Use of Digitalis in Older Adults: A Recent Update
Dr. Golzari is Attending Staff, Department of Medicine, St. Vincent’s Medical Center, Bridgeport, CT.
Plants of the genus Digitalis are the source of digoxin. Historical evidence of pharmacological use of purple foxglove (Digitalis purpurea) is documented as early as 1250, when it was used as a recipe for headache. Its topical form was used in 1466 for wound healing. In 1785, Dr. William Withering, an English physician and botanist, analyzed approximately 200 cases, mostly with “dropsy” in his An Account of the Foxglove and Some of its Medical Uses: With Practical Remarks on Dropsy and Other Diseases. Dr. Withering considered digitalis to be a diuretic.
Digoxin is the most frequently used digitalis glycoside in the United States. It is the fifth most frequently prescribed medication, particularly in the elderly due to increased prevalence of its indications.
For the purpose of this discussion, only studies that included patients more than 70 years of age are presented.
Mechanism of Action
Digoxin inhibits the Na,K-ATPase pump in myocardial cells. Therefore, the transmembrane sodium gradient is reduced. This reduction in turn raises intracellular calcium concentration, which leads to enhanced isolated myocyte contractile performance (positive inotropic effect).This effect is more pronounced in decompensated heart failure (HF) and systolic dysfunction. Digoxin reduces plasma renin-angiotensin system activity (neurohormonal deactivation effect) and decreases norepinephrine levels.1,2
Digoxin increases parasympathetic tone (via central and peripheral effects) and slows conduction through the sinoatrial and atrioventricular (AV) nodes. It increases baroreceptor sensitivity, which results in decrease of sympathetic activation. This sympatholytic activity of digoxin diminishes systemic vascular resistance (SVR) and venous tone. Digoxin increases contractility without increasing heart rate.2
With lower doses (serum level of 1-2 ng/mL), digoxin decreases automaticity, decreases AV nodal velocity, and prolongs the effective refractory period.
Digoxin has positive inotropic effect at higher serum levels (eg, usually achieved by doses of 0.25 mg/day or more), but at the lower serum levels (eg, doses less than 0.25 mg/day) it has more neurohormonal effect and negligible inotropic effect. Digoxin improves renal perfusion (thus renal function) via increasing cardiac inotropic effect. It directly inhibits renal tubular sodium reabsorption due to the inhibition of renal Na,K-ATPase pump.
Digoxin is rapidly absorbed from the gastrointestinal tracts (70-80% oral bioavailability). When oral route cannot be used, it should be administered intravenously. Due to erratic absorption and local pain, its intramuscular administration should be avoided.
Age-related changes in the gastrointestinal tract (increase in gastric pH, decrease in gastrointestinal motility and blood flow) do not appear to alter the absorption of digoxin significantly. Its extent of absorption may be increased in elderly patients with hypochlorhydria. Digoxin is converted into inactive metabolite by intestinal bacteria Eubacterium lentum. This bacterium is found in 10% of the general population and is responsible for “resistance” to standard oral doses of digoxin.
Digoxin has a large volume of distribution in young healthy individuals. With advancing age and accompanying decrease in lean body mass and increase in adipose tissue, its volume of distribution is reduced. The result is increased half-life and higher serum concentration for hydrophilic medications (eg, digoxin, ethanol). Hence, the average half-life of digoxin in the geriatric population is longer (70 hr), but can range between 24 to 129 hours.
Digoxin is 20-30% protein-bound. However, the decrease in albumin frequently seen in the geriatric population does not alter its distribution. Consequently, digoxin half-life remains unchanged due to hypoalbuminemia.
Approximately 60-80% of digoxin is excreted by passive glomerular filtration and active tubular secretion. The remainder is excreted via hepatic metabolism. Both renal blood flow and glomerular filtration rates decline with advancing age. Mean creatinine clearance of 140 mL/min in 30-year-old individuals decreases to 97 mL/min in 80-year-old individuals.
