Skip to main content

Advertisement

SpringerLink
Log in

The influence of tocolytic drugs on cardiac function, large arteries, and resistance vessels

  • Pharmacodynamics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Beta-2 adrenoceptor agonistic drugs like ritodrine have been the reference tocolytic drugs, but are associated with cardiovascular side-effects. Atosiban, a newer drug, is a competitive antagonist of oxytocin and has been claimed to have fewer cardiovascular side effects. Until now, there has mainly been a subjective reporting of adverse reactions and few objective cardiovascular data. Evaluation of the acute effects of therapeutic doses of ritodrine and atosiban compared with placebo on cardiac function, large artery properties, blood pressure, and resistance vessels.

Methods

A double-blind, randomized trial was carried out in 20 non-pregnant female volunteers. Hemodynamic measurements were made under standardized conditions during kinetic steady state. Cardiac output was measured with echocardiography, large artery properties with an echo-tracking device. The effect on the microcirculation was estimated using the total peripheral resistance index (TPRI).

Results

Atosiban did not differ from placebo. With ritodrine, cardiac function increased by 79% compared with placebo because of a rise in heart rate (91%). TPRI decreased by 48%. Ritodrine increased the distensibility of the common carotid artery by 62% and the compliance by 83%, independent of blood pressure. Compliance of the common femoral artery increased independently of pressure by 33% and the distensibility by 59%. Aortic pulse wave velocity was not influenced by either medication.

Conclusions

The present study shows potential beneficial vascular effects of ritodrine that are counterbalanced by the cardiac effects. Atosiban has no clinically relevant cardiovascular effects and may be a good alternative for ritodrine in pregnant women at risk of cardiovascular complications.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

AD :

Arterial cross-section at end-diastole

Ao:

Aorta

BSA:

Body surface area

CC:

Cross-sectional compliance

CCA:

Common carotid artery

CCISO :

Isobaric cross-sectional compliance

CFA:

Common femoral artery

CI:

Cardiac index

CO:

Cardiac output

CSA:

Cross-sectional area

D:

Diameter

DCISO :

Isobaric distensibility coefficient

DBP:

Diastolic blood pressure

FVI:

Flow velocity index

HR:

Heart rate

ICH:

International Conference on Harmonization

MAP:

Mean arterial pressure

PP:

Pulse pressure

PWF:

Pressure waveforms

PWV:

Pulse wave velocity

RAAS:

Renin–angiotensin–aldosterone system

SBP:

Systolic blood pressure

SI:

Stroke index

SSN:

Supra-sternal notch

SV:

Stroke volume

TPRI:

Total peripheral resistance index

ΔA:

Systolic-diastolic change in arterial cross-section

ΔP:

Local change in pulse pressure

ΔS :

Arterial diameter at end-systole

ΔD :

Arterial diameter at end-diastole

References

  1. De Heus R, Mol BW, Erwich JJ, van Geijn HP, Gyselaers WJ, Hanssens M, Harmark L, van Holsbeke CD, Duvekot JJ, Schobben FF, Wolf H, Visser GH (2009) Adverse drug reactions to tocolytic treatment for preterm labour: prospective cohort study. BMJ 338:b744

    Article  PubMed  Google Scholar 

  2. Kwong MS, Egan EA (1986) Reduced incidence of hyaline membrane disease in extremely premature infants following delay of delivery in mother with preterm labor: use of ritodrine and betamethasone. Pediatrics 78:767–774

    PubMed  CAS  Google Scholar 

  3. Caughey AB, Parer JT (2001) Tocolysis with beta-adrenergic receptor agonists. Semin Perinatol 25:248–255

    Article  PubMed  CAS  Google Scholar 

  4. Shim JY, Park YW, Yoon BH, Cho YK, Yang JH, Lee Y, Kim A (2006) Multicentre, parallel group, randomised, single-blind study of the safety and efficacy of atosiban versus ritodrine in the treatment of acute preterm labour in Korean women. BJOG 113:1228–1234

    Article  PubMed  CAS  Google Scholar 

  5. Shubert PJ (1995) Atosiban. Clin Obstet Gynecol 38:722–724

    Article  PubMed  CAS  Google Scholar 

  6. Chan J, Cabrol D, Ingemarsson I, Marsal K, Moutquin JM, Fisk NM (2006) Pragmatic comparison of beta2-agonist side effects within the Worldwide Atosiban versus Beta Agonists study. Eur J Obstet Gynecol Reprod Biol 128:135–141

