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Amiodarone-Associated Hypothyroidism — A Possible Cause of Digoxin Intoxication
Case Report: Amiodarone-Associated Hypothyroidism A Possible Cause of Digoxin Intoxication BY ELDAD BEN-CHETRIT. MD, ZVI ACKERMAN. MD, AND MARCEL ELiAKIM, MD
ABSTRACT: The problem of a possible interaction between amiodarone and digoxin is still unsettled. We have recently treated two patients with digoxin intoxication who had received amiodarone for eight and 36 months respectively. Both developed extreme bradycardia requiring temporary pacemakers. The presence of hypothyroidism was confirmed in both cases by laboratory data. Judging by present knowledge concerning the interaction between amiodarone, thyroid function, and digoxin, it is suggested that digoxin intoxication was not the result of its direct interaction with amiodarone. The possibility that amiodaroneinduced hypothyroidism precipitated digoxin intoxication seems to be more plausible. Prevention of digitalis toxicity in amiodarone-treated patients would therefore require monitoring of thyroid function every From the Department of Internal Medi· cine A, Hadassah University Hospital, and the Hebrew University Medical School, Jerusalem, Israel. Reprint requests: E. Ben·Chetrit, MD, Department of Medicine A, Hadassah Uni· versity Hospital, P.O. Box 12000, Jerusalem 91120, Israel.
114
three to six months. Frequent monitoring of digitalis blood levels is also indicated in patients with amiodarone associated hypothyroidism. Early detection of hypothyroidism and digitalis intoxication is necessary in view of the severity of the course of the disease. KEY INDEXING TERMS: Amiodarone; Thyroxine; Digoxin. [Am J Med Sci 1985; 289(3):114-116.]
A
miodarone is a potent antiarrhythmic agent frequently used together with digoxin in the treatment of supraventicular arrhythmias in patients with congestive heart failure. Adverse reactions to amiodarone include disturbance in thyroid function, skin and corneal depositions, and interstitial lung disease. 1 The possibility of interact.ion between digoxin and amiodarone was examined by several investigators, but the findings were inconsistent. 2 ,3 We have recently treated two patients with digoxin intoxication who had also received amiodarone for eight-to-36 months. Both patients developed extreme bradycardia that required the inser-
tion of a temporary pacemaker. Both had amiodarone-induced hypothyroidism confirmed by laboratory data. The aim of this article is to discuss the interrelationship between amiodarone, thyroid function and digoxin and its therapeutic implication. Case Reports Case 1. A 65-year-old female was admitted because of nausea and vomiting of five days duration. Eleven years prior to admission, she started to suffer from angina pectoris, congestive heart failure, and recurrent episodes of supraventicular tachycardia. During the last three years she received amiodarone 200 mg and furosemide 40 mg daily and digoxin 0.25 mg, six days a week. Physical examination showed an obese (81 kg) and dyspneic patient, pulse regular, 40 beats/min and blood pressure 160/90 mmHg. The thyroid gland was not palpable. An ejection murmur was heard over the aortic area. The liver was not palpable. Relevant laboratory data were as follows: Hemoglobin 13.9 g%, leukocytes 8,OOO/cm mm, serum sodium 133 mEq/l, potassium 4.1 mEq/l, urea 7.2 mmolll, creatinine 82 fLmolll, calcium 2.3 mmolll, phosphorus 1.05 mmolll, albumin 38 gIl, cholesterol 12 mmolll and creatine phosphokinase 340 IU (normal ,,;:;100). Serum thyroxine was 1.5 fLg/dl (normal 4 to 12 fLg/ dl), T3 resin uptake 41. 7% (normal 38 to 65) and TSH more than 60 fLu/ml (normal 1 to 6). Serum digoxin was 5.1 ng/ml. The elecMarch 1985 Volume 289 Number 3
