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Jaundice due to prochlorperazine (Compazine)
Jaundice
Due to Prochlorperazine (Compazine)
FRANK A.
SOLOMON,
JR.,
*
M.D. and FRANCIS A.
CAMPAGNA, M.D.
San Francisco, California
T
Her habits were very moderate; she used no tobacco, .had two cups of coffee daily and drank a glass of wine with her main meal. Dietary habits included three meals and no essential omission of food. The patient was 5 feet, 5 inches tall and weighed 125 pounds. The blood pressure was lZO/SO mm. Hg. There was a scar on the left membrana tympani. The uterus was retroverted. Physical examination was otherwise not significant. The hemogram, urine and roentgenogram of the chest revealed no abnormalities. Within a week of administration of a prescription containing 20 mg. of phenobarbital and 0.5 cc. of tincture of belladonna a pruritic, erythematous eruption of the ankles, legs and arms developed. The condition disappeared promptly on substituting 200 mg. of meprobamate. However, this was quickly changed to administration of liquid hydroxyzine (Ataraxm) because the patient stated that “pieces seemed to stick in my throat.” One month later, in spite of persistent hot flushes, the patient decided she preferred taking no medication. In particular she declined any hormonal support stating she had heard “this will prolong the ‘change’ and may cause cancer.” One year later on June 20, 1957, she presented herself for examination of a tumor she had found only the day before in the left breast. She weighed 118 pounds. Except for the findings in the breasts the examination was not significantly different. In the left breast, as the patient indicated, there was a hard, movable mass in the upper outer quadrant, 2 by 4 cm. in size, and there were several moderate-sized, axillary nodes. In the right breast in the extreme upper, outer quadrant there was a discrete firm, freelymovable nodule 1 cm. in size; no nodes were palpable in the axilla. On June 25 a left radical mastectomy was performed. The permanent section revealed adenocarcinoma in the tumor and axillary lymph nodes. The I cm. nodule was removed from the right breast; tissue sections showed adenocarcinoma, and on June 28 right radical mastectomy was performed. One liter of blood was administered at the first operation and 500 cc. at the second. On June 24 and June 25 she received 0.25 gm. of
HERE have been many reports of intrahepatic obstructive jaundice following the administration of an apparently heterogeneous group of medications since Hanger and Gutman [7] first elaborated its occurrence with arsphenamine in 1940. Some fifteen drugs have been described in which jaundice has occurred as a complication [Z], but none has evoked the widespread comment that has been given to chlorpromazine (Thorazine@) since its introduction. To this time we have not found any documented reference to jaundice as a complication of prochlorperazine (Compazine@), although a communication from the manufacturers indicates that this drug has been given to “over one million patients” and “while jaundice has been reported in a few instances it has not been possible to definitely attribute this condition to the use of the drug” [3]. It is for this reason that the following case is reported. CASE
REPORT
The patient was a housewife of Italian extraction born in California in 1908. Her husband and one child are living, the latter having had asthma since the occurrence of pertussis in childhood. Her mother was well, and the father had died of “rupture of a large blood vessel” at forty-three years of age. Two aunts had had cancer. The patient’s previous medical experiences had been confined to a “running ear” at the age of twenty-two and appendectomy at the age of twelve. Her opening statement when she was first seen in May 1956 for nervousness and fatigue was “all my life I have done too much,” and “I hate to see my house dirty.” After two years of menstrual irregularity she had skipped three periods. The reappearance of vaginal bleeding had prompted consultation. There had been mild flushing and sweating, aching of the legs and puffiness of the ankles at the end of the day. She had used Metamucil” to improve bowel function and had taken gelatin and a vitamin preparation on the advice of a friend.
* From the Department of Medicine, St. Mary’s Hospital, San Francisco, California. 840
AMERICIAN
JOURNAL
OF
MEDIUINE
Jaundice Due to Prochlorperazine (Compazine)-Solomon,
841
Cam.ugna
TABLE I LABORATORY
FINDINGS
Data
Urine.
... .. ..
Red blood cells (cu. mm.). . . Hemoglobin
. 1 (cu. mm.). . . . .
.. . .
..
.......
Alkaline phosphatase (units). .. ~ Serum bilirubin, total ,,i;z
bpi;.r;;)
s2ZZ JEZ!i c~zEtgo;
..
d;,,;
(per cent esters). Urine urobilinogen (mg./24hr.).
