Pharmacological response indirect

More complex integrated PK/PD models are necessary to link and account for a possible temporal dissociation between the plasma concentration and the observed effect. Four basic attributes may be used to characterize PK/PD models First, the link between measured concentration and the pharmacological response mechanism that mediates the observed effect (direct versus indirect link) second, the response mechanism that mediates the observed effect (direct versus indirect response) third, the information used to establish the link between measured concentration and observed effect (hard versus soft link) and, fourth, the time dependency of the involved PD parameters (time variant versus time invariant) (Danhof et al., 1993 Steimer et al., 1993 Aarons, 1999 Lees et al., 2004). The expanded and early use of PK/PD modeling in drug discovery and development is highly beneficial for increasing the success rate of drug discovery and development and will most likely improve the current state of applied therapeutics. 

Opioids produce a large variety of pharmacological responses by interacting with multiple opioid receptors. The indirect evidence for the presence of these multiple receptors is as follows ... 

When a lag time of E (t) is observed with respect to the c (t) time course, the use of a combined pharmacokinetic-dynamic model, the indirect-link model, is needed to relate the drug concentration c (t) to the receptor site drug concentration y (t) (which cannot be measured directly) and the y (t) to the pharmacological response E (t).1... 

In contrast to the direct pharmacological responses discussed above, some pharmacological responses are indirect and represent the net result of several... 

Sharma A, Jusko WJ. 1997. Characterization of four basic models of indirect pharmacological responses . J. Pharmacokinet. Biopharm. 24 611-635. 

N. L. Dyneka, V. Garg, and W. J. Jusko, Comparison of four basic models of indirect pharmacologic responses. J Pharmacokin Biopharm 21 457-478 (1993). 

For at least the last 30 years several types of PD models (6, 8-17) have been coupled to PK models to give a full description from input (i.e., dose) to effect (i.e., observed pharmacological response). Several classifications have arisen to describe the PD aspect empirical, direct, and indirect. This chapter focuses on empirical and direct models, which are sometimes used synonymously in pharmacokinetics/phar-macodynamics. Although empirical models have parameters that tend not to be based on mechanistic underpinnings, direct models have some mechanistic reahty, as well as empirical attributes (18). 

It is emphasized that drug activity is observed through a translation process controlled by cells. The aim of pharmacology is to derive system-independent constants characterizing drug activity from the indirect product of cellular response. 

Mathematical models are the link between what is observed experimentally and what is thought to occur at the molecular level. In physical sciences, such as chemistry, there is a direct correspondence between the experimental observation and the molecular world (i.e., a nuclear magnetic resonance spectrum directly reflects the interaction of hydrogen atoms on a molecule). In pharmacology the observations are much more indirect, leaving a much wider gap between the physical chemistry involved in drug-receptor interaction and what the cell does in response to those interactions (through the cellular veil ). Hence, models become uniquely important. 

Asthma is the most serious of the atopic diseases and has become epidemic, affecting more than 155 million individuals in the developed world. It is the most common chronic childhood disease in developed nations [1], and carries a very substantial direct and indirect economic cost worldwide [2]. A number of pharmacological treatments have been developed for asthma. These treatments have a modest efficacy overall, due in part to widely variable individual responses to asthma drugs. Because of such variability, it is clear that some of the substantial resources expended on asthma medication, estimated to exceed U.S. 3 billion per annum in the U.S. alone [3], would be better spent targeting those patients who... 

Pharmacological studies primarily have contributed to the idea that 5-HT has an inhibitory effect on feeding behavior. Drugs that either directly or indirectly activate postsynaptic 5-HT receptors decrease food consumption whereas agents that inhibit serotonergic transmission increase food intake. Precisely how this occurs is controversial, with claims that 5-HT governs the selection of macronutrients in the diet, or influences responses to the taste qualities of food, or modulates gastric activity to... 

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