Ben Chetrit et al
trocardiogram showed sinus bradycardia. On the second day of hospitalization, the pulse rate decreased to 30/min and episodes of sinoatrial block appeared necessitating insertion of a temporary pacemaker (Figure 1). Digoxin and amiodarone were discontinued, and on day 25 she was discharged with a pulse rate of 60/min. Thyroid function tests after three weeks of therapy with L-thyroxine showed: T4 3.2 flog/dl, T3 93 ng/ml and T3 resin uptake 41.9%. Case 2. A 74-year-old male was admitted because of severe dyspnea of four days duration. Eight years before, he suffered from an anterior wall myocardial infarction complicated by congestive heart failure and recurrent episodes of ventricular tachycardia. During the last eight months he was treated with amiodarone 200 mg and furosemide 80 mg daily and, intermittently, by digoxin 0.25 mg daily. Physical examination showed a dyspneic patient with a pulse of 90/min, blood pressure 135/65 mmHg and body weight 49 kg. Crepitant rales were heard over both lungs and a systolic murmur compatible with aortic sclerosis was audible. Laboratory findings were: Hemoglobin 13.5 g/%, leukocytes 6,600 cu mm. Serum concentration of sodium was 134 mEqll, potassium 4.6 mEq/l, urea 5.9 mmolll, creatinine 107 mmolll, calcium 2.28 mmoV I, phosphorus 1.18 mmolll and albumin 36 gil. Digoxin was undetectable in the serum. An electrocardiogram showed multiple ventricular premature beats and left bundle branch block. Chest radiogram revealed cardiomegaly and left pleural effusion. Because of the severity of cardiac failure, a daily dose of 0.25 mg digoxin was added to his other medications. Ten days later the patient complained of nausea and vomiting. His pulse rate decreased to 40 beats/min necessitating insertion of a temporary pacemaker (Figure 2). Digoxin serum level at that time was 4.2 ng/ml. The blood level of thyroxine was 2.2 flog/dl, T3 resin 50% and TSH more than 60 floulml. Digoxin and amiodarone were discontinued, the patient's symptoms subsided and he was discharged after 20 days with a pulse rate of 56/min. The patients described above illustrate the interesting interaction between amiodarone, thyroid function, and digoxin therapy.
Amlodarone and Thyroid Function
It is well established that amiodarone can alter thyroid function, because ~f the resemblance of its molecule to thyroxine and its high iodine content (40% of the molecular weight). This results in inhibition of
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Figure 1. Electrocardiogram from Case 1. Upper strip sinus bradycardia 30/min; Lower strip 2:1 A-V block.
Figure 2. Electrocardiogram from Case 2. Sinus bradycardia of 40/,itin.
peripheral and possibly, intrapituitary production of active T 3 by blockage of 5' iodination ofT4 .4 This, in turn, leads to suppression of pituitary TSH and enhancement of T 4 production. The incidence of amiodarone-induced hyperthyroidism has been estimated to be about 3%.5 A study of 92 patients treated with amiodarone for up to 48 months revealed alterations of thyroid function in 70%.6 Two patients developed clinical and laboratory evidence of thyrotoxicosis while 11 developed hypothyroidism. The disturbance in · thyroid function appeared after at least six months of treatment. The high incidence of hypothyroidism in this study as compared with other reports was attributed to the long duration of treatment and close follow-up. Hypothyroidism was expressed clinically only when the thyroxine blood level decreased to 1 to 2 I-Lgi dl.
