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Contains the following key public domain (not copyrighted) U.S. Government publication(s) on one CD-ROM in both Microsoft PowerPoint and Adobe Acrobat PDF file formats:
TITLE:
Clinical Pharmacology and Cellular Mechanisms of Anesthesia, 110 pages (slides)
SLIDE TOPICS, SUBTOPICS and CONTENTS:
Clinical Pharmacology and Cellular Mechanisms of Anesthesia John F. Capacchione, MD Staff Anesthesiologist Clinical Pharmacology Pharmacokinetics Pharmacodynamics Stereochemistry Description of Drug Response Pharmacology of Injected Drugs Pharmacodynamics of Injected Drugs Pharmacokinetics of Inhaled Anesthetics Pharmacodynamics of Inhaled Anesthetics Pharmacokinetics The quantitative study of the absorption, distribution, metabolism, and excretion of injected and inhaled drugs and their metabolites May be viewed as what the body does to a drug Pharmacodynamics The study of the intrinsic sensitivity or responsiveness of receptors to a drug and the mechanisms by which these effects occur May be viewed as what the drug does to the body Stereochemistry The study of how molecules are structured in three dimensions Chirality refers to molecules that have centers of 3-dimensional asymmetry Enantiomerism—pairs of molecules that exist in two forms that are non-superimposable mirror images Enantiomers distinguished by the direction that they rotate polarized light, either dextro (d or +) or levo (l or -) rotatory Stereochemistry Optical isomers refers to enantiomers that rotate polarized light in opposite directions Racemic mixtures consist of 2 enantiomers in equal proportions and are optically neutral A 2nd nomenclature exists based on absolute configuration of the molecule uses the designation sinister S and rectus R, depending on how the molecules are sequenced Stereochemistry Molecular interactions that are the mechanistic foundation of pharmacokinetics and pharmacodynamics are either stereoselective or stereospecific Stereoselective—relative difference between enantiomers Stereospecific—absolute difference between enantiomers Enantiomers may represent two different drugs with distinctly different pharmacokinetic and pharmacodynamic profiles Description of Drug Response Hyperactive—term used for people in whom an unusually low dose produces its expected effect Hypersensitive—term usually reserved for people who are allergic (sensitized) to a drug Hyporeactive—describes persons who require exceptionally large doses of drug to evoke expected effects Tolerance—hyporeactivity acquired from chronic exposure to a drug
Description of Drug Response Cross-tolerance—develops between drugs of different classes that produce similar pharmacologic effects (EtOH and inhaled anesthetics) Tachyphylaxis—tolerance that develops acutely within only a few doses of a drug Cellular Tolerance—tolerance that develops from neuronal adaptation Description of Drug Response Additive Effect—a second drug acting with the first drug produces an effect equal to an algebraic summation Synergistic Effect—two drugs interact to produce an effect greater than an algebraic summation Antagonism—two drugs interact to produce an effect less than an algebraic summation Description of Drug Response Agonist—a drug that activates a receptor by binding to that receptor Antagonist—a drug that binds to the receptor without activating the receptor and at the same time prevents an agonist from stimulating the receptor Competitive Antagonism—increasing concentrations of antagonist progressively inhibit the response to an unchanging concentration of agonist Description of Drug Response Noncompetitive Antagonism—after administration of an antagonist, even high concentrations of agonist cannot completely overcome the antagonism Partial Agonist—binds only weakly to receptors and produces minimal pharmacologic effects despite a maximal concentration of drug being present Pharmacology of Injected Drugs Compartmental Models Plasma Concentration Curves Elimination Half-Time Context-Sensitive Half-Time Time to Recovery Effect-Site Equilibration Route of Administration and Systemic Absorption of Drug Pharmacology of Injected Drugs Distribution of Drugs after Systemic Absorption Volume of Distribution Ionization Protein Binding Clearance of Drugs from the Systemic Circulation Metabolism of Drugs Pharmacology of Injected Drugs Dose-Response Curves Drug Interactions Compartmental Models Two-compartment Model Central compartment—composed of intravascular fluid and highly perfused tissues (lungs, heart, brain, kidneys, liver) into which uptake of drug is rapid Highly perfused tissues receive 75% of cardiac output but represent only 10% of body mass Compartmental Models Peripheral compartment—all other tissues Rate constants that characterize intercompartmental transfer of drugs are k12 and k21, and ke is the rate constant for overall drug elimination from the body Plasma