Basic Principles of Pharmacology PDF

Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library Lippincott® Clinical Context  Health Library Aneshesiology Search... This Book This Book  Advanced Search   Texts Updates Stoelting’s Pharmacology & Physiology in...

Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library Lippincott® Clinical Context  Health Library Aneshesiology Search... This Book This Book  Advanced Search   Texts Updates Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e  Video  Chapter Contents Cases More Collections CHAPTER 2: Basic Principles of Pharmacology  Pamela Flood, Steven L. Shafer Text Figures Tables  Views   Share   Get Permissions This chapter combines Dr. Stoelting’s original elegant description of pharmacology with mathematical underpinnings frs presented by Dr. Shafer[ 1] in 1997 and mos recently in Miller’s Aneshesia., The combination of approaches sets a foundation for the pharmacology presented in the subsequent chapters. It also explains the fundamental principles of drug behavior and drug interaction that govern our daily practice of aneshesia. https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM]  Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library Receptor Theory  Listen   A drug that activates a receptor by binding to that receptor is called an agonis. Mos agoniss bind through a combination of ionic, hydrogen, and van der Waals interactions (the sum of the attractive or repulsive forces between molecules), making them reversible. Rarely, an agonis will bind covalently to the receptor, rendering the interaction irreversible. Receptors are often envisioned as proteins that are either unbound or are bound to the agonis ligand. When the receptor is bound to the agonis ligand, the efect of the drug is produced. When the receptor is not bound, there is no efect. The receptor sate is seen as binary: It is either unbound, resulting in one conformation, or it is bound, resulting in another conformation. Agoniss are often portrayed as simply activating a receptor (Figure 2.1). In this view, the magnitude of the drug efect refects the total number of receptors that are bound. In this simplisic view, the “mos” drug efect occurs when every receptor is bound. FIGURE 2.1  View Original Download Slide (.ppt) The interaction of a receptor with an agonis may be portrayed as a binary bound versus unbound receptor. The unbound receptor is portrayed as inactive. When the receptor is bound to the agonis ligand, it becomes the activated, R*, and mediates the drug efect. This view is too simplisic, but it permits undersanding of basic agonis behavior. This simple view helps to undersand the action of an antagonis (Figure 2.2). An antagonis is a drug that https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library to the receptor without activating the receptor. Antagoniss typically bind with ionic, hydrogen, and van der Waals interactions, rendering them reversible. Antagoniss block the action of agoniss simply by getting in the way of the agonis, preventing the agonis from binding to the receptor and producing the drug efect. Competitive antagonism is present when increasing concentrations of the antagonis progressively inhibit the response to the agonis. This causes a rightward displacement of the agonis dose-response (or concentration-response) relationship. Noncompetitive antagonism is present when, after adminisration of an antagonis, even high concentrations of agonis cannot completely overcome the antagonism. In this insance, either the agonis is bound irreversibly (and probably covalently) to the receptor site or it binds to a diferent site on the molecule and the interaction is alloseric (occurring at another site that fundamentally alters the activity of the receptor). Noncompetitive antagonism causes both a rightward shift of the dose-response relationship as well as a decreased maximum efcacy of the concentration versus response relationship. FIGURE 2.2  View Original Download Slide (.ppt) The simple view of receptor activation also explains the action of antagonist. In this case, the antagonis (red) binds to the receptor, but the binding does not cause activation. However, the binding of the antagonis blocks the agonis from binding, and thus blocks agonis drug efect. If the binding is reversible, this is competitive antagonism. If it is not reversible, then it is noncompetitive antagonism. https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library Although this simple view of activated and inactivated receptors explains agoniss and antagoniss, it has a more difcult time with partial agoniss and inverse agoniss (Figure 2.3). A partial agonis is a drug that binds to a receptor (usually at the agonis site) where it activates the receptor but not as much as a full agonis. Even at supramaximal doses, a partial agonis cannot cause the full drug efect. Partial agoniss may also have antagonis activity in which case they are also called agonis-antagoniss. When a partial agonis is adminisered with a full agonis, it decreases the efect of the full agonis. For example, butorphanol acts as a partial agonis at the μopioid receptor. Given alone, butorphanol is a modesly efcacious analgesic. Given along with fentanyl, it will partly reverse the fentanyl analgesia. Individuals using high doses of full agonis opioids withdraw after receiving buprenorphine. Inverse agoniss bind at the same site as the agonis (and likely compete with it), but they produce the opposite efect of the agonis. Inverse agoniss “turn of” the consitutive activity of the receptor. The simple view of receptors as bound or unbound does not explain partial agoniss or inverse agoniss. FIGURE 2.3  View Original Download Slide (.ppt) The concentration versus electroencephalogram (EEG) response relationship for four benzodiazepine ligands: midazolam (full agonis), bretazenil (partial agonis), fumazenil (competitive antagonis), and RO 19-4063 (inverse agonis). Reprinted from Shafer SL. Principles of pharmacokinetics and pharmacodynamics. In: Longnecker DE, Tinker JH, Morgan GE, eds. https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library Principles and Practice of Aneshesiology. 2nd ed. St Louis, MO: Mosby-Year Book; 1997:1159 , based on Mandema JW, Kuck MT, Danhof M. In vivo modeling of the pharmacodynamic interaction between benzodiazepines which difer in intrinsic efcacy. J Pharmacol Exp Ther. 1992;261(1):56–61. Copyright © 1997 Elsevier. With permission. It turns out that receptors have many natural conformations, and they naturally fuctuate between these diferent conformations (Figure 2.4). Some of the conformations are associated with the pharmacologic efect, and some are not. In the example shown, the receptor only has two sates: an inactive sate and an active sate that produces the same efect as if an agonis were bound to the receptor, although at a reduced level because the receptor only spends 20% of its time in this activated sate. FIGURE 2.4  View Original Download Slide (.ppt) Receptors have multiple sates, and they switch spontaneously between them. In this case, the receptor has jus two sates. It spends 80% of the time in the inactive sate and 20% of the time in the active sate in the absence of any ligand. In this view, ligands do not cause the receptor shape to change. That happens spontaneously. However, ligands change the ratio of active to inactive sates by (thermodynamically) favoring one of the sates. Figure 2.5 shows the receptor as seen in Figure 2.4 in the presence of an agonis, a partial agonis, an antagonis, and an inverse agonis. Presence of the full agonis causes the conformation of the active sate to be srongly favored, causing the receptors to be in this sate nearly 100% of the time. The partial agonis is not as efective in sabilizing the receptor in the active sate, so the bound receptor only spends 50% of its time in this sate. The antagonis does not favor either sate; it jus gets in the way of binding (as before; see Figure 2.2). The inverse agonis favors the inactive sate, reversing the baseline receptor activity. https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library FIGURE 2.5  View Original Download Slide (.ppt) The action of agoniss (A), partial agoniss (B), antagoniss (C), and inverse agoniss (D) can be interpreted as changing the balance between the active and inactive forms of the receptor. In this case, in the absence of agonis, the receptor is in the activated sate 20% of the time. This percentage changes based on nature of the ligand bound to the receptor. Using this information, we can now interpret the action of several ligands for the benzodiazepine receptor (see Figure 2.3). The actions include full agonism (midazolam), partial agonism (bretazenil), competitive antagonism (fumazenil), and inverse agonism (RO 19-4063). This range of actions can be explained by considering receptor sates. Assume that the γ-aminobutyric acid (GABA) receptor has several conformations, one of which is particularly sensitive to endogenous GABA. Typically, there are some GABA receptors in this more sensitive conformation. As a full agonis, midazolam causes nearly all of the GABA receptors to be in the confrmation with increased sensitivity to GABA. Bretazenil does the same thing but not as well. Even when every benzodiazepine receptor is occupied by bretazenil, fewer GABA receptors are in the more sensitive confrmation. Bretazenil simply does not favor that conformation as well as midazolam. When fumazenil is in the binding pocket, it does not change the relative probabilities of the receptor being in any conformation. Flumazenil jus gets in the way of other drugs that would otherwise bind to the pocket. RO 19-4063 actually decreases the number of GABA https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library receptors in the more sensitive conformation. Usually, some of them are in this more sensitive conformation, but that number is decreased by the inverse agonis RO 19-4063 (which was never developed as a drug because endogenous benzodiazepines, although anticipated, have not been described). The notion of receptors having multiple conformations with disinct activity, and drugs acting through favoring particular conformations, helps to undersand the action of agoniss, partial agoniss, antagoniss, and inverse agoniss. Receptor Action The number for receptors in cell membranes is dynamic and increases (upregulates) or decreases (downregulates) in response to specifc simuli. For example, a patient with pheochromocytoma has an excess of circulating catecholamines. In response, there is a decrease in the numbers of β-adrenergic receptors in cell membranes in an attempt to maintain homeosasis. Likewise, prolonged treatment of ashma with a β-agonis may result in tachyphylaxis (decreased response to the same dose of β-agonis, often indisinguishable from tolerance) because of the decrease in β-adrenergic receptors. Conversely, lower motor neuron injury causes an increase in the number of nicotinic acetylcholine receptors in the neuromuscular junction, leading to an exaggerated response to