Digoxin, a cardiac glycoside, is commonly prescribed for the management of congestive heart failure, atrial fibrillation or flutter, and certain cardiac arrhythmias. However, its clinical use is limited by its narrow therapeutic index, which predisposes patients to toxicity. At elevated concentrations, digoxin toxicity can present with gastrointestinal disturbances, visual changes, and cardiac arrhythmias. This systematic review aims to summarize reported cases of digoxin toxicity, focusing on associated risk factors, drug-drug interactions, and clinical manifestations. A comprehensive literature search was conducted using PubMed and Ovid MEDLINE with the keywords “digoxin” and “toxicity.” Clinical and laboratory features of toxicity were extracted and analyzed. Of the 2,399 articles identified, only 10 met the inclusion criteria for final review. In 4 of the 10 cases, diuretics were implicated as interacting medications. Commonly reported symptoms included nausea, vomiting, visual disturbances, bradycardia, and elevated serum digoxin levels. Identified risk factors for toxicity included female sex, advanced age (60–91 years), renal impairment, and concomitant drug use. Notably, toxicity was observed even at therapeutic or low serum digoxin concentrations in the presence of these risk factors. The most frequent clinical manifestations were gastrointestinal symptoms, vision changes, and bradycardia.
Digoxin, a cardiac glycoside, is commonly prescribed for the management of congestive heart failure, atrial fibrillation or flutter, and certain cardiac arrhythmias. However, its clinical use is limited by its narrow therapeutic index, which predisposes patients to toxicity. At elevated concentrations, digoxin toxicity can present with gastrointestinal disturbances, visual changes, and cardiac arrhythmias [1-6]. This systematic review aims to summarize reported cases of digoxin toxicity, focusing on associated risk factors, drug-drug interactions, and clinical manifestations.
A comprehensive literature search was performed using PubMed and Ovid MEDLINE, focusing on case reports published until 2020. The search was conducted using the keywords “digoxin” and “toxicity,” and only articles detailing cases of digoxin toxicity were included.
The titles and abstracts were initially screened for relevance based on the following inclusion criteria:
Case reports: Only studies presenting real-life clinical cases of digoxin toxicity were included.
Human subjects: The studies had to involve human patients.
Language: Articles were required to be published in English or have an English translation.
Content requirements: Studies that described the digoxin dose administered, possible drug-drug interactions (DDIs), risk factors, and clinical symptoms of digoxin toxicity were considered.
Studies focusing on interactions between digoxin and herbal medicines were excluded. After the initial screening, full-text articles were reviewed, and redundant studies were removed.
Relevant data from the selected studies were carefully extracted and organized into the following categories:
Reference information: Author(s), year of publication, journal source.
Patient information: Demographic details, such as age and gender, for the patient(s).
Digoxin therapy: The dose of digoxin used, the purpose for which it was prescribed, and the duration of the treatment.
Potential causes of toxicity: Identification of factors contributing to toxicity, including whether the patient was on digoxin monotherapy or was taking other drugs that could interact with digoxin.
Case presentation: Detailed information on the patient’s medical history, the clinical manifestations of digoxin toxicity, the ECG results, and serum digoxin concentration levels.
Risk factors: Identified from the cases, including advanced age, female gender, renal impairment, drug-drug interactions, and ineffective communication between healthcare providers.
All data extracted from the articles were presented as a descriptive summary, with no additional statistical analysis performed.
The quality of each case report was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for case reports. This checklist includes eight domains:
Patient demographics: Were the patient’s characteristics described?
Timeline: Was the patient’s history documented in detail?
Clinical presentation: Was the patient’s condition on presentation clearly described?
Diagnostic tests and results: Were diagnostic methods and results presented?
Treatment and intervention: Was the treatment approach outlined?
Post-intervention outcome: Was the patient’s condition after treatment detailed?
Adverse events: Were any adverse effects or unanticipated events identified and described?
Lessons learned: Were any conclusions or lessons learned clearly provided?
Each study was carefully evaluated against these criteria to determine whether it was included in the systematic review.
All collected data were systematically arranged in tables according to their thematic relevance. These tabulated findings were subsequently evaluated and interpreted through a qualitative approach.
The initial database search yielded 2,399 articles—1,827 from PubMed and 572 from Ovid. The keyword “case report” was used as a filter, and further screening was conducted by applying inclusion criteria, including studies involving human subjects and publications in English. Articles that described toxicity caused by agents other than digoxin were excluded. After this process, 80 articles were identified as potentially relevant.
A more detailed evaluation led to the exclusion of 63 articles due to duplication and lack of accessibility. The remaining studies were examined for full-text eligibility. Nine articles were later dismissed because they involved either falsely elevated digoxin levels due to plant ingestion or toxicity unrelated to digoxin intake. Ultimately, eight articles that specifically addressed digoxin-induced toxicity were included in the final analysis.
