Coma secondary to apathetic thyrotoxicosis OMAR SERRI, MD; ROGER-MARIE GAGNON, MD, FRCP[C]; YVON GOULET, MD, FRCP[C]; MAURICE SOMMA, MD, M SC
Thyrotoxic crisis, commonly called goitre had been noted when she was thyroid storm, is usually easily rec- 35 years old. The family history was ognized; however, if it develops in a unremarkable. The woman appeared severely ill; she case of apathetic thyrotoxicosis diagnosis may be difficult and appro- was depressed, prostrated and slightly confused. The blood pressure was priate treatment delayed. 110/60 mm Hg, the heart rate was In the past few years propranolol 120 beats! mm and irregular. and she has been increasingly used in the had a temperature of 36.70C. Her treatment of thyrotoxicosis, while weight was 41 kg. There was slight iodine therapy has been disregarded. lid lag but no other ocular abnormaliIn this report we emphasize the im- ties were present. The thyroid gland portance of rehydration and therapy was slightly enlarged, there was generwith combinations of drugs, including alized muscular weakness and atrophy, iodine especially, in the management and the tendon reflexes were increased. Because of the history of weight loss of thyrotoxic crisis and coma.
Case report A 47-year-old woman was admitted to our hospital with asthenia and palpitations. For several months she had complained of anorexia, weight loss and fatigue. During the 2 weeks before admission she had had five to six loose stools each day. However, she denied intolerance to heat, abnormal sweating and tremor. A small asymptomatic From the department of medicine,
University of Montreal and Notre-Dame Hospital, Montreal Reprint requests to: Dr. Maurice Somma, Laboratoire d'endocrinologie, H6pital Notre-Dame, 1560 est, rue Sherbrooke,
Montreal, PQ H2L 4K8
and asthenia and the atrial fibrillation, a diagnosis of apathetic thyrotoxicosis was made. The leukocyte count was 4.5 X 10'/L with 64% lymphocytes, 23% neutrophils and 13 % monocytes. Concentrations of pertinent serum constituents were as follows: albumin 2.9 g/dL, cholesterol 94 mg/dL, alkaline phosphatase 153 U (normal 22 to 95 U), total bilirubin 2.2 mg/dL, direct
bilirubin 1.3 mg/dL and electrolytes normal. Thyroid function tests confirmed the diagnosis of thyrotoxicosis (Table I). There was no evidence of immunofluorescent thyroid antibodies. Electrocardiograms showed atrial fibrillation, with a ventricular rate of 100 to 120
beats/mm. A chest roentgenogram was normal. Shortly after admission the patient became psychotic, with paranoid delusions, and within 48 hours she was comatose. Neurologic examination revealed decreased tendon reflexes and muscular hypotonia but no localized abnormality. Repeated electroencephalograms showed diffuse cortical abnormalities consistent with a diagnosis of metabolic coma. A roentgenogram of the skull was normal. Serum electrolyte concentrations were also normal. Atrial fibrillation persisted despite administration of propranolol, 120 mg/d, and digoxin, 0.25 mg/d after a loading dose of 1 mg. The patient was dehydrated, the urine output was reduced to 450 mL/d and the blood pressure was 100/60 mm Hg. The serum cortisol concentration was 2.3 .g/d (normal 6 to 25 ,ig/d). Despite the absence of fever, a diagnosis of thyrotoxic coma was made and she was transferred to the intensive care unit for appropriate monitoring. A SwanGanz catheter was placed in the right pulmonary artery: the pulmonary artery pressure was 35/5 mm Hg and the mean pulmonary wedge pressure was 5 mm Hg, both consistent with a diagnosis of hypovolemia. Appropriate fluids as well as propylthiouracil, iodine and hydrocortisone
CMA JOURNAL/SEPTEMBER 23, 1978/VOL. 119 605
were given intravenously (Fig. 1). Within 24 hours the atrial fibrillation had reverted to a normal rhythm, and 48 hours later the patient was conscious, with almost normal mental function. While the patient was comatose aspiration pneumonia developed and her temperature was 39.40C. She responded well to appropriate antibiotic therapy. The daily dose of hydrocortisone was progressively decreased until the 20th hospital day, when the drug was discontinued. However, iodine therapy was stopped after 5 days, and, despite an increase in the daily dose of propranolol to 240 mg, the thyrotoxic signs of atrial fibrillation with a rapid ventricular rate, diarrhea and psychosis recurred. These manifestations disappeared when iodine therapy was reinstituted. Five weeks after admission, treatment with iodine and propylthiouracil was stopped. Three days later the thyroid uptake of iodine-131 was 49% in 24 hours; 15 mCi of '.'I was then administered. The leukocyte count and the results of liver function tests were normal. One week later the patient was discharged taking propylthiouracil, 800 mg/d, and iodine in the form of Lugol's solution, 5 drops tid. One month later there was no clinical or laboratory evidence of thyroid dysfunction, and the daily doses of propylthiouracil and iodine were progressively decreased.