The principal reservoir of digoxin is skeletal muscle. Therefore, its dose should be based on lean body mass as well as renal function, both of which are critical determinants in the elderly. The blood level should also be used to monitor dosing in this population (see “Digoxin Toxicity” below). To calculate lean body mass, the following formula can be utilized:
Lean body mass = ideal body weight + 0.4 (actual body weight - ideal body weight)
Ideal body weight:
Male = 50 kg + (2.3 kg for each inch of height > 5 feet)
Female = 45.5 kg + (2.3 kg for each inch of height > 5 feet)
Digoxin cannot effectively be removed by peritoneal dialysis, hemodialysis, and exchange transfusion, or during cardiopulmonary bypass. The absorption of digoxin is impaired in patients with extensive jejunal and ileal resection, jejunoileal bypass procedure, or malabsorption syndrome.
There are three main indications for digoxin: (1) to improve cardiac contractility in HF patients with systolic dysfunction; (2) to control ventricular rate in patients with chronic atrial fibrillation (AF) or atrial flutter; and (3) to prevent recurrence of certain types of re-entrant paroxysmal supraventricular tachycardia (RPSVT).
To Improve Cardiac Contractility in Heart Failure Patients with Systolic Dysfunction
It is estimated that 4 to 5 million people in the United States and 10 million people in countries represented by the European Society of Cardiology have HF.3 In the United States, approximately 500,000 patients are diagnosed each year. The prevalence of HF increases dramatically with age, with a mean age in such patients of 74 years.4-6
Digoxin improves hemodynamics both at rest and during exercise. It reduces pulmonary capillary wedge pressure (PCWP), enhances left ventricular ejection fraction (EF), and increases cardiac output in patients with abnormal hemodynamics and systolic dysfunction. In decompensated HF due to systolic dysfunction, it increases stroke volume, while end-diastolic and end-systolic volumes, as well as ventricular filling pressures, are decreased. Additionally, it improves exercise capacity. In the study by Gheorghiade et al7 in patients with severe HF (New York Heart Association functional class III or IV) and sinus rhythm, intravenous captopril and digoxin were given in combination or separately. Compared to placebo, at rest, both captopril and digoxin independently decreased PCWP by 24% (P = 0.003) and 34% (P = 0.004), respectively. There was a reduction in SVR by 23% (P = 0.09) and 20% (P = 0.03), respectively. Only digoxin increased cardiac index by 23% (P = 0.03) and stroke work index (SWI) by 52% (P = 0.01). The combination of captopril and digoxin resulted in a decrease in PCWP and SVR and increase in cardiac index and SWI, both at rest and during exercise. In this investigation, the decrease in PCWP and SVR and increase in cardiac index and SWI were greater with the combination of captopril and digoxin, compared to each medication alone, both at rest and during exercise. In this study, the mean age of patients was 57 (range, 33-81 yr).
The largest trial, assessing the therapeutic value of digoxin in HF, was the Digitalis Investigation Group (DIG) study.8 This prospective, randomized, double-blind, placebo-controlled trial enrolled 6800 patients with normal sinus rhythm and EF less than 45%. The percentage of patients older than age 70 years was similar in both groups (26.7% in the digoxin group and 27.4% in the placebo group). All patients received a diuretic and an angiotensin-converting enzyme (ACE) inhibitor, but were randomized to either a placebo (3403) or digoxin (3397). Patients in the digoxin group received 0.125-0.500 mg of medication daily. Patients were followed up to an average of 37 months. At the end of the trial, there were no differences in the primary end point (mortality) between two groups (34.8% with digoxin vs 35.1% with placebo; risk ratio = 0.99; 95% confidence interval [CI], 0.91-1.07; P = 0.80). No statistically significant difference was observed in the secondary end point of the trial: mortality from cardiovascular causes (29.9% with digoxin vs 29.5% with placebo; risk ratio = 1.01; 95% CI, 0.93-1.10; P = 0.78) and death from worsening of congestive HF (11.6% with digoxin vs 13.2% with placebo; risk ratio = 0.88; 95% CI, 0.77-1.01; P = 0.06). In contrast, patients on digoxin experienced significantly less hospitalization for cardiovascular event (49.9% with digoxin vs 54.4% with placebo; risk ratio = 0.87; 95% CI, 0.81-0.93; P < 0.001) and less hospitalization due to worsening of congestive HF (26.8% with digoxin vs 34.7% with placebo; risk ratio = 0.72; 95% CI, 0.66-0.79; P < 0.001). This trial did not show any benefit of overall survival and demonstrated neutral effect on all-cause mortality. There was a reduction in the overall number of hospitalizations and the combined outcome of death or hospitalization due to worsening of HF.