succinylcholine. Changing receptor numbers is one of many mechanisms that contribute to variability in response to drugs. Receptor Types Receptors for drug action can be classifed by location. Many of the receptors thought to be the mos critical for aneshetic action are located in the lipid bilayer of cell membranes. For example, opioids, intravenous sedative hypnotics, benzodiazepines, β-blockers, catecholamines, and muscle relaxants (mos of which are antagoniss) all interact with membrane-bound receptors. Some receptors are intracellular proteins. Drugs such as cafeine, insulin, seroids, theophylline, and milrinone interact with intracellular proteins. Circulating proteins can also be drug targets. The coagulation cascade comprises an ensemble of circulating proteins, many of which are therapeutic targets for modifying coagulation. There are also drugs that do not interact with proteins at all. Stomach antacids such as sodium citrate simply work by changing gasric pH. Chelating drugs work by binding divalent cations. Iodine kills bacteria by osmotic pressure (intracellular desiccation, which is why it is bes to let iodine prep solutions dry), and intravenous sodium bicarbonate changes plasma pH. The mechanism of action of these drugs does not involve receptors per se, and hence, these drugs will not be further considered in this section. Proteins are small machines whose cogs, cams, and wheels catalyze enzymatic reactions, permit ions to traverse cell membranes, exert mechanical force, or the myriad of other protein-based activities. When a drug binds to a receptor, it changes the activity of the machine, typically by enhancing its activity (eg, propofol increases the https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library sensitivity of the GABAA receptor to GABA, the endogenous ligand), decreasing its activity (ketamine decreases the activity of the N-methyl- d-aspartate [NMDA] receptor), or triggering a chain reaction (opioid binding to the μopioid receptor activates an inhibitory G protein that decreases adenylyl cyclase activity). The protein’s response to binding of the drug is responsible for the drug efect. Pharmacokinetics  Listen   Pharmacokinetics is the quantitative sudy of the absorption, disribution, metabolism, and excretion of injected and inhaled drugs and their metabolites. Pharmacokinetics describes what the body does to the drug. Pharmacodynamics is the quantitative sudy of the body’s response to a drug. Pharmacodynamics describes what the drug does to the body. This section introduces the basic principles of pharmacokinetics. The next section discusses the basic principles of pharmacodynamics. Pharmacokinetics determines the concentration of a drug in the plasma or at the site of drug efect. Pharmacokinetic variability is a signifcant component of patient-to-patient variability in drug response. Pharmacokinetic variability may result from genetic modifcations in metabolism; interactions with other drugs; or diseases of the liver, kidneys, or other organs of metabolism.[ 4] The basic principles of pharmacokinetics are absorption, metabolism, disribution, and elimination. These processes are fundamental to all drugs. They can be described in basic physiologic terms or using mathematical models. Each serves a purpose. Physiology can be used to predict how changes in organ function will afect the disposition of drugs. Mathematical models can be used to calculate the concentration of drug in the blood or tissue following any arbitrary dose at any arbitrary time. We initially tackle the physiologic principles that govern disribution, metabolism, elimination, and absorption, in that order. We then turn to the mathematical models. Disribution Intravenously adminisered drugs mix with body tissues and are immediately diluted from the concentrated injectate in the syringe to the more dilute concentration measured in the plasma or tissue. This initial disribution (within 1 minute) after bolus injection is considered mixing within the “central compartment” (Figure 2.6). The central compartment is physically composed of those elements of the body that dilute the drug within the frs minute after injection: the venous blood volume of the arm, the volume of the great vessels, the heart, the lung, and the upper aorta, and whatever uptake of drug occurs in the frs passage through the lungs. Many of these volumes are fxed regardless of the drug that is given. The lungs are diferent. Drugs that are highly fat soluble may be avidly taken up in the frs passage through the lung, reducing the concentration measured in the arterial blood. This results in an apparent increase in size of the central compartment. For example, frs-pass pulmonary https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library uptake of the initial dose of lidocaine, propranolol, meperidine, fentanyl, sufentanil, and alfentanil exceeds 65% of the dose. FIGURE 2.6  View Original Download Slide (.ppt) The central volume is the volume that intravenously injected drug initially mixes into. Reprinted from Shafer SL, Flood P, Schwinn DA. Basic principles of pharmacology. In: Miller RD, Eriksson LI, Fleisher LA, et al, eds. Miller’s Aneshesia. Vol 1. 7th ed. Philadelphia, PA: Churchill Livingsone; 2010:479–514 , with permission. Copyright © 2010 Elsevier. With permission. The body is a complex space, and mixing within the myriad body fuids and tissues is an ongoing process. The central compartment is the small initial mixing volume. Several minutes later, the drug will fully mix with the entire blood volume. However, it may take hours or even days for the drug to fully mix with all bodily tissues because some tissues have very low perfusion. In the process of mixing, molecules are drawn to other molecules, some with specifc binding sites. A drug that is polar will be drawn to water, where the polar water molecules fnd a low-energy sate by associating with the charged aspects of the molecule. A drug that is nonpolar has a higher afnity for fat, where van der Waals binding provides numerous weak binding sites. Many aneshetic drugs are highly fat soluble and poorly soluble in water. High fat solubility means that the molecule will have a large volume of disribution because it will be preferentially taken up by fat, diluting the concentration in the plasma. The extreme example of this is propofol, https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library which is almos inseparable from fat. The capacity of body fat to hold propofol is so vas that in some sudies, the total volume of disribution of propofol has been reported as exceeding 5,000 L. Of course, nobody has a total volume of 5,000 L! It is important to undersand that those 5,000 L refer to imaginary liters of plasma required to dilute the initial dose of propofol to achieve the measured concentration. Because propofol is so fat soluble, a large amount of propofol is held in the body’s fatty tissues, with jus a tiny fraction measured in the plasma. Following bolus injection, the drug initially goes to the tissues that receive the bulk of arterial blood fow: the brain, heart, kidneys, and liver. These tissues are often called the vessel-rich group. The rapid blood fow to these highly perfused tissues ensures that the tissue drug concentration rapidly equilibrates with arterial blood. However, for highly lipid-soluble drugs, the capacity of the fat to hold the drug greatly exceeds the capacity of highly perfused tissues. Initially, the fat compartment is almos invisible because the blood supply to fat is quite limited. However, with time, the fat gradually absorbs more and more drug, sequesering it away from the highly perfused tissues. This redisribution of drug from the highly perfused tissue to the fat accounts for a subsantial part of the ofset of drug efect following a bolus of an intravenous aneshetic or fat-soluble opioid (eg, fentanyl). Muscles play an intermediate role in this process, having (at res) blood fow that is intermediate between highly perfused tissues and fat, and also having intermediate solubility for lipophilic drugs. Protein Binding Mos drugs are bound to some extent to plasma proteins, primarily albumin, α1-acid glycoprotein, and lipoproteins. Mos acidic drugs bind to albumin, whereas basic drugs bind to α1-acid glycoprotein. Protein binding efects both the disribution of drugs (because only the free or unbound fraction can readily cross cell membranes) and the apparent potency of drugs, again because it is the free fraction that determines the concentration of bound drug on the receptor. The extent of protein binding parallels the lipid solubility of the drug. This is because drugs that are hydrophobic are more likely to bind to proteins in the plasma and to lipids in the fat. For intravenous aneshetic drugs, which tend to be quite potent, the number of available protein binding sites in the plasma vasly exceeds the number of sites actually bound. As a result, the fraction bound is not dependent on the concentration of the aneshetic and only dependent on the protein concentration. Binding of drugs to plasma albumin is nonselective, and drugs with similar physicochemical characterisics may compete with each other and with endogenous subsances for the same protein binding sites. For example, sulfonamides can displace unconjugated bilirubin from binding sites on albumin, leading to the risk of bilirubin encephalopathy in the neonate. Age, hepatic disease, renal failure, and pregnancy can decrease plasma protein concentration. Alterations in https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library protein binding are important only for drugs that are highly protein bound (eg, >90%). For such drugs, the free fraction changes as an inverse proportion with a change in protein concentration. If the free fraction is 2% in the normal sate, then in a patient with 50% decrease in plasma proteins, the free fraction will increase to 4%, a 100% increase. Theoretically, an increase in free fraction of a drug may increase the pharmacologic efect of the drug, but in practice, it is far from certain that there will be any change in pharmacologic efect at all. The reason is that it is the unbound fraction that equilibrates throughout the body, including with the receptor. Plasma proteins only account for a small portion of the total binding sites for drug in the body. Because the free drug concentration in the plasma and tissues represents partitioning with all binding sites, not jus the plasma binding sites, the actual free drug concentration that drives drug on and of receptors may change fairly little with changes in plasma protein concentration. Metabolism Metabolism converts pharmacologically active, lipid-soluble drugs into water-soluble and usually pharmacologically inactive metabolites. However, this is not always the case. For example, diazepam and propranolol may be metabolized to active compounds. Morphine-6-glucuronide, a metabolite of morphine, is a more potent opioid than morphine itself. In some insances, an inactive parent compound (prodrug) is metabolized to an active drug. This is the case with codeine, which