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Paying Attention to Pharmacokinetic and Pharmacodynamic Mechanisms to Progress in the Area of Anticholinergic Use in Geriatric Patients

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Many naturalistic studies agree that adverse drug reactions (ADRs), particularly cognitive deficits, frequently occur when medications with anticholinergic activity are used in geriatric patients. However, the studies disagree on which anticholinergic drugs may have clinical relevance. The three most important methods to establish clinically relevant anticholinergic activity are: 1) the drug's affinity for muscarinic receptors, demonstrated by in vitro studies and a profile compatible with antagonist properties; 2) serum anticholinergic activity measured by radioreceptor assay; and 3) the presence of typical antimuscarinic ADRs, such as dry mouth and constipation, in patient studies or clinical trials. More recently, brain imaging of muscarinic receptors and scales for quantifying antimuscarinic activity were developed.

A comprehensive approach can be crafted only by paying attention to the pharmacodynamic and pharmacokinetic mechanisms of these drugs. ADR studies on drugs with anticholinergic activity should not only consider central muscarinic receptor blockade, but also peripheral receptor blockade. The ability to cross the blood-brain barrier is important in the drug's ADR profile. Patient personal characteristics, drug-drug interactions (DDIs) and probably genetic variations may contribute to increased ADR risk through pharmacokinetic and/or pharmacodynamic mechanisms. Sophisticated clinical designs and the evidence-based medicine approach cannot succeed unless the list of drugs of anticholinergic activity is agreed upon, and the studies include a sophisticated pharmacological approach guided by our current understanding of their pharmacodynamic and pharmacokinetic mechanisms. If one agrees that antimuscarinic ADRs are probably dose-related, future studies must consider all drugs, administration routes, doses, muscarinic receptor affinity, DDIs, and brain access.

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Keywords: Anticholinergic; Parkinson's disease; cholinergic antagonists; diphenhydramine; muscarinic antagonists; muscarinic receptors; pharmacodynamics; pharmacokinetics; serum anticholinergic activity; trihexyphenidyl

Document Type: Research Article

Publication date: September 1, 2011

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  • Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism and disposition. The journal serves as an international forum for the publication of timely reviews in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the latest and most important developments. The journal covers the following areas:

    In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites and adducts.
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