Until recently published data from the DIG trial,9 the long-term effect of discontinuation of digoxin therapy on mortality and morbidity in HF was unclear. In this study, of 7788 participants in the DIG trial,8 43% of them (3365 patients) who were taking digoxin at the enrollment time subsequently were randomized to placebo (discontinued digoxin) and digoxin (continued on long-term digoxin therapy). Patients who were taking digoxin were divided into low (0.5-0.9 ng/mL) and high (≥ 1.0 ng/mL) serum digoxin concentration (SDC) groups. Mean age of patients was 63 years. At the end of the study (median duration of follow-up of 39.7 months), there was no significant difference in all-cause mortality between two groups (39.1% with placebo vs 38% with digoxin, adjusted hazard ratio [AHR] = 1.06; 95% CI, 0.95-1.19; P = 0.272). Compared to the digoxin group, patients taking placebo had significantly higher rate of all-cause hospitalization (70% with placebo vs 67.5% with digoxin, AHR = 1.18; 95% CI, 1.09-1.28; P < 0.0001) and HF hospitalization (39.6% with placebo vs 32.3% with digoxin, AHR = 1.35; 95% CI, 1.20-1.51; P < 0.0001). Compared to placebo, patients in the low SDC group had significant reduction in all-cause mortality (38% with placebo vs 32% with digoxin, AHR = 0.75; 95% CI, 0.63-0.90; P = 0.002), all-cause hospitalization (70% with placebo vs 66% with digoxin, AHR = 0.80; 95% CI, 0.70-0.91; P = 0.001), and HF hospitalization (40% with placebo vs 29% with digoxin, AHR = 0.60; 95% CI, 0.50-0.73; P < 0.0001). Patients taking high SDC, compared to placebo, did not show any difference in all-cause mortality (38% with placebo vs 45% with digoxin, AHR = 1.03; 95% CI, 0.86-1.12; P = 0.580) and all-cause hospitalization (70% with placebo vs 69% with digoxin, AHR = 0.94; 95% CI, 0.88-1.01; P = 0.102). However, patients in the high SDC group had significantly lower rate of HF hospitalization compared to placebo (40% with placebo vs 34% with digoxin, AHR = 0.83; 95% CI, 0.76-0.92; P < 0.0001). This study demonstrates that continuation of digoxin at low SDC is associated with a reduction in both mortality and hospitalization in ambulatory patients with chronic HF receiving background therapy with ACE inhibitors and diuretics.
One small crossover, randomized, double-blind trial showed that oral digoxin as compared to placebo improved HF scores in patients with HF who are in sinus rhythm. The severity of HF was expressed by a score that was based on clinical and radiologic observations. The age of the patients ranged between 40 to 83 years, and they were maintained on diuretic therapy. The score of HF severity decreased from 3.6 ± 0.7 to 2.0 ± 0.4 (P < 0.05). In multivariate analysis, the third heart sound was the strongest correlate of the response to digoxin therapy.10
Digoxin has been approved by the Food and Drug Administration for treatment of chronic mild-to-moderate HF, but it has never been tested in acute HF. Digoxin should not be discontinued abruptly in patients with chronic HF.
