Practical Pharmacokinetics and Pharmacodynamics

Chapter

Abstract

The physiological responses to surgery, critical illness, and subsequent resuscitation can alter both pharmacokinetics (PK) and pharmacodynamics (PD) [1]. As a result of these changes, pharmacotherapy may need to be altered to produce the desired outcomes. A basic understanding of the principles of pharmacokinetics, or the movement of drugs in the body, and pharmacodynamics, the cells responses to drugs, is needed to maximize pharmacotherapy [2]. This chapter will review basic pharmacokinetic and pharmacodynamic principles and some changes in the critically ill surgical patient.

Keywords

Drug dosing Drug metabolism Pharmacodynamics Pharmacokinetics Neuromuscular blockade Opiates Sedatives Drug monitoring 

Abbreviations

α

Distribution half-life

AUC

Area under the curve

β

Terminal half-life

Cl

Clearance

Cmax

Maximum concentration

Cmaxss

Steady-state maximum concentration

Css

Steady-state concentration

CYP

Cytochrome P450

F

Bioavailability

fT>MIC

Free concentration time above minimum inhibitory concentration

ICU

Intensive care unit

Ke

Elimination constant

LD

Loading dose

LOS

Length of stay

MIC

Minimum inhibitory concentration

PD

Pharmacodynamics

PK

Pharmacokinetics

PK/PD

Pharmacokinetics and pharmacodynamics

TDM

Therapeutic drug monitoring

T1/2

Half-life

T>MIC

Time above mean inhibitory concentration

Vd

Volume of distribution

References

  1. 1.
    Gerlach AT. Pharmacotherapy self-assessment program. In: Schumock GBD, Richardson M, editors. Critical care and transplantation. 5th ed. Kansas City: American College of Clinical Pharmacy; 2006. p. 111–38.Google Scholar
  2. 2.
    In: Bauer LA, editor. Applied clinical pharmacokinetics. 3rd ed. New York: McGraw-Hill; 2014.Google Scholar
  3. 3.
    Brundage RC, Mann HJ. General principles of pharmacokinetics and pharmacodymanics. In: Fink M, Abraham E, Vincet J-L, Kockanek PM, editors. Textbook of critical care. 5th ed. Philadelphia: Saunders/Elsevier Publishing; 2005. p. 1573–85.Google Scholar
  4. 4.
    Shargel L, Wu-Pong S, Yu, ABC. In: Applied biopharmaceutics & pharmacokinetics. 6th Ed. McGraw-Hill; 2012Google Scholar
  5. 5.
    Roberts JA, Lipman J. Pharmacokinetic issues for antibiotics in the critically ill patient. Crit Care Med. 2009;37(3):840–51; quiz 59.CrossRefGoogle Scholar
  6. 6.
    Dipiro JT, Spruill WJ, Wade WE, Blouin RA, Preumer JM, In: Concepts in Clinical Pharmacokinetics. 5th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2010.Google Scholar
  7. 7.
    Smith HS. Opioid metabolism. Mayo Clin Proc. 2009;84(7):613–24.CrossRefGoogle Scholar
  8. 8.
    Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. 2013;138(1):103–41.CrossRefGoogle Scholar
  9. 9.
    Delgado Almandoz JE, Crandall BM, Scholz JM, Fease JL, Anderson RE, Kadkhodayan Y, et al. Pre-procedure P2Y12 reaction units value predicts perioperative thromboembolic and hemorrhagic complications in patients with cerebral aneurysms treated with the Pipeline Embolization Device. J Neurointerv Surg. 2013;5 Suppl 3:iii3–10.CrossRefGoogle Scholar
  10. 10.
    Holford NH, Sheiner LB. Kinetics of pharmacologic response. Pharmacol Ther. 1982;16(2):143–66.CrossRefGoogle Scholar
  11. 11.