is an exceedingly weak opioid. Codeine is metabolized to morphine, which is responsible for the analgesic efects of codeine. Pathways of Metabolism The four basic pathways of metabolism are (1) oxidation, (2) reduction, (3) hydrolysis, and (4) conjugation. Traditionally, metabolism has been divided into phase I and phase II reactions. Phase I reactions include oxidation, reduction, and hydrolysis, which increase the drug’s polarity prior to the phase II reactions. Phase II reactions are conjugation reactions that covalently link the drug or metabolites with a highly polar molecule (carbohydrate or an amino acid) that renders the conjugate more water-soluble for subsequent excretion. Hepatic microsomal enzymes are responsible for the metabolism of mos drugs. Other sites of drug metabolism include the plasma (Hofmann elimination, eser hydrolysis), lungs, kidneys, and gasrointesinal tract and placenta (tissue eserases). Hepatic microsomal enzymes, which participate in the metabolism of many drugs, are located principally in hepatic smooth endoplasmic reticulum. These microsomal enzymes are also present in the kidneys, gasrointesinal tract, and adrenal cortex. Microsomes are vesicle-like artifacts reformed from pieces of the endoplasmic reticulum bilayer sliced apart as cells are cut up in a blender. Microsomal enzymes are those enzymes that are concentrated in these vesicle-like artifacts. https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library Phase I Enzymes Enzymes responsible for phase I reactions include cytochrome P450 (CYP) enzymes, non-CYP enzymes, and favin-containing monooxygenase enzymes. The CYP enzyme sysem is a large family of membrane-bound proteins containing a heme cofactor that catalyzes the metabolism of compounds. The P450 enzymes are predominantly hepatic microsomal enzymes, although there are also mitochondrial P450 enzymes. The designation CYP is derived from their characterisic absorption peak at 450 nm when heme is combined with carbon monoxide. The CYP sysem is also known as the mixed function oxidase sysem because it involves both oxidation and reduction seps; the mos common reaction catalyzed by CYP is the monooxygenase reaction, for example, insertion of one atom of oxygen into an organic subsrate while the other oxygen atom is reduced to water. The CYP functions as the terminal oxidase in the electron transport chain. Individual CYP enzymes have evolved from a common protein.[ 7 ] The CYP enzymes, often called CYPs, tha share more than 40% sequence homology are grouped in a family designated by a number (eg, “CYP2”), those that share more than 55% homology are grouped in a subfamily designated by a letter (eg, “CYP2A”), and individual CYP enzymes are identifed by a third number (eg, “CYP2A6”). Ten isoforms of CYP are responsible for the oxidative metabolism of mos drugs. The preponderance of CYP activity for aneshetic drugs is generated by CYP3A4, which is the mos abundantly expressed P450 isoform, comprising 20% to 60% of total P450 activity. The P450 3A4 metabolizes more than one-half of all currently available drugs, including opioids (alfentanil, sufentanil, fentanyl), benzodiazepines, local aneshetics (lidocaine, ropivacaine), immunosuppressants (cyclosporine), and antihisamines (terfenadine). Drugs can alter the activity of these enzymes through induction and inhibition. Induction occurs through increased expression of the enzymes. For example, phenobarbital induces microsomal enzymes and thus can render drugs less efective through increased metabolism. Conversely, other drugs directly inhibit enzymes, increasing the exposure to their subsrates. Famously, grapefruit juice (not exactly a drug) inhibits CYP 3A4, possibly increasing the concentration of aneshetics and other drugs. Oxidation CYP enzymes are crucial for oxidation reactions. These enzymes require an electron donor in the form of reduced nicotinamide adenine dinucleotide and molecular oxygen for their activity. The molecule of oxygen is split, with one atom of oxygen oxidizing each molecule of drug and the other oxygen atom being incorporated into a molecule of water. Examples of oxidative metabolism of drugs catalyzed by CYP enzymes include hydroxylation, deamination, desulfuration, dealkylation, and dehalogenation. Demethylation of morphine to normorphine is an example of oxidative dealkylation. Dehalogenation involves oxidation of a carbon-hydrogen bond to form an intermediate metabolite that is unsable and spontaneously loses a halogen atom. Halogenated volatile aneshetics https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library are susceptible to dehalogenation, leading to release of bromide, chloride, and fuoride ions. Aliphatic oxidation is oxidation of a side chain. For example, oxidation of the side chain of thiopental converts the highly lipid-soluble parent drug to the more water-soluble carboxylic acid derivative. Thiopental also undergoes desulfuration to pentobarbital by an oxidative sep. Epoxide intermediates in the oxidative metabolism of drugs are capable of covalent binding with macromolecules and may be responsible for some drug-induced organ toxicity, such as hepatic dysfunction. Normally, these highly reactive intermediates have such a transient exisence that they exert no biologic action. When enzyme induction occurs, however, large amounts of reactive intermediates may be produced, leading to organ damage. This is especially likely to occur if the antioxidant glutathione, which is in limited supply in the liver, is depleted by the reactive intermediates. Reduction The CYP enzymes are also essential for reduction reactions. Under conditions of low oxygen partial pressures, CYP enzymes transfer electrons directly to a subsrate such as halothane rather than to oxygen. This electron gain imparted to the subsrate occurs only when insufcient amounts of oxygen are present to compete for electrons. Conjugation Conjugation with glucuronic acid involves CYP enzymes. Glucuronic acid is synthesized from glucose and added to lipid-soluble drugs to render them water-soluble. The resulting water-soluble glucuronide conjugates are then excreted in bile and urine. In premature infants, reduced microsomal enzyme activity interferes with conjugation, leading to neonatal hyperbilirubinemia and the risk of bilirubin encephalopathy. The reduced conjugation ability of the neonate increases the efect and potential toxicity of drugs that are normally inactivated by conjugation with glucuronic acid. Hydrolysis Enzymes responsible for hydrolysis of drugs, usually at an eser bond, do not involve the CYP enzymes sysem. Hydrolysis often occurs outside of the liver. For example, remifentanil, succinylcholine, esmolol, and the eser local aneshetics are cleared in the plasma and tissues via eser hydrolysis. Phase II Enzymes Phase II enzymes include glucuronosyltransferases, glutathione-S-transferases, N-acetyl-transferases, and sulfotransferases. Uridine diphosphate glucuronosyltransferase catalyzes the covalent addition of glucuronic acid to a variety of endogenous and exogenous compounds, rendering them more water-soluble. Glucuronidation is an important metabolic pathway for several drugs used during aneshesia, including propofol, morphine (yielding https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library morphine-3-glucuronide and the pharmacologically active morphine-6-glucuronide), and midazolam (yielding the pharmacologically active α1-hydroxymidazolam). Glutathione-S-transferase enzymes are primarily a defensive sysem for detoxifcation and protection agains oxidative sress. N-acetylation catalyzed by N-acetyl-transferase is a common phase II reaction for metabolism of heterocyclic aromatic amines (particularly serotonin) and arylamines, including the inactivation of isoniazid. Hepatic Clearance The rate of metabolism for mos aneshetic drugs is proportional to drug concentration, rending the clearance of the drug consant (ie, independent of dose). This is a fundamental assumption for aneshetic pharmacokinetics. Exploring this assumption will provide insight into the critical role of clearance in governing the metabolism of drugs. Although the metabolic capacity of the body is large, it is not possible that metabolism is always proportional to drug concentration because the liver does not have infnite metabolic capacity. At some rate of drug fow into the liver, the organ will be metabolizing drug as fas as the metabolic enzymes in the organ allow. At this point, metabolism can no longer be proportional to concentration because the metabolic capacity of the organ has been exceeded. Undersanding metabolism sarts with a simple mass balance: The rate at which drug fows out of the liver mus be the same as the rate at which drug fows into the liver minus the rate at which the liver metabolizes drug. The rate at which drug fows into the liver is liver blood fow, Q, times the concentration of drug fowing in, Cinfow. The rate at which drug fows out of the liver is liver blood fow, Q, times the concentration of drug fowing out, Coutfow. The rate of hepatic metabolism by the liver, R, is the diference between the drug concentration fowing into the liver and the drug concentration fowing out of the liver, times the rate of liver blood fow: EQUATION 2.1 This relationship is illusrated in Figure 2.7. FIGURE 2.7 https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library  View Original Download Slide (.ppt) The relationship between drug rate of metabolism can be computed as the rate of liver blood fow times the diference between the infowing and outfowing drug concentrations. This is a common approach to analyzing metabolism or tissue uptake across an organ in mass-balance pharmacokinetic sudies. Reprinted from Shafer SL, Flood P, Schwinn DA. Basic principles of pharmacology. In: Miller RD, Eriksson LI, Fleisher LA, WienerKronish JP, Young WL, eds. Miller’s Aneshesia. Vol 1. 7th ed. Philadelphia, PA: Churchill Livingsone; 2010:479–514. Copyright © 2010 Elsevier. With permission. Metabolism can be saturated because the liver does not have infnite metabolic capacity. A common equation used for this saturation processes is as follows: EQUATION 2.2 “Response” in Equation 2.2 varies from 0 to 1, depending on the value of C. In this context, Response is the fraction of maximal metabolic rate. Response = 0 means no metabolism, and response = 1 means metabolism at the maximal possible rate. C refers to whatever is driving the response. In this chapter, concentration. When C is 0, the response is 0. If C means drug C is greater than 0 but much less than C50, the denominator is approximately C50 and the response is nearly proportional to C: https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library. If we increase C even further to exactly C50, then the response is , which is simply 0.5. That is where the name “ C50” comes from: It is the concentration associated with 50% response. As C becomes much greater than C50, the equation approaches , which is 1. The shape of this relationship is shown in Figure 2.8. The relationship is nearly linear at low concentrations, but at high concentrations, the response saturates at 1. FIGURE 2.8  View Original Download Slide (.ppt) The shape of the saturation equation. Reprinted from Shafer SL, Flood P, Schwinn DA. Basic principles of pharmacology. In: Miller RD, Eriksson LI, Fleisher LA, WienerKronish JP, Young WL, eds. Miller’s Aneshesia. Vol 1. 