To Control Ventricular Rate in Patients with Chronic Atrial Fibrillation or Atrial Flutter
Digoxin is the drug of choice in patients with HF and AF. It can be used to slow the ventricular rate. However, it may not be very efficacious in certain circumstances (eg, in patients with high sympathetic discharge due to conditions such as hypoxemia or thyrotoxicosis). Digoxin can be used in conjunction with beta blockers and calcium channel blockers for better rate control. In cases of beta blocker contraindication, amiodarone can be added to digoxin for rate control.11
A very effective strategy for patients who have systolic dysfunction and are in AF with high ventricular rate is a combination of digoxin and a beta blocker. In a randomized, controlled, double-blind, parallel-arm study by Khand et al,12 patients with persistent AF (> 1 month duration) and HF (mean left ventricular EF, 24%) were examined. Most patients were treated with ACE inhibitor, diuretic, and warfarin. Mean age of patients in the placebo and carvedilol groups were 68.4 ± 9.8 and 68.6 ± 9.4 years, respectively (not statistically significant). In phase 1 (4 months duration), digoxin was compared with the combination therapy (carvedilol plus digoxin). Compared with digoxin, the combination therapy reduced the 24-hour mean ventricular rate by ambulatory electrocardiographic monitoring (beat/min) (74.9 ± 11.2 with digoxin vs 65.2 ± 15 with combination therapy; P < 0.0001), as well as peak ventricular rate with submaximal exercise (123 with digoxin vs 106 with combination therapy; P < 0.05), and improved symptom score (based on chest pain/discomfort, fatigue, shortness of breath, palpitations, “global health,” sense of well-being) (8 with digoxin vs 7 with combination therapy; P < 0.05) and left ventricular EF (26 ± 12.4 with digoxin vs 30.6 ± 9.6 with combination therapy; P < 0.05). In contrast, New York Heart Association functional class, 6-minute walk distance (414 ± 114 with digoxin vs 394 ± 82 with combination therapy; P = 0.49) and serum brain natriuretic peptide (120.5 with digoxin vs 153 with combination therapy; P < 0.11) were not significantly different between the two groups. In the second phase (6 months duration), digoxin alone was compared with carvedilol alone. There was no statistically significant difference between digoxin and carvedilol in any of the aforementioned variables. This study indicates that the combination of digoxin and carvedilol improves symptoms, reduces ventricular rate, and improves ventricular function in patients with HF and persistent AF.
Two randomized trials of intravenous digoxin, the Digitalis in Acute Atrial Fibrillation (DAAF) Trial Group13 (with a mean age of 66 ± 12.9 years [range, 21-89 yr]) and Jordaens et al14 (with a mean age of 64 ± 17 years), have not shown digoxin to be effective in converting recent-onset AF to normal sinus rhythm.
In a multicenter, randomized, double-blind, crossover trial (mean age, 58.2 ± 11.2 yr), as compared to placebo, oral digoxin did not reduce the frequency, the duration, or the mean ventricular rate during paroxysms of AF.15 In a multicenter, double-blind, placebo-controlled trial from Atarashi et al,16 patients with a history of symptomatic paroxysmal or cardioverted persistent AF to normal sinus rhythm were randomized to aprindine (40 mg/day), digoxin (0.25 mg/day), and placebo. The ages between the three groups were not significantly different (60 ± 10, 62 ± 12, and 61 ± 12 yr, respectively). After the 6-month follow-up period, the percentage of patients who remained free of recurrent symptomatic AF did not differ significantly between the three groups (33.3%, 29.2%, and 21.5%, respectively). Among the patients who remained in sinus rhythm at 15 days, there were significantly higher proportions of patients free from recurrence in the aprindine group (56.7%) than the placebo group (40.7%; P = 0.0414), but there was no difference between the digoxin group and the placebo group (P = 0.206).
In the randomized crossover trials of Bianconi et al,17 intravenous digoxin was found to be to be less efficacious for conversion of recent-onset (less than 72 hr) of AF, compared to intravenous propafenone. The mean age of patients in the propafenone and digoxin groups were 59 ± 13 and 59 ± 12 years, respectively. At the end of the trial, 50% of patients in the propafenone group and 25% in the digoxin group converted to normal sinus rhythm (P < 0.01).
