The pharmacodynamic phase

Pharmacodynamics is concerned with the result of the interaction of drug and body at its site of action, that is, what the drug does to the body. It is now known that a drug is most effective when its shape and electron distribution, that is, its stereoelectronic structure, is complementary to the steroelectronic structure of the active site or receptor. 

The role of the medicinal chemist is to design and synthesize a drug structure that has the maximum beneficial effects with a minimum of toxic side effects. This design has to take into account the stereoelectronic characteristics of the target active or receptor site and also such factors as the drug s stability in situ, 

The R and S isomers of the antimalarial chloroquine have equal potencies. 

The E isomer of diethylstilbesterol, an estrogen is only 7% as active as the Z isomer 

Thalidomide the S isomer is a sedative and has teratogenic side effects. The R isomer is also a sedative but has no teratogenic activity. 

---

Among chemical-physics properties, lipophilicity is certainly a key parameter to understand and predict absorption, distribution, metabolism, excretion, and toxicity (ADMET) of NCE furthermore, it contributes to model ligand-target interactions underlying the pharmacodynamic phase [15],... 

Optimization of the lead compound for the pharmacodynamic phase (section 3.4)... 

When using QSAR calculations to optimize a drug for the pharmacodynamic phase, it is important to use relevant biological activities. If in vivo activities are used, the bioactivities will be influenced by pharmacokinetic and pharmaceutical factors. In order for QSAR calculations to reflect the pharmacodynamic phase, the bioactivities should be based on in vitro data — optimally, receptor binding studies. 

QSAR studies are not restricted to the optimization of biological activity at the pharmacodynamic phase. Since toxicity also arises from drug-receptor interactions, the QSAR... 

Once the lead dmg molecule has been optimized for the pharmacodynamic phase, it must next be optimized for the pharmacokinetic and pharmaceutical phases. If a dmg molecule cannot withstand the trip from the gut to the receptor microenvironment, it makes no difference whether the drug actually binds to the receptor. 

Figure 3.11 Failure of drug molecules. Many drugs that are successful in the pharmacodynamic phase ultimately fail to become useful drugs. This pie-chart presents the reasons for failure at this stage of the development process. Toxicity is an important cause of failure.

For definitions see Section 2.7. The factors affecting the pharmacokinetic phase are ADME. The factor affecting the pharmacodynamic phase is the stereoelectronic structure of the drug molecule. 

Shape and stereochemical. These properties affect the pharmacodynamic phase of drug action and influence the drug s interaction with its target receptor. Shape and stereochemical properties describe the structural arrangement of the drug molecule s constituent atoms and influence the molecule s final approach toward the target receptor. 

Electronic. Electronic properties also affect the pharmacodynamic phase of drug action. The electronic properties of a molecule are governed by the... 

In both pharmacokinetic and pharmacodynamic considerations, an important emphasis concerns the rate at which events occur and the rate at which circumstances change. The pharmacokinetic phase covers the relationship between drug input and the concentration achieved over time. The pharmacodynamic phase covers the relationship between concentration and the therapeutic effect over time (toxicodynamics is concerned with the relationship between concentration and adverse effects over time). 

In the foregoing sections, pharmacon metabolism has been considered in relation to the pharmacodynamic, especially toxic aspects of action. Drug distribution also plays a role in the pharmacodynamic phase of drug action. Modulation of drug distribution, for instance, exclusion of penetration of particular barriers in the organism (e.g. the blood-brain barrier), or preferential bioactivation or bioinactivation in particular tissues, can modulate the spectrum of action of compounds and possibly exclude particular undesired effects. 

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. 

Dmg activity is divided into the pharmaceutic phase, pharmacokinetic phase and the pharmacodynamic phase. The pharmaceutic phase is the disintegration and dissolution of a dmg taken orally. The pharmacokinetic phase is the mechanism used to absorb, distribute, and eliminate a dmg. The pharmacodynamics is a dmg s effect on the physiology of the ceU and the mechanism that causes the pharmaceutical response. 

---