Advertisement

Pharmacotherapy in Women

  • Karin Schenck-GustafssonEmail author
  • Mia von Euler
Chapter

Abstract

Pharmacokinetic properties such as absorption, distribution, metabolism, and elimination of drugs often differ between men and women and change over lifetime. Women experience more adverse events and side-effects of medications than men. Hormonal changes during the menstrual cycle usually have limited effect on the pharmacokinetics of drugs, except for drugs that interfere with QT-interval. It is debated whether there is a systematic difference in compliance to medication in women compared to men. Drug interactions and drug safety during pregnancy are discussed.

Keywords

Anti-arrhythmic drugs Beta-blockers CYP3A4 inhibitors Drug interactions Drug safety Estrogen Glomerular filtration rate (GFR) Medication adherence Menopause Pharmacodynamics Pharmacokinetics Pregnancy QT-interval Sex-hormones Side-effects Statins Torsade de Pointes (TdP) 

References

  1. 1.
    Socialstyrelsen. Statistik om läkemedel år 2015 (Drug Statistics, Swedish Board of Health and Welfare). http://www.socialstyrelsen.se/publikationer2016/2016-4-4. Accessed 31 Jul 2016.
  2. 2.
    Loikas D, Wettermark B, von Euler M, Bergman U, Schenck-Gustafsson K. Differences in drug utilisation between men and women: a cross-sectional analysis of all dispensed drugs in Sweden. BMJ Open. 2013;3(5):e002378.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Mattison D, Mattison FA. Drug disposition and effect. In: Handbook of clinical gender medicine. Basel: Karger Medical and Scientific Publishers; 2012. p. 473–9.CrossRefGoogle Scholar
  4. 4.
    Koren G. Sex dependent pharmacokinetics and bioequivalence—time for a change. J Popul Ther Clin Pharmacol. 2013;20:e358–61.PubMedGoogle Scholar
  5. 5.
    Anderson GD. Gender differences in pharmacological response. Int Rev Neurobiol. 2008;83:1–10.CrossRefPubMedGoogle Scholar
  6. 6.
    Anderson GD. Sex and racial differences in pharmacological response: where is the evidence? Pharmacogenetics, pharmacokinetics, and pharmacodynamics. J Women’s Health. 2005;14:19–29.CrossRefGoogle Scholar
  7. 7.
    Franconi F, Campesi I. Pharmacogenomics, pharmacokinetics and pharmacodynamics: interaction with biological differences between men and women. Br J Pharmacol. 2014;171:580–94.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Fischer M, Baessler A, Schunkert H. Renin angiotensin system and gender differences in the cardiovascular system. Cardiovasc Res. 2002;53:672–7.CrossRefPubMedGoogle Scholar
  9. 9.
    Hutson WR, Roehrkasse RL, Wald A. Influence of gender and menopause on gastric emptying and motility. Gastroenterology. 1989;96:11–7.CrossRefPubMedGoogle Scholar
  10. 10.
    Mearadji B, Penning C, Vu MK, van der Schaar PJ, van Petersen AS, Kamerling IM, Masclee AA. Influence of gender on proximal gastric motor and sensory function. Am J Gastroenterol. 2001;96:2066–73.CrossRefPubMedGoogle Scholar
  11. 11.
    Sadik R, Abrahamsson H, Stotzer PO. Gender differences in gut transit shown with a newly developed radiological procedure. Scand J Gastroenterol. 2003;38:36–42.CrossRefPubMedGoogle Scholar
  12. 12.
    Schwartz JB. The influence of sex on pharmacokinetics. Clin Pharmacokinet. 2003;42:107–21.CrossRefPubMedGoogle Scholar
  13. 13.
    Singer AJ, Brandt LJ. Pathophysiology of the gastrointestinal tract during pregnancy. Am J Gastroenterol. 1991;86:1695–712.PubMedGoogle Scholar