The American Journal of the Medical Sciences
Thyroid Function and Digoxin
Early observations by Wenckebach and others indicated that larger doses of digitalis glycosides
are required to control ventricular rate in hyperthyroid patients with atrial fibrillation, while smaller doses are needed in patients with myxedema. 7 Serum digoxin levels in hyperthyroidism have been found to be significantly lower than those measured after normalization of thyroid function. The opposite was noted in hypothyroidism. Possible mechanisms for these changes are as follows: 1. Elevation in apparent volume of distribution in hyperthyroidism may account for low plasma digoxin concentrations and the reverse is true in hypothyroidism;8 2. The glomerular filtration rate and the renal clearance of digoxin are higher in hyperthyroidism and lower in hypothyroidism, therefore, the half-life of the drug may be decreased or increased respectively;9 3. Patients with hyperthyroidism may have gastrointestinal hypermotility and a malabsorption defect in either fat or D-xylose absorption, which may lead to 115
Amiodarone-Associated Hypothyroidism
decreased digoxin absorption and low blood levels 10 ; 4. Hyperthyroid rats have an increased rate of biliary digoxin excretion, possibly due to accelerated hepatic drug metabolism, and the same may be true for humans,!1 Irrespective of which mechanism is active, the relation between serum T 3 and digoxin concentrations is inverse, thereby explaining the high level of digoxin in hypothyroidism. 12 Amiodarone and Digoxin
The observation that patients receiving maintenance digoxin treatment may develop clinical evidence of toxicity upon the addition of amiodarone, raised the question of a direct interaction between these drugs. Moysey et al studied seven patients who were on maintenance digoxin and amiodarone to control refractory arrhythmias. The mean blood level of digoxin increased by 69% within seven days of addition of amiodarone. 2 On the other hand, Achilli et al compared two groups of patients on digoxin, to whom either amiodarone or quinidine were added. 3 Quinidine increased the blood levels of digoxin significantly, while amiodarone had no effect. Thus, the issue concerning
116
the direct interaction between amiodarone and digoxin remains unsettled. The two patients described above received amiodarone for eight-to-36 months before the manifestation of hypothyroidism became overt, and their thyroxine blood levels were about 1.5 J-l.g/dl. The serum concentration of digoxin at that time ranged between 4.2 and 5.1 ng/ml. In the presence of normal serum creatinine levels it is unlikely that digoxin intoxication was precipitated by deteriorating renal function. Since the question of amiodarone-digoxin interaction is controversial, the occurrence of hypothyroidism precipitating digitalis intoxication is more attractive as an explanation. Prevention of digitalis toxicity in amiodarone-treated patients would require monitoring of thyroid function at three-to-six month intervals. Frequent monitoring of digitalis blood levels is also indicated in patients with amiodarone associated hypothyroidism. Early detection of hypothyroidism and digitalis toxicity is necessary in view of the severity of the course of the disease.
2:330-340, 1983. 2. Moysey JO, Jaggarao NSV, Grundy EN, Chamberlain DA: Amiadarone increases plasma digoxin concentrations. Br Med J 282:272, 1981. 3. Achilli A, Serra N: Amiodal'one increases plasma digoxin concentrations. Br Med J 282(ietter):1630, 1981. 4. Burger A, Dinichert D, Nicod P, Jenny M, Lemarchand-Beraud T, ValJotton MB: Effect of amiodarone on serum triodothyronine, reverse triodothyronine, thyroxine and thyrotropin. J Clin Invest 58:255-259, 1976. 5. Bekaert J, Solvay H, Van Schepdael S: Etude de l'efTect de l'amiodarone sur la fonction thyroidienne. Cellr Med Interne 18:241-242, 1979. 6. PosnerJ, Sobel RJ, GlickS: The effect of amiodarone on thyroid economy. Isr J Med Sci 1984, to be published. 7. Eichelbaum M: Drug metabolism in thyroid disease . Clin Pharmacahin 1:339-350, 1976. 8. Doherty JE, Perkins WH: Digoxin metabolism in hypo- and hyperthyroidism. Studies with tritiated digoxin in thyroid disease. Ann Intern Med 64:489-507,1966. 9. Croxon MS, Ibbertson HK: Serum digoxin in patients with thyroid disease. Br Med J 3:566-568, 1975. 10. Watters K, Tomkin GH: Serum digoxin in patients with thyroid disease. Br Med J 4(ietter):102. 11. Huffman DH, Klaassen CD, Hartman CR: Digoxin in hyperthyroidism. Clin Pharmacal Therap 22:533-538, 1977. 12. Nielse TP, Bodfish RE, Kabok A: Serum digoxin and thyroid hormones. Ann Intern Med 81:126-127, 1974.
