Pharmacokinetics of Inhaled Anesthetics PDF

3 Pharmacokinetics of Inhaled Anesthetics ANDREW E. HUDSON AND HUGH C. HEMMINGS, JR. CHAPTER OUTLINE Historical Perspective Classes of Inhaled Anesthetics Physical Properties Measuring Anesthetic Potency as MAC Monitoring Inhaled Anesthetic Delivery Differences Between Inhaled and Intravenous Anesth...

3 Pharmacokinetics of Inhaled Anesthetics ANDREW E. HUDSON AND HUGH C. HEMMINGS, JR. CHAPTER OUTLINE Historical Perspective Classes of Inhaled Anesthetics Physical Properties Measuring Anesthetic Potency as MAC Monitoring Inhaled Anesthetic Delivery Differences Between Inhaled and Intravenous Anesthetic Delivery Agent Analysis Monitoring Neurophysiologic Effect Metabolism and Degradation Metabolism Chemical Degradation Carbon Monoxide Production Uptake and Distribution General Principles Determinants of Wash-In Special Factors Tissue Uptake Recovery and Elimination Nitrous Oxide: Concentration Effect, Second Gas Effect, Diffusion Hypoxia, and Effects on Closed Gas Spaces Gas Delivery Systems Reaction of CO2 With Barium Hydroxide Lime (Baralyme, Obsolete) Reaction of CO2 With Lithium Hydroxide (in Current Use) Low-Flow Anesthesia Pharmacoeconomic Considerations Emerging Developments Intravenous Delivery of Volatile Anesthetics Volatile Anesthetics in the Intensive Care Unit Historical Perspective The discovery of drugs with anesthetic properties was a landmark event in the history of pharmacology, medicine, and even civilization, in that it made otherwise painful surgical treatments of disease possible. Without a means of providing anesthesia, it was impossible for the modern discipline of surgery to develop. Before the discovery of anesthetic drugs, surgical intervention was limited to simple operations that could be completed quickly. The first anesthetics were administered by inhalation before the evolution of techniques for intravenous drug administration, and anesthetics remain the most important class of inhaled drugs (barring oxygen, of course). Diethyl ether was first used clinically as a general anesthetic by Long in 1842, and was independently developed by Morton in 1846. Morton’s public demonstration of the anesthetic properties of ether at the Massachusetts General Hospital on October 16, 1846, is one of the most important moments in the history of medicine and is now commemorated as Ether Day in Boston and World Anaesthesia Day throughout the world; Long’s contribution is also honored as National Doctor’s Day in the United States, marking the day that he administered the first ether anesthetic for surgery (March 30, 1842). Ether remains in clinical use in developing countries given its low cost and relatively high therapeutic index, but its high volatility and explosivity limit its general use. Nitrous oxide was first used for dental analgesia by Wells in 1844, and in 1847 Simpson introduced chloroform (trichloromethane) as a nonexplosive alternative to ether. The first century of anesthesia was dominated by these drugs, of which only nitrous oxide is still widely used.1 Since its early origins the practice of anesthesia has been driven by the development of techniques to facilitate the safe delivery of inhaled anesthetics, and these concepts remain important. Administration of drugs by inhalation has a number of unique and important attributes primarily owing to special pharmacokinetic and chemical properties that guide the safe and effective use of inhaled anesthetics. Classes of Inhaled Anesthetics General anesthetics include a range of structurally diverse inhaled and injectable compounds that are defined by their ability to induce a reversible comatose state characterized by unconsciousness, amnesia, and immobility. The inhaled anesthetic drugs belong to three broad classes: ethers, alkanes, and gases (Fig. 3.1). (The latter classification is somewhat arbitrary as all inhaled anesthetics are delivered as gases, but gaseous anesthetics are those that normally exist as gases at standard temperature and pressure: nitrous oxide, cyclopropane, noble gases). The ethers