Meanwhile, extracellular potassium (K⁺) facilitates dephosphorylation, or removing the phosphate group from the previously phosphorylated site, thereby reducing the binding affinity of cardiac glycosides for the enzyme. In other words, an increase in extracellular K⁺ levels decreases the toxicity of these drugs (digitalis toxicity), which explains why, in clinical settings, providing potassium or having higher extracellular K⁺ levels can help alleviate some of the side effects of cardiac glycosides.

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The effects of digitalis glycosides are mainly caused by inhibiting Na+, K+ pumps in cell membranes, including the sarcolemmal Na+, K+-ATPase pump of cardiac myocytes. Inhibiting the pump increases intracellular calcium, which enhances cardiac contractility. 

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One more mechanism of digoxin in HF patients is to sensitize Na +, K +-ATPase activity in vagal afferent nerves, leading to an increase in vagal tone that counterbalances the increased activation of the adrenergic system in advanced HF. The increase in vagal tone also helps regulate the ventricular rate in patients with atrial fibrillation.  Digoxin is not an effective agent for controlling the heart rate in atrial fibrillation during periods of high adrenergic activity, such as exercise, thyroid storm, or sepsis.

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Digoxin also inhibits Na+, K+ ATPase activity in the kidney, thereby reducing renal tubular reabsorption of sodium.

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Pharmacokinetics

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Absorption: Digoxin has an oral bioavailability of approximately 75%, but its effectiveness may decrease when consumed with high-fiber foods. Some patients' gut flora can metabolize digoxin into dihydro-digoxin, further reducing its absorption.

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Distribution: Digoxin is distributed throughout the body tissues within 6 to 8 hours after administration, followed by a gradual decline in serum concentration as it is eliminated. It has a large volume of distribution, estimated at approximately 475 to 500 liters, and can cross both the blood-brain barrier and the placenta. This results in similar serum concentrations of the drug in both mothers and newborns at delivery time. Additionally, about 25% of plasma digoxin is protein-bound.

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Metabolism: Approximately 13% of a digoxin dose is metabolized into urinary metabolites, such as dihydro-digoxin and polar glucuronides, through oxidation, hydrolysis, and conjugation.

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​Elimination: Digoxin is primarily eliminated through P-glycoprotein-mediated efflux into bile and urine. Drugs that inhibit P-glycoprotein-mediated elimination can increase digoxin concentration. Renal disease necessitates adjustments to the dosage of digoxin.

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Digoxin is contraindicated in patients with moderate to severe renal impairment, ongoing ischemia, or advanced atrioventricular block.​

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The average intravenous loading dose is 0.5 - 0.75 mg, administered slowly to avoid systemic vasoconstriction. Twelve hours after the initial dose, an oral or intravenous dose of 0.25 mg should follow. Digoxin can be initiated with a maintenance dose and adjusted to ensure the trough serum concentration does not exceed 1.0 ng/mL.

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Evidence of digitalis use in patients with heart failure.

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The Effect of Digoxin on Mortality and Morbidity in Patients with Heart Failure (DIG) trial: Patients with left ventricular ejection fractions of 0.45 or lower were randomly assigned to digoxin (3,397 patients) or placebo (3,403 patients), alongside diuretics and angiotensin-converting enzyme inhibitors. The median digoxin dose was 0.25 mg daily, with an average follow-up of 37 months.

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Mortality rates were similar between the groups, with 1,181 deaths (34.8 percent) in the digoxin group and 1,194 deaths (35.1 percent) in the placebo group, resulting in a risk ratio of 0.99 (95 percent confidence interval, 0.91 to 1.07; P = 0.80).

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The DIG trial found a trend (P = 0.06) of reduced deaths from progressive pump failure, which was offset by an increase in sudden and other cardiac deaths (P = 0.04).

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The DIG trial was conducted before the introduction of beta blockers, and there are no large studies examining the use of digoxin in combination with both ACE inhibitors and beta blockers. The other medications utilized for heart failure in the DIG trial included furosemide (81.7%), ACE inhibitors (94.4%), nitrates (42.6%), and other vasodilators (1.2%).

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These benefits were observed particularly in patients with a very low ejection fraction, increased cardiothoracic ratio, or severe signs and symptoms.

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In men enrolled in the DIG trial, trough levels of digitalis between 0.6 and 0.8 ng/mL were associated with decreased mortality. This suggests that trough levels of digitalis should be maintained between 0.5 and 1.0 ng/mL.

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Women are more likely to experience adverse events, possibly because of the relatively lower body weights in women,

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Complication of digoxin​​​

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(1) cardiac arrhythmias, including heart block (especially in older patients) and ectopic and reentrant cardiac rhythms

(2) neurologic complaints such as visual disturbances, disorientation, and confusion

(3) gastrointestinal symptoms such as anorexia, nausea, and vomiting.​

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These side effects can be minimized by maintaining trough levels of 0.5 to 1.0 ng/ mL. In heart failure (HF) patients, clinical toxicity usually appears at serum concentrations over 2.0 ng/mL. Still, there is considerable overlap in levels between those showing toxicity symptoms and those without clinical evidence of intoxication. Amiodarone, carvedilol, and spironolactone are common medications used in heart failure that can interact with digoxin, necessitating a reduced digoxin dose.

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Ischemia, hypokalemia, and hypomagnesemia may increase the risk of developing digitalis toxicity, even at therapeutic doses. Digitalis toxicity may occur with lower digoxin levels, particularly if hypokalemia or hypomagnesemia coexist. 

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Disturbances in cardiac impulse formation, conduction, or both are the hallmarks of digitalis toxicity. Common electrocardiographic manifestations include ectopic beats of AV junctional or ventricular origin, first-degree AV block, an excessively slow ventricular rate response to atrial fibrillation, or an accelerated AV junctional pacemaker. ​ These manifestations may require only dosage adjustment and monitoring. Sinus bradycardia, sinoatrial arrest or exit block, and second- or third-degree AV conduction delay often respond to atropine, but temporary ventricular pacing is sometimes necessary and should be available.​​

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Management of digoxin intoxication

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Gastrointestinal (GI) decontamination for digoxin overdose typically involves activated charcoal, if administered in a timely manner. 

 

If charcoal is given later, multidose activated charcoal (MDAC) may be used due to digoxin's enterohepatic metabolism. Additionally, steroid-binding resins like cholestyramine and colestipol can help prevent further absorption and reduce the serum half-life.

 

However, methods such as forced diuresis, hemoperfusion, and hemodialysis are ineffective for digoxin elimination because of its large volume of distribution (4 to 10 L/kg).

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Oral potassium administration is often helpful, even when the serum potassium is in the normal range, unless high-grade AV block is also present. However, [K +] must be monitored carefully to avoid hyperkalemia, especially in patients with renal failure.

 

Magnesium may be helpful in patients with atrial fibrillation in an accessory pathway in whom digoxin administration has facilitated a rapid accessory pathway-mediated ventricular response; again, careful monitoring is required, in this case to avoid hypermagnesemia.​

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Antidigoxin Immunotherapy

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Life-threatening digoxin or digitoxin toxicity can be reversed with antidigoxin immunotherapy. The Fab dosage is calculated based on the estimated drug ingested or total body digoxin burden and is given intravenously in saline over 30 to 60 minutes. The time to response is approximately 30 minutes (range 20 to 90 minutes).

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If digoxin-specific fragments are not readily available, phenytoin (50 mg per minute, up to a total of 1000 mg) or lidocaine may be given until the arrhythmia is controlled. Anti-arrhythmic drugs of class Ia are contraindicated.

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