What are the signs symptoms and issues with digoxin toxicity?

Adverse effects

Digoxin toxicity, if untreated, can be fatal. The first symptoms of digoxin toxicity are gastrointestinal (abdominal cramps, vomiting, diarrhea) and visual disturbances (green or yellow halos, “fuzzy shadows”—like driving at night with dirty glasses). Confusion and yellow vision may occur with chronic toxicity, followed by atrioventricular blockade, bradycardia, and ventricular arrhythmias. Digoxin toxicity is managed according to the information presented in Box 8-11. Digoxin toxicity is also worsened by hypokalemia. Because digoxin binds to the K+ site of the Na+/K+-ATPase pump, low serum potassium levels increase the risk of digoxin toxicity. Conversely, hyperkalemia diminishes digoxin's effectiveness. Because the typical patient taking digoxin is elderly, often with K+ imbalances and poor renal function, toxicities are not uncommon. A number of other cardiovascular drugs predispose patients to digoxin toxicity, including verapamil, diltiazem, quinidine, and amiodarone. The dosage of digoxin must be substantially reduced if given concomitantly with these drugs. The presumed mechanism underlying this interaction involves the ability of these drugs to inhibit the P-glycoprotein transporter.

Itraconazole

Itraconazole increases steady-state serum digoxin concentrations, perhaps by inhibiting the renal tubular secretion of digoxin [289–291]. An alternative proposed mechanism is inhibition of CYP3A [292], and this has been reported in rats with ketoconazole [293], although an effect on P glycoprotein was also possible. Whatever the mechanism, ketoconazole increased the systemic availability of digoxin from 0.68 to 0.84 and reduced the mean absorption time from 1.1 hours to 0.3 hours. The increased systemic availability could have been explained by inhibition of CYP3A or P glycoprotein in the gut, but the increased rate of absorption could only be explained by inhibition of the P glycoprotein. Since the tmax was unaffected, the authors hypothesized that inhibition of P glycoprotein increased the absorption rate, which would have tended to reduce the tmax, while inhibition of CYP3A, which would have reduced the elimination rate of digoxin, would have tended to increase the tmax. Thus a combination of these two effects would have had no effect on tmax. It should be noted that CYP3A is an important route of metabolism of digoxin in rats, but not in man.

Digoxin toxicity sometimes accompanies this interaction.

A 62-year-old woman who was taking digoxin took itraconazole 400 mg/day for 3 days developed nausea, anorexia, and lethargy; the symptoms improved within 48 hours after withdrawal of itraconazole [294]. The serum digoxin concentrations were not reported.

In a 75-year-old man who took itraconazole in a low dose (200 mg/day) the steady-state serum digoxin concentration only rose from 0.8 to 1.1 ng/ml after 8 days [295].

Two renal transplant patients developed digoxin toxicity when they also took itraconazole [296].

Itraconazole increases the digoxin AUC0 → 72 by about 50%, and reduces its renal clearance by about 20% [297]. Apart from inhibition of the renal secretion of digoxin, which is probably mediated by inhibition of P glycoprotein, a study in guinea pigs also showed significantly reduced biliary excretion of digoxin by itraconazole, suggesting that the interaction between itraconazole and digoxin may be due not only to a reduction in renal clearance, but also to a reduction in the metabolic clearance of digoxin by itraconazole [298].

Digitalis Toxicity: Signs and Symptoms

Digitalis toxicity can produce general systemic symptoms as well as specific cardiac arrhythmias and conduction disturbances. Common non-cardiac symptoms include weakness, lethargy, anorexia, nausea, and vomiting. Visual effects with altered color perception, including yellowish vision (xanthopsia), and mental status changes may occur.

As a general clinical rule virtually any arrhythmia and all degrees of AV heart block can be produced by digitalis excess. However, certain arrhythmias and conduction disturbances are particularly suggestive of digitalis toxicity (Box 20.1). In some cases, combinations of arrhythmias will occur, such as AF with (1) a slow, often regularized ventricular response and/or (2) increased ventricular ectopy (Fig. 20.3).

Two distinctive arrhythmias, when encountered, should raise heightened concern for digitalis toxicity. The first is bidirectional ventricular tachycardia (VT) (Fig. 20.4), a rare type of VT in which each successive beat in any lead alternates in direction. However, this rare arrhythmia may also be seen in the absence of digitalis excess (e.g., with catecholaminergic polymorphic VT; see Chapters 16 and 21).

The second arrhythmia suggestive of digitalis toxicity in the appropriate clinical context is atrial tachycardia (AT) with AV block (Fig. 20.5). Not uncommonly, 2 : 1 AV block is present so that the ventricular rate is half the atrial rate. Atrial tachycardia with AV block is usually characterized by regular, rapid P waves occurring at a rate between 150 and 250 beats/min (due to increased automaticity) and a slower ventricular rate (due to AV block). Superficially, AT with block may resemble atrial flutter; however, when atrial flutter is present, the atrial rate is faster (usually 250–350 beats/min). Furthermore, in AT with block the baseline between P waves is isoelectric. Note: Clinicians should be aware that most cases of AT with block encountered clinically are not due to digitalis excess, but it is always worth checking to rule out the possibility that the patient is or might be taking digoxin.