Concentration Curves Graphic plot of the logarithm of the decrease in the plasma concentration of a drug versus time after a rapid (bolus) iv injection that characterizes the distribution (alpha) and elimination (beta) phase of that drug The traditional concept that a drug’s pharmacologic effect parallels its plasma (presumably receptor) concentration is not always valid—pharmacologic effect may be increasing as plasma concentration is decreasing Elimination Half-Time The time necessary for the plasma concentration of a drug to decrease to 50% during the elimination phase Directly proportional to its Vd and inversely proportional to its clearance Independent of the dose of drug administered Descriptor used most often to characterize a drug’s pharmacokinetic behavior Elimination Half-Life The time necessary to eliminate 50% of the drug from the body after its rapid iv injection Not equal to elimination half-time when the decrease in the drug’s plasma concentration does not parallel its elimination from the body Five elimination half-times are required for nearly total (96.9%) elimination of drug from the body Context-Sensitive Half-Time Describes the time necessary for the plasma drug concentration to decrease by 50% after discontinuing a continuous infusion of a specific duration Computer simulated multicompartmental pharmacokinetic models of drug disposition Considers the combined effects of distribution and metabolism as well as duration of continuous iv administration on drug pharmacokinetics Bears no constant relationship to drug’s elimination half-time Time to Recovery Depends on how far the plasma concentration of drug must decrease to reach levels compatible with awakening If the concentration of drug maintained by continuous infusion is only just above that required for awakening, the time to recovery will be more rapid than that after a continuous infusion that maintained the plasma drug concentration at a level much higher than associated with awakening Effect-Site Equilibration The half-time of equilibration between drug concentration in the plasma and the drug effect This time is a particularly relevant concept in the logical timing of iv drug administration Drugs with short effect-site equilibration time will produce a more rapid onset of pharmacologic effect compared with drugs that have a longer effect-site equilibration time Route of Administration and Systemic Absorption of Drugs Oral Administration First-Pass Hepatic Effect Oral Transmucosal Administration Transdermal Administration Rectal Administration Parental Administration Systemic Absorption The systemic absorption rate of a drug determines its intensity and duration of action Regardless of the route of drug administration, systemic absorption depends on the drug’s solubility Local conditions at the site of absorption alter solubility Blood flow to the site of absorption is also important in the rapidity of absorption Oral Administration Onset of drug effect determined by rate and extent of absorption from the gastrointestinal tract Principal site of absorption is small intestine due to its large surface area Changes in the pH of gastrointestinal fluid that favor the presence of a drug in its nonionized (lipid-soluble) fraction thus favor systemic absorption First-Pass Hepatic Effect Drugs absorbed from the gastrointestinal tract enter the portal venous blood and thus pass through the liver before entering the systemic circulation for delivery to tissue receptors This is the reason for large differences in the pharmacologic effect between oral and iv doses for drugs that undergo extensive hepatic extraction and metabolism (propranolol, lidocaine) Oral Transmucosal Administration Sublingual or buccal route of administration permits a rapid onset of drug effect because it bypasses the liver and prevents first-pass hepatic effect on the initial plasma concentration of drug, i.e. sublingual NTG Venous drainage from the sublingual area is into the superior vena cava Transdermal Administration Provides sustained therapeutic plasma concentrations and decreases the likelihood of loss of therapeutic efficacy due to peaks and valleys associated with conventional intermittent drug injections The rate-limiting step is diffusion across the stratum corneum of the epidermis Rectal Administration Drugs administered into the proximal rectum are absorbed into the superior hemorrhoidal veins and are transported via the portal venous system to the liver (first-pass hepatic effect), where they are exposed to metabolism before entering the system circulation Drugs absorbed from a low rectal administration site reach the systemic circulation without first passing through the liver Explains the unpredictable responses following rectal administration Parental Administration Systemic absorption after subcutaneous or intramuscular injection is usually more rapid and predictable than after oral administration