drugs that do not appear to have any clinically relevant pharmacokinetic interactions with digoxin. These include procainamide , disopyramide mexiletine, flecainide and ethmozine.
 
 
 
– Interaction of Digoxin With Calcium Channel
Blocking Drugs Interaction of Digoxin With Calcium Channel Blocking Drugs The pharmacokinetic interaction between digoxin and calcium channel blocking drugs varies from none with nifedipine to an increased serum digoxin level of more than 70% when verapamil and digoxin are given concomitantly.
Verapamil : They found that the effect of verapamil on serum digoxin concentration developed gradually within the first few days after verapamil was co-administered with digoxin and approached the new steady state value within 7 days after the start of verapamil therapy. When the serum digoxin levels are markedly elevated as a result of administration of verapamil, lethal cardiac toxicity may occur . The elevated plasma digoxin concentration induced by verapamil is associated with an inotropic effect as assessed by a measurement of systolic time intervals . The mechanism of the digoxin-verapamil interaction consists of decreases in both renal and extra renal clearance of digoxin by verapamil . Since the creatinine clearance does not change under the influence of verapamil , the decreased renal clearance of digoxin appears to be due to an inhibition of tubular secretion. reported that serum digoxin levels increased 70% during concurrent treatment with verapamil .
Diltiazem,: An average increase in steady state plasma digoxin concentration of 22% was observed when diltiazem, 180 mg/day, was given to 24 normal subjects who were receiving l3-acetyldigoxin, 0.2 mg daily . There is minimal pharmacokinetic interaction between diltiazem and digoxin . The magnitude of the diltiazem interaction is small; therefore, digoxin dose adjustment is probably unnecessary
Nifedipine : There is no pharmacokinetic interaction between nifedipine and digoxin, either in patients or in normal subjects .
Tiapamil, a congener of verapamil, causes an increase in serum digoxin levels of 60%, similar to that of verapamil .
 
– Interaction With Diuretic Drugs
Furosemide and sodium-induced diuresis one of the mechanisms responsible for the increase in digoxin clearance due to sodium loading was diminished passive proximal back diffusion of filtered and secreted digoxin. reported that diuresis caused a 70% increase in digoxin clearance and a 20% decrease in serum digoxin levels in 10 patients who were taking digoxin for atrial fibrillation and who did not have congestive heart failure. Mechanisms that have been identified for renal excretion of digoxin include glomerular filtration, tubular secretion and proximal tubular reabsorption of digoxin. When the sodium diet was liberalized to a moderately high sodium diet, the digoxin clearance increased by 70% and the serum digoxin levels decreased by 20%.
Diuresis-induced hypokalemia It is well known that hypokalemia is associated with sensitivity to digitalis and, thus, increases its toxicity , but it is not well appreciated that when the serum potassium is as low as 2 to 3 mEq/liter, the tubular secretion of digoxin is nearly blocked. Although thiazides and loop diuretic drugs themselves do not alter the kinetics of digoxin excretion, they induce a dose-dependent loss of potassium from the body, resulting in a decreased serum potassium concentration.
Potassium-sparing diuretic drugs Possible mechanisms for these observations include an increased tubular secretion of digoxin to account for the increased renal clearance and a decrease in the hepatic elimination rate of digoxin to account for the decrease in extra renal clearance. This combination of quinidine and spironolactone caused significant reductions in total body clearance of digoxin, no renal digoxin clearance and digoxin renal clearance beyond the reductions induced by either drug alone . The clinical significance of an anticipated elevation of steady state serum digoxin levels induced by the potassium-sparing diuretic drugs is not clear. The effects of the potassium-sparing diuretic drugs on steady state serum digoxin levels have not been adequately evaluated. The potassium sparing diuretic drugs, spironolactone, triamterene and amiloride, have been reported to induce changes in digoxin kinetics . Since the magnitude of this interaction of potassium- sparing diuretic drugs has not been established, measurement of the steady state serum digoxin levels may be warranted. Potassium-sparing diuretic drugs have different mechanisms and sites of action, which may account for their differing effects on digoxin pharmacokinetics. Triamterene does not alter renal elimination of digoxin, but reduces the extra renal clearance of digoxin. Patients with cardiac disease are frequently treated with multiple medications and the combination of a potassium- sparing diuretic drug, digoxin and quinidine is not unusual.
– Miscellaneous Drug Interactions With Digoxin
Anti-inflammatory drugs : Indomethacin therapy did not alter digoxin pharmacokinetics in healthy adult volunteers with normal renal function , but was found to cause an increase of 45% in serum digoxin levels in preterm infants when co-administered with digoxin for the treatment of patent ductus arteriosus . The increase in serum digoxin level associated with indomethacin may also apply to adult patients since a lowering of effective renal plasma flow has been observed in patients after indomethacin administration . Administration of indomethacin to the infants was associated with a significant decrease in urinary output, suggesting that the increase in serum digoxin level was due to a decreased glomerular filtration rate and a decrease in the renal clearance of digoxin.
Rifampin : It was postulated that rifampin increased the metabolism of quinidine; in tum, the interaction between quinidine and digoxin was diminished, thereby lowering serum digoxin levels. Rifampin, an antibiotic used for the treatment of tuberculosis, has been shown to remarkably lower the steady state serum digoxin level in several patients dependent on dialysis . Therapy with rifampin produced a decline in both the serum quinidine concentration and serum digoxin concentration. Other possible explanations for the digoxin-rifampin interaction include decreased absorption of digoxin or increased biliary excretion. There is limited evidence to suggest that this interaction is due to an increased biotransformation of digoxin in these patients with minimal to no renal function.
Cimetidine: who studied the pharmacokinetics of oral digoxin in eight healthy volunteers, both with and without concurrent cimetidine. It was reported a 25% decrease in steady state serum digoxin concentrations when digoxin was given together with cimetidine. They concluded that cimetidine had no effect on the area under the plasma concentration versus time curve of digoxin.
Vasodilator drugs: Total renal clearance of digoxin was increased by 50% in 8 patients during administration of nitroprusside or hydralazine . It is not yet known whether long-term vasodilator therapy increases the dosage requirements for digoxin in patients with congestive heart failure. Because the glomerular filtration rate was unchanged and the estimated renal blood flow was increased, the mechanism of this alteration in digoxin renal clearance was thought to be an increase in tubular secretion of digoxin.
 
Conclusion :
The accumulated information regarding drug interactions with digoxin should contribute to greater safety in the use of the drug, provided that the physician maintains constant vigilance whenever any medication is added to or withdrawn from a therapeutic regimen that indudes digoxin. Although there has been a tremendous increase in our knowledge of the drug interactions, more investigation is needed to define the full scope and magnitude of these interactions with digitalis, particularly during steady state. Patients with heart disease may be treated concomitantly with anticholesterolemic drugs, diuretic drugs, calcium channel blocking agents, vasodilators and antimicrobials, some of which have been shown to interact with digoxin. We are also greatly in need of accurate and sensitive methods to reliably measure the inotropic and vagotonic effects of digitalis to assess the effects of these drug interactions.