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Cardiovascular effects of (R)- and (S)-verapamil and racemic verapamil in humans: a placebo-controlled study

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

Abstract

Objective

To characterise the comparative potency of optically pure (R)- and (S)-verapamil as regards negative dromotropic effects on atrioventricular (AV) node conduction and to compare the hemodynamic effects of single doses of the enantiomers in healthy volunteers.

Methods

Eight healthy volunteers received a single oral dose of 120 mg (S)-verapamil, 480 mg (R)-verapamil, 240 mg racemic verapamil (rac-verapamil) or placebo on 4 separate occasions. Serum concentrations of (R)- and (S)-verapamil were measured up to 24 h. Cardiovascular effects were assessed by electrocardiography, measurement of blood pressure and transthoracic impedance cardiography (cardiac output and total peripheral resistance). The comparative potency of (R)- and (S)-verapamil with regard to prolongation of the PR interval in the surface ECG was estimated by use of the areas under the effect-time and serum concentration-time curves and linear regression analyses of per cent change in PR interval from baseline versus the logarithm of serum (R)- or (S)-verapamil concentration.

Results

The PR interval was significantly prolonged after all verapamil treatments as compared with placebo. (S)-verapamil was 20.6–21.8 times more potent than (R)-verapamil with regard to negative dromotropic effects. (R)-verapamil caused a significantly greater maximum reduction in the mean arterial pressure (MAP) than placebo [15.9±6.8 versus 8.7±3.2 mmHg (mean±SD); 95% CI on the difference, 0.79–13.7 mmHg; p<0.05], whereas MAP was not affected by the other verapamil treatments. No significant changes were observed in heart rate, cardiac output and total peripheral resistance after any verapamil treatment as compared with placebo.

Conclusions

(S)-verapamil was about 20 times more potent than (R)-verapamil with regard to negative dromotropic effects on AV node conduction. (R)-verapamil but not (S)-verapamil significantly reduced the MAP as compared with placebo.

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References

  1. Falk RH (2001) Atrial fibrillation. N Engl J Med 344:1067–1078

    Article  PubMed  CAS  Google Scholar 

  2. McNamara RL, Tamariz LJ, Segal JB, Bass EB (2003) Management of atrial fibrillation: review of the evidence for the role of pharmacologic therapy, electrical cardioversion, and echocardiography. Ann Intern Med 139:1018–1033

    PubMed  Google Scholar 

  3. Fumeaux T, Cornuz J, Polikar R, Blanc E, Junod A, Kappenberger L, Nicod P, Schlapfer J (2004) Guidelines for the clinical management of atrial fibrillation: a practical perspective. Swiss Med Wkly 134:235–247

    PubMed  Google Scholar 

  4. McTavish D, Sorkin EM (1989) Verapamil. An updated review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension. Drugs 38:19–76

    Article  PubMed  CAS  Google Scholar 

  5. Klein HO, Kaplinsky E (1986) Digitalis and verapamil in atrial fibrillation and flutter. Is verapamil now the preferred agent? Drugs 31:185–197

    Article  PubMed  CAS  Google Scholar 

  6. Lundstrom T, Ryden L (1990) Ventricular rate control and exercise performance in chronic atrial fibrillation: effects of diltiazem and verapamil. J Am Coll Cardiol 16:86–90

    Article  PubMed  CAS  Google Scholar 

  7. Kowey PR, Marinchak RA, Rials SJ, Filart RA (1998) Acute treatment of atrial fibrillation. Am J Cardiol 81:16C–22C

    Article  PubMed  CAS  Google Scholar 

  8. Prystowsky EN (2000) Management of atrial fibrillation: therapeutic options and clinical decisions. Am J Cardiol 85:3D–11D

    Article  PubMed  CAS  Google Scholar 

  9. Eichelbaum M, Mikus G, Vogelgesang B (1984) Pharmacokinetics of (+)−, (−)- and (+/−)-verapamil after intravenous administration. Br J Clin Pharmacol 17:453–458

    PubMed  CAS  Google Scholar 

  10. Vogelgesang B, Echizen H, Schmidt E, Eichelbaum M (1984) Stereoselective first-pass metabolism of highly cleared drugs: studies of the bioavailability of L- and D-verapamil examined with a stable isotope technique. Br J Clin Pharmacol 18:733–740

