Pharmacodynamic processes

The attraction of lipophilicity in medicinal chemistry is mainly due to Corwin Hansch s work and thus it is traditionally related to pharmacodynamic processes. However, following the evolution of the drug discovery process, lipophilicity is today one of the most relevant properties also in absorption, distribuhon, metabolism, excretion and toxicity (ADMET) prediction, and thus in drug profiling (details are given in Chapter 2). 

Within the medical community it has been acknowledged that elderly patients often respond to drug therapy differently from their younger counterparts. Aside from alteration of various pharmacokinetic and pharmacodynamic processes, elderly patients tend to suffer from a number of chronic conditions and, thus, have more complex dosage regimens. Additionally, a variety of physical limitations prevalent among the elderly may hinder their ability to self-administer medication. 

Apart from patient-specific parameters, external factors - most importantly the concomitant uptake of certain other chemicals present in diet, environment and especially other drugs - influence drug actions. Possible effects are manifold and can affect all stages of pharmacokinetic and pharmacodynamic processes in the body. Also direct interaction and inactivation of concomitantly administered substances are possible. Drug-drug interactions via modulation of metabolism present a very hot topic in pharmaceutical research and drug design. 

Dokoumetzidis, A., Contribution on the study of heterogeneity of biophar-maceutical, pharmacokinetic and pharmacodynamic processes, Ph.D. thesis, National University of Athens, 2002. 

Drug action refers to all the pharmacokinetic and pharmacodynamic processes involved in producing a drug effect on the disease. The effect ot the drug is assumed to influence the disease status. Pharmacokinetic and pharmacodynamic drug properties are the major attributes determining drug action and its... 

The importance of genetic factors in pharmacokinetic and pharmacodynamic processes is becoming more widely recognized, particularly in... 

Drug disposition and metabolism are of essential significance in pharmaceutical research because of the interdependence of pharmacokinetic and pharmacodynamic processes. Limited intestinal absorption, inadequate distribution, fast metabolism, and toxic metabolites are some of the causes of failure of drug candidates during development. To reduce the rate of attrition resulting from such pharmacokinetic defects, disposition and metabolic studies should be initiated as early as possible in the screening of lead candidates. 

Figure 1.1 A schematic presentation of the fate of a drug in the body following oral administration. Pharmacokinetic processes are in blue, with the components of oral bioavailability in dark blue. Pharmacodynamic processes are in green, with the clinical effects in dark green.

In drug research and development, metabolism is of pivotal importance due to the interconnectedness between pharmacokinetic and pharmacodynamic processes. Very early in the testing of a newly isolated or synthesized promising compound metabolic studies must be initiated to identify the metabolites, the pathways by which they are formed and the possible intermediates. Based on these findings, the metabolites can be synthesized and tested for their own pharmacological and toxicological effects. 

The ability to quantify the benetidal and toxic effects of chemicals in the skin is important for many reasons. The skin is a dynamic and complex organ that is directly exposed to the enviromnent. It serves several important protective functions and is on the front hne in the battle to keep hostile environments from dismpting the essential internal balance. This characteristic virlnerability to the local enviromnent can be exploited pharmacologically but can cause concern when deleterious effects are considered. In both cases, it is the concentration of a compound or chemical inside the skin that interferes with normal skin stmcture and function in beneficial or deleterious ways. The effects produced by exogenoirs compounds are dependent on both the local concentration at the site of action in the skin and the potency of the compound. These components of the effect arc classically separated into pharmacokinetic and pharmacodynamic processes. The pharmacokinetic process in the skin relates the external concentration on the skin to the target tissue dose or cellular dose in the skin. The pharmacodynamic process involves understanding the rela-... 

We have developed a preliminary kinetic model of the interleukin 1 (IL-1)-stimulated intracellular signaling pathway in epidermal keratinocytes as an initial effort toward the pharmacodynamic modeling of the skin. On exposure to external stimuli, such as chemical irritants, the skin secretes various cytokines and chemo-kines and evokes a cascade of events in the subcutaneous tissue. Therefore, the pharmacodynamic process of the skin primarily involves the responses of the skin cells to these endogenous proteins. Among them, one of central importance is IL-1, a proinflammatory cytokine that mediates the host defense activities of the skin. The model captures the series of biochemical events initiated from IL-1 a binding to IL-1 receptor (type I) on the cell surface that activates the transcriptional factor nuclear factor (NFk-B) and leads to production of a responsive protein, IL-6, as illustrated in Figure 6.6. 

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