CASE REPORTS
Propranolol in Human Plasma and Breast Milk
JOHN H. BAUER, MD BRIAN PAPE, PhD JAMES ZAJICEK TED GROSHONG, MD Columbia, Missouri
To assess the problem of continuing propranolol therapy in a breastfeeding mother, studles were performed to determine simultaneously plasma and breast milk concentrations of propranolol after single dose (40 mg) and continuous dose (40 mg 4 times daily) treatment with this drug. Breast milk and.plasma concentrations of propranolol peaked between 2 and 3 hours after dosing. Propranolol concentrations in breast milk were less than 40 and 64 percent, respectively, of peak plasma propranolol concentrations after single dose and continuous dose administration. It was estimated that the maximal cumulative propranolol load to this breast-feeding infant, consuming 500 ml of whole milk, when the mother received 4O’mg of propranolol4 timeidaily would be 21 pg/24 hours. This dose is conqiderably less than the usual therapeutic dose of propranolol for infants.
There are limited published data to assist the physician deciding whether to continue propranolol therapy in a breast-feeding mother. The current widespread use of psopranolol and its recognized toxic manifestations of respiratory depression, hypoglycemia and bradycardia in neonates make this an important clinical question.lm3 To provide further information on propranolol concentrations in breast milk and their relation to plasma concentrations we measured these concentrations simultaneously in a hypertensive postpartum woman after single dose (40 mg) and continuous dose (40 mg 4 times daily) propranolol therapy. Methods
From the Medical Services, Harry S. Truman Memorial Veterans Hospital and the Departments of Medicine, Pathology and Child Health, University of Missouri Medical Center, Columbia, Missouri. This study was supported in part by the Medical Research Service of the Veterans Administration, Washington, D.C. and General Clinical Research Grant RR0287 from the U.S. Public Health Service. Bethesda, Maryland. Manuscript received August 28, 1978; revised manuscript received November 6, 1976. accepted November 9,1976. Address for reprints: John H. Sauer, MD, Medical Services Ill. Harry S. Truman Memorial Veterans Hospital, Colulnbia. Missduri 65201.
860
April 1979
Patient and protocol: A 30 year old white postpartum woman, suffering from palpitations (unifocal ventricular premature beats) and hypertension, agreed to participate in the study. She had been treated for these conditions with a diuretic drug (Dyazide”) and propranolol for 2 years. During her pregnancy, diuretic therapy was discontinued; 24 hours before delivery propranolol (40 mg 4 times daily) was discontinued. The study was approved by the University of Missouri Committee for Research Involving Human Subjects and the patient gave informed consent. The patient gave birth to a normal 2.7 kg male infant on January lo,1978 and began breast-feeding. Diuretic therapy Was resumed on February 3, but her blood pressure and palpitations were inadequately controlled. On February 23 and 28, she underwent studies to determine plasma and breast milk concentrations of propranolol before and at 1 hour intervals after ingesting 40 mg of propranolol in a single dose. On each occasion, breast-feeding was discontinued for 12 hours after the administration of propranolol. On March 4, she began taking propranolol, 40 mg 4 times daily, continuously without curtailment of breast-feeding. On March 6, a study was performed to determine plasma and breast milk concentrations of propranolol in the mother. After these studies, the propranolol dosage was increased to 240 mglday. After 30 days, a pre-dose and a 3 hour post-dose breast milk sample was obtained for quantitation of propranolol concentration.
The American Journal of CARDfOLOGY
Volume 43
PROPRANOLOLAND BREAST MILK-BAUER ET AL.
Sample collection and analysis: Whole blood samples (10 ml) were obtained from a forearm vein using a beparinized glass syringe. Plasma was separated from the red cells by centrifugation and was frozen until analysis. The breasts were emptied of milk (approximately 5 ml after the initial sample) at each sampling period. Breast milk samples were pooled to provide a representative sampling from both breasts and were frozen until analysis. Plasma and breast milk concentrations
TAB& I Propr’anolol Concentration (ng/ml) in Breast Milk and Plasma After Single Dose Therapy 2/23/i% Time*
of propranolol
were determined
by a modification of the method of Shand et a1.4 Samples were made alkaline, and the propranolol was extracted into a mixture of 2 percent isoamyl alcohol in nheptane. The propranolol was then partitioned from the organic phase into 0.1 N hydrochloric acid. This acidic phase was analyzed spectrofluorometrically, and propranolol concentration was determined from a standard curve prepared by the extraction of aqueous standards of propranolol hydrochloride.
