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http://www.pharmacopeia.cn/v29240/usp29nf24s0_c785.html http://en.wikipedia.org/wiki/Plasma_osmolality http://en.wikipedia.org/wiki/Osmometer OSMOLALITY AND OSMOLARITY Definitions: www.osmolality.com Solutions: A homogeneous mixture of solutes in a solvent Solvent: The major, liquid component of a solution Solutes: The minor components of a solution – usually solids Concentration: The relative amount of solute in a solution. Can be expressed in many ways: solute to solvent, solute to solution, mass to mass, mass to volume, etc. Molarity: Molar concentration: grams of solute per litre of solution Molality: Molal concentration: grams of solute per kilogram of solvent Measured by alteration of colligative properties 1. Elevation of boiling point 2. Depression of freezing point 3. Depression of vapour pressure 4. Elevation of osmotic pressure Molecular weight: The sum of the atomic weights of all the atoms in a molecule Mole: Gram molecular weight, molecular weight expressed in grams. One mole of sodium chloride weighs 58.44 grams. Ionic solution: Certain molecules, when dissolved, dissociate into charged particles called ions Non-ionic solution: Certain molecules, when dissolved, do not dissociate or ionize into charged particles. Avogadro’s Number: The number of molecules in one mole (gram molecular weight) of a substance. One mole of non-ionic solute (such as sucrose) dissolved in one kilogram of water will yield Avogadro’s number of molecules. One mole of ionic solute dissolved in one kilogram of water will yield almost twice Avogadro’s number of particles. Colligative / Concentrative properties: When a solute is dissolved in a solvent, certain properties of the solvent (freezing point, boiling point, vapor pressure and osmotic pressure) are changed nearly in proportion to the concentration of the solute, expressed in dissolved particles. Avogadro’s number of particles, regardless of their size or shape, when dissolved in a kilogram of water, will change each of the concentrative properties a specific amount. INTRODUCTION Osmotic pressure plays a critical role in all biological processes that involve diffusion of solutes or transfer of fluids through membranes. Osmosis occurs when solvent but not solute molecules cross a semi-permeable membrane from regions of lower to higher concentrations to produce equilibrium. The knowledge of osmotic pressures is important for practitioners in determining whether a parenteral solution is hypo-osmotic, iso-osmotic, or hyperosmotic. A quantitative measure of osmotic pressure facilitates the dilution required to render a solution iso-osmotic relative to whole blood. OSMOTIC PRESSURE The osmotic pressure of a solution depends on the number of particles in solution, and is therefore referred to as a colligative property. A particle can be a molecule or an ion or an aggregated species (e.g., a dimer) that can exist discretely in solution. A solution exhibits ideal behavior when no interaction occurs between solutes and solvent, except where solvent molecules are bound to solutes by hydrogen bonding or coordinate covalency. For such a solution containing a nondissociating solute, the osmotic pressure ( ) is directly proportional to its molality (number of moles of solute per kilogram of the solvent): = ( RT/1000)m, where is the density of the solvent at the temperature T (in the absolute scale); R is the universal gas constant; and m is the molality of the solution. For a real solution containing more than one solute, the osmotic pressure is given by the formula: = ( RT/1000)Σ imiΦm,i, where i is the number of particles formed by the dissociation of one molecule of the ith solute; i = 1 for non-ionic (nondissociating) solutes; mi is the molality of the ith solute; and Φm,i is the molal osmotic coefficient of the ith solute. The molal osmotic coefficient takes into account the deviation of a solution from ideal behavior. Its value depends upon the concentration of the solute(s) in solution, its chemical properties, and ionic characteristics. The value of the molal osmotic coefficient of a solute can be determined experimentally by measuring the freezing point depression at different molal concentrations. At concentrations of pharmaceutical interest, the value of the molal osmotic coefficient is less than one. The molal osmotic coefficient decreases with the increase in concentration of the solute (Table 1). OSMOLALITY The osmolality of a solution m is given by m = Σ imiΦm,i. The osmolality of a real solution corresponds to the molality of an ideal solution containing nondissociating solutes and is expressed in osmoles or milliosmoles per kilogram of solvent (Osmol per kg or mOsmol per kg, respectively), a unit that is similar to the molality of the solution. Thus, osmolality is a measure of the osmotic pressure exerted by a real solution across a semi-permeable membrane. Like osmotic pressure, other colligative properties of a solution, such as vapour pressure lowering, boiling point elevation, and