This document discusses principles of applied pharmacokinetics in critically ill adult patients. It covers topics like why pharmacokinetics is important, the four components of pharmacokinetics (absorption, distribution, metabolism, excretion), factors affecting drug absorption like routes of administration and the gastrointestinal tract, distribution and protein binding, phases of drug metabolism, and considerations for drug dosing in renal impairment. Case examples are provided to demonstrate practical applications of pharmacokinetic principles.

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

6. Sites of pre-systemic metabolism via CYP 3A and efflux by P-glycoprotein GI drug absorption and pre-systemic metabolism

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.

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

19. Consequences of Drug Metabolism Substrate (drug) Enzyme Metabolite Active Inactive Inactive Active Toxic Nontoxic Nontoxic Toxic Detoxification Prodrug Reactive metabolite Activation

22. Phases of Drug Metabolism Phase I Phase II benzene phenol phenyl sulfate Increasing polarity of drug/metabolite

25. Contribution of CYP to Drug Metabolism Adapted from Clin Pharmacokinet 1997;32:210.

26. 3A4/5 30% 1A2 13% 2E1 7% 2D6 4% 2C8 < 1% 2B6 < 1% 2A6 4% 2C19 2% 2C9 18% Nicotine Buproprion Mephenytoin Omeprazole Diazepam Coumarin Losartan NSAIDs Warfarin Tolbutamide Phenytoin Midazolam CyA/Tacrolimus CCBs Statins Cisapride Terfenadine Caffeine Theophyline Imipramine Chlorzoxazone Acetaminophen Nitrosamines Anesthetics Azoles Macrolides Cimetidine Grapefruit Barbs Rifampin Dexamethasone Carbamazepine St. John’s Wort Azoles Macrolides Cimetidine Grapefruit CYP450 Substrates SSRIs Desipramine Nortriptyline ß-blockers Debrisoquine D-methorphan Retinoids Paclitaxel Inhibitors Disulfiram Quinidine Methadone Cimetidine Azoles Azoles Inducers Barbs Rifampin Barbs Rifampin Omeprazole Barbs Rifampin PAHs Ethanol Isoniazid Benzene Rifampin

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

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

41. Pharmacogenetics N Engl J Med. 2003;348:529.

44. Relationship between CYP2D6 genetic status and nortriptyline pharmacokinetics Clin Pharmacol Ther. 1998;63:444. TIPS. 1999;20:342.

45. Utility of Pharmacogenetics Ann Rev Genomics Hum Genet. 2001;2:9.