Results Single
dose propranolol:
Plasma and breast milk concentrations of propranolol after the administration of a single 40 mg test dose of propranolol are shown in Table I. Both plasma and breast milk concentrations of propranolol peaked between 2 and 3 hours after administration of propranolol. Breast milk concentrations were less than 40 percent of peak plasma propranolol concentrations. Continuous dose propranolol: Plasma and breast milk propranolol concentrations after the continuous administration of propranolol, 40 mg 4 times daily, are shown in Figure 1.Plasma and breast milk concentrations peaked 3 hours after dosing, and the peak breast milk concentration was 64 percent of the corresponding plasma concentration. There were equal concentrations of propranolol in plasma and breast milk 8 hours after the last dose of 40 mg (0 hours). After a 30 day regimen of 240 mg/day propranolol, the pre-dose and 3 hour post-dose propranolol concentrations in breast milk were 26 and 64 ng/ml, respectively. No symptoms or signs of respiratory depression, hypoglycemia or bradycardia were observed in the infant throughout the periods of propranolol administration to the mother.
Breast Milk
Plasma
0:
84
3
4
:;
42
::
: l
2/28/78
Hours
Breast Milk
07
after administration
Plasma
8
8
:
:;
94
of a single
:;
dose
of propranolol
(40
mg).
of 3 hours. Propranolol was found to penetrate into the breast milk in a dose-dependent manner. The milk to plasma ratio was reported to be approximately 1. In our study, propranolol concentrations in plasma
and breast milk obtained after single dose and continuous dose drug regimens suggest a plasma to breast milk concentration ratio of 2.5:1 and 1.5:1, respectively. The elimination of propranolol after peak drug concentrations does not suggest preferential storage or elimination of propranolol by way of the breast. Increased concentrations of propranolol in breast milk after the 30 day dosage regimen (240 mg/day) were expected. In addition to a dose-dependent relation between propranolol ingestion (mg/kg) and plasma concentration, the long-term administration of propranolol has been
Discussion The administration of any drug to a lactating woman is potentially hazardous to the breast-feeding infant, especially if toxic concentrations are ingested. The benefits of breast-feeding to both mother and infant are well recognized. w There has been a lack of accurate knowledge concerning whole milk concentrations of propranolol in lactating women receiving propranolol therapy. Indeed, misinformation has been published. It was reported7 in 1973 that a maximal dose of 15 to 20 mg of propranolol/day could be ingested by a nursing infant from a mother receiving a 40 mg oral dose. However, the propranolol concentration units reported were in error (they should have been 15 to 20 pg/24 hours), and the retraction was not published until 1976.s To our knowledge, the only published data on propranolol therapy in breast-feeding mothers are in a letter to the editor by Karlberg et al9 In their study, two nursing mothers received propranolol in single oral doses ranging from 20 to 160 mg, at intervals of several days. The concentration of total propranolol in the plasma and in breast milk was estimated over a period
n
= plasma
l
= milk
1
I
I
I
I
1
0
1
2
3
4
5
Hours
after administration 40 mg dose propranolol 1160 mq cumulative daily dose1
FIGURE 1. Propranolol concentrations in plasma and breast milk after continuous dose administration (40 mg 4 times daily):
April 1979
The American
Journal of CARDIOLOGY
Volume
43
061
PROPFlANOLOL AND BREAST MILK-BAUER
ET AL.
shown to result in increased plasma concentrations and a longer elimination half-life-l0 Therapeutic implications: Using the peak propranolol concentration after dosage at 160 mg/day (42 ng/ml of propranolol in breast milk) and assuming that the infant’s total ingestion will not exceed 500 ml/day (usual infant milk ingestion 100 to 150 ml/kg per day), the maximal cumulative propranolol load would be 21 pg/24 hours. Using the peak propranolol concentration after dosage at 240 mg/day for 30 days (64 ng/ml propranolol in breast milk), the maximal cumulative propranolol load would be 32 pg/24 hours. Assuming 100 percent bioavailability and a 4 kg infant, this latter dose would represent a dietary intake equivalent to 8 pglkg body weight. Currently, therapeutic dosage of propranolol for infants and small children has not been established.
Recommended dosages have ranged from 0.2 to 0.5 mg/kg per day l1 to 0.5 to 2.0 mg/kg per day.12 The dosage ingested by the breast-feeding infant would therefore be approximately l/100 of that used for therapeutic purposes. However, hepatic microsomal enzyme systems responsible for metabolism are immature in newborn infants, and an accumulation of this drug might be expected to be beyond that anticipated in older patients.13 Therefore, close observations for bradycardia or evidence of hypoglycemia should be carried out in these nursing infants. Acknowledgment We express our appreciation for the technical assistance of James Kohrs, Fred Rosen and Ronald Carey, the nursing support of the Clinical Research Center staff and the secretarial support of Velma Henthorne.