All selected case reports met the comprehensive reporting criteria outlined in the Joanna Briggs Institute (JBI) Critical Appraisal Checklist across the eight domains. A total of 10 case reports met the inclusion standards and were analyzed in this systematic review.
Digoxin, a cardiac glycoside, is commonly prescribed for managing arrhythmias such as atrial fibrillation and is also used in the symptomatic treatment of congestive heart failure, typically in combination with other drugs. In the reviewed cases, four reports documented its use for atrial fibrillation [7–10], one case for congestive heart failure alone [11], and another for both conditions simultaneously [12]. Additional cases noted the use of digoxin in treating dilated cardiomyopathy with a reduced left ventricular ejection fraction (LVEF) [13] and paroxysmal supraventricular tachycardia [14].
The prescribed digoxin dosage in 4 of the reviewed cases (50%) was 0.25 mg/day [7, 8, 10, 12], whereas a lower dosage of 0.125 mg/day was reported in 2 cases [9, 11].
In two cases, digoxin toxicity was observed without any evident association with drug-drug interactions [8, 9]. However, the remaining six cases revealed multiple co-administered medications that may have enhanced digoxin’s toxic effects through pharmacokinetic or pharmacodynamic interactions.
Among these, diuretics were the most frequently reported class of potentially interacting agents, noted in four separate cases. One case explicitly confirmed a drug interaction involving digoxin and a diuretic [12], while the other three were flagged as having a high potential for such interactions [11, 13, 14]. The specific diuretics mentioned included Furosemide, a loop diuretic, and Spironolactone, a potassium-sparing diuretic, in three cases [11–13]. In another case, a digoxin-diuretic interaction was suspected, although the specific diuretic was not identified [14].
Diltiazem was another frequently cited agent involved in possible drug interactions with digoxin, appearing in two cases [7, 11]. According to Renard et al. [7], the increased systemic exposure to digoxin may have been due to Diltiazem’s inhibition of P-glycoprotein, although the precise mechanism remains uncertain. In the case described by Yang et al. [11], Diltiazem was discontinued based on clinical suspicion of digoxin toxicity. In addition to Diltiazem, other atrioventricular (AV) nodal blocking drugs, such as Carvedilol, were also implicated in potential interactions.
Further medications suspected of contributing to digoxin toxicity included Dronedarone, an antiarrhythmic agent [10], as well as Celecoxib, a nonsteroidal anti-inflammatory drug, and Levothyroxine, typically used in thyroid disorders [12]. Renard et al. [7] also noted that the combined use of Torsemide and Lisinopril could exacerbate renal dysfunction, dehydration, and electrolyte disturbances, thereby increasing susceptibility to digoxin toxicity.
Among the case reports included, nausea and vomiting were the most commonly reported symptoms associated with digoxin toxicity. A critical parameter used to confirm the toxicity diagnosis was the serum digoxin level, with the accepted therapeutic range typically 0.8-2.0 ng/mL.
Nausea and vomiting were the most frequently reported clinical manifestations and were often associated with elevated serum digoxin levels. Visual symptoms also featured prominently in four cases, presenting as changes in vision, disturbances such as blurred or snowy vision, and, in some instances, visual hallucinations. One case specifically described visual disturbances as flashing lights and colored halos—either yellow or red—surrounding objects [14]. Renard et al. [7] documented snowy and blurry vision, whereas Kolev [8] reported a loss of color perception. Additionally, Naha et al. [14] reported visual hallucinations in their case report.
Bradycardia was documented in three separate reports [10, 11, 14], highlighting its significance as a common cardiovascular sign of digoxin toxicity. Other reported clinical features included generalized weakness and fatigue [11] and lethargy [8]. Further symptoms such as altered consciousness [12], palpitations, chest discomfort, and difficulty swallowing were also noted [7]. Cardiovascular complications extended to more serious presentations, including a complete atrioventricular block [11], and gastrointestinal symptoms like loss of appetite were mentioned as well [8].
In the majority of the reported cases, the serum digoxin level (SDL) exceeded the upper therapeutic limit of 2.0 ng/mL, further supporting the diagnosis of toxicity [7, 9–11, 13, 14].
Table 1 presents symptoms of digoxin toxicity.