References 1. Sloskey GE: Amiodarone: A .unique antiarrhythmic agent. Clin Pharmacal
March 1985 Volume 289 Number 3
ABSTRACT: The problem of a possible interaction between amiodarone and digoxin is still unsettled. We have recently treated two patients with digoxin intoxication who had received amiodarone for eight and 36 months respectively. Both developed extreme bradycardia requiring temporary pacemakers. The presence of hypothyroidism was confirmed in both cases by laboratory data. Judging by present knowledge concerning the interaction between amiodarone, thyroid function, and digoxin, it is suggested that digoxin intoxication was not the result of its direct interaction with amiodarone. The possibility that amiodaroneinduced hypothyroidism precipitated digoxin intoxication seems to be more plausible. Prevention of digitalis toxicity in amiodarone-treated patients would therefore require monitoring of thyroid function every From the Department of Internal Medi· cine A, Hadassah University Hospital, and the Hebrew University Medical School, Jerusalem, Israel. Reprint requests: E. Ben·Chetrit, MD, Department of Medicine A, Hadassah Uni· versity Hospital, P.O. Box 12000, Jerusalem 91120, Israel.
114
three to six months. Frequent monitoring of digitalis blood levels is also indicated in patients with amiodarone associated hypothyroidism. Early detection of hypothyroidism and digitalis intoxication is necessary in view of the severity of the course of the disease. KEY INDEXING TERMS: Amiodarone; Thyroxine; Digoxin. [Am J Med Sci 1985; 289(3):114-116.]
A
miodarone is a potent antiarrhythmic agent frequently used together with digoxin in the treatment of supraventicular arrhythmias in patients with congestive heart failure. Adverse reactions to amiodarone include disturbance in thyroid function, skin and corneal depositions, and interstitial lung disease. 1 The possibility of interact.ion between digoxin and amiodarone was examined by several investigators, but the findings were inconsistent. 2 ,3 We have recently treated two patients with digoxin intoxication who had also received amiodarone for eight-to-36 months. Both patients developed extreme bradycardia that required the inser-
tion of a temporary pacemaker. Both had amiodarone-induced hypothyroidism confirmed by laboratory data. The aim of this article is to discuss the interrelationship between amiodarone, thyroid function and digoxin and its therapeutic implication. Case Reports Case 1. A 65-year-old female was admitted because of nausea and vomiting of five days duration. Eleven years prior to admission, she started to suffer from angina pectoris, congestive heart failure, and recurrent episodes of supraventicular tachycardia. During the last three years she received amiodarone 200 mg and furosemide 40 mg daily and digoxin 0.25 mg, six days a week. Physical examination showed an obese (81 kg) and dyspneic patient, pulse regular, 40 beats/min and blood pressure 160/90 mmHg. The thyroid gland was not palpable. An ejection murmur was heard over the aortic area. The liver was not palpable. Relevant laboratory data were as follows: Hemoglobin 13.9 g%, leukocytes 8,OOO/cm mm, serum sodium 133 mEq/l, potassium 4.1 mEq/l, urea 7.2 mmolll, creatinine 82 fLmolll, calcium 2.3 mmolll, phosphorus 1.05 mmolll, albumin 38 gIl, cholesterol 12 mmolll and creatine phosphokinase 340 IU (normal ,,;:;100). Serum thyroxine was 1.5 fLg/dl (normal 4 to 12 fLg/ dl), T3 resin uptake 41. 7% (normal 38 to 65) and TSH more than 60 fLu/ml (normal 1 to 6). Serum digoxin was 5.1 ng/ml. The elecMarch 1985 Volume 289 Number 3