References 1. Gladstone GR, Hordof A, Gersony WM: Propranolol administration during pregnancy: effects on the fetus. J Pediatr 86:962-964, 1975 2. Habib A, McCarthy JS: Effects on the neonate of propranolol administration during pregnancy. J Pediatr 91:808-811, 1977 3. Cottrill CM, McAllister RG, Gettes L, Noonan JA: Propranolol therapy during pregnancy, labor and delivery: evidence for transplacental drug transfer and impaired neonatal drug disposition. J Pediatr 91:812-814, 1977 4. Shand DE, Nuckolls EM, Oates JA: Plasma propranolol levels in adults with observations in four children. Clin Pharmacol Ther 11:112-120,197o 5. Jelllffe DB, Jelllffe EF: Breast is best: Modern meanings. N Eng J Med 297:942-915, 1977 6. Committee on Nutrition, Am. Academy Pediatrics: Commentary on breast-feeding and infant formulas. Pediatrics 57:278-285, 1976
882
April 1979
The American
Journal of CARDIOLOGY
Volume 43
7. Levltan AA, Marion JC: Propranolol therapy during pregnancy and lactation [Letter]. Am J Cardiol 32:247, 1973 8. Anderson PO, Salter FJ: Propranolol therapy during pregnancy and lactation [Letter]. Am J Cardiol 37:325, 1976 9. Karlberg B, Lundberg D, Aberg H: Excretion of propranolol in human breast milk. Acta Pharmacol Toxicol 34:222-223, 1974 10. Chldsey CA, Morselli P, Blanchettl G. Morgantl A, Leonettl G, Zanchettl A: Studies of the absorption and removal of propranolol in hypertensive patients during therapy. Circulation 52:313-318, 1975 11. Nadas A, Fyler DC: Pediatriccardiology. Philadelphia, WB Saunders, 1972, p 674 12. Adelman RD: Neonatal hypertension. Pediatr Clin North Am 25: 107, 1978 13. Conney AH: Drug metabolism and therapeutics. N Engl J Med 280:653, 1969
Propranolol in Human Plasma and Breast Milk
JOHN H. BAUER, MD BRIAN PAPE, PhD JAMES ZAJICEK TED GROSHONG, MD Columbia, Missouri
To assess the problem of continuing propranolol therapy in a breastfeeding mother, studles were performed to determine simultaneously plasma and breast milk concentrations of propranolol after single dose (40 mg) and continuous dose (40 mg 4 times daily) treatment with this drug. Breast milk and.plasma concentrations of propranolol peaked between 2 and 3 hours after dosing. Propranolol concentrations in breast milk were less than 40 and 64 percent, respectively, of peak plasma propranolol concentrations after single dose and continuous dose administration. It was estimated that the maximal cumulative propranolol load to this breast-feeding infant, consuming 500 ml of whole milk, when the mother received 4O’mg of propranolol4 timeidaily would be 21 pg/24 hours. This dose is conqiderably less than the usual therapeutic dose of propranolol for infants.
There are limited published data to assist the physician deciding whether to continue propranolol therapy in a breast-feeding mother. The current widespread use of psopranolol and its recognized toxic manifestations of respiratory depression, hypoglycemia and bradycardia in neonates make this an important clinical question.lm3 To provide further information on propranolol concentrations in breast milk and their relation to plasma concentrations we measured these concentrations simultaneously in a hypertensive postpartum woman after single dose (40 mg) and continuous dose (40 mg 4 times daily) propranolol therapy. Methods
From the Medical Services, Harry S. Truman Memorial Veterans Hospital and the Departments of Medicine, Pathology and Child Health, University of Missouri Medical Center, Columbia, Missouri. This study was supported in part by the Medical Research Service of the Veterans Administration, Washington, D.C. and General Clinical Research Grant RR0287 from the U.S. Public Health Service. Bethesda, Maryland. Manuscript received August 28, 1978; revised manuscript received November 6, 1976. accepted November 9,1976. Address for reprints: John H. Sauer, MD, Medical Services Ill. Harry S. Truman Memorial Veterans Hospital, Colulnbia. Missduri 65201.
