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Pharmacokinetics
1. Applied Pharmacokinetics in the Adult Critically Ill Gil Fraser, PharmD, FCCM Critical Care Tom Nolin, PharmD, PhD Nephrology and Transplantation Maine Medical Center Portland, ME
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6. Sites of pre-systemic metabolism via CYP 3A and efflux by P-glycoprotein GI drug absorption and pre-systemic metabolism
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12. Why Does Midazolam Change From a Short- to a Long-acting Benzodiazepine When Given for a Prolonged Period of Time? Hours Duration of midazolam therapy Chest. 1993;103:55.
13. Context Specific Half-life Accumulation in a deep compartment is a function of fat solubility and may explain the long duration of action of midazolam after long-term use.
14. How can the volume of distribution help predict removal by hemodialysis? How about the extent of protein binding? If a drug has a large volume of distribution, very little resides in the circulation and is available for removal via hemodialysis. Examples - digoxin and tricyclic antidepressants Highly protein bound drugs are typically not removed by hemodialysis.
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17. The transmembrane protein P-glycoprotein is believed to function as an energy-dependent efflux pump or drug transporter. P-gp Inhibitors: Verapamil Grapefruit juice Amiodarone Quininidine Clarithromycin Tariquidar P-gp Inducers: Rifampin St. John’s Wort
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19. Consequences of Drug Metabolism Substrate (drug) Enzyme Metabolite Active Inactive Inactive Active Toxic Nontoxic Nontoxic Toxic Detoxification Prodrug Reactive metabolite Activation
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22. Phases of Drug Metabolism Phase I Phase II benzene phenol phenyl sulfate Increasing polarity of drug/metabolite
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25. Contribution of CYP to Drug Metabolism Adapted from Clin Pharmacokinet 1997;32:210.
37. Steady-state plasma concentration Effect of increasing daily dose on steady-state drug concentrations for drugs undergoing nonlinear ( ) and linear ( ) kinetics Daily Dose Enzyme saturation for nonlinear drug
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40. Pharmacogenetics The study of heredity as it relates to the absorption, distribution, elimination, and action of medicines A tool to limit variability and individualize therapy