Table 1. Symptoms of digoxin toxicity
Author (Year) | Dose (mg/day) | Presenting symptoms | Serum Digoxin level Normal: 0.8-2.0 ng/mL | |||
Nausea and Vomiting | Change in vision | Bradycardia | Other symptoms | |||
0.25 | / | -Snowy and blurry vision |
| Dysphagia | 5.7 | |
0.25 | / | The disappearance of color vision |
| -Lethargy -Loss of appetite -Slow AF:35-38 bpm | - | |
0.125 |
|
|
| Ventricular fibrillation following bidirectional tachycardia | 2.4 | |
0.75 |
|
| Junctional bradycardia | Dizziness | >5 | |
0.125 |
|
| / | -Recurrent episode of syncope associated with coughing - Increasing weakness -Dyspnoea -Become nonresponsive -Complete atrioventricular heart block was shown by electrocardiogram (ECG) |
4.3 | |
0.25 | / |
|
| -Increasing confusion -Reduced level of consciousness | 3.0 | |
Not stated | / |
|
|
| 2.5 | |
Not stated | Recurrent vomiting for 3 days | -Photophobia -Visual hallucination -Yellow vision |
| -Condition persisted, although symptomatic treatment with antiemetics | 3.63 | |
Four primary risk factors were frequently linked to digoxin toxicity in the reviewed case reports: female sex, advanced age (between 60 and 91 years), the presence of drug-drug interactions, and renal dysfunction (ranging from impairment to full renal disease). The majority of reported cases involved at least one of these contributing factors. Additional elements highlighted in some reports included electrolyte disturbances such as hypomagnesemia, endocrine abnormalities like hypothyroidism, complex medication regimens with uncertain adherence, and poor coordination between healthcare providers, notably between general practitioners and cardiologists. These factors are collectively presented in Table 2.
Table 2. Summary of risk factors identified in digoxin toxicity cases
Author | Dose (mg) | Female | Age (years) | Drug-drug interaction | Renal problem | Other risk factors |
0.25 | ✓ | 91 | Diltiazem, Torsemide, Lisinopril | Pre-existing advanced kidney disease | Polypharmacy with questionable adherence | |
0.25 | ✓ | 76 | — | Impaired renal function | — | |
0.125 | ✓ | 79 | — | — | — | |
0.75 | ✓ | 82 | Dronedarone | — | Hypomagnesemia | |
0.125 | — | 73 | Carvedilol, Diltiazem (AV nodal blockers) | Chronic renal insufficiency | — | |
0.25 | ✓ | 69 | Celecoxib, Furosemide, Levothyroxine, Spironolactone | Acute renal impairment | Hypothyroidism | |
— | ✓ | 30 | Furosemide | — | — | |
— | ✓ | 65 | Diuretics (unspecified) | — | — |
This review identified congestive heart failure and atrial fibrillation as the most common indications for digoxin therapy. In heart failure, digoxin exerts positive inotropic effects primarily by inhibiting the sodium-potassium ATPase enzyme. This inhibition increases intracellular sodium, indirectly enhancing intracellular calcium via the sodium-calcium exchanger, thereby prolonging the cardiac action potential. The result is a reduced heart rate and enhanced myocardial contractility due to greater calcium availability for excitation-contraction coupling [15].
In atrial fibrillation, digoxin contributes to rate control by exerting vagomimetic effects on the atrioventricular (AV) node. Activation of the parasympathetic nervous system slows electrical conduction through the AV node, thereby decreasing the ventricular response rate. This vagally mediated action prolongs phases 4 and 0 of the cardiac action potential and extends the AV node refractory period, reducing overall heart rate [1].
Digoxin is categorized as a high-alert medication due to its narrow therapeutic index and significant potential for drug-drug interactions (DDIs). Variations in its serum concentration are often attributed to patient-specific factors, including physiological characteristics, concurrent disease states, and concomitant pharmacotherapies. Administering inappropriate doses can result in elevated serum levels, potentially triggering a range of adverse effects involving multiple organ systems [16]. Orally, digoxin is available in both solution form (0.05 mg/mL) and as tablets in strengths of 0.0625 mg, 0.125 mg, and 0.25 mg. Typically, dosing is initiated and maintained at 0.125-0.25 mg/day, with a lower initial dose recommended for individuals aged 70 years and above [12].
For atrial fibrillation, the therapeutic serum digoxin concentration target generally ranges from 1 to 2 ng/mL. In contrast, based on evidence supporting improved clinical outcomes at lower levels, the recommended range for heart failure management has been revised downward in recent years—from 0.8–2.0 ng/mL to 0.5–0.9 ng/mL. Although elevated serum digoxin concentration is a known predictor of toxicity, adverse effects can still occur even within therapeutic thresholds [17].
Regarding drug-drug interactions, six out of ten reported cases (60%) demonstrated that digoxin toxicity was attributable to pharmacological interactions. Among the implicated drug classes, diuretics emerged as the most frequent contributors. These medications, commonly used as first-line options for managing chronic heart failure regardless of etiology, patient age, sex, or clinical profile, are favored for their rapid symptom relief and fluid-regulation capabilities [18]. In this review, Furosemide and Spironolactone were the diuretics most commonly associated with digoxin interaction [11–13].
