Side Effects

It should be noted, however, that even though drugs are designed to be relatively specific toward their molecular substrates, and such molecular specificity or specificity for a physiological effect is often emphasized in drug promotion, it would be unrealistic to expect absolute specificity from any drug. Specificity rather means that a drug should

log [DOPAMINE]

log [DOPAMINE]

Figure A.5. A competitive antagonist shifts the dose-response curve of an agonist to the right. This experiment describes the inhibition of dopamine stimulation of [35S]GTPyS binding by (+)butaclamol, a D2 receptor antagonist. Binding of [35S]GTPyS to rat striatal membranes was measured at the indicated concentration of dopamine in the absence (O) and in the presence of increasing concentrations (1 to 1000 nM) of (+)butaclamol. On abscissa, concentration of dopamine added to the assay. On ordinate, percent of maximal effect. On inset: Schild plot, a pharmacological tool to measure whether the antagonism at receptors is truly competitive. (Courtesy of Dr Ago Rinken, Department of Organic and Bioorganic Chemistry, Tartu University.)

act on other physiological substrates at much higher concentrations than to its target receptors. There are several sources of limitations to the specificity a drug can have in its action. The fact that living organisms generally use basic biochemical mechanisms in different settings makes it inevitable that drugs in general have either a plethora of physiological effects or at least a few. For example, endogenous opioids serve as messengers in the antinociceptive circuits in the brain and spinal cord, but in the enteric nervous system they also control gastroenteral secretions and motility, and in immune system, opioids modulate the inflammatory response, affecting, for example, phagocytic activity and responses to various chemoattractant molecules. Limitations to specificity for drug targets, due to the partial overlaps in spatial conformation, increases the potential for undesirable side effects. An example can be found in the present chapter: Fig. A.3 and A.4 feature 8-OH-DPAT as a partial agonist at D2 dopamine receptors, but those familiar with experimental manipulations of serotonin know this drug as a full agonist at 5-HT1A receptors. Thus, there is a vast potential for side effects with any drug, but usually only a few of these occur frequently in most individuals.

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