Skip to main content
Log in

Effect of Pregnancy on the Pharmacokinetics of Antihypertensive Drugs

  • Review Article
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

In the US, approximately 12% of women have hypertension during their pregnancy. Antihypertensive drugs are often given to lower maternal blood pressure in those with severe hypertension to prevent stroke and hypertensive crises. There is no conclusive evidence that antihypertensive treatment is beneficial to the mother in mild to moderate hypertension; however, approximately 3% of all pregnant women receive an antihypertensive drug at some time during their pregnancy.

There are only limited data on the effects of pregnancy on the pharmacokinetics of antihypertensive drugs. However, knowledge of the pharmacokinetic properties of a drug in the nonpregnant adult and use of a mechanistic-based approach allow an estimation of the effect of pregnancy on the pharmacokinetics of drugs when data are limited or not available. In general, an increased plasma volume and decreased protein binding can alter the volume of distribution of the drug. Clearance can increase or decrease, depending on the pathway of elimination of the drug. Through changes in the volume of distribution and clearance, pregnancy can cause a change in the elimination half-life, resulting in the need for modification of the dosing frequency. The few studies in pregnant women with hypertension have included small numbers of women in the third trimester and postpartum, with little or no data in early pregnancy. In addition, many studies evaluating the efficacy of antihypertensive medications have been performed using dosing regimens of medications that have not been substantiated by pharmacological data in pregnant women. There is a need for well designed pharmacokinetic and pharmacodynamic studies of antihypertensive medications that include analysis during all three trimesters of pregnancy and postpartum. Higher doses and altered dosage intervals may be needed for antihypertensive drugs used in pregnant women.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Table I
Table II
Fig. 1
Table III
Table IV

Similar content being viewed by others

References

  1. Koonin LM, MacKay AP, Berg CJ, et al. Pregnancy-related mortality surveillance: United States, 1987–1990. MMWR CDC Surveill Summ 1997 Aug 8; 46(4): 17–36

    PubMed  CAS  Google Scholar 

  2. Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. Am J Obstet Gynecol 2000 Jul; 183 (1): S1-22

  3. Rey E, LeLorier J, Burgess E, et al. Report of the Canadian Hypertension Society Consensus Conference: 3. Treatment of hypertensive disorders in pregnancy. CMAJ 1997 Nov 1; 157(9): 1245–54

    PubMed  CAS  Google Scholar 

  4. Coppage KH, Sibai BM. Treatment of hypertensive complications in pregnancy: current pharmaceutical design. Curr Pharm Des 2005; 11(6): 749–57

    Article  PubMed  CAS  Google Scholar 

  5. Andrade SE, Raebel MA, Brown J, et al. Outpatient use of cardiovascular drugs during pregnancy. Pharmacoepidemiol Drug Saf 2008 Mar; 17(3): 240–7

    Article  PubMed  Google Scholar 

  6. Ferrer RL, Sibai BM, Mulrow CD, et al. Management of mild chronic hypertension during pregnancy: a review. Obstet Gynecol 2000 Nov; 96(5 Pt 2): 849–60

    Article  PubMed  CAS  Google Scholar 

  7. Abalos E, Duley L, Steyn DW, et al. Antihypertensive drug therapy for mild to moderate hypertension during pregnancy. Cochrane Database Syst Rev 2001; (2): CD002252

    PubMed  Google Scholar 

  8. Magee LA, Duley L. Oral beta-blockers for mild to moderate hypertension during pregnancy. Cochrane Database Syst Rev 2003; (3): CD002863

  9. Anderson GD. Pregnancy-induced changes in pharmacokinetics: a mechanisticbased approach. Clin Pharmacokinet 2005; 44(10): 989–1008

    Article  PubMed  CAS  Google Scholar 

  10. Nakai A, Sekiya I, Oya A, et al. Assessment of the hepatic arterial and portal venous blood flows during pregnancy with Doppler ultrasonography. Arch Gynecol Obstet 2002 Jan; 266(1): 25–9