    Article  PubMed  CAS  Google Scholar 

  7. Stergiotou I, Talbot F, Yoong W (2007) The use of atosiban and ritodrine in external cephalic version. Acta Obstet Gynecol Scand 86:927–929

    Article  PubMed  CAS  Google Scholar 

  8. Ferriols LR, Nicolas PJ, Alos AM (2005) Pharmacoeconomic assessment of two tocolysis protocols for the inhibition of premature delivery. Farm Hosp 29:18–25

    Article  Google Scholar 

  9. Worldwide Atosiban versus Beta-agonists Study Group (2001) Effectiveness and safety of the oxytocin antagonist atosiban versus beta-adrenergic agonists in the treatment of preterm labour. BJOG 108:133–142

    Google Scholar 

  10. Fabry I, De PP, Kips J, Vermeersch S, Van BL (2011) Different effects of tocolytic medication on blood pressure and blood pressure amplification. Eur J Clin Pharmacol 67:11–17

    Article  PubMed  CAS  Google Scholar 

  11. Van Bortel LM, Duprez D, Starmans-Kool MJ, Safar ME, Giannattasio C, Cockcroft J, Kaiser DR, Thuillez C (2002) Clinical applications of arterial stiffness, Task Force III: recommendations for user procedures. Am J Hypertens 15:445–452

    Article  PubMed  Google Scholar 

  12. Gerris J, Thiery M, Bogaert M, De SA (1980) Randomized trial of two beta-mimetic drugs (ritodrine and fenoterol) in acute intra-partum tocolysis. Eur J Clin Pharmacol 18:443–448

    Article  PubMed  CAS  Google Scholar 

  13. Papatsonis DN, van Geijn HP, Ader HJ, Lange FM, Bleker OP, Dekker GA (1997) Nifedipine and ritodrine in the management of preterm labor: a randomized multicenter trial. Obstet Gynecol 90:230–234

    Article  PubMed  CAS  Google Scholar 

  14. Rasmussen BB, Larsen LS, Senderovitz T (2005) Pharmacokinetic interaction studies of atosiban with labetalol or betamethasone in healthy female volunteers. BJOG 112:1492–1499

    Article  PubMed  Google Scholar 

  15. Tsatsaris V, Carbonne B, Papatsonis D, Goffinet F (2000) Nifedipine versus ritodrine for suppression of preterm labor; a meta-analysis. Acta Obstet Gynecol Scand 79:618–619

    PubMed  CAS  Google Scholar 

  16. Vanmolkot FH, Van Bortel LM, de Hoon JN (2007) Altered arterial function in migraine of recent onset. Neurology 68:1563–1570

    Article  PubMed  Google Scholar 

  17. Bos WJ, Verrij E, Vincent HH, Westerhof BE, Parati G, van Montfrans GA (2007) How to assess mean blood pressure properly at the brachial artery level. J Hypertens 25:751–755

    Article  PubMed  CAS  Google Scholar 

  18. Huntsman LL, Stewart DK, Barnes SR, Franklin SB, Colocousis JS, Hessel EA (1983) Noninvasive Doppler determination of cardiac output in man. Clinical validation. Circulation 67:593–602

    PubMed  CAS  Google Scholar 

  19. Du BD, Du Bois EF (1989) A formula to estimate the approximate surface area if height and weight be known. Nutrition 5:303–311

    Google Scholar 

  20. Wilkinson IB, Cockcroft JR, Webb DJ (1998) Pulse wave analysis and arterial stiffness. J Cardiovasc Pharmacol 32 [Suppl 3]:S33–S37

    PubMed  CAS  Google Scholar 

  21. Vlachopoulos C, Aznaouridis K, Stefanadis C (2010) Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis. J Am Coll Cardiol 55:1318–1327

    Article  PubMed  Google Scholar 

  22. Vermeersch SJ, Rietzschel ER, De Buyzere ML, De BD, De BG, Van Bortel LM, Gillebert TC, Verdonck PR, Segers P (2008) Age and gender related patterns in carotid-femoral PWV and carotid and femoral stiffness in a large healthy, middle-aged population. J Hypertens 26:1411–1419

