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Emetine therapy and heart disease
EMETINE
TH-ERAPY WILLIAM
AND
HEART
A. SODEMAN,
NEW ORLEANS,
DISEASE
M.D.
I,.\.
U
NTIL recently, emetine has been the only effective drug in extraintestinal amebiasis. The introduction of chloroquine for the treatment of the hepatic phases of the diseasehas not entirely supplanted this time-honored drug, and it still has a place in the treatment of some phasesof hepatic amebiasis and of other extraintestinal manifestations. It is useful, too, in certain other parasitoses. The continued importance of this drug has prompted the author to report his experiences with patients requiring emetine despite the presence of contraindicating heart disease. The present data were obtained from a general study’ of the toxic effects of emetine in 111 patients. Of these, ninety-four, or 84.7 per cent, had hepatic amebiasis; eleven, or 9.9 per cent, colonic amebiasis of a refractory type in which emetine was used in combination with other drugs; and six, or 5.4 per cent, nonamebic disease in which emetine was the drug of choice. In the entire group there were five instances of symptomatic intoxication, three of the neuromuscular variety and two of the cardiovascular type. Minor symptoms were excluded from this evaluation. In the three patients in the neuromuscular group, one had, in addition, a tachycardia, one nausea and vomiting, and the third diarrhea along with nausea and vomiting. In the cardiovascular group, one patient had tachycardia and a marked reduction in blood pressure, the other tachycardia, vertigo, and syncope. One of these showed electrocardiographic changes attributable to emetine. All five of the patients with symptoms of emetine intoxication had normal hearts previous to and following therapy. In the entire group of 111 patients there were eight in whom advanced heart disease was present before emetine was administered. The drug was given because it was thought that the condition requiring its use was a greater threat to life than the heart disease, and no other therapeutic agent was available. Of the eight patients, five had arteriosclerotic and one each hypertensive, congenital, and rheumatic heart disease. Of the five with arteriosclerotic heart disease,four had signs of cardiac enlargement, and the fifth, along with one of the others, had previously had congestive heart failure. Both of these were under digitalis therapy. Two of the patients were women. The ages of the arteriosclerotic group were 62, 6.5, 69, 69, and 72 years and the total doses of emetine administered 11, 6.9, 5, 12, and 8.8 mg. per kilogram of body weight, respectively. From the Department of Tropical Medicine Isniversity of Louisiana. and the Charity Hospital Received for publication Xov. 9. 19.51.
and Public of Louisiana 582
Health. School of Medicine, at Xew Orleans.
The
Tulane
SODEMAN
:
EMETINE
THERAPY
AND
HEART
DISEASE
583
The patient with hypertensive heart disease, a 63-year-old woman, had cardiac enlargement, an abnormal electrocardiogram, and a history of previous congestive failure. The patient with congenital heart disease, a man in the twenties, had findings typical of interventricular septal defect and an electrocardiogram showing bundle branch block. The man with rheumatic heart disease, 21 years old, had findings typical of mitral stenosis, a normal mechanism, and a past history of congestive heart failure. At the time of treatment he was under digitalis:therapy. In all three of these patients the total dose of emetine was 10 mg. per,kilogram of body weight or less. In seven of the eight patients with cardiac disease, electrocardiograms were taken during emetine therapy. All the tracings but one, that of the 72-year-old man with arter$sclerotic heart disease, were abnormal before emetine was started. Significant change as the result of emetine administration was recognized in one instance only. None of the eight patients developed symptoms or signs of heart failure during or after treatment, and in none of the eight were significant changes of any type noted in the cardiovascular system. In the follow-up periods two deaths were noted, one three and one-half months and the other one year following emetine therapy. Both, we believe, were unrelated to the drug. The death at three and one-half months occurred in one of the women with arteriosclerotic heart disease. Autopsy disclosed severe coronary sclerosis with marked narrowing of the anterior descending branch. Furthermore, the interval between treatment with emetine and death, the absence of symptoms and signs during the three and one-half months, and the lack of electrocardiographic evidence of damage attributable to emetine make it difficult to consider emetine a factor in the patient’s death. DISCUSSION