  14. 14.
    Spoletini I, Vitale C, Malorni WMC, Rosano GM. Sex differences in drug effects: interaction with sex hormones in adult life. Sex and gender differences in pharmacology. In: Regitz-Zagrosek W, editor. Handbook of experimental pharmacology, vol. 214. Berlin: Springer; 2012. p. 91–105.Google Scholar
  15. 15.
    Rodriguez I, Kilborn MJ, Liu XK, Pezzullo JC, Woosley RL. Drug-induced QT prolongation in women during the menstrual cycle. JAMA. 2001;285:1322–6.CrossRefPubMedGoogle Scholar
  16. 16.
    Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA. 1998;279:1200–5.CrossRefPubMedGoogle Scholar
  17. 17.
    von Euler M, Eliasson E, Öhlén G, Bergman U. Adverse drug reactions causing hospitalization can be monitored from computerized medical records and thereby indicate the quality of drug utilization. Pharmacoepidemiol Drug Saf. 2006;15:179–84.CrossRefGoogle Scholar
  18. 18.
    Leise MD, Poterucha JJ, Talwalkar JA. Drug-induced liver injury. Mayo Clin Proc. 2014;89:95–106.CrossRefPubMedGoogle Scholar
  19. 19.
    Amacher DE. Female gender as a susceptibility factor for drug-induced liver injury. Hum Exp Toxicol. 2014;33:928–39.CrossRefPubMedGoogle Scholar
  20. 20.
    Melloni C, Berger JS, Wang TY, Gunes F, Stebbins A, Pieper KS, Dolor RJ, Douglas PS, Mark DB, Newby LK. Representation of women in randomized clinical trials of cardiovascular disease prevention. Circ Cardiovasc Qual Outcomes. 2010;3:135–42.CrossRefPubMedGoogle Scholar
  21. 21.
    Eriksson I, Bergman U, Vlahovic-Palcevski V, von Euler M. Drug utilization studies across patient and prescriber characteristics. In: Elseviers M, Wettermark B, Birna Almarsdóttir A, Andersen M, Benko R, Bennie M, Eriksson I, Godman B, Krska J, Poluzzi E, Taxis K, Vlahovic-Palcevski V, Vander Stichele R, editors. Drug utilization research: methods and applications. Hoboken: Wiley; 2016.Google Scholar
  22. 22.
    Stephen M, Wiggins HS, Englyst HN. The effect of age, sex and level of intake of dietary fibre from wheat on large-bowel function in thirty healthy subjects. Br J Nutr. 1986;56:349–61.CrossRefPubMedGoogle Scholar
  23. 23.
    Goodman DE, Israel E, Rosenberg M, Johnston R, Weiss ST, Drazen JM. The influence of age, diagnosis, and gender on proper use of metered-dose inhalers. Am J Respir Crit Care Med. 1994;150:1256–61.CrossRefPubMedGoogle Scholar
  24. 24.
    Atkinson AJ, Anernathy DR, Daniels CE, Dedrick RL, Markey SP, editors. Principles of clinical pharmacology. 2nd ed. San Diego: Academic/Elsevier; 2007.Google Scholar
  25. 25.
    Frezza M, di Padova C, Pozzato G, Terpin M, Baraona E, Lieber CS. High blood alcohol levels in women. The role of decreased gastric alcohol dehydrogenase activity and first-pass metabolism. N Engl J Med. 1990;322:95–9.CrossRefPubMedGoogle Scholar
  26. 26.
    SBU. Skattning av njurfunktion: en systematisk litteraturöversikt. Rapport nr: 214. Mölnlycke: Elanders; 2013. ISBN: 978-91-85413-53-9.Google Scholar
  27. 27.
    Skoglund P. Farmakokinetiska grundbegrepp. Apoteket AB. Marknads-/Försäljningsstöd; 2001.Google Scholar
  28. 28.
    Pieper PG. Use of medication for cardiovascular disease during pregnancy. Nat Rev Cardiol. 2015;12:718–29.CrossRefPubMedGoogle Scholar
  29. 29.
    Mitoff PR, Gam D, Ivanov J, Al-hesayen A, Azevedo ER, Newton GE, Parker JD, Mak S. Cardiac-specific sympathetic activation in men and women with and without heart failure. Heart. 2011;97:382–7.CrossRefPubMedGoogle Scholar