series of thyrotoxic patients. direct effects of thyroid hormones on The incidence of thyrotoxic coma heart rate and contractility are well has decreased substantially in the established. These hormones act by last decade, probably because early mechanisms independent of catediagnosis and therapy are now avail- cholamines."'8 The direct effect of able. thyroid hormones may be additive The pathophysiology of thyrotoxic with those induced by catecholacoma and crisis is not well known. mines, and whether they "potentiate" Iodine deficiency,3 accelerated de- or "sensitize" the cardiac adrenergic iodination6 and uncoupling between receptors is controversial. Despite the uncertainty about the oxidation and phosphorylation7 have been suggested as possible mechan- nature of the interaction between isms. More recently, enhanced acti- thyroid hormones and catecholavity of the sympathetic nervous sys- mines, the adrenergic-blocking agents tem was considered to be a possible are still considered useful adjuncts in important factor in initiating the the management of selected patients thyroid storm.8 Although it appears with thyrotoxicosis. In the past few years propranolol that in hyperthyroidism sympathetic activity may be normal or even has been administered intravenously slightly suppressed,9-" it is possible
as a first-line treatment of thyrotoxic
that normal sympathetic activity may crisis.'9 Recently Shand'0 recognized be inappropriately high for the per- the therapeutic value of propranolol, son with hyperthyroidism." Another but recommended that caution be finding of possible significance is the exercised when the intravenous route reported sudden increase in the plas- is used in older patients. Propranolol ma triiodothyronine (T3) concentra- can also be effective in lowering the tion in one patient during a thyroid plasma T3 concentration, probably by storm.13 This observation has not yet inhibiting the peripheral conversion of T4 to T3.2' been confirmed. The cardiovascular manifestations Our patient was treated with 120 of hyperthyroidism are well known. mg/d of propranolol and later 240 The increase in the metabolic rate mg/d, but the higher dose may have and the rate of oxygen consumption been inadequate since the metabolism is responsible for the increased car- of most drugs is increased in hyperdiac output, which not only is sec- thyroidism. However, the beneficial ondary to the tachycardia and in- effect of iodine in thyrotoxicosis is Discussion creased metabolic needs, but also is well known. Its action on the hyperThis case illustrates an unusual a result of direct effects of thyroxine active thyroid gland dramatically incomplication of apathetic thyrotoxi- (T4) on myocardial contractility.'4 The hibits the secretion of thyroid horcosis and its favourable response to I ICOMAI iodine treatment with rapid correc7004 T3 (RIA) ng/dL tion of arrhythmia and coma, but lack of response to propranolol therapy. Lahey' in 1931 was the first to -40 describe the apathetic form of thyrotoxicosis, writing that it was charac-30 terized by severe prostration and -20 mental apathy leading to coma. -10 Zondek2 soon gave a similar description of this form of thyrotoxicosis -0 and called it "coma basedowicum". Since then others have studied the neurologic and psychiatric complications of hyperthyroidism. Waldenstr6m' in 1945 described the syndrome of thyrotoxic encephalomyoDAYS pathy, in which the usual myo- 100W41 mg 120 240 120 pathy of hyperthyroidism was asso- PTU mg 600 ciated with signs of involvement of .OPRANO-. LOL 120 160 240 160 120 the central nervous system. McArthur mg HYDROCORand colleagues,4 and more recently TISONE mg 300 0 Waldstein and associates,5 have reported a few cases of thyrotoxic FIG. 1-Clinical and biologic response to treatment. T3 = triiodothyronine; coma and psychosis in their large RIA = radloimmunoassay; T4 = thyroxine; PTU = propyithiouracil. 606 CMA JOURNAL/SEPTEMBER 23, 1978/VOL. 119