Emetine has a direct effect on normal heart muscle, although these changes are not necessarily correlated with symptomatic features. When the total dose/ weight ratio of emetine did not exceed 10 mg. per kilogram of body weight in the group of 111 patients from which the eight cases were derived, 26.4 per cent of the patients demonstrated electrocardiographic changes characterized by significant lowering or inversion of the T waves in one or more leads. These changes, which are indicative of the effect of the drug upon the heart, began to appear as early as the third or fourth day of treatment. The electrocardiographic findings were not accompanied by tachycardia nor by clinical evidences of myocardial insufficiency and were, therefore, not considered contraindications to further use of the drug. When the course of treatment was continued to completion under these circumstances, no ill effects were noted, indicating that such changes are not necessarily the forerunners of symptomatic cardiovascular intoxication. In the one patient who showed electrocardiographic changes who also had symptomatic caidiovascular intoxication, the drug was immediately discontinued as it was in all patients showing symptomatic intoxication. Our experience is similar to that of others. Cottrell and Hayward,2 in following 250 patients under treatment with emetine, found no evidences of
584
AMERICAN
HEART
JOURNAL
myocardial insufficiency. In three of Charters’ patients3 who had slight electrocardiographic abnormalities before emetine, presumably due to the severe general effects of the disease, improvement occurred after emetine. Heilig and Visveswar* reported similar effects. Even when large doses of the drug are given, effects on the heart may not be evident. In one of the patients with marked neuromuscular symptoms, a tremendous amount of emetine had been given. The author saw the patient for emetine intoxication after she had received elsewhere 22 gr. of the drug in eight days. An electrocardiogram at the time was normal, as was the clinical examination of the heart. A repeat electrocardiogram two months later was unchanged. Our experience, therefore, indicates that patients demonstrating electrocardiographic changes during therapy may usually continue their course of treatment, under careful observation, until the total course of 10 mg. per kilogram of body weight is completed. Only once in this series did a symptomatic cardiovascular picture develop when medication was continued after electrocardiographic changes had appeared. In general, no prediction could be made as to which patients would develop cardiovascular symptoms, and, when one of the several systems often involved in intoxication was affected, even to severe degree, there was no evidence of involvement in one or both of the others. It is possible that in individuals with normal hearts emetine could affect myocardial function extensively without the appearance of tachycardia or heart failure. Histologic damage has been described as the result of emetine poisoning. It is obvious from studies on experimental animal9 that electrocardiographic changes may be seen within one minute after intravenous emetine, an indication How that a biochemical lesion may be responsible without histologic damage. extensive such changes may be before they adversely affect myocardial function in patients whose cardiac reserve is great is debatable. However, administration of the drug to patients with definite heart disease and a known reduction in reserve to the point where failure has previously existed and is being prevented by digitalis therapy might throw some light on the problem. The present group of patients includes such examples; yet none of them developed symptoms or signs of heart failure, and only one showed the usual, but here additional, electrocardiographic changes. CONCLUSIONS
1. The usual moderate T-wave changes which occur during emetine therapy were not, in themselves, an indication to stop treatment in the dosage schedules used in this study. 2. The definite effects of emetine upon the heart would indicate that this drug should not be used in patients with cardiac disease unless the condition for which it is being used is a greater threat to life than the heart disease, and then only when no other therapeutic agent is satisfactory. 3. When it was elected to use emetine in the presence of heart disease in this study, a total dose of no more than 10 mg. per kilogram of body weight
SODEMAN
:
EMETINE
THERAPY
AND
HEART
DISEASE
585
produced adequate clinical results and did not adversely affect the heart as far as we could determine. One patient died after three and one-half months, the death apparently being unrelated to the emetine therapy. 4. The number of patients with heart disease involved great enough for statistical generalization.
in this study
is not
REFERENCES 1.
2. 3. 4. 5.
Sodeman, W. A., D’Antoni, J. S., and Doerner, A. A.: Emetine Intoxication, Tr. Roy. Sot. Trap. Med. & Hyg. In press. Cottrell, J. D., and Hayward, G. W.: The Effects of Emetine on the Heart, Brit. Heart .1. 7:168. 1945. Charters, A. D.: Toxic Action of Emetine on the Cardiovascular System, Tr. Roy. Sot. Trop. Med. & Hyg. 43513, 1950. Heilig, R.: and Visves&r, S. K.: On Cardiac Effects of Emetine, Indian M. Gaz. 78:419, 1943. Boyd, L. J., and Scherf, D.: The Electrocardiogram in Acute Emetine Intoxication, J. Pharmacol. & Exper. Therap. 71:362, 1941.
