Abstract
Pharmacokinetics (PK) is the study of drug concentration in the body with respect to time. The four major processes affecting drug concentration are drug absorption, distribution, metabolism, and excretion. In examining the PK processes, this chapter aims to provide considerations in drug absorption, the concept of drug distribution, metabolism and drug interactions, and renal excretion. PK parameters area under the curve (AUC), elimination rate constant (k), half-life (t1/2), clearance (Cl), and volume of distribution (Vd) are introduced to provide clinicians an understanding of the PK of anesthetic agents. Pharmacodynamics (PD) is the study of drug action in the body with respect to time. Taken together, the understanding of PK and PD will aid a clinician in the design of anesthetic doses and dosing frequencies to achieve desired therapeutic effects while minimizing adverse reactions.
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Keywords
- Therapeutic Drug Monitoring
- Intravenous Anesthetic
- Cytochrome P450 Enzyme System
- Salt Factor
- Advanced Drug Delivery System
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
Introduction
Our understanding of the numerous barriers and cascades that govern drug kinetic and dynamic behavior of clinical response(s) continues to grow in complexity as the inextricable link between pharmacokinetics (PK) and pharmacodynamics (PD) becomes increasingly apparent. Colloquially, PK is described as “what the body does to the drug” and PD is described as “what the drug does to the body.” The key element to those phrases is “what is changing?”: In PK, it is the drug concentration; in PD, it is the “body” or the physiological and pharmacological systems and cascades that convert drug concentrations into responses. More precisely, PK encompasses all of the kinetic processes from the drug released from its dosage form (e.g., i.v., p.o., i.m., extended release) to the delivery of the drug to its site or tissue responsible for initiating the translation of drug concentration/exposure into a response (shown as the solid arrows in Fig. 1.1). And where PK ends, PD begins by explaining the time-course translation/transduction of drug concentration into a “biological signal” or “messenger” (e.g., intracellular Ca2+ concentration) that ultimately leads to the end desired response or effect (e.g., increased pain relief) (shown as the broken line arrow in Fig. 1.1).
Upon closer examination, PK includes even the kinetics of drug released from the dosage form prior to absorption—such as drug being transferred from syringe to systemic circulation (i.e., i.v. bolus) or the complex disintegration, solvation, and dissolution of drug released by an advanced drug delivery system (ADDS) into the gastrointestinal (GI) tract milieu for permeation (passive diffusion and active or facilitated transport) across the GI endothelial barrier to the systemic circulation. Additional terms associated with the PK of a drug include absorption, distribution, excretion, and metabolism (see Fig. 1.1). A general term describing the sum of drug excretion and metabolism is elimination. An even more general PK term, disposition, describes the kinetic time course of drug distribution, excretion, and metabolism. The input function of drug (e.g., i.v. bolus, p.o.) combined with the disposition is the drug PK. Most importantly, clinicians can generally only control the input function of drugs, while the “body” or physiology controls the disposition.
An essential hypothesis of PK is that there is a quantitative relationship between drug concentration and pharmacological effect [1]. Clinical PK incorporates the fundamentals of PK to dose calculations, infusion rates, predictions of drug concentrations, dosing intervals, and time to eliminate the drug from the body. The primary objective of clinical PK is to maximize efficacy while minimizing toxicities, through a process called therapeutic drug monitoring (TDM). A complete TDM protocol entails monitoring-defined therapeutic endpoints (which include plasma drug concentration if appropriate) and adverse reactions. Adjustments of doses can be guided by TDM to provide individualized regimens. Clinical PK can be affected by numerous covariates, such as age, genetics, gender, race, comorbid disease states, and concomitant medications, resulting in drug interactions. These factors should be considered into the dosing regimen for each patient.
Absorption
The absorption of a drug is largely dependent on the route of delivery. Drugs can be administered by depot type of routes: oral, inhaled, subcutaneous, intramuscular, sublingual, rectal, intraocular, intranasal, vaginal, and transdermal. Although intravenous and intra-arterial technically do have an aspect of absorption (i.e., release of drug from a syringe or i.v./i.a. bag), these routes deliver drug directly into the systemic circulation and are a special subset of PK input (i.e., instantaneous absorption processes having a bioavailability of 1.0). The physicochemical properties (i.e., solubility, pKa, ionization, polarity, molecular weight, partition coefficient) play a critical role in the absorption of drugs. The route of delivery impacts the rate of absorption as well as the extent of absorption. Bioavailability is defined as the rate and extent of drug absorption or the percentage or fraction of the parent compound that reaches systemic (plasma) circulation. The bioavailability of the same drug in the same patient may be different depending on the route of administration. Drug references frequently provide the bioavailabilities of drugs and are typically denoted as F. The extent of absorption, but not the rate, can be described by the parameter area under the curve (AUC). In an acute setting, the rate of absorption, generally k a , tends to be more important, whereas the extent of absorption tends to be more important in chronic use medications. The salt factor (S) is the fraction of a dose that is the active base form of the drug and pragmatically can be viewed as an attenuation of F (e.g., “effective dose” = F*S*dose). Probably, the most frequently used routes of administration of drugs in anesthesiology are oral, intravenous/intra-arterial, inhaled, and local (epidural, interscalene, etc.).
The absolute bioavailability, F, is determined by comparing the availability for any given extravascular (e.v.) route of administration measured against an i.v. point of reference of availability of the drug administered intravenously (Eq. 1.1):
Since anesthetics and pain management medications can be delivered via numerous routes of administration, the value of F is important in determining the “effective dose” for these e.v. drugs. The physicochemical properties, previously mentioned, of the drug affect the drug’s ability to partition from lipid to aqueous phases, and therefore, F. Food, drug interactions, and gastrointestinal (GI) motility can all affect drug solubility and absorption. First-pass metabolism, which is pre-systemic metabolism of the drug, can occur in the GI tract and the liver prior to reaching systemic circulation. All of these factors can affect F and the route will sometimes dictate the countersalt needed, thus affecting S, as well.
For inhaled anesthetics, three major factors influencing absorption are solubility in the blood, alveolar blood flow, and the partial pressure gradient between alveolar gas and venous blood. The solubility of inhaled anesthetics in blood is described by blood/gas partition coefficients (Table 1.1). The inhaled anesthetics are absorbed almost completely and rapidly through the lungs. A lower blood/gas partition coefficient indicates a more rapid onset and dissipation of anesthetic action.
Volume of Distribution
The volume of distribution V d is a PK parameter characterizing the extent of drug distribution into the tissue from the blood. The physicochemical properties of a drug, plasma protein binding, and tissue binding influence V d. It has also been termed apparent volume of distribution because it does not correlate with an actual physiological volume compartment in the human body, but rather, it is the inferred volume in which the drug appears to be dissolved. It is inferred because as Eq. 1.2 shows, the clinician knows the dose given and Cp (drug plasma concentration) is measured; the V d is inferred or calculated from the two values of dose and Cp. The lower limit for nearly all drugs is 3 L or the actual average volume of human plasma. As the apparent or inferred volume of distribution increases in size, the interpretation begins to focus on the distribution of drug into extravascular tissues. The apparent or inferred V d can be calculated using Eq. 1.2:
If the plasma concentration Cp of a drug is small immediately following a single-bolus dose, this generally indicates substantial drug permeation into the tissue(s), and the resultant V d is >40–80 L, indicating extensive distribution into the tissue. In contrast, if V d is small (close to 3 L), a large fraction of the drug is assumed to reside in the blood plasma, thus suggesting a little amount of drug has permeated into the extravascular tissue(s). While V d provides insight as to whether the drug is residing in the blood or tissue, its value does not determine which specific tissue compartment the drug permeates into.
V d is useful in determining the loading dose necessary to achieve a targeted Cp. The usual loading dose equation is Loading Dose = V d × Cptarget. For drugs that have a large V d, a greater loading dose is necessary to achieve the targeted Cp. Drugs with a small V d require a reduced loading dose to obtain the targeted Cp.
As shown in Table 1.1, the inhaled anesthetics have high brain/blood, muscle/blood, and fat/blood partition coefficients. In particular, most inhaled anesthetics distribute extensively into the fat tissues.
Clearance
Clearance is an independent PK parameter quantifying the rate the body is able to eliminate a drug. More specifically, clearance is the volume of blood that is completely cleared of the drug per unit time. The units are in volume/time, usually liters per hour (L/h) or milliliters per minute (mL/min). While the liver is primarily responsible for drug metabolism and the kidneys are primarily responsible for parent drug and metabolite excretion (filtration and secretion), other routes of elimination include the chemical decomposition, feces, skin, and lungs. Hepatic metabolism and elimination are components of drug clearance. Total clearance is characterized by Eq. 1.3:
Total clearance ClTotal is used in most dose calculations without taking into account the specific route of elimination. Clearance is an important parameter because it controls the steady-state concentration Cpss as shown in Eq. 1.4:
S is the salt factor, F is the bioavailability, and tau (τ) is the dosing interval.
Metabolism
Drug metabolism occurs primarily in the liver, though metabolism can also occur at other sites such as the gastrointestinal wall, kidneys, and blood-brain barrier. Metabolism can be characterized as phase I or phase II reactions. Phase I reactions include oxidation, epoxidation, dealkylation, and hydroxylation reactions catalyzed by the cytochrome P450 enzyme system. A majority of the cytochrome P450 enzymes reside in the microsomes of hepatocytes where it metabolizes the highest number of substrates (chemical, drugs, and pollutants) in the body. Phase II reactions are glucuronidation and sulfation processes.
Many drug interactions involve the cytochrome P450 enzyme system. Certain drugs, termed inducers, may increase the activity of specific cytochrome P450 isozymes, leading to increased metabolism of drugs which are substrates of that particular isozyme. The reduction in plasma concentration of the drug substrates may lead to decreased therapeutic effects. Other drugs are inhibitors of cytochrome P450 enzymes, decreasing the metabolism of drugs that are substrates. The increase in substrate plasma concentration may result in not only enhanced pharmacological effects but also enhanced toxicological effects. Clinicians are encouraged to consider dosing adjustments based on known drug interactions to achieve therapeutic effects while minimizing adverse reactions.
Excretion
Excretion frequently refers to the irreversible clearance of a drug typically through the kidneys. The three major physiological processes occurring in the kidneys governing renal excretion are glomerular filtration, active secretion, and reabsorption. The glomerular filtration of an adult patient may be estimated by the Cockcroft-Gault equation [3] (Eq. 1.5):
ClCr is the creatinine clearance in mL/min, the age of the patient is in years, SCr is the serum creatinine, and IBW is the ideal body weight of the patient in kilograms (kg). For female patients, the resultant ClCr is multiplied by 85 % to account for lower muscle mass typically exhibited by females. The Cockcroft-Gault equation utilizes serum creatinine, which is a by-product of muscle metabolism and is freely filtered by the glomerulus. Creatinine is not actively secreted nor is it reabsorbed. For drugs that are primarily eliminated via the renal route, dose adjustments may be made on the basis of creatinine clearance (ClCr) and are provided by drug package inserts or drug information references.
Elimination Rate Constant and Half-Life
The dependent parameter K is a first-order rate constant. It is a function of V d and Cl. K can be described as the percentage or fraction of the amount of drug that is cleared from the body per unit time. The units are typically expressed as 1/h (hr−1) or 1/min (min−1). As shown in Eq. 1.6, K can be viewed as a proportionality constant between V d and Cl:
A large K value indicates rapid elimination of the drug. If two drug concentrations are drawn within the same dosing interval, K can be determined using Eq. 1.7 [4]:
Ln is natural log and Δt is the time elapsed between Cp1 and Cp2. The determination of K is integral to calculating half-life, t 1/2, as shown in Eq. 1.8:
Equation 1.8 also shows the relationship among t 1/2 and V d and Cl. The t 1/2 is the amount of time it takes for the drug currently in the body to reduce by 50 %. The t 1/2 can also predict the amount of time it takes for a patient to achieve steady-state drug concentrations (assuming no loading dose and the same dose was administered at the same interval). For example, after one t 1/2, Cp is 50 % of the final steady-state Cpss. Under these conditions, a patient is considered to be clinically at steady state if the drug concentration is >90 % of the true steady-state level. As shown in Table 1.2, it would take approximately 3.3 half-lives for a patient to achieve 90 % of the true steady state. Conversely, it would take 3.3 half-lives for a patient to eliminate 90 % of the drug once the administration of the drug has ceased. To note, t 1/2 determines the dosing interval, but V d and Cl determine the size of the dose.
Pharmacodynamics
The time-course conversion of drug concentration (Ce) into a pharmacological effect (response) is pharmacodynamics. The biosensor process is the detection of the drug’s presence, Ce. Frequently, the biosensor process is the receptor system on the cell’s surface. The white and black biosensor process rectangles indicate that the drug (Ce) either stimulates (white) or inhibits (black) the zero-order and first-order constants k in or k out, respectively. The biosignal is similar to the second messenger, in that it directs the end response. While the pathway in between the biosignal and the response can contain nonlinear and time-varying processes (circadian, drug-induced—such as drug tolerance), it still is the biosignal that is responsible for the end response. Alterations of k in or k out are frequently the sites for the nonlinearities or time-varying processes. This model is known as an “indirect” model and is relatively general; the most important aspect of this model is that a change in Cp is not instantaneously realized as a change in response (Fig. 1.2). Somewhere along the pathway of D, drug, diffusing out of Cp in to Ce or in the translation of D binding to the receptors to produce the response, there is a rate-limiting step that causes the response to lag behind changes in Cp.
A subset model of the indirect model is the direct model. In the direct model, the pharmacodynamic system very rapidly converts the Ce concentration of drug to response relative to the rate at which the Ce or Cp steady state is achieved. Or in other words, there is no time lag, as in the indirect model, between changes in Cp or Ce and response. Typical direct models have the form of \( E={E}_0\pm \frac{E_{\max }{\mathrm{Cp}}^{\gamma }}{{\mathrm{EC}}_{50}^{\gamma }+{\mathrm{Cp}}^{\gamma }} \), where E 0 is the endogenous baseline (i.e., value of E in the absence of drug), E max is the maximal effect achievable, EC50 is the concentration of drug that produces ½ of the E max response, and γ is the Hill coefficient. When γ > 1, the PD is said to have positive cooperativity; when γ < 1, the PD has negative cooperativity; and when γ = 1, the PD has no cooperativity (see Fig. 1.3 for a comparison of γ).
In the more commonly used model, notice that as “dose” or the x-axis changes, the effect or response instantaneously changes. Another way to view this relationship between “dose” and “response” is to assume that the “dose” or “log (Cp)” has reached steady state or equilibrium before the effect has been measured. The direct model can still be used to simulate drug tolerance by either attenuating E max or increasing EC50 as a function of Cp or Ce. The utility of this model cannot be overstated as it has provided many researchers and clinicians with useful pharmacodynamic insights.
Therapeutic Range and Therapeutic Monitoring
Most drugs have established therapeutic ranges. Therapeutic ranges are typically expressed as a range of drug plasma concentrations that achieve an optimal effect while minimizing adverse reactions. However, drugs that require constant monitoring of drug concentrations are ones that have narrow therapeutic ranges, a low threshold for serious adverse reactions, or must reach a minimum plasma concentration to achieve an effect.
In anesthesiology, the minimum alveolar concentration (MAC; Table 1.3) of inhaled anesthetics is used as the target to achieve the necessary therapeutic effect. MAC is the amount of inhaled anesthetic required to inhibit physical movement in response to a noxious stimuli in 50 % of patients [5]. MAC values can also be used to compare the relative potencies between two inhaled anesthetic agents.
The continuous monitoring of plasma concentrations of intravenous anesthetics is not performed due to practicality. The half-lives and durations of action of most intravenous anesthetics are relatively short. It may take several hours for the laboratory to determine anesthetic concentrations. Therefore, anesthetic concentrations do not provide rapid feedback for clinicians to make necessary adjustments to doses during the course of surgery or medical intervention. Thus, monitoring of intravenous anesthetics is reliant on the signs and symptoms of anesthesia for the attainment of therapeutic efficacy and respiratory depression and blood pressure for toxicology.
Table 1.4 summarizes the pharmacokinetic (distribution, metabolism, and renal excretion) and pharmacodynamic properties (onset of action and duration of action) of various anesthetic agents.
Drug Tables (Tables 1.5 and 1.6)
The mechanism of action, indications, contraindications, cautions, pregnancy category, clinical pearls, dosing options, drug interactions, and side effects of commonly-used anesthetic agents are presented in Table 1.5 Lidocaine, with its numerous routes of delivery and dosing options, are presented in Table 1.6.
References
Buxton ILO, Benet LZ. Chapter 2. Pharmacokinetics: the dynamics of drug absorption, distribution, metabolism, and elimination. In: Brunton LL, Chabner BA, BC K, editors. Goodman & Gilman’s the pharmacological basis of therapeutics. New York: McGraw-Hill; 2011.
Wagner JG, Northam JI. Estimation of volume of distribution and half-life of a compound after rapid intravenous injection. J Pharm Sci. 1967;56(4):529–31. Epub 1967/04/01.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31–41. Epub 1976/01/01.
Gibaldi M, Perrier D. Pharmacokinetics, vol. 8. 2nd ed. New York: M. Dekker; 1982. p. 494.
Eger 2nd EI, Saidman LJ, Brandstater B. Minimum alveolar anesthetic concentration: a standard of anesthetic potency. Anesthesiology. 1965;26(6):756–63. Epub 1965/11/01.
Eger 2nd EI. The pharmacology of isoflurane. Br J Anaesth. 1984;56 Suppl 1:71S–99. Epub 1984/01/01.
Product information: FORANE(R) inhalation liquid, isoflurane inhalation liquid. Deerfield: Baxter Healthcare Corporation; 2010.
Strum DP, Eger 2nd EI. Partition coefficients for sevoflurane in human blood, saline, and olive oil. Anesth Analg. 1987;66(7):654–6. Epub 1987/07/01.
Saito S, Goto F, Kadoi Y, Takahashi T, Fujita T, Mogi K. Comparative clinical study of induction and emergence time in sevoflurane and enflurane anaesthesia. Acta Anaesthesiol Scand. 1989;33(5):389–90. Epub 1989/07/01.
Sutton TS, Koblin DD, Gruenke LD, Weiskopf RB, Rampil IJ, Waskell L, et al. Fluoride metabolites after prolonged exposure of volunteers and patients to desflurane. Anesth Analg. 1991;73(2):180–5. Epub 1991/08/01.
Wrigley SR, Fairfield JE, Jones RM, Black AE. Induction and recovery characteristics of desflurane in day case patients: a comparison with propofol. Anaesthesia. 1991;46(8):615–22. Epub 1991/08/01.
Stenqvist O. Nitrous oxide kinetics. Acta Anaesthesiol Scand. 1994;38(8):757–60. Epub 1994/11/01.
Hudson RJ, Stanski DR, Burch PG. Pharmacokinetics of methohexital and thiopental in surgical patients. Anesthesiology. 1983;59(3):215–9. Epub 1983/09/01.
O'Leary J. A clinical investigation of methohexital sodium. Med J Aust. 1962;49(1):594–5. Epub 1962/04/21.
Dhuner KG, Peterhoff V. Clinical trials with methohexital. A new ultra-short-acting barbiturate for intravenous anesthesia. Acta Chir Scand. 1962;123:339–42. Epub 1962/05/01.
Schuttler J, Stoeckel H, Schwilden H. Pharmacokinetic and pharmacodynamic modelling of propofol (‘Diprivan’) in volunteers and surgical patients. Postgrad Med J. 1985;61 Suppl 3:53–4. Epub 1985/01/01.
Oda Y, Hamaoka N, Hiroi T, Imaoka S, Hase I, Tanaka K, et al. Involvement of human liver cytochrome P4502B6 in the metabolism of propofol. Br J Clin Pharmacol. 2001;51(3):281–5. Epub 2001/04/12.
McCollum JS, Dundee JW, Halliday NJ, Clarke RS. Dose response studies with propofol (‘Diprivan’) in unpremedicated patients. Postgrad Med J. 1985;61 Suppl 3:85–7. Epub 1985/01/01.
White PF, Way WL, Trevor AJ. Ketamine–its pharmacology and therapeutic uses. Anesthesiology. 1982;56(2):119–36. Epub 1982/02/01.
Orlando R, Piccoli P, De Martin S, Padrini R, Floreani M, Palatini P. Cytochrome P450 1A2 is a major determinant of lidocaine metabolism in vivo: effects of liver function. Clin Pharmacol Ther. 2004;75(1):80–8. Epub 2004/01/30.
Prilocaine. In: DRUGDEX system [internet database]. Greenwood Village: Thomson Reuters (Healthcare) Inc. Updated periodically.
Reynolds F. Metabolism and excretion of bupivacaine in man: a comparison with mepivacaine. Br J Anaesth. 1971;43(1):33–7. Epub 1971/01/01.
Moore DC, Bridenbaugh LD, Bridenbaugh PO, Tucker GT. Bupivacaine. A review of 2,077 cases. JAMA J Am Med Assoc. 1970;214(4):713–8.
Brockway MS, Bannister J, McClure JH, McKeown D, Wildsmith JA. Comparison of extradural ropivacaine and bupivacaine. Br J Anaesth. 1991;66(1):31–7. Epub 1991/01/01.
van Oss GE, Vree TB, Baars AM, Termond EF, Booij LH. Pharmacokinetics, metabolism, and renal excretion of articaine and its metabolite articainic acid in patients after epidural administration. Eur J Anaesthesiol. 1989;6(1):49–56. Epub 1989/01/01.
Thomas JM, Schug SA. Recent advances in the pharmacokinetics of local anaesthetics. Long-acting amide enantiomers and continuous infusions. Clin Pharmacokinet. 1999;36(1):67–83. Epub 1999/02/16.
Burm AG. Clinical pharmacokinetics of epidural and spinal anaesthesia. Clin Pharmacokinet. 1989;16(5):283–311. Epub 1989/05/01.
Jensen OT, Upton LG, Hayward JR, Sweet RB. Advantages of long-acting local anesthesia using etidocaine hydrochloride. J Oral Surg. 1981;39(5):350–3. Epub 1981/05/01.
Axelsson K, Nydahl PA, Philipson L, Larsson P. Motor and sensory blockade after epidural injection of mepivacaine, bupivacaine, and etidocaine–a double-blind study. Anesth Analg. 1989;69(6):739–47. Epub 1989/12/01.
Isoflurane. In: DRUGDEX System [Internet database]. Greenwood Village: Thomson Reuters (Healthcare) Inc. Updated periodically.
Isoflurane. In: DRUG-REAX® system [internet database]. Greenwood Village: Thomson Healthcare. Updated periodically.
Grasshoff C, Antkowiak B. Effects of isoflurane and enflurane on GABAA and glycine receptors contribute equally to depressant actions on spinal ventral horn neurones in rats. Br J Anaesth. 2006;97(5):687–94. Epub 2006/09/16.
Eger 2nd EI, Stevens WC, Cromwell TH. The electroencephalogram in man anesthetized with forane. Anesthesiology. 1971;35(5):504–8. Epub 1971/11/01.
Wade JG, Stevens WC. Isoflurane: an anesthetic for the eighties? Anesth Analg. 1981;60(9):666–82. Epub 1981/09/01.
Product information: ULTANE(R) inhalation liquid, sevoflurane inhalation liquid. North Chicago: Abbott Laboratories (per FDA); 2012.
Sevoflurane. In: DRUGDEX system [internet database]. Greenwood Village: Thomson Reuters (Healthcare) Inc. Updated periodically.
Product information: sevoflurane, USP – volatile liquid for inhalation. Deerfield: Baxter Healthcare Corporation; 2008.
Sevoflurane. In: DRUG-REAX® system [internet database]. Greenwood Village: Thomson Healthcare. Updated periodically.
Wu J, Harata N, Akaike N. Potentiation by sevoflurane of the gamma-aminobutyric acid-induced chloride current in acutely dissociated CA1 pyramidal neurones from rat hippocampus. Br J Pharmacol. 1996;119(5):1013–21. Epub 1996/11/01.
Stabernack CR, Eger 2nd EI, Warnken UH, Forster H, Hanks DK, Ferrell LD. Sevoflurane degradation by carbon dioxide absorbents may produce more than one nephrotoxic compound in rats. Canadian journal of anaesthesia. J Can Anesth. 2003;50(3):249–52.
Product information: SUPRANE(R) liquid for inhalation, desflurane liquid for inhalation. Deerfield: Baxter Healthcare Corporation; 2005
Desflurane. In: DRUGDEX system [internet database]. Greenwood Village: Thomson Reuters (Healthcare) Inc. Updated periodically.
Nishikawa K, Harrison NL. The actions of sevoflurane and desflurane on the gamma-aminobutyric acid receptor type A: effects of TM2 mutations in the alpha and beta subunits. Anesthesiology. 2003;99(3):678–84. Epub 2003/09/10.
Fletcher JE, Sebel PS, Murphy MR, Smith CA, Mick SA, Flister MP. Psychomotor performance after desflurane anesthesia: a comparison with isoflurane. Anesth Analg. 1991;73(3):260–5. Epub 1991/09/01.
Desflurane. In: DRUG-REAX® system [internet database]. Greenwood Village: Thomson Healthcare. Updated periodically.
Rampil IJ, Lockhart SH, Zwass MS, Peterson N, Yasuda N, Eger 2nd EI, et al. Clinical characteristics of desflurane in surgical patients: minimum alveolar concentration. Anesthesiology. 1991;74(3):429–33. Epub 1991/03/01.
Caldwell JE. Desflurane clinical pharmacokinetics and pharmacodynamics. Clin Pharmacokinet. 1994;27(1):6–18. Epub 1994/07/01.
Sakai EM, Connolly LA, Klauck JA. Inhalation anesthesiology and volatile liquid anesthetics: focus on isoflurane, desflurane, and sevoflurane. Pharmacotherapy. 2005;25(12):1773–88. Epub 2005/11/25.
Sweetman SC, editor. Martindale: the complete drug reference. [online] London: Pharmaceutical Press. http://www.medicinescomplete.com. Accessed 30 Mar 2013.
Nitrous oxide. In: DRUGDEX system [internet database]. Greenwood Village: Thomson Reuters (Healthcare) Inc. Updated periodically.
Yamakura T, Harris RA. Effects of gaseous anesthetics nitrous oxide and xenon on ligand-gated ion channels. Comparison with isoflurane and ethanol. Anesthesiology. 2000;93(4):1095–101. Epub 2000/10/06.
Mennerick S, Jevtovic-Todorovic V, Todorovic SM, Shen W, Olney JW, Zorumski CF. Effect of nitrous oxide on excitatory and inhibitory synaptic transmission in hippocampal cultures. J Neurosci. 1998;18(23):9716–26. Epub 1998/11/21.
Micromedex healthcare series: nitrous oxide. Greenwood Village: Thomson Reuters (Healthcare) Inc. Updated periodically.
Kunitz O, Baumert JH, Hecker K, Beeker T, Coburn M, Zuhlsdorff A, et al. Xenon does not prolong neuromuscular block of rocuronium. Anesth Analg. 2004;99(5):1398–401; table of contents. Epub 2004/10/27.
Derwall M, Coburn M, Rex S, Hein M, Rossaint R, Fries M. Xenon: recent developments and future perspectives. Minerva Anestesiol. 2009;75(1–2):37–45. Epub 2008/05/14.
Senno A, Schweitzer P, Merrill C, Clauss R. Arteriovenous fistulas of the internal mammary artery. Rev Lit J Cardiovasc Surg. 1975;16(3):296–301. Epub 1975/05/01.
Hanne P, Marx T, Musati S, Santo M, Suwa K, Morita S. Xenon: uptake and costs. Int Anesthesiol Clin. 2001;39(2):43–61. Epub 2001/08/17.
Sanders RD, Ma D, Maze M. Xenon: elemental anaesthesia in clinical practice. Br Med Bull. 2004;71:115–35. Epub 2005/02/25.
Reinelt H, Marx T, Kotzerke J, Topalidis P, Luederwald S, Armbruster S, et al. Hepatic function during xenon anesthesia in pigs. Acta Anaesthesiol Scand. 2002;46(6):713–6. Epub 2002/06/13.
Zhang P, Ohara A, Mashimo T, Imanaka H, Uchiyama A, Yoshiya I. Pulmonary resistance in dogs: a comparison of xenon with nitrous oxide. Can J Anaesth. 1995;42(6):547–53.
Prielipp RC. An anesthesiologist’s perspective on inhaled anesthesia decision-making. Am J Health Syst Pharm. 2010;67(8 Suppl 4):S13–20. Epub 2010/04/14.
Baur CP, Klingler W, Jurkat-Rott K, Froeba G, Schoch E, Marx T, et al. Xenon does not induce contracture in human malignant hyperthermia muscle. Br J Anaesth. 2000;85(5):712–6. Epub 2000/11/30.
Petersen-Felix S, Luginbuhl M, Schnider TW, Curatolo M, Arendt-Nielsen L, Zbinden AM. Comparison of the analgesic potency of xenon and nitrous oxide in humans evaluated by experimental pain. Br J Anaesth. 1998;81(5):742–7. Epub 1999/04/08.
Lachmann B, Armbruster S, Schairer W, Landstra M, Trouwborst A, Van Daal GJ, et al. Safety and efficacy of xenon in routine use as an inhalational anaesthetic. Lancet. 1990;335(8703):1413–5. Epub 1990/06/16.
Product information: PENTOTHAL(R) IV injection, thiopental sodium IV injection. Lake Forest: Hospira, Inc; 2004.
Thiopental. In: DRUGDEX system [internet database]. Greenwood Village: Thomson Reuters (Healthcare) Inc. Updated periodically.
Thiopental. In: DRUG-REAX® system [internet database]. Greenwood Village: Thomson Healthcare. Updated periodically.
Higashi H, Nishi S. Effect of barbiturates on the GABA receptor of cat primary afferent neurones. J Physiol. 1982;332:299–314. Epub 1982/11/01.
Wada DR, Bjorkman S, Ebling WF, Harashima H, Harapat SR, Stanski DR. Computer simulation of the effects of alterations in blood flows and body composition on thiopental pharmacokinetics in humans. Anesthesiology. 1997;87(4):884–99. Epub 1997/11/14.
Pandele G, Chaux F, Salvadori C, Farinotti M, Duvaldestin P. Thiopental pharmacokinetics in patients with cirrhosis. Anesthesiology. 1983;59(2):123–6. Epub 1983/08/01.
Product information: BREVITAL(R) SODIUM intravenous injection, rectal injection, intramuscular injection, methohexital sodium intravenous injection, rectal injection, intramuscular injection. Rochester: JHP Pharmaceuticals; 2009.
Methohexital. In: DRUGDEX system [internet database]. Greenwood Village: Thomson Reuters (Healthcare) Inc. Updated periodically.
Product information: Brevital(R), methohexital. Indianapolis: Eli Lilly and Company; 2001.
Methohexital. In: DRUG-REAX® system [internet database]. Greenwood Village: Thomson Healthcare. Updated periodically.
Bahn EL, Holt KR. Procedural sedation and analgesia: a review and new concepts. Emerg Med Clin North Am. 2005;23(2):503–17. Epub 2005/04/15.
Product information: DIPRIVAN(R) IV injectable emulsion, propofol IV injectable emulsion. Schaumburg: APP Pharmaceuticals LLC; 2008.
Propofol. In: DRUGDEX system [internet database]. Greenwood Village: Thomson Reuters (Healthcare) Inc. Updated periodically.
Propofol. In: DRUG-REAX® system [internet database]. Greenwood Village: Thomson Healthcare. Updated periodically.
Hara M, Kai Y, Ikemoto Y. Propofol activates GABAA receptor-chloride ionophore complex in dissociated hippocampal pyramidal neurons of the rat. Anesthesiology. 1993;79(4):781–8. Epub 1993/10/01.
Product information: AMIDATE (etomidate) injection, solution. Lake Forest: Hospira, Inc; 2011.
Etomidate. In: DRUGDEX System [Internet database]. Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc. Updated periodically.
Etomidate. In: DRUG-REAX® system [internet database]. Greenwood Village: Thomson Healthcare. Updated periodically.
Morgan M, Lumley J, Whitwam JG. Etomidate, a new water-soluble non-barbiturate intravenous induction agent. Lancet. 1975;1(7913):955–6. Epub 1975/04/26.
Doenicke A, Lorenz W, Beigl R, Bezecny H, Uhlig G, Kalmar L, et al. Histamine release after intravenous application of short-acting hypnotics. A comparison of etomidate, Althesin (CT1341) and propanidid. Br J Anaesth. 1973;45(11):1097–104.
Product information: KETAMINE HYDROCHLORIDE injection, solution. Rockford: Mylan Institutional, LLC; 2012.
Ketamine. In: DRUGDEX system [internet database]. Greenwood Village: Thomson Reuters (Healthcare) Inc. Updated periodically.
Anis NA, Berry SC, Burton NR, Lodge D. The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N-methyl-aspartate. Br J Pharmacol. 1983;79(2):565–75. Epub 1983/06/01.
Product information: KETAMINE HYDROCHLORIDE injection. Bedford: Bedford Laboratories; 2012.
Product information: NESACAINE – chloroprocaine hydrochloride injection. Wilmington: AstraZeneca; 2004.
Chloroprocaine. In: DRUGDEX system [internet database]. Greenwood Village: Thomson Reuters (Healthcare) Inc. Updated periodically.
Product information: novocaine (procaine hydrochloride) injection, solution. Lake Forest: Hospira, Inc.; 2004.
Procaine. In: DRUGDEX system [internet database]. Greenwood Village: Thomson Reuters (Healthcare) Inc. Updated periodically.
Lidocaine. In: Lexi-comp online. Hudson: Lexi-Comp, Inc.
Product information: XYLOCAINE (lidocaine hydrochloride) injection, solution. Schaumburg: APP Pharmaceuticals, LLC; 2011.
Lidocaine. In: DRUGDEX System [Internet database]. Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc. Updated periodically.
Product information: lidocaine hydrochloride and dextrose – lidocaine hydrochloride anhydrous and dextrose monohydrate injection, solution. Lake Forest: Hospira, Inc.; 2010.
Strichartz GR. The inhibition of sodium currents in myelinated nerve by quaternary derivatives of lidocaine. J Gen Physiol. 1973;62(1):37–57. Epub 1973/07/01.
Product information: prilocaine hydrochloride – prilocaine hydrochloride injection, solution. Louisville: Novocol Pharmaceutical of Canada, Inc.; 2010.
Product information: marcaine spinal – bupivacaine hydrochloride injection, solution. Lake Forest: Hospira, Inc.; 2011.
Bupivacaine. In: DRUGDEX system [internet database]. Greenwood Village: Thomson Reuters (Healthcare) Inc. Updated periodically.
Moore PA. Bupivacaine: a long-lasting local anesthetic for dentistry. Oral Surg Oral Med Oral Pathol. 1984;58(4):369–74. Epub 1984/10/01.
Product information: NAROPIN (ropivacaine hydrochloride monohydrate) injection, solution. East Schaumburg: APP Pharmaceuticals; 2009.
Ropivacaine. In: DRUGDEX system [internet database]. Greenwood Village: Thomson Reuters (Healthcare) Inc. Updated periodically.
Raeder JC, Drosdahl S, Klaastad O, Kvalsvik O, Isaksen B, Stromskag KE, et al. Axillary brachial plexus block with ropivacaine 7.5 mg/ml. A comparative study with bupivacaine 5 mg/ml. Acta Anaesthesiol Scand. 1999;43(8):794–8.
Product information: carbocaine (mepivacaine hydrochloride) injection, solution. Lake Forest: Hospira, Inc.; 2010.
Mepivacaine. In: DRUGDEX system [internet database]. Greenwood Village: Thomson Reuters (Healthcare) Inc. Updated periodically.
Product information: articadent – articaine hydrochloride and epinephrine bitartrate injection, solution. Cambridge: Novocol Pharmaceutical of Canada, Inc.; 2009.
Articaine. In: DRUGDEX system [internet database]. Greenwood Village: Thomson Reuters (Healthcare) Inc. Updated periodically.
Product information: tetracaine hydrochloride – tetracaine hydrochloride solution. Fort Worth: Alcon Laboratories, Inc.; 2010.
Tetracaine. In: DRUGDEX system [internet database]. Greenwood Village: Thomson Reuters (Healthcare) Inc. Updated periodically.
Levobupivacaine. In: DRUGDEX system [internet database]. Greenwood Village: Thomson Reuters (Healthcare) Inc. Updated periodically.
Levobupivacaine. In: DRUG-REAX® system [internet database]. Greenwood Village: Thomson Healthcare. Updated periodically.
Etidocaine. In: DRUGDEX system [internet database]. Greenwood Village: Thomson Reuters (Healthcare) Inc. Updated periodically.
Etodicaine. In: DRUG-REAX® system [internet database]. Greenwood Village: Thomson Healthcare. Updated periodically.
Aziz TS. Xenon in anesthesia. Int Anesthesiol Clin. 2001;39(2):1–14. Epub 2001/08/17.
Van Hamme MJ, Ghoneim MM, Ambre JJ. Pharmacokinetics of etomidate, a new intravenous anesthetic. Anesthesiology. 1978;49(4):274–7. Epub 1978/10/01.
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Chan, P., Uchizono, J.A. (2015). Pharmacokinetics and Pharmacodynamics of Anesthetics. In: Kaye, A., Kaye, A., Urman, R. (eds) Essentials of Pharmacology for Anesthesia, Pain Medicine, and Critical Care. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-8948-1_1
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