freezing point depression, are also directly related to the osmolality of the solution. Indeed, the osmolality of a solution is typically determined most accurately and conveniently by measuring freezing point depression (∆Tf): ∆Tf = kf m, where kf is the molal cryoscopic constant, which is a property of the solvent. For water, the value of kf is 1.860 per Osmol. That is, 1 Osmol of a solute added to 1 kg of water lowers the freezing point by 1.860 . OSMOLARITY Osmolarity of a solution is a theoretical quantity expressed in osmoles per L (Osmol per L) of a solution and is widely used in clinical practice because it expresses osmoles as a function of volume. Osmolarity cannot be measured but is calculated theoretically from the experimentally measured value of osmolality. Sometimes, osmolarity ( c) is calculated theoretically from the molar concentrations: c = Σ ici, where i is as defined above, and ci is the molar concentration of the ith solute in solution. For example, the osmolarity of a solution prepared by dissolving 1 g of vancomycin in 100 ml of 0.9% sodium chloride solution can be calculated as follows: [3 × 10 g/L/1468 (mol. wt. of vancomycin) + 2 × 9 g/L/58.5 (mol. wt. of sodium chloride)] × 1000 = 328 mOsmol/L. The results suggest that the solution is slightly hyperosmotic since the osmolality of blood ranges between 285 and 310 mOsmol per kg. However, the solution is found to be hypo-osmotic and has an experimentally determined osmolality of 255 mOsmol per kg.1 The example illustrates that osmolarity values calculated theoretically from the concentration of a solution should be interpreted cautiously and may not represent the osmotic properties of infusion solutions. The discrepancy between theoretical (osmolarity) and experimental (osmolality) results is, in part, due to the fact that osmotic pressure is related to osmolality and not osmolarity. More significantly, the discrepancy between experimental results and the theoretical calculation is due to the fact that the osmotic pressure of a real solution is less than that of an ideal solution because of interactions between solute molecules or between solute and solvent molecules in a solution. Such interactions reduce the pressure exerted by solute molecules on a semipermeable membrane, reducing experimental values of osmolality compared to theoretical values. This difference is related to the molal osmotic coefficient (Φm,i). The example also illustrates the importance of determining the osmolality of a solution experimentally, rather than calculating the value theoretically. MEASUREMENT OF OSMOLALITY The osmolality of a solution is commonly determined by the measurement of the freezing point depression of the solution. Apparatus— The apparatus, an osmometer for freezing point depression measurement, consists of the following: a means of cooling the container used for the measurement; a resistor sensitive to temperature (thermistor), with an appropriate current- or potential-difference measurement device that may be graduated in temperature change or in osmolality; and a means of mixing the sample. Osmometers that measure the vapor pressures of solutions are less frequently employed. They require a smaller volume of specimen (generally about 5 µL), but the accuracy and precision of the resulting osmolality determination are comparable to those obtained by the use of osmometers that depend upon the observed freezing points of solutions. Standard Solutions— Prepare Standard Solutions as specified in Table 1, as necessary. Table 1. Standard Solutions for Osmometer Calibration2 Standard Solutions Osmolality (Weight in g of sodium chloride per kg (mOsmol/kg) of water) ( m) Molal Osmotic Coefficient (Φm, NaCl) Freezing Point Depression ( ) ∆Tf 3.087 100 0.9463 0.186 6.260 200 0.9337 0.372 9.463 300 0.9264 0.558 12.684 400 0.9215 0.744 15.916 500 0.9180 0.930 19.147 600 0.9157 1.116 22.380 700 0.9140 1.302 2 Adapted from the European Pharmacopoeia, 4th Edition, 2002, p. 50. Test Solution— For a solid for injection, constitute with the appropriate diluent as specified in the instructions on the labeling. For solutions, use the sample as is. [NOTE—A solution can be diluted to bring it within the range of measurement of the osmometer, if necessary, but the results must be expressed as that of the diluted solution and must NOT be multiplied by a dilution factor to calculate the osmolality of the original solution. The molal osmotic coefficient is a function of concentration. Therefore, it changes with dilution.] Procedure— Set the zero of the apparatus using water. To calibrate the apparatus, choose at least two solutions from Table 1 such that the osmolalities of the Standard Solutions span the expected range of osmolality of the Test Solution. Introduce an appropriate volume of each Standard Solution into the measurement cell as per the manufacturer's instructions, and start the cooling system. Usually, the mixing device is programmed to operate at a temperature below the lowest temperature expected from the freezing point