TH-ERAPY WILLIAM
AND
HEART
A. SODEMAN,
NEW ORLEANS,
DISEASE
M.D.
I,.\.
U
NTIL recently, emetine has been the only effective drug in extraintestinal amebiasis. The introduction of chloroquine for the treatment of the hepatic phases of the diseasehas not entirely supplanted this time-honored drug, and it still has a place in the treatment of some phasesof hepatic amebiasis and of other extraintestinal manifestations. It is useful, too, in certain other parasitoses. The continued importance of this drug has prompted the author to report his experiences with patients requiring emetine despite the presence of contraindicating heart disease. The present data were obtained from a general study’ of the toxic effects of emetine in 111 patients. Of these, ninety-four, or 84.7 per cent, had hepatic amebiasis; eleven, or 9.9 per cent, colonic amebiasis of a refractory type in which emetine was used in combination with other drugs; and six, or 5.4 per cent, nonamebic disease in which emetine was the drug of choice. In the entire group there were five instances of symptomatic intoxication, three of the neuromuscular variety and two of the cardiovascular type. Minor symptoms were excluded from this evaluation. In the three patients in the neuromuscular group, one had, in addition, a tachycardia, one nausea and vomiting, and the third diarrhea along with nausea and vomiting. In the cardiovascular group, one patient had tachycardia and a marked reduction in blood pressure, the other tachycardia, vertigo, and syncope. One of these showed electrocardiographic changes attributable to emetine. All five of the patients with symptoms of emetine intoxication had normal hearts previous to and following therapy. In the entire group of 111 patients there were eight in whom advanced heart disease was present before emetine was administered. The drug was given because it was thought that the condition requiring its use was a greater threat to life than the heart disease, and no other therapeutic agent was available. Of the eight patients, five had arteriosclerotic and one each hypertensive, congenital, and rheumatic heart disease. Of the five with arteriosclerotic heart disease,four had signs of cardiac enlargement, and the fifth, along with one of the others, had previously had congestive heart failure. Both of these were under digitalis therapy. Two of the patients were women. The ages of the arteriosclerotic group were 62, 6.5, 69, 69, and 72 years and the total doses of emetine administered 11, 6.9, 5, 12, and 8.8 mg. per kilogram of body weight, respectively. From the Department of Tropical Medicine Isniversity of Louisiana. and the Charity Hospital Received for publication Xov. 9. 19.51.
and Public of Louisiana 582
Health. School of Medicine, at Xew Orleans.
The
Tulane
SODEMAN
:
EMETINE
THERAPY
AND
HEART
DISEASE
583
The patient with hypertensive heart disease, a 63-year-old woman, had cardiac enlargement, an abnormal electrocardiogram, and a history of previous congestive failure. The patient with congenital heart disease, a man in the twenties, had findings typical of interventricular septal defect and an electrocardiogram showing bundle branch block. The man with rheumatic heart disease, 21 years old, had findings typical of mitral stenosis, a normal mechanism, and a past history of congestive heart failure. At the time of treatment he was under digitalis:therapy. In all three of these patients the total dose of emetine was 10 mg. per,kilogram of body weight or less. In seven of the eight patients with cardiac disease, electrocardiograms were taken during emetine therapy. All the tracings but one, that of the 72-year-old man with arter$sclerotic heart disease, were abnormal before emetine was started. Significant change as the result of emetine administration was recognized in one instance only. None of the eight patients developed symptoms or signs of heart failure during or after treatment, and in none of the eight were significant changes of any type noted in the cardiovascular system. In the follow-up periods two deaths were noted, one three and one-half months and the other one year following emetine therapy. Both, we believe, were unrelated to the drug. The death at three and one-half months occurred in one of the women with arteriosclerotic heart disease. Autopsy disclosed severe coronary sclerosis with marked narrowing of the anterior descending branch. Furthermore, the interval between treatment with emetine and death, the absence of symptoms and signs during the three and one-half months, and the lack of electrocardiographic evidence of damage attributable to emetine make it difficult to consider emetine a factor in the patient’s death. DISCUSSION