    Cody RJ, Pickworth KK. Approaches to diuretic therapy and electrolyte imbalance in congestive heart failure. Cardiol Clin. 1994;12(1):37–50.PubMedGoogle Scholar
  12. 12.
    Gerlach AT, Murphy CV, Dasta JF. An updated focused review of dexmedetomidine in adults. Ann Pharmacother. 2009;43(12):2064–74.CrossRefGoogle Scholar
  13. 13.
    Meibohm B, Derendorf H. Basic concepts of pharmacokinetic/pharmacodynamic (PK/PD) modelling. Int J Clin Pharmacol Ther. 1997;35(10):401–13.PubMedGoogle Scholar
  14. 14.
    Nielsen EI, Friberg LE. Pharmacokinetic-pharmacodynamic modeling of antibacterial drugs. Pharmacol Rev. 2013;65(3):1053–90.CrossRefGoogle Scholar
  15. 15.
    Yang H, Feng Y, Xu XS. Pharmacokinetic and pharmacodynamic modeling for acute and chronic pain drug assessment. Expert Opin Drug Metab Toxicol. 2014;10(2):229–48.CrossRefGoogle Scholar
  16. 16.
    Lepak AJ, Andes DR. Antifungal PK/PD considerations in fungal pulmonary infections. Semin Respir Crit Care Med. 2011;32(6):783–94.CrossRefGoogle Scholar
  17. 17.
    Mawer GE, Ahmad R, Dobbs SM, McGough JG, Lucas SB, Tooth JA. Prescribing aids for gentamicin. Br J Clin Pharmacol. 1974;1(1):45–50.CrossRefGoogle Scholar
  18. 18.
    Nagashima R, O’Reilly RA, Levy G. Kinetics of pharmacologic effects in man: the anticoagulant action of warfarin. Clin Pharmacol Ther. 1969;10(1):22–35.CrossRefGoogle Scholar
  19. 19.
    Drusano GL, Preston SL, Hardalo C, Hare R, Banfield C, Andes D, et al. Use of preclinical data for selection of a phase II/III dose for evernimicin and identification of a preclinical MIC breakpoint. Antimicrob Agents Chemother. 2001;45(1):13–22.CrossRefGoogle Scholar
  20. 20.
    Mouton JW, Brown DF, Apfalter P, Canton R, Giske CG, Ivanova M, et al. The role of pharmacokinetics/pharmacodynamics in setting clinical MIC breakpoints: the EUCAST approach. Clin Microbiol Infect. 2012;18(3):E37–45.CrossRefGoogle Scholar
  21. 21.
    Burgess SV, Mabasa VH, Chow I, Ensom MH. Evaluating outcomes of alternative dosing strategies for cefepime: a qualitative systematic review. Ann Pharmacother. 2015;49(3):311–22.CrossRefGoogle Scholar
  22. 22.
    Bauer KA, West JE, O’Brien JM, Goff DA. Extended-infusion cefepime reduces mortality in patients with Pseudomonas aeruginosa infections. Antimicrob Agents Chemother. 2013;57(7):2907–12.CrossRefGoogle Scholar
  23. 23.
    Rea RS, Capitano B. Optimizing use of aminoglycosides in the critically ill. Semin Respir Crit Care Med. 2007;28(6):596–603.CrossRefGoogle Scholar
  24. 24.
    Baddley JW, Patel M, Bhavnani SM, Moser SA, Andes DR. Association of fluconazole pharmacodynamics with mortality in patients with candidemia. Antimicrob Agents Chemother. 2008;52(9):3022–8.CrossRefGoogle Scholar
  25. 25.
    Rodriguez-Tudela JL, Almirante B, Rodriguez-Pardo D, Laguna F, Donnelly JP, Mouton JW, et al. Correlation of the MIC and dose/MIC ratio of fluconazole to the therapeutic response of patients with mucosal candidiasis and candidemia. Antimicrob Agents Chemother. 2007;51(10):3599–604.CrossRefGoogle Scholar
  26. 26.
    Pai MP, Turpin RS, Garey KW. Association of fluconazole area under the concentration-time curve/MIC and dose/MIC ratios with mortality in nonneutropenic patients with candidemia. Antimicrob Agents Chemother. 2007;51(1):35–9.CrossRefGoogle Scholar