Ben Chetrit et al
trocardiogram showed sinus bradycardia. On the second day of hospitalization, the pulse rate decreased to 30/min and episodes of sinoatrial block appeared necessitating insertion of a temporary pacemaker (Figure 1). Digoxin and amiodarone were discontinued, and on day 25 she was discharged with a pulse rate of 60/min. Thyroid function tests after three weeks of therapy with L-thyroxine showed: T4 3.2 flog/dl, T3 93 ng/ml and T3 resin uptake 41.9%. Case 2. A 74-year-old male was admitted because of severe dyspnea of four days duration. Eight years before, he suffered from an anterior wall myocardial infarction complicated by congestive heart failure and recurrent episodes of ventricular tachycardia. During the last eight months he was treated with amiodarone 200 mg and furosemide 80 mg daily and, intermittently, by digoxin 0.25 mg daily. Physical examination showed a dyspneic patient with a pulse of 90/min, blood pressure 135/65 mmHg and body weight 49 kg. Crepitant rales were heard over both lungs and a systolic murmur compatible with aortic sclerosis was audible. Laboratory findings were: Hemoglobin 13.5 g/%, leukocytes 6,600 cu mm. Serum concentration of sodium was 134 mEqll, potassium 4.6 mEq/l, urea 5.9 mmolll, creatinine 107 mmolll, calcium 2.28 mmoV I, phosphorus 1.18 mmolll and albumin 36 gil. Digoxin was undetectable in the serum. An electrocardiogram showed multiple ventricular premature beats and left bundle branch block. Chest radiogram revealed cardiomegaly and left pleural effusion. Because of the severity of cardiac failure, a daily dose of 0.25 mg digoxin was added to his other medications. Ten days later the patient complained of nausea and vomiting. His pulse rate decreased to 40 beats/min necessitating insertion of a temporary pacemaker (Figure 2). Digoxin serum level at that time was 4.2 ng/ml. The blood level of thyroxine was 2.2 flog/dl, T3 resin 50% and TSH more than 60 floulml. Digoxin and amiodarone were discontinued, the patient's symptoms subsided and he was discharged after 20 days with a pulse rate of 56/min. The patients described above illustrate the interesting interaction between amiodarone, thyroid function, and digoxin therapy.
Amlodarone and Thyroid Function
It is well established that amiodarone can alter thyroid function, because ~f the resemblance of its molecule to thyroxine and its high iodine content (40% of the molecular weight). This results in inhibition of
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Figure 1. Electrocardiogram from Case 1. Upper strip sinus bradycardia 30/min; Lower strip 2:1 A-V block.
Figure 2. Electrocardiogram from Case 2. Sinus bradycardia of 40/,itin.
peripheral and possibly, intrapituitary production of active T 3 by blockage of 5' iodination ofT4 .4 This, in turn, leads to suppression of pituitary TSH and enhancement of T 4 production. The incidence of amiodarone-induced hyperthyroidism has been estimated to be about 3%.5 A study of 92 patients treated with amiodarone for up to 48 months revealed alterations of thyroid function in 70%.6 Two patients developed clinical and laboratory evidence of thyrotoxicosis while 11 developed hypothyroidism. The disturbance in · thyroid function appeared after at least six months of treatment. The high incidence of hypothyroidism in this study as compared with other reports was attributed to the long duration of treatment and close follow-up. Hypothyroidism was expressed clinically only when the thyroxine blood level decreased to 1 to 2 I-Lgi dl.