    Article  PubMed  CAS  Google Scholar 

  23. Hoeks AP, Brands PJ, Smeets FA, Reneman RS (1990) Assessment of the distensibility of superficial arteries. Ultrasound Med Biol 16:121–128

    Article  PubMed  CAS  Google Scholar 

  24. Kelly R, Hayward C, Avolio A, O’Rourke M (1989) Noninvasive determination of age-related changes in the human arterial pulse. Circulation 80:1652–1659

    PubMed  CAS  Google Scholar 

  25. Kelly R, Fitchett D (1992) Noninvasive determination of aortic input impedance and external left ventricular power output: a validation and repeatability study of a new technique. J Am Coll Cardiol 20:952–963

    Article  PubMed  CAS  Google Scholar 

  26. Goodwin TM, Millar L, North L, Abrams LS, Weglein RC, Holland ML (1995) The pharmacokinetics of the oxytocin antagonist atosiban in pregnant women with preterm uterine contractions. Am J Obstet Gynecol 173:913–917

    Article  PubMed  CAS  Google Scholar 

  27. Goodwin TM, Valenzuela G, Silver H, Hayashi R, Creasy GW, Lane R (1996) Treatment of preterm labor with the oxytocin antagonist atosiban. Am J Perinatol 13:143–146

    Article  PubMed  CAS  Google Scholar 

  28. Moutquin JM, Sherman D, Cohen H, Mohide PT, Hochner-Celnikier D, Fejgin M, Liston RM, Dansereau J, Mazor M, Shalev E, Boucher M, Glezerman M, Zimmer EZ, Rabinovici J (2000) Double-blind, randomized, controlled trial of atosiban and ritodrine in the treatment of preterm labor: a multicenter effectiveness and safety study. Am J Obstet Gynecol 182:1191–1199

    Article  PubMed  CAS  Google Scholar 

  29. Papatsonis DN, van Geijn HP, Bleker OP, Ader HJ, Dekker GA (2003) Hemodynamic and metabolic effects after nifedipine and ritodrine tocolysis. Int J Gynaecol Obstet 82:5–10

    Article  PubMed  CAS  Google Scholar 

  30. Hosenpud JD, Morton MJ, O’Grady JP (1983) Cardiac stimulation during ritodrine hydrochloride tocolytic therapy. Obstet Gynecol 62:52–58

    PubMed  CAS  Google Scholar 

  31. Lamont RF (2000) The pathophysiology of pulmonary oedema with the use of beta-agonists. BJOG 107:439–444

    Article  PubMed  CAS  Google Scholar 

  32. Tsatsaris V, Carbonne B, Cabrol D (2004) Atosiban for preterm labour. Drugs 64:375–382

    Article  PubMed  CAS  Google Scholar 

  33. Schneider KT, Deckardt R (1991) The implication of upright posture on pregnancy. J Perinat Med 19:121–131

    Article  PubMed  CAS  Google Scholar 

  34. Dennedy MC, Houlihan DD, McMillan H, Morrison JJ (2002) Beta2- and beta3-adrenoreceptor agonists: human myometrial selectivity and effects on umbilical artery tone. Am J Obstet Gynecol 187:641–647

    Article  PubMed  CAS  Google Scholar 

  35. Lantelme P, Mestre C, Lievre M, Gressard A, Milon H (2002) Heart rate: an important confounder of pulse wave velocity assessment. Hypertension 39:1083–1087

    Article  PubMed  CAS  Google Scholar 

  36. Duvekot JJ, Peeters LL (1994) Maternal cardiovascular hemodynamic adaptation to pregnancy. Obstet Gynecol Surv 49:S1–S14

    Article  PubMed  CAS  Google Scholar 

  37. Gimpl G, Fahrenholz F (2001) The oxytocin receptor system: structure, function, and regulation. Physiol Rev 81:629–683

    PubMed  CAS  Google Scholar 

  38. Mitchell BF, Schmid B (2001) Oxytocin and its receptor in the process of parturition. J Soc Gynecol Investig 8:122–133

    Article  PubMed  CAS  Google Scholar 

  39. Cekici L, Valipour A, Kohansal R, Burghuber OC (2009) Short-term effects of inhaled salbutamol on autonomic cardiovascular control in healthy subjects: a placebo-controlled study. Br J Clin Pharmacol 67:394–402