depression. The apparatus indicates when the equilibrium is attained. Calibrate the osmometer using an appropriate adjustment device such that the reading corresponds to either the osmolality or freezing point depression value of the Standard Solution shown in Table 1. [NOTE—Some instruments indicate osmolality and some others show freezing point depression.] Before each measurement, rinse the measurement cell at least twice with the solution to be tested. Repeat the procedure with each Test Solution. Read the osmolality of the Test Solution directly, or calculate it from the measured freezing point depression. Assuming that the value of the osmotic coefficient is essentially the same whether the concentration is expressed in molality or molarity, the experimentally determined osmolality of a solution can be converted to osmolarity in the same manner in which the concentration of a solution is converted from molality to molarity. Unless a solution is very concentrated, the osmolarity of a solution ( c) can be calculated from its experimentally determined osmolality ( m): c = 1000 m / (1000 / where wi is the weight in g; and + Σwi i), i is the partial specific volume, in mL per g, of the ith solute. The partial specific volume of a solute is the change in volume of a solution when an additional 1 g of solute is dissolved in the solution. This volume can be determined by the measurement of densities of the solution before and after the addition of the solute. The partial specific volumes of salts are generally very small, around 0.1 mL per g. However, those of other solutes are generally higher. For example, the partial specific volumes of amino acids are in the range of 0.6–0.9 mL per g. 1 Kastango, E.S. and Hadaway, L. International Journal of Pharmaceutical Compounding 5, (2001) 465-469. Auxiliary Information— Staff Liaison : Horacio Pappa, Ph.D. Expert Committee : (GC05) General Chapters 05 USP29–NF24 Page 2718 Pharmacopeial Forum : Volume No. 31(3) Page 845 Phone Number : 1-301-816-8319 Osmometer From Wikipedia, the free encyclopedia Jump to: navigation, search An osmometer is a device for measuring the osmotic strength of a solution, colloid, or compound. There are several different techniques employed in osmometry: • • • Vapor pressure depression osmometers determine the concentration of osmotically active particles that reduce the vapor pressure of a solution. Membrane osmometers measure the osmotic pressure of a solution separated from pure solvent by a semipermeable membrane. Freezing point depression osmometer may also be used to determine the osmotic strength of a solution, as osmotically active compounds depress the freezing point of a solution. Osmometers are useful for determining the concentration of dissolved salts or sugars in blood or urine samples. Osmometry is also useful in determining the molecular weight of unknown compounds and polymers. Osmometry is the measurement of the osmotic strength of a substance [1]. This is often used by chemists for the determination of average molecular weight Pharmacokinetics and anaesthesia Fred Roberts MB ChB FRCA Dan Freshwater-Turner MA MB BChir MRCP Key points General principles Membrane transfer Drugs need to cross cell membranes in order to produce their effects (e.g. gastro-intestinal absorption, reaching intracellular sites of action). Such transfer occurs more readily with a: † † † † low degree of ionization low molecular weight high lipid solubility high concentration gradient The extent of ionization is influenced substantially by environmental pH, an effect that is used to prepare highly ionized, aqueous solutions of acidic drugs such as thiopental (solution pH 10.5) or basic ones such as lidocaine (solution pH 5.2), as shown in Fig. 1. In the more neutral pH of the body, much of the drug reverts to the unionized form enabling membrane transfer to reach its site of action. If this change in pH does not occur, the drug cannot become unionized and will be ineffective (e.g. lidocaine in the acidic environment of infected tissue). Partial pressure and solubility For an inhaled drug, it is the partial pressure that largely determines its behaviour, both for moving between phases and producing pharmacodynamic effects at the site of action. In a gas mixture at sea level, because atmospheric pressure is 101.3 kPa, partial pressure (kPa) is often used interchangeably with fractional concentration (%). However, in solution, partial pressure cannot be equated to blood concentration because of wide variation in solubility. Gas solubility in blood is usually expressed as the blood– gas partition coefficient (BGPC), defined as the volume of gas dissolved in a unit volume of blood when at equilibrium with the gas alone. A more soluble drug (high BGPC) requires a greater number of molecules to be dissolved to exert a given partial pressure than a less-soluble one (low BGPC). Recommended drug doses are derived from average values in population studies and provide no certainty of response in a specific individual. Elimination half-life