Skip to main content
NCBI home page
British Journal of Clinical Pharmacology logoLink to British Journal of Clinical Pharmacology
. 1989 Nov;28(5):517–526. doi: 10.1111/j.1365-2125.1989.tb03537.x

Concentration-effect relationships and individual responses to doxazosin in essential hypertension.

R Donnelly 1, H L Elliott 1, P A Meredith 1, J L Reid 1
PMCID: PMC1380011  PMID: 2531605

Abstract

1. This study investigates aspects of the pharmacokinetics, pharmacodynamics and concentration-effect relationships in 10 patients with essential hypertension during acute and chronic treatment with doxazosin, an alpha 1-adrenoceptor antagonist. 2. Following the first dose of doxazosin (2 mg) there were significant reductions in blood pressure, increases in heart rate and in plasma noradrenaline, and parallel rightward shifts of the phenylephrine pressor response curves, consistent with alpha-adrenoceptor antagonism. There was no significant change in the pressor response to angiotensin II. 3. Using an integrated kinetic-dynamic model, individual blood pressure responsiveness was characterised as the fall in blood pressure (mm Hg) per unit drug concentration. Responsiveness to the first dose of doxazosin was directly correlated with the responsiveness after 1 and 6 weeks treatment although there was a systemic reduction (of approximately 30%) which occurred during the first week of treatment. 4. Neither the acute nor long-term responsiveness to doxazosin was related to age, plasma renin activity, plasma noradrenaline or the pretreatment sensitivity to phenylephrine. There was a significant relationship between responsiveness and the height of the initial (pretreatment) blood pressure. 5. Integration of pharmacokinetic and pharmacodynamic data provides a reproducible index of responsiveness which can be used to investigate the consistency of the long-term anti-hypertensive response, to identify factors which influence the magnitude of the response, and to optimise the choice of dose and dose interval.

