Pharmacodynamics adverse reactions

The overall objective of clinical trials is to establish a drug therapy that is safe and effective in humans, to the extent that the risk-benefit relationship is acceptable. The ICH process has developed an internationally accepted definition of a clinical trial as Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of one or more investigational medicinal product(s), and/or to identify any adverse reactions to one or more investigational medicinal product(s) and/or to study absorption, distribution, metabolism and excretion of one or more investigational medicinal product(s) with the object of ascertaining its (their) safety and/or efficacy. ... 

Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of an investigational product, and/or to identify any adverse reactions to an investigational prodnct, and/or to study absorption, distribution, metabolism, and excretion of an investigational product with the object of ascertaining its safety and/or efficacy. 

Adverse drug reactions and drug interactions W McCaughey Introduction Definitions Adverse reactions Drug interactions Pharmacokinetic Pharmacodynamic Clinically important interactions INTRODUCTION... 

Consider the difference in response to drugs between older and younger people. Treatment should reflect biological age (rather than chronological). Pharmacokinetics, pharmacodynamics, tolerability, adverse reactions, economy and patient choice will all influence therapy chosen. Most commonly, car-bamazepine or sodium valproate are chosen for older people as their effects in older people are well documented. Both show a favourable balance of safety, efficacy and economy. Phenytoin is less preferable because of drug interactions, adverse effects and potential for toxicity (zero order kinetics). 

The physician may consciously use all of the factors listed above in therapeutic practice. But it is still not enough that patients get better, it is essential to know why they do so. This is because potent drugs should only be given if their pharmacodynamic effects are needed many adverse reactions have been shown to be due to drugs that are not needed, including some severe enough to cause hospital admission. 

Although the physicochemical features, pharmacokinetics, and pharmacodynamics of individual NSAIDs differ, it is not known to what extent these differences are significant in the benefit-to-harm balance in the individual patient (8). Certainly they influence the adverse reactions and the general pattern of action of a particular subgroup of NSAIDs or a specific compound within a class, but this still provides no reliable prediction of what the individual patient will experience. 

The investigation of tolerability must cover a number of doses thought to be in the range required for therapeutic benefit. The relevance of these data can only be interpreted when they are related to plasma concentrations and, when appropriate, measurements of pharmacodynamic activity. Adverse reactions occurring at ten times the therapeutic dose may not pose a problem conversely, the absence of adverse reactions at one-tenth the therapeutic dose is of little relevance and, if misinterpreted, may give unfounded confidence. This may seem obvious but has important implications for study design that are frequendy ignored (see Section 4.7). 

Differences seen across regions and nations, both in reports of efficacy and incidence of adverse reactions, are much greater than can be accounted for by ethnic variations of pharmacokinetics and pharmacodynamics. Other objective differences are now discussed. 

The case reports detailed above suggest that some patients may develop a pharmacodynamic interaction. Concurrent use of lithium and olanzapine need not be avoided but be aware that there is some risk of developing adverse reactions to the combination. The presence of other serotonergic drugs (e.g. antidepressants such as SSRIs) or dopamine antagonists (e.g. antipsychotics such as haloperidol) is likely to increase the risk of an interaction. 

Drug interactions occur when the presence of one drug affects the activity of another. This may occur either because both drugs act through the same pathway(s) - these are called pharmacodynamic interactions - or through effects on absorption, distribution, metabolism or excretion - pharmacokinetic interactions. The result may be an adverse reaction or modified effectiveness. Some specific examples are given below ... 

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