at steady state is of limited value in describing the recovery profile of a drug administered for a short period only. Contextsensitive half-time provides more useful information under these circumstances. If a drug is given as a constant rate infusion, steady-state concentration will only be achieved after four to five halflives. Partial pressure largely determines the behaviour of an inhaled drug. For maintenance of anaesthesia, a predictable steady state is easier to achieve with an inhalational agent than an i.v. one. Exponential processes Pharmacokinetic processes usually occur at a rate proportional to the concentration gradient at the time. As the process continues, the concentration gradient falls, thus progressively slowing the rate of change. This results in an exponential relationship between concentration and time and applies to most drug elimination and transfer between tissues. There are two ways in which an exponential function can be described (Fig. 2). If a specified time period is set, the decline is defined by the fraction by which the concentration has been reduced during this interval. This is the elimination rate constant (k), expressed as time21. Alternatively, a given fractional reduction in concentration is set, and the time doi:10.1093/bjaceaccp/mkl058 Continuing Education in Anaesthesia, Critical Care & Pain | Volume 7 Number 1 2007 & The Board of Management and Trustees of the British Journal of Anaesthesia [2007]. All rights reserved. For Permissions, please email: [email protected] Fred Roberts MB ChB FRCA Consultant Anaesthetist and Honorary Clinical Lecturer Department of Anaesthesia Royal Devon and Exeter Hospital (Wonford) Barrack Road, Exeter EX2 5DW UK Tel: þ 44 01392 402474 E-mail: [email protected] (for correspondence) Dan Freshwater-Turner MA MB BChir MRCP Associate Lecturer University of Queensland and Senior Registrar in Intensive Care Medicine Royal Brisbane and Women’s Hospital Brisbane Australia 25 Downloaded from ceaccp.oxfordjournals.org by Richard Hodgson on October 3, 2010 Pharmacokinetics explains what happens to a drug in the body, whereas pharmacodynamics describes the actions produced by the drug on the body. Therefore, the effects of a drug result from a combination of its pharmacokinetic and pharmacodynamic characteristics in that individual. Wherever possible, drug administration should be based on a measured patient response, which will incorporate both of these aspects of its pharmacology. However, such an approach may not always be possible. The response may be masked by other factors (e.g. neuromuscular blockers masking signs of anaesthetic depth) or difficult to quantify precisely (e.g. action of antibiotics or anti-emetics). Under these circumstances, previously established pharmacokinetic and pharmacodynamic data are used to guide administration. This article aims to explain and simplify the principles of pharmacokinetics so that their application to clinical practice can be better understood. Pharmacokinetics and anaesthesia taken to achieve this level is found. If a 50% reduction in concentration is used, the time taken is the half-life (t1/2); this will be constant whatever starting drug concentration is used. Another time period that can be used to describe the curve is the time constant (t). This is the point at which the elimination of drug would have been completed if the process had continued at its initial rate; it corresponds with a reduction in concentration to 37% of the original value. Pharmacological compartments Drugs are not distributed uniformly throughout the body. The speed with which a drug reaches a particular tissue is largely dependent on its local blood flow, and for analytical convenience, similar tissue types are often grouped together into various ‘compartments’ depending on their blood supply. The capacity of each compartment to act as a reservoir for the drug is determined by a combination of its size and affinity for the drug. It is important to note that pharmacokinetic compartments are mathematical models and do not correspond to actual tissues; Fig. 3 Illustration of a three-compartment model for a lipid-soluble drug. Pipe size represents blood flow and tank size the capacity as a drug reservoir. they are a concepts enabling the prediction of the pharmacokinetic behaviour of drugs. When performing mathematical modelling, it is likely that a lipid-soluble drug that is widely distributed is likely to have several compartments; a highly ionized drug that remains in the extracellular space is likely to be best described by assuming a one-compartment model. An example of a three-compartment model is shown in Fig. 3; these correspond to vessel-rich, intermediate, and vessel-poor tissues, with a central compartment (blood), through which drugs must pass during uptake or elimination. Because movement between compartments is dependent on the concentration difference between them, the process is exponential and the rate of transfer to the slower tissues decreases as they accumulate more drug. Volume of distribution When a drug has been fully distributed throughout the body and the system is at equilibrium, the volume within which the drug is contained is called the volume of distribution at steady state (Vss d ). It is a theoretical value expressed as the volume of blood which would be necessary to contain the entire drug present in the body, at the equilibrium concentration (units litre kg21). For a lipid-soluble drug (e.g. fentanyl) a litre of fat will hold many times more drug than a litre of blood, and thus its Vss d (4 litre kg21) will be much greater than the total body volume. In contrast, a highly ionized drug (e.g. glycopyrrolate) that does not 21 readily cross lipid membranes has a Vss . d of only 0.16 litre kg Clearance Fig. 2 Exponential decline. C0 initial concentration; t12 half-life; t, time constant 26 Although a drug may be widely distributed throughout the body, it is usually removed only from the blood. Clearance (Cl) is a concept used to describe this, and it represents the volume of blood from which the drug is completely eliminated in unit time. For example, if the concentration in blood is reduced by 20% in an hour, the result is equivalent to removing the entire drug from 20% Continuing Education in Anaesthesia, Critical Care & Pain j Volume 7 Number 1 2007 Downloaded from ceaccp.oxfordjournals.org by Richard Hodgson on October 3, 2010 Fig. 1 Ionization and environmental pH. Red arrows indicate the pH at which lidocaine (a weak base) and thiopental (a weak acid) are prepared in solution. At body pH, much of the drug becomes unionized and can cross membranes. Pharmacokinetics and anaesthesia of the blood volume (1000 ml), corresponding to a clearance of 1000 ml h21 or 16.7 ml min21; it is stated that clearance is also often adjusted for body weight. A large elimination rate constant (k) produces a short elimination half-life (t12); this will result from a high (Cl) or a small volume of distribution (Vss d ). Pharmacokinetic pathway In general, the passage of a drug through the body can be separated into three distinct phases: uptake, distribution, and elimination. Different routes of administration produce variability in the rate of drug uptake and amount of drug delivered effectively to the body. I.V. administration of a drug results in the entire dose entering the plasma immediately, although it must pass initially through the pulmonary circulation and some drugs (e.g. fentanyl) have significant take-up by the lungs. Gastrointestinal (GI) administration requires the drug to cross the intestinal wall. The rate of absorption depends on surface area, pH, and, in some drugs, active systems. In general, unionized drugs (e.g. ethanol) are well absorbed throughout the intestine; absorption of weak acids (e.g. aspirin) is facilitated by a low pH and weak bases (e.g. morphine) by a high pH. For drugs that remain completely ionized throughout the gut (e.g. glycopyrrolate), passive GI absorption is negligible. Even after GI absorption, a drug may not reach the systemic circulation. Metabolism can occur in the gut mucosa (e.g. dopamine) or in the liver during its first pass via the portal vein (e.g. propranolol). This problem can be circumvented by administration at a site that avoids the portal circulation such as sublingual or, to some extent, rectal. The degree to which an administered drug reaches the systemic bloodstream is termed its bioavailability (Fig. 4). Uptake after intramuscular or subcutaneous administration is largely dependent on local blood flow rather than ionization or lipid solubility. The transdermal route can be used for highly Fig. 4 Oral bioavailability. Same dose administered i.v. and orally on separate occasions. Oral bioavailability ¼ area under curveoral/area under curvei.v.. † high fractional concentration of inhaled drug † high minute ventilation † low BGPC Downloaded from ceaccp.oxfordjournals.org by Richard Hodgson on October 3, 2010 Uptake lipid-soluble drugs (e.g. GTN, fentanyl), where slow absorption eventually produces sustained blood concentrations. A fundamentally different pattern of uptake is seen for an inhaled drug in that it crosses the alveolar membrane into the blood along its partial pressure gradient. This produces an exponential wash-in, until at equilibrium (i.e. the partial pressure in blood equals that in the inspired and expired gas) no further net uptake occurs. A clinical effect requires sufficient uptake to exert an adequate partial pressure in the body tissues; it is achieved most rapidly by a: The faster speed of onset produced by a low BGPC reflects the smaller number of molecules needed in solution to exert a partial pressure. A low cardiac output can also accelerate the uptake somewhat, with reduced perfusion to areas outside the vessel-rich group resulting in less drug needed to be taken up from the alveoli. Alveolar partial pressure, measurable from end-tidal exhaled gas, closely reflects that of arterial blood and, in turn, that of the brain, enabling continuous monitoring of an indirect measure