7th ed. Philadelphia, PA: Churchill Livingsone; 2010:479–514. Copyright © 2010 Elsevier. With permission. To undersand hepatic clearance, we mus undersand the relationship between hepatic metabolism and drug concentration. But what concentration determines the rate of metabolism: the concentration fowing into the liver, https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library the average concentration within the liver, or the concentration fowing out of the liver? All have been used, but the mos common views the rate of metabolism as a function of the concentration fowing out of the liver, Coutfow The rationale for using Coutfow is the same as the rationale for using end tidal aneshetic concentration to assess the seady sate concentration in the lungs. We can expand our equation of metabolism to include the observation that the rate of metabolism, R, approaches saturation at the maximum metabolic rate, Vm, as a function of Coutfow: EQUATION 2.3 The saturation equation appears at the end of the Equation 2.3 equation. The Vm is the maximum possible metabolic rate. The saturation part of this equation, , determines fraction of the maximum metabolic rate. Km, the “Michaelis consant,” is the outfow concentrati which the metabolic rate is 50% of the maximum rate (Vm). This relationship is shown in Figure 2.9. The x-ax the outfow concentration, Coutfow, as a fraction Km. The y-axis is the rate of drug metabolism as a fraction of Vm. By normalizing the x- and y-axis in this manner, the relationship shown in Figure 2.9 is true for all values o Vm and Km. As long as the outfow concentration is less than one-half of Km (true for almos all aneshetic drugs), there is a nearly proportional change in metabolic rate with a proportional change in outfow concentration. Another interpretation is that metabolism will be proportional to concentration as long as the metabolic rate is less than one-third of the maximum metabolic capacity. FIGURE 2.9 https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library  View Original Download Slide (.ppt) The relationship between concentration, here shown as a fraction of the Michaelis consant (Km), and drug metabolism, here shown as a fraction of the maximum rate (Vm). Metabolism increases proportionally with concentration as long as the outfow concentration is less than half Km, which corresponds to a metabolic rate that is roughly one-third of the maximal rate. Metabolism is proportional to concentration, meaning that clearance is consant, for typical doses of all intravenous drugs used in aneshesia. Reprinted from Shafer SL, Flood P, Schwinn DA. Basic principles of pharmacology. In: Miller RD, Eriksson LI,Fleisher LA, WienerKronish JP, Young WL, eds. Miller’s Aneshesia. Vol 1. 7th ed. Philadelphia, PA: Churchill Livingsone; 2010:479–514. Copyright © 2010 Elsevier. With permission. So far, we have talked about the rate of metabolism and not about hepatic clearance. If the liver could completely extract the drug from the aferent fow, then clearance would equal liver blood fow, Q. However, the liver cannot remove every las drug molecule. There is always some drug in the efuent plasma. The fraction of infowing drug extracted by the liver is. This is called the extraction ratio. Clearance is the amount of blood completely cleared of drug per unit time. We can calculate clearance as the liver blood fow times the extraction ratio: https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library EQUATION 2.4 With this basic undersanding of clearance, let us divide each part of Equation 2.3 by Cinfow: EQUATION 2.5 The third term in the above equation is clearance as defned in Equation 2.4 : Q times the extraction ratio. T each term in Equation 2.4 mus be clearance. Let us consider them in order. The frs term tells us that. This indicates that clearance is a proportionality consant that relates infowing (eg, arterial) concentration to the rate of metabolism. If we want to maintain a given seady-sate arterial drug concentration, we mus infuse drug at the same rate that it is being metabolized. With this undersanding, we can rearrange the equation to say the following:. Thus, the infusion rate to maintain a given arterial concentration ( Cinfow) is the clearance times the desired concentration. The third and fourth terms https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library are particularly interesing when taken together. Remembering that is the extraction ratio, these equations relate clearance to liver blood fow and the extraction ratio, as shown in Figure 2.10. For drugs with an extraction ratio of nearly 1 (eg, propofol), a change in liver blood fow produces a nearly proportional change in clearance. For drugs with a low extraction ratio (eg, alfentanil), clearance is nearly independent of the rate of liver blood fow. This makes intuitive sense. If nearly 100% of the drug is extracted by the liver, then the liver has tremendous metabolic capacity for the drug. In this case, fow of drug to the liver is what limits the metabolic rate. Metabolism is “fow limited.” The reduction in liver blood fow that accompanies aneshesia can be expected to reduce clearance. However, moderate changes in hepatic metabolic function per se will have little impact on clearance because hepatic metabolic capacity is overwhelmingly in excess of demand. FIGURE 2.10 https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library  View Original Download Slide (.ppt) The relationship between liver blood flow (Q), clearance, and extraction ratio. For drugs with a high extraction ratio, clearance is nearly identical to liver blood fow. For drugs with a low extraction ratio, changes in liver blood fow have almos no efect on clearance. Reprinted from Shafer SL, Flood P, Schwinn DA. Basic principles of pharmacology. In: Miller RD, Eriksson LI, Fleisher LA, WienerKronish JP, Young WL, eds. Miller’s Aneshesia. Vol 1. 7th ed. Philadelphia, PA: Churchill Livingsone; 2010:479–514. Copyright © 2010 Elsevier. With permission. Conversely, for drugs with an extraction ratio considerably less than 1, clearance is limited by the capacity of the liver to take up and metabolize the drug. This is called “capacity-limited” clearance. When clearance is capacity limited, changes in liver blood fow (as might be caused by the aneshetic sate itself) have little infuence on the clearance because the liver can only handle a fraction of the drug fowing through it. It does not matter if liver blood fow is doubled, or cut in half, because the liver’s enzymatic capacity is “maxed out” regardless of the amount of drug fowing through it. When clearance is fow limited, it is generally unafected by modes changes in hepatic capacity. However, when https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library clearance is capacity limited, changes in liver metabolic capacity produce nearly proportional changes in clearance rate. For these drugs, clearance can be signifcantly decreased by hepatic disease or increased by enzymatic induction. This relationship can be seen in Figure 2.11. FIGURE 2.11  View Original Download Slide (.ppt) Changes in maximum metabolic velocity ( Vm) have little efect on drugs with a high extraction ratio (ER) but cause a nearly proportiona decrease in clearance for drugs with a low extraction ratio. Reprinted from Shafer SL, Flood P, Schwinn DA. Basic principles of pharmacology. In: Miller RD, Eriksson LI, Fleisher LA, WienerKronish JP, Young WL, eds. Miller’s Aneshesia. Vol 1. 7th ed. Philadelphia, PA: Churchill Livingsone; 2010:479–514. Copyright © 2010 Elsevier. With permission. Figure 2.11 allows us to also see how extraction ratio helps identify fow-limited from capacity-limited drugs. The vertical line at Vm = 1 shows the extraction ratio for each line (labeled to the left), based on a liver blood fow of 1.4 L per minute. Changes in Vm, as might be caused by liver disease (reduced Vm) or enzymatic induction https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library (increased Vm) have little efect on drugs with a high extraction ratio. However, drugs with a low extraction ratio have a nearly linear change in clearance with a change in intrinsic metabolic capacity (Vm). Vm and Km are usually not known and condensed into a single term,. This term summarizes the hepatic metabolic capacity and is called intrinsic clearance. Because , consider what happens if hepatic blood fow increases to infnity (this is a thought experiment—do not try this at home). At super high hepatic blood fow, Coutfow becomes indisinguishable from Cinfow because the fnite hepa capacity only metabolizes an infnitesimal fraction of the drug fowing through the liver. As a result, clearance becomes. This is clearance when blood fow is infnitely fas. There mus be a linear portion, where metabolism is proportional to concentration. We can solve for clearance in the “linear range” by solving for Cinfow = Coutfow = 0,. This is the intrinsic clearance, Clint. It can be demonsrated algebraically from the defnition of Clint that in the linear range (ie, when km ≫ Coutfow), Clint is related to the extraction ratio and hepatic blood fow: EQUATION 2.6 This relationship between intrinsic clearance and extraction ratio is shown in Figure 2.12 , calculated at a hepatic blood fow of 1,400 mL per minute. It shows that the intrinsic clearance for drugs like propofol with an extraction https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library ratio of approximately 1 is enormous, somewhere around 100 L per minute! Finally, we can combine Equation 2.6 with Equation 2.5 to solve for the relationship between hepatic clearanc and Clint: EQUATION 2.7 In general, true hepatic clearance and extraction ratio are more useful concepts for aneshetic drugs than the intrinsic clearance. However, intrinsic clearance is introduced here because it is occasionally used in pharmacokinetic analyses of drugs used during aneshesia. FIGURE 2.12  View Original Download Slide (.ppt) The extraction ratio as a function of the intrinsic calculated for a liver blood flow of 1,400 mL per minute. Reprinted from Shafer SL, Flood P, Schwinn DA. Basic principles of pharmacology. In: Miller RD, Eriksson LI, Fleisher LA, WienerKronish JP, Young WL, eds. Miller’s Aneshesia. Vol 1. 7th ed. Philadelphia, PA: Churchill Livingsone; 2010:479–514. Copyright © 2010 Elsevier. With permission. https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library So far, we have focused on linear pharmacokinetics, that is, the pharmacokinetics of drugs whose metabolic rate at clinical doses is less than Vm/3. The clearance of such drugs is generally expressed as a consant (eg, propofol clearance = 1.6 L per minute). Some drugs, such as phenytoin, exhibit saturable pharmacokinetics (ie, have such low Vm that typical doses exceed the linear portion of Figure 2.9). The clearance of drugs with saturable metabolism is a function of drug concentration, rather than a consant fow (ie, volume per unit time). There are almos no drugs with saturable clearance in aneshesia, so they will not be discussed in greater detail. However, the clearance for these drugs as a function of concentration can be calculated from Equations 2.5 and 2.7. Renal Clearance Renal excretion of drugs involves (1) glomerular fltration, (2) active tubular secretion, and (3) passive tubular reabsorption. The amount of drug that enters the renal tubular lumen depends on the fraction of drug bound to protein and the glomerular fltration rate (GFR). Renal tubular secretion involves active transport processes, which may be selective for certain drugs and metabolites, including protein-bound compounds. Reabsorption from renal tubules removes drug that has entered tubules by glomerular fltration and tubular secretion. This reabsorption is mos prominent for lipid-soluble drugs that can easily cross cell membranes of renal tubular epithelial cells to enter pericapillary fuid. Indeed, a highly lipid-soluble drug, such as thiopental, is almos completely reabsorbed such that little or no unchanged drug is excreted in the urine. Conversely, production of less lipid-soluble metabolites limits renal tubule reabsorption and facilitates excretion in the urine. The rate of reabsorption from renal tubules is infuenced by factors such as pH and rate of urine fow in the renal tubules. Passive reabsorption of weak bases and acids is altered by urine pH, which infuences the fraction of drug that exiss in the ionized form. For example, weak acids are excreted more rapidly in alkaline urine. This occurs because alkalinization of the urine results in more ionized drug that cannot easily cross renal tubular epithelial cells, resulting in less passive reabsorption. Renal blood fow is inversely correlated with age, as is creatinine clearance, which is closely related to GFR because creatinine is water-soluble and not resorbed in the tubules. Creatinine clearance can be predicted from age and weight according to the equation of Cockcroft and Gault: EQUATION 2.8 https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library Equation 2.8 shows that age is an independent predictor of creatinine clearance. Elderly patients with normal serum creatinine have about half the GFR than younger patients. This can be seen graphically in Figure 2.13. FIGURE 2.13  View Original Download Slide (.ppt) Creatinine clearance as a function of age and serum creatinine based on the equation of Cockcroft and Gault. Derived from Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31–41. https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library Absorption Classically, pharmacokinetics is taught as “absorption, disribution, metabolism, and elimination.” Because mos aneshetic drugs are adminisered intravenously, and inhaled aneshetic pharmacokinetics are discussed elsewhere, this order has been changed in this textbook to put absorption at the end of the lis. Absorption is not particularly relevant for mos aneshetic drugs. Ionization Mos drugs are weak acids or bases that are present in both ionized and nonionized forms in solution. The nonionized molecule is usually lipid soluble and can difuse across cell membranes including the blood–brain barrier, renal tubular epithelium, gasrointesinal epithelium, placenta, and hepatocytes (Table 2.1). As a result, it is usually the nonionized form of the drug that is pharmacologically active, undergoes reabsorption across renal tubules, is absorbed from the gasrointesinal tract, and is susceptible to hepatic metabolism. Conversely, the ionized fraction is poorly lipid soluble and cannot penetrate lipid cell membranes easily (see Table 2.1). A high degree of ionization thus impairs absorption of drug from the gasrointesinal tract, limits access to drugmetabolizing enzymes in the hepatocytes, and facilitates excretion of unchanged drug, as reabsorption across the renal tubular epithelium is unlikely. TABLE 2.1 Characteristics of nonionized and ionized drug molecules Nonionized Ionized Pharmacologic efect Active Inactive Solubility Lipids Water Yes No No Yes Cross lipid barriers (gasrointesinal tract, blood–brain barrier, placenta) Renal excretion https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library Hepatic metabolism Yes No Determinants of Degree of Ionization The degree of drug ionization is a function of its dissociation consant (pK) and the pH of the surrounding fuid. When the pK and the pH are identical, 50% of the drug exiss in both the ionized and nonionized form. Small changes in pH can result in large changes in the extent of ionization, especially if the pH and pK values are similar. Acidic drugs, such as barbiturates, tend to be highly ionized at an alkaline pH, whereas basic drugs, such as opioids and local aneshetics, are highly ionized at an acid pH. Acidic drugs are usually supplied in a basic solution to make them more soluble in water and basic drugs are usually supplied in an acidic solution for the same reason, unless the pH afects drug sability, as is the case for mos eser local aneshetics. Ion Trapping Because it is the nonionized drug that equilibrates across lipid membranes, a concentration diference of total drug can develop on two sides of a membrane that separates fuids with diferent pHs because the ionized concentrations will refect the local equilibration between ionized and nonionized forms based on the pH. This is an important consideration because one fraction of the drug may be more pharmacologically active than the other fraction. Sysemic adminisration of a weak base, such as an opioid, can result in accumulation of ionized drug (ion trapping) in the acid environment of the somach. A similar phenomenon occurs in the transfer of basic drugs, such as local aneshetics, across the placenta from mother to fetus because the fetal pH is lower than maternal pH. The lipid-soluble nonionized fraction of local aneshetic crosses the placenta and is converted to the poorly lipidsoluble ionized fraction in the more acidic environment of the fetus. The ionized fraction in the fetus cannot easily cross the placenta to the maternal circulation and thus is efectively trapped in the fetus. At the same time, conversion of the nonionized to ionized fraction maintains a gradient for continued passage of local aneshetic into the fetus. The resulting accumulation of local aneshetic in the fetus is accentuated by the acidosis that accompanies fetal disress. The kidneys are the mos important organs for the elimination of unchanged drugs or their metabolites. Watersoluble compounds are excreted more efciently by the kidneys than are compounds with high lipid solubility. This emphasizes the important role of metabolism in converting lipid-soluble drugs to water-soluble metabolites. Drug elimination by the kidneys is correlated with endogenous creatinine clearance or serum creatinine concentration. The magnitude of change in these indices provides an esimate of the necessary change adjusment https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library in drug dosage. Although age and many diseases are associated with a decrease in creatinine clearance and requirement for decreased dosing, pregnancy is associated with an increase in creatinine clearance and higher dose requirements for some drugs. Ion trapping and extraction ratio featured, somewhat unexpectedly, in the trial of Conrad Murray for the death of Michael Jackson. The initial defense srategy was to blame Michael Jackson for his death, claiming that he drank a mixture of propofol and lidocaine when Conrad Murray sepped out of the room. We already know why the propofol claim is bogus. As discussed earlier, the extraction ratio for propofol is nearly 1. The extraction ratio does not care if the propofol enters the liver from the hepatic artery or portal vein. The liver will jus as happily remove all the propofol from the portal vein as from the hepatic artery. As a result, any propofol that is swallowed will be metabolized in the liver before ever reaching the sysemic circulation. The defense also observed that the concentration of lidocaine in Michael Jackson’s somach was 22.9 μg/mL, far exceeding the concentration of lidocaine in Michael Jackson’s blood of 0.8 μg/mL. Surely this was evidence that Michael Jackson drank a mixture of lidocaine and propofol! Nope. It is jus ion trapping, nothing more. We can quantitate the extent of ion trapping using the Henderson-Hasselbalch equation: EQUATION 2.9 This assumes that the dissociating moiety is an acid that releases a proton. However, lidocaine is a proton receptor, requiring we use the form of the Henderson-Hasselbalch equation adapted for bases: EQUATION 2.10 where pOH is the negative logarithm (base 10) of the hydroxide ion concentration, pKb is the base dissociation consant (readily calculated as 14 − pKa), [B] is the concentration of the base (uncharged lidocaine), and [BH+] is the concentration of the conjugate acid (protonated lidocaine). We can rearrange the second equation to calculate the ratio of [BH+] / [B] as 10 pOH − pKb. https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library The pH of blood is 7.4, the pH of the somach is 1 to 3.5, and the pKa of lidocaine is 8.01. Therefore, the pOH of blood is 6.6, the pOH of the somach is 10.5 to 13, and the pKb of lidocaine is 5.99. Figure 2.14 was presented in pretrial tesimony to explain the mathematics of ion trapping. The left shows blood, where the total lidocaine was measured on autopsy as 0.84 μg/mL. From the Henderson-Hasselbalch equation, we can calculate that the uncharged moiety was 0.17 μg/mL and the balance was charged. Because the uncharged moiety esablishes equilibrium across gasric epithelium, we expect the lidocaine concentration in the somach to be the same, 0.17 μg/mL. Knowing this, and the gasric pH, we can calculate the charged lidocaine concentration at equilibrium would have been 5,357 μg/mL, about 200 times higher than actually measured on autopsy. Of course, the sysem was not in equilibrium at the time of autopsy, which is why the somach concentration was only 22.9 μg/mL, not 5,357 μg/mL. However, all that we know about Michael Jackson is that charged lidocaine accumulated in his somach, exactly as expected from ion trapping. FIGURE 2.14  View Original Download Slide (.ppt) Ion trapping can result in signifcant sequesration of drugs based on local pH. The molecule shown is lidocaine, which has a nitrogen group that can accept protons in an acidic environment. Only neutrally changed lidocaine equilibrates across membranes. The fgure is taken from the trial of Conrad Murray for the death of Michael Jackson. The defense claimed that the measured lidocaine concentration in the somach, 22 μg/mL, proved that Mr. Jackson drank a mixture of lidocaine and propofol. However, the measured concentration can be https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library entirely explained by ion trapping, which was not even close to the equilibrium concentration of 5,357 μg/mL. Route of Adminisration and Sysemic Absorption of Drugs Drugs adminisered by intravenous injection or inhalation reach the sysemic circulation almos insantly. However, for drugs not adminisered by these two routes, there is an initial delay between adminisering the drug (eg, swallowing a pill or applying a patch) and appearance of the drug in the sysemic circulation. The rate of sysemic absorption determines the magnitude of the drug efect and duration of action. Changes in the rate of sysemic absorption rate may require adjusing the dose or time interval between repeated drug doses. Sysemic absorption, regardless of the route of drug adminisration, depends on the drug’s solubility. Local conditions at the site of absorption alter solubility, particularly in the gasrointesinal tract. Blood fow to the site of absorption also afects the rate of sysemic transfer. For example, increased blood fow evoked by rubbing or applying heat at the subcutaneous or intramuscular injection site enhances sysemic absorption, whereas decreased blood fow due to vasoconsriction impedes drug absorption. Finally, the area of the absorbing surface available for drug absorption is an important determinant of drug entry into the circulation. Oral Adminisration Oral adminisration of a drug is often the mos convenient and inexpensive route of adminisration. Disadvantages of the oral route include (1) emesis caused by irritation of the gasrointesinal mucosa by the drug, (2) desruction of the drug by digesive enzymes or acidic gasric fuid, and (3) irregularities in absorption in the presence of food or other drugs. Furthermore, drugs may be metabolized by enzymes or bacteria in the gasrointesinal tract before sysemic absorption can occur. With oral adminisration, the onset of drug efect is largely determined by the rate and extent of absorption from the gasrointesinal tract. The principal site of mos drug absorption after oral adminisration is the small intesine due to the large surface area of this portion of the gasrointesinal tract. Changes in the pH of gasrointesinal fuid that favor the presence of a drug in its nonionized (lipid-soluble) fraction thus favor sysemic absorption. Some absorption occurs in the somach, where the fuid is obviously acidic, enhancing the absorption of weak acids such as aspirin. However, mos drug absorption occurs in the alkaline environment of the small intesine. The alkalinity enhances absorption of weak bases such as opioids, but even weak acids are mosly absorbed in the small intesine because of the large surface area. Firs-Pass Hepatic Efect Drugs absorbed from the gasrointesinal tract enter the portal venous blood and thus pass through the liver before https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library entering the sysemic circulation for delivery to tissue receptors. This is known as the frs-pass hepatic metabolism. For drugs that undergo extensive hepatic extraction and metabolism (propranolol, lidocaine), it is the reason for large diferences in the pharmacologic efect between oral and intravenous doses. As mentioned earlier, it is also the reason that propofol exerts no pharmacologic efect when swallowed—none gets pas the liver. Sublingual, Buccal, and Nasal Adminisration The sublingual or buccal route of adminisration permits a rapid onset of drug efect because this blood bypasses the liver, preventing frs-pass metabolism for the initial dose. Drugs absorbed from the oral cavity fow into the superior vena cava. Evidence of the value of bypassing the frs-pass hepatic efect is the efcacy of sublingual nitroglycerin. Sublingual nitroglycerin works quickly, while oral nitroglycerin tablets are inefective because of extensive frs-pass hepatic metabolism. It is also why oral transmucosal fentanyl citrate results in a rapid rise in fentanyl concentration for “breakthrough” cancer pain where rapid onset of pain relief is clinically important. Oral fentanyl has an extraction ratio of about 50%, which greatly limits the utility of oral adminisration. Buccal adminisration is an alternative to sublingual placement of a drug; it is better tolerated and less likely to simulate salivation. Buccal buprenorphine is an example of efective buccal adminisration. The nasal mucosa also provides an efective absorption surface for certain drugs. For example, in 2019, the US Food and Drug Adminisration approved nasally adminisered s-ketamine for treatment resisant depression. Nasally adminisered naloxone is now widely available to emergency medical technicians for treatment of opioid overdose. The nasal route afords very rapid reversal of opioid overdose. Transdermal Adminisration Transdermal adminisration of drugs provides susained therapeutic plasma concentrations of the drug and decreases the likelihood of loss of therapeutic efcacy due to peaks and valleys associated with conventional intermittent drug injections. This route of adminisration is devoid of the complexity of continuous infusion techniques, and the low incidence of side efects (because of the small doses used) contributes to high patient compliance. Characterisics of drugs that favor predictable transdermal absorption include (1) combined water and lipid solubility, (2) molecular weight of β > γ by about 1 order of magnitude. At time 0 (t = 0), Equation 2.22 reduces to. In other words, the sum of the coefcients A, B, and C equals the concentration immediately following a bolu thus follows that. Consructing pharmacokinetic models represents a trade-of between accurately describing the data, having confdence in the results, and mathematical tractability. Adding exponents to the model usually provides a better description of the observed concentrations. However, adding more exponent terms usually decreases our confdence in how well we know each coefcient and exponential and greatly increases the mathematical burden of the models. This is why mos pharmacokinetic models are limited to two or three exponents. Polyexponential models can be mathematically transformed from the admittedly unintuitive exponential form to a more easily visualized compartmental form, as shown in Figures 2.17 and 2.20. Micro-rate consants, expressed as kij, defne the rate of drug transfer from compartment i to compartment j. Compartment 0 is the compartment outside the model, so k10 is the micro-rate consant for irreversible removal of drug from the central compartment (analogous to k for a one-compartment model). The intercompartmental micro-rate consants ( k12, k21, etc) describe the movement of drug between the centra and peripheral compartments. Each peripheral compartment has two micro-rate consants, one for drug entry and one for drug exit. The micro-rate consants for the two- and three-compartment models can be seen in Figure 2.17. The diferential equations describing the rate of change for the amount of drug in compartments 1, 2, and 3 follow https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library directly from the micro-rate consants. For the two-compartment model, the diferential equations for each compartment are as follows: EQUATION 2.27 where I is the rate of drug input. For the three-compartment model, the diferential equations for each compartment are as follows: EQUATION 2.28 For the one-compartment model, k was both the rate consant and the exponent. For multicompartment models, relationships are more complex. The interconversion between the micro-rate consants and the exponents becomes exceedingly complex as more exponents are added because every exponent is a function of every micro-rate consant and vice versa. Individuals interesed in such interconversions can fnd them in the Excel spreadsheet “convert.xls,” which can be downloaded from https://github.com/StevenLShafer/Pharmacokinetics/blob/maser/convert.xls. This is useful because publications on pharmacokinetics may use one or another sysem, and it is difcult to compare without converting the exponents to micro-rate consants. The Time Course of Drug Efect The plasma is not the site of drug efect for aneshetic drugs. There is a time lag between plasma drug concentration and efect site drug concentration. Consider the diferent rate of onset for fentanyl and alfentanil. Figure 2.21 is from work by Stanski and colleagues., The black bar in Figure 2.22A shows the duration of fentanyl infusion. Rapid arterial samples document the rise in fentanyl concentration. The time course of https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library electroencephalogram efect (spectral edge) lags 2 to 3 minutes behind the rapid rise in arterial concentration. This lag is called hyseresis. The plasma concentration peaks at the moment the infusion is turned of. Following the peak plasma concentration (and the Disney logo that appears at peak plasma concentration), the plasma fentanyl concentration rapidly decreases. However, the ofset of fentanyl drug efect lags well behind the decrease in plasma concentration. Figure 2.22B shows the same sudy design in a patient receiving alfentanil. Because of alfentanil’s rapid blood–brain equilibration, there is less hyseresis (delay) with alfentanil than with fentanyl. FIGURE 2.22  View Original Download Slide (.ppt) Fentanyl and alfentanil arterial concentrations (circles) and electroencephalographic (EEG) response (irregular line) to an intravenous infusion. Alfentanil shows a less time lag between the rise and fall of arterial concentration and the rise and fall of EEG response than fentanyl because it equilibrates with the brain more quickly. Reprinted with permission from Scott JC, Ponganis KV, Stanski DR. EEG quantitation of narcotic efect: the comparative pharmacodynamics of fentanyl and alfentanil. Aneshesiology. 1985;62(3):234–241. Copyright © 1985 American Society of Aneshesiologiss, Inc. The relationship between the plasma and the site of drug efect is modeled with an “efect site” model, as shown in Figure 2.23. The site of drug efect is connected to the plasma by a frs-order process. The equation that relates efect site concentration to plasma concentration is EQUATION 2.29 https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library FIGURE 2.23  View Original Download Slide (.ppt) The three-compartment model from Figure 2.16 with an added efect site to account for the equilibration delay between the plasma concentration and the observed drug efect. The efect site has a negligible volume. As a result, the only parameter that afects the delay is ke0. where Ce is the efect site concentration and Cp is the plasma drug concentration. ke0 is the rate consant for elimination of drug from the efect site. It is mos easily undersood in terms of its reciprocal, 0.693/ke0, the halftime for equilibration between the plasma and the site of drug efect. Figure 2.24 shows the plasma and efect site concentrations predicted by the model (see Figure 2.22) for fentanyl and alfentanil. The plasma concentrations (black lines) are not very diferent. However, the efect site concentrations (red lines) show that alfentanil equilibrates more quickly. There are two consequences. Firs, the peak efect is sooner (obviously). Second, the rapid equilibration of alfentanil allows the brain to “see” the initial high plasma concentrations, producing a relatively greater rise in efect site concentrations than observed with fentanyl. This permits alfentanil to deliver relatively more “bang” for a bolus. FIGURE 2.24 https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library  View Original Download Slide (.ppt) Plasma (black line) and efect site (red line) concentrations following a bolus dose of fentanyl (A) or alfentanil (B). Adapted with permission from Shafer SL, Varvel JR. Pharmacokinetics, pharmacodynamics, and rational opioid selection. Aneshesiology. 1991;74(1):53–63. Copyright © 1991 American Society of Aneshesiologiss, Inc. The consant ke0 has a large infuence on the rate of rise of drug efect, the rate of ofset of drug efect, the time to peak efect, and the dose that is required to produce the desired drug efect. Dose Calculations Bolus Dosing We noted previously that we can rearrange the defnition of concentration to fnd the amount of drug required to produce any desired target concentration for a known volume,. Many introductory pharmacokinetic texts sugges using this formula to calculate the loading bolus required to achieve a given concentration. The problem with applying this concept to the aneshetic drugs is that there are several volumes: V1 (central compartment); V2 and V3 (the peripheral compartments); and Vdss, the sum of the individual volumes. V1 is usually much smaller than Vdss, and so it is tempting to say that the loading dose should be something between CT × V1 and CT × Vdss. That proves to be a useless suggesion. Consider the initial dose of fentanyl. The C50 for fentanyl to attenuate hemodynamic response to intubation (when combined with an intravenous hypnotic) is approximately 2 ng/mL. The V1 and Vdss for fentanyl are 13 L and 360 L, respectively. The dose of fentanyl thus ranges from a low of 26 μg (based on the V1 of 13 L) to a high 720 μg (based on the Vdss of 360 L). A fentanyl bolus of 26 μg achieves the https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library desired concentration in the plasma for an initial insant (Figure 2.25). Unfortunately, the plasma levels almos insantly decrease below the desired target, and the efect site levels are never close to the desired target. A fentanyl bolus of 720 μg, not surprisingly, produces an enormous overshoot in the plasma levels that persiss for hours. It is absurd to use equations to calculate the fentanyl dose if the resulting recommendation is “pick a dose between 26 and 720 μg.” FIGURE 2.25  View Original Download Slide (.ppt) The volume of the central compartment of fentanyl is 13 L. The volume of disribution at seady sate is 360 L. For a target concentration of 2 μg/L (dotted line), the dose calculated on V1, 26 μg, results in a subsantial undershoot. The dose calculated using Vdss, 720 μg, produces a profound overshoot. Only a dose based on Vdpeak efect, 150 μg, produces the desired concentration in the efect site. The black lines show plasma concentration over time. Red lines show efect site concentration over time. Conventional approaches to calculate a bolus dose are designed to produce a specifc plasma concentration. This makes little sense because the plasma is not the site of drug efect. By knowing the ke0 (the rate consant for elimination of drug from the efect site) of an intravenous aneshetic, we can design a dosing regimen that yields the desired concentration at the site of drug efect. If we do not want to overdose the patient, we should select the bolus that produces the desired peak concentration in the efect site. The decline in plasma concentration after the bolus, up to the time of peak efect, can be thought of as a dilution of the bolus into a larger volume than the volume of the central compartment. One interesing characterisic of the https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library equilibration between the plasma and the efect site is that at the time of peak efect, the plasma and the efect site concentrations are the same (if they were not the same, then it would not be the peak because there would be a gradient driving drug in or out of the efect site). This introduces the concept of Vdpe, the apparent volume of disribution at the time of peak efect. The size of this volume can be readily calculated from the observation that the plasma and efect site concentrations are the same at the time of peak efect: EQUATION 2.30 where Cpe is the plasma concentration at the time of peak efect. We can arrange this equation to calculate the dose that provides the desired peak efect site concentration: bolus. For example, the Vdpe for fentanyl is 75 L. Producing a peak fentanyl efect site concentration of 2 ng/mL requires 150 μg for the typical patient, which produces a peak efect in 3.6 minutes. This is a much more reasonable dosing guideline than the previous recommendation of picking a dose between 26 and 760 μg. Table 2.2 liss V1 and Vdpe for fentanyl, alfentanil, sufentanil, remifentanil, propofol, thiopental, and midazolam. Table 2.3 liss the time to peak efect and the t½ ke0 (half-life at the site of drug efect) of the commonly used intravenous aneshetics. Of course, individuals may difer from the typical patient. The individual characterisics that drive the diferences may be known (age, weight, renal or hepatic dysfunction) in which case they can be built into the pharmacokinetic model if they are found to be signifcant. On the other hand, they may be unknown, in which case pharmacodynamic monitoring is required to fne tune dosing. TABLE 2.2 Volume of distribution at the time of peak effecta Drug V1 (L) Vdpe (L) Fentanyl 12.7 75 https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library Alfentanil 2.19 5.9 Sufentanil 17.8 89 Remifentanil 5.0 17 Propofol 6.7 37 Thiopental 5.6 14.6 Midazolam 3.4 31 Abbreviations: V1, volume of the central compartment; Vdpe, apparent volume of disribution at the time of peak efect. aReprinted from Glass PSA, Shafer SL, Reves JG. Intravenous drug delivery sysems. In: Miller RD, Eriksson LI, Fleisher LA, et al, eds. Miller’s Aneshesia. Vol 1. 7th ed. Philadelphia, PA: Churchill Livingsone; 2010:825–858. Copyright © 2010 Elsevier. With permission. TABLE 2.3 https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library  View Original The time to peak effect and Download Slide (.ppt) t½ ke0 following a bolus dose a Maintenance Infusion Rate As explained previously, to maintain a given target concentration, CT, drug mus be delivered at the same rat drug is exiting the body. Thus, the maintenance infusion rate at seady sate is maintenance infusion. However, this equation only applies after peripheral tissues have fully equilibrated with the plasma, which may require many hours. At all other times, this maintenance infusion rate underesimates the infusion rate to maintain a target concentration. https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library In some situations, this simple rate calculation may be acceptable. For example, if an infusion at this rate is used after a bolus based on Vdpe (apparent volume of disribution at time of peak efect), and the drug has a long delay between the bolus and peak efect, then much of the disribution of drug into the tissues may have occurred by the time of peak efect site concentration. In this case, the maintenance infusion rate calculated as clearance times target concentration may be satisfactory because Vdpe is sufciently higher than V1 to account for the disribution of drug into peripheral tissues. Unfortunately, mos drugs used in aneshesia have sufciently rapid plasma-efect site equilibration that Vdpe does not adequately encompass the disribution process, making this approach unsuitable. The pharmacokinetically sound approach should account for tissue disribution. Initially, the infusion rate is higher than CT · Cl because it is necessary to replace the drug that gets taken up by peripheral tissues. However, the net fow of drug into peripheral tissues decreases over time. Therefore, the infusion rate required to maintain any desired concentration mus also decrease over time. Following bolus injection, the equation to maintain the desired concentration is: EQUATION 2.31 This equation indicates that a high infusion rate is initially required to maintain CT. Over time, the infusion rate gradually decreases (Figure 2.26). At equilibrium (t = ∞), the infusion rate decreases to CT V1 k10, which is the same as CT · Cl. FIGURE 2.26 https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library  View Original Download Slide (.ppt) Fentanyl infusion rate to maintain a plasma concentration of 1 μg per hour. The rate sarts of quite high because fentanyl is avidly taken up by body fat. The necessary infusion rate decreases as the fat equilibrates with the plasma. No aneshetic in hisory has ever been so boring as to merit mentally solving such an equation while adminisration of an aneshetic. Fortunately, there are simple techniques that can be used in place of solving such a complex expression. Figure 2.27 is a nomogram in which the Equation 2.14 has been solved, showing the infusion rates over time necessary to maintain any desired concentration of fentanyl, alfentanil, sufentanil, and propofol. This nomogram is complex, and we don’t use it even though one of us (SLS) created this nomogram. The point in including it is to show how infusion rates mus be turned down over time as drug accumulates. The y-axis represents the target concentration, CT. The suggesed target initial concentrations (shown in red) are based on the work of Vuyk a colleagues and appropriately scaled for fentanyl and sufentanil. The x-axis is the time since the beginning of the aneshetic. The intersections of the target concentration line and the diagonal lines indicates the infusion rate appropriate at each point in time. For example, to maintain a fentanyl concentration of 1.0 ng/mL, the appropriate rates are 3.0 μg/kg/hour at 15 minutes, 2.4 μg/kg/hour at 30 minutes, 1.8 μg/kg/hour at 60 minutes, 2.1 μg/kg/hour at 120 minutes, and 0.9 μg/kg/hour at 180 minutes. FIGURE 2.27 https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library  View Original Download Slide (.ppt) Dosing nomogram, showing the infusion rates (numbers on the perimeter) required to maintain sable concentrations of fentanyl (1.0 μg/mL), alfentanil (75 μg/mL), sufentanil (0.1 μg/mL), and propofol (3.5 ng/mL). https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library Another approach to determine infusion rates for maintenance of aneshesia to a desired target concentration is through the use of a specialized slide rule. Figure 2.28 illusrates such a slide rule for propofol. As described by Bruhn et al, “The bolus dose required to reach a given target plasma concentration is the product of the (weight-related) disribution volume and required concentration. Similarly, the infusion rate at a particular time point is the product of target concentration, body weight, and a correction factor that depends on the time elapsed from the sart of the initial infusion. This factor can be determined for each time point using a PK simulation program.” FIGURE 2.28  View Original Download Slide (.ppt) Propofol slide ruler to calculate maintenance infusion rate, based on the patient’s weight and the time since the sart of the infusion, as proposed by Bruhn and colleagues. To make use of the calculator, make a photocopy and cut in to top (body weight), middle (time since sart of infusion/propofol target concentration), and bottom (infusion rate propofol 1%) sections—calculation requires sliding the middle piece in relationship to the top and bottom segments, which are fxed. Adapted with permission from Bruhn J, Bouillon TW, Röpcke H, et al. A manual slide rule for target-controlled infusion of propofol: development and evaluation. Anesh Analg. 