INDEX pharmacological effects

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. 

It relates the pharmacologically effective dose to the toxic or lethal dose (Fig. 2.8). The therapeutic index gives some indication of the safety of the compound in use, as the larger the ratio, the greater the relative safety. However, as already indicated, simple comparison of parameters derived from the dose-response curve such as the LD50 and TD50 may be... 

FIGURE 1.11 a) The concept of antagonism or potentiation of pharmacologic effects, b) Drugs with higher therapeutic indices are safer. TI = therapeutic index, LD50 = median lethal dose, ED50 = median effective dose. 

Drugs with a narrow therapeutic index are candidates for therapeutic drug monitoring, as in the case of the anticoagulant warfarin. The adverse effect of warfarin, namely excessive anticoagulation that can result in fatal hemorrhaging, is an extension of its pharmacological effect (inhibition of the synthesis of... 

Nephrotoxicity is intrinsic to the pharmacological effect of certain anticancer drugs. Because anti-neoplastic drugs have a narrow therapeutic index, the amount of drug required to significantly reduce tumor burden usually induces significant nephrotoxicity. Furthermore, the dosage used in clinical trials often represents the maximum tolerated doses determined dur-... 

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). 

Thioxanthenes differ structurally from phenothiazine in that the nitrogen atom of the central ring of the tricyclic system is replaced by carbon, which is joined to a side chain with a double bond. Their pharmacological action is similar to the corresponding phenothiazine analogues. They have the exact mechanism of action and an analogons effect on the CNS. Drugs of this series differ from one another by quantitative indexes. 

Venlafaxine is converted by CYP 2D6 to ODV, which is subsequently cleared by CYP 3A3/4 ( 501). ODV has virtually the same in vitro pharmacology as venlafaxine. Thus, the total of venlafaxine plus ODV is believed to be the relevant concentration determining clinical effect ( 137). Theoretically, venlafaxine should be relatively impervious to even substantial CYP 2D6 inhibition because ODV levels would decrease proportionate to the increase in venlafaxine levels such that the total level would remain the same. In contrast, the inhibition of CYP 3A3/4 would be potentially more clinically relevant because it should decrease ODV clearance and thus increase total levels. Nevertheless, such an interaction would not be expected to do more than increase the usual dose-dependent adverse effects of venlafaxine because of its wide therapeutic index. 

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