Rate of systemic absorption is limited by the surface area of the absorbing capillary membranes and the solubility of the drug in interstitial fluid Parental Administration The desired concentration of drug in the blood can be achieved more rapidly and precisely by the iv route, which circumvents those factors that limit systemic absorption by other routes Distribution of Drugs after Systemic Absorption Uptake into the Lungs Central Nervous System Distribution Volume of Distribution Ionization Protein Binding Distribution of Drugs after Systemic Absorption The highly perfused tissues (heart, brain, kidneys, liver) receive a disproportionately large amount of the total dose As plasma concentration decreases below that in highly perfused tissues, drug leaves these tissues to be redistributed to less well-perfused sites, i.e. skeletal muscle, fat; e.g. thiopental Uptake of drug by tissues is principally determined by tissue blood flow if the drug can penetrate membranes rapidly Distribution of Drugs after Systemic Absorption The concentration gradient for the diffusible fraction of drug (nonionized, lipid soluble, and unbound to protein) determines both rate and direction of net transfer between plasma and tissue Uptake into the Lungs First-pass pulmonary uptake of initial dose of lidocaine, propranolol, meperidine, fentanyl, sufentanil, and alfentanil exceeds 65% of the dose Pulmonary uptake may influence peak arterial concentration and serve as a reservoir to release drug back into the systemic circulation Central Nervous System Distribution Ionized water-soluble drugs are restricted from the CNS due to the limited permeability characteristics of brain capillaries, blood-brain barrier Cerebral blood flow is the only limitation to permeation of the CNS by nonionized lipid-soluble drugs Volume of Distribution Vd is calculated as the dose administered iv divided by the resulting plasma concentration of drug before elimination begins or when steady-state conditions have been achieved Vd is influenced by physicochemical properties of the drug, i.e. lipid solubility, protein binding, molecular size Volume of Distribution Drug protein binding and poor lipid solubility limit passage to tissues, thus maintaining high concentration in plasma and a small calculated Vd, e.g. nondepolarizing neuromuscular blockers A lipid-soluble drug that is highly concentrated in tissues with a resulting low plasma concentration will have a calculated Vd that exceeds total body water, e.g. thiopental Ionization Most drugs are weak acids or bases present in solution as both ionized and nonionized molecules Solubility characteristics of ionized and nonionized molecules determine ease with which they diffuse through lipid cell membranes Ionization repels molecules from portions of cells with similar charge Nonionized molecules are usually lipid soluble, diffuse across cell membranes, and are the fraction that is pharmacologically active Protein Binding Important influence on distribution of drugs because only the free or unbound fraction is available to cross cell membranes Vd is inversely related to protein binding Clearance of Drugs from the Systemic Circulation Hepatic Clearance Biliary Excretion Renal Clearance Clearance of Drugs from the Systemic Circulation The volume of plasma cleared of drug by renal excretion and/or metabolism in the liver or other organs Examples of nonorgan clearance of drugs are Hofman elimination and ester hydrolysis Clearance is one of the most important pharmacokinetic variables to consider when defining a constant drug infusion regimen Hepatic Clearance Defined as the product of hepatic blood flow and the hepatic extraction ratio If hepatic extraction ratio is high (>0.7), the clearance of drug will depend on hepatic blood flow and changes in enzyme activity will have minimal influence High hepatic extraction ratio results in perfusion-dependent elimination If hepatic extraction ratio is <0.3, only a small fraction of drug delivered to the liver is removed per unit of time Hepatic Clearance With low hepatic extraction ratio, changes in blood flow will not greatly influence hepatic clearance Decrease in protein binding or increase in enzyme activity, as associated with enzyme induction, will increase hepatic clearance of a drug with low hepatic extraction ratio This type of hepatic elimination is termed capacity-dependent elimination Biliary Excretion Most metabolites of drugs produced in the liver are excreted in bile into the gi tract Metabolites are often reabsorbed from the gi tract into the circulation for elimination in the urine Organic anions, like glucuronides, are transported actively into bile by carrier systems similar to those that transport these anions into renal tubules Renal Clearance Kidneys are most important organs for the elimination of unchanged drugs or their metabolites Water-soluble compounds excreted more efficiently