TAILIEUCHUNG - Chapter 005. Principles of Clinical Pharmacology (Part 5)

Adjusting Drug Dosages While elimination half-life determines the time required to achieve steadystate plasma concentrations (Css), the magnitude of that steady state is determined by clearance (Cl) and dose alone. For a drug administered as an intravenous infusion, this relationship is When drug is administered orally, the average plasma concentration within a dosing interval (Cavg,ss) replaces Css, and bioavailability (F) must be included: Genetic variants, drug interactions, or diseases that reduce the activity of drug-metabolizing enzymes or excretory mechanisms may lead to decreased clearance and hence a requirement for downward dose adjustment to avoid toxicity. Conversely, some drug interactions and genetic. | Chapter 005. Principles of Clinical Pharmacology Part 5 Adjusting Drug Dosages While elimination half-life determines the time required to achieve steadystate plasma concentrations Css the magnitude of that steady state is determined by clearance Cl and dose alone. For a drug administered as an intravenous infusion this relationship is When drug is administered orally the average plasma concentration within a dosing interval Cavg ss replaces Css and bioavailability F must be included Genetic variants drug interactions or diseases that reduce the activity of drug-metabolizing enzymes or excretory mechanisms may lead to decreased clearance and hence a requirement for downward dose adjustment to avoid toxicity. Conversely some drug interactions and genetic variants increase CYP expression and hence increased drug dosage may be necessary to maintain a therapeutic effect. The Concept of High-Risk Pharmacokinetics When drugs utilize a single pathway exclusively for elimination any condition that inhibits that pathway be it disease-related genetic or due to a drug interaction can lead to dramatic changes in drug concentrations and thus increase the risk of concentration-related drug toxicity. For example administration of drugs that inhibit P-glycoprotein reduces digoxin clearance since P-glycoprotein is the major mediator of digoxin elimination the risk of digoxin toxicity is high with this drug interaction unless digoxin dosages are reduced. Conversely when drugs undergo elimination by multiple drug metabolizing or excretory pathways absence of one pathway due to a genetic variant or drug interaction is much less likely to have a large impact on drug concentrations or drug actions. Active Drug Metabolites From an evolutionary point of view drug metabolism probably developed as a defense against noxious xenobiotics foreign substances . from plants to which our ancestors inadvertently exposed themselves. The organization of the drug uptake and efflux pumps and the .

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