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Aplastic Anemia Resulting From the use of Carbonic Anhydrase Inhibitors
A P L A S T I C A N E M I A R E S U L T I N G FROM T H E U S E O F CARBONIC ANHYDRASE INHIBITORS NATHANIEL W I S C H , M.D., FREDERIC I. FISCHBEIN, M.D., RICHARD SIEGEL, JOSEPH L. GLASS, M.D., AND IRVING LEOPOLD, M.D.
M.D.,
New York, New York platelets/mm3. The differential count showed 10% bands, 5% segmented polys, 80% lymphocytes, and S'% monocytes. Sedimentation rate was 115 mm/hour. A sternal bone marrow specimen showed a markedly hypocellular marrow with a decrease in both erythroid and granulocytic precursors. Megakaryocytes were rarely seen. A diagnosis of aplastic anemia was made and the patient was treated with oxymethalone, prednisone, and blood transfusions. The hospital course was marked by repeated hemorrhages and continued fall in hemoglobin. After six units of packed cells, the patient's hemoglobin was 10.8 g%. No change was noted in the white cells or platelets. Three weeks after admission, melena occurred and three additional units of packed cells were given, followed by four units of fresh whole blood. Several days later the stools were no longer dark. The patient then experienced a shaking chill followed by a sharp rise in tempera ture. Blood cultures grew out a Gram-negative ba cillus. Urine cultures recovered B. pyocyaneus. The patient was treated with ampicillin. Subsequently, pain developed in both calves. The patient experi enced brief periods of unconsciousness and suddenly expired. The essential findings at autopsy were severe hypoplasia of the bone marrow, severe pulmonary edema, multiple erosions and hemorrhages of the gastric mucosa, generalized atherosclerotic heart disease. Final diagnosis was pancytopenia secondary to aplastic anemia with sepsis. CASE REPORTS Case 2—A 71-year-old white woman with a 40Case 1—A 72-year-old white man entered the year history of diabetes mellitus had mild chronic Mount Sinai Hospital for control of glaucoma. One intermittent hypertension. She was seen by an oph year previously, he suffered a central vein occlusion thalmologist one year prior to admission. The visual in the right eye. He received pilocarpine, which was acuity in the left eye was noted then to be 20/400, discontinued because of a browache. Because of in which was attributed to an old vitreous hemor creasing intraocular pressure and pain, treatment rhage. Ocular tension was normal. Ascorbic acid, began with acetazolamide (125 mg orally four 150 units per day, and vitamin A, 50,000 units twice times a day). During the next several months, the daily, were prescribed. The patient was taking patient experienced anorexia, increasing malaise, multi-vitamins and clofibrate. The diabetes was con trolled for many years with tolbutamide 1.5 g daily. and weight loss. Hemoglobin was 6.3 g%. Past medical history revealed a coronary occlu Four months prior to admission, the ocular tension sion in 1951. There were no known allergies, and no was slightly elevated in both eyes and methazola other significant illnesses. The only other medica mide tablets, 100 mg daily, were prescribed. The clo fibrate was discontinued. At that time, the patient tion the patient was taking was potassium chloride. was also taking potassium chloride tablets, multi-vi Initial laboratory data included a hemoglobin of 6.3 g%, 1.95 million red blood cells/mm3, and 8,000 tamins, and dextro propoxyphene HC1 (Darvon). One week prior to admission, she experienced pain on swallowing, which responded symptomatiFrom the departments of medicine (hematology) and ophthalmology of the Mount Sinai School of cally to erythromycin tablets. Three days prior to admission, the patient noted chest pain (which was Medicine of the City University of New York. Reprint requests to Nathaniel Wisch, M.D., 920 not relieved by antacids), increasing weakness, fa tigue, and recurrence of the sore throat. Immediately Park Avenue, New York, New York. Side effects associated with acetazolamide and methazolamide are numerous, but for the most part minor in nature. Those associ ated with acetazolamide include paresthesias, gastrointestinal distress, hyperchloremic acidosis, fever, rash, drowsiness, convul sions, and crystalluria. The only known ocu lar side effect of acetazolamide is occasional, transient myopia which may also follow the use of sulfonamides. Agranulocytosis and thrombocytopenia are rare complications, while aplastic anemia is rarer still.1"10 In one series, acetazolamide accounted for 10 of 652 cases of agranulocytosis, and three of 266 cases of aplastic anemia.8 The side effects of methazolamide are essentially simi lar to those of acetazolamide, with the excep tion that there are no reported cases of blood dyscrasia secondary to methazolamide. This paper reports two cases of aplastic anemia, one due to acetazolamide and the other secondary to methazolamide.