and alkanes are volatile liquids (i.e., they have a vapor pressure that is less than atmospheric pressure at room temperature; see later text) and are delivered as 44 Downloaded for Vicente Gonzalez ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on April 29, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved. CHAPTER 3 Pharmacokinetics of Inhaled Anesthetics Abstract Keywords Inhaled anesthetics, beginning with diethyl ether, were first introduced into clinical practice in the 1840s. Since then a wide variety of inhaled agents, including ethers, alkanes, nitrous oxide, cyclopropane, and xenon, have been used to induce unconsciousness, amnesia, and immobility. The pharmacokinetics of these drugs depends on their physical properties. The rate of inhaled anesthetic uptake and elimination from the alveoli is driven largely by blood solubility; both are faster with less soluble agents. The effects of inhaled anesthetics depend on the anesthetic concentration at their effect sites, which parallels the alveolar anesthetic concentration and not the total amount of absorbed anesthetic. The potency of different agents can be compared using the minimum alveolar concentration of anesthetic required to prevent movement in 50% of subjects in response to a standardized surgical stimulus. Physiologic factors that govern inhaled anesthetic uptake and elimination include alveolar ventilation and cardiac output. Extrinsic factors that affect inhaled anesthetic uptake and elimination, by determining changes in the alveolar concentration, include minute ventilation, fresh gas flow, and inspired concentration. Inhaled anesthetic tissue distribution depends on relative perfusion, the gradient between arterial and venous anesthetic concentration, and intertissue distribution. Inhaled anesthetics differ dramatically in their degree of metabolism, mostly by the cytochrome P450 system; the volatile anesthetics in use today are minimally metabolized. Emerging developments in inhaled anesthetics include alternative delivery methods and anesthetic applications outside of the operating room. minimum alveolar concentration partition ratio FA:FI ratio concentration effect second gas effect low flow anesthesia Downloaded for Vicente Gonzalez ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on April 29, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved. 44.e1 CHAPTER 3 Pharmacokinetics of Inhaled Anesthetics develop hepatitis, rare but often fatal, or ventricular arrhythmias) led to the development in the 1960s by Terrell and others of a series of halogenated methyl ethyl ethers, including methoxyflurane (2,2-dichloro-1,1-difluoro-1-methoxyethane), enflurane (2-chloro1-[difluoromethoxy]-1,1,2-trifluoro-ethane), isoflurane (2-chloro2-[difluoromethoxy]-1,1,1-trifluoro-ethane), and subsequently in the 1990s, desflurane (2-[difluoromethoxy]-1,1,1,2-tetrafluoroethane) and sevoflurane (1,1,1,3,3,3-hexafluoro-2-[fluoromethoxy] propane).1 Ethers Diethyl ether O Methoxypropane O Vinyl ether O FF F Enflurane F O F Cl Methoxyflurane FF Cl O Cl Cl Isoflurane F3C F O F F Desflurane F F3C O F O F F3C Sevoflurane F3C Alkanes H Chloroform Cl C Cl Cl Cl Cl Cl H Trichloroethylene Cl F3C Halothane Br Gases Cyclopropane H H C Ethylene C H Nitrous oxide Xenon H + N N O– –N 45 + N O Xe Fig. 3.1 Inhaled anesthetic agents by class, with chemical structure and space-filling model drawn to scale. vapors (the gas phase in equilibrium with the liquid phase at a given temperature; a condensable gas). The modern era of volatile anesthetics—those halogenated with fluorine—began with the synthesis of halothane (2-bromo-2-chloro-1,1,1-trifluoroethane) by Suckling in 1951, which was successfully introduced as an anesthetic in clinical trials in 1956. Subsequent attempts to minimize the adverse effects of halothane (particularly the propensity to Physical Properties Inhaled drugs differ from intravenous drugs in that their delivery depends on uptake into the blood by the lungs, followed by delivery to their effect sites in the central nervous system in the case of anesthetics. The