of drug delivery to the target site. Distribution After i.v. administration of a drug, the peak blood concentration is determined by the dose, the rate of administration, and the cardiac output. With a high cardiac output, the effective volume of blood in which the drug is initially diluted is larger, leading to a lower peak concentration. However, the high cardiac output transports the drug quickly to the vessel-rich tissues (including brain), and for highly lipid-soluble drugs, rapid equilibration occurs, leading to a fast onset of action. It is the high blood supply more than the lipid solubility that explains this. Conversely, a low cardiac output leads to a higher initial peak concentration, because the drug is mixed with a smaller volume of blood during injection, though it will take longer to reach its target site. This explains why a smaller dose of induction agent is required in an elderly or shocked patient but may have a slower onset of action, while a young patient may require a much larger dose, yet will start to feel the effects more quickly. Other tissues may also have a high affinity for the drug, but can only take up the drug slowly as they receive a lower proportion of the cardiac output. As they do so, however, the blood concentration decreases, soon falling below the brain concentration, whereupon the drug leaves the brain to be redistributed to other tissues. This redistribution is referred to as the a phase and explains the rapid termination of effect of lipid-soluble drugs such as propofol or thiopental following a bolus dose. As the less well-perfused tissues accumulate more drug, the concentration difference between compartments falls and the rate of redistribution slows in a declining exponential fashion. This also acts to slow down the redistribution if further drug is given, and subsequent doses should therefore be amended accordingly. Continuing Education in Anaesthesia, Critical Care & Pain j Volume 7 Number 1 2007 27 Pharmacokinetics and anaesthesia For inhalational agents, the pharmacokinetic model for distribution is similar; however, because the rate of administration is slower, the various compartments fill simultaneously, although at different rates depending on their blood supplies. Because there is never a rapid loading dose to any one compartment, redistribution between compartments is minimal. As administration continues, the vessel-poor and intermediate compartments become progressively saturated, delaying subsequent recovery, particularly for agents with a high lipid solubility.1 Regardless of the period of administration, however, the partial pressure in any tissue will never exceed that administered. Although the initial effects of a drug may wear off because of redistribution, full recovery depends upon the removal of the drug from the body. Such elimination may result from excretion, metabolism, or a combination of both. Large molecular weight drugs are often excreted in the bile, but most drugs are renally excreted. In order for the kidneys to handle lipid-soluble drugs, they need to be metabolized into a polar, water-soluble form. Most of this metabolism occurs in the liver and can be divided into Phase 1 and Phase 2 reactions. Phase 1 reactions include oxidation, reduction, and hydrolysis; in Phase 2 reactions, the resulting metabolites are conjugated with sulphate, glucuronide, or other groups. For most drugs, elimination occurs in an exponentially declining manner, the rate of elimination being proportional to the plasma concentration, as the downstream end of the gradient remains at zero. This system (i.e. the amount of drug being removed is a constant fraction in unit time rather than a constant amount) is known as first-order kinetics. For some drugs, elimination may depend on the action of an enzyme or transporters which can become saturated. Once the relevant blood concentration is reached, elimination becomes constant, limited to a maximum amount in unit time. This is referred to as zero-order kinetics and can result in dangerously high concentrations with continued, unmonitored drug administration. It may be encountered at high concentrations with aspirin, ethanol, phenytoin, or thiopental. With inhalational agents (halothane excepted), metabolism occurs and elimination is via the reverse process to uptake. Recovery is reliant on adequate ventilation, but its duration is usually more dependent on the extent of tissue saturation. Practical applications Establishing steady state If a drug is given as a constant infusion, it will eventually reach a steady state (i.e. with the whole V ss d containing the drug at a stable concentration, and elimination occurring at the same rate as administration). It takes four to five elimination half-lives to achieve this. The target concentration can be attained far more rapidly using an initial loading dose followed by further additional drug in a 28 Fig. 5 Context-sensitive half-times of fentanyl, alfentanil, and remifentanil. declining exponential fashion as redistribution to other tissues occurs. Computer-driven target-controlled infusion (TCI) systems deliver this pattern automatically,2 adjusted for patient age, weight, and target concentration. Alternatively, this can be approximated closely using a stepped manual infusion scheme.3 Context-sensitive half-time Elimination half-life relates to the decline in plasma drug concentration from steady state following distribution throughout the whole V ss d . It provides a useful guide to dosage intervals for longterm drug maintenance. However, in anaesthetic practice, few drugs are administered long enough to reach the steady state. The context-sensitive half-time (CST) then becomes a more useful descriptor,4 detailing the plasma half-life after an infusion of a specified duration (Fig. 5). For drugs such as fentanyl, in which redistribution is the main mechanism responsible for the decline in plasma concentration after a brief infusion or bolus, the CST will initially be short. As the duration of infusion continues, redistribution becomes progressively less important and the CST increases, until ultimately it equals the elimination half-life. For a drug with a small volume of distribution, such as remifentanil, redistribution is very limited and the CST changes little even with prolonged infusion. Predictability Established pharmacokinetic and pharmacodynamic data are derived from averaged population studies. When based on these, even the most sophisticated dosage schemes for i.v. drugs will produce substantial variation in response between individuals, in both the blood/brain concentration ( pharmacokinetics) and the subsequent effects ( pharmacodynamics).5 In contrast, for inhalational anaesthetic agents, although pharmacodynamic variability will still occur, pharmacokinetic behaviour will be far more predictable, because of the physics of gas/ vapour solution in a liquid. Indeed, at equilibrium the partial pressure of an inhalational agent in blood (and other tissues) will precisely equal that in the inhaled gas mixture. Furthermore, Continuing Education in Anaesthesia, Critical Care & Pain j Volume 7 Number 1 2007 Downloaded from ceaccp.oxfordjournals.org by Richard Hodgson on October 3, 2010 Elimination Pharmacokinetics and anaesthesia the end-tidal partial pressure of an inhalational agent can be measured in real-time, providing a value very close to that in arterial blood. References 3. Roberts FL, Dixon J, Lewis GT, Tackley RM, Prys-Roberts C. Induction and maintenance of propofol anaesthesia. A manual infusion scheme. Anaesthesia 1988; 43(Suppl.): 14– 7 4. Hughes MA, Glass PS, Jacobs JR. Context-sensitive half-time in multicompartment pharmacokinetic models for intravenous anesthetic drugs. Anesthesiology 1992; 76: 334–41 1. Eger E. II, Saidman LJ. Illustrations of inhaled anesthetic uptake, including intertissue diffusion to and from fat. Anesth Analg 2005; 100: 1020–33 5. Hoymork SC, Raeder J, Grimsmo B, Steen PA. Bispectral index, serum drug concentrations and emergence associated with individually adjusted target-controlled infusions of remifentanil and propofol for laparoscopic surgery. Br J Anaesth 2003; 91: 773–80 2. Gray JM, Kenny GN. Development of the technology for ‘Diprifusor’ TCI systems. Anaesthesia 1998; 53(Suppl. 1): 22– 7 Please see multiple choice questions 22 –25 Downloaded from ceaccp.oxfordjournals.org by Richard Hodgson on October 3, 2010 Continuing Education in Anaesthesia, Critical Care & Pain j Volume 7 Number 1 2007 29 PHARMACOLOGY REVIEW From the Cleveland Clinic’s Comprehensive Anesthesiology Review, presented April 30 to May 5, 2005 Basic Pharmacology for the Anesthesiologist— John E. Tetzlaff, MD, Professor of Anesthesiology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, and Program Director, Center for Anesthesiology Education, Division of Anesthesiology and Critical Care Medicine, Cleveland Clinic Foundation, Cleveland Pharmacokinetics: simple model considers body as single box or compartment; amount of drug injected defined as dose; concentration of drug in compartment determined by volume of distribution (physiologic distribution); drug-specific volume of distribution equals amount of drug in body divided by concentration in blood Metabolism: half-life—time required for plasma concentration to decrease by half; first-order elimination—constant fraction of change in clearance per unit time; zeroorder elimination—constant amount of change in clearance per unit time Central compartment: contains high-volume or high blood flow (BF) organs (eg, heart, great vessels, lungs); instant peak blood levels attained; with drugs metabolized or rapidly redistributed, relatively rapid fall in concentration without continuous infusion; highly related to initial drug action for most anesthetic drugs Peripheral compartment: includes several compartments; size depends on peripheral BF and whether tissue in question ionic or lipid-soluble; change much slower, especially in highly lipid-soluble peripheral compartments; peak levels achieved slowly and decrease slowly; in general, intial effect of drugs in central compartment and sustained effects in peripheral compartment Clearance Hepatic: major source of drug clearance; main metabolic actions oxidation, reduction, hydrolysis, and conjugation; cytochrome system capable of oxidation and reduction; conjugation of large or lipid-soluble molecules occurs by unique enzymes; elimination of anesthetic drugs directly proportional to hepatic BF; drugs administered orally pass through liver before redistribution to central compartment Renal clearance: as primary source of elimination, favors small molecules, and water-soluble over lipid-soluble molecules; decreases slightly with age; proportional to renal BF Tissue clearance: minor component to elimination of majority of anesthetic agents; may be enzyme-mediated ester hydrolysis; classic examples are succinylcholine and ester local anesthetics; also some spontaneous ester hydrolysis; amount of clearance limited and rapidly shifts from first-order to zero-order elimination; subject to BF, but to lesser extent Protein binding: contributes to drug clearance to extent that agents protein affiliated; determined by protein-binding capacity; principal proteins in plasma and serum involved in protein binding include albumin and α1 -acid glycoprotein; influenced by nutrition and aging Factors that alter clearance Continuous infusion: avoids competition between sudden effect in central compartment and sustained effect in peripheral compartment; achieve steady state by determining balance between rate of administration and clearance; steady state achieved by continuous infusion or infusion as adjunct to loading dose Route of administration: uptake slower when drug administered into poorly vascularized area or area with low regional BF; target effect achieved quickly when drug injected into area with high BF; accelerated redistribution in areas of high BF and slow redistribution in areas of low BF; ionic substances can have absorbance limited by pH; ion trapping may cause artificially elevated concentrations Patient variability: coadministration of other medications may induce enzymes that accelerate or reduce clearance; renal BF decreases with increasing age; variety of metabolic enzyme systems dependent on maturity; maternal and fetal α1 -acid glycoproteins can be reduced; illness or severe comorbidity in mother may cause reduced albumin concentration Disease: renal clearance proportional to creatinine clearance; liver disease affects molecules metabolized in liver; also reduces protein binding; causes reduction in metabolic capacity as hepatic parenchyma damaged; intrahepatic shunting causes molecules to pass through shunts without exposure to enzyme system, resulting in lower metabolism; cardiac failure influences elimination (hepatically and renally); causes diminished hepatic BF, alters regional BF, decreases renal BF, and alters tissue clearance Postoperative period: absorption from gastrointestinal (GI) tract reduced; metabolic rates also reduced; in patient with multiple surgical procedures or critical care needs, reduced drug binding because of catabolism eliminating serum proteins; intra-abdominal or intrathoracic procedure associated with diminished liver BF Metabolism: many anesthetic drugs have first-order elimination, but some have high molecular weight, high lipid solubility, or both; depends on metabolic alteration to be further metabolized or excreted intact through renal system; involves adding polar molecules and oxidation, reduction, and hydrolysis steps to allow renal elimination of smaller molecules; oxidation occurs in smooth endoplasmic reticulum almost exclusively in liver; oxidation can involve aliphatic substitution, desulfuration, or dehalogenation; reduction occurs at anaerobic conditions almost completely in liver via cytochrome P450 system; hydrolysis can occur via variety of enzyme systems in liver, lung, and other tissues; pseudocholinesterase system highly active; phase II reactions modify molecules to facilitate clearance; most common reactions glucuronic acid conjugation on amine side or acetylation on hydrophobic side; others include mercapturic acid synthesis for sulfurcontaining molecules, sulfate formation, amide synthesis, and methylation Pharmacogenetics: ≈6 sites where cytochrome P450 system active; lesions known to cause specific conditions Pharmacodynamics: relationship between plasma concentration and designed drug effects; majority of receptors have balance between agonist and antagonist activity; receptor activity dependent on concentration and altered by drugs, physiologic conditions, and disease; receptor structure and function related; complex chemical event involving G-proteins, ion channels, ion restoration pumps, and second messengers (including hormones) Compounding local anesthetics to reduce toxicity: depends on selection of local anesthetics; ideally, choose short-acting anesthetic from one category and longer-acting anesthetic from another category to reduce toxicity. 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