130
APLASTIC ANEMIA AND DRUGS
VOL. 75, NO. 1
prior to admission, the patient was seen by one of us (N.W.) and was noted to be anemic (hemoglo bin 7.7 g%), leukopenic (white blood count 950), and thrombocytopenic (platelets less than 50,000). A sternal bone marrow aspirate revealed a few scattered plasma cells, but was otherwise almost acellular. Physical examination revealed a normally devel oped and nourished white woman in no acute dis tress. Her blood pressure was 140/90 mm Hg, pulse 104, temperature 101 F, respirations 20. There was a 2 by 3 cm, irregular ecchymotic area on the hard palate. Numerous small white patches were scat tered diffusely on the palate, and left tonsillar pil lar. The pharynx was erythematous, and a few soft, slightly tender nodes were palpable in the left ante rior cervical chain. The remainder of the examina tion was unremarkable. On admission, there was 4 + glycosuria and insu lin coverage was initiated. Admission laboratory studies including blood culture, chemistries, and protein electrophoresis were unremarkable. The hé matologie picture revealed: hemoglobin 7.7 g%, white blood count 950, lymphocytes 96%, platelet count 9000. The following day, two units of packed red cells were given without incident. On the third hospital day, the patient had an episode of atrial fibrillation which was treated satisfactorily with digitalis. One week after admission, she showed signs of a left cerebral vascular accident, became unresponsive, and died several hours later. DISCUSSION
Aplastic anemia is a condition in which there is a severe depression of the blood cell precursors in the marrow with resulting pancytopenia in the peripheral blood. It can occur in an idiopathic form, or can be pro duced following exposure to a chemical or physical agent. The latter can be divided into two groups. Certain agents can be expected to cause marrow aplasia whenever a suffi cient amount is administered. These agents include benzene, ionizing radiation, nitrogen mustard, and other such drugs. There is, however, another group of drugs which only occasionally produce marrow aplasia. This group poses a much greater problem because the manner in which they cause hématologie toxicity is unknown, and it is impossible to predict which patients will have this type of reaction. Furthermore, the evidence implicating any given drug as the causative agent is frequently circumstantial and it is only after many cases that one can
131
be convinced of the etiologic relationship. For example, the second case is complicated by the fact that the patient had been taking both tolbutamide and clofibrate. The tolbutamide had been in use for many years and the clofibrate was discontinued four months prior to the onset of symptoms. The possibil ity of these agents being involved etiologically cannot be negated. Both acetazolamide and methazolamide are carbonic anhydrase inhibitors, related struc turally to sulfonamide.11 Their chemical for mulas are quite similar. There are many the ories regarding the mechanism of action of these drugs, and their role in lowering ocular tension. However, none are fully accepta ble.12 Methazolamide penetrates the aqueous humor approximately three to five times as readily as acetazolamide, which may account for its effectiveness in lowering intraocular pressure at lower doses than that required for the latter. Methazolamide penetrates the blood-aqueous barrier more rapidly than ace tazolamide and is excreted more slowly.13"15 The limitations of long-term treatment with acetazolamide, ethoxzolamide, and dichlorphenamide result more often from intoler ance of side effects than from failure of pressure control. Methazolamide finds its major usefulness in the long term treatment of patients with uncontrolled glaucoma who fail to respond to other carbonic anhydrase inhibitors.16 As we mentioned earlier, acetazolamide has been associated with depression of pe ripheral blood elements, but no such data are available for methazolamide. In this regard, several case reports have noted improvement with cessation of therapy.2 ' 6 · 7 The effect of acetazolamide on the bone marrow has been variable. Individuals demonstrating a toxic effect may have a hypocellular or normocellular marrow. The prognosis for recovery with a hypocellular marrow is most guarded. The etiology of the bone marrow depres sion is unknown. Several observers have noted that the addition of acetazolamide to a
132
AMERICAN JOURNAL OF OPHTHALMOLOGY
suspension of platelets in plasma of patients with acetazolamide-induced agranulocytosis results in platelet agglutination. Acetazola mide added to platelet suspensions in normal subjects does not cause agglutination.2"4 These studies hardly yield any definitive information regarding the cause of aplastic anemia with acetazolamide. There is evi dence drawn from patients who have re covered from chloramphenicol-induced marrow aplasia that there is a biochemical susceptibility involving some essential meta bolic pathway involved in nucleic acid syn thesis.17"18 This has not yet been demon strated with acetazolamide. Since recovery from hématologie toxicity secondary to acetazolamide has been re ported after discontinuation of the drug, it appears that awareness of and early recogni tion of the problem is a key factor in therapy. However, once the condition has progressed to complete aplasia of the bone marrow, the prognosis is indeed grave. It is necessary, therefore, that the physician not only evaluate the patient's need for therapy with any drugs but also to be able to recognize its toxicity as early as possible. Certainly, periodic blood counts should be done to detect early signs of bone marrow toxicity before irreversible changes occur. SUMMARY
Aplastic anemia followed the use of aceta zolamide in a 72-year-old man and the use of methazolamide in a 71-year-old woman. The mechanism by which these drugs suppress bone marrow function is unknown and in fact the etiologic role of these drugs causing aplasia of the bone marrow is presumptive. Periodic blood counts are important to detect early signs of marrow suppression when these drugs are administered.
JANUARY, 1973
REFERENCES
1. Pearson, J. R., Binder, C. I., and Neber, J. : Agranulocytosis following diamox therapy. J.A.M.A. 157:339, 1955. 2. Reisner, E. K., Jr., and Morgan, M. C. : Thrombocytopenia following acetazolamide (Dia mox) therapy. J.A.M.A. 160:206, 1956. 3. Underwood, L. C. : Fatal bone marrow depres sions after treatment with acetazolamide (Diamox). J.A.M.A. 161:1477, 1956. 4. Bertino, J. R., Rodman, T., and Myerson, R. M. : Thrombocytopenia and renal lesions associ ated with acetazolamide (Diamox) therapy. Arch. Int. Med. 99.1006,1957. 5. Hoffman, F. G., Zimmerman, S. L., and Reese, J. D. : Fatal agranulocytosis associated with aceta zolamide. New England J. Med. 262:242, 1960. 6. Turtz, C. A., and Turtz, A. I. : Toxicity due to acetazolamide (Diamox). Arch. Ophth. 60:130, 1958. 7. Arora, Y. C. : Agranulocytosis following ace tazolamide therapy. New York J. Med. 59:1119, 1959. 8. Erslev, A. J. : Drug-induced blood dyscrasias. I. Aplastic anemias. J.A.M.A. 188:531, 1964. 9. Lübeck, J. J. : Aplastic anemia following ace tazolamide therapy. Am. J. Ophth. 69:684, 1970. 10. Englund, G. W. : Fatal pancytopenia and ace tazolamide therapy. J.A.M.A. 210:2282, 1969. 11. Mudge, G. H. : Diuretics and other agents employed in the mobilization of edema fluid. In Goodman, L. S. and Gilman, A. (eds.) : The Phar macological Basis of Therapeutics, 3rd ed. New York, Macmillan, 1965, p. 838. 12. Adler, F. H. : Physiology of the eye, 4th ed. St. Louis, Mosby, 1965, p. 166. 13. Langham, M. E. : Specificity and comparative activity of the carbonic anhydrase inhibitors neptazane and diamox on animal and human eyes. Brit. J. Ophth. 42:577, 1958. 14. Coop, D. H. : Neptazane in glaucoma : A pre liminary clinical report. Brit. J. Ophth. 43:602, 1959. 15. De Roetth, A., Jr. : Ophthalmic pharmacology and toxicology. Arch. Ophth. 62:292, 1960. 16. Becker, B. : Use of methazolamide (Nepta zane) in the therapy of glaucoma. Am. J. Ophth. 49:1307, 1960. 17. Yunis, A. A., and Arimura, G. K. : Biochemi cal predisposition to chloramphenicol-induced bone marrow aplasia. Clin. Res. 11:201, 1963. 18. Yunis, A. A., and Bloomberg, G. R. : Chloramphenicol toxicity: Clinical features and pathogenesis. In Progress in Hematology, vol. 4. New York, Grune and Stratton, 1964, p. 138.
