Elsevier

Critical Care Clinics

Volume 15, Issue 1, 1 January 1999, Pages 55-75
Critical Care Clinics

PHARMACOKINETIC CONSIDERATIONS

https://doi.org/10.1016/S0749-0704(05)70039-7Get rights and content

Achieving and maintaining therapeutic levels of analgesic medications while avoiding adverse drug reactions in seriously ill patients are challenges faced by all critical care practitioners. A sound knowledge of the pharmacokinetic and pharmacodynamic characteristics of analgesic drugs enables clinicians to optimize use of these agents. An understanding of the physiological alterations in critically ill patients and their effects on pharmacokinetics and pharmacodynamics is also important for the management of pain in the intensive care unit (ICU). Opioid narcotic drugs, including fentanyl and morphine, are the most commonly used analgesic agents in the critical care setting and are administered by several different routes using many different dosing techniques and schedules. Intravenous (IV), intramuscular (IM), transdermal, oral, intranasal, rectal, epidural, and intrathecal routes have all been utilized for analgesic drugs in the ICU and are associated with different advantages and disadvantages. Different dosing techniques including continuous infusion, intermittent bolus, and patient-controlled analgesia (PCA) have all been employed in the ICU. This article describes general pharmacokinetic and pharmacodynamic principles, different routes and techniques for administering analgesic medication, pharmacokinetic parameters for commonly used analgesic drugs, and pharmacokinetic and pharmacodynamic alterations in ICU patients.

Section snippets

PHARMACOKINETICS AND PHARMACODYNAMICS

Pharmacokinetics is the study of drug disposition in the body over time including absorption, distribution, metabolism, and elimination of drug molecules.3, 12, 39, 44, 46, 72 Pharmacodynamics describes the relationship between the concentration of the drug at the site of action and the physiological response.3, 29, 46, 59 The relationship between pharmacokinetics and pharmacodynamics is illustrated in Figure 1. The pharmacologic effect of a drug can be described by the interaction of the drug

PHYSIOLOGIC CHANGES AFFECTING PHARMACOKINETICS IN THE CRITICALLY ILL PATIENT

Unfortunately, very few studies have evaluated the pharmacokinetic and pharmacodynamic properties of drugs in critically ill patients. Most pharmacokinetic studies are performed using healthy volunteers or patients who are only minimally ill, with these data extrapolated to critically ill patients. Unstable patients often present significant hemodynamic alterations and organ dysfunction, which may significantly alter drug transport throughout the body and movement into tissue. The alterations

OPIOID NARCOTIC ANALGESICS

Opioid narcotic analgesics such as morphine, fentanyl, meperidine, and hydromorphone are extensively used in the ICU for providing both analgesia and sedation.40, 68, 75 The partial agonists and mixed agonist-antagonist opioids such as pentazocine, butorphanol, and buprenorphine are associated with a ceiling effect for analgesia, have a high incidence of psychotomimetic effects, and may induce acute opioid withdrawal in opioid-dependent patients; as a result they are not usually useful agents

Oral

Narcotic analgesic drugs may be administered orally in the ICU only to those patients with functioning GI tracts. Many ICU patients will not tolerate enteral therapy and should initially receive parenteral analgesia. Patients who have altered absorptive surface of the intestines may have decreased absorption due to decreased microvilli, but they may also have a higher percentage of drug reaching the blood if metabolic enzymes in the microvilli cells are decreased in amount or activity. The oral

Patients at Risk

Opioid analgesics are commonly administered in the ICU to control pain or to reduce anxiety. The means of administration may be bolus injection, continuous infusion, or patient-controlled analgesia. The primary risks of sedation and respiratory depression are compounded by additive/synergistic effects of tissue injury, concomitant drugs, and accumulation of metabolic waste products. While it is advantageous for the caregiver to administer a constant infusion of narcotic analgesic, drug

SUMMARY

Limited studies of the pharmacokinetics of pain medication suggest altered serum elimination when the liver is hypoperfused or affected by severe cirrhosis. Drugs that are eliminated by Phase I oxidation reactions are sensitive to changes in hepatic blood flow, while drugs eliminated by Phase II glucuronidation are more affected by diseased hepatocytes. Additionally, alterations in renal function decrease elimination of both parent drugs and metabolites, resulting in toxicity for selected

References (80)

  • G.R. Park

    Molecular mechanisms of drug metabolism in the critically ill

    Br J Anaesth

    (1996)
  • R.V. Patwardhan et al.

    Normal metabolism of morphine in cirrhosis

    Gastroenterology

    (1981)
  • D. Pessayre et al.

    Mechanisms for reduced drug clearance in patients with cirrhosis

    Gastroenterology

    (1978)
  • R. Roberts et al.

    Effect of age and cirrhosis on the disposition and elimination of chlordiazepoxide

    Gastroenterology

    (1978)
  • M.P. Shelly et al.

    Pharmacokinetics of morphine in patients following orthotopic liver transplantation

    Br J Anaesth

    (1989)
  • E. Teeple

    Pharmacology and physiology of narcotics

    Crit Care Clin

    (1990)
  • R. Veselis

    Intravenous narcotics in the ICU

    Crit Care Clin

    (1990)
  • A.P. Wheeler

    Sedation, analgesia, and paralysis in the intensive care unit

    Chest

    (1993)
  • F. Azzollini et al.