860
April 1979
Patient and protocol: A 30 year old white postpartum woman, suffering from palpitations (unifocal ventricular premature beats) and hypertension, agreed to participate in the study. She had been treated for these conditions with a diuretic drug (Dyazide”) and propranolol for 2 years. During her pregnancy, diuretic therapy was discontinued; 24 hours before delivery propranolol (40 mg 4 times daily) was discontinued. The study was approved by the University of Missouri Committee for Research Involving Human Subjects and the patient gave informed consent. The patient gave birth to a normal 2.7 kg male infant on January lo,1978 and began breast-feeding. Diuretic therapy Was resumed on February 3, but her blood pressure and palpitations were inadequately controlled. On February 23 and 28, she underwent studies to determine plasma and breast milk concentrations of propranolol before and at 1 hour intervals after ingesting 40 mg of propranolol in a single dose. On each occasion, breast-feeding was discontinued for 12 hours after the administration of propranolol. On March 4, she began taking propranolol, 40 mg 4 times daily, continuously without curtailment of breast-feeding. On March 6, a study was performed to determine plasma and breast milk concentrations of propranolol in the mother. After these studies, the propranolol dosage was increased to 240 mglday. After 30 days, a pre-dose and a 3 hour post-dose breast milk sample was obtained for quantitation of propranolol concentration.
The American Journal of CARDfOLOGY
Volume 43
PROPRANOLOLAND BREAST MILK-BAUER ET AL.
Sample collection and analysis: Whole blood samples (10 ml) were obtained from a forearm vein using a beparinized glass syringe. Plasma was separated from the red cells by centrifugation and was frozen until analysis. The breasts were emptied of milk (approximately 5 ml after the initial sample) at each sampling period. Breast milk samples were pooled to provide a representative sampling from both breasts and were frozen until analysis. Plasma and breast milk concentrations
TAB& I Propr’anolol Concentration (ng/ml) in Breast Milk and Plasma After Single Dose Therapy 2/23/i% Time*
of propranolol
were determined
by a modification of the method of Shand et a1.4 Samples were made alkaline, and the propranolol was extracted into a mixture of 2 percent isoamyl alcohol in nheptane. The propranolol was then partitioned from the organic phase into 0.1 N hydrochloric acid. This acidic phase was analyzed spectrofluorometrically, and propranolol concentration was determined from a standard curve prepared by the extraction of aqueous standards of propranolol hydrochloride.
Results Single
dose propranolol:
Plasma and breast milk concentrations of propranolol after the administration of a single 40 mg test dose of propranolol are shown in Table I. Both plasma and breast milk concentrations of propranolol peaked between 2 and 3 hours after administration of propranolol. Breast milk concentrations were less than 40 percent of peak plasma propranolol concentrations. Continuous dose propranolol: Plasma and breast milk propranolol concentrations after the continuous administration of propranolol, 40 mg 4 times daily, are shown in Figure 1.Plasma and breast milk concentrations peaked 3 hours after dosing, and the peak breast milk concentration was 64 percent of the corresponding plasma concentration. There were equal concentrations of propranolol in plasma and breast milk 8 hours after the last dose of 40 mg (0 hours). After a 30 day regimen of 240 mg/day propranolol, the pre-dose and 3 hour post-dose propranolol concentrations in breast milk were 26 and 64 ng/ml, respectively. No symptoms or signs of respiratory depression, hypoglycemia or bradycardia were observed in the infant throughout the periods of propranolol administration to the mother.
Breast Milk
Plasma
0:
84
3
4
:;
42
::
: l
2/28/78
Hours
Breast Milk
07
after administration
Plasma
8
8
:
:;
94
of a single
:;
dose
of propranolol
(40
mg).
of 3 hours. Propranolol was found to penetrate into the breast milk in a dose-dependent manner. The milk to plasma ratio was reported to be approximately 1. In our study, propranolol concentrations in plasma
and breast milk obtained after single dose and continuous dose drug regimens suggest a plasma to breast milk concentration ratio of 2.5:1 and 1.5:1, respectively. The elimination of propranolol after peak drug concentrations does not suggest preferential storage or elimination of propranolol by way of the breast. Increased concentrations of propranolol in breast milk after the 30 day dosage regimen (240 mg/day) were expected. In addition to a dose-dependent relation between propranolol ingestion (mg/kg) and plasma concentration, the long-term administration of propranolol has been
Discussion The administration of any drug to a lactating woman is potentially hazardous to the breast-feeding infant, especially if toxic concentrations are ingested. The benefits of breast-feeding to both mother and infant are well recognized. w There has been a lack of accurate knowledge concerning whole milk concentrations of propranolol in lactating women receiving propranolol therapy. Indeed, misinformation has been published. It was reported7 in 1973 that a maximal dose of 15 to 20 mg of propranolol/day could be ingested by a nursing infant from a mother receiving a 40 mg oral dose. However, the propranolol concentration units reported were in error (they should have been 15 to 20 pg/24 hours), and the retraction was not published until 1976.s To our knowledge, the only published data on propranolol therapy in breast-feeding mothers are in a letter to the editor by Karlberg et al9 In their study, two nursing mothers received propranolol in single oral doses ranging from 20 to 160 mg, at intervals of several days. The concentration of total propranolol in the plasma and in breast milk was estimated over a period
n
= plasma
l
= milk
1
I
I
I
I
1
0
1
2
3
4
5
Hours
after administration 40 mg dose propranolol 1160 mq cumulative daily dose1
FIGURE 1. Propranolol concentrations in plasma and breast milk after continuous dose administration (40 mg 4 times daily):
April 1979
The American
Journal of CARDIOLOGY
Volume
43
061
PROPFlANOLOL AND BREAST MILK-BAUER
ET AL.