    Article  PubMed  CAS  Google Scholar 

  40. Waring WS, Sinclair HM, Webb DJ (2006) Effects of salbutamol and glyceryl trinitrate on large arterial stiffness are similar between patients with hypertension and adults with normal blood pressure. Br J Clin Pharmacol 62:621–626

    Article  PubMed  CAS  Google Scholar 

  41. Dawes M, Chowienczyk PJ, Ritter JM (1997) Effects of inhibition of the L-arginine/nitric oxide pathway on vasodilation caused by beta-adrenergic agonists in human forearm. Circulation 95:2293–2297

    PubMed  CAS  Google Scholar 

  42. Anumba DO, Ford GA, Boys RJ, Robson SC (1999) Stimulated nitric oxide release and nitric oxide sensitivity in forearm arterial vasculature during normotensive and preeclamptic pregnancy. Am J Obstet Gynecol 181:1479–1484

    Article  PubMed  CAS  Google Scholar 

  43. Vesalainen RK, Ekholm EM, Jartti TT, Tahvanainen KU, Kaila TJ, Erkkola RU (1999) Effects of tocolytic treatment with ritodrine on cardiovascular autonomic regulation. Br J Obstet Gynaecol 106:238–243

    Article  PubMed  CAS  Google Scholar 

  44. Bussen SS, Sutterlin MW, Steck T (1998) Plasma renin activity and aldosterone serum concentration are decreased in severe preeclampsia but not in the HELLP-syndrome. Acta Obstet Gynecol Scand 77:609–613

    Article  PubMed  CAS  Google Scholar 

  45. Noori M, Donald AE, Angelakopoulou A, Hingorani AD, Williams DJ (2010) Prospective study of placental angiogenic factors and maternal vascular function before and after preeclampsia and gestational hypertension. Circulation 122:478–487

    Article  PubMed  CAS  Google Scholar 

  46. Simmons LA, Hennessy A, Gillin AG, Jeremy RW (2000) Uteroplacental blood flow and placental vascular endothelial growth factor in normotensive and pre-eclamptic pregnancy. BJOG 107:678–685

    Article  PubMed  CAS  Google Scholar 

  47. Wex J, Connolly M, Rath W (2009) Atosiban versus betamimetics in the treatment of preterm labour in Germany: an economic evaluation. BMC Pregnancy Childbirth 9:23

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank all the subjects included, Mr Dries Mahieu, Mrs Tine De Backer, Mrs Fabienne De Boeck, Mrs Griet Van Lancker, Mrs Charline Wehlou, Mr Marc Twagirumukiza for the blinded medication preparation, the staff of the Drug Research Unit Ghent for their excellent technical support and Mr Sebastian Vermeersch for his know-how.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Heymans Institute of Pharmacology, Department of Clinical Pharmacology, Ghent University Hospital, De Pintelaan 185, 9000, Ghent, Belgium

    Isabelle G. Fabry, Peter De Paepe, Jan G. Kips & Luc M. Van Bortel

  2. Emergency Department, Ghent University Hospital, Ghent, Belgium

    Peter De Paepe

Authors
  1. Isabelle G. Fabry
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter De Paepe
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jan G. Kips
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Luc M. Van Bortel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Isabelle G. Fabry.

Additional information

What is already known about the subject?

1. Mainly reports of ritodrine on the blood pressure and cardiovascular side effects are known

2. Apart from blood pressure, no cardiovascular effects have been studied during atosiban infusion

3. Therefore, there is a need for in-depth research on the effects of the two commonly used tocolytic drugs on the cardiovascular system to better understand their pharmacodynamic effects

What this study adds:

Comparison of the effects of ritodrine and atosiban on macrocirculation (arterial stiffness and compliance), microcirculation (peripheral resistance), and cardiac function

Original manuscript with agreement of all the authors to the content of the work

Trial Number

EudractNr: 2008-000845-76

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fabry, I.G., De Paepe, P., Kips, J.G. et al. The influence of tocolytic drugs on cardiac function, large arteries, and resistance vessels. Eur J Clin Pharmacol 67, 573–580 (2011). https://doi.org/10.1007/s00228-011-1040-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-011-1040-5

Keywords

Search

Navigation