    Elimination of chloramphenicol and thiamphenicol in subjects with cirrhosis of the liver

    Int J Clin Pharmacol Ther Toxicol

    (1972)
  • V. Bandi et al.

    Pharmacologic principles

  • C.M. Bernards et al.

    Physical and chemical properties of drug molecules governing their diffusion through the spinal meninges

    Anesthesiology

    (1992)
  • A. Bodenham et al.

    The altered pharmacokinetics and pharmacodynamics of drugs commonly used in critically ill patients

    Clin Pharmacokinet

    (1988)
  • R.A. Branch et al.

    The clearance of antipyrine and indocyanine green in normal subjects and in patients with liver disease

    Clin Pharmacol Ther

    (1976)
  • T.G. Bushnell et al.

    Choosing the right analgesic: A guide to selection

    Drugs

    (1993)
  • R. Callagham et al.

    Hepatic enzyme activity is the major factor determining elimination rate of high-clearance drugs in cirrhosis

    Hepatology

    (1993)
  • W. Cawello et al.

    The correlation between pharmacodynamics and pharmacokinetics: Basics of pharmacokinetics-pharmacodynamics modeling

    J Clin Pharmacol

    (1997)
  • G.L.C. Chan et al.

    Effects of renal insufficiency on the pharmacokinetics and pharmacodynamics of opioid analgesics

    Drug Intelligence and Clinical Pharmacy

    (1987)
  • M.A. Chaney

    Side effects of intrathecal and epidural opioids

    Can J Anaesth

    (1995)
  • N.I. Cherny

    Opioid analgesics: Comparative features and prescribing guidelines

    Drugs

    (1996)
  • B. Crotty et al.

    Hepatic extraction of morphine is impaired in cirrhosis

    Eur J Clin Pharmacol

    (1989)
  • G. Davies et al.

    Pharmacokinetics of opioids in renal dysfunction

    Clin Pharmacokinet

    (1996)
  • G. D'Honneur et al.

    Plasma and cerebrospinal fluid concentrations of morphine and morphine glucuronides after oral morphine: The influence of renal failure

    Anesthesiology

    (1994)
  • B.L. Erstad et al.

    Site-specific pharmacokinetics and pharmacodynamics of intramuscular meperidine in elderly postoperative patients

    Ann Pharmacother

    (1997)
  • C. Ferrier et al.

    Alfentanil pharmacokinetics in patients with cirrhosis

    Anesthesiology

    (1985)
  • P.O. Gubbins et al.

    Drug absorption in gastrointestinal disease and surgery

    Clin Pharmacokinet

    (1991)
  • J.P. Haberer et al.

    Fentanyl pharmacokinetics in anesthetized patients with cirrhosis

    Br J Anaesth

    (1982)
  • K.O. Hagmeyer et al.

    Meperidine-related seizures associated patient-controlled analgesia pumps

    Ann Pharmacother

    (1993)
  • J. Hasselstrom et al.

    The metabolism and bioavailability of morphine in patients with severe liver cirrhosis

    Br J Clin Pharmac

    (1990)
  • H.F. Hill et al.

    Patient-controlled-analgesia: Pharmacokinetic and therapeutic considerations

    Clin Pharmacokinet

    (1993)
  • H.L. Isenhower et al.

    Selection of narcotic analgesics for pain associated with pancreatitis

    Am J Health-Syst Pharm

    (1998)
  • Cited by (31)

    • Pharmacokinetics and Pharmacology of Drugs Used in Children

      2019, A Practice of Anesthesia for Infants and Children
    • Pharmacokinetics and Pharmacology of Drugs Used in Children

      2018, A Practice of Anesthesia for Infants and Children
    • Sedation Analgesia and Neuromuscular Blockade in Pediatric Critical Care: Overview and Current Landscape

      2017, Pediatric Clinics of North America
      Citation Excerpt :

      Fentanyl is more lipid soluble than morphine and has a more rapid onset of action because of quicker penetration of the central nervous system. Fentanyl may be administered by the intravenous, intramuscular, epidural, transdermal, intranasal, and intrathecal routes.15,17 Long-term continuous infusions of fentanyl may result in a prolonged elimination half-life and duration of action as a result of drug accumulation in peripheral tissues.

    • Pharmacokinetics and Pharmacodynamics in the Critically Ill Child

      2008, Pediatric Clinics of North America
      Citation Excerpt :

      Fentanyl is more lipid soluble than morphine and has a more rapid onset of action because of quicker penetration of the central nervous system. Fentanyl may be administered by the intravenous, intramuscular, epidural, transdermal, intranasal, or intrathecal routes [26,28]. Long-term continuous infusions of fentanyl may result in a prolonged elimination half-life and duration of action as a result of drug accumulation in peripheral tissues.

    • Pharmacology and pharmacokinetics of sedatives and analgesics

      2004, Gastrointestinal Endoscopy Clinics of North America
    View all citing articles on Scopus

    Address reprint requests to David F. Volles, PharmD, BCPS, University of Virginia Health System, Department of Pharmacy Services, P.O. Box 10002, Charlottesville, VA 22906–0002

    View full text