mones. It has no effect on peripheral utilization of thyroid hormones.22 Its early discontinuation in our patient led to recurrence of the thyrotoxic signs, which suggests that the active gland contained large stores of hormones. Propyithiouracil inhibits the production of thyroid hormones and theoretically has an advantage over methimazole since it appears to be more active in preventing the peripheral conversion of T4 to T3.23 Glucocorticoids are also beneficial in persons with thyroid storm. They may inhibit the peripheral conversion of T4 to T3 and correct relative adrenal insufficiency, which was probably present in our patient as shown by the low serum cortisol concentration. Combination therapy with propylthiouracil, glucocorticoids and iodine seems very effective in rapidly lowering the serum T3 concentration.24 These specific measures, along with appropriate rehydration, allowed our patient to recover from thyrotoxic coma. References 1. LAHEY FH: Non-activated (apathetic) type of hyperthyroidism. N Engi J Med 204: 747, 1931 2. ZONDEK H (ed): The comatose form of Graves diseases, in Diseases of the Endocrine Glands, 2nd ed, Arnold,
London, 1935, p 155 3. WALDENSTR6M J: Acute thyrotoxic encephalo- or myopathy, its cause and treatment. Acta Med Scand 121: 251,
1945
4. MCARTHUR JW, RAWSON RW, MEANS JH, et al: Thyrotoxic crisis; analysis of 36 cases seen at Massachusetts General Hospital during the past 25 years. JAMA 134: 868, 1947 5. WALDSTEJN SS, SLODKI SH, KAGANIEC GI, et al: A clinical study of thyroid
storm. Ann Intern Med 52: 626, 1960 6. WAHLBERG P, LAMBERG BA: Iodine metabolism in a case of thyrotoxic crisis. J Clin Endocrinol Metab 23: 397, 1963 7. HocH FL: Thyrotoxicosis as a disease of mitochondria. N Engi J Med 266:
498, 1962 8. ROSENBERG I: Thyroid storm (C). N
Engi J Med 283: 1052, 1970 9. BAYLISS RIS, EDWARDS OM: Urinary excretion of free catecholamines in Graves' disease. J Endocrinol 49: 167, 1971 10. STOFFER SS, JIANG NS, GORMAN CA, et al: Plasma catecholamines in hypothyroidism and hyperthyroidism. J
Gun Endocrinol Metab 36: 587, 1973 11. COULOMBE P, DUSSAULT JH, LETARTE J, et al: Catecholamines metabolism in thyroid diseases. I. Epinephrine secretion rate in hyperthyroidism and hypothyroidism. J Gun Endocrinol Metab 42: 125, 1976 12. LANDSBERG L: Catecholamines and
hyperthyroidism. Clin Endocrinol Metab 6: 697, 1977 13. JAcoBs HS, MACKIE DB, EASTMAN CJ. et al: Total and free triiodothyronine and thyroxine levels in thyroid storm and recurrent hyperthyroidism. Lancet
2: 236, 1973 14. LEONARD JJ, DEGROOT U: The thy-
roid state and the cardiovascular system. Mod Concepts Cardiovasc Dis 38: 23, 1969
15. WILDENTHAL K: Responses to cardioactive drugs of fetal mouse hearts maintained in organ culture. Am J Physiol 221: 238, 1971 16. NEMECEK GM, HESS ME:
Cardio-
vascular and metabolic responses to thyroid hormones in animals after sympathectomy or treatment with nerve growth factor. Neuropharmacology 13: 317, 1974 17. TAYLOR RR, COVELL JW, Ross J .n.: Influence of the thyroid state on left ventricular tension-velocity relations in the intact, sedated dog. J Clin Invest 48: 775, 1969 18. LEvEY GS: Catecholamine sensitivity, thyroid hormone and the heart. A re-evaluation. Am J Med 50: 413, 1971 19. MACKIN iF, CANARY JJ, PITTMAN CS:
Thyroid storm and its management. N Engi J Med 291: 1396, 1974 20. SHAND DO: Propranolol. N Engi J Med 293: 280, 1975 21. WIERSINGA WM, TOUBER JL: The in-
fluence of 13-andrenoceptor blocking agents on plasma thyroxine and triiodothyronine. J Clin Endocrinol Metab 45: 293, 1977 22. DE GROOT U, STANBURY JB: The Thyroid and Its Diseases, 4th ed, Wiley, New York, 1975, p 371
23. ABuID J, LARSEN PR: Triiodothyronine and thyroxine in hyperthyroidism. Comparison of the acute changes during therapy with antithyroid agents. J Gun Invest 54: 201, 1974 24. CROXSON MS, HALL TD, NICOLOFF JT: Combination drug therapy for treatment of hyperthyroid Graves disease. J Glitz Endocrinol Metab 45: 623, 1977
Probable interaction of loperamide and cholestyramine T.Y. Ti, MD; H.G. GILES, PH D. E.M. SELLERS, MD, PH D, FRCP[C]
Loperamide hydrochloride (Imo- rapid onset of action and is longer dium) is a new antidiarrheal agent acting than other agents. Loperamide that is effective in the treatment of acts in the gastrointestinal tract on both acute and chronic diarrhea.1 both cholinergic and noncholinergic Physical dependence on this drug has mechanisms, thereby decreasing the not been documented in humans. activity of both longitudinal and cirMore important, the drug has fewer cular muscles. In patients in whom a substantial systemic side effects, has a more amount of fluid has been lost from From the division of clinical pharmacology, the gastrointestinal tract after bowel Toronto Western Hospital and Addiction surgery, various therapeutic apResearch Foundation, and the departments proaches are often tried before motilof medicine and pharmacology, ity and fluid loss can be controlled. University of Toronto We recently treated a patient in Reprint requests to: Dr. E.M. Sellers, whom the efficacy of loperamide was 33 Russell St., Toronto, Ont. M5S 2S1
decreased by concurrent administration of cholestyramine resin (Cuemid). Cholestyramine is a chloride salt of a strongly basic anion-exchange resin used as a bile salt sequestrant. The binding of drugs by cholestyramine has resulted in some clinically important drug interactions. Cholestyramine decreases the absorption of digoxin, digitoxin,2 thyroid hormones,3 warfarin4'5 and phenylbutazone, and binds many acidic drugs, including acetylsalicylic acid, chlorothiazide, phenobarbital, tetracycline and vitamin K.6
CMA JOURNAL/SEPTEMBER 23, 1978/VOL 119 607
Thyrotoxic crisis, commonly called goitre had been noted when she was thyroid storm, is usually easily rec- 35 years old. The family history was ognized; however, if it develops in a unremarkable. The woman appeared severely ill; she case of apathetic thyrotoxicosis diagnosis may be difficult and appro- was depressed, prostrated and slightly confused. The blood pressure was priate treatment delayed. 110/60 mm Hg, the heart rate was In the past few years propranolol 120 beats! mm and irregular. and she has been increasingly used in the had a temperature of 36.70C. Her treatment of thyrotoxicosis, while weight was 41 kg. There was slight iodine therapy has been disregarded. lid lag but no other ocular abnormaliIn this report we emphasize the im- ties were present. The thyroid gland portance of rehydration and therapy was slightly enlarged, there was generwith combinations of drugs, including alized muscular weakness and atrophy, iodine especially, in the management and the tendon reflexes were increased. Because of the history of weight loss of thyrotoxic crisis and coma.