M.D.,
New York, New York platelets/mm3. The differential count showed 10% bands, 5% segmented polys, 80% lymphocytes, and S'% monocytes. Sedimentation rate was 115 mm/hour. A sternal bone marrow specimen showed a markedly hypocellular marrow with a decrease in both erythroid and granulocytic precursors. Megakaryocytes were rarely seen. A diagnosis of aplastic anemia was made and the patient was treated with oxymethalone, prednisone, and blood transfusions. The hospital course was marked by repeated hemorrhages and continued fall in hemoglobin. After six units of packed cells, the patient's hemoglobin was 10.8 g%. No change was noted in the white cells or platelets. Three weeks after admission, melena occurred and three additional units of packed cells were given, followed by four units of fresh whole blood. Several days later the stools were no longer dark. The patient then experienced a shaking chill followed by a sharp rise in tempera ture. Blood cultures grew out a Gram-negative ba cillus. Urine cultures recovered B. pyocyaneus. The patient was treated with ampicillin. Subsequently, pain developed in both calves. The patient experi enced brief periods of unconsciousness and suddenly expired. The essential findings at autopsy were severe hypoplasia of the bone marrow, severe pulmonary edema, multiple erosions and hemorrhages of the gastric mucosa, generalized atherosclerotic heart disease. Final diagnosis was pancytopenia secondary to aplastic anemia with sepsis. CASE REPORTS Case 2—A 71-year-old white woman with a 40Case 1—A 72-year-old white man entered the year history of diabetes mellitus had mild chronic Mount Sinai Hospital for control of glaucoma. One intermittent hypertension. She was seen by an oph year previously, he suffered a central vein occlusion thalmologist one year prior to admission. The visual in the right eye. He received pilocarpine, which was acuity in the left eye was noted then to be 20/400, discontinued because of a browache. Because of in which was attributed to an old vitreous hemor creasing intraocular pressure and pain, treatment rhage. Ocular tension was normal. Ascorbic acid, began with acetazolamide (125 mg orally four 150 units per day, and vitamin A, 50,000 units twice times a day). During the next several months, the daily, were prescribed. The patient was taking patient experienced anorexia, increasing malaise, multi-vitamins and clofibrate. The diabetes was con trolled for many years with tolbutamide 1.5 g daily. and weight loss. Hemoglobin was 6.3 g%. Past medical history revealed a coronary occlu Four months prior to admission, the ocular tension sion in 1951. There were no known allergies, and no was slightly elevated in both eyes and methazola other significant illnesses. The only other medica mide tablets, 100 mg daily, were prescribed. The clo fibrate was discontinued. At that time, the patient tion the patient was taking was potassium chloride. was also taking potassium chloride tablets, multi-vi Initial laboratory data included a hemoglobin of 6.3 g%, 1.95 million red blood cells/mm3, and 8,000 tamins, and dextro propoxyphene HC1 (Darvon). One week prior to admission, she experienced pain on swallowing, which responded symptomatiFrom the departments of medicine (hematology) and ophthalmology of the Mount Sinai School of cally to erythromycin tablets. Three days prior to admission, the patient noted chest pain (which was Medicine of the City University of New York. Reprint requests to Nathaniel Wisch, M.D., 920 not relieved by antacids), increasing weakness, fa tigue, and recurrence of the sore throat. Immediately Park Avenue, New York, New York. Side effects associated with acetazolamide and methazolamide are numerous, but for the most part minor in nature. Those associ ated with acetazolamide include paresthesias, gastrointestinal distress, hyperchloremic acidosis, fever, rash, drowsiness, convul sions, and crystalluria. The only known ocu lar side effect of acetazolamide is occasional, transient myopia which may also follow the use of sulfonamides. Agranulocytosis and thrombocytopenia are rare complications, while aplastic anemia is rarer still.1"10 In one series, acetazolamide accounted for 10 of 652 cases of agranulocytosis, and three of 266 cases of aplastic anemia.8 The side effects of methazolamide are essentially simi lar to those of acetazolamide, with the excep tion that there are no reported cases of blood dyscrasia secondary to methazolamide. This paper reports two cases of aplastic anemia, one due to acetazolamide and the other secondary to methazolamide.