Emetine has a direct effect on normal heart muscle, although these changes are not necessarily correlated with symptomatic features. When the total dose/ weight ratio of emetine did not exceed 10 mg. per kilogram of body weight in the group of 111 patients from which the eight cases were derived, 26.4 per cent of the patients demonstrated electrocardiographic changes characterized by significant lowering or inversion of the T waves in one or more leads. These changes, which are indicative of the effect of the drug upon the heart, began to appear as early as the third or fourth day of treatment. The electrocardiographic findings were not accompanied by tachycardia nor by clinical evidences of myocardial insufficiency and were, therefore, not considered contraindications to further use of the drug. When the course of treatment was continued to completion under these circumstances, no ill effects were noted, indicating that such changes are not necessarily the forerunners of symptomatic cardiovascular intoxication. In the one patient who showed electrocardiographic changes who also had symptomatic caidiovascular intoxication, the drug was immediately discontinued as it was in all patients showing symptomatic intoxication. Our experience is similar to that of others. Cottrell and Hayward,2 in following 250 patients under treatment with emetine, found no evidences of
584
AMERICAN
HEART
JOURNAL
myocardial insufficiency. In three of Charters’ patients3 who had slight electrocardiographic abnormalities before emetine, presumably due to the severe general effects of the disease, improvement occurred after emetine. Heilig and Visveswar* reported similar effects. Even when large doses of the drug are given, effects on the heart may not be evident. In one of the patients with marked neuromuscular symptoms, a tremendous amount of emetine had been given. The author saw the patient for emetine intoxication after she had received elsewhere 22 gr. of the drug in eight days. An electrocardiogram at the time was normal, as was the clinical examination of the heart. A repeat electrocardiogram two months later was unchanged. Our experience, therefore, indicates that patients demonstrating electrocardiographic changes during therapy may usually continue their course of treatment, under careful observation, until the total course of 10 mg. per kilogram of body weight is completed. Only once in this series did a symptomatic cardiovascular picture develop when medication was continued after electrocardiographic changes had appeared. In general, no prediction could be made as to which patients would develop cardiovascular symptoms, and, when one of the several systems often involved in intoxication was affected, even to severe degree, there was no evidence of involvement in one or both of the others. It is possible that in individuals with normal hearts emetine could affect myocardial function extensively without the appearance of tachycardia or heart failure. Histologic damage has been described as the result of emetine poisoning. It is obvious from studies on experimental animal9 that electrocardiographic changes may be seen within one minute after intravenous emetine, an indication How that a biochemical lesion may be responsible without histologic damage. extensive such changes may be before they adversely affect myocardial function in patients whose cardiac reserve is great is debatable. However, administration of the drug to patients with definite heart disease and a known reduction in reserve to the point where failure has previously existed and is being prevented by digitalis therapy might throw some light on the problem. The present group of patients includes such examples; yet none of them developed symptoms or signs of heart failure, and only one showed the usual, but here additional, electrocardiographic changes. CONCLUSIONS
1. The usual moderate T-wave changes which occur during emetine therapy were not, in themselves, an indication to stop treatment in the dosage schedules used in this study. 2. The definite effects of emetine upon the heart would indicate that this drug should not be used in patients with cardiac disease unless the condition for which it is being used is a greater threat to life than the heart disease, and then only when no other therapeutic agent is satisfactory. 3. When it was elected to use emetine in the presence of heart disease in this study, a total dose of no more than 10 mg. per kilogram of body weight
SODEMAN
:
EMETINE
THERAPY
AND
HEART
DISEASE
585
produced adequate clinical results and did not adversely affect the heart as far as we could determine. One patient died after three and one-half months, the death apparently being unrelated to the emetine therapy. 4. The number of patients with heart disease involved great enough for statistical generalization.
in this study
is not
REFERENCES 1.
2. 3. 4. 5.
Sodeman, W. A., D’Antoni, J. S., and Doerner, A. A.: Emetine Intoxication, Tr. Roy. Sot. Trap. Med. & Hyg. In press. Cottrell, J. D., and Hayward, G. W.: The Effects of Emetine on the Heart, Brit. Heart .1. 7:168. 1945. Charters, A. D.: Toxic Action of Emetine on the Cardiovascular System, Tr. Roy. Sot. Trop. Med. & Hyg. 43513, 1950. Heilig, R.: and Visves&r, S. K.: On Cardiac Effects of Emetine, Indian M. Gaz. 78:419, 1943. Boyd, L. J., and Scherf, D.: The Electrocardiogram in Acute Emetine Intoxication, J. Pharmacol. & Exper. Therap. 71:362, 1941.