than highly lipid soluble compounds Lipid-soluble drugs must be metabolized to water-soluble metabolites Metabolism of Drugs Rate of Metabolism—First-Order and Zero-Order Kinetics Pathways of Metabolism Metabolism of Drugs The role of biotransformation is to convert pharmacologically active, lipid-soluble drugs into water-soluble and often inactive metabolites Increased water-solubility decreases Vd and enhances renal excretion First-Order Kinetics Linear kinetics such that a constant fraction of available drug is metabolized in a given period of time Zero-Order Kinetics Occurs when the plasma concentration of drug exceeds the capacity of metabolizing enzymes This reflects saturation of available enzymes and results in metabolism of a constant amount of drug per unit time The amount of drug eliminated per unit time is the same, regardless of the drug’s plasma concentration Pathways of Metabolism Hepatic Microsomal Enzymes Enzyme Induction Nonmicrosomal Enzymes Oxidative Metabolism Reductive Metabolism Hydrolysis Conjugation Hepatic Microsomal Enzymes Includes an iron-containing protein termed cytochrome P-450 Cytochrome P-450 system also known as mixed function oxidase system because it involves both oxidation and reduction steps Cytochrome P-450 functions as the terminal oxidase in the electron transport scheme Considering the large number of different drugs metabolized by the cytochrome P-450 system, it is likely that it is actually a large number of different protein systems Enzyme Induction Hepatic microsomal enzyme activity can be stimulated by certain drugs and chemicals Increased enzyme activity produced by drugs or chemicals is known as enzyme induction, e.g. phenobarbital Nonmicrosomal Enzymes Catalyze reactions responsible for metabolism of drugs by conjugation, hydrolysis, and, to a lesser extent, oxidation and reduction All conjugation rxns except conjugation of glucuronic acid are catalyzed by nonmicrosomal enzymes Nonspecific esterases in the liver, plasma, and gi tract are examples of nonmicrosomal enzymes responsible for hydrolysis of drugs that contain ester bonds Nonmicrosomal Enzymes Nonmicrosomal enzymes such as plasma cholinesterase and acetylating enzymes do not undergo enzyme induction The activity of these enzymes is determined genetically, as emphasized by patients with atypical cholinesterase enzyme and individuals classified as rapid or slow acetylators Oxidative Metabolism Hepatic microsomal enzymes, including cytochrome P-450 enzymes, are crucial for the oxidation and resulting metabolism of many drugs These enzymes require an electron donor in the form of reduced nicotinamide adenine dinucleotide (NAD) and molecular oxygen for their activity A loss of electrons results in oxidation, whereas a gain of electrons results in reduction Oxidative Metabolism Examples of oxidative metabolism of drugs catalyzed by cytochrome P-450 enzymes include hydroxylation, deamination, desulfuration, dealkylation, and dehalogenation Reductive Metabolism Reductive pathways of metabolism, like oxidative pathways, involve cytochrome P-450 enzymes Under low oxygen partial pressures, cytochrome P-450 enzymes tranfer electrons directly to a substrate Hydrolysis Does not involve cytochrome P-450 system Often involve ester bonds Nonmicrosomal enzymes Does not involve enzyme induction Conjugation Conjugation with glucuronic acid involves cytochrome P-450 enzymes Glucuronic acid is readily available from glucose When conjugated to a lipid-soluble drug or metabolite, hydrophilic glucuronic acid renders the substance inactive and more water soluble and preferentially excreted in bile and urine Dose-Response Curves Potency Slope Efficacy Individual Responses
Dose-Response Curves Depict relationship between dose administered and resulting pharmacologic effect Logarithmic transformation of dosage often used to display wide range of doses Curves are characterized by differences in potency, slope, efficacy, and individual responses Potency Depicted by location along the dose axis of the dose-response curve Influenced by absorption, distribution, metabolism, excretion, and affinity for the receptor Increased affinity of drug for receptor moves the curve to the left The dose required to produce a given effect is designated the effective dose (ED) necessary to produce that effect in a given percentage of patients (ED50, ED90) Slope Influenced by the number of receptors that must be occupied before a drug effect occurs Steep slope reflects majority of receptor occupancy occurring in order to get an effect Steep slope often reflects small difference between therapeutic and toxic concentration Efficacy Also known as intrinsic activity and is depicted by the plateau of the curve, i.e. maximal effect Therapeutic index, or margin of safety, is the difference between the desired effect dose and the undesired effect dose Therapeutic index defined as ratio between median