. .
.
6,300
........
4
.
4.4
. .
same
.. .
.
.
.
. . . .
16
18
19.2
18
10.8
10.6
Liver biopsy
.
.
35
.....
.
1
. .... *. .
.
.
.
.
.
.
.
.
... . ..
.
.
.
.
12.2
5.6
3.6
1.4
1.05
0.95
4.7
1.8
1.9
3.95
0.7
0.3
.. .
....
....
.
....
...*
.
Negative
.
.
.
.
.
....
.
3.7
243
... ..
.
...
I
.
.. . .
164 (repeated)
..
....
..
.
.......1
6
11
.
.
. . .
27
9
.
13.5
t&
cent) .‘.
30
19
..
.
: . : : 1 3.2 . . 14 sec., control
Pr$;oz;i;t;t)e
-
. ..
4,540,000
....
wCP&P&=~~
Thymol turbidity (units) . . . . . Serum albumin (gm. per cent) Serum globulin
13
15-20 white bloodI . cells
.
-
-7
12
7
C)ctobex !Jovember
September
August
-
.
;
. .
. . .
-
chloral hydrate to induce sleep; nightly between June 26 and July 8 she received 0.100 gm. of pentobarbital sodium (Nembutale), and between July 9 and 19 0.500 gm. of glutethimide (Doridene), was given. Preoperative medication on June 25 consisted of meperidine (Demerole) and scopolamine. Between July 1 and July 3 she received a total of 40 mg. of prochlorperazine (Compazine) given as 5 mg. tablets every four hours as necessary for nausea. X-ray therapy was begun on July 11 and continued in the outpatient department after hospital discharge on July 19. She received a total of 2,000 r by August 5. On July 31 she was given a prescription for twentyfour tablets of prochlorperazine (Compazine) 5 mg. each to be taken before meals for nausea if necessary. She did not start the prescription until August 1 and had taken twelve tablets when the x-ray therapist noted that the patient was jaundiced at her regular appointment on August 5. The medication was stopped and she was readmitted to the hospital on August 7 intensely jaundiced. The liver was but slightly enlarged, although quite tender. The surgical scars were well NOVEMBER,
1959
healed; there was no clinical sign of local or remote metastases, and roentgenogram of the chest showed no abnormalities. The urine was dark, the tstool light. The patient was treated with a high carbohydrate, high protein, low fat diet with supplemental vitamins and bed rest. Prednisone, 5 mg. four times daily, was added to the therapy on August 14. She was discharged from the hospital August 22 continuing restricted activity, diet and prednisone. The prednisone was gradually reduced and finally discontinued on September 9. By October 11 there was no clinical sign of jaundice and on November 18 bilateral oophorectomy was performed without incident. In May she weighed 127 pounds, felt well, and there was no clinical or roentgenographic evidence of recurrence. The laboratory studies made during the course of the jaundice are to be found in Table I. Figure 1 is a photomicrograph of a biopsy specimen of the liver taken with a Vim-Silverman needle on August 13. It shows changes similar to those described in many
842
Jaundice
Due to Prochlorperazine
Campapn
(Compazine)-Solomon,
FIG. 1. Photomicrograph of section of liver biopsy showing distention of bile capillaries with inspissated bile and infiltration with lymphocytes and eosinophils.