    Article  PubMed  CAS  Google Scholar 

  11. Robson SC, Mutch E, Boys RJ, et al. Apparent liver blood flow during pregnancy: a serial study using indocyanine green clearance. Br J Obstet Gynaecol 1990 Aug; 97(8): 720–4

    Article  PubMed  CAS  Google Scholar 

  12. Morgan DJ, Smallwood RA. Clinical significance of pharmacokinetic models of hepatic elimination. Clin Pharmacokinet 1990 Jan; 18(1): 61–76

    Article  PubMed  CAS  Google Scholar 

  13. Dean M, Stock B, Patterson RJ, et al. Serum protein binding of drugs during and after pregnancy in humans. Clin Pharmacol Ther 1980 Aug; 28(2): 253–61

    Article  PubMed  CAS  Google Scholar 

  14. Tsen LC, Tarshis J, Denson DD, et al. Measurements of maternal protein binding of bupivacaine throughout pregnancy. Anesth Analg 1999 Oct; 89(4): 965–8

    PubMed  CAS  Google Scholar 

  15. Benet LZ, Hoener BA. Changes in plasma protein binding have little clinical relevance. Clin Pharmacol Ther 2002 Mar; 71(3): 115–21

    Article  PubMed  CAS  Google Scholar 

  16. Davison JM, Dunlop W. Renal hemodynamics and tubular function normal human pregnancy. Kidney Int 1980 Aug; 18(2): 152–61

    Article  PubMed  CAS  Google Scholar 

  17. Saavedra JA, Reid JL, Jordan W, et al. Plasma concentration of alphamethyldopa and sulphate conjugate after oral administration of methyldopa and intravenous administration of methyldopa and methyldopa hydrochloride ethyl ester. Eur J Clin Pharmacol 1975 Aug 14; 8(6): 381–6

    Article  PubMed  CAS  Google Scholar 

  18. Barnett AJ, Bobik A, Carson V, et al. Pharmacokinetics of methyldopa: plasma levels following single intravenous, oral and multiple oral dosage in normotensive and hypertensive subjects. Clin Exp Pharmacol Physiol 1977 Jul–Aug; 4(4): 331–9

    Article  PubMed  CAS  Google Scholar 

  19. Magee LA. Treating hypertension in women of child-bearing age and during pregnancy. Drug Saf 2001; 24(6): 457–74

    Article  PubMed  CAS  Google Scholar 

  20. Horvath JS, Phippard A, Korda A, et al. Clonidine hydrochloride: a safe and effective antihypertensive agent in pregnancy. Obstet Gynecol 1985 Nov; 66(5): 634–8

    PubMed  CAS  Google Scholar 

  21. Buchanan ML, Easterling TR, Carr DB, et al. Clonidine pharmacokinetics during pregnancy: an OPRU Network study [abstract]. Annual Meeting, American College of Clinical Pharmacy; 2007 Mar 21–24; Denver (CO)

  22. Frisk-Holmberg M, Paalzow L, Edlund PO. Clonidine kinetics in man: evidence for dose dependency and changed pharmacokinetics during chronic therapy. Br J Clin Pharmacol 1981 Nov; 12(5): 653–8

    Article  PubMed  CAS  Google Scholar 

  23. Cunningham FE, Baughman VL, Peters J, et al. Comparative pharmacokinetics of oral versus sublingual clonidine. J Clin Anesth 1994 Sep–Oct; 6(5): 430–3

    Article  PubMed  CAS  Google Scholar 

  24. Easterling TR, Brateng D, Schmucker B, et al. Prevention of preeclampsia: a randomized trial of atenolol in hyperdynamic patients before onset of hypertension. Obstet Gynecol 1999 May; 93(5 Pt 1): 725–33

    Article  PubMed  CAS  Google Scholar 

  25. Butters L, Kennedy S, Rubin PC. Atenolol in essential hypertension during pregnancy. BMJ 1990 Sep 22; 301(6752): 587–9

    Article  PubMed  CAS  Google Scholar 

  26. Magee LA, Elran E, Bull SB, et al. Risks and benefits of beta-receptor blockers for pregnancy hypertension: overview of the randomized trials. Eur J Obstet Gynecol Reprod Biol 2000 Jan; 88(1): 15–26