  30. 30.
    Momen A, Gao Z, Cohen A, Khan T, Leuenberger UA, Sinoway LI. Coronary vasoconstrictor responses are attenuated in young women as compared with age-matched men. J Physiol. 2010;588:4007–16.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Kneale BJ, Chowienczyk PJ, Brett SE, Coltart DJ, Ritter JM. Gender differences in sensitivity to adrenergic agonists of forearm resistance vasculature. J Am Coll Cardiol. 2000;36:1233.CrossRefPubMedGoogle Scholar
  32. 32.
    Wheeldon NM, Newnham DM, Coutie WJ, Peters JA, McDevitt DG, Lipworth BJ. Influence of sex-steroid hormones on the regulation of lymphocyte beta 2-adrenoceptors during the menstrual cycle. Br J Clin Pharmacol. 1994;37:583–8.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Kam KW, Qi JS, Chen M, Wong TM. Estrogen reduces cardiac injury and expression of beta1-adrenoceptor upon ischemic insult in the rat heart. J Pharmacol Exp Ther. 2004;309:8–15.CrossRefPubMedGoogle Scholar
  34. 34.
    Thawornkaiwong A, Preawnim S, Wattanapermpool J. Upregulation of β1-adrenergic receptors in ovariectomized rat hearts. Life Sci. 2003;72:1813–24.CrossRefPubMedGoogle Scholar
  35. 35.
    Kotecha D, Manzano L, Krum H, et al. Effect of age and sex on efficacy and tolerability of β-blockers in patients with heart failure with reduced ejection fraction: individual patient data meta-analysis. BMJ. 2016;353:i18.Google Scholar
  36. 36.
    Weinberger AH, McKee SA, Mazure CM. Inclusion of women and gender-specific analyses in randomized clinical trials of treatments for depression. J Womens Health (Larchmt). 2010;19:1727–32.CrossRefGoogle Scholar
  37. 37.
    Tannenbaum C, Schwarz JM, Clayton JA, de Vries GJ, Sullivan C. Evaluating sex as a biological variable in preclinical research: the devil in the details. Biol Sex Differ. 2016;7:13. doi: 10.1186/s13293-016-0066-x.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Ward KE, Archambault R, Mersfelder TL. Severe adverse skin reactions to nonsteroidal anti-inflammatory drugs: a review of the literature. Am J Health Syst Pharm. 2010;67:206–13.CrossRefPubMedGoogle Scholar
  39. 39.
    Willis CM, Shaw S, De Lacharrière O, Baverel M, Reiche L, Jourdain R, Bastien P, Wilkinson JD. Sensitive skin: an epidemiological study. Br J Dermatol. 2001;145:258–63.CrossRefPubMedGoogle Scholar
  40. 40.
    Moss AJ. The QT interval and Torsade de pointes. Drug Saf. 1999;21(Suppl. 1):5–10.CrossRefPubMedGoogle Scholar
  41. 41.
    Taylor CJ, Hodgkinson J, Hobbs FD. Rhythm control agents and adverse events in patients with atrial fibrillation. Int J Clin Pract. 2010;64:1069–75.CrossRefPubMedGoogle Scholar
  42. 42.
    Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med. 2004;350:1013–22.CrossRefPubMedGoogle Scholar
  43. 43.
    Makkar RR, Fromm BS, Steinman RT, Meissner MD, Lehmann MH. Female gender as a risk factor for Torsades de pointes associated with cardiovascular drugs. JAMA. 1993;270:2590–7.CrossRefPubMedGoogle Scholar
  44. 44.
    Fitzgerald PT, Ackerman MJ. Drug-induced torsades de pointes: the evolving role of pharmacogenetics. Heart Rhythm. 2005;2:S30–7.CrossRefPubMedGoogle Scholar
  45. 45.
    Lehmann MH, Hardy S, Archibald D, MacNeil DJ. QTc prolongation with d,l-sotalol in women versus men. Am J Cardiol. 1999;83:354–9.CrossRefPubMedGoogle Scholar
  46. 46.
