In pharmacodynamics

Ciraulo DA, Sands BE, Shader RI Critical review of liability for benzodiazepine abuse among alcoholics. Am J Psychiatry 145 1501-1506, 1988b Ciraulo DA, Barnhill JG, Ciraulo AM, et al Parental alcoholism as a risk factor in benzodiazepine abuse a pilot smdy. Am J Psychiatry 146 1333-1335, 1989 Ciraulo DA, Antal EJ, Smith RB, et al The relationship of alprazolam dose to steady-state plasma concentrations. J Clin Psychopharmacol 10 27—32, 1990 Ciraulo DA, Sarid-Segal O, Knapp C, et al Liability to alprazolam abuse in daughters of alcoholics. Am J Psychiatry 153 956-958, 1996 Ciraulo DA, Barnhill JG, Ciraulo AM, et al Alterations in pharmacodynamics of anxiolytics in abstinent alcoholic men subjective responses, abuse liability, and electroencephalographic effects of alprazolam, diazepam, and buspirone. J Clin Pharmacol 37 64-73, 1997... 

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]. 

The Renwick work can be applied in the following way. Suppose it were possible in a specific case to develop a reasonably thorough picture of the comparative pharmacodynamic characteristics of a compound in humans and rats, and that the work revealed that no difference in pharmacodynamic response (at comparable doses) was expected. We would then turn to Table 9.1 and see that the typical pharmacodynamic difference between humans and animals (the default) puts humans at 2.5 times greater risk than animals. But now in our new case, the difference is seen to be a factor of 1.0 (no difference). We should be allowed to reduce the overall UF of 10 to a factor of 4.0, which is the default for pharmacokinetic differences (which we have not studied). Data substitute for defaults. Use of the Renwick defaults allows us to make some headway without having to take on... 

Inter-individual variability in pharmacodynamics. Although over the last 30 years it has been the common view that the opposite holds true, Levy demonstrated that PD variability in humans is extensive, reproducible and usually more pronounced than PK variability [53,54]. 

Reanalysis of the data of Hattis et al. (1987) showed that the variation between individuals for the elimination half-life was quite small (Schaddelee 1997, as cited in Vermeire et al. 1999, 2001). Defining the interindividual factor as the ratio of the P50 (50th percentile) and P05 (5th percentile) resulted in a factor of 1.4. It was emphasized that although it appeared from this analysis that a 10-fold factor would be sufficient for pharmacokinetic variation, the real median to sensitive human variability is underestimated because variation also exists in pharmacodynamics and only data of healthy volunteers were available. 

Alvan G, Paintaud G, Wakelkamp M. The efficiency concept in pharmacodynamics. Clin Pharmacokinet 1999 36 375-89. 

Finally, developmental differences in pharmacodynamics can be observed in the absence of age-associated changes in the dose versus plasma concentration relationship. Marshall and Kearns demonstrated developmental differences in the pharmacodynamics of cyclosporin. In this study, the IC50 for interleukin-2 (IL-2) expression observed in peripheral blood monocytes obtained from infants less than 12 months of age and exposed in vitro to cyclosporin was approximately 50% of the value observed for older children. In this particular example, the pharmacodynamic differences appeared not to be the consequence of developmental dependence on pharmacokinetics but rather, in the true drug-receptor interaction. 

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. 

Members of this class of antidepressants are likely to be involved in pharmacodynamic and CYP-mediated pharmacokinetic drug-drug interactions. The latter are of concern because of the narrow therapeutic index of TCAs. 

Changes in pharmacodynamics further complicate the pharmacology of many drugs in the neonate and infant. The blood-brain barrier is poorly developed, allowing more rapid transfer of drugs into the central nervous system (CNS). However, the response to higher brain concentrations may be tempered by an inadequate response due to lack of receptor maturation. 

The varied and complex mechanisms involved can be broadly classified as pharmacokinetic interactions or pharmacodynamic interactions. In pharmacokinetic interactions, drugs interfere with and may alter the absorption, distribution, biotransformation, or excretion of other drugs. In pharmacodynamic interactions, which have been discussed in Chapter 2, drugs modify the intended and expected actions of other drugs. Before elaborating on the pharmacokinetic interactions, some terms will be defined. 

Sun.Y.N. and W.J. Jusko. 1998. Transit compartments versus gamma distribution function to model signal transduction processes in pharmacodynamics. 

One feature commonly experienced in pharmacodynamics but much less in pharmacokinetics is saturability, giving rise to nonlinearity. Typically in pharmacodynamics, on raising the concentration of dmg, the magnitude of response rises initially sharply and then more slowly on approach to the maximum effect,... 

Table 13.2 Examples of stereoselective differences in pharmacodynamics and pharmaocokinetics ...

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