    Article  PubMed  CAS  Google Scholar 

  27. Easterling TR, Carr DB, Brateng D, et al. Treatment of hypertension in pregnancy: effect of atenolol on maternal disease, preterm delivery, and fetal growth. Obstet Gynecol 2001 Sep; 98(3): 427–33

    Article  PubMed  CAS  Google Scholar 

  28. De Paco C, Kametas N, Rencoret G, et al. Maternal cardiac output between 11 and 13 weeks of gestation in the prediction of preeclampsia and small for gestational age. Obstet Gynecol 2008 Feb; 111(2 Pt 1): 292–300

    Article  PubMed  Google Scholar 

  29. Hardman J, Endres L, Fischer P, et al. Pharmacokinetics of labetalol in pregnancy. Pharmacotherapy 2005; 25: 1493–000

    Google Scholar 

  30. Rubin PC, Butters L, Kelman AW, et al. Labetalol disposition and concentration-effect relationships during pregnancy. Br J Clin Pharmacol 1983 Apr; 15(4): 465–70

    Article  PubMed  CAS  Google Scholar 

  31. Rogers RC, Sibai BM, Whybrew WD. Labetalol pharmacokinetics in pregnancy-induced hypertension. Am J Obstet Gynecol 1990 Feb; 162(2): 362–6

    PubMed  CAS  Google Scholar 

  32. Jeong H, Choi S, Song JW, et al. Regulation of UDP-glucuronosyltransferase (UGT) 1A1 by progesterone and its impact on labetalol elimination. Xenobiotica 2008 Jan; 38(1): 62–75

    Article  PubMed  CAS  Google Scholar 

  33. Sibai BM, Mabie WC, Shamsa F, et al. A comparison of no medication versus methyldopa or labetalol in chronic hypertension during pregnancy. Am J Obstet Gynecol 1990 Apr; 162(4): 960–7

    PubMed  CAS  Google Scholar 

  34. Hurst AK, Shotan A, Hoffman K, et al. Pharmacokinetic and pharmacodynamic evaluation of atenolol during and after pregnancy. Pharmacotherapy 1998 Jul–Aug; 18(4): 840–6

    PubMed  CAS  Google Scholar 

  35. Thorley KJ, McAinsh J, Cruickshank JM. Atenolol in the treatment of pregnancy-induced hypertension. Br J Clin Pharmacol 1981 Nov; 12(5): 725–30

    Article  PubMed  CAS  Google Scholar 

  36. Hebert MF, Carr DB, Anderson GD, et al. Pharmacokinetics and pharmacodynamics of atenolol during pregnancy and postpartum. J Clin Pharmacol 2005; 45: 25–33

    Article  PubMed  CAS  Google Scholar 

  37. Hogstedt S, Lindberg B, Peng DR, et al. Pregnancy-induced increase in metoprolol metabolism. Clin Pharmacol Ther 1985 Jun; 37(6): 688–92

    Article  PubMed  CAS  Google Scholar 

  38. Hogstedt S, Lindberg B, Rane A. Increased oral clearance of metoprolol in pregnancy. Eur J Clin Pharmacol 1983; 24(2): 217–20

    Article  PubMed  CAS  Google Scholar 

  39. Lindeberg S, Holm B, Lundborg P, et al. The effect of hydralazine on steady-state plasma concentrations of metoprolol in pregnant hypertensive women. Eur J Clin Pharmacol 1988; 35(2): 131–5

    Article  PubMed  CAS  Google Scholar 

  40. Lubbe WF, Hodge JV. Combined alpha- and beta-adrenoceptor antagonism with prazosin and oxprenolol in control of severe hypertension in pregnancy. NZ Med J 1981 Sep 9; 94(691): 169–72

    CAS  Google Scholar 

  41. Rubin PC, Butters L, Low RA, et al. Clinical pharmacological studies with prazosin during pregnancy complicated by hypertension. Br J Clin Pharmacol 1983 Nov; 16(5): 543–7