In another prospective randomized trial by Baroffio et al,18 intravenous propafenone converted 88% (22 of 25 patients) to normal sinus rhythm, as compared to 32% (8 of 25 patients) in the digoxin group (P = 0.00005). None of the patients had clinical evidence of HF, and the mean age in the propafenone and digoxin groups were 60 ± 14 and 56 ± 12 years, respectively.
Digoxin shortens the atrial effective refractory period. This electrophysiologic effect may predispose patients with paroxysmal AF to the sustained, chronic form. Therefore, evidence-based medicine does not support digoxin for suppression of paroxysmal AF or conversion of AF to normal sinus rhythm.
To Prevent Recurrence of Certain Types of Re-entrant Paroxysmal Supraventricular Tachycardia
Recurrent episodes of supraventricular tachycardia should be treated with prophylactic medication. Those with AV nodal re-entrant tachycardia or AV re-entrant tachycardia mediated by a concealed accessory pathway can primarily be treated with digoxin (0.125-0.375 mg/day).19
Contraindications of Digoxin Therapy
Digoxin should not be used to treat high-output HF due to anemia or thyrotoxicosis. It should be avoided in patients in acute stage of myocardial infarction, since it increases myocardial oxygen consumption by increasing cardiac contractility, inducing peripheral and coronary vasoconstriction, thereby increasing the infarct size. Other contraindications include:
• Wolf-Parkinson-White (WPW) syndrome: Digoxin may increase the risk of rapid ventricular response, therefore may cause AF to degenerate into ventricular fibrillation. Digoxin can be used in WPW syndrome only when the accessory pathway has a long refractory period (300 msec or more).19
• Patients with preserved left ventricular systolic function: Namely, restrictive cardiomyopathy, constrictive pericarditis, amyloid heart disease, acute cor pulmonale, idiopathic hypertrophic subaortic stenosis.
Additionally, digoxin may predispose patients to carotid sinus syncope, which mainly affects men older than 60 years of age.
In recent years, there has been a decline in the incidence of digoxin toxicity. The advent of the new medications for treatment of HF (ie, ACE inhibitors, angiotensin II receptor blockers, beta blockers, and aldosterone antagonists) have been a contributing factor in this decline.
Numerous age-related changes in pharmacokinetics predispose elderly patients to digoxin intoxication (see above). These changes, in conjunction with a greater likelihood of polypharmacy, place the geriatric population at increased risk for significant drug interactions (Table). For example, administration of a nonsteroidal anti-inflammatory agent may reduce its renal clearance. The addition of a beta blocker may not only increase the serum digoxin level but may also prolong the AV conduction and predispose to AV block and bradycardia.
Certain disease states that reduce creatinine clearance (eg, HF) raise the serum digoxin level. However, with improvement of HF, increase in cardiac output and renal blood flow mediated by other medications (eg, ACE inhibitors, angiotensin II receptor blockers), the dose of digoxin should be adjusted accordingly.
In a retrospective study, among 219 hospitalized patients with HF (mean age, 75 ± 11 yr), definite digoxin toxicity was seen in 0.8% of patients and possible digoxin toxicity in another 4%.20 In the DIG study,8 there was no significant difference between the digoxin group (3397) and the placebo group (3403) in the risk of ventricular fibrillation or ventricular tachycardia (1.1% with digoxin vs 0.8% with placebo; relative risk = 1.40; 95% CI, 0.84-2.30; P = 0.20). However, compared to placebo, digoxin significantly increased the rate of both supraventricular arrhythmia (2.5% with digoxin vs 1.2% with placebo; relative risk = 2.10; 95% CI, 1.45-3.07; P < 0.001) and 2nd and 3rd degree AV block (1.2% with digoxin vs 0.4% with placebo; relative risk = 2.87; 95% CI, 1.56-5.28; P < 0.001).
Miura et al21 showed there was an overlapping toxic and nontoxic range of SDC (1.4-2.9 ng/mL), in which the incidence of digoxin toxicity was patient-dependent. The overlapping range tended to broaden and shift to a lower concentration with increasing age. Therefore, digoxin toxicity may occur despite therapeutic SDC.