In a related way, the designation of “paroxysmal atrial tachycardia (PAT) with block” may be misleading. Atrial tachycardia due to digoxin excess is more likely to be sustained, not truly paroxysmal, and should be more properly noted as “AT with block.” Furthermore, this arrhythmia is both a relatively insensitive and a nonspecific marker of digitalis toxicity.

Digitalis toxicity is not a primary cause of AF or of atrial flutter with a rapid ventricular response. However, clinicians should be aware that digitalis toxicity may occur in patients with these arrhythmias. In such cases, as noted above, toxicity may be evidenced by marked slowing of the ventricular rate, e.g., to less than 50 beats/min (Fig. 20.6) or the appearance of frequent premature ventricular complexes (PVCs). In some cases, the earliest sign of digitalis toxicity in a patient with AF may be a subtle regularization of the ventricular cadence (Fig. 20.7).

In summary, digitalis toxicity causes a number of important arrhythmias and conduction disturbances. You should suspect digitalis toxicity in any patient taking a digitalis preparation who has an unexplained new arrhythmia until you can prove otherwise.

CLINICAL SIGNIFICANCE

Digitalis intoxication is the predominant cause of PAT with block. Among the 112 episodes of this arrhythmia reviewed by Lown and Levine in 1958,58 73 percent were attributed to digitalis. Other reports implicated digitalis toxicity in 40 to 82 percent of cases.63,64 In recent years the digitalis dosage used generally has been reduced, resulting in a marked decline of this arrhythmia. In patients not receiving digitalis, this arrhythmia has diverse etiology; it is found usually in patients with advanced heart disease. Body potassium depletion from the use of diuretics was often the precipitating factor, although the serum potassium level was not necessarily below normal. In one reported series of patients with this arrhythmia, chronic pulmonary disease was found in more than half of the patients treated with digitalis.65

CONCLUSIONS AND PROGNOSIS

Digoxin toxicity is often manifested by several clinical signs, most importantly cardiac arrhythmias. Even with the ability to measure serum digoxin levels, it may prove difficult to differentiate between arrhythmias secondary to the drug versus those resulting from intrinsic heart disease. However, treatment of the arrhythmias is often primarily accomplished by withdrawal of the drug, although more sophisticated treatment strategies do exist, as explained earlier. Hemodialysis is not useful because most of the drug has a large volume of distribution and is tissue bound.

The most important aid in the treatment of digoxin toxicity is prevention, especially because there is a narrow window of therapeutic safety. Most animals can be successfully treated by withdrawal of the drug and antiarrhythmic therapy, although life-saving treatment with digoxin-specific Fab fragments may be necessary and are often cost prohibitive in larger animals.

141 A 78-year-old man with a longstanding history of CHF and chronic AF presents with increasing generalized weakness, anorexia, nausea, and vomiting for the last few days. He has been receiving increasing digoxin doses up to 0.5 mg/day to slow the ventricular response to his AF and furosemide 120 mg twice a day to relieve his pulmonary congestive symptoms. What clinical diagnosis should you suspect in this patient?

Digitalis toxicity. Any patient receiving digitalis who presents with GI symptoms, such as anorexia, nausea, or vomiting, should be suspected of having digitalis toxicity. The nausea and vomiting are thought to be mediated by stimulation of the area postrema in the medulla oblongata of the brainstem rather than by any direct effects of digitalis on the GI mucosa. These GI manifestations may occur in patients receiving excessive oral or IV doses of digitalis for the management of heart failure or rapid AF or both. Another diagnosis to consider in an elderly man receiving digoxin and with known peripheral vascular disease presenting with worsening GI symptoms is acute mesenteric ischemia, which is precipitated or worsened by digoxin's mesenteric vasoconstrictor effect. Early clinical suspicion and diagnosis followed by prompt and effective treatment of acute mesenteric ischemia are critically important to improve the clinical outcome. Acute mesenteric ischemia is a life-threatening vascular emergency associated with a 60–80% mortality and is almost uniformly fatal if unsuspected and not effectively and promptly treated.

Oldenbure QA, Lau LL, Rosenberg TJ, et al: Acute mesenteric ischemia: A clinical review, Arch Intern Med 164:1054–1062, 2004.

