Potency, pharmacodynamics

Unlike mass transport across membranes, which relates to chemical structure in predictable ways, the potencies of drugs as seen in pharmacological, pharmacodynamic, or other tests are highly structurally specific within a class of drugs and are without commonality across classes. A drug s activity involves a complex merging of these separate structural influences, with bioavailability always one of the concerns. Such concern is minimal when a truly superficial effect is involved, however. For example, the most potent antiseptic as measured in the test tube is likely to have... 

J. Patel, M. J. Katovich, K. B. Sloan, S. H. Curry, R. J. Prankerd, A Prodrug Approach to Increasing the Oral Potency of a Phenolic Drug. Part 2. Pharmacodynamics and Preliminary Bioavailabihty of an Orally Administered O-(Imidomethyl) Derivative of 17/3-Estradiol , J. Pharm. Sci. 1995, 84, 174- 178. 

One frequently encounters the case where the equilibrium dissociation constant (iQ, see above) is defined by microconstants with Tast rates on and off the receptor. However, any change in potency in a chemical series (affinity) must represent an increase in the on (k+i) rate or a decrease in the off rate (fe i). Occasionally, either by accident or design, the off rate is altered dramatically enough to redefine the receptor kinetics of the compound such that the rates influence the actual pharmacodynam-... 

Extensive medicinal chemistry optimization of potency, selectivity pharmacokinetic, and pharmacodynamic properties finally led to potent, selective, and orally bioavailable GSK-221149A, which is synthesized as shown on Scheme 17 [35, 37, 38]. Peptidic oxytocin receptor antagonists are currently used to treat preterm labor, the main reason for infant death. The peptide derivatives by their nature are not orally bioavailable but must be administered i.v. Surprisingly, the peptide derivatives are less potent and less selective against several related receptors than GSK-221149A with half the molecular weight [39]. 

At the beginning of the project, it is often difficult to have a precise idea of the projected therapeutic dose. Projects usually start with an estimated average potency of 1 mg/kg, once daily dose as an optimal approach. When initial pharmacokinetic/ pharmacodynamic (PK/PD) data becomes available one can better refine the TCP. Table 3.1 gives some guidelines on how to adjust the solubility requirement depending on the therapeutic dose and compound permeability. 

A number of limitations related to PK/PD modeling are also a reality in situations where predictability of the animal model to man is questionable, where the time course of the pharmacodynamic effect cannot be assessed for drug candidates and when, for example, no accessible/ valid pharmacodynamic endpoint for PK/PD is available. The relevance of the animal model for human could be addressed to some extent at least by measuring relative potency in animal versus man in vitro. In situations where no relevant PD endpoint is available (e.g., for CNS efficacy models), effects at target level (i.e., enzyme inhibition, receptor occupancy) might represent a valuable alternative. In this context however the level and duration of target effect required for clinical efficacy requires careful considerations. 

In pharmacodynamic interactions, the pharmacological effect of a drug is changed by the action of a second drug at a common receptor or bioactive site. For example, low-potency antipsychotics and tertiary amine TCAs have anticholinergic, antihistaminic, a-adrenergic antagonist, and quinidine-Kke effects. Therefore, concurrent administration of chlorpromazine and imipramine results in additive sedation, constipation, postural hypotension, and depression of cardiac conduction. 

In conclusion, the investigation of peptidic and non-peptidic tool compounds for the 5 receptor have demonstrated the potential use of 5 agonists and antagonists for a variety of clinical applications, especially for the treatment of pain. Full exploitation of this potential will however only be possible with ideal non-peptidic compounds having high potency, selectivity and, above all, optimal drug metabolism and pharmacodynamic characteristics. 

Due to its high selectivity and potency at H3 receptors (/ )-a-methylhistamine (12) is nowadays used as the standard agonist in pharmacological assays related to this receptor. With regard to its pharmacodynamic properties, which were substantiated in preclinical studies [40], (R)-a-methylhistamine (12) meets all criteria of a potential drug substance. However, in contrast to its pharmacodynamic potential (ft)-a-methyl-histamine (12) suffers from its pharmacokinetic drawbacks which limit its use in both pharmacological and conceivable clinical studies. 

Ideal drug candidate for controlled release delivery systems. From a pharmacokinetic and pharmacodynamic perspective, the ideal drug candidate for controlled release delivery systems would have high potency and... 

Although the mechanisms of action for antisense oligodeoxynucleotide and 2 -MOE partially modified ASOs are the same, the 2 -MOE modifications provide increased affinity to the target mRNA while maintaining favorable RNase H activity and, therefore, enhanced potency and specificity over the first-generation ASOs [28, 40, 44, 45]. The pharmacodynamic section of this chapter will, once again, focus on 2 -MOE partially modified ASOs. 

As drug development became of greater importance during the first half of the twentieth century, a more quantitative and analytical foundation was needed to assess drug potency per se as well as comparative drug potency. The standardization and quantification of technique and experimental design, and the rigorous application of statistical analysis, have provided pharmacodynamics with a necessary solid base. 

Although the pharmaceutical industry strives to develop drags with appropriate pharmacokinetic and pharmacodynamic properties to ensure effective drag delivery, it is often difficult to obtain effective potency, low toxicity and acceptable bioavailability. In such cases the optimization of the dosage form becomes particularly important. Methods to improve delivery by manipulating the dosage form are described below and in the relevant chapters. 

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