delivery of inhaled drugs to the lungs depends on the physical properties of the drugs themselves, in particular their solubility in blood and their vapor pressure (Table 3.1).61 Vapor pressure is the partial pressure of a vapor in thermodynamic equilibrium with a liquid—that is, the partial pressure at which the rate of liquid evaporation into the gaseous phase equals the rate of gaseous condensation into liquid. Vapor pressure varies nonlinearly with temperature according to the Clausius-Clapeyron relationship (Fig. 3.2). The boiling point is the temperature at which the vapor pressure equals ambient atmospheric pressure. Substances that have high vapor pressures at room temperature (e.g., many of the inhaled anesthetics) are volatile. Partial pressure is the portion of the total pressure of a gaseous mixture supplied by a particular gas; for an ideal gas, this is the mole fraction of the mixture multiplied times the total pressure of the gas. Inhaled anesthetic partial pressures are commonly expressed as volume percent (vol%), which is the percent of the total volume contributed by a particular gas, or for an ideal gas, the mole percent. At standard temperature and pressure, the volume percent times total pressure equals the partial pressure, but importantly, partial pressure changes with temperature. The solubility of a gas is the amount of gas that can be dissolved homogenously into a solvent at equilibrium; it is a function of the partial pressure of the gas above the liquid solvent and the ambient temperature. Solubility depends on the solvent—for example, polar substances tend to be more soluble in polar solvents. According to Henry’s law, for a given solvent at a given temperature the amount of gas dissolved in solution is directly proportional to the partial pressure of the gas. Relative solubilities can be described according to the partition ratio (also known as the partition coefficient), which is defined as the ratio at equilibrium of the concentration of the dissolved gas in one solvent to the concentration of the dissolved gas in the other solvent (or in the gaseous phase). At equilibrium the partial pressure of the dissolved gas in the two solvents is equal, even though the concentrations are not (Fig. 3.3). The concentration of a gas in a liquid is derived by multiplying the gas partial pressure times its solubility expressed as its solvent:gas partition ratio (at standard temperature and pressure). For inhaled anesthetics, the blood:gas partition ratio is critically important to alveolar uptake. More soluble agents, such as ether or halothane, have high blood gas partition ratios and take longer to reach an equilibrium between inhaled and exhaled partial pressure owing to their greater uptake into blood and tissues. Conversely, less soluble agents, such as nitrous oxide and desflurane, dissolve in lower quantities and approach equilibrium more rapidly (see later text). Following Henry’s law, the solubility of gases such as inhaled anesthetics in aqueous liquids increases at lower temperatures. Various tissues also have tissue-specific partition ratios Downloaded for Vicente Gonzalez ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on April 29, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved. 46 SE C T I O N I Basic Principles of Pharmacology TABLE Properties of Inhaled Anesthetics 3.1 Agent Boiling Point (°C) at 1 Atm Vapor Pressure (mm Hg) at 20°C MAC For 40-Yr-Old in O2 (%) Blood:Gas Partition Ratio at 37°C Oil:Gas Partition Ratio at 37°C Halothane 50.2 243 0.75 2.4 224 Enflurane 56.5 172 1.7 1.8 97 Isoflurane 48.5 240 1.2 1.4 98 Sevoflurane 58.5 160 2 0.65 47 Desflurane 22.8 669 6 0.45 19 −88.5 39,000 104 0.47 1.4 −108.1 — 60–70 0.14 1.9 Nitrous oxide Xenon (Modified from Eger EI 2nd, Eisenkraft JB, Weiskopf RB. Metabolism of potent inhaled anesthetics. In: Eger EI 2nd, Eisenkraft JB, Weiskopf RB, eds. The Pharmacology of Inhaled Anesthetics. Chicago: Healthcare Press; 2003:167–176.) 