Pharmacodynamics signal transduction

Perlstein, I. Stepensky, D. Krzyzanski, W. Hoffman, A. A signal transduction pharmacodynamic model of the kinetics of the parasympathomimetic activity of low-dose scopolar-mine and atropine in rats. J. Pharm. Sci. 2002, 91 (12), 2500-2510. 

Desensitization describes the rapid signal attenuation in response to stimulation of cells by receptor agonists. Changes in the coupling efficiency of receptors to signal transduction pathways and receptor internalization can account for desensitization and the development of pharmacodynamic tolerance. 

Drug-receptor interactions Dose-response relationships Molecular models of receptors and signal transduction mechanisms Biotransformation Pharmacokinetics Pharmacodynamics... 

Sun.Y.N. and W.J. Jusko. 1998. Transit compartments versus gamma distribution function to model signal transduction processes in pharmacodynamics. 

Intracellular signaling can now be visualized in peripheral blood lymphocytes with phosphospecific antibodies to MEK, ERK, p38 MAPK, STAT, JNK/ SAPK, and other signal transducers. This allows pharmacodynamic monitoring of signal transduction agonists or inhibitors (especially when coupled with ex vivo T cell activation by phorbal esters or other agents, which can be performed in whole blood) [42-46]. 

Jonker DM, Vermeij DA, Edelbroek PM, Voskuyl RA, Piotrovsky VK, Danhof M. 2003. Pharmacodynamic analysis of the interaction between tiagabine and midazolam with an allosteric model that incorporates signal transduction. Epilepsia 44 329-338. 

Signal Transduction Model The pharmacological effects of drugs may be mediated by a time-dependent signal transduction process, which involves multiple steps. Sun and Jusko proposed a signal transduction model to account for the delayed effect of pharmacodynamic responses. This model has been used to characterize the parasympathomimetic activity of scopolamine and atropine in rats. ... 

The pharmacodynamics phase corresponds to the way in which a drug binds to receptors, transporters, and channels in order to elicit a particular action from a cell (this is called signal transduction). This is referred to as the mechanism of action. While researchers attempt to determine the mechanism of action of promising compounds in order to better predict therapeutic outcomes and unexpected effects, often times the exact mechanism remains unknown, even after the drug has been approved for use. 

FIGURE 20.2 The different processes within pharmacodynamics. The biophase kinetics account for distributional kinetics between the plasma and effect site. The biosensor kinetics describe the dynamic behavior between drug and biosensing machinery. The biosignal is the first messenger in the transduction process that converts the signal to secondary messengers or the observed response. (Adapted from Ref. 19.)... 

---