reports of chlorpromazine jaundice. There is distention of the bile capillaries with areas of bile inspissation and infiltration with lymphocytes and some eosinophils. COMMENTS
Several facts about this case are interesting. In the first place, it lends some support to the allergic theory of pathogenesis, for the patient’s son had asthma, she had previously shown a reaction to medication (probably phenobarbital), and the jaundice appeared promptly with a second course of the prochlorperazine (60 mg.) one month after an initial three-day course totaling 40 mg. Biopsy specimen of the liver showed a picture similar in every way to previously described sections in cases of jaundice involving chlorpromazine [d]. In addition, there is to be noted the marked elevation of the serum alkaline phosphatase to which attention has been called in cases of jaundice due to that drug [5]. Furthermore, the many possible etiologies for the jaundice in this case only serve to emphasize again the need to include an awareness of the ever widening sphere of liability of drugs in the differential diagnosis. Lastly, as has been pointed out in the comparison of the formulas and reactions of chlorpromazine and promazine, an apparently minor change in the structure (in that instance one Cl ion) may be able to reduce greatly its allergenic attributes. This would
appear to be true also of prochlorperazine since there has been no previously reported case of jaundice in spite of what must be by now fairly extensive use. The mechanism of the production of jaundice in these cases has been well discussed in several excellent articles ([&?I, among others) and need not be elaborated further here. CONCLUSION
A case of jaundice due to prochlorperazine is presented, with pertinent laboratory data including liver biopsy. The jaundice was of the intrahepatic obstructive type resembling in every way that reported in association with the administration of chlorpromazine. ADDENDUM
Since this report was submitted for publication one other case of jaundice has been reported which is attributed to the administration of prochlorperazine [I]. REFERENCES
F. M. and GUTMAN, A. B. Post-arsphenamine jaundice, apparently due to intrahepatic biliary tract obstruction. J. A. M. A., 115: 263-271, 1940. 2. KINROSS-WRIGHT, V. and MOYER, J. H. Chlor1. HANGER,
AMERICAN
JOURNAL
OF MEDICINE
Jaundice Due to Prochlorperazine (Compazine)-Solomon, promazine and hepatic function. Arch. Neurol. C? Psychiat., 76: 675-680, 1956. 3. Medical department; Smith, Kline and French. Personal communication, November, 1957. 4. STERN, A. A. and WRIGHT, A. W. Hepatic damage in jaundice due to chlorpromazine. J. A. M. A., 161: 508-511, 1956. 5. SHAY, H. and SIPLET, H. Study of chlorpromazine
NOVEMBER,
1959
Cumpagna
843
jaundice, its mechanism and prevention. Gastroenterology, 32: 571-591, 1957. 6. HOLLISTER, L. E. Allergic reactions to tranquilizing drugs. Ann. Int. Med., 49: 17-29, 1958. 7. MECHANIC, R. C. and MEYERS, L. Chlorpromazinetype cholangitis: report of a case occurring after administration of prochlorperazine. N~UI En,&& J. Med., 259: 778-780, 1958.
Due to Prochlorperazine (Compazine)
FRANK A.
SOLOMON,
JR.,
*
M.D. and FRANCIS A.
CAMPAGNA, M.D.
San Francisco, California
T
Her habits were very moderate; she used no tobacco, .had two cups of coffee daily and drank a glass of wine with her main meal. Dietary habits included three meals and no essential omission of food. The patient was 5 feet, 5 inches tall and weighed 125 pounds. The blood pressure was lZO/SO mm. Hg. There was a scar on the left membrana tympani. The uterus was retroverted. Physical examination was otherwise not significant. The hemogram, urine and roentgenogram of the chest revealed no abnormalities. Within a week of administration of a prescription containing 20 mg. of phenobarbital and 0.5 cc. of tincture of belladonna a pruritic, erythematous eruption of the ankles, legs and arms developed. The condition disappeared promptly on substituting 200 mg. of meprobamate. However, this was quickly changed to administration of liquid hydroxyzine (Ataraxm) because the patient stated that “pieces seemed to stick in my throat.” One month later, in spite of persistent hot flushes, the patient decided she preferred taking no medication. In particular she declined any hormonal support stating she had heard “this will prolong the ‘change’ and may cause cancer.” One year later on June 20, 1957, she presented herself for examination of a tumor she had found only the day before in the left breast. She weighed 118 pounds. Except for the findings in the breasts the examination was not significantly different. In the left breast, as the patient indicated, there was a hard, movable mass in the upper outer quadrant, 2 by 4 cm. in size, and there were several moderate-sized, axillary nodes. In the right breast in the extreme upper, outer quadrant there was a discrete firm, freelymovable nodule 1 cm. in size; no nodes were palpable in the axilla. On June 25 a left radical mastectomy was performed. The permanent section revealed adenocarcinoma in the tumor and axillary lymph nodes. The I cm. nodule was removed from the right breast; tissue sections showed adenocarcinoma, and on June 28 right radical mastectomy was performed. One liter of blood was administered at the first operation and 500 cc. at the second. On June 24 and June 25 she received 0.25 gm. of
HERE have been many reports of intrahepatic obstructive jaundice following the administration of an apparently heterogeneous group of medications since Hanger and Gutman [7] first elaborated its occurrence with arsphenamine in 1940. Some fifteen drugs have been described in which jaundice has occurred as a complication [Z], but none has evoked the widespread comment that has been given to chlorpromazine (Thorazine@) since its introduction. To this time we have not found any documented reference to jaundice as a complication of prochlorperazine (Compazine@), although a communication from the manufacturers indicates that this drug has been given to “over one million patients” and “while jaundice has been reported in a few instances it has not been possible to definitely attribute this condition to the use of the drug” [3]. It is for this reason that the following case is reported. CASE
REPORT
The patient was a housewife of Italian extraction born in California in 1908. Her husband and one child are living, the latter having had asthma since the occurrence of pertussis in childhood. Her mother was well, and the father had died of “rupture of a large blood vessel” at forty-three years of age. Two aunts had had cancer. The patient’s previous medical experiences had been confined to a “running ear” at the age of twenty-two and appendectomy at the age of twelve. Her opening statement when she was first seen in May 1956 for nervousness and fatigue was “all my life I have done too much,” and “I hate to see my house dirty.” After two years of menstrual irregularity she had skipped three periods. The reappearance of vaginal bleeding had prompted consultation. There had been mild flushing and sweating, aching of the legs and puffiness of the ankles at the end of the day. She had used Metamucil” to improve bowel function and had taken gelatin and a vitamin preparation on the advice of a friend.
* From the Department of Medicine, St. Mary’s Hospital, San Francisco, California. 840
AMERICIAN
JOURNAL
OF
MEDIUINE
Jaundice Due to Prochlorperazine (Compazine)-Solomon,
841
Cam.ugna
TABLE I LABORATORY
FINDINGS
Data
Urine.
... .. ..
Red blood cells (cu. mm.). . . Hemoglobin
. 1 (cu. mm.). . . . .
.. . .
..
.......
Alkaline phosphatase (units). .. ~ Serum bilirubin, total ,,i;z
bpi;.r;;)
s2ZZ JEZ!i c~zEtgo;
..
d;,,;
(per cent esters). Urine urobilinogen (mg./24hr.).
. .
.
6,300
........
4
.
4.4
. .
same
.. .
.
.
.
. . . .
16
18
19.2
18
10.8
10.6
Liver biopsy
.
.
35
.....
.
1
. .... *. .
.
.
.
.
.
.
.
.
... . ..
.
.
.
.
12.2
5.6
3.6
1.4
1.05
0.95
4.7
1.8
1.9
3.95
0.7
0.3
.. .
....
....
.
....
...*
.
Negative
.
.
.
.
.
....
.
3.7
243
... ..
.
...
I
.
.. . .
164 (repeated)
..
....
..
.
.......1
6
11
.
.
. . .
27
9
.
13.5
t&
cent) .‘.
30
19
..
.
: . : : 1 3.2 . . 14 sec., control
Pr$;oz;i;t;t)e
-
. ..
4,540,000
....
wCP&P&=~~
Thymol turbidity (units) . . . . . Serum albumin (gm. per cent) Serum globulin
13
15-20 white bloodI . cells
.
-
-7
12
7
C)ctobex !Jovember
September
August
-
.
;
. .
. . .