    Article  PubMed  CAS  Google Scholar 

  42. Bourget P, Fernandez H, Edouard D, et al. Disposition of a new ratecontrolled formulation of prazosin in the treatment of hypertension during pregnancy: transplacental passage of prazosin. Eur J Drug Metab Pharmacokinet 1995 Jul–Sep; 20(3): 233–41

    Article  PubMed  CAS  Google Scholar 

  43. Wood AJ, Bolli P, Simpson FO. Prazosin in normal subjects: plasma levels, blood pressure and heart rate. Br J Clin Pharmacol 1976 Feb; 3(1): 199–201

    Article  PubMed  CAS  Google Scholar 

  44. Prevost RR, Akl SA, Whybrew WD, et al. Oral nifedipine pharmacokinetics in pregnancy-induced hypertension. Pharmacotherapy 1992; 12(3): 174–7

    PubMed  CAS  Google Scholar 

  45. Barton JR, Prevost RR, Wilson DA, et al. Nifedipine pharmacokinetics and pharmacodynamics during the immediate postpartum period in patients with preeclampsia. Am J Obstet Gynecol 1991 Oct; 165(4 Pt 1): 951–4

    PubMed  CAS  Google Scholar 

  46. Ferguson 2nd JE, Schutz T, Pershe R, et al. Nifedipine pharmacokinetics during preterm labor tocolysis. Am J Obstet Gynecol 1989 Dec; 161(6 Pt 1): 1485–90

    PubMed  Google Scholar 

  47. Silberschmidt AL, Kuhn-Velten WN, Juon AM, et al. Nifedipine concentration in maternal and umbilical cord blood after nifedipine gastrointestinal therapeutic system for tocolysis. Br J Obstet Gynaecol 2008 Mar; 115(4): 480–5

    Article  Google Scholar 

  48. Marin TZ, Meier R, Kraehenmann F, et al. Nifedipine serum levels in pregnant women undergoing tocolysis with nifedipine. J Obstet Gynaecol 2007 Apr; 27(3): 260–3

    Article  PubMed  CAS  Google Scholar 

  49. Schulz M, Schmoldt A. Therapeutic and toxic blood concentrations of more than 800 drugs and other xenobiotics. Die Pharmazie 2003 Jul; 58(7): 447–74

    PubMed  CAS  Google Scholar 

  50. Beely L. Adverse effects of drugs in later pregnancy. Clin Obstet Gynecol 1981; 24: 275–90

    Google Scholar 

  51. Carr DB, Gavrila D, Brateng D, et al. Maternal hemodynamic changes associated with furosemide treatment. Hypertens Pregnancy 2007; 26(2): 173–8

    Article  PubMed  CAS  Google Scholar 

  52. Ponto LL, Schoenwald RD. Furosemide (frusemide): a pharmacokinetic/pharmacodynamic review (part I). Clin Pharmacokinet 1990 May; 18(5): 381–408

    Article  PubMed  CAS  Google Scholar 

  53. Riva E, Farina P, Tognoni G, et al. Pharmacokinetics of furosemide in gestosis of pregnancy. Eur J Clin Pharmacol 1978 Dec 18; 14(5): 361–6

    Article  PubMed  CAS  Google Scholar 

  54. Tang BK, Kadar D, Qian L, et al. Caffeine as a metabolic probe: validation of its use for acetylator phenotyping. Clin Pharmacol Ther 1991 Jun; 49(6): 648–57

    Article  PubMed  CAS  Google Scholar 

  55. Begg EJ, Duffull SB, Hackett LP, et al. Studying drugs in human milk: time to unify the approach. J Hum Lact 2002 Nov; 18(4): 323–32

    Article  PubMed  Google Scholar 

  56. Larsen LA, Ito S, Koren G. Prediction of milk/plasma concentration ratio of drugs. Ann Pharmacother 2003 Sep; 37(9): 1299–306

    Article  PubMed  CAS  Google Scholar 

  57. Atkinson HC, Begg EJ. Prediction of drug distribution into human milk from physicochemical characteristics. Clin Pharmacokinet 1990 Feb; 18(2): 151–67