Case report A 47-year-old woman was admitted to our hospital with asthenia and palpitations. For several months she had complained of anorexia, weight loss and fatigue. During the 2 weeks before admission she had had five to six loose stools each day. However, she denied intolerance to heat, abnormal sweating and tremor. A small asymptomatic From the department of medicine,
University of Montreal and Notre-Dame Hospital, Montreal Reprint requests to: Dr. Maurice Somma, Laboratoire d'endocrinologie, H6pital Notre-Dame, 1560 est, rue Sherbrooke,
Montreal, PQ H2L 4K8
and asthenia and the atrial fibrillation, a diagnosis of apathetic thyrotoxicosis was made. The leukocyte count was 4.5 X 10'/L with 64% lymphocytes, 23% neutrophils and 13 % monocytes. Concentrations of pertinent serum constituents were as follows: albumin 2.9 g/dL, cholesterol 94 mg/dL, alkaline phosphatase 153 U (normal 22 to 95 U), total bilirubin 2.2 mg/dL, direct
bilirubin 1.3 mg/dL and electrolytes normal. Thyroid function tests confirmed the diagnosis of thyrotoxicosis (Table I). There was no evidence of immunofluorescent thyroid antibodies. Electrocardiograms showed atrial fibrillation, with a ventricular rate of 100 to 120
beats/mm. A chest roentgenogram was normal. Shortly after admission the patient became psychotic, with paranoid delusions, and within 48 hours she was comatose. Neurologic examination revealed decreased tendon reflexes and muscular hypotonia but no localized abnormality. Repeated electroencephalograms showed diffuse cortical abnormalities consistent with a diagnosis of metabolic coma. A roentgenogram of the skull was normal. Serum electrolyte concentrations were also normal. Atrial fibrillation persisted despite administration of propranolol, 120 mg/d, and digoxin, 0.25 mg/d after a loading dose of 1 mg. The patient was dehydrated, the urine output was reduced to 450 mL/d and the blood pressure was 100/60 mm Hg. The serum cortisol concentration was 2.3 .g/d (normal 6 to 25 ,ig/d). Despite the absence of fever, a diagnosis of thyrotoxic coma was made and she was transferred to the intensive care unit for appropriate monitoring. A SwanGanz catheter was placed in the right pulmonary artery: the pulmonary artery pressure was 35/5 mm Hg and the mean pulmonary wedge pressure was 5 mm Hg, both consistent with a diagnosis of hypovolemia. Appropriate fluids as well as propylthiouracil, iodine and hydrocortisone
CMA JOURNAL/SEPTEMBER 23, 1978/VOL. 119 605
were given intravenously (Fig. 1). Within 24 hours the atrial fibrillation had reverted to a normal rhythm, and 48 hours later the patient was conscious, with almost normal mental function. While the patient was comatose aspiration pneumonia developed and her temperature was 39.40C. She responded well to appropriate antibiotic therapy. The daily dose of hydrocortisone was progressively decreased until the 20th hospital day, when the drug was discontinued. However, iodine therapy was stopped after 5 days, and, despite an increase in the daily dose of propranolol to 240 mg, the thyrotoxic signs of atrial fibrillation with a rapid ventricular rate, diarrhea and psychosis recurred. These manifestations disappeared when iodine therapy was reinstituted. Five weeks after admission, treatment with iodine and propylthiouracil was stopped. Three days later the thyroid uptake of iodine-131 was 49% in 24 hours; 15 mCi of '.'I was then administered. The leukocyte count and the results of liver function tests were normal. One week later the patient was discharged taking propylthiouracil, 800 mg/d, and iodine in the form of Lugol's solution, 5 drops tid. One month later there was no clinical or laboratory evidence of thyroid dysfunction, and the daily doses of propylthiouracil and iodine were progressively decreased.
series of thyrotoxic patients. direct effects of thyroid hormones on The incidence of thyrotoxic coma heart rate and contractility are well has decreased substantially in the established. These hormones act by last decade, probably because early mechanisms independent of catediagnosis and therapy are now avail- cholamines."'8 The direct effect of able. thyroid hormones may be additive The pathophysiology of thyrotoxic with those induced by catecholacoma and crisis is not well known. mines, and whether they "potentiate" Iodine deficiency,3 accelerated de- or "sensitize" the cardiac adrenergic iodination6 and uncoupling between receptors is controversial. Despite the uncertainty about the oxidation and phosphorylation7 have been suggested as possible mechan- nature of the interaction between isms. More recently, enhanced acti- thyroid hormones and catecholavity of the sympathetic nervous sys- mines, the adrenergic-blocking agents tem was considered to be a possible are still considered useful adjuncts in important factor in initiating the the management of selected patients thyroid storm.8 Although it appears with thyrotoxicosis. In the past few years propranolol that in hyperthyroidism sympathetic activity may be normal or even has been administered intravenously slightly suppressed,9-" it is possible