The American Journal of the Medical Sciences
Thyroid Function and Digoxin
Early observations by Wenckebach and others indicated that larger doses of digitalis glycosides
are required to control ventricular rate in hyperthyroid patients with atrial fibrillation, while smaller doses are needed in patients with myxedema. 7 Serum digoxin levels in hyperthyroidism have been found to be significantly lower than those measured after normalization of thyroid function. The opposite was noted in hypothyroidism. Possible mechanisms for these changes are as follows: 1. Elevation in apparent volume of distribution in hyperthyroidism may account for low plasma digoxin concentrations and the reverse is true in hypothyroidism;8 2. The glomerular filtration rate and the renal clearance of digoxin are higher in hyperthyroidism and lower in hypothyroidism, therefore, the half-life of the drug may be decreased or increased respectively;9 3. Patients with hyperthyroidism may have gastrointestinal hypermotility and a malabsorption defect in either fat or D-xylose absorption, which may lead to 115
Amiodarone-Associated Hypothyroidism
decreased digoxin absorption and low blood levels 10 ; 4. Hyperthyroid rats have an increased rate of biliary digoxin excretion, possibly due to accelerated hepatic drug metabolism, and the same may be true for humans,!1 Irrespective of which mechanism is active, the relation between serum T 3 and digoxin concentrations is inverse, thereby explaining the high level of digoxin in hypothyroidism. 12 Amiodarone and Digoxin
The observation that patients receiving maintenance digoxin treatment may develop clinical evidence of toxicity upon the addition of amiodarone, raised the question of a direct interaction between these drugs. Moysey et al studied seven patients who were on maintenance digoxin and amiodarone to control refractory arrhythmias. The mean blood level of digoxin increased by 69% within seven days of addition of amiodarone. 2 On the other hand, Achilli et al compared two groups of patients on digoxin, to whom either amiodarone or quinidine were added. 3 Quinidine increased the blood levels of digoxin significantly, while amiodarone had no effect. Thus, the issue concerning
116
the direct interaction between amiodarone and digoxin remains unsettled. The two patients described above received amiodarone for eight-to-36 months before the manifestation of hypothyroidism became overt, and their thyroxine blood levels were about 1.5 J-l.g/dl. The serum concentration of digoxin at that time ranged between 4.2 and 5.1 ng/ml. In the presence of normal serum creatinine levels it is unlikely that digoxin intoxication was precipitated by deteriorating renal function. Since the question of amiodarone-digoxin interaction is controversial, the occurrence of hypothyroidism precipitating digitalis intoxication is more attractive as an explanation. Prevention of digitalis toxicity in amiodarone-treated patients would require monitoring of thyroid function at three-to-six month intervals. Frequent monitoring of digitalis blood levels is also indicated in patients with amiodarone associated hypothyroidism. Early detection of hypothyroidism and digitalis toxicity is necessary in view of the severity of the course of the disease.
2:330-340, 1983. 2. Moysey JO, Jaggarao NSV, Grundy EN, Chamberlain DA: Amiadarone increases plasma digoxin concentrations. Br Med J 282:272, 1981. 3. Achilli A, Serra N: Amiodal'one increases plasma digoxin concentrations. Br Med J 282(ietter):1630, 1981. 4. Burger A, Dinichert D, Nicod P, Jenny M, Lemarchand-Beraud T, ValJotton MB: Effect of amiodarone on serum triodothyronine, reverse triodothyronine, thyroxine and thyrotropin. J Clin Invest 58:255-259, 1976. 5. Bekaert J, Solvay H, Van Schepdael S: Etude de l'efTect de l'amiodarone sur la fonction thyroidienne. Cellr Med Interne 18:241-242, 1979. 6. PosnerJ, Sobel RJ, GlickS: The effect of amiodarone on thyroid economy. Isr J Med Sci 1984, to be published. 7. Eichelbaum M: Drug metabolism in thyroid disease . Clin Pharmacahin 1:339-350, 1976. 8. Doherty JE, Perkins WH: Digoxin metabolism in hypo- and hyperthyroidism. Studies with tritiated digoxin in thyroid disease. Ann Intern Med 64:489-507,1966. 9. Croxon MS, Ibbertson HK: Serum digoxin in patients with thyroid disease. Br Med J 3:566-568, 1975. 10. Watters K, Tomkin GH: Serum digoxin in patients with thyroid disease. Br Med J 4(ietter):102. 11. Huffman DH, Klaassen CD, Hartman CR: Digoxin in hyperthyroidism. Clin Pharmacal Therap 22:533-538, 1977. 12. Nielse TP, Bodfish RE, Kabok A: Serum digoxin and thyroid hormones. Ann Intern Med 81:126-127, 1974.
References 1. Sloskey GE: Amiodarone: A .unique antiarrhythmic agent. Clin Pharmacal
March 1985 Volume 289 Number 3