130
APLASTIC ANEMIA AND DRUGS
VOL. 75, NO. 1
prior to admission, the patient was seen by one of us (N.W.) and was noted to be anemic (hemoglo bin 7.7 g%), leukopenic (white blood count 950), and thrombocytopenic (platelets less than 50,000). A sternal bone marrow aspirate revealed a few scattered plasma cells, but was otherwise almost acellular. Physical examination revealed a normally devel oped and nourished white woman in no acute dis tress. Her blood pressure was 140/90 mm Hg, pulse 104, temperature 101 F, respirations 20. There was a 2 by 3 cm, irregular ecchymotic area on the hard palate. Numerous small white patches were scat tered diffusely on the palate, and left tonsillar pil lar. The pharynx was erythematous, and a few soft, slightly tender nodes were palpable in the left ante rior cervical chain. The remainder of the examina tion was unremarkable. On admission, there was 4 + glycosuria and insu lin coverage was initiated. Admission laboratory studies including blood culture, chemistries, and protein electrophoresis were unremarkable. The hé matologie picture revealed: hemoglobin 7.7 g%, white blood count 950, lymphocytes 96%, platelet count 9000. The following day, two units of packed red cells were given without incident. On the third hospital day, the patient had an episode of atrial fibrillation which was treated satisfactorily with digitalis. One week after admission, she showed signs of a left cerebral vascular accident, became unresponsive, and died several hours later. DISCUSSION
Aplastic anemia is a condition in which there is a severe depression of the blood cell precursors in the marrow with resulting pancytopenia in the peripheral blood. It can occur in an idiopathic form, or can be pro duced following exposure to a chemical or physical agent. The latter can be divided into two groups. Certain agents can be expected to cause marrow aplasia whenever a suffi cient amount is administered. These agents include benzene, ionizing radiation, nitrogen mustard, and other such drugs. There is, however, another group of drugs which only occasionally produce marrow aplasia. This group poses a much greater problem because the manner in which they cause hématologie toxicity is unknown, and it is impossible to predict which patients will have this type of reaction. Furthermore, the evidence implicating any given drug as the causative agent is frequently circumstantial and it is only after many cases that one can
131
be convinced of the etiologic relationship. For example, the second case is complicated by the fact that the patient had been taking both tolbutamide and clofibrate. The tolbutamide had been in use for many years and the clofibrate was discontinued four months prior to the onset of symptoms. The possibil ity of these agents being involved etiologically cannot be negated. Both acetazolamide and methazolamide are carbonic anhydrase inhibitors, related struc turally to sulfonamide.11 Their chemical for mulas are quite similar. There are many the ories regarding the mechanism of action of these drugs, and their role in lowering ocular tension. However, none are fully accepta ble.12 Methazolamide penetrates the aqueous humor approximately three to five times as readily as acetazolamide, which may account for its effectiveness in lowering intraocular pressure at lower doses than that required for the latter. Methazolamide penetrates the blood-aqueous barrier more rapidly than ace tazolamide and is excreted more slowly.13"15 The limitations of long-term treatment with acetazolamide, ethoxzolamide, and dichlorphenamide result more often from intoler ance of side effects than from failure of pressure control. Methazolamide finds its major usefulness in the long term treatment of patients with uncontrolled glaucoma who fail to respond to other carbonic anhydrase inhibitors.16 As we mentioned earlier, acetazolamide has been associated with depression of pe ripheral blood elements, but no such data are available for methazolamide. In this regard, several case reports have noted improvement with cessation of therapy.2 ' 6 · 7 The effect of acetazolamide on the bone marrow has been variable. Individuals demonstrating a toxic effect may have a hypocellular or normocellular marrow. The prognosis for recovery with a hypocellular marrow is most guarded. The etiology of the bone marrow depres sion is unknown. Several observers have noted that the addition of acetazolamide to a
132
AMERICAN JOURNAL OF OPHTHALMOLOGY
suspension of platelets in plasma of patients with acetazolamide-induced agranulocytosis results in platelet agglutination. Acetazola mide added to platelet suspensions in normal subjects does not cause agglutination.2"4 These studies hardly yield any definitive information regarding the cause of aplastic anemia with acetazolamide. There is evi dence drawn from patients who have re covered from chloramphenicol-induced marrow aplasia that there is a biochemical susceptibility involving some essential meta bolic pathway involved in nucleic acid syn thesis.17"18 This has not yet been demon strated with acetazolamide. Since recovery from hématologie toxicity secondary to acetazolamide has been re ported after discontinuation of the drug, it appears that awareness of and early recogni tion of the problem is a key factor in therapy. However, once the condition has progressed to complete aplasia of the bone marrow, the prognosis is indeed grave. It is necessary, therefore, that the physician not only evaluate the patient's need for therapy with any drugs but also to be able to recognize its toxicity as early as possible. Certainly, periodic blood counts should be done to detect early signs of bone marrow toxicity before irreversible changes occur. SUMMARY
Aplastic anemia followed the use of aceta zolamide in a 72-year-old man and the use of methazolamide in a 71-year-old woman. The mechanism by which these drugs suppress bone marrow function is unknown and in fact the etiologic role of these drugs causing aplasia of the bone marrow is presumptive. Periodic blood counts are important to detect early signs of marrow suppression when these drugs are administered.
