Section 4 Pharmacodynamics

A basic understanding of the interaction between drugs and receptors underlies much of what is covered in the examinations. 

A ligand is a chemical messenger able to bind to a receptor. May be endogenous or exogenous (drugs). 

A receptor is a component of a cell that interacts selectively with a compound to initiate the biochemical change or cascade that produces the effects of the compound  

The rate of a reaction is proportional to the concentration of the reacting components. 

At equilibrium, the rates of the forward and back reactions will be the same and the equation can be rearranged 

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Some specific thio-derivatives of thiazoles have been synthesized for pharmacodynamic, pesticidal, or rubber industry studies they are shown in Tables VII-13 and VII-14 described in Section III. Their chemistry has... 

Sporadic use (e.g., for the induction of sleep after a psychostimulant binge) does not require specific detoxification. Sustained use can be treated as described in the previous sections on detoxification from therapeutic or high dosages but with added caution. In mixed opioid and benzodiazepine abuse, the patient should be stabilized with methadone (some clinicians use other oral preparations of opioids) and a benzodiazepine. Buprenorphine should not be administered with benzodiazepines, because a pharmacodynamic interaction is possible (Ibrahim et al. 2000 Kilicarslan and Sellers 2000) and fatalities have been reported with the combination (Reynaud et al. 1998). Sedative-hypnotic withdrawal is the more medically serious procedure, and we usually... 

What are called physiologically based pharmacokinetic (PBPK) and pharmacodynamic (PBPD) models are more mechanistically complex and often include more compartments, more parameters, and more detailed expressions of rates and fluxes and contain more mechanistic representation. This type of model is reviewed in more detail in Section 22.5. Here, we merely classify such models and note several characteristics. PBPK models have more parameters, are more mechanistic, can exploit a wider range of data, often represent the whole body, and can be used both to describe and interpolate as well as to predict and extrapolate. Complexity of such models ranges from moderate to high. They typically contain 10 or more compartments, and can range to hundreds. The increase in the number of flux relationships between compartments and the related parameters is often more than proportional to compartment count. 

The relevance of lipophilicity in pharmacodynamics is due to the fact that inter-and intramolecular interactions governing lipophiUcity (Sections 12.1.1.2 and 12.1.1.3) are of the same nature as those that govern drug recognition and binding to biological sites of action [3, 4, 15]. 

Figure 3 Rodent pharmacodynamic effects versus CbjU for 6. Dashed lines represent a twofold separation from the in vitro functional assay EC50 (122 nM, dashed arrow). mSLA, mouse spontaneous locomotor activity mPPI, mouse prepulse inhibition DRC, dose-response curve SD, single dose. (See Color Plate 4.3 in the Color Plate Section.)...

The ICH S7A guidance states that "supplemental" studies are meant to evaluate potential adverse pharmacodynamic effects on organ systems functions that are not acutely essential for the maintenance of human life and not addressed by the "core battery" or repeated dose toxicity studies when there is a cause for concern.25 Examples of physiological functions that fall into that category include, but are not limited to, the renal/urinary, immune, GI, endocrine and autonomic nervous systems. This section focuses on the renal and GI systems based on their potential impact on the clinical development program. 

In previous sections, we discussed pharmacokinetics and pharmacodynamics. Remember, these are simply fancy medical terms for what the body does to a medication and what a medication does to the body. These twin pillars of pharmacology form the basis for understanding and being able to predict drug interactions. 

Pharmacodynamic (PD) models are used to describe the relationship between drug concentration and drug effect. An overview of various PD models can be found in the literature [21]. The essential elements will be treated in the following sections. 

Pharmacodynamics. Although this chapter concentrates on clinical pharmacokinetics, it would be wrong to omit mention of pharmacod)mamic interactions in a section on drug interactions. It is difficult to generalise, but drugs with marked pharmacological effects, particularly on the cardiovascular system and CNS are potentially subject to clinically important pharmacod)mamic interactions. 

For FTIH trials, all applications should include a summary of projected free plasma concentrations of the new active substance (NAS) in humans and a brief description of any pharmacokinetic modelling programs used to generate the estimates. A comparison with the concentrations obtained in the nonclinical toxicity studies and projected safety margins should be given. In the same section, an estimate of the extent of the intended pharmacological or pharmacodynamic response at the expected plasma concentrations should be included, with a list of the assumptions used in deriving that estimate. 

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

This section deals with the question of whether there are quantitatively detectable and interpretable correlations between the dose of an administered drug, or the concentration of a drug and its metabolites measured in the blood or plasma (blood or plasma level), and the therapeutic action or side effects observed. Investigations relating to questions of this type are called PK PD (pharmacokinetic pharmacodynamic) studies. The PK PD analysis is a bidirectional approach pharmacokinetics represent what the body does with a drug, and pharmacodynamics describes what a drug does to the body. The PK PD analyses are key elements of early drug development, and PK PD trials are able to answer specific disease-related efficacy and safety questions. 

The CYP450 enzymes and the pharmacokinetic actions they represent must be contrasted with the pharmacodynamic actions of antidepressants, which were discussed in the previous section on the mechanism of action of antidepressants. Although... 

In this section several articles pertaining to pharmacokinetic/pharma-codynamic considerations in controlled release delivery systems design will be presented. These articles tend to indicate whether pharmacokinetics alone or pharmacokinetics and pharmacodynamics are needed to design specific controlled release delivery systems. 

Compared to polyclonal antibodies, mAbs display molecular homogeneity and significantly higher specificity leading to increased in-vivo activity. For example, 100-170 mg serum containing polyclonal antibodies against the tetanus toxin are necessary to achieve the same effect as 0.7 mg of a respective mAb. This section will provide an overview on therapeutic antibodies which have either been approved or are in clinical development, and will classify them according to different pharmacodynamically relevant properties. 

Three different pharmacodynamic principles of action can be distinguished for mAbs, comprising lysis or apoptotic activity, coating activity, and inactivating activity (see Section 3.5.2), depending on the type of antigen and the antigen-antibody interaction. 

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. 

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