shown to result in increased plasma concentrations and a longer elimination half-life-l0 Therapeutic implications: Using the peak propranolol concentration after dosage at 160 mg/day (42 ng/ml of propranolol in breast milk) and assuming that the infant’s total ingestion will not exceed 500 ml/day (usual infant milk ingestion 100 to 150 ml/kg per day), the maximal cumulative propranolol load would be 21 pg/24 hours. Using the peak propranolol concentration after dosage at 240 mg/day for 30 days (64 ng/ml propranolol in breast milk), the maximal cumulative propranolol load would be 32 pg/24 hours. Assuming 100 percent bioavailability and a 4 kg infant, this latter dose would represent a dietary intake equivalent to 8 pglkg body weight. Currently, therapeutic dosage of propranolol for infants and small children has not been established.
Recommended dosages have ranged from 0.2 to 0.5 mg/kg per day l1 to 0.5 to 2.0 mg/kg per day.12 The dosage ingested by the breast-feeding infant would therefore be approximately l/100 of that used for therapeutic purposes. However, hepatic microsomal enzyme systems responsible for metabolism are immature in newborn infants, and an accumulation of this drug might be expected to be beyond that anticipated in older patients.13 Therefore, close observations for bradycardia or evidence of hypoglycemia should be carried out in these nursing infants. Acknowledgment We express our appreciation for the technical assistance of James Kohrs, Fred Rosen and Ronald Carey, the nursing support of the Clinical Research Center staff and the secretarial support of Velma Henthorne.
References 1. Gladstone GR, Hordof A, Gersony WM: Propranolol administration during pregnancy: effects on the fetus. J Pediatr 86:962-964, 1975 2. Habib A, McCarthy JS: Effects on the neonate of propranolol administration during pregnancy. J Pediatr 91:808-811, 1977 3. Cottrill CM, McAllister RG, Gettes L, Noonan JA: Propranolol therapy during pregnancy, labor and delivery: evidence for transplacental drug transfer and impaired neonatal drug disposition. J Pediatr 91:812-814, 1977 4. Shand DE, Nuckolls EM, Oates JA: Plasma propranolol levels in adults with observations in four children. Clin Pharmacol Ther 11:112-120,197o 5. Jelllffe DB, Jelllffe EF: Breast is best: Modern meanings. N Eng J Med 297:942-915, 1977 6. Committee on Nutrition, Am. Academy Pediatrics: Commentary on breast-feeding and infant formulas. Pediatrics 57:278-285, 1976
882
April 1979
The American
Journal of CARDIOLOGY
Volume 43
7. Levltan AA, Marion JC: Propranolol therapy during pregnancy and lactation [Letter]. Am J Cardiol 32:247, 1973 8. Anderson PO, Salter FJ: Propranolol therapy during pregnancy and lactation [Letter]. Am J Cardiol 37:325, 1976 9. Karlberg B, Lundberg D, Aberg H: Excretion of propranolol in human breast milk. Acta Pharmacol Toxicol 34:222-223, 1974 10. Chldsey CA, Morselli P, Blanchettl G. Morgantl A, Leonettl G, Zanchettl A: Studies of the absorption and removal of propranolol in hypertensive patients during therapy. Circulation 52:313-318, 1975 11. Nadas A, Fyler DC: Pediatriccardiology. Philadelphia, WB Saunders, 1972, p 674 12. Adelman RD: Neonatal hypertension. Pediatr Clin North Am 25: 107, 1978 13. Conney AH: Drug metabolism and therapeutics. N Engl J Med 280:653, 1969