as a first-line treatment of thyrotoxic
that normal sympathetic activity may crisis.'9 Recently Shand'0 recognized be inappropriately high for the per- the therapeutic value of propranolol, son with hyperthyroidism." Another but recommended that caution be finding of possible significance is the exercised when the intravenous route reported sudden increase in the plas- is used in older patients. Propranolol ma triiodothyronine (T3) concentra- can also be effective in lowering the tion in one patient during a thyroid plasma T3 concentration, probably by storm.13 This observation has not yet inhibiting the peripheral conversion of T4 to T3.2' been confirmed. The cardiovascular manifestations Our patient was treated with 120 of hyperthyroidism are well known. mg/d of propranolol and later 240 The increase in the metabolic rate mg/d, but the higher dose may have and the rate of oxygen consumption been inadequate since the metabolism is responsible for the increased car- of most drugs is increased in hyperdiac output, which not only is sec- thyroidism. However, the beneficial ondary to the tachycardia and in- effect of iodine in thyrotoxicosis is Discussion creased metabolic needs, but also is well known. Its action on the hyperThis case illustrates an unusual a result of direct effects of thyroxine active thyroid gland dramatically incomplication of apathetic thyrotoxi- (T4) on myocardial contractility.'4 The hibits the secretion of thyroid horcosis and its favourable response to I ICOMAI iodine treatment with rapid correc7004 T3 (RIA) ng/dL tion of arrhythmia and coma, but lack of response to propranolol therapy. Lahey' in 1931 was the first to -40 describe the apathetic form of thyrotoxicosis, writing that it was charac-30 terized by severe prostration and -20 mental apathy leading to coma. -10 Zondek2 soon gave a similar description of this form of thyrotoxicosis -0 and called it "coma basedowicum". Since then others have studied the neurologic and psychiatric complications of hyperthyroidism. Waldenstr6m' in 1945 described the syndrome of thyrotoxic encephalomyoDAYS pathy, in which the usual myo- 100W41 mg 120 240 120 pathy of hyperthyroidism was asso- PTU mg 600 ciated with signs of involvement of .OPRANO-. LOL 120 160 240 160 120 the central nervous system. McArthur mg HYDROCORand colleagues,4 and more recently TISONE mg 300 0 Waldstein and associates,5 have reported a few cases of thyrotoxic FIG. 1-Clinical and biologic response to treatment. T3 = triiodothyronine; coma and psychosis in their large RIA = radloimmunoassay; T4 = thyroxine; PTU = propyithiouracil. 606 CMA JOURNAL/SEPTEMBER 23, 1978/VOL. 119
mones. It has no effect on peripheral utilization of thyroid hormones.22 Its early discontinuation in our patient led to recurrence of the thyrotoxic signs, which suggests that the active gland contained large stores of hormones. Propyithiouracil inhibits the production of thyroid hormones and theoretically has an advantage over methimazole since it appears to be more active in preventing the peripheral conversion of T4 to T3.23 Glucocorticoids are also beneficial in persons with thyroid storm. They may inhibit the peripheral conversion of T4 to T3 and correct relative adrenal insufficiency, which was probably present in our patient as shown by the low serum cortisol concentration. Combination therapy with propylthiouracil, glucocorticoids and iodine seems very effective in rapidly lowering the serum T3 concentration.24 These specific measures, along with appropriate rehydration, allowed our patient to recover from thyrotoxic coma. References 1. LAHEY FH: Non-activated (apathetic) type of hyperthyroidism. N Engi J Med 204: 747, 1931 2. ZONDEK H (ed): The comatose form of Graves diseases, in Diseases of the Endocrine Glands, 2nd ed, Arnold,
London, 1935, p 155 3. WALDENSTR6M J: Acute thyrotoxic encephalo- or myopathy, its cause and treatment. Acta Med Scand 121: 251,