JANUARY, 1973
REFERENCES
1. Pearson, J. R., Binder, C. I., and Neber, J. : Agranulocytosis following diamox therapy. J.A.M.A. 157:339, 1955. 2. Reisner, E. K., Jr., and Morgan, M. C. : Thrombocytopenia following acetazolamide (Dia mox) therapy. J.A.M.A. 160:206, 1956. 3. Underwood, L. C. : Fatal bone marrow depres sions after treatment with acetazolamide (Diamox). J.A.M.A. 161:1477, 1956. 4. Bertino, J. R., Rodman, T., and Myerson, R. M. : Thrombocytopenia and renal lesions associ ated with acetazolamide (Diamox) therapy. Arch. Int. Med. 99.1006,1957. 5. Hoffman, F. G., Zimmerman, S. L., and Reese, J. D. : Fatal agranulocytosis associated with aceta zolamide. New England J. Med. 262:242, 1960. 6. Turtz, C. A., and Turtz, A. I. : Toxicity due to acetazolamide (Diamox). Arch. Ophth. 60:130, 1958. 7. Arora, Y. C. : Agranulocytosis following ace tazolamide therapy. New York J. Med. 59:1119, 1959. 8. Erslev, A. J. : Drug-induced blood dyscrasias. I. Aplastic anemias. J.A.M.A. 188:531, 1964. 9. Lübeck, J. J. : Aplastic anemia following ace tazolamide therapy. Am. J. Ophth. 69:684, 1970. 10. Englund, G. W. : Fatal pancytopenia and ace tazolamide therapy. J.A.M.A. 210:2282, 1969. 11. Mudge, G. H. : Diuretics and other agents employed in the mobilization of edema fluid. In Goodman, L. S. and Gilman, A. (eds.) : The Phar macological Basis of Therapeutics, 3rd ed. New York, Macmillan, 1965, p. 838. 12. Adler, F. H. : Physiology of the eye, 4th ed. St. Louis, Mosby, 1965, p. 166. 13. Langham, M. E. : Specificity and comparative activity of the carbonic anhydrase inhibitors neptazane and diamox on animal and human eyes. Brit. J. Ophth. 42:577, 1958. 14. Coop, D. H. : Neptazane in glaucoma : A pre liminary clinical report. Brit. J. Ophth. 43:602, 1959. 15. De Roetth, A., Jr. : Ophthalmic pharmacology and toxicology. Arch. Ophth. 62:292, 1960. 16. Becker, B. : Use of methazolamide (Nepta zane) in the therapy of glaucoma. Am. J. Ophth. 49:1307, 1960. 17. Yunis, A. A., and Arimura, G. K. : Biochemi cal predisposition to chloramphenicol-induced bone marrow aplasia. Clin. Res. 11:201, 1963. 18. Yunis, A. A., and Bloomberg, G. R. : Chloramphenicol toxicity: Clinical features and pathogenesis. In Progress in Hematology, vol. 4. New York, Grune and Stratton, 1964, p. 138.