202409281933
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Tags: pharmacology, toxicology
Digoxin
Digoxin inhibits sodium-potassium ATPase, so that there is more sodium inside the cell and therefore less of a sodium gradient. In turn, the sodium-calcium exchanger cannot pump as much calcium out of the cell, resulting in higher intracellular concentrations of calcium. The excess calcium binds with troponin C and other contractile proteins that rely on calcium coupling, thus leading to an enhanced myocardial inotropic response and increased force of contraction.
Digoxin’s effect on cardiac contractility is seen primarily in patients with decreased left ventricular function, in whom digoxin improves left ventricular ejection fraction and decreases pulmonary capillary wedge pressure. These effects are not seen in patients with normal left ventricular ejection fraction
↑ calcium inside the cell leads to inactivation of L-type calcium channels (the main route for calcium entry into cardiomyocytes), which shortens the duration of the action potential and refractory period of cardiomyocytes, a mechanism that favors reentry arrhythmias.
↓ potassium and ↑ sodium in the cell lead to ↑ diastolic repolarization and automaticity, which may favor supraventricular arrhythmias and lead to rapid spontaneous rhythms of Purkinje fibers
At ↑ digoxin concentrations, the sarcoplasmic reticulum becomes overloaded with calcium and can spontaneously release enough calcium to depolarize the cell, resulting in extrasystoles, bigeminy, and a higher risk of ventricular fibrillation.
In the autonomic nervous system, digoxin ↓ sympathetic response and ↑ parasympathetic response, mainly by stimulating the central vagal nucleus.
It also restores baroreceptor sensitivity, which is attenuated in low-output heart failure, and as such improves heart rate variability and decreases catecholamine release.
In conjuction with digoxin’s inotropic effect, these neurohormonal changes lead to favorable hemodynamic changes in heart failure. Decreased preload and afterload with increased contractility lead to reduced chamber dilation and wall stress, thereby reducing myocardial oxygen consumption.
The vagal (parasympathetic) effects of digoxin result in a lower sinus rate, decreased automaticity and conduction velocity, and a prolonged refractory period of the atrioventricular node, which makes it effective for rate control in atrial fibrillation
Pharmacokinetics
oral bioavailability of about 70%
25% of serum digoxin is albumin-bound, and its volume of distribution is large (5–10 L/kg) due to extensive binding to muscle tissue.
The drug penetrates the blood-brain and placental barriers and cannot be removed from plasma with dialysis. Serum digoxin levels are typically checked at least 6 hours after an oral dose
The onset of action after an oral dose is at about 2 hours, and the peak effect is at 6 hours. Given intravenously, the onset of action is within 5 to 30 minutes, with maximum effect within 1.5 to 4 hours.
Digoxin is excreted primarily by the kidneys; its half-life is 36 to 48 hours in patients with normal kidney function, but up to 6 to 8 days in anuric patients
When digoxin is used for rate control in atrial fibrillation, intravenous loading is usually required for faster onset of action. In this setting, an initial intravenous dose of 0.25 to 0.5 mg is given over several minutes, followed by 0.25 mg every 6 hours for a total of 0.75 to 1.5 mg over 24 hours (10–12 μg/kg of lean body weight).
For patients with low body weight (ie, 45–70 kg), digoxin loading should be limited to 0.75 to 1.0 mg in the first 24 hours
Drugs ↑ risk of digoxin toxicity:
| Medication | Mechanism of interaction | Comments |
|---|---|---|
| Amiodarone, quinidine, dronedarone, nondihydropyridine calcium channel blockers (diltiazem and verapamil), propafenone, flecainide, clarithromycin, cyclosporine, itraconazole | Inhibition of P-glycoprotein, a drug efflux pump that mediates secretion of digoxin in the kidney, liver, and gut | Digoxin dose may have to be decreased to half when starting any of these medications Check digoxin levels 1 week after starting any P-glycoprotein inhibitor |
| Macrolides (azithromycin, clarithromycin, erythromycin) and tetracycline | Decreased initial degradation of digoxin by gut microflora, leading to increased drug absorption | Monitor levels closely when co-administering digoxin with these antibiotics |
| Diuretics, amphotericin B | Decreased glomerular filtration rate and hypokalemia can increase digoxin toxicity | Monitor potassium levels to avoid hypokalemia |
| Nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, cyclosporine | Decreased glomerular filtration rate and acute kidney injury | Telmisartan increases digoxin concentration by about 50% |
| Beta-blockers, nondihydropyridine calcium channel blockers | Slowing of atrioventricular conduction can lead to bradycardia compounding on digoxin’s vagotonic effects | Increased risk of bradycardia; carvedilol can increase digoxin concentration |
| Amiodarone, sotalol, quinidine, procainamide, dofetilide, ibutilide, quinolones, macrolides, azole antifungals, tricyclic antidepressants, antipsychotics, methadone | QT-prolonging agents increase risk of life-threatening arrhythmias as digoxin increases early afterdepolarizations, which can lead to R-on-T phenomenon and torsade de pointes | Monitor QT closely when adding any of these medications |
Drug interactions
P-glycoprotein is a drug efflux pump that mediates secretion of digoxin in the kidney, liver, and gut. Drugs that inhibit P-glycoprotein raise the serum level of digoxin and can lead to toxicity. These include several antiarrhythmics such as amiodarone, quinidine, dronedarone, nondihydropyridine calcium channel blockers, propafenone, and flecainide, as well as other drugs such as clarithromycin, cyclosporine, and itraconazole
Quinidine can double the serum digoxin concentration, and amiodarone increases it by 60%.