    Article  PubMed  CAS  Google Scholar 

  58. Notarianni LJ, Belk D, Aird SA, et al. An in vitro technique for the rapid determination of drug entry into breast milk. Br J Clin Pharmacol 1995; 40: 333–7

    Article  PubMed  CAS  Google Scholar 

  59. Anderson GD. Using pharmacokinetics to predict the effects of pregnancy and maternal-infant transfer of drugs during lactation. Expert Opin Drug Metab Toxicol 2006 Dec; 2(6): 947–60

    Article  PubMed  CAS  Google Scholar 

  60. Schimmel MS, Eidelman AI, Wilschanski MA, et al. Toxic effects of atenolol consumed during breast feeding. J Pediatr 1989 Mar; 114(3): 476–8

    Article  PubMed  CAS  Google Scholar 

  61. Atkinson HC, Begg EJ, Darlow BA. Drugs in human milk: clinical pharmacokinetic considerations. Clin Pharmacokinet 1988 Apr; 14(4): 217–40

    Article  PubMed  CAS  Google Scholar 

  62. Kulas J, Lunell NO, Rosing U, et al. Atenolol and metoprolol: a comparison of their excretion into human breast milk. Acta Obstet Gynecol Scand Suppl 1984; 118: 65–9

    Article  PubMed  CAS  Google Scholar 

  63. Devlin RG, Fleiss PM. Captopril in human blood and breast milk. J Clin Pharmacol 1981 Feb–Mar; 21(2): 110–3

    PubMed  CAS  Google Scholar 

  64. Bunjes R, Schaefer C, Holzinger D. Clonidine and breast-feeding. Clin Pharm 1993 Mar; 12(3): 178–9

    PubMed  CAS  Google Scholar 

  65. Hartikainen-Sorri AL, Heikkinen JE, Koivisto M. Pharmacokinetics of clonidine during pregnancy and nursing. Obstet Gynecol 1987 Apr; 69(4): 598–600

    PubMed  CAS  Google Scholar 

  66. Okada M, Inoue H, Nakamura Y, et al. Excretion of diltiazem in human milk. N Engl J Med 1985 Apr 11; 312(15): 992–3

    Article  PubMed  CAS  Google Scholar 

  67. Redman CW, Kelly JG, Cooper WD. The excretion of enalapril and enalaprilat in human breast milk. Eur J Clin Pharmacol 1990; 38(1): 99

    Article  PubMed  CAS  Google Scholar 

  68. Lunell NO, Kulas J, Rane A. Transfer of labetalol into amniotic fluid and breast milk in lactating women. Eur J Clin Pharmacol 1985; 28(5): 597–9

    Article  PubMed  CAS  Google Scholar 

  69. Michael CA. Use of labetalol in the treatment of severe hypertension during pregnancy. Br J Clin Pharmacol 1979; 8 Suppl. 2: 211S–5S

    PubMed  CAS  Google Scholar 

  70. White WB, Andreoli JW, Cohn RD. Alpha-methyldopa disposition in mothers with hypertension and in their breast-fed infants. Clin Pharmacol Ther 1985 Apr; 37(4): 387–90

    Article  PubMed  CAS  Google Scholar 

  71. Penny WJ, Lewis MJ. Nifedipine is excreted in human milk. Eur J Clin Pharmacol 1989; 36(4): 427–8

    Article  PubMed  CAS  Google Scholar 

  72. Manninen AK, Juhakoski A. Nifedipine concentrations in maternal and umbilical serum, amniotic fluid, breast milk and urine of mothers and offspring. Int J Clin Pharmacol Res 1991; 11(5): 231–6

    PubMed  CAS  Google Scholar 

  73. Davison JM, Hytten FE. Glomerular filtration during and after pregnancy. J Obstet Gynaecol Br Commonw 1974 Aug; 81(8): 588–95

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

Both authors provided substantial contributions to the manuscript. No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Gail D. Anderson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Anderson, G.D., Carr, D.B. Effect of Pregnancy on the Pharmacokinetics of Antihypertensive Drugs. Clin Pharmacokinet 48, 159–168 (2009). https://doi.org/10.2165/00003088-200948030-00002

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003088-200948030-00002

Keywords

Navigation