2003;96(1):142–147. Copyright © 2003 International Aneshesia Research Society. The bes approach is through the use of target-controlled drug delivery. With target-controlled drug delivery, the user simply sets the desired plasma or efect site concentration. Based on the drug’s pharmacokinetics and the mathematical relationship between patient covariates (eg, weight, age, gender) and individual pharmacokinetic parameters, the computer calculates the dose of drug necessary to rapidly achieve and then maintain any desired concentration. Mos critically, it can raise and lower concentrations in a controlled fashion, a calculation that cannot be captured in any simple nomogram. Such computerized controlled drug delivery sysems are now widely available. An alternative approach is to use sanpumpR, which can be found online at http://sanpumpR.io. sanpumpR is an https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library online, open-source (see https://github.com/StevenLShafer/sanpumpR) pharmacokinetic simulator for intravenous aneshetic drugs and oral opioids. It was primarily developed by one of the authors (SLS) and remains in active development. Figure 2.29 shows the screen of sanpumpR simulating an aneshetic with a propofol bolus and infusion, a fentanyl bolus, a remifentanil infusion, and two boluses of rocuronium. sanpumpR can be used to model specifc aneshetic srategies before aneshesia or to model an ongoing aneshetic to see approximately what the drug levels are for the adminisered drugs. FIGURE 2.29 https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library  View Original Download Slide (.ppt) sanpumpR (https://sanpumpR.io) is a pharmacokinetic (PK)/pharmacodynamic (PD) simulation program for aneshesia. The program implements published PK/PD models for alfentanil, dexmedetomidine, etomidate, fentanyl, hydromorphone, ketamine, lidocaine, methadone, midazolam, morphine, naloxone, oxycodone, oxytocin, pethidine, propofol, remifentanil, rocuronium, and sufentanil. Context-Sensitive Half-time Special signifcance is often ascribed to the smalles exponent, which determines the slope of the fnal log-linear portion of the curve. When the medical literature refers to the half-life of a drug, unless otherwise sated, the halflife is based on the terminal half-life (ie, 0.693/smalles exponent). However, the terminal half-life for drugs with more than one exponential term is nearly impossible to interpret. The terminal half-life sets an upper limit on the time required for the concentrations to decrease by 50% after drug adminisration. Usually, the time for a 50% decrease will be much faser than that upper limit. A more useful concept is the “context-sensitive half-time,” shown in Figure 2.30 , which is the time for the plasma concentration to decrease by 50% from an infusion that maintains a consant concentration. The “context” is the duration of the infusion. The context-sensitive half-time increases with longer infusion durations because it takes longer for the concentrations to fall if drug has accumulated in peripheral tissues. FIGURE 2.30 https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library  View Original Download Slide (.ppt) Context-sensitive half-times as a function of the duration of intravenous drug infusion for alfentanil, sufentanil, propofol, midazolam, and thiopental. Reprinted with permission from Hughes MA, Glass PSA, Jacobs JR. Context-sensitive half-time in multicompartment pharmacokinetic models for intravenous aneshetic drugs. Aneshesiology. 1992;76(3):334–341. Copyright © 1992 American Society of Aneshesiologiss, Inc. The context-sensitive half-time is based on the time for a 50% decrease, which was chosen both to provide an analogy to half-life, and because, very roughly, a 50% reduction in drug concentration appears necessary for recovery after adminisration of mos intravenous hypnotics at the termination of surgery. Of course, decreases other than 50% may be clinically relevant. Additionally, the context-sensitive half-time does not consider plasmaefect site disequilibrium and thus may be misleading for drugs with very slow plasma-efect site equilibration. A related but more clinically relevant representation is the context-sensitive efect site decrement time, as shown in Figure 2.31. For example, the upper black line in Figure 2.31 is the context-sensitive 20% efect site decrement time for fentanyl, that is, the time required for fentanyl efect site concentrations to fall by 20%, based on the duration of a fentanyl infusion. Context-sensitive half-time and efect site decrement times are more useful than elimination half-time in characterizing the clinical responses to drugs. FIGURE 2.31 https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library  View Original Download Slide (.ppt) Effect site decrement times. The 20%, 50%, and 80% decrement times for fentanyl (black), alfentanil (green), sufentanil (red), and remifentanil (blue). When there is subsantial plasma-efect site disequilibrium, the efect site decrement time will provide a better esimate of the time required for recover than the context-sensitive half-time. Adapted from Youngs EJ, Shafer SL. Pharmacokinetic parameters relevant to recovery from opioids. Aneshesiology. 1994;81:833–842. Pharmacodynamics https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library  Listen   Pharmacodynamics is the sudy of the intrinsic sensitivity or responsiveness of the body to a drug and the mechanisms by which these efects occur. Thus, pharmacodynamics may be viewed as what the drug does to the body. Structure-activity relationships link the actions of drugs to their chemical sructure and facilitate the design of drugs with more desirable pharmacologic properties. The intrinsic sensitivity is determined by measuring plasma concentrations of a drug required to evoke specifc pharmacologic responses. The intrinsic sensitivity to drugs varies among patients and within patients over time with changes in physiology such as aging, disease, and injury. As a result, at similar plasma concentrations of a drug, some patients show a therapeutic response, others show no response, and others develop toxicity. The basic principles of receptor theory were covered in the frs section of this chapter. This section focuses on methods of evaluating clinical drug efects such as dose-response curves, efcacy, potency, the median efective dose (ED50), the median lethal dose (LD 50), and the therapeutic index. Concentration Versus Response Relationships The mos fundamental relationship in pharmacology is the concentration (or dose) versus response curve, shown in Figure 2.32. This is the time-independent relationship between exposure to the drug (x-axis) and the measured efect (y-axis). The exposure can be the concentration, the dose, the area under the concentration versus time curve, or any other measure of drug exposure that is clinically meaningful. The measured efect can be an absolute response (eg, twitch height), a normalized response (eg, percentage of twitch depression), a population response (eg, fraction of subjects moving at incision), or any physiologic response (chloride current). The sandard equation for this relationship is the “Hill” equation, sometimes called the sigmoid-Emax relationship: EQUATION 2.32 FIGURE 2.32 https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library  View Original Download Slide (.ppt) Drug exposure (dose, concentration, etc) versus drug effect relationship. Potency refers to the position of the curve along the x-axis. Efcacy refers to the position of the maximum efect on the y-axis. In this equation, E0 is the baseline efect in the absence of drug, and Emax is the maximum possible drug ef is typically concentration or dose, although other measures of drug exposure (eg, dose, peak concentration, area under the concentration vs time curve) can be used. C50 is the concentration associated with 50% of peak drug efect and is a measure of drug potency. The term is a modifcation of the saturation equation presented in the prior section. Previously, it did not have an exponent. However, when used in pharmacodynamic models, the exponent γ, also called the Hill coefcient, appears. The exponent relates to the “sigmoidicity” and seepness of the curve. If γ is less than 1 and the curve is plotted on a sandard x-axis, then the curve appears hyperbolic (see Figure 2.8). If γ is greater than 1, then the curve appears sigmoidal, as in Figure 2.32. If the x-axi is plotted on a log scale, then the curve will always appear sigmoidal regardless of the value of γ. Potency and Efcacy https://anesthesiology-lwwhealthlibrary-com.ezproxylocal.library.nova.edu/content.aspx?sectionid=250487889&bookid=3088[5/13/2024 8:16:28 AM] Basic Principles of Pharmacology | Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 6e | Anesthesiology | Health Library There are two problems with the term potency. Clinicians often use potency to refer to the relative dose of two drugs, such as the relative potency of fentanyl and morphine. The problem with this defnition is that when drugs have very diferent time courses, the relative potency varies depending on the time of the measurement. Fentanyl reaches peak efect 3.5 minutes after injection. Morphine reaches peak efect 90 minutes after injection. As a result, the “relative potency” 3.5 minutes after injection indicates that fentanyl is far more potent than morphine. However, when morphine has reached its peak efect 90 minutes after injection, the efect of the fentanyl has almos entirely dissipated. Measured 90 minutes after injection, morphine is more potent. From therapeutic perspective, potency is often defned in terms of relative doses without regard to time. This common practice, unfortunately, is scientifcally fawed. From a pharmacologic perspective, potency is described based on the concentration versus response relationship. As shown in Figure 2.33 , a drug with a left-shifted concentration versus response curve (ie, lower C50) is considered more potent, whereas a drug with a right-shifted dose versus response curve is less potent. To be precise, potency should be defned in terms of a specifc drug efect (eg, 50% of maximal efect of a full agonis). This is particularly impor