In general, when higher doses of digoxin are used (greater than 0.25 mg/day), the incidence of digoxin toxicity increases. Lower doses of digoxin should be used in elderly individuals (0.125-0.25 mg/day). Serum digoxin concentration of 0.5-0.9 ng/mL is recommended by the Heart Failure Society of America.22 This recommendation is consistent with the results of recent published data from the DIG trial.9
Digoxin toxicity is seen not only in patients taking digitalis, but in individuals taking other herbal supplements with similar pharmacological activities. These include yellow oleander (Thevetia peruviana), purple foxglove (Digitalis purpurea), Grecian foxglove (Digitalis lanata), squill (Urginea maritima), lily of the valley (Convallaria majalis), rhododendron, and secretions of Bufo toad skin. Therefore, in the presence of characteristic clinical and/or electrocardiographic manifestations and undetectable serum digoxin level, toxicity with the above substances should be considered.
There are numerous medications that interact with digoxin. Therefore, it is essential to be familiar with medications that may change the SDC or predispose to its toxicity (Table).
Symptoms and signs of digoxin toxicity are divided into two broad categories: noncardiac manifestations and cardiac manifestations.
These are quite nonspecific in nature and can be the sole manifestation of toxicity. They include anorexia, generalized muscle weakness, fatigue, hyperkalemia, and weight loss.
Gastrointestinal. Includes nausea, vomiting, diarrhea, abdominal pain, copious salivation, mesenteric ischemia, dysphagia, black color of stool, and nonocclusive mesenteric infarction.
Neuropsychiatric. Includes psychosis, nightmares (dream anxiety disorder), delirium, disorientation, confusion, aphasia, chorea, dysphonia, headache, dizziness, hallucination, paranoia, depression, neuralgic pain mimicking trigeminal neuralgia, and neuralgic pain in the extremities and lumbar area (accompanied by paresthesia). Neuropsychiatric symptoms are more likely to occur in elderly patients with atherosclerosis. Rarely, convulsions have occurred.
Ophthalmologic. Patients may develop color blindness, which can be a presenting complaint. In the study done by Lawrenson and Groves,23 among elderly hospitalized patients (mean age, 81.3 yr) taking digoxin, a significant number of red-green errors, as compared to a control group, was observed. Interestingly, there was no correlation between SDC and the number of red-green errors, tritan errors, and total errors.
Chromatopsia is most common for yellow and green, less frequently red, brown, and blue. White vision, blurred vision, corneal edema (with topical application), transitory amblyopia, diplopia, scotoma, retrobulbar neuritis, miosis, and photophobia were reported.
Hematologic. Agranulocytosis, eosinophilia, and thrombocytopenia can be seen.
Dermatologic. Skin lesion in the form of urticarial or scarlatiniform rash were observed.
Pulmonary. Acute lung injury, decrease in FEV1 in a patient with asthma (taking 0.5 mg/day) was reported. Bronchial hyperresponsiveness may increase.
Urogenital. Vaginal cornification in postmenopausal women.
Endocrine. Gynecomastia, sexual dysfunction, increase in serum estrogen level in both older women and men, decrease in luteinizing hormone and testosterone serum level in older men.
Cardiac Manifestations and Predisposing Factors
Several factors increase the risk of digoxin toxicity: renal insufficiency, hypernatremia, hypokalemia, hypomagnesemia, hypercalcemia, alkalosis, acidosis, hyperthermia, hypothyroidism, hyperthyroidism, lung disease, advanced age, severe heart disease, myocardial infarction, myocarditis, recent cardiac surgery, cor pulmonale, hemodialysis, hypoxia, amyloidosis, and acute cerebral vascular events.
Nearly all types of arrhythmias are seen with digoxin toxicity. Bidirectional ventricular tachycardia, AV junctional rhythms (accelerated junctional rhythm), and atrial tachycardia with AV block (usually 2:1 AV block; less likely 3:2 and 4:3 AV block) are relatively specific for digoxin toxicity. Atrial fibrillation/atrial flutter and Mobitz type II, 2nd degree AV block are less likely to occur due to digoxin intoxication.