lethal dose and median effective dose (LD50/ED50) Individual Responses May vary as reflections of differences in pharmacokinetics and/or pharmacodynamics Influenced by metabolic rate, which is determined by genetics, dynamic state of receptor concentration, as caused by diseases and other drugs Individual Responses Elderly Patients Enzyme Activity Genetic Disorders Elderly Patients Variations in drug response most likely reflect decreased cardiac output, enlarged fat content, decreased protein binding, and decreased renal function Age does not seem to cause changes in receptor responsiveness Enzyme Activity Alterations as caused by enzyme induction Because of enzyme induction, accelerated metabolism may manifest as tolerance or cross-tolerance Genetic Disorders Genetic variation in metabolic pathways, i.e. rapid vs. slow acetylators Genetic differences may affect receptor sensitivity Pharmacogenetics describes genetically determined disease states that are initially revealed by altered responses to specific drugs, i.e. atypical cholinesterase, malignant hyperthermia, G-6-PD deficiency, intermittent porphyria Drug Interactions Occurs when a drug alters the intensity of pharmacologic effects of another drug given concurrently May reflect alterations in pharmacokinetics and dynamics Net result is to enhance or diminish effects of one or both drugs, leading to desired or undesired effects Pharmacodynamics of Injected Drugs Drugs exert their effects by interacting with specific transmembrane protein macromolecules called receptors located within the lipid bilayer of cell membranes These receptors exist for endogenous regulatory substances such as hormones and neurotransmitters A drug-receptor interaction alters the fxn or conformation of a specific cellular component that initiates or prevents a series of changes that characterize the pharmacologic effects of the drug Pharmacodynamics Drugs can also evoke cellular changes (pharmacologic effect) via cytoplasmic receptors (steriod hormones), stimulation or inhibition of enzyme systems (phosphodiesterase inhibitors), by forming strong bonds with metallic cations (chelating agents), and direct neutralization of gastric acid (antacids) Excitable Transmembrane Proteins Represented by voltage-sensitive ion channels, ligand-gated ion channels, and transmembrane receptors Voltage-sensitive ion channels open and close depending on cell membrane voltage, i.e. Na, Cl, K, & Ca channels Ligand-gated ion channels fxn as receptor-ion channel complexes in which the ion channel is an integral part of a larger and more complex transmembrane protein, i.e. GABA Excitable Transmembrane Proteins Transmembrane receptors interact selectively with extracellular compounds (drugs, hormones, neurotransmitters) to initiate a cascade of biochemical changes that lead to the pharmacologic or physiologic response Receptor occupancy is referred to signal transduction, which triggers second messengers within the cell to execute biochemical changes, i.e. guanine nucleotide proteins (G proteins) Guanine Nucleotide Proteins G proteins are essential intermediaries in cell communication Many different transmembrane receptors are part of the large superfamily of G protein-coupled receptors, including adrenergic, opioid, muscarinic, dopamine, and histamine receptors Multiple subtypes exist for each receptor Concentration of Receptors The concentration of receptors in the lipid portion of cell membranes is dynamic, either increasing (up-regulation) or decreasing (down-regulation) in response to specific stimuli Chronic exposure by an agonist may lead to receptor concentration down-regulation Chronic exposure by an antagonist may lead to receptor concentration up-regulation Receptor Occupancy Theory Assumes the intensity of effect is proportional to the fraction of receptors occupied This theory does not explain differences in intrinsic activity between drugs that occupy the same number of receptors and produce responses ranging from full stimulation to antagonism State of Receptor Activation Theory states that agonist binding converts receptors form nonactivated to activated states Full agonists activate most receptors, partial agonists activate a fraction of receptors, and antagonists do not activate any of the receptors they bind and occupy Opioid agonist-antagonists are partial agonists that can competitively antagonize full agonists Drug-Receptor Bond A covalent bond is formed by sharing a pair of electrons between atoms, forming a strong bond that plays little role in reversible binding of drugs to receptors, i.e. alpha-adrenergic blockade produced by phenoxybenzamine Ionic bonds arise from electrostatic forces existing between groups of opposite charge Acidic or basic drugs ionized at plasma pH can combine with charged groups on proteins Drug-Receptor Bond Hydrogen bonds occur between hydroxyl or amino groups and an electronegative