Full text

PDF
517

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Baez M. A., Garg D. C., Jallad N. S., Weidler D. J. Antihypertensive effect of doxazosin in hypertensive patients: comparison with atenolol. Br J Clin Pharmacol. 1986;21 (Suppl 1):63S–67S. doi: 10.1111/j.1365-2125.1986.tb02855.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bateman D. N., Hobbs D. C., Twomey T. M., Stevens E. A., Rawlins M. D. Prazosin, pharmacokinetics and concentration effect. Eur J Clin Pharmacol. 1979 Sep;16(3):177–181. doi: 10.1007/BF00562058. [DOI] [PubMed] [Google Scholar]
  3. Cox D. A., Leader J. P., Milson J. A., Singleton W. The antihypertensive effects of doxazosin: a clinical overview. Br J Clin Pharmacol. 1986;21 (Suppl 1):83S–90S. doi: 10.1111/j.1365-2125.1986.tb02858.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cubeddu L. X., Fuenmayor N., Caplan N., Ferry D. Clinical pharmacology of doxazosin in patients with essential hypertension. Clin Pharmacol Ther. 1987 Apr;41(4):439–449. doi: 10.1038/clpt.1987.54. [DOI] [PubMed] [Google Scholar]
  5. Da Prada M., Zürcher Simultaneous radioenzymatic determination of plasma and tissue adrenaline, noradrenaline and dopamine within the femtomole range. Life Sci. 1976 Oct 15;19(8):1161–1174. doi: 10.1016/0024-3205(76)90251-4. [DOI] [PubMed] [Google Scholar]
  6. Derkx F. H., Bouma B. N., Tan-Tjiong H. L., Man in 't Veld A. J., de Bruyn J. H., Wenting G. J., Schalekamp M. A. Role of plasma kallikrein in the proteolytic activation of the renin-angiotensin system. Clin Exp Hypertens. 1980;2(3-4):575–592. doi: 10.3109/10641968009037131. [DOI] [PubMed] [Google Scholar]
  7. Donnelly R., Meredith P. A., Elliott H. L. Pharmacokinetic-pharmacodynamic relationships of alpha-adrenoceptor antagonists. Clin Pharmacokinet. 1989 Oct;17(4):264–274. doi: 10.2165/00003088-198917040-00004. [DOI] [PubMed] [Google Scholar]
  8. Elliott H. L., McLean K., Sumner D. J., Meredith P. A., Reid J. L. Immediate cardiovascular responses to oral prazosin--effects of concurrent beta-blockers. Clin Pharmacol Ther. 1981 Mar;29(3):303–309. doi: 10.1038/clpt.1981.40. [DOI] [PubMed] [Google Scholar]
  9. Elliott H. L., Meredith P. A., Reid J. L. Pharmacokinetic overview of doxazosin. Am J Cardiol. 1987 May 29;59(14):78G–81G. doi: 10.1016/0002-9149(87)90162-7. [DOI] [PubMed] [Google Scholar]
  10. Elliott H. L., Meredith P. A., Sumner D. J., McLean K., Reid J. L. A pharmacodynamic and pharmacokinetic assessment of a new alpha-adrenoceptor antagonist, doxazosin (UK33274) in normotensive subjects. Br J Clin Pharmacol. 1982 May;13(5):699–703. doi: 10.1111/j.1365-2125.1982.tb01439.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Frick M. H., Halttunen P., Himanen P., Huttunen M., Pörsti P., Pitkäjärvi T., Pöyhönen L., Pyykönen M. L., Reinikainen P., Salmela P. A long-term double-blind comparison of doxazosin and atenolol in patients with mild to moderate essential hypertension. Br J Clin Pharmacol. 1986;21 (Suppl 1):55S–62S. doi: 10.1111/j.1365-2125.1986.tb02854.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Grahnén A., Seideman P., Lindström B., Haglund K., von Bahr C. Prazosin kinetics in hypertension. Clin Pharmacol Ther. 1981 Oct;30(4):439–446. doi: 10.1038/clpt.1981.186. [DOI] [PubMed] [Google Scholar]
  13. Holford N. H., Sheiner L. B. Understanding the dose-effect relationship: clinical application of pharmacokinetic-pharmacodynamic models. Clin Pharmacokinet. 1981 Nov-Dec;6(6):429–453. doi: 10.2165/00003088-198106060-00002. [DOI] [PubMed] [Google Scholar]
  14. Kaye B., Cussans N. J., Faulkner J. K., Stopher D. A., Reid J. L. The metabolism and kinetics of doxazosin in man, mouse, rat and dog. Br J Clin Pharmacol. 1986;21 (Suppl 1):19S–25S. doi: 10.1111/j.1365-2125.1986.tb02849.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Larochelle P., du Souich P., Hamet P., Larocque P., Armstrong J. Prazosin plasma concentration and blood pressure reduction. Hypertension. 1982 Jan-Feb;4(1):93–101. doi: 10.1161/01.hyp.4.1.93. [DOI] [PubMed] [Google Scholar]
  16. MacCarthy E. P., Frost G. W., Monaghan J. C., Mennie B. A., Stokes G. S. Prediction of response to antihypertensive therapy with prazosin. Med J Aust. 1980 Jul 26;2 (Suppl 1):12–14. [PubMed] [Google Scholar]
  17. McKenzie J. K., Clements J. A. Simplified radioimmunoassay for serum aldosterone utilizing increased antibody specificity. J Clin Endocrinol Metab. 1974 Apr;38(4):622–627. doi: 10.1210/jcem-38-4-622. [DOI] [PubMed] [Google Scholar]
  18. McNeil J. J., Drummer O. H., Conway E. L., Workman B. S., Louis W. J. Effect of age on pharmacokinetics of and blood pressure responses to prazosin and terazosin. J Cardiovasc Pharmacol. 1987 Aug;10(2):168–175. doi: 10.1097/00005344-198708000-00006. [DOI] [PubMed] [Google Scholar]
  19. Rosendorff C. Prazosin: severe side effects are dose-dependent. Br Med J. 1976 Aug 28;2(6034):508–508. doi: 10.1136/bmj.2.6034.508. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Rubin P. C., Brunton J., Meredith P. Determination of the vasodilator UK33274 by high-performance liquid chromatography using fluorescence detection. J Chromatogr. 1980 Nov 14;221(1):193–195. doi: 10.1016/s0378-4347(00)81025-7. [DOI] [PubMed] [Google Scholar]
  21. Rubin P. C., Scott P. J., Reid J. L. Prazosin disposition in young and elderly subjects. Br J Clin Pharmacol. 1981 Sep;12(3):401–404. doi: 10.1111/j.1365-2125.1981.tb01234.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Seideman P., Grahnén A., Haglund K., Lindström B., von Bahr C. Prazosin dynamics in hypertension: relationship to plasma concentration. Clin Pharmacol Ther. 1981 Oct;30(4):447–454. doi: 10.1038/clpt.1981.187. [DOI] [PubMed] [Google Scholar]
  23. Shionoiri H., Yasuda G., Yoshimura H., Umemura S., Miyajima E., Miyakawa T., Takagi N., Kaneko Y. Antihypertensive effects and pharmacokinetics of single and consecutive administration of doxazosin in patients with mild to moderate essential hypertension. J Cardiovasc Pharmacol. 1987 Jul;10(1):90–95. doi: 10.1097/00005344-198707000-00013. [DOI] [PubMed] [Google Scholar]
  24. Stokes G. S., Monaghan J. C., MacCarthy E. P., Oates H. F. Responsiveness of hypertensive subjects to prazosin. Clin Exp Pharmacol Physiol. 1980 Mar-Apr;7(2):215–217. doi: 10.1111/j.1440-1681.1980.tb00064.x. [DOI] [PubMed] [Google Scholar]
  25. Sumner D. J., Elliott H. L., Reid J. L. Analysis of the pressor dose response. Clin Pharmacol Ther. 1982 Oct;32(4):450–458. doi: 10.1038/clpt.1982.188. [DOI] [PubMed] [Google Scholar]
  26. Sumner D. J., Meredith P. A., Howie C. A., Elliott H. L. Initial blood pressure as a predictor of the response to antihypertensive therapy. Br J Clin Pharmacol. 1988 Dec;26(6):715–720. doi: 10.1111/j.1365-2125.1988.tb05310.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Vincent J., Elliott H. L., Meredith P. A., Reid J. L. Doxazosin, an alpha 1-adrenoceptor antagonist: pharmacokinetics and concentration-effect relationships in man. Br J Clin Pharmacol. 1983 Jun;15(6):719–725. doi: 10.1111/j.1365-2125.1983.tb01556.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from British Journal of Clinical Pharmacology are provided here courtesy of British Pharmacological Society

RESOURCES