    Schenck-Gustafsson K, Dahlqvist R. Pharmacokinetics of digoxin in patients subjected to the quinidine-digoxin interaction. Br J Clin Pharmacol. 1981;11(2):181–6.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Reinoehl J, Frankovich D, Machado C, Kawasaki R, Baga JJ, Pires LA, et al. Probucol associated tachyarrhythmic events and QT prolongation: importance of gender. Am Heart J. 1996;131:1184–91.CrossRefPubMedGoogle Scholar
  48. 48.
    Lim HE, Pak HN, Ahn JC, Song WH, Kim YH. Torsade de pointes induced by short-term oral amiodarone therapy. Europace. 2006;8:1051–3.CrossRefPubMedGoogle Scholar
  49. 49.
    Os I, Bratland B, Dahlof B, Gisholt K, Syvertsen JO, Tretli S. Female sex as an important determinant of lisinopril-induced cough. Lancet. 1992;339:372.CrossRefPubMedGoogle Scholar
  50. 50.
    Pasternak RC, Smith Jr SC, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. Circulation. 2002;106:1024–8.CrossRefPubMedGoogle Scholar
  51. 51.
    Hou Q, Li S, Li L, Li Y, Sun X, Tian H. Association between SLCO1B1 gene T521C, polymorphism and statin-related myopathy risk: a meta-analysis of case-control studies. Medicine (Baltimore). 2015;94(37):e1268.CrossRefGoogle Scholar
  52. 52.
    Luzum JA, Kitzmiller JP, Isackson PJ, Ma C, Medina MW, Dauki AM, et al. GATM polymorphism associated with the risk for statin-induced myopathy does not replicate in case-control analysis of 715 dyslipidemic individuals. Cell Metab. 2015;21:622–7.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Rosano GM, Lewis B, Agewall S, Wassmann S, Vitale C, Schmidt H, et al. Gender differences in the effect of cardiovascular drugs: a position document of the working group on pharmacology and drug therapy of the ESC. Eur Heart J. 2015;36:2677–80.CrossRefPubMedGoogle Scholar
  54. 54.
    Kardas P, Lewek P, Matyjaszczyk M. Determinants of patient adherence: a review of systematic reviews. Front Pharmacol. 2013;4:1–16.CrossRefGoogle Scholar
  55. 55.
    DiMatteo MR. Variations in patients’ adherence to medical recommendations: a quantitative review of 50 years of research. Med Care. 2004;42:200–9.CrossRefPubMedGoogle Scholar
  56. 56.
    Regitz-Zagrosek V, Blomstrom Lundqvist C, Borghi C, Cifkova R, Ferreira R, Foidart J-M, Gibbs JSR, Gohlke-Baerwolf C, Gorenek B, Iung B, Kirby MC, Maas AHEM, Morais J, Nihoyannopoulos P, Pieper PG, Presbitero P, Roos-Hesselink JW, Schaufelberger M, Seeland U, Torracca L. ESC guidelines on the management of cardiovascular diseases during pregnancy. Eur Heart J. 2011;32:3147–97.CrossRefPubMedGoogle Scholar
  57. 57.
    Lupattelli A, Spigset O, Björnsdóttir I, Hämeen-Anttila K, Mårdby AC, Panchaud A, Juraski RG, Rudolf G, Odalovic M, Drozd M, Twigg MJ, Juch H, Moretti ME, Kennedy D, Rieutord A, Zagorodnikova K, Passier A, Nordeng H. Patterns and factors associated with low adherence to psychotropic medications during pregnancy—a cross-sectional, multinational web-based study. Depress Anxiety. 2015;32:426–36.CrossRefPubMedGoogle Scholar
  58. 58.
  59. 59.

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Department of Medicine, Cardiac UnitCenter of Gender Medicine, Karolinska Institutet, Karolinska University HospitalStockholmSweden
  2. 2.Karolinska Institutet Stroke Research Network, SödersjukhusetStockholmSweden
  3. 3.Department of Clinical Science and EducationKarolinska Institutet, SödersjukhusetStockholmSweden
  4. 4.Department of Clinical PharmacologyKarolinska University HospitalStockholmSweden

Personalised recommendations