The interaction mechanism between digoxin and diuretics is believed to be primarily related to electrolyte imbalance. Thiazide and loop diuretics can lead to potassium and magnesium depletion, thereby enhancing digoxin’s cardiotoxic potential [19]. In addition, potassium-sparing agents such as spironolactone have been reported to interfere with digoxin elimination. This occurs by inhibiting digoxin’s tubular secretion, thereby reducing both renal and extrarenal clearance and elevating serum levels [20].
Diltiazem was another medication identified as a possible interacting agent. Although the exact mechanism remains uncertain, its interaction with digoxin is hypothesized to involve the inhibition of P-glycoprotein (P-GP) [7]. P-GP is an ATP-dependent efflux transporter located on the apical surface of intestinal epithelial cells (enterocytes). It functions by pumping drug molecules back into the intestinal lumen, thereby reducing systemic drug absorption. Inhibition of P-GP increases digoxin absorption and elevates plasma concentrations by reducing efflux [21].
Additionally, digoxin has been reported to interact with Levothyroxine, a thyroid hormone replacement therapy. In hypothyroid patients, initiating or adjusting Levothyroxine to achieve a euthyroid state may enhance either digoxin clearance or tissue sensitivity to the drug. Therefore, careful monitoring is advised when thyroid therapy is introduced, modified, or discontinued [22]. Other agents implicated in enhancing digoxin serum levels include Dronedarone, through P-glycoprotein inhibition; Lisinopril, which may elevate digoxin plasma concentrations; and Torsemide, which can lower serum potassium and potentiate digoxin’s effects.
In this review, seven out of ten reported cases of digoxin toxicity were primarily characterized by gastrointestinal manifestations, with nausea and vomiting being the most frequently observed symptoms, occurring in 70% of the cases. In four of these seven cases, the symptoms were associated with elevated serum digoxin levels exceeding the therapeutic range of 0.8 to 2.0 ng/mL. In addition to gastrointestinal complaints, some cases also presented with visual disturbances and bradycardia. The reported visual changes included phenomena such as flashing lights, perception of yellow or red halos around objects, loss of color vision, and, in some cases, visual hallucinations.
Several clinical and demographic factors appear to increase susceptibility to digoxin toxicity, including hypothyroidism, advanced age, and impaired renal function [23]. A significant number of cases reviewed indicated that underlying renal insufficiency or kidney disease was a critical contributor to elevated serum digoxin concentrations. In patients with compromised renal function, the impaired elimination of digoxin may lead to its accumulation in systemic circulation, thereby increasing the risk of toxicity. Supporting this observation, a separate study revealed that approximately 50% of individuals experiencing digoxin toxicity also had concurrent renal impairment. Given this correlation, it is imperative to closely monitor serum digoxin levels in patients with compromised renal function, particularly among elderly individuals [24].
Advanced age was also highlighted as a notable predisposing factor. The age range among the patients in the reviewed cases was 30 to 91 years, with an average age of 68 years. Older adults are inherently more susceptible to cardiovascular conditions such as congestive heart failure and atrial fibrillation, both of which are common indications for digoxin therapy. Furthermore, aging is associated with a physiological decline in renal function and a reduction in the drug’s volume of distribution, both of which may increase the risk of digoxin toxicity [25]. Hypothyroidism emerged as another relevant risk factor, as thyroid dysfunction can significantly affect digoxin pharmacokinetics. Specifically, hypothyroidism is known to decrease both the volume of distribution and clearance of digoxin, whereas a hyperthyroid state can elevate both parameters [12]. Conversely, while some studies have mentioned potential sex-related differences in digoxin response, the exact mechanisms through which sex might influence the risk of toxicity remain unclear.
Digoxin remains a frequently prescribed medication for the management of congestive heart failure (CHF) and atrial fibrillation (AF), typically administered at doses of either 0.125 mg or 0.25 mg. Among the reported cases, diuretics emerged as the most commonly implicated interacting agents, with several pharmacokinetic and pharmacodynamic mechanisms contributing to this interaction. The predominant clinical manifestations of digoxin toxicity included gastrointestinal symptoms such as nausea and vomiting, as well as visual disturbances and bradycardia. Identified risk factors that may predispose patients to digoxin toxicity include female sex, advanced age (ranging from 60 to 91 years), concurrent use of interacting medications, and impaired renal function. Given the narrow therapeutic window of digoxin, regular monitoring of serum digoxin concentrations is strongly advised in these vulnerable populations to optimize therapeutic outcomes and minimize the risk of toxicity.
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