The treatment of digoxin toxicity is beyond the scope of this article.
Measurement of Serum Digoxin Concentration
Many herbs, medications, and disease states may interfere with SDC measurement. Falsely low SDC can be encountered due to negative cross-reactivity from canrenone and spironolactone (by AxSYM Microparticle Enzyme Immunoassay [MEIA] technique). Spironolactone and its metabolites have been reported to falsely elevate the SDC when radioimmunoassay or fluorescence-polarization immunoassay (FPIA) is used. Progesterone, hydrocortisone, and other corticosteroids can falsely elevate the SDC when the Abbott TDx method is used.
Digoxin-like immunoreactive substance(s) is an endogenous natriuretic substance(s) that is found in the blood of neonates, seriously ill older infants, pregnant women, patients with chronic renal failure, hepatobiliary disease, or HF, hypertensive patients, patients taking danshen (Chinese herb), Asian ginseng (Panax), or Siberian ginseng (Eleutherococcus senticosus). Therefore, the SDC may be falsely elevated in these situations. Concomitant administration of digoxin with Asian or Siberian ginseng can produce falsely elevated SDC when FPIA is used, or falsely diminished SDC when the MEIA method is used. In patients taking digoxin, five to ten days is necessary to reach a steady state. Once the steady state is achieved, blood samples should be drawn at least 6 hours after the administration of a dose.
Miscellaneous Medications, Tests, and Food That May Interact with Digoxin
Digoxin may increase the risk of bradycardia as well as heart block when used in conjunction with beta blockers. Even with relatively low blood levels, it may cause AV nodal block, particularly in the elderly population because of age-related impairment of AV nodal conduction.
Concomitant administration of digoxin with midodrine enhances the risk of bradycardia or AV block. Increasing AV block and eventual cardiac arrest was reported, upon administration of edrophonium in digitalized patient.24 The incidence of arrhythmia is increased when it is used with pancuronium or suxamethonium. Concomitant administration with succinylcholine increases the risk of arrhythmia through exacerbation of digoxin-induced ventricular irritability and/or shift of intracellular potassium.
Canrenoate displaces digoxin from its Na,K-ATPase receptor site and causes increased myocardial contractility. It also reverses the hyporeninemic effect of digoxin and interferes with radioimmunoassay of digoxin. The alteration of heart rate induced by digoxin may also interfere with the arbutamine test. Calcium should not be given intravenously since it may precipitate serious life-threatening arrhythmia.
Licorice ingestion may cause hypokalemia and therefore may be a predisposing factor to digoxin toxicity. Older individuals with constipation may have lower serum digoxin levels if they consume a diet of high-fiber foods.
Based on the data supported by evidence-based medicine, digoxin decreases hospitalization in patients with HF and systolic dysfunction. Continuation of long-term digoxin therapy with SDC of 0.5-0.9 ng/mL in ambulatory patients with chronic HF is associated with decrease in hospital admission and mortality.
Digoxin is not indicated in patients with HF and preserved systolic function. It should not be used for suppression of paroxysms of AF or for acute conversion of AF to normal sinus rhythm. Digoxin can be used for rate control in AF and in certain types of RPSVT.
Digoxin should be used with caution or not at all in those with predisposing factors for digoxin toxicity (eg, electrolyte imbalance). Moreover, with the growing geriatric population and the increasing likelihood of polypharmacy, it is of paramount importance to be cognizant of digoxin’s interactions with other medications and disease states. Lower doses of digoxin should be used in the geriatric population (0.125-0.25 mg/day).
It is surprising that most of the clinical trials have a limited number of elderly patients. In order to draw plausible conclusions that can be applicable to the geriatric population, it is necessary to conduct well-designed randomized, double-blind trials that embrace adequate numbers of these patients.
The author reports no relevant financial relationships.