1945
4. MCARTHUR JW, RAWSON RW, MEANS JH, et al: Thyrotoxic crisis; analysis of 36 cases seen at Massachusetts General Hospital during the past 25 years. JAMA 134: 868, 1947 5. WALDSTEJN SS, SLODKI SH, KAGANIEC GI, et al: A clinical study of thyroid
storm. Ann Intern Med 52: 626, 1960 6. WAHLBERG P, LAMBERG BA: Iodine metabolism in a case of thyrotoxic crisis. J Clin Endocrinol Metab 23: 397, 1963 7. HocH FL: Thyrotoxicosis as a disease of mitochondria. N Engi J Med 266:
498, 1962 8. ROSENBERG I: Thyroid storm (C). N
Engi J Med 283: 1052, 1970 9. BAYLISS RIS, EDWARDS OM: Urinary excretion of free catecholamines in Graves' disease. J Endocrinol 49: 167, 1971 10. STOFFER SS, JIANG NS, GORMAN CA, et al: Plasma catecholamines in hypothyroidism and hyperthyroidism. J
Gun Endocrinol Metab 36: 587, 1973 11. COULOMBE P, DUSSAULT JH, LETARTE J, et al: Catecholamines metabolism in thyroid diseases. I. Epinephrine secretion rate in hyperthyroidism and hypothyroidism. J Gun Endocrinol Metab 42: 125, 1976 12. LANDSBERG L: Catecholamines and
hyperthyroidism. Clin Endocrinol Metab 6: 697, 1977 13. JAcoBs HS, MACKIE DB, EASTMAN CJ. et al: Total and free triiodothyronine and thyroxine levels in thyroid storm and recurrent hyperthyroidism. Lancet
2: 236, 1973 14. LEONARD JJ, DEGROOT U: The thy-
roid state and the cardiovascular system. Mod Concepts Cardiovasc Dis 38: 23, 1969
15. WILDENTHAL K: Responses to cardioactive drugs of fetal mouse hearts maintained in organ culture. Am J Physiol 221: 238, 1971 16. NEMECEK GM, HESS ME:
Cardio-
vascular and metabolic responses to thyroid hormones in animals after sympathectomy or treatment with nerve growth factor. Neuropharmacology 13: 317, 1974 17. TAYLOR RR, COVELL JW, Ross J .n.: Influence of the thyroid state on left ventricular tension-velocity relations in the intact, sedated dog. J Clin Invest 48: 775, 1969 18. LEvEY GS: Catecholamine sensitivity, thyroid hormone and the heart. A re-evaluation. Am J Med 50: 413, 1971 19. MACKIN iF, CANARY JJ, PITTMAN CS:
Thyroid storm and its management. N Engi J Med 291: 1396, 1974 20. SHAND DO: Propranolol. N Engi J Med 293: 280, 1975 21. WIERSINGA WM, TOUBER JL: The in-
fluence of 13-andrenoceptor blocking agents on plasma thyroxine and triiodothyronine. J Clin Endocrinol Metab 45: 293, 1977 22. DE GROOT U, STANBURY JB: The Thyroid and Its Diseases, 4th ed, Wiley, New York, 1975, p 371
23. ABuID J, LARSEN PR: Triiodothyronine and thyroxine in hyperthyroidism. Comparison of the acute changes during therapy with antithyroid agents. J Gun Invest 54: 201, 1974 24. CROXSON MS, HALL TD, NICOLOFF JT: Combination drug therapy for treatment of hyperthyroid Graves disease. J Glitz Endocrinol Metab 45: 623, 1977
Probable interaction of loperamide and cholestyramine T.Y. Ti, MD; H.G. GILES, PH D. E.M. SELLERS, MD, PH D, FRCP[C]
Loperamide hydrochloride (Imo- rapid onset of action and is longer dium) is a new antidiarrheal agent acting than other agents. Loperamide that is effective in the treatment of acts in the gastrointestinal tract on both acute and chronic diarrhea.1 both cholinergic and noncholinergic Physical dependence on this drug has mechanisms, thereby decreasing the not been documented in humans. activity of both longitudinal and cirMore important, the drug has fewer cular muscles. In patients in whom a substantial systemic side effects, has a more amount of fluid has been lost from From the division of clinical pharmacology, the gastrointestinal tract after bowel Toronto Western Hospital and Addiction surgery, various therapeutic apResearch Foundation, and the departments proaches are often tried before motilof medicine and pharmacology, ity and fluid loss can be controlled. University of Toronto We recently treated a patient in Reprint requests to: Dr. E.M. Sellers, whom the efficacy of loperamide was 33 Russell St., Toronto, Ont. M5S 2S1
decreased by concurrent administration of cholestyramine resin (Cuemid). Cholestyramine is a chloride salt of a strongly basic anion-exchange resin used as a bile salt sequestrant. The binding of drugs by cholestyramine has resulted in some clinically important drug interactions. Cholestyramine decreases the absorption of digoxin, digitoxin,2 thyroid hormones,3 warfarin4'5 and phenylbutazone, and binds many acidic drugs, including acetylsalicylic acid, chlorothiazide, phenobarbital, tetracycline and vitamin K.6
CMA JOURNAL/SEPTEMBER 23, 1978/VOL 119 607