Digoxin

Digoxin toxicity may cause various arrhythmias and should be suspected in any patient in whom a new arrhythmia develops during digoxin therapy. Likewise, digoxin ingestion should be considered in patients with acute arrhythmias, particularly those associated with CNS and gastrointestinal symptoms (although noncardiac adverse effects may be absent with acute ingestion). Accelerated junctional rhythm may be the first arrhythmia seen. Progressive AV block is common. Sinus bradycardia resulting from either SA node exit block or sinus arrest may occur, as can atrial fibrillation (but usually not atrial flutter). Ectopic atrial arrhythmias may occur. Nearly any ventricular arrhythmia may occur, including multiform ventricular extrasystoles, bigeminy, ventricular tachycardia (particularly “bidirectional” VT, otherwise only seen in rare genetic arrhythmia syndromes; Figure 28-18), and ventricular fibrillation.74

In general, digoxin concentrations less than 2 ng/mL are considered nontoxic. Neonates usually tolerate levels as high as 3.5 ng/mL. Nevertheless, neonates and other intensive care patients may be more susceptible to digoxin toxicity because of renal dysfunction, electrolyte imbalances, and hypoxia. Hypokalemia, excessive calcium infusions, and rapid sinus rates exacerbate digitalis-related arrhythmias.

Purified digoxin-specific Fab antibody fragment, which binds the drug and is eliminated in the urine, is used to treat digoxin toxicity. Prophylactic treatment with this preparation should be gauged according to the quantity ingested, the time since ingestion, and the serum digoxin level. Magnesium sulfate is a useful temporizing treatment while specific antibody treatment is being implemented. Cardioversion should be reserved for life-threatening tachycardias or those unresponsive to these therapies.

Antifungal imidazoles

Itraconazole increases steady-state serum digoxin concentrations, perhaps by inhibiting the renal tubular secretion of digoxin (SEDA-22, 202) (227–229). An alternative proposed mechanism is inhibition of CYP3A (SEDA-21, 196), and this has been reported in rats with ketoconazole (230), although an effect on P glycoprotein was also possible. Whatever the mechanism, ketoconazole increased the systemic availability of digoxin from 0.68 to 0.84 and reduced the mean absorption time from 1.1 hours to 0.3 hours. The increased systemic availability could have been explained by inhibition of CYP3A or P glycoprotein in the gut, but the increased rate of absorption could only be explained by inhibition of the P glycoprotein. Since the tmax was unaffected, the authors hypothesized that inhibition of P glycoprotein increased the absorption rate, which would have tended to reduce the tmax, while inhibition of CYP3A, which would have reduced the elimination rate of digoxin, would have tended to increase the tmax. Thus a combination of these two effects would have had no effect on tmax. It should be noted that CYP3A is an important route of metabolism of digoxin in rats, but not in man.

Digoxin toxicity sometimes accompanies this interaction.

A 62-year-old woman who was taking digoxin took itraconazole 400 mg/day for 3 days developed nausea, anorexia, and lethargy; the symptoms improved within 48 hours after withdrawal of itraconazole (231). The serum digoxin concentrations were not reported.

In a 75-year-old man who took itraconazole in a low dose (200 mg/day) the steady-state serum digoxin concentration only rose from 0.8 to 1.1 ng/ml after 8 days (232).

Two renal transplant patients developed digoxin toxicity when they also took itraconazole (233).

Itraconazole increases the digoxin AUC0–72 by about 50%, and reduces its renal clearance by about 20% (234). Apart from inhibition of the renal secretion of digoxin, which is probably mediated by inhibition of P glycoprotein, a study in guinea pigs also showed significantly reduced biliary excretion of digoxin by itraconazole, suggesting that the interaction between itraconazole and digoxin may be due not only to a reduction in renal clearance, but also to a reduction in the metabolic clearance of digoxin by itraconazole (235).

PAROXYSMAL ATRIAL TACHYCARDIA WITH ATRIOVENTRICULAR BLOCK

Digitalis toxicity causes 70% of cases of paroxysmal atrial tachycardia (PAT) with AV block. Digoxin and diuretics causing hypokalemia should be stopped in these persons. If the serum potassium is low or low-normal, potassium chloride is the treatment of choice. Intravenous propranolol will cause conversion to sinus rhythm in about 85% of persons with digitalis-induced PAT with AV block and in about 35% of persons with PAT with AV block not induced by digitalis.204 By increasing AV block, propranolol may also be beneficial in slowing a rapid ventricular rate in PAT with AV block.

22 What are the electrocardiographic findings of digoxin toxicity?

Digoxin toxicity can result in a variety of ventricular and supraventricular arrhythmias and AV conduction abnormalities. These arrhythmias result from the electrophysiologic effects of digoxin: Increased intracellular Ca2+ levels predispose to Ca2+-induced delayed afterdepolarizations and hence increased automaticity (especially in the junction, Purkinje system, and ventricles); excessive vagal effects predispose to sinus bradycardia/arrest and AV block. Bradyarrhythmias and blocks are more common when the patient is also taking amiodarone. Specific ECG findings include the following:

Sinus bradycardia

Sinus arrest

First- and second-degree AV block

AV junctional escape

Paroxysmal atrial tachycardia with AV block

Bidirectional ventricular tachycardia (VT)

Premature ventricular beats

Bigeminy

Regularized atrial fibrillation or atrial fibrillation with slow ventricular response (common)