    PubMed  CAS  Google Scholar 

  11. Echizen H, Brecht T, Niedergesass S, Vogelgesang B, Eichelbaum M (1985) The effect of dextro-, levo-, and racemic verapamil on atrioventricular conduction in humans. Am Heart J 109:210–217

    Article  PubMed  CAS  Google Scholar 

  12. Echizen H, Vogelgesang B, Eichelbaum M (1985) Effects of d,l-verapamil on atrioventricular conduction in relation to its stereoselective first-pass metabolism. Clin Pharmacol Ther 38:71–76

    Article  PubMed  CAS  Google Scholar 

  13. Echizen H, Manz M, Eichelbaum M (1988) Electrophysiologic effects of dextro- and levo-verapamil on sinus node and AV node function in humans. J Cardiovasc Pharmacol 12:543–546

    Article  PubMed  CAS  Google Scholar 

  14. Eichelbaum M, Vogelgesang B, Echizen H, Schmidt E, Eichelbaum M (2004) Stereoselective first-pass metabolism of highly cleared drugs: studies of the bioavailability of L- and D-verapamil examined with a stable isotope technique. 1984. Br J Clin Pharmacol 58:S796–S803

    Article  PubMed  Google Scholar 

  15. Eichelbaum M, Somogyi A (1984) Inter- and intra-subject variation in the first-pass elimination of highly cleared drugs during chronic dosing. Studies with deuterated verapamil. Eur J Clin Pharmacol 26:47–53

    Article  PubMed  CAS  Google Scholar 

  16. Kaumann AJ, Serur JR (1975) Optical isomers of verapamil on canine heart. Prevention of ventricular fibrillation induced by coronary artery occlusion, impaired atrioventricular conductance and negative inotropic and chronotropic effects. Naunyn Schmiedebergs Arch Pharmacol 291:347–358

    Article  PubMed  CAS  Google Scholar 

  17. Raschack M (1976) Relationship of antiarrhythmic to inotropic activity and antiarrhythmic qualities of the optical isomers of verapamil. Naunyn Schmiedebergs Arch Pharmacol 294:285–291

    Article  PubMed  CAS  Google Scholar 

  18. Satoh K, Yanagisawa T, Taira N (1979) Effects on atrioventricular conduction and blood flow of enantiomers of verapamil and of tetrodotoxin injected into the posterior and the anterior septal artery of the atrioventricular node preparation of the dog. Naunyn Schmiedebergs Arch Pharmacol 308:89–98

    Article  PubMed  CAS  Google Scholar 

  19. Gloor HO, Urthaler F (1983) Differential effect of verapamil isomers on sinus node and AV junctional region. Am J Physiol 244:H80–88

    PubMed  CAS  Google Scholar 

  20. Curtis MJ, Walker MJ (1986) The mechanism of action of the optical enantiomers of verapamil against ischaemia-induced arrhythmias in the conscious rat. Br J Pharmacol 89:137–147

    PubMed  CAS  Google Scholar 

  21. Dilger K, Eckhardt K, Hofmann U, Kucher K, Mikus G, Eichelbaum M (1999) Chronopharmacology of intravenous and oral modified release verapamil. Br J Clin Pharmacol 47:413–419

    Article  PubMed  CAS  Google Scholar 

  22. Fromm MF, Dilger K, Busse D, Kroemer HK, Eichelbaum M, Klotz U (1998) Gut wall metabolism of verapamil in older people: effects of rifampicin-mediated enzyme induction. Br J Clin Pharmacol 45:247–255

    Article  PubMed  CAS  Google Scholar 

  23. Bloom HL (2004) Concise review of atrial fibrillation: treatment update considerations in light of AFFIRM and RACE. Clin Cardiol 27:495–500

    Article  PubMed  Google Scholar 

  24. Dorian P, Mangat I, Pinter A, Korley V (2004) The burden of atrial fibrillation: should we abandon antiarrhythmic drug therapy? J Cardiovasc Pharmacol Ther 9:257–262

    Article  PubMed  Google Scholar 

  25. de Denus S, Sanoski CA, Carlsson J, Opolski G, Spinler SA (2005) Rate versus rhythm control in patients with atrial fibrillation: a meta-analysis. Arch Intern Med 165:258–262

    Article  PubMed  Google Scholar 

  26. Ahmed JH, Godden J, Meredith PA, Elliott HL (1993) R-verapamil: pharmacokinetics and effects on PR interval, blood pressure and heart rate. Br J Clin Pharmacol 36:93–98