1600 Desflurane Isoflurane Halothane Enflurane Sevoflurane Liquid Solid Gas Vapor pressure (mm Hg) Pressure 1400 1200 1000 800 600 400 200 0 Temperature A 0 B 5 10 15 20 25 30 35 40 45 50 55 60 65 Temperature (°C) Fig. 3.2 Pressure and temperature relationships. A, A qualitative state diagram for water. The vapor pressure is the pressure at which the liquid and gaseous phases are in equilibrium for a given temperature, as indicated by the line between the liquid and gaseous phases in the state diagram. B, Vapor pressure data for a number of common anesthetics. Note that the vapor pressure of desflurane is much higher at a given temperature than the vapor pressure of the other agents, and that the vapor pressure of desflurane reaches 760 mm Hg (or 1 atm) at approximately 22.8°C (its boiling point), indicating that it will boil in a warm room. that depend largely on their biochemical composition. This determines relative anesthetic uptake and concentrations in each tissue. Because of differing partition ratios, the actual concentrations can be very different between various tissues at equilibrium even though the partial pressure will eventually be the same, and even two agents with low blood:gas partition ratios, such as nitrous oxide and desflurane, will differ in their rate of uptake into the central nervous system (CNS) because their CNS:blood partition ratios differ.2 Fig. 3.4 demonstrates that even after a 10-minute wash-in period the differences in partial pressure are pronounced as the different tissue compartments take up the agent. Measuring Anesthetic Potency as MAC The potency of inhaled anesthetics is commonly expressed using the concept of minimum alveolar concentration (MAC) as described by Eger and colleagues.3 The MAC of an anesthetic vapor is the steady-state concentration at which 50% of “normal” (healthy, nonpregnant, adult) human subjects under standard conditions (normal body temperature, 1 atm, no other drugs) do not move (are immobile) in response to a defined stimulus (surgical incision; laboratory studies often substitute application of a tail clamp to rodents). Although MAC is defined in terms of a gas concentration in volume percent or fractional atm at 1-atm ambient pressure, it is the partial pressure and resultant concentration at the effect site that is critical to the pharmacologic response (immobility). Thus anesthetic potency expressed in terms of alveolar partial pressure or tissue concentration is constant for a given physiologic state. MAC is expressed as a gas concentration at 1-atm ambient pressure. The vaporizer setting in volume percent delivers an equivalent alveolar partial pressure that varies with atmospheric pressure; this is significant at high altitudes where higher inspired concentrations Downloaded for Vicente Gonzalez ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on April 29, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved. CHAPTER 3 Pharmacokinetics of Inhaled Anesthetics Halothane λ = 2.4 Isoflurane λ = 1.4 47 Desflurane λ = 0.45 100 mL Gas 100 mL Gas 100 mL Gas 2% Halothane 2 mL Halothane Partial pressure 15 mm Hg 2% Isoflurane 2 mL Isoflurane Partial pressure 15 mm Hg 2% Desflurane 2 mL Desflurane Partial pressure 15 mm Hg 100 mL Blood 100 mL Blood 100 mL Blood 4.8 mL Halothane Partial pressure 15 mm Hg 2.8 mL Isoflurane Partial pressure 15 mm Hg 0.9 mL Desflurane Partial pressure 15 mm Hg Fig. 3.3 Blood:gas partitioning of inhaled anesthetics at 37°C. At equilibrium, the partial pressures of the anesthetics in the gas and liquid (blood) phases (100 mL of each) are equal (15 mm Hg for 2 vol% at standard atmospheric pressure of 760 mm Hg). In contrast, blood concentrations differ depending on the drug specific blood:gas partition ratios (λ). Note that λ increases ~4% per 1°C decrease in temperature. Inspired sevoflurane 2.56 vol% 19.5 mm Hg concentration Expired sevoflurane 2.0 vol% 15 mm Hg concentration Alveolar gas 2.0 vol% 15 mm Hg concentration Mixed venous blood 0.89 vol% 10.5 mm Hg concentration Arterial blood 1.28 vol% 15 mm Hg concentration 75% of cardiac output Fat group 0.3 vol% 0.07 mm Hg concentration Fig. 3.4 5% of cardiac output Vessel poor group