  27. 27.
    Pascual A, Calandra T, Bolay S, Buclin T, Bille J, Marchetti O. Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes. Clin Infect Dis: Off Publ Infect Dis Soc Am. 2008;46(2):201–11.CrossRefGoogle Scholar
  28. 28.
    Murray MJ, Cowen J, DeBlock H, Erstad B, Gray Jr AW, Tescher AN, et al. Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient. Crit Care Med. 2002;30(1):142–56.CrossRefGoogle Scholar
  29. 29.
    Barr J, Fraser GL, Puntillo K, Ely EW, Gelinas C, Dasta JF, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med. 2013;41(1):263–306.CrossRefGoogle Scholar
  30. 30.
    Hirsh J, Raschke R. Heparin and low-molecular-weight heparin: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 Suppl):188S–203.CrossRefGoogle Scholar
  31. 31.
    Gerlach AT, Folino J, Morris BN, Murphy CV, Stawicki SP, Cook CH. Comparison of heparin dosing based on actual body weight in non-obese, obese and morbidly obese critically ill patients. Int J Crit Illn Inj Sci. 2013;3(3):195–9.CrossRefGoogle Scholar
  32. 32.
    Burcham PK, Abel EE, Gerlach AT, Murphy CV, Belcher M, Blais DM. Development and implementation of a nurse-driven, sliding-scale nomogram for bivalirudin in the management of heparin-induced thrombocytopenia. Am J Health Syst Pharm: AJHP: Off J Am Soc Health Syst Pharm. 2013;70(11):980–7.CrossRefGoogle Scholar
  33. 33.
    Doepker B, Mount KL, Ryder LJ, Gerlach AT, Murphy CV, Philips GS. Bleeding risk factors associated with argatroban therapy in the critically ill. J Thromb Thrombolysis. 2012;34(4):491–8.CrossRefGoogle Scholar
  34. 34.
    Kiser TH, Burch JC, Klem PM, Hassell KL. Safety, efficacy, and dosing requirements of bivalirudin in patients with heparin-induced thrombocytopenia. Pharmacotherapy. 2008;28(9):1115–24.CrossRefGoogle Scholar
  35. 35.
    Wisler JW, Washam JB, Becker RC. Evaluation of dose requirements for prolonged bivalirudin administration in patients with renal insufficiency and suspected heparin-induced thrombocytopenia. J Thromb Thrombolysis. 2012;33(3):287–95.CrossRefGoogle Scholar
  36. 36.
    Pisegna JR. Pharmacology of acid suppression in the hospital setting: focus on proton pump inhibition. Crit Care Med. 2002;30(6 Suppl):S356–61.CrossRefGoogle Scholar
  37. 37.
    Olsen KM, Devlin JW. Comparison of the enteral and intravenous lansoprazole pharmacodynamic responses in critically ill patients. Aliment Pharmacol Ther. 2008;28(3):326–33.CrossRefGoogle Scholar
  38. 38.
    Schaefer C, Cawello W, Waitzinger J, Elshoff JP. Effect of age and sex on lacosamide pharmacokinetics in healthy adult subjects and adults with focal epilepsy. Clin Drug Inv. 2015;35(4):255–65.CrossRefGoogle Scholar
  39. 39.
    Spencer DD, Jacobi J, Juenke JM, Fleck JD, Kays MB. Steady-state pharmacokinetics of intravenous levetiracetam in neurocritical care patients. Pharmacotherapy. 2011;31(10):934–41.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Open Access This chapter is distributed under the terms of the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

Authors and Affiliations

  1. 1.Department of PharmacyThe Ohio State University Wexner Medical CenterColumbusUSA
  2. 2.Department of PharmacyYale-New Haven HospitalNew HavenUSA

Personalised recommendations