    PubMed  CAS  Google Scholar 

  27. Schwartz JB, Troconiz IF, Verotta D, Liu S, Capili H (1993) Aging effects on stereoselective pharmacokinetics and pharmacodynamics of verapamil. J Pharmacol Exp Ther 265:690–698

    PubMed  CAS  Google Scholar 

  28. Gupta S, Modi NB, Sathyan G, Ho PL, Aarons L (2002) Pharmacokinetics of controlled-release verapamil in healthy volunteers and patients with hypertension or angina. Biopharm Drug Dispos 23:17–31

    Article  PubMed  CAS  Google Scholar 

  29. Wilson WH, Jamis-Dow C, Bryant G, Balis FM, Klecker RW, Bates SE, Chabner BA, Steinberg SM, Kohler DR, Wittes RE (1995) Phase I and pharmacokinetic study of the multidrug resistance modulator dexverapamil with EPOCH chemotherapy. J Clin Oncol 13:1985–1994

    PubMed  CAS  Google Scholar 

  30. Tolcher AW, Cowan KH, Solomon D, Ognibene F, Goldspiel B, Chang R, Noone MH, Denicoff AM, Barnes CS, Gossard MR, Fetsch PA, Berg SL, Balis FM, Venzon DJ, O’Shaughnessy JA (1996) Phase I crossover study of paclitaxel with r-verapamil in patients with metastatic breast cancer. J Clin Oncol 14:1173–1184

    PubMed  CAS  Google Scholar 

  31. Weinlander G, Kornek G, Raderer M, Hejna M, Tetzner C, Scheithauer W (1997) Treatment of advanced colorectal cancer with doxorubicin combined with two potential multidrug-resistance-reversing agents: high-dose oral tamoxifen and dexverapamil. J Cancer Res Clin Oncol 123:452–455

    Article  PubMed  CAS  Google Scholar 

  32. Messerli FH (2002) Calcium antagonists in hypertension: from hemodynamics to outcomes. Am J Hypertens 15:94S–97S

    Article  PubMed  CAS  Google Scholar 

  33. Busse D, Fromm MF, Morike K, Drescher S, Kuhlkamp V, Eichelbaum M (2001) Disposition and pharmacologic effects of R/S-verapamil in patients with chronic atrial fibrillation: an investigation comparing single and multiple dosing. Clin Pharmacol Ther 69:324–332

    Article  PubMed  CAS  Google Scholar 

  34. Kates RE, Keefe DL, Schwartz J, Harapat S, Kirsten EB, Harrison DC (1981) Verapamil disposition kinetics in chronic atrial fibrillation. Clin Pharmacol Ther 30:44–51

    Article  PubMed  CAS  Google Scholar 

  35. Schwartz JB, Keefe DL, Kirsten E, Kates RE, Harrison DC (1982) Prolongation of verapamil elimination kinetics during chronic oral administration. Am Heart J 104:198–203

    Article  PubMed  CAS  Google Scholar 

  36. Anderson P, Bondesson U, Sylven C (1982) Clinical pharmacokinetics of verapamil in patients with atrial fibrillation. Eur J Clin Pharmacol 23:49–57

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported by grants from the Robert-Bosch Foundation (Stuttgart, Germany), Federal Ministry of Education and Research (grant no. 01EC9405; Bonn, Germany), Knoll (Ludwigshafen, Germany) and Chiroscience (Cambridge, UK).

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Authors and Affiliations

  1. Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany

    Dagmar Busse, Silke Templin, Gerd Mikus, Matthias Schwab, Ute Hofmann & Michel Eichelbaum

  2. Department of Pharmacological Sciences, Medical School, University of Tampere, Tampere, Finland

    Kari T. Kivistö

Authors
  1. Dagmar Busse
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  2. Silke Templin
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  3. Gerd Mikus
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  4. Matthias Schwab
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  5. Ute Hofmann
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  6. Michel Eichelbaum
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  7. Kari T. Kivistö
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Corresponding author

Correspondence to Kari T. Kivistö.

Additional information

Dagmar Busse and Silke Templin contributed equally to this work.

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Busse, D., Templin, S., Mikus, G. et al. Cardiovascular effects of (R)- and (S)-verapamil and racemic verapamil in humans: a placebo-controlled study. Eur J Clin Pharmacol 62, 613–619 (2006). https://doi.org/10.1007/s00228-006-0154-7

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  • DOI: https://doi.org/10.1007/s00228-006-0154-7

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