carboxyl oxygen group Van der Waals forces are weak bonds between two atoms or groups of atoms of different molecules—occurs when configuration between drug and receptor is sterically similar Relationship of Plasma and Receptor Drug Concentration The plasma concentration of a drug is the most practical measurement for monitoring the receptor concentration Plasma concentration should be representative of receptor concentration during steady state Vd A direct relationship exists between dose given, resulting plasma conc., and intensity of effect Onset and duration are related to the increase and decrease of drug concentration at responsive receptors as reflected by corresponding changes in plasma concentration Pharmacokinetics of Inhaled Anesthetics Absorption (uptake) from alveoli into pulmonary capillary blood Distribution in the body Metabolism Elimination, principally via the lungs Pharmacokinetics of Inhaled Anesthetics A series of partial pressure gradients beginning at the machine serve to propel the inhaled anesthetic across various barriers (alveoli, capillaries, cell membranes) to their sites of action in the CNS The principal objective of inhalation anesthesia is to achieve a constant and optimal brain partial pressure of the inhaled gas The brain and all other tissues equilibrate with the partial pressures of inhaled anesthetics delivered to them by arterial blood (Pa) Pharmacokinetics of Inhaled Anesthetics Arterial blood equilibrates with the alveolar partial pressures (PA), which mirrors brain partial pressure Pbr This is the reason that PA is used as an index of depth of anesthesia, recovery from anesthesia, and anesthetic equal potency (MAC) Determinants of Alveolar Partial Pressure The PA and ultimately the Pbr of inhaled anesthetics are determined by input (delivery) into alveoli minus uptake (loss) of the drug from alveoli into arterial blood Input of anesthetics into alveoli depends on the inhaled partial pressure (PI), alveolar ventilation, characteristics of the anesthetic breathing system, and patient FRC Determinants of Alveolar Partial Pressure Uptake of inhaled anesthetics from alveoli into the pulmonary capillary blood depends on solubility of the anesthetic in body tissues, cardiac output, and alveolar to venous partial pressure differences Transfer of inhaled anesthetic from arterial blood to brain depends on brain:blood partition coefficient, cerebral blood flow, and arterial to venous partial pressure differences Concentration Effect The impact of the inhaled partial pressure (PI) on the rate of rise of the alveolar partial pressure (PA) is known as the concentration effect The higher the PI, the more rapidly the PA approaches the PI The higher PI provides anesthetic molecule input to offset uptake and thus speeds the rate at which the PA increases Second-Gas Effect High-volume uptake of one gas (first gas) accelerates the rate of increase of the PA of a concurrently administered “companion” gas (second gas) Initial large-volume uptake of nitrous oxide accelerates the uptake of companion (second) gases such as oxygen and volatile anesthetics Solubility Solubility of inhaled anesthetics in blood and tissue is denoted by the partition coefficient A partition coefficient is a distribution ratio describing how the inhaled anesthetic distributes itself between two phases at equilibrium May be thought as reflecting the relative capacity of each phase to accept anesthetic Blood:Gas Partition Coefficient The rate of increase of the PA towards the PI is inversely related to the solubility of the anesthetic in blood Based on blood:gas partition coefficients, inhaled anesthetics are categorized as soluble, intermediately soluble, and poorly soluble Blood is a pharmacologically inactive reservoir Blood:Gas Partition Coefficient When the blood:gas partition coefficient is high, a large amount of anesthetic must be dissolved in the blood before the Pa equilibrates with the PA, thus slowing the rate of induction of anesthesia When blood solubility is low, minimal amounts of inhaled anesthetic must be dissolved before equilibration is achieved, and the rate of increase of PA and Pa speeds the onset of induction Oil:Gas Partition Coefficients Oil:gas partition coefficients parallel anesthetic requirements, i.e. predict potency or MAC Nitrous Oxide Transfer to Closed Gas Spaces The blood:gas partition coefficient of nitrous oxide (0.46) is about 34 times greater than that of nitrogen (0.014). This differential solubility means that nitrous oxide can leave the blood to enter an air-filled cavity 34 times more rapidly than nitrogen can leave the cavity to enter blood, leading to increased pressure in air-filled cavities. Recovery from Anesthesia Recovery is depicted by the rate of decrease in the Pbr as reflected by the PA Rate of washout from the brain should be rapid because inhaled anesthetics are not highly soluble in brain and the brain