Common Pharmacokinetic Features of Opioids

Representative pharmacokinetic parameters for the opioids commonly used in anesthesia are displayed in Table 11-7 .

After intravenous injection, arterial plasma concentrations of opioids rise to a peak within one circulation time. Thereafter, they exhibit a rapid redistribution phase and a slower elimination phase typical of drugs whose pharmacokinetics are described by compartmental models.^[295]

Figure 11-11 Pharmacokinetic and pharmacodynamic variability of the opioid. The upper panel demonstrates alfentanil plasma concentration in 45 patients administered with 50 µg/kg alfentanil. The lower panel shows dose-response relationships of alfentanil from 34 patients receiving alfentanil and 66% nitrous oxide during intraabdominal surgery. The black circles represent the Cp₅₀ from each patient. Cp₅₀ , the concentration needed to obtund responses to stimuli adequately in 50% of patients. (From Maitre PO, Vozeh S, Heykants J, et al: Population pharmacokinetics of alfentanil: The average dose-plasma concentration relationship and interindividual variability in patients. Anesthesiology 66:3–12, 1987; and Ausems ME, Hug CC Jr, Stanski DR, Burm AG: Plasma concentrations of alfentanil required to supplement nitrous oxide anesthesia for general surgery. Anesthesiology 65:362–367, 1986.)

After administration into a central compartment, opioids are either eliminated from the central compartment (by excretion or biotransformation) or distributed to peripheral compartments. In general, opioids are cleared from the plasma by biotransformation in the liver. However, extrahepatic metabolism is important for some opioids.

As a rule, because of their high lipid solubility, opioids are widely distributed in body tissues. In pharmacokinetic terms, this means that opioids typically have a high apparent volume of distribution at steady state. Because opioids are distributed so widely and so rapidly to various body tissues, redistribution has a prominent impact on

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Figure 11-12 Distribution of fentanyl within the body compartments at the extracellular pH of 7.4. The accumulation of fentanyl by the tissue is assumed to be 13-fold. In the extracellular space, an equilibrium exists between the ionized fentanyl (F⁺ ), the free base (F), and the fentanyl molecules bound to macromolecules (F_b ). The concentration of ionized fentanyl within the interstitial fluid (encircled F⁺ ) determines the pharmacologic effect, because the opioid receptors are located at the cell surface. Fentanyl as free base readily penetrates into the cells and becomes bound to cytomembranes, lysosomes, and other structures (thick arrows) and thus accumulates in the cell. A small decrease of the extracellular pH will shift the equilibrium between F and F⁺ toward higher F⁺ concentrations and will induce a marked release of fentanyl from the cellular compartment as a result of the decrease of the concentration of F in the interstitium. An increase of the extracellular H⁺ concentration by pH 0.2 might roughly double the concentration of ionized fentanyl within the interstitial fluid and accordingly enhance its pharmacologic effect. (From Lullmann H, Martins BS, Peters T: pH-dependent accumulation of fentanyl, lofentanil and alfentanil by beating guinea pig atria. Br J Anaesth 57:1012–1017, 1985.)

Opioid uptake by the lung is a significant implication of opioid pharmacokinetics. The time necessary to reach peak concentration of an opioid is influenced by the percentage of pulmonary uptake. A very substantial proportion of the initial dose of a highly lipophilic opioid such as fentanyl is taken up by the lung (75%) and subsequently is rapidly released.^[296]