Digoxin dosing should be reduced, typically to half of the previous dose, when it is given concomitantly with most P-glycoprotein inhibitors. Digoxin levels should be checked 1 week after starting these drugs.
Some antibiotics can decrease initial degradation of digoxin by gut microflora and thereby increase its absorption. In about 10% of patients, digoxin undergoes sequential hydrolysis in the proximal gastrointestinal tract. Macrolides and tetracycline increase serum digoxin levels by inhibiting this mechanism, and digoxin levels should be closely monitored when giving these antibiotics.
Diuretics can increase serum digoxin concentrations by decreasing the glomerular filtration rate and causing hypokalemia, which increases digoxin’s potential for arrhythmias.
Hyperkalemia reduces digoxin’s binding affinity for sodium-potassium ATPase
hypokalemia reduces repolarizing potassium currents in the action potential, leading to increased diastolic depolarizations and automaticity and thus enhancing the arrhythmogenic effects of digoxin.
Hypercalcemia and hypomagnesemia contribute to calcium overload in the sarcoplasmic reticulum and therefore promote spontaneous depolarizations
Cardiac manifestations of digoxin toxicity include virtually any type of arrhythmia and are the most serious and potentially lethal complications of toxicity. Digoxin toxicity can lead to all degrees of atrioventricular block and result in clinically significant bradycardia that can be refractory to pacing, as well as sinus arrest and sinus exit block through its action on the sinus node. Ventricular ectopy is an early sign of digoxin toxicity but is not always present
Bidirectional ventricular tachycardia and nonparoxysmal junctional tachycardia (> 80 beats per minute) are suggestive of but not specific to digoxin toxicity. Enhanced automaticity can lead to supraventricular tachycardia as well as ventricular tachycardia and fibrillation
Other electrocardiographic changes of digoxin toxicity include PR prolongation, shortening of the QT and QTc intervals, and a change in ventricular repolarization resulting in nonspecific ST-segment depressions classically described as “sagging” depressions. These changes do not imply toxicity and can be present with therapeutic drug levels
DigiFab
Digoxin-fab is an ovine (sheep) monovalent immunoglobulin with 100 to 1,000 times more affinity for digoxin than digoxin’s binding site in sodium-potassium ATPase. It rapidly binds free digoxin in the serum and creates a gradient for intracellular digoxin to move into the serum, where it is subsequently bound by antibodies.
Digoxin-fab is eliminated by the kidneys and liver; it has a half-life of 19 to 30 hours, but this can increase up to 10 times in patients with renal dysfunction. The onset of action to reversal of digoxin toxicity after acute ingestion is around 30 to 45 minutes. The main adverse effect is a hypersensitivity reaction to sheep protein.
One vial contains 38 to 40 mg of digoxin-fab, which binds approximately 0.5 mg of digoxin.
In the case of acute ingestion in which the total ingested dose is known, the number of required vials is calculated by dividing the total body load (ingested dose × 0.8) by 0.5 and rounding up to the nearest digit.
If steady-state serum digoxin levels are known in a stable patient with chronic toxicity, the dose of vials can be calculated by dividing the product of the serum concentration (in ng/mL) and the patient’s weight (in kg) by 100 and rounding up to the nearest digit
If the digoxin level is not known or cannot be accurately measured due to recent ingestion (< 6 hours), 2 vials can be given, with repeated dosing if there is no apparent clinical response. This approach can also be used if a patient has relative hemodynamic instability and waiting for serum digoxin levels is impractical.
The use of digoxin-fab can precipitate rebound heart failure or atrial fibrillation due to the sudden binding of free serum digoxin. If this is a clinical concern, half of the calculated dose can be given instead.
In general, vials should be administered over 30 minutes, unless a patient is in imminent cardiac arrest, in which case 10 vials (or 5 vials for pediatric patients) can be given empirically over several minutes.
Digoxin-fab causes redistribution of digoxin from tissues into serum, and digoxin bound to antibodies is also recognized by immunoassays, both of which can result in rising levels of serum digoxin if these are checked after digoxin-fab administration. In general, digoxin levels should not be used for clinical decision-making up to 3 weeks after using digoxin-fab, since assays will measure antibody-bound digoxin as well as unbound digoxin in serum. Because antibody half-life increases up to 10-fold in patients with renal dysfunction, these patients might require closer monitoring and even measurement of digoxin-binding antibodies before digoxin therapy is restarted