receives a large fraction of the CO Time to recovery is dependent on duration of anesthesia and the degree of equilibration and concentration gradients that exist between tissues and blood Recovery from Anesthesia Time to recovery is prolonged in proportion to the duration of anesthesia for soluble anesthetics (halothane and isoflurane), whereas the impact of duration of administration on time to recovery is minimal with poorly soluble anesthetics (sevoflurane and desflurane) Context-Sensitive Half-Time Pharmacokinetics of the elimination of inhaled anesthetics depends on the length of administration and the blood-gas solubility of the inhaled anesthetic It is possible to use computer simulations to determine context-sensitive half-times for volatile anesthetics Diffusion Hypoxia Occurs when inhalation of nitrous oxide is abruptly stopped, leading to reversal of partial pressure gradients such that nitrous oxide leaves the blood to enter alveoli Initial high-volume outpouring of nitrous oxide from blood into alveoli can so dilute the PAO2 that the PaO2 decreases There is also dilution of the PACO2, which decreases the stimulus to breath
Pharmacodynamics of Inhaled Anesthetics Minimal Alveolar Concentration (MAC) is defined as that concentration at 1 atm that prevents skeletal muscle movement in response to a supramaximal painful stimulus in 50% of patients MAC impacted by various physiologic and pharmacologic factors MAC values for inhaled anesthetics are additive Mechanism of Anesthesia Mechanism by which inhaled anesthetics produce progressive, and occasionally selective, depression of the CNS is unknown A single mechanism of action is unlikely Mechanisms producing immobility and amnesia most likely occur at different sites in the spinal cord and brain, respectively Mechanism of Anesthesia Most evidence is consistent with inhibition of synaptic transmission through multineuronal polysynaptic pathways, especially in the reticular activating system At the molecular level, anesthetics almost certainly act by binding directly to proteins rather than by perturbing lipid bilayers Anesthetics probably act by binding directly to protein sites, causing small changes in protein conformation Mechanism of Anesthesia Voltage-Gated Ion Channels Ligand-Gated Ion Channels Stereoselectivity Meyer-Overton Theory (Critical Volume Hypothesis) Voltage-Gated Ion Channels It is unlikely that changes in voltage-gated Na, K, or Ca play a substantial role in the production of anesthesia because the MAC of halothane occurs at a concentration 4 to 30 times lower than the EC50 needed to half-inhibit peak current flows through these channels Ligand-Gated Ion Channels May be important sites of anesthetic action as about one-third of all synapses in the CNS are responsive to GABA, with resulting activation leading to increased chloride permeability of neurons Most anesthetics are effective in potentiating responses to GABA, leading to CNS depression There is little evidence that second messenger systems are involved in general anesthesia Meyer-Overton Theory (Critical Volume Hypothesis) Correlation between lipid solubility and potency has historically been presumed to be evidence that inhaled anesthetics act by disrupting the structure or dynamic properties of the lipid portions of nerve membranes When a sufficient number of molecules (critical concentration) dissolve in crucial hydrophobic sites such as lipid cell membranes, there is distortion of channels necessary for ion flux and subsequent action potentials needed for synaptic transmission Meyer-Overton Theory Evidence supporting distortion of sodium channels by dissolved anesthetic molecules is that high pressures (40 to 100 atm) partially antagonize the action of inhaled anesthetics, presumably by returning (compressing) lipid membranes and their sodium channels to their “awake” contour Meyer-Overton Theory Evidence against the theory is the fact that the effects on lipid bilayers are implausibly small and can be mimicked by temperature changes of 1 degree C Also, not all lipid-soluble drugs are anesthetic, in fact, some are convulsants An explanation might be a combination of protein binding and dissolving in lipids Stereoselectivity Inhalation anesthetics exist as isomers, and isoflurane has been shown to act stereoselectively on neuronal channels, with the levoisomer being more potent than the dextroisomer in enhancing potassium conductance in neurons This finding suggests the basis for a specific protein receptor binding interaction, and not a lipid bilayer perturbation phenomenon Autonomic Nervous System Parasympathetic Nervous System—craniosacral distribution, nicotinic and muscarinic receptors, acetylcholine neurotransmission Sympathetic Nervous System—thoracoabdominal distribution, alpha 1 & 2 and beta 1 & 2 adrenergic receptors, epinephrine neurotransmission
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