-
chloral hydrate to induce sleep; nightly between June 26 and July 8 she received 0.100 gm. of pentobarbital sodium (Nembutale), and between July 9 and 19 0.500 gm. of glutethimide (Doridene), was given. Preoperative medication on June 25 consisted of meperidine (Demerole) and scopolamine. Between July 1 and July 3 she received a total of 40 mg. of prochlorperazine (Compazine) given as 5 mg. tablets every four hours as necessary for nausea. X-ray therapy was begun on July 11 and continued in the outpatient department after hospital discharge on July 19. She received a total of 2,000 r by August 5. On July 31 she was given a prescription for twentyfour tablets of prochlorperazine (Compazine) 5 mg. each to be taken before meals for nausea if necessary. She did not start the prescription until August 1 and had taken twelve tablets when the x-ray therapist noted that the patient was jaundiced at her regular appointment on August 5. The medication was stopped and she was readmitted to the hospital on August 7 intensely jaundiced. The liver was but slightly enlarged, although quite tender. The surgical scars were well NOVEMBER,
1959
healed; there was no clinical sign of local or remote metastases, and roentgenogram of the chest showed no abnormalities. The urine was dark, the tstool light. The patient was treated with a high carbohydrate, high protein, low fat diet with supplemental vitamins and bed rest. Prednisone, 5 mg. four times daily, was added to the therapy on August 14. She was discharged from the hospital August 22 continuing restricted activity, diet and prednisone. The prednisone was gradually reduced and finally discontinued on September 9. By October 11 there was no clinical sign of jaundice and on November 18 bilateral oophorectomy was performed without incident. In May she weighed 127 pounds, felt well, and there was no clinical or roentgenographic evidence of recurrence. The laboratory studies made during the course of the jaundice are to be found in Table I. Figure 1 is a photomicrograph of a biopsy specimen of the liver taken with a Vim-Silverman needle on August 13. It shows changes similar to those described in many
842
Jaundice
Due to Prochlorperazine
Campapn
(Compazine)-Solomon,
FIG. 1. Photomicrograph of section of liver biopsy showing distention of bile capillaries with inspissated bile and infiltration with lymphocytes and eosinophils.
reports of chlorpromazine jaundice. There is distention of the bile capillaries with areas of bile inspissation and infiltration with lymphocytes and some eosinophils. COMMENTS
Several facts about this case are interesting. In the first place, it lends some support to the allergic theory of pathogenesis, for the patient’s son had asthma, she had previously shown a reaction to medication (probably phenobarbital), and the jaundice appeared promptly with a second course of the prochlorperazine (60 mg.) one month after an initial three-day course totaling 40 mg. Biopsy specimen of the liver showed a picture similar in every way to previously described sections in cases of jaundice involving chlorpromazine [d]. In addition, there is to be noted the marked elevation of the serum alkaline phosphatase to which attention has been called in cases of jaundice due to that drug [5]. Furthermore, the many possible etiologies for the jaundice in this case only serve to emphasize again the need to include an awareness of the ever widening sphere of liability of drugs in the differential diagnosis. Lastly, as has been pointed out in the comparison of the formulas and reactions of chlorpromazine and promazine, an apparently minor change in the structure (in that instance one Cl ion) may be able to reduce greatly its allergenic attributes. This would
appear to be true also of prochlorperazine since there has been no previously reported case of jaundice in spite of what must be by now fairly extensive use. The mechanism of the production of jaundice in these cases has been well discussed in several excellent articles ([&?I, among others) and need not be elaborated further here. CONCLUSION
A case of jaundice due to prochlorperazine is presented, with pertinent laboratory data including liver biopsy. The jaundice was of the intrahepatic obstructive type resembling in every way that reported in association with the administration of chlorpromazine. ADDENDUM
Since this report was submitted for publication one other case of jaundice has been reported which is attributed to the administration of prochlorperazine [I]. REFERENCES
F. M. and GUTMAN, A. B. Post-arsphenamine jaundice, apparently due to intrahepatic biliary tract obstruction. J. A. M. A., 115: 263-271, 1940. 2. KINROSS-WRIGHT, V. and MOYER, J. H. Chlor1. HANGER,
AMERICAN
JOURNAL
OF MEDICINE
Jaundice Due to Prochlorperazine (Compazine)-Solomon, promazine and hepatic function. Arch. Neurol. C? Psychiat., 76: 675-680, 1956. 3. Medical department; Smith, Kline and French. Personal communication, November, 1957. 4. STERN, A. A. and WRIGHT, A. W. Hepatic damage in jaundice due to chlorpromazine. J. A. M. A., 161: 508-511, 1956. 5. SHAY, H. and SIPLET, H. Study of chlorpromazine
NOVEMBER,
1959
Cumpagna
843
jaundice, its mechanism and prevention. Gastroenterology, 32: 571-591, 1957. 6. HOLLISTER, L. E. Allergic reactions to tranquilizing drugs. Ann. Int. Med., 49: 17-29, 1958. 7. MECHANIC, R. C. and MEYERS, L. Chlorpromazinetype cholangitis: report of a case occurring after administration of prochlorperazine. N~UI En,&& J. Med., 259: 778-780, 1958.