Pharmacodynamics INDEX

The therapeutic efficacy of a dmg is generally measured in terms of ED q or ID q which represent the concentration of dmg which produces 50% of the maximum effect or 50% of maximum inhibition. LD q represents the concentration of dmg that produces 50% fataUties in test animals. The therapeutic index is the ratio of the ED q versus LD q. Detailed descriptions of the terminology and fundamental principles of pharmacology are available (32) (see Pharmacodynamics). 

The applicant should provide justification for using the racemate. Where the interconversion of the enantiomers in vivo is more rapid than the distribution and elimination rates, then use of the racemate is justified. In cases where there is no such interconversion or it is slow, then differential pharmacological effects and fate of the enantiomers may be apparent. Use of the racemate may also be justified if any toxicity is associated with the pharmacological action and the therapeutic index is the same for both isomers. For preclinical assessment, pharmacodynamic, pharmacokinetic (using enantiospecific analytical methods) and appropriate toxicological studies of the individual enantiomers and the racemate will be needed. Clinical studies on human pharmacodynamics and tolerance, human pharmacokinetics and pharma-cotherapeutics will be required for the racemate and for the enantiomers as appropriate. 

Pharmacodynamic tolerance, probably on the basis of down-regulation of receptors, develops more rapidly to the effects of barbiturates on mood and sedation than to the anticonvulsant and lethal action. This results in a marked decrease in therapeutic index and the ratio of LD50 and ED50 can approach 1. Furthermore, barbiturates induce P450 enzymes and thus increase their own metabolism resulting in time dependent pharmacokinetic behavior. 

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. 

Kelly HW. Establishing a therapeutic index for the inhaled corticosteroids. Part I. Pharmacokinetic/pharmacodynamic comparison of the inhaled corticosteroids. J Allergy Clin Immunol 1998 102(4 Pt 2) S36-51. 

Tabrizi-Fard, M.A. and H.L. Fung. 1998. Effects of nitro-L-arginine on blood pressure and cardiac index in anesthetized rats a pharmacokinetic-pharmacodynamic analysis. Pharm. Res. 15 1063-1068. 

While it is often held that genetic polymorphisms are most important when they affect drugs that have a narrow therapeutic index for which dangerous toxicity may result or perilous lack of effect may ensue/ this need not be the case. For example/ CYP2D6 converts codeine/ likely the most widely prescribed opiate in the world and the mainstay of pain control for a large number of patientS/ to its active metabolite morphine. ThuS/ patients who have deficient CYP2D6 are unable to make morphine/ and pharmacodynamic studies have shown that this results in decreased pain... 

In a comprehensive comparison of the pharmacokinetics and pharmacodynamics of dextran and etherified starch (8), the effects of etherified starch on the cardiovascnlar system have been delineated. The mean arterial pressnre, central venous pressure, wedge pressure, cardiac index, left ventricular stroke work index, and stroke output aU rise, whereas the pulmonary vascular resistance falls. Oxygen availability to the tissues is improved. The effects of etherified starch on blood viscosity and erythrocjde aggregation, in particular, are more pronounced than with dextran. 

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