uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Pharmacodynamic modeling of cardiovascular effects of Σb-antagonists and moxonidine: Special emphasis on tolerance and rebound effects
Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
1999 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Pharmacodynamic (PD) modeling was used to characterize and quantify the short- and long-term changes in cardiovascular effects following treatment with β-antagonists or imidazoline receptor agonist moxonidine, in spontaneous hypertensive rats and patients with congestive heart failure, respectively. The complex cardiovascular system is regulated by several feedback mechanisms with different time domains and gains. Both tolerance development and rebound effect are not unusual events during and after withdrawal of cardiovascular drugs. Because of complex or unknown mechanisms of action, empirical PD models are used.

Acute concentration-effect relationships of l-propranolol and metoprolol were characterized by an Emax and a linear component. The two components were interpreted as a specific β-antagonist effect and a membrane-stabilizing effect at lower and higher plasma concentrations, respectively. Available empirical tolerance models were studied with respect to their interchangability and predictive performance. No reliable mechanistic information can be deduced from a model based on the fit to effect data alone without additional knowledge about physiological mechanism(s) behind the pharmacological effect. To improve PD models, knowledge of the physiology and the mechanism of drug action need to be incorporated.

Chronic administration of l-propranolol resulted in a rebound effect after drug cessation. A mechanism-based model was developed which included norepinephrine, competitive receptor binding, receptor density and sensitization of the transduction system. This model was adequate even when different dosing regimens and experimental conditions were administered. No rebound effect, but rather a positive effect on heart rate and circadian rhythm was observed.

Effects of moxonidine on norepinephrine, blood pressure, and heart rate were quantified by both the common empirical parallel analysis, where the drug concentration is related to the PD effects, and a sequential analysis where one PD effect is driving another. Both disease progression and circadian variation were included in the models.

This thesis shows that mechanism-based modeling is feasible and can increase knowledge about the underlying biological processes involved in the pharmacological effect of the investigated drug. When the mechanism-based models can quantitatively describe the PD phenomena observed, extrapolations can be more reliable and the adequacy of the model can often be assessed from independent information on pharmacological and physiological information. For these cardiovascular agents, mechanism-based modeling has included not only a mimicking of the receptor event, but also circadian rhythms, disease progression or improvement, tolerance development and rebound effect.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 1999. , 58 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 0282-7484 ; 211
Keyword [en]
Pharmacy
Keyword [sv]
FARMACI
National Category
Pharmaceutical Sciences
Research subject
Biopharmaceutics
Identifiers
URN: urn:nbn:se:uu:diva-997ISBN: 91-554-4541-1 (print)OAI: oai:DiVA.org:uu-997DiVA: diva2:173337
Public defence
1999-10-09, lecture hall B42, Biomedical Center, Uppsala, Uppsala, 10:15
Available from: 1999-09-18 Created: 1999-09-18Bibliographically approved

Open Access in DiVA

No full text
Buy this publication >>

By organisation
Department of Pharmacy
Pharmaceutical Sciences

Search outside of DiVA

GoogleGoogle Scholar

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 399 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf