Uniformed Services University Nurse Anesthesia Program Anesthesia Pharmacology Note Set

Transcription

1 Uniformed Services University Nurse Anesthesia Program Anesthesia Pharmacology Note Set AUGUST, 2004 Fourth Revision i

2 Table of Contents CHAPTER 1: Pharmacokinetic Principles 1 Absorption 2 First Pass Hepatic Effect 3 Bioavailability 7 Volume of Distribution 7 Plasma Concentration Curve 9 Redistribution 9 Drug Metabolism 10 Phase I & 11 Reactions 10 Drug Excretion 13 Elimination Kinetics 15 First-Order Elimination 15 Elimination Half-Times 16 Zero-Order Elimination 17 Compartmental Pharmacokinetic Models 17 Context-Sensitive Half-Times 22 Factors Altering Drug Pharmacokinetics 23 CHAPTER 2: Uptake and Distribution of Inhaled Agents 25 Partition Coefficients 27 Partial Pressure Gradients 29 Tissue Uptake and Major Tissue Groups 32 The Concentration Effect 33 The Second-Gas Effect 33 Time Constants 34 Minimum Alveolar Concentration (MAC) 44 Closed-Circuit Anesthesia 46 CHAPTER 3: Basic Concepts Related to General Anesthesia 49 Stages of Anesthesia 49 Theories of General Anesthesia 51 CHAPTER 4: Basic Math in Anesthesia Pharmacology 53 Intravenous Infusions 55 Concentration Ratios 55 Cylinder Calculations 56 Vaporizer Calculations 56 CHAPTER 5: Physics Applied to Anesthesia 59 The General Gas Laws 60 Laws of Gas Diffusion 61 Physics Applied to Monitors and Equipment 62 ii

3 CHAPTER 6: Inhaled Anesthetic Agents 66 Physical and Chemical Properties 68 Diffusion Hypoxia 69 Organ System Effects 74 Coronary Steal Syndrome 77 Halothane Hepatitis 79 Nephrotoxicity 80 CHAPTER 7: Intravenous Induction Agents 82 Barbiturates 82 Ketamine 86 Etomidate 88 Propofol 90 CHAPTER 8: Opioids 94 Opioid Receptors 95 Neuroaxial Opioids 96 Opioid Agonists 97 Context-Sensitive Half-Times 101 Major Physiologic Effects 102 Opioid Agonist-Antagonists 104 Opioid Antagonists 106 CHAPTER 9: Benzodiazepines 110 Midazolam 112 Diazepam 114 Lorazepam 115 Benzodiazepine Antagonists (Flumazenil) 115 CHAPTER 10: Neuromuscular Blocking Drugs 118 Depolarizing Neuromuscular Blockers 119 Phase I Block 120 Phase 2 Conversion Block 120 Defasciculation 122 Atypical Plasma Cholinesterase 125 Nondepolarizing Neuromuscular Blockers 127 Priming Dose 134 Altered Clinical Responses 135 Depth of Paralysis 137 CHAPTER 11: Anticholinesterase Drugs 139 Nicotinic and Muscarinic Receptors 139 Mechanism of Action 141 Reversible Anticholinesterase Drugs 142 Irreversible Anticholinesterase Drugs 145 Major Pharmacokinetic Principles 146 Major Organ System Effects 147 Antagonism of Nondepolarizing Blocks 147 Assessing Depth of Recovery 149 iii

4 CHAPTER 12: Anticholinergic Drugs 151 Pharmacological Considerations 152 Central Anticholinergic Syndrome 155 CHAPTER 13: Nerve Agent Exposure and Treatment 157 Physiologic Effects of Nerve Agent Poisoning 158 Treatment of Nerve Agent Exposure 158 Current Field Doctrine 160 Anesthesia Implications 161 CHAPTER 14: Local Anesthetics 164 Understanding pk a and ph 165 Pharmacokinetic Profile 167 Adding Vasoconstrictors 169 Local Anesthetic Toxicity 170 Primary Clinical Uses 172 Adding Sodium Bicarbonate 174 Differential Conduction Blockade 176 Common Epidural Infusion Mixtures 178 CHAPTER 15: Herbal Medicine 180 Anesthesia Management Concerns 180 Commonly Used Herbal Supplements 181 Internet Resources 187 CHAPTER 16: Gastrointestinal and Antiemetic Drugs 188 Factors increasing PONV HT 3 Receptor Antagonists 191 Butyrophenones 192 Substituted Benzamides 193 Anticholinergics 194 Antihistamines 195 Phenothiazines 196 Corticosteroids 196 Dosing Guidelines for Antiemetic Medications 198 Triad of Aspiration Pneumonitis Prophylaxis 199 H 2 Receptor Antagonists 200 Gastroprokinetic Agents 201 Nonparticulate Antacids 202 CHAPTER 17: Adrenergic Drugs 203 Alpha and Beta Adrenoreceptors 203 Synthesis of Norepinephrine 206 Sympathomimetics 208 Natural Catecholamines 208 Synthetic Catecholamines 211 Synthetic Noncatecholamines 212 Adrenergic Receptor Antagonists 215 Adrenergic Agonists 218 iv

5 Appendix I: Miscellaneous Summative Drug Tables 221 Seizure Disorders 221 Cardiovascular Disease 221 Increased Intracranial Pressure 221 Asthma 222 Histamine 222 Liver Dysfunction 222 Renal Dysfunction 222 Nausea and Vomiting 223 Malignant Hyperthermia 223 Atypical Pseudocholinesterase 223 REFERENCES 224 v

6 CHAPTER 1 Pharmacokinetic Principles 1. Pharmacokinetics a. What the body does to the drug b. Includes: i. Absorption (entry) ii. Distribution iii. Elimination 1. Metabolism (biotransformation) 2. Excretion c. Determines drug concentration at receptor sites d. Factors altering drug pharmacokinetics i. Bioavailability ii. Renal Function iii. Hepatic Function iv. Cardiac Function v. Patient Age Dose Blood Concentration Receptor Site Concentration 2. Pharmacodynamics a. What the drug does to the body b. Includes: i. Biochemical and physiological effects ii. Mechanism of action c. Relates the response or effect of a drug as a function of dose or concentration (which you as a nurse anesthetist can change) d. Factors altering drug pharmacodynamics i. Enzyme activity ii. Genetic differences iii. Drug interactions Receptor Site Concentration Pharmacological Clinical Response Response Therapeutic Outcome Ultimate goal of anesthesia is a pharmacologic response. Pharmacokinetic principles guide decisions made in the O.R. to administer certain drug doses in a certain fashion. Measured or Calculated Pharmacokinetic Parameters: Bioavailability Clearance Volume of Distribution Elimination Half-Time Context-Sensitive Half-Time Effect-Site Equilibration Recovery Time 1

7 Dose of drug administered PHARMACOKINETICS Drug concentration in systemic circulation DISTRIBUTION Drug in tissues of distribution ELIMINATION Drug metabolized or excreted Drug concentration at site of action Pharmacologic Effect PHARMACODYNAMICS Clinical Response Toxicity Efficacy Fig. 1-1: (Katzung, Bertram G., Basic & Clinical Pharmacology. 2001, p. 36.) Absorption Many factors affect systemic absorption of drugs. Some of the most important factors are listed below. 1. Route of administration 2. Drug properties (solubility) 3. Circulation to site of absorption 4. Local tissue conditions 5. Area of absorbing surface **Absorption does NOT occur with intravenously administered drugs. 2

8 Common Routes of Administration Oral Administration Common route of administration of anesthesia drugs, to include oral Midazolam for sedation, as well as Sodium Bicitra as a gastric prep. Disadvantages: 1. Emesis related to irritation of GI mucosa or bad taste. 2. Drug destruction by digestive enzymes 3. Irregularities in absorption in the presence of food or other drugs ** Principle site of drug absorption after oral administration is from the small intestines. First Pass Hepatic Effect Very important concept to understand! Drugs absorbed from the GI tract pass through the portal circulation of the liver before entering the systemic circulation. All drugs have different hepatic extraction ratios, known as first pass drug metabolism. ** Clinical application of this concept is seen in the large differences between effective oral and intravenous doses of many drugs. For example, Lidocaine undergoes extensive hepatic first pass extraction, resulting in the inability to give this drug orally. Propranolol also has significant first pass extraction, resulting in large variations in effective oral and IV doses (Oral mg / IV mg) Fig 1-2: (Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 1999, p 8.) Sublingual Administration Common route of administration of anesthesia drugs, to include Nitroglycerin and Procardia. This route permits rapid onset of drug delivery because the drugs bypass the liver. Venous drainage from this area is directly into the superior vena cava. Disadvantages: 1. Salivation may cause the medicine to dissolve more quickly, leading to swallowing, rendering less active. 2. Small absorbing surface area makes this route only effective for highly lipid-soluble drugs. Subcutaneous Administration This is also a common route of administration of drugs in the operating room, to include such drugs as Insulin, Terbutaline, and Epinephrine. Sustained drug release is achieved related to slow absorption. Disadvantages: 1. Slower than IV. 2. Rate limiting factor is diffusion across the epidermis. 3. Local skin irritation 3

9 Transcutaneous Administration Commonly used to administer medications in patch form, such as Nitroglycerin, Scopolamine, Catapres, and opioids used in chronic pain management. Disadvantages: 1. Only lipid-soluble drugs can penetrate intact skin. 2. Onset time is delayed related to slow, passive diffusion of drug. Intramuscular Administration Very common route of drug delivery in anesthesia, to include such drugs as Atropine, Toradol, and Morphine. Drug is deposited into vessel rich muscle mass, allowing for rapid absorption. Disadvantages: 1. High local concentration deposited into muscle mass can cause tissue damage. 2. Rate limiting factor includes local blood flow. Intravenous Administration Most common route of drug delivery in anesthesia. Full dose of delivered drug is diluted in circulating blood. Desired concentrations can be more rapidly and precisely achieved, as absorption is bypassed. Disadvantages: 1. Bolus concentrations initially reach the heart during the first pass after administration. 2. Higher incidence of adverse drug reactions and overdose. Inhalational Administration Widely used route of drug delivery in anesthesia, to include administration of volatile agents, local anesthetics and beta-agonists. Onset is very rapid, comparable to injected drugs. Disadvantages: 1. Irritation to the respiratory mucosa, results in lack of tolerance by the patient. 2. Requires a spontaneously or mechanically ventilated patient. Rectal Administration Not as commonly used. Can be utilized for administration of sedatives in anesthesia, to include Methohexital, Ketamine, and Midazolam. This route limits first pass exposure to the liver. Disadvantages: 1. Highly invasive 2. Irritation of rectal mucosa 3. Unpredictable absorption patterns Intranasal Administration Frequently used route of drug delivery in anesthesia, primarily for the administration of Midazolam. This route avoids first pass metabolism of the liver and is fairly rapid, dependent upon concentration delivered. Disadvantages: 1. Irritation to the nasal mucosa 2. Invasive 3. Usually, some or most of drug is swallowed, rendering it less active. 4

10 Intrathecal Administration Frequently used route of drug delivery for local anesthetics and narcotics. This route allows for the use of very low drug doses, as the site of action is at the spinal cord. This limits likelihood of systemic side effects. Disadvantages: 1. Requires expertise in the technique of administration. 2. Adverse drug effects. Epidural/Perineural Administration Frequent route of drug delivery for regional anesthesia, using primarily local anesthetics. Disadvantages: 1. Requires expertise in the technique of administration 2. Requires use of larger volumes of drug to elicit clinical effect. 3. Adverse drug effects. Routes of Administration for Drug Delivery ROUTE TISSUE LOCAL ph FIRST PASS EFFECT Sublingual (SL) No (SVC) Oral (PO) Stomach 1-3 Yes Duodenum Yes Jejunum, Ileum Yes Rectal Colon Yes/No (~ 50%) Intranasal No Intratracheal Trachea, Bronchi No Transcutaneous Skin No Subcutaneous No Intramuscular (IM) Muscle No Intravenous (IV) Venous No Intrathecal No Epidural No Inhalational Lungs No Intraorbital Orbit (eye) No Intraarticular Joint No Table 1-1: (Produced from information in Miller, R.D. Anesthesia. 2000, Chapter 2 & Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 1999, Chapter 1.) 5

11 Impact of Circulation on Absorption Blood flow to the site can greatly affect the rate of absorption of a drug. Vasodilatation (heat, rubbing) Increased rate of absorption Vasoconstriction (hypothermia) Decreased rate of absorption Body Tissue Composition and Relative Blood Flow (Average 70 kg adult) Tissue Group Organ/Tissue % Body Mass % Cardiac Output VRG Lungs (Vessel Rich) Heart Brain Liver Kidney Muscle Group Skeletal Muscle Skin Fat Group Adipose 20 6 VPG Bone 20 < 1 (Vessel Poor) Cartilage Table 1-2: (Produced from information in Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 1999, Chapter 1 & Woerlee, G.M. 1992, Kinetics and Dynamics of Intravenous Anesthetics. p.47) Local Tissue Conditions The condition of the tissue at the site of administration also greatly affects drug absorption. Traumatic injuries disrupt local capillary integrity and impede absorption. Factors altering tissue ph at the site of administration, such as an infectious process, may alter the amount of unionized drug fraction available for absorption. Area of Absorbing Surface Increased surface area for absorption accelerates entry of the drug into circulation. Examples of areas in the body with increased surface area are the blood, pulmonary tree, and GI tract. 6

12 Bioavailability Refers to the fraction of total drug that reaches the systemic circulation to elicit a therapeutic effect. Drug bioavailability is affected by: Absorption pattern from site of injection First-pass hepatic effects Pulmonary uptake Drug formulation (binders, dispersing agents, crystal polymorphism) DISTRIBUTION Major Determinants Blood flow (see table 1-2) Concentration gradient (administered dose) Drug physical/chemical properties Blood-brain barrier Volume of Distribution (V d ) This is a phrase that is often used in anesthesia to describe drugs, and is a concept that should be conceptually understood by the anesthesia provider. V d is a mathematical expression in liters of the distribution of a drug throughout plasma (central compartment) and tissue (peripheral compartment). It is the apparent volume that is required to give a known concentration following a known initial dose. V d reflects the ratio of drug in extraplasmic spaces (tissue) relative to the plasma space. Mathematical calculation: V d = Dose of drug Plasma concentration before elimination V d is primarily influenced by: 1. Variations in tissue amount and blood flow 2. Drug physicochemical properties o Lipid solubility o Plasma protein binding o Molecular size ** Clinical Examples** 1. Thiopental is highly lipid soluble, and results in a low plasma concentration, as it distributes into the peripheral compartments. It is said to have a high V d. 2. Vecuronium is a large, poorly soluble compound that stays primarily in the central compartment. Its V d is said to be very small, and is similar to extracellular fluid. 7

13 ** The smallest V d for a drug is the plasma volume. (See table below) Body compartment Blood plasma Blood volume Extracellular water Total Body Water Volume (70 kg) 3.5 L 5.5 L 13 L 42 L V ss = Sum of the V d of all compartments at steady state or equilibrium. V d of some commonly used drugs in anesthesia Fig. 1-3: (Barash, P.G. Clinical Anesthesia. 2001, p. 250) Plasma Concentration Curve (Decay Curve) Once a drug is injected into the central compartment, its plasma concentration as measured over time follows two distinct phases. 1. Distribution Phase (Alpha Phase) a. Begins immediately after IV injection of a drug. b. Reflects distribution from the central compartment to the periphery. 2. Elimination Phase (Beta Phase) a. Represents a gradual decline in drug plasma concentration, as the drug is redistributed back into the central compartment. b. Reflects elimination by renal and hepatic clearance mechanisms. 8

14 (Alpha Phase) (Beta Phase) Fig. 1-4: (Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 1999, p.5 with modification.) Redistribution This is a concept applied primarily to highly lipophilic drugs that distribute out of the central compartment to richly perfused organs to elicit a pharmacologic effect. These drugs will also rapidly redistribute back into the central compartment following a concentration gradient. As a result, recovery from the pharmacologic effects of the drug is a result of its redistribution away from its primary site of action to other less perfused tissue groups. 250 mg Thiopental PLASMA 250 mg Thiopental BRAIN Anesthetic Effect 250 mg Thiopental PLASMA REDISTRIBUTION Patient Awakens 0 MG PLASMA 200 MG MUSCLE 50 MG FAT Fig. 1-5: Hypothetical redistribution model of a single IV bolus injection of 250 mg Sodium Thiopental 9

15 Blood: Brain Barrier Brain capillaries lack standard aqueous channels found in other capillaries of the body. Diffusion of water-soluble drugs into the brain is severely limited. Diffusion of lipid-soluble drugs is limited only by cerebral blood flow. Therefore, distribution of water-soluble (highly ionized) drugs is limited by the blood: brain barrier. Placental Drug Transfer Most drugs cross the placenta by simple diffusion across the lipid bilayer of the placental membrane. Only free, unbound drug crosses the placenta. Lipid soluble, low molecular weight drugs easily cross the placenta, such as Thiopental. Water soluble, high molecular weight drugs do not readily cross the placenta, such as neuromuscular blocking drugs. Polar compounds (charged, ionized) do not readily cross the placenta; however, due to the porous nature of the placental membrane (in contrast to the blood: brain barrier), diffusion is likely. ELIMINATION Elimination refers to all processes that remove drugs from the body. This includes: 1. Metabolism (biotransformation) 2. Excretion of unchanged drug or metabolites Drug Metabolism The primary organ involved with drug metabolism is the liver. Lipophilic compounds that are not extensively redistributed are primarily rendered pharmacologically inactive by hepatic metabolic pathways. Metabolism, or biotransformation of drugs to more polar compounds facilitates excretion of metabolites in the bile and urine. Major Hepatic Biotransformation Pathways Phase I Reactions Phase II Reactions Phase I Reactions LIPOPHILIC COMPOUND POLAR SUBSTRATE The molecular structure of the compound is altered by adding or altering a functional group, or splitting the compound into two fragments. Major Phase I reactions o Oxidation o Reduction o Hydrolysis 10

16 Phase II Reactions POLAR + SUBSTRATE ENDOGENOUS COMPOUND EXCRETABLE HYDROPHILIC SUBSTANCE Involves the conjugation of endogenous compounds (glucuronic acid, amino acids, acetate) to polar substances. Products of Phase II reactions are excretable, water-soluble metabolites. Phase I Reactions Polar Substrates Excretable Hydrophilic Substances Phase II Reactions MAJOR BIOTRANSFORMATION REACTIONS Phase I Phase II OXIDATION CONJUGATION N-dealkylation Glucuronide Conjugation O-dealkylation Glycine Conjugation Side chain Hydroxylation Sulfur Conjugation N-Hydroxylation Methylation N-Oxidation Amino Acid Conjugation S-Oxidation Acetate Conjugation Oxidative Deamination Desulfuration Dehalogenation N-demethylation O-demethylation REDUCTION Azoreduction Nitroreduction HYDROLYSIS Ester hydrolysis Amide hydrolysis Table 1-3: (Produced from information in Barash, P.G., Cullen, B.F., & Stoelting, R.K. Clinical Anesthesia. 2001, Chapter 11, & Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 1999, Chapter 1.) 11

17 Major Anesthesia Drugs & Principle Metabolic Pathways Inhaled Agents Oxidative metabolism (C-P-450) Halothane Oxidative and reductive metabolism Morphine Glucuronidation Fentanyl N-demethylation Sufentanil N-dealkylation, O-demethylation Alfentanil N-dealkylation Remifentanil Nonspecific plasma esterases (major) N-dealkylation (minor) Demerol Demethylation, Hydrolysis Sodium Thiopental Hydroxylation, Desulfuration Propofol Desulfuration, Glucuronidation Etomidate Ester Hydrolysis in liver and plasma Ketamine Demethylation, Hydroxylation, Glucuronidation Midazolam Hydroxylation, Glucuronidation Diazepam N-demethylation, Glucuronidation Ester Local Anesthetics Hydrolysis by plasma cholinesterase Amide Local Anesthetics Hydrolysis, dealkylation Succinylcholine Plasma cholinesterase hydrolysis Pancuronium, Vecuronium Deacetylation Atracurium Hofmann Elimination Nonspecific esterase metabolism Rocuronium Biliary and renal excretion Cis-atracurium Hofmann Elimination Mivacurium Plasma cholinesterase hydrolysis Neostigmine Hydroxylation Renal excretion Glycopyrrolate Renal excretion Table 1-4: (Produced from information in Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 1999, Chapters 2-10.) The Cytochrome P-450 System (C-P-450) This system is a complex of enzymes (primarily) that catalyzes most oxidative and some reductive metabolic processes in the body. Location of these enzyme complexes include: o Smooth endoplasmic reticulum of hepatocytes (liver) o Kidneys o Lungs o Skin o Upper intestinal enterocytes The majority of anesthesia drugs metabolized in the liver are biotransformed by the C- P-450 system. A variety of factors can alter the C-P-450 system, leading to induction (acceleration) or inhibition of enzyme activity. Major factors are listed below: 12

18 C-P-450 Induction Barbiturates Phenytoin Rifampin Macrolide antibiotics (Erythromycin) Imidazole antifungal agents Corticosteroids Carbamazepine Chronic alcohol ingestion Smoking C-P-450 Inhibition Organ Dysfunction Cimetidine Acute alcohol ingestion Drug Excretion Recall that the primary processes of elimination of drugs from the body involve enzymatic pathways primarily in the liver, as well as specific organ clearance mechanisms. Clearance (Cl) refers to the volume of plasma cleared of drug per unit of time. The three primary organs involved with drug clearance include the liver, kidney, and gall bladder. Hepatic Clearance Enzymatic biotransformation pathways Unchanged excretion of drug. Rate of clearance is a product of hepatic blood flow and hepatic extraction ratio. 1. If the hepatic extraction ratio is high (>0.7), drug clearance will depend primarily on hepatic blood flow. 2. If the hepatic extraction ratio is low (<0.3), drug clearance will depend primarily on enzymatic metabolism. **High Hepatic Extraction = Perfusion-dependent elimination **Low Hepatic Extraction = Capacity-dependent elimination Biliary Excretion Hepatic metabolites are excreted into bile GI tract Blood Renal Elimination. Liver may also filter drugs unchanged and transport to the biliary system for ultimate elimination. The biliary system is ultimately involved with excretion of both metabolized and unchanged drug. Renal Clearance The most important organ involved with elimination of both metabolites and unchanged drug. Renal excretion of drugs includes: 1. Glomerular filtration rate (GFR) 2. Active tubular secretion 3. Passive tubular reabsorption The kidneys more efficiently excrete water-soluble metabolites. GFR and fraction of drug bound to protein determines amount of drug that enters the renal tubular lumen. Renal secretion is often used to actively transport protein-bound drugs across the tubular lumen. Renal reabsorption is often used for more lipophilic drugs that can easily cross the cell membrane of the renal tubular epithelium. 13

19 Fig 1-6: Overall Process of Drug Distribution and Elimination Drug Effect Redistribution Blood Tissue Compartments Blood C-P-450 Hepatic Biotransformation Hydrophilic Excretable Metabolites Unchanged Drug Excretion Bile GI Tract Blood Kidneys Protein Bound Drug Hydrophilic Metabolites Lipophilic Metabolites Renal Secretion (Distal Renal Tubule) Filtration (Glomerulus) Renal Tubular Lumen Renal Reabsorption (Proximal Renal Tubule) Excretion from the body 14

20 Elimination Kinetics First Order Kinetics The fraction of drug in the body removed over time remains constant. The amount or concentration of drug removed over time is directly proportional to the amount of drug in the body. log plot Conc linear plot (Fig 1-7) Time Zero-Order Kinetics The fraction of drug in the body removed over time varies. The amount or concentration of drug removed over time is constant, and does not change with the amount of drug in the body. log plot Conc linear plot (Fig 1-8) Time The graphs above illustrate a hypothetical drug exhibiting both first-order (Fig 1-7) and zero-order (Fig 1-8) elimination kinetics in a one-compartment model. Notice that both the linear and logarithmic plots are represented. 15

21 FIRST-ORDER ELIMINATION Most drugs follow first-order elimination, such that a constant fraction of drug is eliminated per unit of time. This fraction of drug is equivalent to the rate constant (k) of the process. Also known as linear kinetics, as portrayed by its logarithmic plot. Elimination Half -Times (T ½ ) To simplify this concept, pharmacokinetic processes are described in terms of half-times, as opposed to rate constants. By definition, elimination half-time is the time that it takes for 50% of the plasma concentration of a drug to decline during the elimination phase. By definition, elimination half-time is also the time required for the concentration to change by a factor of two. The relationship that exists between rate constant and half-time is expressed by the following formula. T ½ = k ** Elimination half time is directly proportional to V d, and indirectly proportional to drug clearance. ** Any factor that alters V d or hepatic or renal clearance, will also alter elimination half time. **The half-time of any first-order kinetic process, including drug absorption, distribution, and elimination, can be calculated. Clinically, the elimination half-time of all drugs used in anesthesia is known, and is derived using a known rate constant established experimentally. Comparison of Half Times to Drug Elimination: Number of Half-Times Fraction of Initial Drug Remaining Percent of Initial Amount Eliminated ½ 50 2 ¼ / / / / Table 1-5: (Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 1999, p.6.) **Approximately five elimination half times are needed for near complete elimination of the drug. 16

22 **Clinical Application** Drug accumulation is a predictable process, if you know the elimination half time of the drug. For example, lets say you know Drug X has an elimination half time of 8 minutes. It should take about 5 half times, or 40 minutes from the initial dose, for Drug X to be 96% eliminated. (This assumes no redosing has occurred during the 40-minute period, and normal clearance mechanisms exist.) ZERO-ORDER ELIMINATION Some drug dosages can exceed the capacity of metabolizing enzymes, such that the biotransformation pathways become saturated. This results in elimination of a constant amount of drug per unit of time. Also known as saturation kinetics or nonlinear kinetics, as portrayed by its logarithmic plot. Some notable drugs that illustrate zero-order elimination, even in therapeutic doses, include Alcohol, Phenytoin, and Aspirin. **Clinical example** If you have 10 pints of beer before midnight, you will still fail the Breathalyzer test the following morning. This effect is due to saturation of the metabolic pathways that clear alcohol, such that only a specific amount of drug will be eliminated in a given time period. This specific amount remains constant, the length of time the metabolic pathways are saturated. This is zero-order elimination. LOWER DOSES = FIRST-ORDER KINETICS HIGHER DOSES = ZERO-ORDER KINETICS 100 Rate of drug metabolism 50 0 First-order metabolism Low Dose of drug High Zero-order metabolism Fig 1-9: (Mycek, M.J., Harvey, R.A., Champe, P.C. Pharmacology. 2000, p.13 with modification.) In addition to elimination, these kinetic models can be applied to drug absorption, distribution, and metabolism. Figure 1-9 illustrates first and zero-order drug metabolism in relationship to concentration. Compartmental Pharmacokinetic Models Compartmental models were developed to simplify the understanding of what happens to an injected drug once it enters the systemic circulation. This concept can be simplified by envisioning the body to be composed of a number of compartments with calculated volumes. Compartmental models help to identify the basic relationships that exist between clearance (Cl), volume of distribution (V d ), and elimination half-times (T ½ ). 17

23 One-Compartment Model This model is an oversimplification for most drugs, but it does help to establish basic kinetic relationships. One Compartment Drug Administered Central Compartment V d (Fig 1-10) Cl K e V d = Volume of distribution K e = First-order elimination rate constant Cl = Clearance Assumptions: 1. The body is a single compartment. 2. Drug distribution is instantaneous. 3. There are no concentration gradients. 4. Concentration decreases only by elimination from the compartment. 5. Prior to elimination, the amount of drug present is equal to the amount of drug injected. Therefore; V d = dose Initial concentration (before elimination) A hypothetical drug with one-compartment first-order kinetics would display a concentration versus time logarithmic curve as shown below. (Fig 1-11) Fig 1-11: (Barash, P.G., Cullen, B.F., & Stoelting, R.K. Clinical Anesthesia. 2001, p.251.) The slope of the log plot is equal to the first-order elimination rate constant (K e ). 18

24 Key Relationships: 1. Clearance (Cl) is equal to the product of the elimination rate constant and the volume of distribution. Cl = K e X V d 2. The elimination half-life is equal to the product of the V d and the constant divided by the Cl. T ½ = X V d Cl Key Concepts: The important conclusions to draw from these equations are: 1. There exists a mathematical relationship between Cl, V d, K e, and T 1/2. 2. The greater the V d, the longer the T ½. (and vise versa) 3. The greater the Cl, the shorter the T ½. (and vise versa) Two-Compartment Model This model illustrates simple kinetic concepts that more accurately portray drug behavior, compared to the one-compartment model. The two-compartment model can be used to illustrate basic concepts of kinetics that can be applied to more complex, multi-compartment models. Two Compartments Drug Administered V d Peripheral Compartment K a V d Central Compartment (Fig 1-12) K b K e K a = Rate constant from central compartment K b = Rate constant from peripheral compartment K e = First-order elimination rate constant Assumptions: 1. The body is composed of two compartments consisting of a central and a peripheral compartment. 2. The central compartment consists of the plasma, and the peripheral compartment consists of other tissue. 3. The entire amount of drug is injected into the central compartment. 19

25 A hypothetical drug with two-compartment, first-order kinetics would display a concentration versus time logarithmic curve as shown below. (Fig 1-13) Fig 1-13: (Barash, P.G., Cullen, B.F., & Stoelting, R.K. Clinical Anesthesia. 2001, p.251.) There are two distinctive phases in the decline of the plasma concentration (biphasic). A. Distribution Phase (Alpha) reflects a rapid decrease in concentration, as drug passes from plasma into vessel-rich tissues. B. Elimination Phase (Beta) reflects slower elimination pathways clearing drug once it returns from the peripheral compartments into the central compartment. Key Concepts: A two-compartment model is still somewhat of an oversimplification of drug kinetics, especially for drugs that have a large V d into different tissue groups. Although the biphasic representation of drug kinetics is more accurate than the onecompartment model, the two-compartment model does not account for variability among drugs regarding tissue distribution. Three-Compartment Model This model most accurately portrays the behavior of a majority of drugs injected into the central compartment. Three Compartments Administered Dose Rapid Peripheral Compartment (Vessel-rich tissue, muscle tissue) K a K b Central Compartment K e K c K d Slow Peripheral Compartment (Fat group) K a = rate constant from central to rapid peripheral compartment K b = rate constant from rapid peripheral to central compartment (Fig 1-14) K c = rate constant from central to slow peripheral compartment K d = rate constant from slow peripheral to central compartment K e = first-order elimination rate constant 20

26 Assumptions: 1. The body is composed of three compartments consisting of a central and two peripheral compartments. 2. The central compartment consists of the plasma, and the peripheral compartments consist of other tissue groups. 3. The entire amount of drug is injected into the central compartment. A hypothetical drug with three-compartment kinetics would display a concentration versus time logarithmic curve as shown below. (Fig 1-15) Rapid distribution Slower distribution Elimination Fig 1-15: (Miller, Ronald D., Anesthesia. 2000, p. 31 with modification.) In this model, there are three distinct phases that can be distinguished. A. Rapid Distribution Phase begins immediately after injection into the central compartment, and represents rapid movement of drugs from the blood into vesselrich tissues (brain, heart, liver, kidneys) and muscle tissue. B. Slower Distribution Phase characterizes drugs moving into slowly equilibrating tissues (fat), and return of drug to the plasma from rapidly equilibrating tissues (redistribution). C. Terminal Elimination Phase represents drugs returning to the blood from either rapidly or slowly-equilibrating tissues to be eliminated by metabolism or excretion. Key Concepts: Most drugs illustrate multi-phasic behavior as they pass in and out of several identified tissue compartments in the body before elimination. Whether a drug illustrates two, three, or multi-compartment kinetics is of little use clinically. Some drugs can illustrate two-compartment kinetics in some patients, and multi-compartment kinetics in other patients. The pharmacokinetic parameters of interest to clinicians, such as clearance, volume of distribution, and half-times are determined by calculations using a two-compartment model. What is most important to understand is that the ultimate behavior of drugs once injected is determined by many factors. These factors are universally considered when ultimately determining drug dosing in patients. 21

27 Other Related Pharmacokinetic Concepts Context-Sensitive Half-Time Elimination half-times help us accurately predict drug kinetics primarily in a one-compartment model. It crudely estimates elimination kinetics in multi-compartment models. This inaccuracy is further magnified when applied to post-infusion elimination kinetics. As a result, the context-sensitive half-time was developed to circumvent these limitations. This halftime describes the amount of time necessary for plasma drug concentration to decrease by a certain percentage after discontinuation of a continuous infusion of a known duration ( context ). Computer simulation using multi-compartmental models of drug kinetics are used to calculate contextsensitive half-times. Factors considered in calculations: 1. Distribution 2. Metabolism 3. Length of continuous infusion Context-sensitive half-time increases as infusion time increases. Context-sensitive half-time bears no relationship to elimination half-time. Time to Recovery This refers to the amount of time that must elapse to allow plasma drug concentration to reach a level that allows patient awakening following an infusion. Best indicator of drug recovery. Affected by alterations in clearance mechanisms. **Context-sensitive half-times and elimination half-times are not useful in predicting when a patient will awaken. In fact, often the elimination half-time is much longer than time to recovery, even for infusions that have reached steady state (compartmental equilibrium). Effect-Site Equilibration Time This concept expresses the amount of time necessary for an injected drug to elicit a therapeutic effect. It suggests that the site of action of most drugs is not in the blood, but at other tissue sites. Short effect-site equilibration time = rapid onset of drug effect Long effect-site equilibration time = slow onset of drug effect **Clinical Application** Knowledge of effect-site equilibration times for various anesthesia drugs can help improve interval timing of bolus drug injections. For instance, drugs with short effect-site equilibration times include Remifentanil, Alfentanil, and Propofol. The time for observation of a clinical effect is much shorter than drugs with longer effect-site equilibration times, such as Fentanyl, Sufentanil, and Midazolam. Therefore, when giving Midazolam for example, you should allow for more time between subsequent doses then you would if you were using Remifentanil. 22

28 Major Factors Altering Drug Pharmacokinetics: 1. Body Weight and Composition a. Extracellular Fluid Volume (ECFV) i. An increased ECFV is seen in pregnancy, infants under one year of age, and individuals with peripheral edema or ascites. This may have an effect on hydrophilic, fat insoluble drugs (muscle relaxants) that are confined to the central compartment. An example of this is the often-increased dosage requirements for muscle relaxants in infants and the parturient. ii. A decreased ECFV is seen in hypovolemia. These patients may need less of an initial drug dose to achieve the same therapeutic effect. b. Total Body Fat i. Morbidly obese patients may have as much as 60% body fat. ii. This may have a profound effect of the V d of lipophilic drugs. **Clinical Debate** Should the obese patient receive a dose of a drug based on their actual body weight (ABW), adjusted (calculated) body weight (CBW), or their ideal body weight (IBW)?? If you read many package inserts, the recommendations vary. For example: 1) When dosing Mivacurium by ABW in obese patients, clinical trials illustrated that there was a greater probability of MAP decreasing by 30% or more. Therefore, manufacturer s recommendations are to use the patient s IBW to calculate initial drug dosing. (Wellcome package insert) 2) The administration of Rocuronium using ABW to patients who were at least 30% or more above IBW was not associated with significant differences in onset, duration, or recovery. However, using the IBW in obese patients did result in a longer onset time, shorter duration, and less optimal intubating conditions. Therefore, the manufacturer recommends using the patients ABW in calculating dosages. (Organon package insert) ** Clinical Pearl** When in doubt, use the patients calculated body weight (CBW), and make adjustments accordingly. It is best to underestimate and recover with additional dosing, than to overestimate and not be able to recover at all. CBW = IBW + (ABW- IBW) 2 or 3 2. Age a. Neonates have a higher % of body water and a lower % of body fat. b. Elderly have reduction in % total body water, causing intracellular dehydration. They also have a higher % of fat and a loss of muscle mass. c. Alterations in body water and fat may require the dose of drugs that distribute to these tissues (hydrophilic or lipophilic) to be adjusted. 23

29 3. Organ Function a. Hepato-renal function may be greatly reduced in neonates and the elderly. b. End-stage renal or hepatic disease may profoundly decrease drug clearance and V d. c. Reduced function of the organs of elimination generally requires administration of drugs dependent upon these organs to be lessened. (Usually by 50% or greater). 4. Plasma Protein Binding a. Drug effect is directly related to plasma free drug fraction (unbound drug). b. It is the free, unbound drug that diffuses from plasma to interstitial fluid to elicit a therapeutic effect. c. Protein binding can range from 0 to > 98% of the delivered drug. Major Plasma Proteins: There are two major plasma proteins primarily responsible for about 95% of all drug binding: 1. Albumin (acidic drugs) 2. Alpha-1-acid glycoprotein (basic drugs) Of most importance to the anesthesia provider is Albumin, which comprises over half of the total plasma protein. Albumin has at least three discrete, high affinity drug binding sites. ** Diazepam, Digoxin, and Warfarin all have a different binding site on albumin, and are all highly protein bound. ** Clinical Application** A number of clinical scenarios can change the plasma concentration of albumin, thus altering the amount of unbound, free drug available to cross into the interstitium. These include: 1. Renal Failure or Nephrotic Syndrome 2. Liver Disease 3. Malabsorption 4. Surgery/Stress 5. Burns 6. Trauma 7. Malnutrition 8. Dilution by I.V. fluids 9. Congenital Analbuminemia 10. Pregnancy 11. Elderly 12. Cancer 24

30 CHAPTER 2 Uptake and Distribution of Inhaled Agents The concept of uptake and distribution of inhaled agents basically describes the pharmacokinetic properties of these drugs, to include: Absorption out of the lungs into the blood Distribution into the body Metabolism Elimination by the lungs primarily There are some basic truths about the concepts related to uptake and distribution that need to be understood. These truths are the following: 1. All anesthetic gases exert a partial pressure Partial Pressure The pressure exerted by a gas in a mixture of gases. Dalton s Law of Partial Pressures States that the sum of the partial pressures of the gases in a mixture will equal the total partial pressure of the mixture. 2. All anesthetic gases must overcome a partial pressure gradient to exert an effect 3. The goal of inhaled anesthesia is to obtain a constant brain partial pressure (P br) 4. Brain partial pressure (P br ) = anesthetic effect ** Ultimate brain partial pressure is affected by a variety of factors. (Fig 2-1) Vaporizer Anesthesia Machine Lungs Brain Other Tissues Blood Fig:

31 *As you can see from Fig: 2-1, there are many barriers that an inhaled agent must overcome in order to reach the brain and elicit an anesthetic effect. We will discuss the impact that each area has in this process. First, lets start with some general definition. General Definition F A = the concentration of anesthetic in the alveoli F I = the inspired concentration of anesthetic F A/ F I = the ratio of alveolar concentration to inspired concentration. At equilibrium, this value equals one. F A /F I ratio is expressed as a curve relative to time. Anesthetic agents can be compared based upon their F A /F I Curves F A /F I Curves Fig 2-2 (Morgan, E., Mikhail, M. & Murray, M. Clinical Anesthesiology. 2002, p.131.) 26

32 General Concepts Blood: Gas Partition Coefficients Each inhalation agent has a specific blood: gas partition coefficient (B:G PC), which describes the way the agent partitions or distributes itself between two phases at equilibrium, in this instance the alveoli and the blood. Agent Blood:Gas Partition Coefficient Brain:Blood Partition Coefficient Muscle:Blood Partition Coefficient Fat:Blood Partition Coefficient Oil:Gas Partition Coefficient Methoxyflurane Halothane Enflurane Isoflurane Nitrous Oxide Desflurane Sevoflurane Table 2-1: (Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 1999, p. 24 with modification.) Highly Soluble Intermediate Solubility Poorly Soluble Methoxyflurane Halothane Nitrous Oxide Enflurane Desflurane Isoflurane Sevoflurane *In examining the table above, remember each number is expressed as a ratio compared to one. We can see that Methoxyflurane has a high B:G PC of 12. This means that for every one part of this gas that exists in the alveoli, 12 parts will be absorbed in blood. This indicates that Methoxyflurane is a highly soluble agent that prefers to be in blood, as opposed to the lungs. *Conversely, if we look at Sevoflurane with a B:G PC of 0.69, we can conclude that for every one part of this gas in the alveoli, only 0.69 parts will be absorbed in blood. This agent, therefore, is considered relatively insoluble, as it would prefer to stay in the lungs. 27

33 Solubility As we discussed, the B:G PC value comparatively speaking, can allow us to make basic assumptions about the solubility of the drug. In other words, the solubility of an inhaled agent in blood and tissue is reflected by its partition coefficient. 1. The lower the blood-gas partition coefficient, the lower the solubility of the gas. 2. The lower the solubility, the greater the rate of rise of the agent on the F A /F I curve and the quicker the agent will reach an F A /F I ratio of one. ** Refer to Figure 2-1. In observing this graph, notice how nitrous oxide has the fastest rate of rise compared to the other agents. This is a result of the poor solubility characteristics of Nitrous Oxide, such that the majority of the agent stays in the central circulation, and is not absorbed into the tissues. This allows the inspired concentration to quickly approximate the blood concentration. When this happens, the ratio will approach the value of one. Partial Pressures All inhaled agents exert a partial pressure in the compartment they exist in. For example, when an agent is in the alveoli, it possesses an alveolar partial pressure, signified by P A. Other common abbreviations are listed below: P I = Inhaled Partial Pressure P A = Alveolar Partial Pressure P a = Arterial Partial Pressure P br = Brain Partial Pressure Important Related Concepts 1. The brain and all other tissues in the body will eventually equilibrate with the partial pressure of inhaled agents delivered by arterial blood. 2. The arterial partial pressure will eventually equilibrate with alveolar partial pressure. This is expressed as: This relationship holds true assuming a continuous inspired concentration of gas. **An important relationship then exists between P A and P br, in that P A eventually mirrors P br. As a result the following conclusion can be made. P A can be used as an indirect measurement of anesthetic partial pressure at the brain. 28

34 **Clinical Application** In the operating room, we have the ability to measure end-tidal concentrations of inhaled gases via our gas analyzers. This measurement indirectly allows us to assume what brain concentration is, and make adjustments to our anesthetic accordingly. Partial Pressure Gradients Many factors affect the gradients that an inhaled agent must face in order to achieve equilibrium of partial pressure. As an anesthetist, it is imperative that these factors are well understood to allow for better control of anesthetic dose delivered to the brain, and overall anesthetic depth. Factors Affecting Transfer of Agent From Machine to Alveoli: Inspired Gas Concentration Alveolar Ventilation Anesthesia Breathing System Factors Affecting Transfer From Alveoli to Blood: Blood-Gas Partition Coefficient Cardiac Output Alveolar-to-Venous Partial Pressure Differences Factors Affecting Transfer From Blood to Brain: Brain-Blood Partition Coefficient Cerebral Blood Flow Arterial-to-Venous Partial Pressure Differences As you can see, there are many partial pressure gradients to consider. I would like to touch upon a few of these concepts. FACTORS AFFECTING TRANSFER FROM MACHINE TO ALVEOLI This is one area that the anesthetist has a lot of control over. Lets see how. Inspired Gas Concentration This is basically what you have dialed in on your vaporizer. (% delivered gas) Initially, a high % concentration is needed to offset the effects of tissue uptake. As a result, the rate of induction is accelerated, and the rate of rise of the F A /F I curve is quicker, as F A approaches F I. % gas delivered = P A = P br This is also known as the concentration effect. 29

35 **Clinical Application** This concept is frequently used with pediatric inductions, where the initial % agent delivered is much higher (concentrated) to overcome the effects of dead space dilution of gases, as well as the effects of uptake of agent into other tissues. Sevoflurane is often utilized in this fashion, by filling the breathing circuit with 8% vapor prior to induction. Alveolar Ventilation Increased minute ventilation (MV) leads to accelerated uptake of gases into the blood, simply by providing an increased delivery of drug in a shorter period of time. rate = delivery = uptake Spontaneous Versus Mechanical Ventilation All volatile agents cause a dose-dependent depression of minute ventilation, by directly inhibiting the respiratory center of the brain. As a result, patients who are spontaneously ventilating will have a slower uptake of agent into the blood compared with a mechanically ventilated patient. SV = agent delivered = alveolar uptake **Clinical Application** This concept is clearly seen when providing mask anesthesia to a SV patient. When utilizing inhalation anesthetics alone, the time from % change in delivered gas concentration and the effect on end-tidal concentration (which indirectly reflects brain concentration) is much slower than in is observed in a MV patient. Anesthesia Breathing Systems Many factors can influence the rate of increase of P A. Three primary factors are: Volume of the breathing system Solubility of the agent in rubber/plastic Gas flow from the machine 1. The volume of the breathing system can have a dilutional effect on delivered concentration of gases. a. Semi-closed circle systems have approximately 8-10 liters of dead space. ( dead space = delivery = uptake by alveoli) b. Semi-open circuits such as the Bain co-axial circuit has a much smaller amount of dead space. Therefore, alveolar uptake would be expected to be quicker. 2. Solubility of the agent in rubber/plastic is less of a factor than it was several years ago, when anesthesia circuits were made of butyl rubber and agents were much more soluble than they are today. With the advent of plastic components and less soluble agents (Sevoflurane, Desflurane), this is less of an issue. 3. High fresh gas flows (FGF) from the anesthesia machine will help to negate the buffer effects of dead space in the machine and circuit. ( FGF = uptake) 30

36 **Clinical Application** This concept is often used in anesthesia when quick delivery of gases is needed to increase the end-tidal gas concentration (such as just prior incision). By increasing gas flows, circuit and machine dead space are overcome, and there is accelerated delivery of gases to the alveoli, and subsequently the blood and brain. FACTORS AFFECTING TRANSFER FROM ALVEOLI TO BLOOD Blood:Gas Partition Coefficient Remember this is a reflection of agent solubility, and it is a numeric representation of the distribution of gas in blood compared to alveoli. B:G coefficient = solubility = rate of rise of F A /F I curve B:G coefficient = solubility = rate of rise of F A /F I curve For agents that are highly soluble, a larger amount of the drug must be absorbed into the blood and vessel-rich tissues, before P a = P A, and brain equilibrium is achieved. Cardiac Output Cardiac output = pulmonary blood flow Pulmonary blood flow determines P A, as more or less anesthetic agent is carried away from the lungs. ** A change in cardiac output affects primarily the rate of increase of P A in the soluble agents. Increased cardiac output results in more rapid uptake of agent into the tissue (esp. more soluble agents such as Methoxyflurane, Halothane, and Isoflurane) and results in a slower increase in P A cardiac output = tissue uptake = P A cardiac output = tissue uptake = P A **In agents that are less soluble (Nitrous Oxide, Sevoflurane, Desflurane), the rate of increase of P A is rapid regardless of changes in cardiac output. Alveolar-to-Venous Partial Pressure Differences (A-vD) A-vD reflects the difference in the partial pressures of gas in the alveoli compared to venous blood. This difference reflects tissue uptake. If there were no uptake of gases into the tissues, venous blood returning to the lungs would contain the same amount of gas as it did when it left the lungs and F A /F I would always be one. **Clinical Application** In the operating room, we see this every day, as there usually always exists a difference between inspired and expired gas concentrations (gas analyzer). This is a product of tissue uptake. These two measurements rarely will ever equal each other, but will begin to equilibrate after the vessel-rich compartments are saturated. 31

37 Tissue Uptake and Major Tissue Groups Two major determinants of tissue uptake: Solubility Blood flow to the tissues There are four basic tissue groups in the body that have an effect on the uptake of anesthetic gases, and the equilibration of F A with F I. Vessel Rich Tissue Group Includes the brain, heart, liver, kidneys, and endocrine glands Together, this group receives over 75% of cardiac output, but comprises only 10% of body weight. As a result of a large blood flow to a relatively small area, the vessel-rich tissues achieve rapid equilibration, ** Equilibration is > 90% complete within 3-10 minutes!! Muscle Group Includes all skeletal muscle and comprises 50% of body mass, receiving approximately 19% of cardiac output. ** Equilibration occurs within 1-4 hours in the muscle group!! Fat Group Comprised of all adipose tissue in the body, which is about 20% of body weight, but receives only 6% of cardiac output. The fat group serves as a large reservoir for anesthetic gases, such that equilibration occurs in terms of half times. ** The half time for equilibration in the fat group is hours. In other words, assuming a continuous administration of a constant volumes % of volatile agent, it would take hours for half of this % concentration to equilibrate with adipose tissue. **Clinical Application** This is one of the primary reasons that you rarely see the inspired gas concentration equal the expired gas concentration in the operating room, using the gas analyzer. This is primarily a result of the product of tissue uptake, especially into the adipose tissue. The processes of elimination also affect this difference, but to a lesser extent. Vessel-Poor Tissue Group Includes ligaments, bone, tendons, and cartilage. This group comprises 20% of body mass, but only receives < 1% of cardiac output. As a result, this tissue group has minimal uptake of anesthetic gases, and therefore has little affect on alveolar partial pressure P A. 32

38 Related Topics The Concentration and Second-Gas Effects The Concentration Effect This is a concept that simply states that the higher the inhaled partial pressure of an agent, the more rapidly the P A approaches P I. Two components of the concentration effect include: Concentrating effect which is achieved by increasing the % agent delivered to a small area of volume (lungs). Increased inspired ventilation to replace space left by uptake of gases out of the lungs. The Second Gas Effect This concept applies to induction only. It occurs with the administration of a high volumes % of a first gas (Nitrous Oxide), and the subsequent acceleration of the P A of a concurrently administered second gas (a volatile agent). For example, referring to the graph below, we can see that the lung is initially filled with a total of 100 parts of gas (A). As 50% of the Nitrous Oxide is quickly taken up into the blood (40 parts), this leaves only 60 parts left in the lung. As a result, the remaining second gas is now concentrated in a smaller lung volume, resulting in an increased concentration of the second gas from 1% to 1.7%. This increased concentration of the second gas in a smaller lung volume accelerates the P A of the second gas. 1/60 = 1.7 % 19/60 = 31.7% 40/60 = 66.7% Fig. 2-3 (Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 1999, p.22 with modification.) 33

39 **Clinical Implications** Both the concentration and second-gas effect will hasten induction. These concepts are applied clinically in the pediatric induction. The concentration effect is utilized with over-pressurization of the anesthesia circuit with % inspired gas delivered. The second-gas effect is utilized with the addition of usually 70% Nitrous Oxide to the oxygen mixture prior to or concurrently with the administered volatile agent, during an inhalation induction. Time Constants Time constant is a concept that can be used to calculate the change of the concentration of a substance in a system if the capacity and flow through the system is known. The following information is a given: In one time constant (if you see the term time constant, it is referring to one time constant), there will be 63% change in the concentration of a substance toward the total possible change, assuming that flow into and out of the system is continuous and mixing is uniform. That is, in one time constant (a certain number of minutes) 63% change in the concentration of a substance will have occurred. In two time constants, 86% change in the concentration of a substance will have occurred. In three time constants, 95% change in the concentration of a substance will have occurred. See the table below. To calculate half-time (the time to a 50% change), multiply the time constant by 0.7. The Amount of Change at the End of Each Time Constant One time constant = 63% change Two time constants = 86% change Three time constants = 95% change Four time constants = 98% change This is a simple concept that is often hard to understand. Before applying the concept to anesthesia, lets look a simple example of water flowing through a pipe. Suppose you have water flowing at 2 L/min through a pipe that has a capacity of 15 liters. 2 L/min Capacity = 15L Now keep the water flowing at 2 L/min and add a 3% concentration of Substance X to the 2 L/min flow of water. ASSUME SUBSTANCE X IS COMPLETELY SOLUBLE IN THE WATER - THIS BECOMES IMPORTANT LATER! There is a sensor at the outflow of the pipe measuring the concentration of Substance X. 34

40 Substance X = 3% 2 L/min Capacity = 15 L Substance X? % Intuitively you know that it will take a period of time to see 3% of Substance X at the outflow. The time constant tells you how long it takes to see a change (as measured by the concentration of Substance X at the outflow). You can calculate the time constant for any system if you know the flow through the system and the capacity of the system. Time constant = Capacity of system Flow through system In the example above, the capacity of the system (pipe) = 15 L, the flow through the system (pipe) = 2 L/min Time constant = 15 L 2 L/min 7.5 min = 15 L 2 L/min ** The time constant for this system is 7.5 minutes. So the time constant in this example is 7.5 minutes. What does that tell you? It tells you the system will reach 63% equilibrium in 7.5 minutes, 86% equilibrium in 15 minutes, etc. (See the table below) The Amount of Change at the End of Each Time Constant for a System with a Capacity of 15 L and a Flow Through the System of 2 L/min One time constant = 63% change = 7.5 min Two time constants = 86% change = 15 min Three time constants = 95% change = 22.5 min Four time constants = 98% change = 30 min 35

41 What is the concentration of Substance X at 7.5 minutes after adding 3% of Substance X to the system in our example (capacity = 15 L, flow = 2 L/min)? This is calculated by multiplying the % change seen in one time constant (63%) by the concentration of Substance X added to the system (3%) Concentration of Substance X at outflow in one time constant (7.5 minutes) = 0.63 X 3% = 1.89% How much of Substance X will be measured at the outflow at two, three, and four time constants? (Do the math - it was done to calculate the values below) Concentration of Substance X at the End of Each Time Constant for a System with a Capacity of 15 L, a Flow Through the System of 2 L/min, and 3% of Substance X Introduced into the System One time constant (7.5 min) = 0.63 X 3% = 1.89% Two time constants (15 min) = 0.86 X 3% = 2.58% Three time constants (22.5 min) = 0.95 X 3% = 2.85% Four time constants (30 min) = 0.98 X 3% = 2.94% One time constant (7.5 min) = 0.63 X 3% = 1.89% Substance X = 3% 2 L/min Capacity = 15 L Two time constants (15 min) = 0.86 X 3% = 2.58% Substance X = 3% Substance X = 1.89% 2 L/min Capacity = 15 L Substance X = 2.58% 36

42 Three time constants (22.5 min) = 0.95 X 3% = 2.85% Substance X = 3% 2 L/min Capacity = 15 L Substance X = 2.85% Four time constants (30 min) = 0.98 X 3% = 2.94% Substance X = 3% 2 L/min Capacity = 15 L Substance X = 2.94% Now, lets apply this concept to anesthesia. First, lets look at the anesthesia machine. To begin anesthesia, the inhalation agent must first be washed into the volume of the system. The system in this scenario is the anesthesia machine, which includes the breathing bag, circuit, and CO 2 absorber. The volume of this system is typically 7 L. (3-L bag, 2-L CO 2 absorber, and 2 L of corrugated hoses and fittings). Using higher fresh gas flows accelerates the wash-in into the system. That is, the concentration of the anesthetic coming out of the breathing circuit will more rapidly approximate the concentration delivered from the vaporizer by using a higher fresh gas flow. See the example below. First, lets calculate the time constant of the anesthesia machine using a low fresh gas flow of 0.5 liters per minute. Time constant = Capacity of system Flow through system 37

43 In the example above, the capacity of the system = 7 L, the flow through the system = 0.5 L/min Time constant = 7 L 0.5 L/min 14 min = 7 L 0.5 L/min ** The time constant for this system is 14 minutes. What does this tell you? It tells you the system will reach 63% equilibrium in 14 minutes, 86% equilibrium in 28 minutes, etc. (See the table below) The Amount of Change at the End of Each Time Constant for an Anesthesia Machine With a Capacity of 7 L and a Fresh Gas Flow of 0.5 L/min One time constant = 63% change = 14 min Two time constants = 86% change = 28 min Three time constants = 95% change = 42 min Four time constants = 98% change = 56 min Now, lets set the vaporizer concentration of Isoflurane to 1.2%. Using the information we now have, 63% of 1.2% Isoflurane (0.76%) will be detected at the end of the breathing circuit at one time constant or in this example, 14 minutes. THE ANESTHETIC VAPORS ARE COMPLETELY SOLUBLE IN THE FRESH GAS - THIS BECOMES IMPORTANT LATER! Concentration of isoflurane measured at the end of the breathing circuit in one time constant (14 minutes) = 0.63 X 1.2% = 0.76% How long will it take to measure 1.2% Isoflurane at the end of the breathing circuit in this example? Do the math - it was done to calculate the values below: Concentration of Isoflurane Measured at the End of the Breathing Circuit at Each Time Constant for a System with a Capacity of 7 L, a Fresh Gas Flow Through the System of 0.5 L/min, and the Vaporizer Set to 1.2% Isoflurane One time constant (14min) = 0.63 X 1.2% = 0.76% Two time constants (28 min) = 0.86 X 1.2% = 1.03% Three time constants (42 min) = 0.95 X 1.2% = 1.14% Four time constants (56 min) = 0.98 X 1.2% = 1.18% 38

44 One time constant (14 min) = 0.63 X 1.2% = 0.76% 1.2% Isoflurane Fresh Gas Flow = 0.5 L/min Capacity = 7 L Two time constants (28 min) = 0.86 X 1.2% = 1.03% Isoflurane = 0.76% 1.2% Isoflurane Fresh Gas Flow = 0.5 L/min Capacity = 7 L Isoflurane = 1.03% Three time constants (42 min) = 0.95 X 1.2% = 1.14% 1.2% Isoflurane Fresh Gas Flow = 0.5 L/min Capacity = 7 L Four time constants (56 min) = 0.98 X 1.2% = 1.18% Isoflurane = 1.14% 1.2% Isoflurane Fresh Gas Flow = 0.5 L/min Capacity = 7 L 39 Isoflurane = 1.18%

45 Now let s increase the fresh gas flow to 6 L/min. The capacity of the system is still 7 L. Time constant = Capacity of system Flow through system Time constant = 7 L 6 L/min 1.2 min = 7 L 6 L/min **The time constant for this system is 1.2 minutes. What does that tell you? It tells you the system will reach 63% equilibrium in 1.2 minutes, 86% equilibrium in 2.4 minutes, etc. (See the table below) The Amount of Change at the End of Each Time Constant for an Anesthesia Machine With a Capacity of 7 L and a Fresh Gas Flow of 6 L/min One time constant = 63% change = 1.2 min Two time constants = 86% change = 2.4 min Three time constants = 95% change = 3.6 min Four time constants = 98% change = 4.8 min Lets again set the vaporizer concentration of Isoflurane to 1.2%. Using the information we now have, 63% of 1.2% isoflurane (0.76%) will be detected at the end of the breathing circuit at one time constant or in this example, 1.2 minutes. Concentration of isoflurane measured at the end of the breathing circuit in one time constant (1.2 minutes) = 0.63 X 1.2% = 0.76% How long will it take to measure 1.2% isoflurane at the end of the breathing circuit in this example? (See below) Concentration of Isoflurane Measured at the End of the Breathing Circuit at Each Time Constant for a System with a Capacity of 7 L, a Fresh Gas Flow Through the System of 6 L/min, and the Vaporizer Set to 1.2% Isoflurane One time constant (1.2min) = 0.63 X 1.2% = 0.76% Two time constants (2.4 min) = 0.86 X 1.2% = 1.03% Three time constants (3.6 min) = 0.95 X 1.2% = 1.14% Four time constants (4.8 min) = 0.98 X 1.2% = 1.18% 40

46 From this example, you can see that one way to speed an induction when using a volatile anesthetic is to increase the fresh gas flow. One time constant (1.2 min) = 0.63 X 1.2% = 0.76% 1.2% Isoflurane Fresh Gas Flow = 6 L/min Capacity = 7 L Isoflurane = 0.76% Two time constants (2.4 min) = 0.86 X 1.2% = 1.03% 1.2% Isoflurane Fresh Gas Flow = 6 L/min Capacity = 7 L Threetimeconstants(3.6 min) = 0.95 X 1.2% = 1.14% Isoflurane = 1.03% 1.2% Isoflurane Fresh Gas Flow = 6 L/min Capacity = 7 L Four time constants (4.8 min) = 0.98 X 1.2% = 1.18% Isoflurane = 1.14% 1.2% Isoflurane Fresh Gas Flow = 6 L/min Capacity = 7 L Isoflurane = 1.18% 41

47 The second anesthesia example is using time constants to estimate the time to equilibrium or clearance of the drug from a tissue compartment. That is, time constants can be used in anesthesia to calculate the amount of time required for a 63% change in the F A /F I ratio, thus allowing an estimate of the time to equilibrium or clearance of the drug from a tissue compartment. Three factors must be known to calculate a tissue time constant: The volume of the tissue (Nothing new) Tissue blood flow (Nothing new) Solubility of the anesthetic (IT IS NOW LATER - THIS IS NOW IMPORTANT. In the prior examples we did not have to worry about the solubility of the substance) The partition coefficient of an agent reflects its solubility. Now considering solubility, the now-familiar formula becomes: Tissue capacity X Partition coefficient Tissue blood flow The resulting values of this equation can be applied to the basic known that (this is a reminder of facts covered above): One Time Constant = 63% change (in F A /F I ratio) Two Time Constants = 86% change Three Time Constants = 95% change Four Time Constants = 98% change Lets look at a hypothetical application of time constants in the context of inhaled anesthetics and tissue compartments: Tissue/Blood Flow Per Tissue/Blood Partition Time Constant (Minutes) 100 ml of Tissue Coefficient 100 ml/min ml/min ml/min ml/min Table 2-2: (Eger, E., The Distinguished Professor Program I. 1994, Slide 19.) This table represents four tissue groups. For each, variations in tissue perfusion and anesthetic solubility will produce different time constants for each tissue. For example: Line #1 of Table 2-2 represents a highly perfused tissue (VRG) that has a relatively low partition coefficient of 1. To figure out the time in minutes for one time constant, using the formula above: One time constant = 100 cc (volume of tissue) X 1 (Partition Coefficient) 100 cc/min (tissue flow) = 1 Minute 42

48 ** What this means is that in one minute, the tissue will have gone 63% to equilibrium, and in four time constants (four minutes), the tissue will have gone 98% to equilibrium. Line #2 shows a tissue that is less perfused, receiving 3 ml/min. The time constant calculates to be 33 minutes (100 cc 3 cc/min) X 1. It would take 33 minutes for this tissue to achieve 63% equilibrium. **Clinical Application** Lets try and think of this clinically. The table below illustrates some basic known characteristics of the various tissue groups. CHARACTERISTICS OF TISSUE GROUPS VRG MG FG VPG % Body Mass Liters/70 kg % Cardiac Output * Liters/Min * Cardiac Output = 5.4 Liters/Min Table 2-3 (Eger, E. The Distinguished Professor Program I. 1994, Figure 27.) In this scenario, we have a patient that is 70 kg, and a calculated cardiac output of 5.4 Liters/Minute. We are administering Isoflurane with a known Brain:Blood partition coefficient of 1.6 (Refer to Table 2-1). You are wondering how much time it will take for Isoflurane to equilibrate to 98% with the brain?? Using the known values from the above table, the brain falls under the VRG: (6 liters 4 liters/min X 1.6) = 2.4 minutes for one time constant (63% change) Therefore, to calculate a 98% change (four time constants) you simply multiply 2.4 minutes X 4 to give you a total time of 9.6 minutes. In other words, it will take 9.6 minutes for Isoflurane to equilibrate 98% with the brain using Isoflurane. To take the example further, assume the concentration of Isoflurane in this patient s brain is 1.2%. The Isoflurane is quickly and completely discontinued (we have so far looked at wash-in, now we are looking at washout!). How long will it take for the concentration of Isoflurane to decrease in this patient s brain? Assume same cardiac output and weight information (Table 2-3). Starting concentration in brain is 1.2%. Time constant for this example is 2.4 minutes, as we calculated above. Time 0 = Discontinue Isoflurane 43

49 One time constant Time 2.4 minutes = Concentration of Isoflurane in the brain falls by 63% 0.63 X 1.2 = 0.76% What is the concentration remaining in the brain? 1.2% % = 0.44% (REMEMBER WE ARE LOOKING AT WASHOUT - THUS WE NEED THIS STEP!) Two time constants Time 4.8 minutes = Concentration of Isoflurane in the brain falls by 86% 0.86 X 1.2 = 1.03% What is the concentration remaining in the brain? 1.2% % = 0.17% Three time constants Time 7.2 minutes = Concentration of Isoflurane in the brain falls by 95% 0.95 X 1.2 = 1.14% What is the concentration remaining in the brain? 1.2% % = 0.06% Four time constants Time 9.6 minutes = Concentration of Isoflurane in the brain falls by 98% 0.98 X 1.2 =1.18% What is the concentration remaining in the brain? 1.2% % = 0.02% Remember that kg weight and cardiac output will change with each patient. The values in this table reflect known values that can be altered by simple proportion as weight and cardiac output change. **Calculation of time constants can help you estimate wash-in and washout of inhalation agents from the various tissue groups, and assist in determining time to wakeup. Remember, however, there are many other variables that affect wakeup (co-administered drugs, co-morbidities, etc) and therefore the usefulness of time constant calculations in the operating room is limited. Minimum Alveolar Concentration (MAC) Formally defined, MAC is the concentration of an inhaled agent at one atmosphere (sea level) and 37 C, which prevents skeletal muscle movement in response to noxious stimuli in 50% of all patients. **1 MAC is equivalent to an ED 50 on the dose-response curve. MAC is indirectly related to anesthetic potency. In other words, the higher the MAC value, the less potent the agent. This makes sense, as it would take more of the drug to prevent movement in 50% of patients; therefore it must be less potent. 44

50 The MAC value is clinically derived by the following formula: MAC = 150/O:G PC The value of 150 represents an average value of solubility for several agents. Based upon this formula you can see that agents with a high O:G PC (see Table 2-1) are more soluble, and would have a smaller MAC value. Therefore these agents are more potent. In summary: Solubility = MAC = Potency (N 2 0) Solubility = MAC = Potency (Halothane) **Clinical Application* MAC values for the various inhalation agents allow you to adjust your anesthetic to provide sufficient anesthesia to prevent movement. The end-tidal % concentration of an agent provided by the agent analyzer is a reflection of P br and therefore is also a reflection of MAC concentration delivered. 1 MAC = ED MAC = ED MAC = MAC Awake (50% of patients will wake up in this MAC range for all agents) Inhalation Agents & Comparative MAC Information Agent MAC in 100% oxygen MAC in 70% N 2 0 Oil:Gas Partition Coefficient N Halothane Enflurane Isoflurane Desflurane Sevoflurane Table 2-4 (Produced from information in Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 1999, Chapter 1.) Notice from this table that the MAC values for the volatile agents when administered with nitrous oxide are significantly less, primarily as a result of the second-gas effect. 45

51 Physiologic and Pharmacologic Factors Affecting MAC There are many variables that have a direct affect on MAC values and are important to be aware of in anesthesia. The most significant factors are outlined below. Factors Increasing MAC Requirements Hyperthermia Increased circulating catecholamines Young age Factors Decreasing MAC Requirements Addition of N 2 0 Hypothermia Pregnancy (possibly r/t progesterone) Older age Catecholamine depletion MAP < 50 mm Hg Acute alcohol ingestion or opioid use Premedications Pa0 2 < 38 mm Hg Lithium Factors Having No Impact On MAC Duration of Anesthesia Sex ph (unless CSF ph changes) Chronic alcohol abuse PaCO 2 between mm Hg PaO 2 > 38 mm Hg ** Take home point: All of these values regarding inhalation agents and MAC can prove very useful in the operating room in helping you titrate your anesthetic level. Remember however, that ultimate titration of all drugs, including inhalation agents, is dictated by the hemodynamic parameters of the patient during surgery. Closed-Circuit Anesthesia Closed circuit anesthesia is synonymous with total rebreathing system. The goal of this type of anesthesia is to add only enough oxygen and anesthetic vapor to the breathing circuit to exactly match patient consumption, thereby maintaining a constant circuit volume and a constant expired oxygen concentration. Characteristics: 1. All exhaled gases are rebreathed, except carbon dioxide. 2. The CO 2 absorber neutralizes all carbon dioxide. 3. Exhaled gases are not scavenged. 4. Adjustable pressure-limiting valve is completely closed. 5. Low total fresh gas flows are utilized. 46

52 Determining Fresh Gas Flows: Must be equal to amount of gas taken up by the patient s lungs. [Oxygen Consumption = 3-5 cc/kg/min] Must replace gas sampled from the circuit for analysis, if it is not returned to the circuit. (Generally it is scavenged off) [Gas Sampling = cc/min] For most adults, a fresh gas flow of cc/min to include at least 400 cc/min oxygen, is adequate to replace oxygen consumed and other gases removed, without causing hypoxemia. **Clinical Note** Remember the goal of closed circuit anesthesia is to maintain both a constant circuit volume and a constant expired oxygen concentration. Constant circuit volume is achieved when the end-expiratory breathing bag volume or the ventilator-bellow s height is unchanged. Constant expired oxygen concentration is assessed via the gas analyzer. Sevoflurane is contraindicated for use in closed-circuit anesthesia. Recall that it requires flows of at least two liters per minute. Advantages of Closed-Circuit Anesthesia 1. Rebreathing of gases conserves respiratory heat and humidity. 2. Decreased O.R. pollution, as there is no scavenging of gases. 3. Early detection of circuit leaks and metabolic changes. Reflected by a change in breathing bag volume during SV. 4. Conservation of cylinder oxygen supply. 5. Less expense, as less volatile agent is used. 6. Demonstrates the principles of uptake and distribution. Disadvantages of Closed-Circuit Anesthesia 1. Increased risk of hypoxia if metabolic needs are not properly matched. 2. Increased risk of hypercapnia. 3. Small miscalibrations in the flowmeter or vaporizer can cause significant changes in % concentration of oxygen and agent delivered. Modern vaporizers are accurate down to flows of cc/min. Modern anesthesia machines don t allow oxygen delivery less than 150cc/min. 4. Huge discrepancies exist between delivered concentration (vaporizer dial) and alveolar concentration. Dilutional Effect Approximately 10 liters of deadspace gas exists in a circle system. (Tubing, CO 2 canisters, Breathing Bag, Patient s FRC) Priming Technique Filling the circuit after induction with high % concentration of volatile agent may help to overcome this dilutional effect. 5. Small circuit leaks can significantly alter % oxygen and agent delivery. 6. Requires more vigilance. 47

53 Deployment Application FACTS: Supplies of compressed gases are limited. Ventilators are oxygen driven (FAM 885A) or user selectable between oxygen and air (Narkomed M). Nitrous oxide will not be available. (Removed from field inventory) GOAL: Conserve oxygen resources as much as possible. IMPLICATIONS: Use of ventilators will be limited if compressed gas resources are low. Increased utilization of oxygen, as nitrous oxide and air are not available. Closed circuit anesthesia utilizing SV may be the best way to conserve oxygen resources. **Clinical Note** Closed-circuit anesthesia affords the ability to conserve oxygen resources in a deployed setting, where compressed gas support may be limited. However, the many limitations of closed-circuit anesthesia as outlined above have popularized the use of low-flow anesthesia. Low flow anesthesia (LFA) provides most of the advantages of closed systems, and eliminates the problem of oxygen constancy and controlled anesthetic delivery. LFA is easier to manage, and utilizes fresh gas flows that slightly exceed patient requirements, generally in the range of 1-2 liters/min. LFA also requires a higher % delivered concentration of volatile agent. The APL valve must be adjusted during spontaneous ventilation to allow for scavenging of excess gases. **Closed-circuit anesthesia has come in and out of favor over the years, and remains controversial. In the typical O.R. arena, it is a technique that has been mostly replaced by LFA, but still has important clinical applicability for the military anesthesia provider in an austere environment. 48

54 CHAPTER 3 Basic Concepts Related To General Anesthesia Stages of Anesthesia Stage I: Analgesia ( Clouding ) Begins with the induction of anesthesia and continues until the patient loses consciousness. The sensation of pain is not absent during this stage. Eyes: Some dilation Respirations: Slow, regular pattern CV: Slight increase in HR and BP Reflexes: Intact. Eyelash reflex disappears at the end of Stage I. Stage II: Delirium (Hypersensitivity) This period lasts from the time of loss of consciousness to the onset of a regular pattern of breathing. It often involves uninhibited and potentially dangerous responses to noxious stimuli, to include vomiting, laryngospasm, hypertension, tachycardia, and uncontrolled movement. Eyes: Dilated with a divergent gaze, nystagmus, roving eyeball Respirations: Irregular, breath holding is common CV: Increased HR and BP Reflexes: Hyperactive **Often this stage is not observed with I.V. inductions, as large doses of administered drug allow bypass of this stage. With slow, inhalation inductions, this stage is usually observed. Stage III: Surgical Anesthesia This stage lasts from the onset of a regular pattern of breathing to cessation of respirations. This is the target depth for surgical anesthesia, and consists of four planes (Stage III, Surgical Anesthesia) Plane 1 Light Surgical Eyes: Dilated initially, but become smaller in deeper planes. A fixed, divergent gaze may be seen. Respirations: Regular CV: HR and BP return to normal Reflexes: Laryngeal and pharyngeal reflexes still intact Muscle Tone: Begins to decrease 49

55 Plane 2 Moderate Surgical Eyes: Cessation of eye movement, concentrically fixed Respirations: Regular pattern, TV (may r/q assisted ventilations) CV: Normal Reflexes: Laryngeal and pharyngeal reflexes are abolished Muscle Tone: Greater relaxation of skeletal muscle Plane 3 Deep Surgical Eyes: Dilated, somewhat non-reactive Respirations: Complete ntercostals paralysis. Assisted or controlled ventilation is essential CV: Increased HR, decreased BP Reflexes: Visceral and traction reflexes are obtunded Muscle Tone: Completely lost **With general anesthesia, our anesthetic depth usually lies somewhere between Plane 2 and 3 of Stage III of Surgical Anesthesia. Plane 4 Too Deep Eyes: Dilated, non-reactive Respirations: Diaphragmatic movement only CV: BP and HR drop Reflexes: Absent Muscle Tone: Absent Stage IV: Medullary Paralysis (Pre mortem) This stage is only arrived at in error, and consists of impending or actual respiratory and cardiovascular collapse. ** Clinical Application** There are many observations that an astute anesthesia provider can make to determine what anesthesia stage the patient is in. Some of the most useful include: 1. Assessment of eyelash reflex 2. Presence of swallowing 3. Assessment of depth and quality of respirations 4. Assessment of position of eyes and size of pupils 5. Tightness of jaw muscles 6. Assessment of vital signs in response to stimuli Determination of the appropriate stage of anesthesia will help to avoid many adverse anesthesia outcomes, such as laryngospasm and bronchospasm. 50

56 Theoretical Basis of General Anesthesia Believe it or not, we don t really know how inhalation agents really work to depress the central nervous system. To date, no one theory exists to completely explain the mechanism of action of inhalation agents. There are many postulations as you might guess, and here are some of the most popular regarding mechanism of action. *Meyer-Overton Theory* There is a relatively consistent correlation between an agent s oil: gas partition coefficient, i.e. lipid solubility and potency. Therefore, a hydrophobic site is implicated. Anesthesia results when a critical number of molecules occupy a hydrophobic region of the membrane. *This theory implies that it is the number of molecules present, and not the type that is most important in eliciting a therapeutic effect. This would suggest that different inhaled agents are additive, resulting in a summated effect. (0.5 MAC MAC = 1 MAC) Volume Expansion or Membrane Fluidity Theory This theory holds that when a critical number of anesthetic molecules enter the lipid membrane, expansion of the membrane occurs resulting in altered cell membrane function. Pitfalls: 1. Increasing temperature causes an increase in membrane volume expansion, which should reduce MAC, but the opposite is true. 2. Some highly lipid soluble compounds expand membranes, but don t have any anesthetic action. Lateral Phase Separation This theory suggests that in the normal lipid membrane there are phase separations, such that there are areas of solid-gel protein alternating with areas of liquid-crystalline protein. Inhalation agents increase phase transition temperatures, resulting in greater fluid areas of the membrane. This causes the membrane around a protein channel to remain in the fluid state, allowing the channel to stay open. Pitfalls: 1. Temperature elevations increase membrane fluidity, but result in an increased MAC requirement. 2. Temperature decreases cause an increase in the gel state in the membrane, but result in a decreased MAC requirement. 3. We know that increasing the patient s temperature does not make them more sensitive to anesthetics. 51

57 Protein Conformational Change This theory suggests that inhaled agents have a direct effect on protein receptors, resulting in a conformational change and altered function. Distinct binding sites have been identified on some proteins, such as myoglobin and hemoglobin. Pitfalls: 1. Protein binding of drugs to a specific receptor site is fairly specific for that drug. The diversity of anesthetic agents available, may suggest a non-specific protein-binding site. 2. Very few protein studies have any anesthetic relevance. Metabolic Inhibition This theory hypothesizes that anesthetic agents inhibit the oxidative enzyme systems in the CNS. Evidence of this may exist in the fact that oxygen consumption is depressed during anesthesia, and anesthetic agents decrease oxygen consumption in brain slices. Pitfalls: 1. Greater than clinical doses of anesthetics are required to inhibit mitochondria 2. ATP levels do not decrease during anesthesia 3. Decreased brain oxygen consumption is a consequence of CNS depression, not a cause of it. Opioid Receptor Site This theory states that anesthetic agents affect the opioid receptor, causing possibly an increased output of endogenous opioids. Pitfall: 1. Major pitfall to this theory is that Naloxone does not reverse general anesthesia. **As you can see, there are many theories as to how inhaled gases actually work. It is most widely accepted that the most likely site of action is the cell membrane or the protein elements in the cell membrane lipid bilayer. Most evidence is consistent with some sort of inhibition of synaptic transmission in the CNS, probably in the reticular activating system. 52

58 CHAPTER 4 Basic Math in Anesthesia Pharmacology The intent of this section is to provide you with a summative collection of important formulas and mathematic relationships that exist in anesthesia pharmacology that will prove very helpful to commit to memory. The intent is not to provide you with a mathematics review course. You have already gotten that in Basic Principles of Anesthesia. However, if you would like a refresher review, there is an excellent web site that offers four quizzes with answers and solutions in major categories of anesthesia math. This can be found at: Click on the drug calculations for nurses quiz link. Weight 1 Kg = 2.2 lbs 1 gram = 1000 milligrams 1 mg = 1000 micrograms 1 grain = 60 mg Height 1 inch = 2.5 cm Pressure 1 mmhg = 1.36 cm/h mm Hg = 1 cm/h 2 0 Temperature F = [(ºC X 9)/5] + 32 C = [(ºF 32) X5]/9 ºKelvin = C *Shortcut 5F-9C = 169 Example: What is the Fahrenheit equivalent of 30 C? Simply solve for F. [5F 9(30) = 169] [5F- 270 = 169] [5F = 439] [F = 87.8] Therefore, 30 C = 87.8 F. If you need to know Celsius, simply solve for C. Changing % to mg/cc Whenever you have a % concentration, just remember by simply moving the decimal point one place to the right will give you the amount of mg per cc of the solution. For example, 0.5% Lidocaine is equivalent to 5.0 mg/cc of Lidocaine. 53

59 Changing mg/cc to % Whenever you have a certain mg/cc of a drug, you can always figure out its % concentration by moving the decimal point one place to the left. For example, mg/cc = a 10.0 % solution. Remember % means per 100. Concentration Ratios Sometimes concentrations are expressed as a comparative ratio, such as a 1:1000 solution. Whenever you see this, remember that the first number is always expressed in grams and the second number is always expressed in ml/cc. For example, a vial of epinephrine often comes labeled as a 1:1000 solution. It therefore will contain 1 gram per 1000 cc. This can also be expressed as 1000 mg per 1000 cc or by canceling the zeros out, 1 mg per 1 cc. Common ratios utilized are listed below. It is important to remember how to derive the actual mg/cc content, as you may encounter some less familiar concentrations in your career. Concentration mg/cc ug/cc 1: :10, :100, :200, :400, Table 4-1 ** Frequently you will need to use these values to calculate epinephrine doses for axillary blocks. Fractions To Decimals Often it is necessary to convert fractions to decimals to figure out total drug concentrations. In order to do this, simply divide the numerator by the denominator. For example, if you have a bag labeled 1/16 th % Bupivacaine, you know that by dividing 1 by 16, this also equals %. This now allows you to convert % to mg/cc (as discussed above). By simply moving the decimal point one place to the right, you know this equals mg/cc. You then can make other calculations such as total mg dose received or mg per hour. ** You will frequently use this on the labor deck and in the main O.R. for mixing epidural infusions. Common % fractions utilized are listed below. Fractional % Decimal % mg/cc 1/ / / / / / Table

60 Intravenous Infusions of Cardiotonic (ACLS type) Drugs This is a very important area to completely understand. It is important to know how to calculate ml/hr of a drug you need to infuse to give 1 ug/kg/min of that drug. Using the following formula, this can be quickly calculated. 1 ug/kg/min = kg wt X 60 = cc/hr to be dialed into IMEDD pump ug/cc **For example, if you are in the O.R. and your patient, who has a significant cardiac history begins to have S-T segment elevation, you may want to put that patient on a nitroglycerin infusion at 2 ug/kg/min. How are you going to do that??? Well, you need to know the concentration of NTG on hand as well as the patient s weight. You have 50 mg of NTG in 250 cc of volume, and your patient weighs 80kg. Using the above formula, 1ug/kg/min = 80 X 60 = 4800 = 24 cc/hr 50,000/ ** In other words, in order to provide 1 ug/kg/min of NTG, you need to run an infusion of 24 cc/hr for this patient. If we want 2 ug/kg/min, simply double your infusion rate to 48 cc/hr. No Math Rule For Intravenous Infusions (Donenfeld RF. Anesth Analg 1990; 70:116-7) Very down and dirty method for quickly calculating drug infusions. This method works for Dopamine, Dobutamine, Isoproterenol, Epinephrine, Norepinephrine, Phenylephrine, Theophylline, Nipride, Lidocaine, Procainamide, Nitroglycerine, and Bretylium. It requires no calculations or tables. **Dilute 1 ampule of drug in one 250 cc bag of I.V. fluid. Infusion rates of 60, 30, and 15 ml/hr will give a high, medium, and low dose rate of any of the above agents. (for a 70 kg patient). If a controller pump is not available, these rates are easy to set with micro drip tubing (1 gtt/sec, 1gtt/2sec, 1gtt/4sec, respectively). ** If the patients weight differs from 70 kg, the drop rate needs adjustment accordingly. (Actual kg weight/ 70 kg = Adjusted drop rate) Figuring oxygen concentration in a mixture of gases This is very useful to know how to do in the absence of a gas analyzer, or to help troubleshoot a value that may seem faulty. The goal is to compute the % composition of oxygen compared to the total fresh gas flow. **What is the % oxygen delivered when the total fresh gas flow (TGF) consists of 2 L/min of oxygen and 1 L/min of air?? (3 liters total flow) Answer is calculated as follows: 2000 cc oxygen + (0.21 X 1000 cc air) = 2210 cc oxygen/3000 cc TGF = 73.67% oxygen conc. 55

61 Calculating Cylinder Duration It is critical to be able to calculate cylinder duration, especially during times of emergency reserve gas support, or in field scenarios where pipeline gas does not exist. Some important values to commit to memory are: Full E cylinder of oxygen = 660 liters Full H cylinder of oxygen 5500 liters ( ) If you are transporting a patient to the ICU intubated and are using an ambu bag to ventilate your patient, how long will you have before your E cylinder of oxygen runs empty. You are utilizing a flow of 15 liters/minute and the tank initially reads 800 psi.?? Well. this is how you calculate it. Actual gauge reading (psi) X (known liters full) (total liter flow) Initial Filling pressure (psi) So you have 800/1900 X = 18.5 minutes ** You have 18.5 minutes before your tank runs out. Work quickly!! Vaporization Formulas The new Narkomed M field anesthesia machine is equipped with agent specific, temperaturecompensated vaporizers. This negates the necessity to utilize lengthy vaporizer formulas to calculate % delivery. However, the Narkomed M has NOT completely replaced the FAM Model 885A field anesthesia machine used in Deployable Medical System (DEPMEDS) hospitals fielded by the US Department of Defense. Therefore it is imperative to understand vaporizer calculations using the bubble through, non-temperature compensated vaporizers (copper kettle) that equip the 885A. Long Version (Two Step Calculation) In general, the amount of vapor leaving the copper kettle depends on the vapor pressure of the anesthetic agent (VP), the flow rate of the carrier gas (CG), and the barometric pressure (BP). *In most instances, the standard known vapor pressure for the agent being delivered can be used (assuming 20 C). If temperature extremes exist, the package inserts for the particular agent will usually have the expected vapor pressure at different temperatures. 1. Vapor Output (cc/min) = CG X VP BP-VP 2. % Anesthetic Concentration = Vapor Output (from above) Total Gas Flow 56

62 Short Version #1 Vaporizer Flow Equations (approximate for 20 C/68 F) Isoflurane Vaporizer Flow (ml/min) ~ %Vapor Concentration X Total Flow (L/min) X 20 Halothane Vaporizer Flow (ml/min) ~ %Vapor Concentration X Total Flow (L/min) X 20 Enflurane Vaporizer Flow (ml/min) ~ %Vapor Concentration X Total Flow (L/min) X 30 Sevoflurane Vaporizer Flow (ml/min) ~ %Vapor Concentration X Total Flow (L/min) X 40 ** The above equations are useful as they parallel more the way we think in the O.R. on a day-to-day basis. You just need to know what % concentration you desire to give your patient, plug it into the equations as indicated above, and then dial in your calculated vaporizer flow. You must ensure that your diluent flows are already turned on, to prevent a lethal delivered concentration of agent!! Short Version #2 % Vapor = Vapor Pressure X So, for the most commonly used volatile agents in the field, if we plug in their known vapor pressures, we can calculate their % vapor at standard atmospheric pressure. (or at any atmospheric pressure): Halothane (244 mm Hg) = 32% Isoflurane (240 mm Hg) = 32% Enflurane (172 mm Hg) = 23% Sevoflurane (170 mm Hg) = 22% Carrier Gas: The gas flow through the copper kettle vaporizer. Total Gas Flow: The total volume of gas that flows into the inspiratory circuit. It includes the output from the vaporizer, as well as the additional gases from the flow meters (N 2 0 and O 2 ). Basic Concepts: Whatever carrier gas flow you dial into the vaporizer, that amount will exit the vaporizer. Because the carrier gas picks up vapor, the total volume of gas exiting the vaporizer is greater than what entered it. 57

63 Determining % of Vapor Delivered If we are using Halothane, for example, and have a carrier gas flow of 100cc/min, the % vapor coming out of the vaporizer is calculated by using the formula above. Halothane 244 X 100 = 32% 760 This means that the rest of the gas mixture (68%) must be carrier gas. If we know that our carrier gas rate was 100 cc/min, then we can also figure out how many cc s of anesthesia vapor constitutes the final mixture by simple proportion. How much vapor comes out of the vaporizer? X = X = 3200 X = 47 cc or approximately 50 cc So, for every 100 cc through the vaporizer, 150 cc will come out consisting of 100 cc of carrier gas and 50 cc of Halothane. What is the final concentration of gas delivered to the patient? If your total gas flow is 5 liters, the final % vapor being delivered to the patient is calculated as follows: Vapor Output/TGF 50cc/( ) 50/5050 = 1% Halothane Let s look at another clinical example: You are using Enflurane with a total gas flow of 3000 cc, and a carrier gas flow of 100 cc. What % enflurane are you delivering to the patient?? X = X = 2300 X = 30 cc Total fresh gas flow is 3 liters, so the final % vapor being delivered to the patient is: 30/3030 = 1% Enflurane General Rule of Thumb: When using this calculation method, every 100 cc s of carrier gas will pick up 50 cc s of Halothane and Isoflurane and 30 cc s of Enflurane. Knowing this, you can proportionately adjust your carrier gas or your total gas flow to quickly adjust your % vapor delivered without repetitive calculations. **Clinical Note** Remember that the shorter calculations do not compensate for changes in ambient temperature; therefore they are not as accurate as the longer version. However, unless you have several degrees variation in ambient temperature during the course of an anesthetic, this should be a minimal concern. 58

64 CHAPTER 5 Physics Applied To Anesthesia So, you didn t want to be a physicist, you wanted to be an anesthetist? Well, unfortunately there are many physical concepts applied to anesthesia that you need to be understand, from the drugs you use to the monitors you apply. This chapter will highlight some important definitions and concepts that are critical to understand in anesthesia. Important Definitions Molecular Theory of Matter Matter is made up of minute particles called molecules, which exist in various phases of aggregation (solid, liquid, gas). Kinetic Theory of Matter Molecules are in constant random motion and maintain a degree of attraction between them called van der Waals forces. Vapor Pressure: The pressure exerted by a vapor in an enclosed space. **All volatile agents exist in a liquid state at room temperature, but are very near their boiling points. Vapor pressure is independent of atmospheric pressure, and dependent only upon the physical characteristics of the vapor and temperature. Saturated Vapor Pressure The partial pressure exerted by a vapor above a liquid at equilibrium in a closed container. All volatile liquids have a saturated vapor pressure in their enclosed bottles. Boiling Point The temperature at which the vapor pressure of a gas is equal to atmospheric pressure. ** At higher elevations, boiling point is lower as atmospheric pressure is lower (660 mm Hg in Denver) Latent Heat of Vaporization The amount of heat in calories required to vaporize 1 gram of liquid. As molecules leave the liquid, kinetic energy is also removed resulting in cooling of the liquid with vaporization. Specific Heat The amount of heat in calories needed to increase the temperature of 1 gram of a substance by 1 C. Critical Temperature The temperature above which a gas cannot be liquefied regardless of how much pressure is applied. Critical Pressure The vapor pressure of a gas at its critical temperature. 59

65 Physics of Gases P = Pressure V = Volume T = Temperature Dalton s Law of Partial Pressures The total pressure exerted by a mixture of gases is equal to the sum of the partial pressures of each gas constituting the mixture. P T = P 1 + P 2 + P 3 * The partial pressures are additive because the partial pressure of one gas is independent of the partial pressure of another. The General Gas Laws Boyle s Law At constant temperature, the pressure exerted by a gas is indirectly proportional to the volume. P1V1=P2V2 Charles Law At constant pressure, the volume of a definite quantity of gas is directly proportional to the temperature. V1 = V2 T1 T2 Guy-Lussac s Law At constant volume, pressure varies directly with temperature. P 1 = P 2 T 1 T 2 P B= Boyle s Law V G = Guy-Lussac s Law C = Charles Law Could this guy possibly be a violinist T The simple diagram above can help you remember what variable is held constant with which law. The letter that lies across from the law describes the variable held constant. In Boyle s law, the relationship is indirect; in Charles and Guy-Lussac s law, the relationship is direct. 60

66 Avogadro s Principle Equal volumes of different ideal gases at equal temperatures contain the same number of molecules. Avogadro s Number = 6.02 X molecules in 1 mole of gas * 1 mole of gas occupies 22.4 L Ideal Gas Law Combination of Boyle s law, Charles law, and Avogadro s hypothesis. P1V1 = P2V2 T 1 T 2 Joule-Thompson Effect As a gas expands into a vacuum, energy is lost and the gas cools. ** Clinical Example** Slowly open a cylinder of oxygen to the atmosphere and feel how cold the valve gets. Oxygen tanks that have an undetected slow leak may develop frost or ice on the tank valve. Adiabatic Compression Rapid compression of a gas causes its temperature to increase. This is the reverse of the Joule-Thompson Effect. ** Clinical Examples** Compressed gas in a cylinder is suddenly released by opening the valve. It expands and is then rapidly recompresses as it encounters the diaphragm of the pressure gauge of the attached regulator. This recompression could raise the temperature of the gas enough to ignite grease, dust, or any other combustible particle. Open tanks slowly!! Trans-filling tanks from a large tank to a small tank causes the gas to rapidly expand and recompress, causing ignition of combustible materials. Laws of Gas Diffusion Graham s Law The rate of diffusion of a gas is inversely proportional to the square root of its molecular weight. **Lighter gases diffuse quicker than heavier gases. O2, CO2, He, H Anesthetic vapors Henry s Law At any given temperature, the solubility of a gas in a liquid is directly proportional to the pressure of the gas above the liquid at equilibrium. Another way to say this is the amount of gas absorbed by a liquid is directly proportional to the partial pressure of gas in contact with the liquid. pressure = solubility pressure = solubility 61

67 Poiseuille s Law Defines the relationship between pressure and the flow of fluid through a tube. Factors affecting movement of fluid through a tube are length, diameter, pressure, and viscosity. The rate of discharge through a tube is directly proportional to its radius (r) and pressure (P), but inversely proportional to its viscosity (η) and length (l). Flow = (π Pr 4 )/(8ηl) In other words, the shorter and wider the tube, the better rate of discharge. Doubling or tripling the radius increases flow, 16 and 81 times, respectively. Changing the radius has the greatest effect on the flow rate. **Clinical Example** Infusion of I.V. fluids through a short 16-gauge I.V. catheter on a pressure bag will be significantly greater than infusion of albumin through a long 18-gauge I.V. catheter dripping by gravity. A patient with COPD has increased pulmonary resistance. Selecting a larger sized ETT increases internal diameter, allowing increased flow of gases to the lung, and the capability of providing increased driving pressure without affecting peak airway pressures as much. Fick s Law Describes the diffusion of gases through tissues such that the rate of transfer of a gas through a sheet of tissue is dependent on: 1. Tissue area 2. Tissue thickness 3. Concentration gradient 4. Solubility of the molecules 5. Molecular size and weight 6. Electrical charge **Clinical Application** CO 2 (44) and O 2 (32) are about the same molecular weight but CO 2 is much more soluble in blood. CO 2 therefore diffuses about 20 times faster than O 2. Carbon monoxide (CO) is very soluble in blood as compared to O 2. CO forms a tight bond with Hgb; therefore the partial pressure in blood (what is dissolved) remains low. The difference between its solubility properties and its partial pressure in blood allows increased transfer of CO into the blood. Contrast with N 2 O. This gas is very insoluble in blood. The partial pressure equilibrates very quickly with all spaces; blood, air bubbles, pockets of air, etc. Physics Applied to Monitors and Equipment Bernoulli s Theorem (How pressure and velocity interact) The lateral pressure energy of a fluid flowing through a tube of varying diameters is least at the point of greatest constriction and speed is the greatest. At the widest diameter, lateral pressure energy is greatest, and speed is the least. The total energy of the system is constant. The same volume of fluid must pass through all portion of a tube. Flow will be faster through the constricted portions, and slower in wider portions. Wider Diameter = Lateral Wall Pressure = Speed Narrow Diameter = Lateral Wall Pressure = Speed 62

68 ** This theory assumes a non-viscous, frictionless system with no resistance to fluid flow, where the total energy of the system is constant. Example: The Venturi tube The Venturi tube is simply a tube that is narrower in the middle, and wider at its ends. When fluid passing through the tube reaches the narrow part, it speeds up. According to Bernoulli s theorem, it should also exert less pressure. High Velocity Low Pressure Low Velocity High Pressure Low Velocity High Pressure Fig: 5-1 Venturi Tube Venturi Principle This principle represents an extension of Bernoulli s work on the relationship between velocity of flow and lateral pressure. It states that to restore the lateral pressure of a fluid that has flowed through a constriction to its pre-constriction magnitude, there must exist a gradual passage dilation immediately distal to the constriction, with an angle of divergence not exceeding 15. Flow Fig: Referring to Fig: 5-2, if we measured the pressure at the area of constriction, it would be lower than elsewhere in the tube, and often subatmospheric. This concept is applied in several devices used in anesthesia and respiratory care. **Clinical Application** (Venturi Principle) The side arm in a tube of this construction can be used for aspirating another fluid into the tube, in either a gas or liquid state. Aspiration of another gas by the Venturi effect into a gas mixture flowing through a constriction is called entrainment. This principle is applied to nebulizers and atomizers, as well as the Venturi oxygen mask, which utilizes entrained room air to change administered oxygen concentration. In addition, this concept is applied to trans-tracheal jet ventilators and ventilating bronchoscopes, which entrain pressurized oxygen into the trachea or an endotracheal tube. 63

69 Entrained Gas Needle Valve Driving Gas Mixture Fig: 5-3 Ventilating Bronchoscope Fick Principle This is used in the measurement of cardiac output by following the principle that the total amount of oxygen consumed by the body per minute must equal the product of the cardiac output and the arterial-mixed venous oxygen content difference. Blood flow to an organ = Rate of arrival or departure of a substance Difference in concentration of the substance in arterial and venous blood Thermodilution Technique This is the most common way to calculate cardiac output in the operating room. It requires the placement of a pulmonary artery catheter (PAC) equipped with a distal thermistor- usually a Swan- Ganz catheter. The technique utilizes saline of a known temperature (usually below room temperature) and volume injected into the right atrium. The temperature of the injectate after injection is detected by the thermistor at the distal tip of the PAC in the pulmonary artery. The degree of change in temperature is inversely proportional to cardiac output. * High cardiac output states will allow the temperature detected at the thermistor to return to normal quickly. * Low cardiac output states will cause the thermistor to return to normal more slowly. Beer-Lambert Law There are several types of monitors used during anesthesia that are based upon this law. This law relates the concentration of a solute in solution to the intensity of a specific wavelength of light transmitted through the solution. ** Clinically, pulse oximetry and capnometry utilize this principle. Another concept similar to Beer-Lambert is known as Raman scattering, which utilizes identification of molecules according to their light absorption and re-emission ratio. ** Clinically, monitors used to assess respiratory gases and vapors use this concept, such as our gas analyzers. 64

70 Law/Principle Clinical Application Beer/Lambert Law Pulse Oximetry and Capnometry Bernoulli s Principle Entrainment of air with the jet ventilator (Venturi Effect) Nebulizer/Venturi Oxygen mask Boyle s Law Plethysmography to determine FRC Inspiration/Expiration (as the intrapulmonary pressure in the lungs decreases air enters thereby increasing the volume in the lungs and visa versa) Calculate the volume of gas in a cylinder Explains why a large amount of gas is released from a pressurized cylinder Charles Law Expansion of an LMA cuff during autoclave sterilization Dalton s Law Calculation of the partial pressure of a gas if the % concentration is known Fick Principle Calculation of cardiac output Fick s Law of Diffusion Expansion of closed spaces with the administration of N 2 O (Pneumothorax/Tympanic membrane/gi tract/ett) Concentration Effect Second Gas Effect Diffusion Hypoxia Explains diffusion in relation to substance size as well as solubility Gay-Lussac s Law When the temperature of a closed cylinder increases, cylinder pressure also increases and visa versa Graham s Law Explains diffusion in relation to its molecular weight/density Smaller substances diffuse in greater quantities. At high O 2 flow rates, the flow tube is wider and gas flow is a function of density Henry s Law Calculation of the amount of dissolved O 2 and CO 2 in the blood Joule-Thompson As a cylinder of compressed gas empties, the cylinder cools Effect Law of LaPlace ARDS causes smaller alveoli to empty into larger ones resulting in Atelectasis Dilated ventricles generate greater wall tension than smaller ventricles Ohm s Law Calculation of Systemic Vascular Resistance Poiseuille s Law Decreasing the IV catheter gauge increases the flow rate Decreasing the IV catheter length increases the flow rate Raising the height of the IV bag increases the flow rate Polycythemia decreases blood flow Smaller endotracheal tubes cause increased airway resistance Table

71 CHAPTER 6 Inhaled Anesthetic Agents Inhaled anesthesia agents have come a long way from the days of Ether, Chloroform, and Cyclopropane. Today, there are a wide variety of inhaled gases that offer desirable attributes with limited side-effect profiles. We will examine the physical and chemical properties of these drugs, and correlate basic characteristics of the drug with its chemical structure. The Perfect Inhaled Agent No organ toxicity Non-flammable Smooth rapid induction Quick emergence Rapidly adjustable The search continues today for an inhaled drug that can fulfill all of the criteria listed above as the perfect inhaled agent. Basic Chemical Structure of Inhaled Agents All of the inhaled agents that exist today are either: Aliphatic Hydrocarbons Ether Derivatives Inorganic Compounds Aliphatic Hydrocarbons as you will recall from Chemistry, are straight-chained or branched nonaromatic hydrocarbons with no more than four carbon atoms. Ethers are hydrocarbon chains connected by an oxygen molecule (R-0-R) Inorganic Compounds don t have carbon. (Nitrous Oxide) Inhaled Agent refers to ALL of the gases including Nitrous Oxide. Volatile Agent refers to all of the gases except Nitrous Oxide. All of the inhaled agents available today, with the exception of N 2 0 and Halothane, are derived from modifying diethyl ether. 66

72 Fig 6-1: (Nagelhout, J.J. & Zaglaniczny, K.L. Nurse Anesthesia. 1997, p 384.) Halogenation Halogens are gases that accept one electron into their outer shell. They include Fluoride (Fl), Chloride (Cl), Bromide (Br), and Iodine (I). Halogenation refers to the substitution of an H atom with a halogen. Iodine is generally not used, as it is very unreactive. All of the volatile agents in use today are referred to as halogenated hydrocarbons. Halogenation alters the potency, arrhythmogenicity, flammability, and chemical stability of the drug. Fluorine decreases flammability and increases chemical stability (less biodegradation and metabolism). Bromine increases arrhythmogenicity and potency (Halothane). Parameters For Comparison of Inhaled Agents Common parameters used to compare and contrast the inhaled agents include: MAC Solubility Physical Properties 67

73 We have already discussed the concept of MAC as well as solubility, and the effect it has on uptake and distribution of gases. (Chapter 2). Let s look a bit closer now at the different physical and chemical properties of each of these drugs. Physical and Chemical Properties of Inhaled Agents The physical and chemical properties of anesthetic agents are described according to the following parameter. Chemical structure Boiling point Vapor pressure Blood/gas partition coefficient MAC Amount metabolized Nitrous Oxide (N 2 0) An inorganic gas that is odorless to sweet smelling Nonflammable, but supports combustion Low potency (high MAC of 104) **Commonly combined with opioids or volatile agents to enhance potency. Poorly soluble (BG: PC =0.46) Rapid achievement of brain partial pressure Analgesic effects are prominent Minimal skeletal muscle relaxation Nitrous Oxide Diffusibility N 2 0 is 34X more diffusible than nitrogen (BG: PC 0.46 vs ) Implications: Passage of N 2 0 into air-filled cavities such as the intestines, blebs, existing pneumothorax. Passage of N 2 0 into non-compliant cavities such as the middle ear and cerebral ventricles. **Clinical Implication** Because N 2 0 is 34X more diffusible than nitrogen, it will displace nitrogen out of the space it occupies. If this is in an enclosed space, this becomes a concern in anesthesia. Application of this concept in anesthesia is as follows: 1. Contraindicated for use in patients with such conditions as a bowel obstruction, identified blebs on chest x-ray, existing pneumothorax. 2. N 2 0 must be turned off in procedures involving the middle ear where a tympanic patch is used. 3. N 2 0 will displace nitrogen out of the balloon at the end of your ETT. For long cases, the pressure in the balloon must be frequently checked and adjusted to prevent tracheal mucosal damage. 68

74 Diffusion Hypoxia This concept related to N 2 0 occurs with abrupt discontinuation of this gas. Because N 2 0 is poorly soluble, once the concentration gradient is removed (turning off the gas), the partial pressure will quickly reverse, resulting in a massive diffusion of N 2 0 back into the alveoli. This causes a dilutional hypoxia, which is greatest during the first 1-5 minutes and can be observed on the pulse oximeter. **Clinical Implication** Always turn your N 2 0 off at least 5-10 minutes prior to extubation and administer 100% oxygen to assist in washout. Emergence delirium and post-extubation hypoxia may ensue if sufficient time is not allowed for N 2 0 washout. Halothane (Fluothane) Halogenated alkane derivative Clear, nonflammable liquid at room temperature Sweet, non pungent vapor **favored for inhalation inductions in children High potency (MAC = 0.75) Intermediate solubility (BG: PC = 2.5) **Intermediate solubility + high potency = rapid onset and relatively recovery from anesthesia. Boiling Point Vapor Pressure BG: PC MAC % % Metabolized 50.2 C 244mmHg Table 6-1: (Produced from information obtained in Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 1999, Chapter 2.) 1. Carbon-fluorine bond flammability 2. Carbon-bromine bond stability Halothane is susceptible to decomposition from exposure to light, so it is stored in amber colored bottles Halothane contains thymol, as a preservative: a. Prevents spontaneous oxidative decomposition b. This compound can accumulate in the vaporizer causing malfunction of the temperature-compensating device. 69

75 Enflurane (Ethrane) Halogenated methyl ethyl ether Clear, nonflammable liquid at room temperature Pungent, ethereal odor High potency (MAC = 1.6) Intermediate solubility (BG: PC = 1.9) ** Intermediate solubility + High potency = rapid onset and relative recovery from anesthesia. Boiling Point Vapor Pressure BG: PC MAC % % Metabolized 56.5 C 172 mmhg Table 6-2: (Produced from information obtained in Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 1999, Chapter 2.) Isoflurane (Forane) Halogenated methyl ethyl ether Clear, nonflammable liquid at room temperature Pungent, ethereal odor High potency (MAC = 1.1) Intermediate solubility (BG: PC = 1.4) ** Intermediate solubility + high potency = rapid onset and relative recovery from anesthesia Boiling Point Vapor Pressure BG: PC MAC % % Metabolized 48.5 C 240 mmhg Table 6-3: (Produced from information obtained in Stoelting, R.K. Pharmacology & Physiology in Anesthetic

76 Practice. 1999, Chapter 2.) 1. Isoflurane is an isomer of Enflurane (mirror images) Enflurane Isoflurane 2. Isoflurane is characterized by extreme physical stability 3. There is no detectable deterioration after five years of storage or exposure to sunlight. Sevoflurane (Ultane) Fluorinated methyl isopropyl ether Clear, nonflammable liquid at room temp Non-pungent, ethereal Intermediate potency (MAC = 1.8) Poor solubility (BG: PC = 0.69) ** Intermediate potency and poor solubility produces a quick induction and emergence, easy titratability, with a medium strength agent. Boiling Point Vapor Pressure BG: PC MAC % % Metabolized 58.5 C 170 mmhg Table 6-5: (Produced from information obtained in Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 1999, Chapter 2.) 1. Sevoflurane produces degradation products called Compound A (vinyl ether). 2. This compound has been shown to produce dose-dependent nephrotoxic effects in rats. 3. Package insert recommends a minimum two liter total flow when administering this agent for greater than 2 MAC hours. 71

77 Desflurane (Suprane) Fluorinated methyl ethyl ether Pungent, ethereal odor that is highly irritating *For this reason, Desflurane is not recommended for inhalation inductions. Low potency (MAC 6.6) 1. Highest of all volatile agents 2. Vaporizer % concentration goes up to 18% Poor solubility (BG: PC 0.42) similar to N 2 0 ** Low potency + poor solubility results in rapid inductions and emergence, but requires more agent. Boiling Point Vapor Pressure BG: PC MAC % % Metabolized 23.5 C 669 mmhg Table 6-4: (Produced from information obtained in Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 1999, Chapter 2.) 1. Fluorination vapor pressure and potency (as opposed to chlorination) a. It differs from Isoflurane by substitution of a fluorine atom for the chlorine atom. 2. Vapor pressure of 669 mm Hg is 3X that of Isoflurane. 3. Respiratory irritant (> 6% of awake patients) a. Salivation b. Breath-holding c. Laryngospasm d. Coughing Desflurane s Special Needs Desflurane has an extremely high vapor pressure. As a result, it needs a special vaporizer that can heat the liquid in a controlled fashion, providing for a more regulated gas concentration. Ohmeda Tec 6 Vaporizer This is a special vaporizer designed specifically for Desflurane that contains a reservoir where the liquid is heated to a fixed temperature, giving a fixed vapor pressure (39 degrees and 1500 mm Hg vapor pressure). No fresh gas flows through the sump; instead, the Desflurane gas joins the FGF exiting the vaporizer. 72

78 Fig 6-2: (The Ohmeda Tec 6 Vaporizer Product Guide. 1992, p. 11.) CHEMICAL AND PHYSICAL PROPERTIES OF INHALED AGENTS Agent MAC MAC in 70% N 2 0 Vapor Pressure 20 C B:G Coefficient % Met Boiling Point ( C) N , Trace Pungency Halothane (Fluothane) Enflurane (Ethrane) Isoflurane (Forane) Desflurane (Suprane) Sevoflurane (Ultane) Table 6-6: (Partially reproduced from information in Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 1999, Chapter 2.) 73

79 Inhaled Agents and Organ System Effects All of the inhaled agents have specific physiological effects on many of the organs of the body. This section helps identify the most important effects that these agents have on the central nervous system, circulatory system, pulmonary system, liver, kidney, and skeletal muscle. Central Nervous System Effects (CNS) This area will compare the inhaled agents and their effects on CNS electrophysiology, cerebral metabolic oxygen consumption (CRMO 2 ), cerebral blood flow (CBF), and intracranial pressure (ICP). CNS Electrophysiology All inhaled agents produce a dose-dependent suppression of EEG activity at > 0.4 MAC. Decreased EEG wave form frequency Increased voltage on the EEG Seizure Activity *Enflurane can elicit spike wave EEG activity similar to a seizure. This is more likely at > 2 MAC or P a C0 2 < 30 mm Hg All other agents do NOT evoke seizure activity. ** Volatile agents (except Enflurane) are thought to raise the seizure threshold, making it unlikely that seizures will occur under general anesthesia. Evoked Potential Monitoring All inhaled agents cause a dose-dependent depression of evoked potentials Decreased amplitude Increased latency ** Often times evoked potential monitoring will be utilized in surgical procedures (for example spine and head procedures), and the technician will ask you to keep your inhaled agents below a specific concentration. This will allow for the establishment of a baseline reading, and prevent depression of the evoked potentials. Cerebral Blood Flow (CBF) All inhaled agents produced a dose-dependent increase in cerebral blood flow during normocapnia. Increased cerebral vasodilatation Decreased cerebral vascular resistance Decreased CMRO 2 (mechanism not quite clear, but is possibly related to a direct effect on metabolism, decreasing production of carbon dioxide) Uncoupling of autoregulation **Potency ranking related to increases in CBF (Fig 6-1) (H > E > I = D = S > N 2 0) Note: At equipotent MAC, Nitrous Oxide may be a more potent vasodilator than Isoflurane, but because the MAC of Nitrous Oxide is never clinically approached (104%), it is considered to have a weaker effect than all of the volatile agents. 74

80 Fig 6-3: (Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 1999, p. 41.) Intracranial Pressure (ICP) All inhaled agents produce a dose-dependent increase in ICP This increase is directly related to increases in CBF as a result of cerebral vasodilatation ** Potency ranking related to increases in ICP (H > E > I = D = S > N 2 0) **Clinical Application** Hyperventilation to a P a C0 2 < 30 mm Hg opposes vasodilatory effects of inhaled agents on cerebral vasculature. This is often applied clinically in patients with intracranial pressure elevations during anesthesia. The typical management in this type of patient will involve hyperventilation during induction and maintenance phases to oppose this effect. Remember that autoregulation and the vascular response to CO 2 are totally separate mechanisms. Cardiovascular Effects This section will compare the inhaled agents and their effects on myocardial contractility, mean arterial blood pressure (MAP), heart rate (HR), cardiac output (CO), arrhythmogenicity, and coronary blood flow. Myocardial Contractility All inhaled agents are direct cardiac depressants that elicit a dose-dependent depression of myocardial contractility. **Potency ranking related to myocardial depression H > E > I > S > D > N

81 Mean Arterial Blood Pressure All inhaled agents produce a dose-dependent decrease in MAP. Directly related to myocardial depression (Halothane) Directly related to decreased systemic vascular resistance (Isoflurane, Desflurane, Sevoflurane) Heart Rate All inhaled agents EXCEPT Halothane produce a dose-dependent increase in heart rate. Compensation for decreased MAP ** Desflurane can cause a transient tachycardia during induction of anesthesia and during abrupt increases in the delivered concentration due to direct stimulation of the sympathetic nervous system. **Halothane does not alter heart rate despite decreases in MAP. This is related to other specific direct effects of this agent. 1. Depression of carotid sinus 2. Suppression of SA node 3. Decreased speed of conduction of electrical impulses in the heart Cardiac Output All inhaled agents produce a dose-dependent decrease in cardiac output. As a result of decreased MAP and direct effects on inotropy **Halothane produces the most significant decrease. Liters/Min Halothane Isoflurane Desflurane Sevoflurane Fig 6-4: (Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 1999, p.45.) 76

82 Pulmonary Vascular Resistance (PVR) All volatile agents exert minimal effects on PVR. Nitrous Oxide increases PVR. Exaggerated in patients with pre-existing pulmonary hypertension **Clinical Application** Many children present to the O.R. with pre-existing congenital heart anomalies, of which pulmonary hypertension and open shunts may be prevalent. In these patients, N 2 0 is contraindicated, as increases in PVR may increase R-L shunting, causing arterial hypoxemia. Arrhythmogenicity All volatile agents sensitize the heart to catecholamines. The potential for dysrhythmias is greatest with halothane. The potential for dysrhythmias with all agents is greater with concomitantly administered drugs that also cause increased catecholamine release (i.e. Epinephrine, Ketamine, Pavulon, and Tricyclic antidepressant drugs). **Potency ranking related to arrhythmogenicity H >> I = D = S **Clinical Application** This is applied clinically when providing inhalation anesthesia, especially in pediatrics. The surgical site may be injected with local anesthetics containing Epinephrine. Guidelines for minimizing myocardial sensitization when administering a volatile agent concurrently include limiting the concentration of epinephrine to 1:100,000 or less, as well as the total dose of Epinephrine to the following: Halothane 1-2 ug/kg per 30 minutes All other volatile agent 4 ug/kg per 30 minutes Coronary Blood Flow All volatile agents increase coronary blood flow. **Potency ranking related to coronary blood flow I >> H > E > D = S **Coronary Steal Syndrome (Isoflurane)** This phenomena related to Isoflurane refers to the ability of this agent to cause a maldistribution of coronary blood flow from ischemic areas to non-ischemic areas of the heart. Isoflurane dilates smaller coronary vessels to a greater extent than other agents, leading to the stealing of blood away from areas that really need blood flow. (ischemic areas) *Clinical Application* In patients with known coronary artery disease, it is best to avoid using Isoflurane related to this syndrome. Desflurane and Sevoflurane are good choices in this type of patient. Bottom line: Most important to follow S-T segment trending and provide stable hemodynamics, as these are most indicative of coronary perfusion. 77

83 Respiratory System This section will compare the inhaled agents and their effect on breathing pattern, ventilatory response, airway resistance, and mucociliary function. Breathing Pattern All inhaled agents produce a dose-dependent increase in the frequency of breathing. This is a result of direct CNS stimulation or compensation for a decreased tidal volume. Isoflurane is self-limiting in that at a MAC > 1, respiratory rate does not increase. (mechanism unknown) All inhaled agents produce a dose-dependent decrease in tidal volume. Possibly a direct effect on the respiratory center ** Overall respiratory pattern for patients spontaneously breathing inhaled agents is a rapid, shallow breathing pattern. (This is opposite opioids) Ventilatory Response To Carbon Dioxide All volatile agents produce a dose-dependent increase in P a CO 2 and a decrease in the response to CO 2. It takes a higher CO 2 level to stimulate respirations. Nitrous Oxide elicits a Depressant-Sparing Effect Less depression of ventilation occurs with the volatile agents when they are combined with Nitrous Oxide as MAC requirements are decreased. (Fig 6-3) Fig 6-5: Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 1999, p.54.) Ventilatory Response to Hypoxemia All inhaled agents including nitrous oxide profoundly depress ventilatory response to hypoxemia 0.1 MAC = 50-70% depression 1.1 MAC = 100% depression ** It takes a PO 2 of < 30 mm Hg to drive ventilations under general anesthesia. 78

84 Airway Resistance All volatile agents produce a dose-dependent decrease in airway resistance. All volatile agents dilate bronchioles. Halothane is most potent. **Clinical Application** Status asthmaticus can be treated with high dose halothane administration. Bronchospasm can be treated with high dose volatile agent administration. Mucociliary Function All volatile agents decrease the rate of mucous clearance. Length of exposure and pre-existing factors such as smoking directly affect the rate of depression. Hepatic System The table below summarizes the major hepatic effects of the volatile agents. Agent Portal Vein Flow Hepatic Artery Flow Drug Clearance Liver Enzymes Halothane Slight Isoflurane No change No change Sevoflurane No change No change Desflurane No change No change Table 6-7: (Produced from information obtained in Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 1999, Chapter 2.) Hepatotoxicity Post-operative liver dysfunction has been associated with most volatile agents; however Halothane has been the most implicated. Halothane Hepatotoxicity Two forms of Halothane hepatotoxicity have been observed. Mild, self-limiting post-operative hepatotoxicity Nausea, lethargy, fever, minor increases in liver enzymes 20% incidence Most likely due to alterations in hepatic blood flow Halothane Hepatitis Massive hepatic necrosis 1:10-30,000 incidence Most likely immune-mediated 79

85 **National Halothane Hepatitis Study** This was a landmark study conducted in 1965 that examined over 850,000 anesthetics utilizing halothane. The conclusions of the study suggested that the development of hepatitis from Halothane exposure was related to pre-existing or induced conditions under anesthesia, NOT a direct drug effect. The conditions identified were: Administration of an FIO 2 of < 14% Prolonged hypotension Obesity Repeated exposure at short intervals Abnormal immune response **Clinical Application** Halothane is falling out of favor with the introduction of Sevoflurane. However, it is still a major inhalation agent in many institutions. As a result of the known effects that Halothane has on the liver, the following suggestions are provided when considering administering a halothane anesthetic. 1. Avoid use in patients with hepatic dysfunction or limited reserve 2. Provide an FIO 2 > 30% 3. Avoid prolonged hypotension Renal System All volatile agents produce a dose-dependent decrease in renal blood flow, glomerular filtration rate, and urine output. These are most likely secondary effects from decreased MAP and CO. Key point to remember is that renal autoregulation is not affected, so these effects are usually not of concern unless renal disease exists. **Fluoride-Induced Nephrotoxicity** Associated with Enflurane Large quantities of inorganic fluoride are produced in the presence of other enzyme inducers such as alcohol, Isoniazid, and Phenobarbital. Cytochrome P-450 liver induction results in nephrotoxic doses of fluoride. **Vinyl Halide Nephrotoxicity** Associated with Sevoflurane Reaction with soda lime produces Compound A (vinyl ether) Compound A accumulates in anesthesia breathing circuits with low flows, and has been shown to cause proximal renal tubular injury in rats. Recommendations: Minimum two-liter total fresh gas flow when administering agent for greater than 2 MAC hours. Skeletal Muscle Effects All volatile agents are direct muscle relaxants. All volatile agents illustrate a dose-dependent enhancement of neuromuscular blocking drugs. *Potency ranking (S = D = I = E >> H) ** N 2 0 does not relax skeletal muscle. 80

86 Malignant Hyperthermia (MH) All volatile agents trigger MH in genetically susceptible patients. *Potency ranking H >> I = D = S AVOID ALL VOLATILE AGENTS IN MH PATIENTS!! Current literature on N 2 O from MHAUS (Malignant Hyperthermia Association of the United States) states that it is safe to use in patients predisposed to MH. Obstetrical Effects All volatile agents produce a dose-dependent decrease in uterine smooth muscle tone and blood flow. These changes are greatest at doses exceeding 1 MAC. All readily cross the placenta **Clinical Application** 1. Uterine relaxation provided by volatile agents may be useful for extracting retained placental products or fetal head entrapment (frank breech presentation) during vaginal delivery. 2. Low dose volatile agent (0.5 MAC) with 50% nitrous oxide is commonly used to decrease the incidence of maternal awareness. After delivery, nitrous oxide can be increased to 70% and volatile agents can be decreased to allow for optimal uterine involution. High dose volatile agents can cause uterine atony following delivery. 81

87 CHAPTER 7 Intravenous Induction Agents There are four primary agents used in anesthesia today for the induction of anesthesia. These agents are typically referred to as barbiturate or nonbarbiturate induction agents. *Common Barbiturate Induction Agents* Sodium Thiopental *Common Non-Barbiturate Induction Agents* Propofol Etomidate Ketamine Barbiturates Any drug derived from barbituric acid. Sedative and hypnotic properties are determined by alterations in #2 and #5 carbon atom. (Fig 7-1) Oxybarbiturates retain oxygen on #2 carbon 1. Methohexital 2. Phenobarbital 3. Pentobarbital 4. Secobarbital Thiobarbiturates have sulfur on #2 carbon 1. Thiopental 2. Thiamylal We will dedicate the rest of this section specifically discussing sodium thiopental, as this is the most common barbiturate induction drug you will routinely use in anesthesia. 82

88 THE BARBITURATES Fig 7-1: (Morgan, E., Mikhail, M. & Murray, M. Clinical Anesthesiology. 2002, p. 157.) 83

89 Sodium Thiopental (Thiopental) Mechanism of Action Primarily through depression of the reticular activating system in the brainstem. Mechanism involves depression of acetylcholine (ACh) release and enhancement of gamma-aminobutyric acid (GABA) inhibitory effects. Basic Pharmacokinetic Highlights Protein Binding Highly protein bound to albumin (up to 86%) Distribution Highly lipid soluble with distribution to brain occurring in about 30 seconds. Rapid redistribution from the brain to other tissues accounts for rapid awakening after a single dose. ** With large or repeated dosing of Thiopental, cumulative effects can be seen, as the drug has a great affinity for fat related to its high lipid solubility. Therefore, the dose of thiopental is best calculated based upon ideal or calculated body weight. Metabolism Thiopental undergoes oxidative metabolism in the liver as well as extra hepatic sites such as the kidney and brain. (Note: Oxybarbiturates are metabolized in hepatocytes only.) Rate of metabolism is slow, with as much as 30% of drug remaining after 24 hours. This emphasizes its cumulative potential. Clearance Filtered by renal glomeruli Less than 1% of thiopental is recovered unchanged in the urine. This is related to the high degree of protein binding limiting filtration, and the high lipid solubility favoring reabsorption back into the circulation. Elimination and Volume of Distribution Large volume of distribution overall, and prolonged elimination half time in obese patients related to high lipid solubility. Clinical Applications Induction of anesthesia and the treatment of elevated ICP. Induction of Anesthesia Thiopental has been around since the 1930 s and has proven to be a safe, reliable induction drug over time. **Induction Dose = 3-6 mg/kg IV 84

90 Treatment of Elevated Intracranial Pressure Often used for induction of anesthesia in patients with ICP, as well as the treatment of ICP that is resistant to hyperventilation alone. (trauma patients) Thiopental s ability to protect the brain is related to its direct effects on cerebral dynamics. These effects include: 1. Drug induced cerebrovascular vasoconstriction. 2. This leads to cerebral blood flow. 3. Subsequent intracranial pressure. 4. Decreased cerebral metabolic oxygen consumption. Physiologic Effects Central Nervous System Decreases CBF, ICP, and CRMO 2 Protective effects on the brain Cardiovascular Mild, transient blood pressure reductions in normovolemic patients related to peripheral vasodilatation Compensatory tachycardia often seen (baroreceptor mediated) Ventilation Dose dependent depression of respiratory center Airway reflexes remain intact with smaller dosing May precipitate bronchospasm in patients with reactive airway disease Liver Sustained drug delivery (i.e. infusion over a few days) causes liver enzyme induction that may persist up to 30 days after discontinuation. Phenobarbital is the most potent liver enzyme inducer. Tolerance and Physical Dependence Acute tolerance occurs quickly, primarily related to liver induction. At maximal tolerance, the effective dose of thiopental may be increased 6X. Physical dependence easily occurs, and can lead to withdrawal symptoms if acutely withdrawn. Intra-arterial Injection (BAD!!!) Results in intense vasoconstriction and pain that can lead to tissue necrosis. **TREATMENT** 1. Immediate administration of saline into the artery 2. Drug administration in the affected area a. Lidocaine (most readily available) b. Papaverine c. Heparin 3. Stellate ganglion or brachial plexus block to relieve vasoconstriction. 85

91 Allergic Reactions Incidence is 1:30,000 and is associated more with patients who have chronic allergies and have received thiopental prior. Thiopental stimulates the release of histamine from mast cells. Acute Intermittent Porphyria (AIP) AIP represents a disorder of porphyrin enzyme metabolism, either in the liver or the bone marrow. Porphyrins are involved in heme production. All barbiturates can precipitate an attack of AIP, and must be avoided in patients with a history of this disorder. *Clinically, it may be observed that the urine turns black on standing. **Clinical Note** Thiopental precipitates with SCh and rocuronium, as well as with Lidocaine. Allow the IV line to flush thoroughly before giving either of these drugs after Thiopental. Ketamine (Ketalar) Phencyclidine derivative that is similar to PCP, which produces dissociative anesthesia. The patient may appear to be awake with a slow, nystagmus gaze. However, EEG evidence suggests the contrary, as their exists a dissociation between the thalamus and the limbic system. Mechanism of Action Ketamine elicits intense analgesia, even in small doses. Its mechanism of action is not clearly understood, but may involve depression of the medial thalamic nuclei, as well as opioid receptor binding. It also interacts with N-methyl-D-aspartate (NMDA) receptors and muscarinic receptors. Ketamine does not bind to GABA receptors. Basic Pharmacokinetic Highlights Protein Binding Not highly bound to protein (12%). Leaves the plasma quickly. Distribution Extremely lipid soluble (5-10 X more than Thiopental) with rapid transfer across the bloodbrain barrier. (BBB) Rapid redistribution from brain out of the central circulation to other tissues accounts for rapid awakening after a single dose. Metabolism Extensive metabolism in the liver (cytochrome P-450) Active metabolite - norketamine Clearance Renal clearance mechanisms. Less than 4% of this drug is recovered unchanged in urine. 86

92 Clinical Applications The primary clinical uses of Ketamine today include: Induction of anesthesia (patients who are hemodynamically unstable) Preoperative sedation (can be given IV or IM) Analgesia for painful procedures Induction of Anesthesia Effective IV and IM for the induction of anesthesia. Consciousness is lost in seconds after IV, and 2-4 minutes after IM administration. **Induction Dose = mg/kg IV 5-10 mg/kg IM Other Notable Characteristics of Ketamine Maintenance of normal or slightly depressed airway reflexes with unconsciousness Intense analgesic properties in small IV doses Increases intraocular pressure Causes nystagmus **Clinical Application** Ketamine can be effectively used in the operating room for short procedures of intense pain such as dressing changes, debridements, and lifting patients in severe pain to the O.R. bed. Often it is used to provide supplemental analgesia for breakthrough pain with regional anesthesia. Supports hemodynamics in the face of acute hypovolemia. Bronchodilating properties that is advantageous in asthmatic patients. No retrograde amnesia. Physiologic Effects Central Nervous System Potent cerebral vasodilator, causing increased cerebral blood flow 60%-80% during normocapnia, which can be attenuated with hyperventilation. Ketamine has relative contraindications for use in patients with ICP. Airway/Ventilation Ketamine does NOT produce significant depression of ventilation **This is one reason it is a great analgesic agent. Maintenance of protective reflexes. ** Induction doses still warrant an endotracheal tube for protection of the lungs. Increased airway secretions usually warrant administration of an antisialogogue. (Glycopyrrolate) Intense bronchodilating properties related to its sympathomimetic properties. 87

93 Cardiovascular Effects resemble SNS stimulation. Everything goes up!! MAP, HR, CO, and myocardial oxygen requirements all increase. The mechanism for Ketamine-induced CV effects may include direct SNS stimulation. **Clinical Note** These properties of Ketamine make it an ideal agent to select for induction of anesthesia in a hypovolemic patient. HOWEVER, it must be noted that the use of Ketamine in critically ill or shock-like patients has resulted in profound hypotension. This is presumed to occur as a result of catecholamine depletion, leading to unopposed direct myocardial depression by Ketamine. Emergence Delirium A phenomenon associated during the postoperative period in patients who have received Ketamine anesthesia. 1. Visual, auditory illusions 2. Confusion 3. Delirium **Remember, Ketamine is a phencyclidine derivative similar to PCP, so this phenomenon is not surprising. Incidence is 5-30% Dose-dependent occurrence at > 2mg/kg Prevention 1. Preoperative Midazolam administration 2. Avoidance of Atropine and Droperidol, as they have central properties that may be synergistic 3. Recovery in a quiet, calm environment Etomidate (Amidate) Etomidate is an carboxylated imidazole derivative, chemically unrelated to any other induction agent. The imidazole component allows this drug to be water soluble at an acidic ph, and lipid soluble at physiologic ph. (similar to Midazolam) Mechanism of Action The etiology of the CNS depression observed is thought to be similar to Thiopental, with enhancement of GABA inhibitory effects. Basic Pharmacokinetic Highlights Protein Binding Highly protein bound to albumin (76%) Distribution Moderate lipid solubility with rapid penetration to the brain occurring within a minute. Rapid redistribution from the brain to other tissues accounts for rapid awakening after a single dose. 88

94 Metabolism Rapid metabolism by hepatic microsomal enzymes and plasma esterases. Clearance More rapid than Thiopental (5X quicker) related to less lipid solubility and short elimination half life. Clinical Application The primary clinical use of Etomidate is for the induction of anesthesia. **Induction Dose = mg/kg IV Physiologic Effects Central Nervous System Potent direct cerebral vasoconstrictor, which decreases CBF and CRMO 2 by up to 45%. This is GREAT for patients with ICP. Etomidate may stimulate seizure foci, and therefore should be avoided in patients with focal epilepsy. Cardiovascular Cardiovascular stability is maintained. Minimal change in HR, SV, or CO. MAP may decrease 15% as a result of peripheral vascular resistance. Myocardial depression is less than with Thiopental. **Clinical Application** The CV properties of Etomidate make this drug a popular selection for induction in patients with cardiovascular disease, in elderly patients, and in patients with depleted catecholamines. Ventilation Depressant effects on ventilation are less than with Thiopental. Apnea will ensue with induction doses of this drug. Hiccups upon injection are common. Pain on Injection Frequent occurrence up to 85%. Related to the addition of propylene glycol into the solution. Remedies include injection into larger veins, and use of opioids prior to administration. **Clinical Comment** Pain on injection almost always occurs with this drug. It is described as excruciating at times. Please remember if you are using Etomidate to administer it in a large vein (large forearm or antecubital), through a large catheter (at least 18 gauge), at a quick pace (fluids wide open). This will help minimize this pain significantly. 89

95 Nausea/Vomiting Incidence is as high as 30-40% (compared with 10-20% for Thiopental) Myoclonus Etomidate causes involuntary muscle movements in about 30% of all patients. This activity resembles a seizure, but does not appear to have any effect on the EEG and is not considered harmful to the patient. Minimized by prior administration of Midazolam or an opioid. Adrenocortical Suppression Etomidate decreases plasma cortisol concentrations, and can occur after a single induction dose, lasting up to 8 hours. Etiology = inhibition of 11-beta-hydroxylase activity This is an undesirable effect in patients postoperatively, as it inhibits normal physiologic responses towards stress. **Clinical Relevance** The occurrence of suppression related to dosage and time is relatively unclear and is not a primary consideration in its administration. Exceptions to this may include patients who have had a prolonged, stressful hospital course, or who are being tapered from exogenous steroids. Propofol (Diprivan) Propofol is an isopropylphenol that is manufactured as a 1% emulsion consisting of soybean oil (10%), glycerol (2.25%), and egg lecithin (1.2%). It is a very popular agent that is used in a variety of ways in anesthesia. Mechanism of Action Propofol elicits its hypnotic and sedative effects by interacting with the inhibitory CNS neurotransmitter GABA. Basic Pharmacokinetic Highlights Protein Binding Extensively bound to protein. (98%) Distribution Plasma clearance exceeds hepatic blood flow, suggesting that tissue uptake (lungs?) and metabolism are of primary importance in removal of this drug. Rapid redistribution from brain to other tissues accounts for quick awakening after a single dose. Metabolism Rapid metabolism by the liver creates inactive, water-soluble metabolites. No evidence of impaired metabolism with liver dysfunction. 90

96 Clearance Rapid clearance, with 75% metabolite elimination in first 24 hours by the kidney. Less than 0.3% is excreted unchanged in urine. Cumulative effects are limited due to short elimination half time as well as high clearance rate. **Clinical Application** Propofol has become the induction agent of choice over the last several years. Its pharmacokinetic properties allow for a rapid, predictable awakening that has proven invaluable today. Major clinical applications of this drug include: 1. Induction of anesthesia. **Induction Dose = mg/kg IV 2. Intravenous sedation 3. Maintenance of anesthesia Propofol can be easily titrated, and offers a quick recovery related to its very short elimination half-life and predictable clearance. This is consistent even with prolonged infusions. Physiologic Effects Central Nervous System Propofol decreases CBF, ICP, and CRMO 2. Myoclonia may occur but is less often than with etomidate. Large doses may cause profound decreases in MAP, subsequently decreasing cerebral perfusion pressure. This is not a desirable outcome in patients with neurologic pathology. Cardiovascular Propofol decreases SBP, MAP, CO, and SVR greater than equipotent doses of thiopental. HR often remains unchanged, in contrast to thiopental. Mechanisms involved with these effects are related to the ability of propofol to suppress SNS stimulation. **Clinical Note** The direct suppression of SNS stimulation as discussed above has been related to several reports of bradycardia and asystole in healthy patients who received propofol for induction. (1:100,000 incidence) Lungs Dose-dependent depression of ventilation Decreased response to carbon dioxide and hypoxemia Bronchodilatory effects on the lungs Renal Prolonged infusions may cause green urine. (phenols) Cloudy urine may be observed related to increased excretion of uric acid and crystallization in the urine. Intraocular Pressure Significant decreases in IOP are observed. (unknown mechanism) 91

97 Allergic Reactions Propofol has allergic potential related to its phenyl nucleus and di-isopropyl side chain. Anaphylaxis has been reported. Generic propofol contains sodium metabisulfite, which is contraindicated in patients with sulfite sensitivity. Propofol contains egg lecithin, and may cause an allergic reaction in patients allergic to eggs. Bacterial Growth Propofol strongly supports bacterial growth!! External contamination of propofol has resulted in numerous incidences of post-operative infections, fever, and even sepsis. **Aseptic handling recommendations** 1. Disinfect vial or ampule neck with 70% alcohol. 2. Administer promptly into a sterile syringe. 3. Discard any unused portion within six hours. (revised package recommendations) Pain on Injection Very common occurrence, related to the thick, glycerol-based emulsion **Clinical Note** Propofol will burn in most patients upon administration. Remedies for this include utilization of a large forearm or antecubital vein and prior administration of 1% Lidocaine (or mixed with propofol). Also, administration of propofol through a large-bore catheter utilizing a carrier fluid running quickly will dilute the propofol as it enters the vein, causing less burning on injection. Antiemetic Effects The incidence of postoperative nausea and vomiting (PONV) is decreased with propofol administration regardless of the type of anesthetic. Nausea and vomiting in the PACU can be successfully treated with mg of propofol IV. Mechanism is possibly related to a direct effect on the vomiting center. **Clinical Application** Propofol is a logical choice in patients with a history of PONV, or for procedures where PONV is more likely to occur. (EENT, laparoscopy, GYN) Also, remember that if you use propofol to treat nausea in the PACU, repeated dosing or consideration of another antiemetic may be required based upon the very short elimination half-life of this drug. Antipruritic Effects Propofol can effectively treat opioid-induced pruritus in a dosage of 10 mg IV. Mechanism may be related to spinal cord suppression. **Clinical Note** When propofol is administered for opioid-induced pruritus, it does not seem to reverse the analgesic properties of the opioid. Clinically, this is a very desirable feature of propofol. Propofol may elicit disinhibitory effects in patients when given in incremental boluses or as a light background infusion, manifesting as agitation and disorientation. Deepening the propofol sedation or administering Midazolam IV concurrently may help minimize this effect. 92

98 Agent Generic Name Trade Name Common Intravenous Agents and Dosages Induction Dose (IV) mg/kg Induction Dose (IM) mg/kg Maintenance Dose (IV) ug/kg/min Thiopental Pentothal 3-6 NA NA Propofol Diprivan NA Sedative Dose (IV) mg/kg ug/kg/min Sedative Dose (IM) mg/kg Etomidate Amidate NA NA NA NA Ketamine Ketalar NA mg/kg Table 7-1: (Produced from information in Omoigui, S. Anesthesia Drug Handbook. 1999, p ) NA NA Intravenous Agents & Comparative Pharmacokinetic Properties Agent Elimination Half-Times (hrs) Volume of Distribution (liters/kg) 93 Clearance (cc/kg/min) Systemic Blood Pressure Heart Rate Propofol Thiopental Etomidate No change No change Ketamine Table 7-2: (Produced from information in Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 1999, p.117, 129.) Intravenous Agents & Comparative Neurophysiologic Effects Agent CRMO 2 CBF ICP Thiopental Propofol Etomidate Ketamine CRMO 2 = Cerebral Metabolic Oxygen Requirement CBF = Cerebral Blood Flow ICP = Intracranial Pressure Table 7-3: (Produced from information in Morgan, E., Mikhail, M. & Murray, M. Clinical Anesthesiology. 2002, Chapter 8.)

99 CHAPTER 8 Opioids Opiate describes any drug that is derived from opium, the juice of the poppy plant. One of the first drugs to be isolated in this fashion was Morphine (1803), and it still stands today as the prototype opioid by which all others are compared. Narcotic refers to a state of stupor, and typically refers to any drug that is similar to Morphine in eliciting this effect. Today, some of the most potent narcotics that are available are classified as either semisynthetic, referring to the fact that these drugs are produced from the modification of the morphine molecule, or synthetic, referring to complete synthesis of the drug as opposed to chemical modification of Morphine. Mechanism of Action These drugs bind to stereospecific opioid receptors in the CNS, altering pain modulation. (Table 8-1) Substances produced in the body called endogenous ligands which elicit a narcotic-like effect normally activate these receptors. Three endogenous opioid ligands include enkephalins, endorphins, and dynorphins. Opioids bind to these receptors, causing inhibition of neurotransmission. This effect is principally observed presynaptically, with the inhibition of the release of acetylcholine, dopamine, norepinephrine, and substance P. Opioid Receptors Several different receptors have been identified in the CNS. These include: Mu (with subtype Mu-1 and Mu-2) Kappa Delta Sigma Primary receptor sites include: Brain (periaqueductal gray of brainstem, amygdala, hypothalamus, corpus striatum). Spinal cord (substantia gelatinosa). 94

100 Major Effects Analgesia Spinal Supraspinal Euphoria Miosis Bradycardia Urinary Retention Endogenous Opioid Receptors Mu-1 Mu-2 Kappa Delta Sigma Spinal Dysphoria analgesia Ventilatory Depression Physical Dependence Constipation Analgesia Spinal Supraspinal Dysphoria Sedation Analgesia Spinal Supraspinal Ventilatory Depression Physical Dependence Urinary Retention Ventilatory Stimulation Hypertonia Tachycardia Agonists Endorphins Endorphins Dynorphins Enkephalins Ketamine?? Morphine Morphine Meperidine Antagonists Synthetic opioids Naloxone Naltrexone Nalmefene Synthetic opioids Naloxone Naltrexone Nalmefene Naloxone Naltrexone Nalmefene Naloxone Naltrexone Nalmefene Naloxone Naltrexone Nalmefene Table 8-1: (Produced from information in Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 1999, p.79 & Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 1991, p.72.) * *Note: The table above reflects the most important information that you need to know about these receptors. There are other effects that are not listed, as they are less important, and/or the exact receptor site eliciting the effect is still in clinical debate or not known. Neuraxial Opioids Placement of opioids (primarily Sufentanil and Fentanyl) into the epidural or subarachnoid space produces analgesic effects. Mechanisms of action include: Drug diffusion into the substantia gelatinosa of the spinal cord Systemic absorption Subarachnoid (Intrathecal) administration primarily elicits analgesia by diffusion into the substantia gelatinosa from the cerebral spinal fluid. Epidural administration primarily elicits analgesia by vascular absorption out of the epidural space via the epidural venous plexus. A very small fraction of the opioid will reach the spinal cord. 95

101 **Clinical Application** The comparative differences in analgesia between intrathecal and epidural routes of opioid administration are very obvious. Intrathecal administration results in prompt, reliable, potent analgesia. Epidural injection provides slower, less reliable, and weaker analgesia, which may not be any more advantageous than IV administration. Primary Side Effects (Neuraxial Opioids) Side effects are generally dose-dependent. The four classic side effects are: Pruritus Urinary Retention Ventilatory Depression Nausea and Vomiting Pruritus is the most common side effect observed. It can manifest immediately after injection, or several hours later. The mechanism of action is not well understood. Common treatment for pruritus includes the IM or IV administration of an opioid antagonist (Naloxone) or partial antagonist (Nalbuphine). **Clinical Note** Dosing varies dependent upon the severity and duration of symptoms. Consult package inserts for general recommendations for dosing. Urinary Retention is most likely caused by inhibition of parasympathetic nervous system outflow in the sacral spinal cord, resulting in relaxation of the detrusor muscle of the bladder. Nausea and Vomiting is most likely caused by a direct effect on the vomiting center. This can be treated with the IM or IV administration of an opioid antagonist or other known antiemetics. **Clinical Note** If you have a high degree of suspicion that existing nausea or vomiting is a result of neuraxial opioids, a higher degree of success in treatment usually occurs with the administration of an opioid antagonist, as opposed to other antiemetics. (Remember to treat the cause!!) Ventilatory Depression is the most serious side effect of neuraxial opioids, occurring in about 1% of patients receiving standard dosing regimens. Depression can be early (within two hours) or delayed (6-12 hours) after administration and primarily reflects interaction of the opioid with receptors found in the ventral medulla. **Ventilatory depression generally has not occurred with epidural or intrathecal administration after 24 hours. Factors increasing the risk of ventilatory depression include: High dose Concomitant IV opioid administration Advanced age Low lipid solubility Increased intrathoracic pressures Ventilatory depression can be successfully treated with IV or IM Naloxone, usually titrated to effect. 96

102 OPIOID AGONISTS We will look at the opioids most commonly used in anesthesia, which include Morphine, Hydromorphone, Meperidine, Fentanyl, Alfentanil, Sufentanil, and Remifentanil. Morphine Morphine is the prototype naturally occurring opioid by which all other opioids are compared. It is a phenanthrene alkaloid that elicits its effects at primarily Mu-1 and Mu-2 receptors. Major Pharmacokinetic Properties Usually administered IV to bypass unpredictable drug absorption Minimal absorption into the CNS related to: 1. Poor lipid solubility 2. High degree of protein binding 3. High degree of ionization at physiologic ph Primary metabolic pathway is conjugation in the liver. **Extrahepatic renal sites may account for a significant amount of metabolism as well. Elimination of Morphine may be impaired in patients with renal failure. Metabolites of Morphine are eliminated in the urine. 7-10% undergoes biliary excretion. Primary Clinical Uses of Morphine Perioperative analgesia via IV or IM administration Patient-controlled analgesia (PCA) pumps for postoperative pain Epidural administration as a bolus or continuous infusion (Preservative-free Duramorph) Intrathecal bolus administration. (Preservative-free Duramorph) Combined with local anesthetics for neuraxial anesthesia (Preservative-free Duramorph) Intraarticular injection for orthopedic procedures Hydromorphone (Dilaudid) Hydromorphone is a semisynthetic opioid agonist that elicits its analgesic effects primarily at Mu-1 and Mu-2 receptors. It was derived from morphine in the 1920s. Hydromorphone is approximately eight times more potent than Morphine at equipotent doses. Major Pharmacokinetic Properties Can be administered by oral, rectal and IV routes Shorter duration of action than morphine Primary metabolic pathway is conjugation in the liver. No Active Metabolites Renal elimination, principally as glucuronide conjugates Elimination of hydromorphone is NOT impaired in patients with renal failure. Primary Clinical Uses of Morphine Perioperative analgesia via IV administration, especially in patients with chronic pain or trauma Patient-controlled analgesia (PCA) pumps for postoperative pain Combined with local anesthetics for epidural anesthesia for postoperative pain management 97

103 Meperidine (Demerol) Meperidine is a phenylpiperidine-derivative synthetic opioid agonist that elicits its analgesic effects primarily at Mu-1, Mu-2 and kappa receptors. Meperidine is approximately one tenth as potent as Morphine at equipotent doses. Structure Meperidine is similar to atropine in structure, and therefore possesses some mild vagolytic properties. Major Pharmacokinetic Properties Meperidine has a slightly more rapid onset and shorter duration of action compared to Morphine. Meperidine is well absorbed from the GI tract (unlike Morphine), but is only about half as effective orally compared to the IM route. Metabolism is extensively hepatic (> 90%) and results in the formation of active normeperidine metabolites. Meperidine metabolites 1. Half as potent as parent compound 2. CNS stimulant 3. Prolonged elimination half-life (15 hours) may result in accumulation and toxicity with repeated dosing or patient-controlled infusions. 4. Toxicity manifests as myoclonus, seizures, and delirium. **Clinical Note** Meperidine is not commonly used as a continuous infusion for patient-controlled devices related to the above concerns regarding toxicity, as well as the fact that it is a weaker opioid. Primary Clinical Uses of Meperidine Analgesia in labor and delivery Postoperative pain management as bolus injection or continuous infusion Meperidine is effective in suppressing postoperative shivering by stimulating kappa opioid receptors. (postulated mechanism) Fentanyl (Sublimaze) Fentanyl is a phenylpiperidine-derivative synthetic opioid agonist that elicits its analgesic effects primarily at Mu-1 and Mu-2 receptors. Fentanyl is approximately times more potent than Morphine at equipotent doses. Major Pharmacokinetic Properties Fentanyl has a more rapid onset and shorter duration of action than morphine. Rapid onset is related to its greater lipid solubility than with morphine, which facilitates its passage across the blood: brain barrier. Short duration of action of a single, small to moderate dose represents rapid redistribution out of the central compartment, NOT metabolism. 98

104 **Significant first-pass pulmonary uptake** of about 75% of the initial dose Metabolism is primarily hepatic conjugation. Its elimination half-time is longer than morphine s, despite its short duration of action. This is because the lungs serve as a large, inactive reservoir for Fentanyl, and its volume of distribution (V d ) compared to Morphine is much larger. Primary renal excretion Primary Clinical Uses of Fentanyl Perioperative analgesia via IV bolus or continuous infusion Primary anesthetic agent in high doses for inductions in patients undergoing coronary bypass grafting Patient-controlled analgesia (PCA) pumps for postoperative pain Epidural administration as a bolus or continuous infusion Intrathecal bolus administration Combined with local anesthetics for neuraxial anesthesia Sufentanil (Sufenta) Sufentanil is a synthetic opioid agonist analogue of fentanyl that elicits its analgesic effects primarily at Mu-1 and Mu-2 receptors. Sufentanil is approximately five to ten times more potent than Fentanyl, or times more potent than Morphine at equipotent doses. It is the most potent opioid in clinical use today. Major Pharmacokinetic Properties Onset is rapid related to increased lipophilic properties. Extensive protein binding (92%), predominately to alpha 1 -acid glycoproteins, contributes to a smaller V d compared to Fentanyl. Small doses are quickly redistributed, resulting in a short duration of action. **Pulmonary first-pass uptake** is approximately 60%. Primary hepatic metabolism and urinary excretion. Elimination is somewhat quicker than Fentanyl, related primarily to its smaller V d. Primary Clinical Uses Perioperative analgesia via IV bolus or continuous infusion Epidural administration as a bolus or continuous infusion Intrathecal bolus administration Combined with local anesthetics for neuraxial anesthesia Alfentanil (Alfenta) Alfentanil is a synthetic opioid agonist analogue of fentanyl that elicits its analgesic effects primarily at Mu-1 and Mu-2 receptors. Alfentanil is approximately one fifth to one tenth as potent as Fentanyl at equipotent doses. Major Pharmacokinetic Properties More rapid onset than Fentanyl or Sufentanil with brain equilibration in approximately 90 seconds. This is related to a large non-ionized drug fraction (90%) at physiologic ph. Duration of action is one third that of Fentanyl related to its smaller V d. Primary hepatic metabolism and urinary excretion 99

105 Elimination is quicker than all other opioids, EXCEPT Remifentanil. All of the above results in a rapid onset and offset of intense analgesia. Primary Clinical Uses Perioperative analgesia via IV bolus or continuous infusion Popular for short procedures of intense stimulation, such as direct laryngoscopy, intubation, retrobulbar blocks, and cardioversions. Rarely used for postoperative pain management related to its short duration of action. Not commonly used in neuraxial analgesia Remifentanil (Ultiva) Remifentanil is a selective Mu-1 and Mu-2 agonist. Its analgesic effect is similar to Fentanyl, which is times more potent than Morphine at equipotent doses. Major Pharmacokinetic Properties The pharmacokinetic properties of Remifentanil are characteristically different than any other opioid. Rapid onset Smallest V d similar to Alfentanil Rapid metabolism 1. Uniquely metabolized by nonspecific plasma and tissue esterases **Clinical Note** Remifentanil does not appear to be metabolized by pseudocholinesterase; therefore its duration of action is not prolonged in the presence of cholinesterase deficiencies (i.e. Atypical Pseudocholinesterase). Quickest elimination half life of all opioids Largest clearance rate of all opioids Primary Clinical Uses The combination of a small V d, rapid metabolism and extraordinary clearance rate allows for ease of titration and predictable drug effects. The primary uses of Remifentanil clinically are related to these pharmacokinetic properties. Perioperative analgesia via IV bolus or continuous infusion Popular for short procedures of intense stimulation, such as direct laryngoscopy, intubation, and cardioversions. Intraoperative infusion for cases that require a quick, predictable wake-up with little drug effect (i.e. neuro procedures). **Clinical Application** Remifentanil requires an infusion when used for longer procedures, as the analgesic effects are very short. Infusions of this drug will reach a steady-state plasma concentration within approximately ten minutes. Remifentanil is NOT used for postoperative pain management. If significant postoperative pain is anticipated, a longer-acting opioid should be administered to ensure analgesia prior to cessation of the infusion. 100

106 Opioid Comparative Pharmacokinetic Properties of the Opioids Amount of Protein Binding V d % Nonionized Speed of Elimination Clearance Rate Morphine Meperidine Fentanyl Sufentanil Alfentanil Remifentanil Table 8-2: (Produced from information in Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 1999, p.83. & Nagelhout, J. J. Nurse Anesthesia. 2001, p. 161.) * *Note: The above table is a simplified comparative scale based upon known pharmacokinetic values. Context-Sensitive Half-Times A measure of the time required for a 50% drop in drug concentration after a variable length infusion - a new standard for comparison of the pharmacokinetic profiles of opioids. (See Chapter One for indepth explanation) Opioid Context-Sensitive Half-Times Fig 8-1: (Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 1999, p.94.) These curves are computer-simulated derivations comparing infusion duration to the time required for a 50% decrease in plasma opioid concentration. A comparison of these curves can provide valuable information regarding the pharmacokinetic properties of these drugs. For example, notice that Fentanyl s context-sensitive half-time significantly increases after about two hours compared to all other opioids. This can be attributed to fentanyl s large volume of distribution, and saturation of inactive tissue sites, such as the lung. In contrast, the context-sensitive half-time for Remifentanil is the same regardless of infusion time, owing to its small volume of distribution and quick metabolism by nonspecific plasma and tissue esterases. 101

107 Major Physiologic Effects of Opioids With a few exceptions, the major physiologic effects of opioids are very similar. The incidence of occurrence and degree of the effect may vary between drugs, and this will be delineated in the information below. Cardiovascular Morphine/Hydromorphone Reduces SNS tone to peripheral veins resulting in venodilatation, which can be profound at higher doses. This can lead to hypotension in a hypovolemic patient. Bradycardia may result from a direct depression of the SA node. Hypotension may result from venodilatation, as well as histamine-release. **Morphine does NOT sensitize the heart to catecholamines or cause direct depression of myocardial contractility. Meperidine Frequent orthostatic hypotension may occur related to inhibition of SNS reflexes. Only opioid with direct myocardial depressant effects. Tachycardia may result from the atropine-like properties of Meperidine. **Meperidine in combination with MAO-I s can produce excitation, convulsions, hyperthermia, and hypertensive crisis, possibly related to its vagolytic properties. Synthetic Opioids (Fentanyl, Sufentanil, Alfentanil, Remifentanil) Bradycardia may result from a direct depression of the SA node. This effect is more prominent than with morphine, and could result in decreased cardiac output and decreased blood pressure. Overall hemodynamic stability is observed. No histamine release, even in high doses DO NOT sensitize the heart to catecholamines or cause significant depression of myocardial contractility Neurological Meperidine Causes mydriasis. (All other opioids induce miosis.) May increase intracranial pressure (ICP) related to its tachycardic properties, which could lead to increased cerebral blood flow (CBF). CNS stimulant properties related to normeperidine metabolites. Heart Rate = CBF = ICP All Other Opioids Cause a dose-dependent miosis Slightly decrease or have no effect on CBF or ICP with normocarbia Opioids may increase CBF indirectly by causing a dose-dependent respiratory depression and hypercarbia, which leads to cerebral vasodilatation. **Clinical Note** All opioids are used cautiously in patients with altered intracranial pressure. If they are used in this scenario, close monitoring of P a CO 2 is required to ensure that hypercarbia does not result. 102

108 All opioids suppress the cough reflex by eliciting a direct effect on the medulla. All opioids cause nausea and vomiting by stimulating the chemoreceptor trigger zone in the area postrema of the medulla. Ventilatory All opioids cause a dose-dependent depression of ventilation. This is a Mu-2 effect that results in decreased responsiveness to carbon dioxide in the brainstem. o CO 2 ventilatory response curve is shifted downward and to the right. Results in RR with TV compensatorily. This is the exact opposite effect that volatile agents have on ventilation. Apnea will ensue in larger doses. **Synergistic depression is observed with concomitant delivery of benzodiazepines. Gastrointestinal Opioids can produce spasm of the GI smooth muscle resulting in: 1. Constipation 2. Biliary colic 3. Delayed gastric emptying related to decreased peristalsis **Clinical Application** Some patients who have been receiving opioids on the ward in the form of repeated dosing or infusions may be susceptible to regurgitation and aspiration of gastric content. Consider rapid sequence inductions in this type of patient. Opioids can cause spasm of the biliary smooth muscle, leading to contraction of the Sphincter of Oddi, located at the junction of the common bile duct and the duodenum. This can cause intense pain similar to angina, which can be relieved with Naloxone. **Clinical Application** Sphincter of Oddi pain can also be relieved with nitroglycerin, so it is important to try to make the distinction between chest pain related to the heart versus contraction of the Sphincter of Oddi. Chest pain related to the heart is not relieved with Naloxone. **Clinical Relevance** During an intraoperative cholangiogram for common bile duct exploration, intraoperative opioids may cause spasm of the Sphincter of Oddi, causing interference with this procedure. It may be necessary to reverse this effect with Naloxone ( ug increments titrated to effect) or Glucagon (2 mg IV). Genitourinary Intravenously administered opioids can produce urinary urgency by causing an increase in detrusor muscle tone. (opposite effect of neuraxial opioids) Concurrently there is also an increase in tone of the bladder sphincter, making voiding difficult. Cutaneous Morphine and Hydromorphone cause histamine release, which leads to dilation of cutaneous blood vessels. This leads to flushing of the face, neck and chest, as well as itching and redness usually around the injection site. Other opioids can cause itching, but the mechanism is not well understood. It does NOT appear to be related to histamine release, however. 103

109 Other Notables: All opioids cross the placenta and can lead to neonatal depression. **Clinical Note** There is some evidence to suggest that the parturient that has had a prolonged labor and has received an epidural infusion accompanied by an opioid, may have lower APGAR scores as a result of placental transfer of opioids. (Not irrefutable, but something to consider) Opioids DO NOT trigger malignant hyperthermia. Opioids may induce chest wall rigidity in high doses ( mahogany chest ). This rigidity can be prevented or minimized with administration of a muscle relaxant. All opioids can cause tolerance and physical dependence with repeated dosing that is associated with withdrawal syndrome. **Clinical Application** Chronic pain patients may be prescribed opioids on a daily basis or wear a patch that administers a constant blood level of opioid. These patients may illustrate a tolerance to your opioids in the operating room, requiring larger doses to achieve the same therapeutic effect. OPIOID AGONIST-ANTAGONISTS Opioid agonist-antagonists bind to the various opioid receptors and produce a limited response (partial agonists) or no response (competitive antagonists). Advantages 1. Produce analgesia with minimal ventilatory depression 2. Low potential for physical dependence Disadvantages 1. Can antagonize the analgesic effects of other administered opioids 2. Ceiling effect on dosing Side Effects 1. Similar to opioids 2. Additionally, can cause dysphoria There are many opioid agonist-antagonists available today. Our discussion will be limited to Butorphanol and Nalbuphine, as these are most commonly used in anesthesia. Butorphanol (Stadol) Primary effects of this drug are summarized below. Butorphanol is three to seven times more potent than Morphine, and times more potent than Meperidine. Mu Receptor Low affinity, so unlikely to antagonize these effects. Kappa Receptor Moderate affinity, so analgesia is produced. Sigma Receptor Minimal, so dysphoria is unlikely. 104

110 Pharmacokinetic Properties Available only in the parenteral form. As a result, it is better suited for relief of acute pain. Onset of action is quick. (IV =1-5 min; IM = 10 min) Duration of action is approximately four hours. Elimination is primarily in the bile and to a lesser extent in the kidney. Clinical Use Primary use is as an analgesic for the parturient in early labor. **Clinical Note** Butorphanol is often administered to the parturient in the early stages of labor for pain relief. It must be remembered that the effectiveness of intrathecal or epidurally administered opioids in the presence of Butorphanol may be diminished or its respiratory depressant effects may be potentiated. Side Effects & Other Considerations Butorphanol is not commonly suited for the pain associated with surgery. Ventilatory depression is similar to Morphine in equipotent doses. Cardiovascular effects may include increased blood pressure and cardiac output. Use cautiously in the presence of ischemic heart disease. Drug crosses the placenta and can cause neonatal depression. Nalbuphine (Nubain) Nalbuphine is chemically related to Oxymorphone and Naloxone, and its analgesic potency is similar to Morphine. Mu receptor Moderate affinity, producing analgesia as well as reversal of ventilatory depression. Kappa receptor High affinity, results in sedative effects of this drug. Sigma receptor Moderate affinity, dysphoria can occur. Pharmacokinetic Properties Commonly injected IV, IM, or SQ. Onset of action is quick. (IV =2-3 min; IM/SQ <15 min) Duration of action is approximately 3-6 hours. Elimination is primarily hepatic. Clinical Use Commonly used in anesthesia to reverse ventilatory depression or pruritus associated with Morphine-like drugs (Mu-2 antagonist), while maintaining some analgesia (Kappa agonist). **Clinical Note** Nalbuphine can be used in the operating room as a first-line attempt to reverse opioid-induced respiratory depression while maintaining analgesia, in a dose of 5 mg IV increments. Greater than mg IV is usually associated with increased sedation, and an opioid antagonist (i.e. Naloxone) is indicated for persistent respiratory depression. Nalbuphine also can be used to reverse opioid-induced pruritus caused by systemic or neuraxial opioids. A common dose is 5 mg IV in conjunction with 10 mg IM. If pruritus persists, an opioid antagonist is indicated. 105

111 Side Effects & Other Considerations Nalbuphine is not commonly suited for the pain associated with surgery. Elicits a ceiling effect with ventilatory depression, as well as analgesia Sedation is the most common side effect. Stable cardiovascular profile Drug crosses the placenta and can cause neonatal depression. OPIOID ANTAGONISTS Naloxone (Narcan) A derivative of Oxymorphone, small structural changes convert this drug to a pure opioid antagonist. This drug has no agonist properties. Mu receptor High antagonistic affinity. Kappa receptor Moderate antagonistic affinity. Delta receptor Moderate antagonistic affinity. Pharmacokinetic Properties May be administered IV, IM, SQ, or endotracheal. Onset of action is quick (IV = 1-2 min; IM/SQ/ETT = 2-5 min). **Duration of action is short at minutes. Elimination is primarily hepatic. Clinical Use Reversal of respiratory depression intra-op or post-op. Reversal of pruritus associated with opioids. Reversal of intraoperative sphincter of Oddi spasm. DOSE = 1-4 UG/KG TITRATED TO DESIRED EFFECT. Side Effects and Other Considerations This drug reverses analgesia!! With slow titration ( ug increments), respiratory depression can be reversed while sparing analgesia. Nausea and vomiting can occur with larger doses or rapid administration. Short duration of action may require an infusion for sustained reversal. Cardiovascular stimulant 1. Naloxone presumably increases sympathetic outflow related to an increased perception of pain. 2. This can lead to tachycardia, hypertension, pulmonary edema, cardiac dysrhythmias, and myocardial infarction. 3. Use cautiously in patients with pre-existing heart disease. **Clinical Note** These side effects are commonly associated with larger doses and rapid administration of Naloxone. Pulmonary edema has been consistently reported in the literature, especially in young males who have had painful surgical procedures. TITRATE SLOWLY!!!! 106

112 Nalmefene (Revex) This drug is a pure opioid antagonist with potency similar to Naloxone. This drug has no agonist properties. Pharmacokinetic Properties May be administered IV, IM, or SQ. Duration of action is much longer than Naloxone at several hours when the full reversing dose is utilized. Clinical Uses Sustained reversal of unwanted opioid effects in the post-operative period. Reversal of the effects of intrathecal opioids. **Clinical Note** Nalmefene is used for reversal of unwanted opioid effects usually after Naloxone has been attempted. The use of this drug reduces the need for redosing and minimizes the risk of re-narcotization. Side Effects Similar to Naloxone. Precautions with analgesic reversal are the same as Naloxone. Acute pulmonary edema has been reported with this drug. Common Opioid Agonists and Antagonists Pure Agonists Mixed Agonists- Antagonists Pure Antagonists Meperidine (Demerol) Butorphanol (Stadol) Naloxone (Narcan) Morphine (Astromorph, Duramorph) Hydromorphone (Dilaudid) Fentanyl (Sublimaze) Nalbuphine (Nubain) Pentazocine (Talwin) Buprenorphine (Buprenex) Nalmefene (Revex) Naltrexone (Trexan) (Oral only) Sufentanil (Sufenta) Nalorphine (Nalline) Alfentanil (Alfenta) Remifentanil (Ultiva) Table 8-3: (Partially reproduced from information in Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 1999, p.78.) 107

113 Potency Ranking of Common Opioids Meperidine (Demerol) 0.1 Morphine (Astromorph, Duramorph) 1 Nalbuphine (Nubain) 1 Butorphanol (Stadol) 3-7 Hydromorphone (Dilaudid) 8 Table 8-4 * Alfentanil (Alfenta) 10 Fentanyl (Sublimaze) Remifentanil (Ultiva) 100 Sufentanil (Sufenta) 1000 *The table above reflects relative potencies of commonly used opioids relative to Morphine, which is given a potency of one. For instance, Fentanyl has a potency of 100, which means it is 100 times more potent than Morphine. Meperidine is one tenth as potent as Morphine, etc. Common Neuraxial Opioid Dosing Opioid Epidural Dose Intrathecal Dose Fentanyl Sufentanil Duramorph Hydromorphone Dilaudid Meperidine Bolus: 1-2 ug/kg ( ug) Infusion: ug/kg/hr (25-60 ug/hr) Bolus: ug/kg (10-50 ug) Infusion: ug/kg/hr (5-30 ug/hr) Bolus: ug/kg (2-5 mg) Infusion: 2-20 ug/kg/hr (0.1-1 mg/hr) Bolus: ug/kg (1-2 mg) Infusion: ug/kg/hr ( mg/hr) Bolus: 1-2 mg/kg (25-50 mg) Infusion: mg/kg/hr (5-20 mg/hr) Bolus: ug/kg (5-20 ug) Bolus: ug/kg (1-10 ug) Bolus: 4-20 ug/kg (0.1-1 mg) Bolus: 2-4 ug/kg ( mg) Bolus: mg/kg (10-50 mg) *Table 8-5: (Produced from information in Omoigui, S. Anesthesia Drug Handbook. 1999, p ) * Please note that bolus injections of opioids into the epidural space should be diluted with 10cc of preservative-free normal saline or local anesthetic. 108

114 Agent Meperidine Morphine Hydromorphone Common Intravenous Opioid Dosing Regimens Induction Dose Maintenance Infusion Fentanyl 5-40 ug/kg ug/kg/min Alfentanil ug/kg ug/kg/min Sufentanil 2-10 ug/kg ug/kg/min Remifentanil ug/kg/min ug/kg/min Postoperative Dose mg/kg mg/kg mg/kg Table 8-6: (Produced from information in Omoigui, S. Anesthesia Drug Handbook. 1999, p & GlaxoWellcome package insert for Remifentanil, 2001) 109

115 CHAPTER 9 Benzodiazepines There are many benzodiazepines (BNZ) in clinical use today. Their use in anesthesia has been popularized by the many desirable characteristics that these drugs possess. Favorable pharmacologic characteristics include: 1. Production of amnesia 2. Minimal cardiovascular or respiratory depression 3. Anticonvulsant properties 4. Skeletal muscle relaxant (centrally) 5. Anxiolysis and sedation Commonly used BNZ are listed in the table below. Table 9-1 Generic Name Diazepam Midazolam Lorazepam Chlordiazepoxide Clonazepam Flurazepam Temazepam Triazolam Trade Name Valium Versed Ativan Librium Klonopin Dalmane Restoril Halcion Of these, Diazepam, Midazolam, and Lorazepam are the most commonly used in anesthesia. By far, Midazolam is the most commonly administered of the BNZ in anesthesia, and will be the primary focus of most of this chapter. Mechanism of Action All pharmacologic effects of BNZ are primarily a result of their effect on the central inhibitory neurotransmitter, GABA. Specifically, BNZ bind to the alpha subunits of this receptor, increasing chloride conductance. This causes hyperpolarization of the membrane, increasing nerve resistance to stimulation. 110

116 Chloride Channel Fig. 9-1 (Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 1999, p. 127.) Fig. 9-2 (Richter, JJ. Anesthesiology, 1981; 54: 66-72) **The GABA A receptor is found predominately on postsynaptic nerve endings in the CNS. It contains specific binding sites for BNZ, barbiturates, as well as alcohol, which explains the synergistic effects that these drugs have when used in combination. 111

117 Midazolam (Versed) Midazolam is by far the most popular BNZ used in anesthesia today, replacing Diazepam almost exclusively in a variety of areas. It is critical to understand the characteristics of this drug and the potential benefits its pharmacologic properties can offer in anesthesia. Basic Structural Characteristics Water-soluble BNZ with an imidazole ring (like Etomidate) in its structure. ph-dependent ring-opening phenomena 1. Parenteral solution is very acidic (ph = 3.5), causing imidazole ring to stay open, enhancing water-soluble characteristics. 2. Upon injection, drug is exposed to physiologic ph (7.4), and the imidazole ring closes, enhancing lipid solubility. The ring will close at a ph of > Enhanced lipid solubility increases GABA binding, eliciting a therapeutic effect. FAT SOLUBLE WATER SOLUBLE Fig. 9-3: (Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 1999, p.128 with modification.) Pharmacokinetic Highlights This drug does not burn on injection, as it is water soluble in the bottle. This is a very nice benefit. Midazolam can be administered PO, IV, IM, rectally, or intranasally. Rapid absorption from the gut, with > 50% first-pass hepatic extraction. **Clinical Application** Midazolam is commonly administered to children as a sedative preoperatively. Large oral dosing regimens of mg/kg are utilized to counter the large first-pass hepatic extraction of this drug. Intranasal administration is very painful. Highly protein bound (94-98%) Shortest duration of action of all BNZ, due to rapid redistribution, hepatic metabolism and renal clearance. 112

118 **Advantages over Diazepam** 1. More rapid onset 2. Shorter duration of action 3. Greater amnestic properties 4. Potency is 3-4X greater Organ System Effects Central Nervous System Potent anticonvulsant, effective for treating status epilepticus. Decreases CBF, CRMO 2, and ICP. Midazolam is acceptable for use as in induction drug in patients with intracranial pathology. Thiopental is more effective however in its cerebral protective mechanisms. **Amnestic properties** 1. Strong anterograde amnestic agent, causing the inability to recall events after administration of the drug. This is a desired effect. 2. Weak and unreliable retrograde amnestic agent, causing the inability to recall events that occurred prior to drug administration. This is a side effect. Ventilation Midazolam, like all BNZ, elicits a dose-dependent decrease in ventilation, especially with IV administration. Ventilatory depression is increased with IV opioid administration. OPIOIDS AND BNZ ARE HIGHLY SYNERGISTIC!!! Cardiovascular Dose-dependent decrease in blood pressure and increase in heart rate due to decrease in SVR. No change in cardiac output; no myocardial depressant effects. Possible vagally-mediated bradycardia. **Clinical Application** Be very mindful of the potential vagotonic properties of this drug, especially when used in combination with regional anesthesia. Severe bradycardia and asystole can occur I have seen it with my own eyes twice!! Overall, hemodynamic stability is good in the normovolemic patient, probably related to the central as opposed to peripheral mechanism of action. Clinical Uses of Midazolam Most common preoperative sedative in adults and pediatrics Intravenous sedation alone or in combination with other sedatives Induction of anesthesia Maintenance of anesthesia, as a component of a balanced technique Prophylactic administration to raise the seizure threshold when performing regional anesthetic blocks that utilize large mg doses of local anesthetics (i.e. axillary, epidural blocks) 113

119 Side Effects and Other Considerations Midazolam, like all BNZ, has no analgesic properties. Patients with COPD are very sensitive to the respiratory depressant effects. Reduce dosage with: 1. Concomitantly administered opioids, or alcohol ingestion 2. Elderly 3. Hypovolemia 4. COPD Flumazenil antagonizes all adverse effects. Diazepam (Valium) Diazepam is the prototype BNZ by which all others are compared. Its utilization in anesthesia has diminished over the years with the advent of Midazolam. However, it still has many useful properties as well as distinguishing characteristics that set it apart from Midazolam. These should be well understood by the anesthesia provider. Pharmacokinetic Highlights Administered IV, IM, PO, and rectal Unreliable absorption after oral and IM administration Diazepam burns on injection, (IV and IM) as it is dissolved in propylene glycol and sodium benzoate because it is insoluble in water. Cloudiness will occur when diluted with water, but potency is not altered. Diazac is emulsified Diazepam available in parenteral form, and is associated with a much lower incidence of phlebitis. Highly protein-bound to albumin. (96-98%) Metabolism in the liver produces active metabolites (desmethyldiazepam primarily, as well as oxazepam) that are only slightly less potent than Diazepam. This contributes to a prolonged sedative effect (6-8 hours). **Cimetidine delays the hepatic clearance of Diazepam, prolonging its elimination. This occurs as a result of cimetidine-induced inhibition of hepatic microsomal enzymes necessary for its breakdown in the liver. Diazepam has the longest elimination half time of all BNZ, related to its high V D and active desmethyldiazepam metabolite. Overall Organ System Effects Ventilatory effects are similar to Midazolam and are dose-dependent. Minimal cardiovascular effects. No changes in SVR. Diazepam decreases skeletal muscle tone through a centrally mediated process at the spinal cord. This is NOT a direct effect at the NMJ. Clinical Uses of Diazepam Oral administration as a preoperative sedative Treatment of local anesthetic-induced seizures Management of delirium tremens Chronic/acute management of muscular pain/spasm 114

120 Side Effects and Other Considerations Similar to Midazolam No analgesic properties Sedative and circulatory depressant effects are potentiated by opioids. Use of larger veins for injection will help reduce burning. Antagonized by Flumazenil Lorazepam (Ativan) Lorazepam resembles oxazepam (the pharmacologically active metabolite of Diazepam) in structure. It is less commonly used in anesthesia, as it has a slower onset of action and prolonged duration of action compared with other BNZ. Other notable characteristics of Lorazepam include the following: Insoluble in water, requiring an organic solvent for dilution. Burning does occur on injection, but less so than with Diazepam. Administered IV, IM, or PO, with reliable absorption pattern Inactive metabolites Minimal depressant effects on ventilation or circulation **Intra-arterial injection can lead to gangrene (similar to Thiopental). Treatment includes local infiltration with Phentolamine 5-10 mg in 10cc NS and possibly sympathetic block. Antagonized by Flumazenil Clinical Uses of Lorazepam Oral administration for preoperative sedation in longer cases where prolonged anterograde amnesia is desirable. Treatment of emergence delirium associated with Ketamine. Fairly limited use in anesthesia overall compared to Midazolam or Diazepam. BENZODIAZEPINE ANTAGONISTS Flumazenil (Romazicon) Flumazenil is the only BNZ antagonist in clinical use today in anesthesia. It is frequently utilized to reverse agonist affects associated with BNZ administration. Lets take a look at how it achieves this reversal. Mechanism of Action Flumazenil is a specific BNZ antagonist, with a very high affinity for the GABA/BNZ receptor complex only. Some important points to remember are: Antagonism is a competitive process. This means that it competes with the BNZ to competitively remove it from the receptor complex. In this regard, the antagonism is dose-dependent. Flumazenil does NOT reverse the effects of other drugs that work at the GABA receptor. 115

121 Effects that can be effectively reversed with Flumazenil include: 1. Sedation 2. Respiratory depression 3. Amnesia 4. Psychomotor effects Pharmacokinetic Highlights Quick onset, occurring in 1-2 minutes IV. Duration is approximately minutes, and is dependent upon plasma BNZ concentration at the time of reversal, as well as the total dose of reversal administered. **Supplemental dosing may be needed in lieu of the unpredictable duration of action. Overall Organ System Effects Neurological No direct effect on CBF. However, this drug may reverse the lowering effects of Midazolam on CBF, CRMO 2, and ICP. Respiratory No adverse effects. Cardiovascular No adverse effects on the heart, or hemodynamics (unlike Naloxone). Clinical Uses of Flumazenil Reversal of undesirable BNZ agonist effects, especially increased sedation and respiratory depression caused by Midazolam. Dose should be titrated to effect to achieve the desired result. (Table 9-2) Side Effects and Other Considerations The duration of action of the BNZ may exceed that of Flumazenil. Patients should be monitored for up to two hours for residual BNZ effects. Neuromuscular paralysis should be fully reversed before administering Flumazenil. Seizures and status epilepticus may develop in high-risk populations. Use with caution in the following scenarios: 1. Concurrent sedative-hypnotic drug withdrawal 2. Recent treatment with repeated BNZ dosing 3. Tricyclic antidepressant poisoning Intravenous Dosing Of Flumazenil Bolus Max Single Dose Max Total Hourly Dose Infusion mg * (4-20 ug/kg) 1 mg 3 mg ug/min (0.5-1 ug/kg/min) * 0.2mg/min maximum as a bolus injection. Table 9-2: (Produced from information in Donnelly, A.J., Cunningham, F.E. & Baughman, V.L. Anesthesiology and Critical Care Drug Handbook. 2000, p ) **Clinical Note** Lack of patient response after cumulative dosing of 5 mg suggests that the major cause of adverse clinical effects is unlikely to be related to BNZ. 116

122 Comparative Pharmacokinetics of Benzodiazepines Agent Potency Rating Protein Binding (%) Elimination Half Life (hrs) Clearance (ml/kg/min) Diazepam Midazolam Lorazepam Table 9-3: (Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 1999, p. 129.) Common Midazolam Dosing Regimens Premed Bolus for Conscious Sedation Infusion for Conscious Sedation Induction IV Adult 1-5 mg Titrate to effect mg ( mg/kg) 1-15 mg/hr ( ug/kg/hr) ug/kg IM mg ( mg/kg) PO mg ** (0.5-1 mg/kg) Intranasal mg/kg Rectal mg diluted in 5cc NS ( mg/kg) Table 9-4: (Produced from information in Donnelly, A.J., Cunningham, F.E. & Baughman, V.L. Anesthesiology and Critical Care Drug Handbook. 2000, p ) ** When administering Midazolam by the oral route, use the concentrated form (5mg/cc) and dilute in 3-5 cc of apple juice or tylenol elixir. It is very bitter!! Smaller volumes may be easier to administer to a noncompliant toddler. 117

123 Chapter 10 Neuromuscular Blocking Drugs Neuromuscular blocking drugs have only been used clinically in anesthesia since the early 1940 s, when d-tubocurarine (Curare) was used to provide muscle relaxation for general anesthesia. Since this time, many neuromuscular blockers (NMB) have been developed for clinical use in anesthesia, becoming commonplace in their administration for a variety of general anesthetics. Neuromuscular blockers are also known as muscle relaxants, and are generally categorized according to duration of action or mechanism of action. When described according to duration of action, they are referred to as ultra-short acting, short acting, intermediate acting, and long acting. When described by mechanism of action, they are referred to as depolarizing or nondepolarizing agents. Further delineation can be made with the nondepolarizing agents, as they are further categorized according to structure as either benzyl isoquinoline or aminosteroid compounds. (See Table 10-1 below) Classification of Neuromuscular Blocking Drugs AGENT Succinylcholine (Anectine, Quelicin) Pancuronium (Pavulon) Pipecuronium (Arduan) Vecuronium (Norcuron) Rocuronium (Zemuron) Depolarizers Nondepolarizers STEROIDAL BENZYL ISOQUINOLINE d-tubocurarine (Curare) Doxacurium (Nuromax) Atracurium (Tracrium) Cisatracurium (Nimbex) Mivacurium (Mivacron) DURATION Ultra-short Long Long Intermediate Intermediate Long Long Intermediate Intermediate Short Table 10-1: (Partially reproduced from Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 1999, p. 183.) In Table 10-1, notice that all of the steroidal compounds end in onium. This is a good way to remember which agent goes into which structural group. Physical Structure All neuromuscular blockers are quaternary ammonium compounds that are highly charged and water-soluble. As a result, these drugs do not cross lipid bilayers such as the blood:brain barrier or the placenta. 118

124 DEPOLARIZING NEUROMUSCULAR BLOCKERS Succinylcholine (Anectine) Succinylcholine (SCh) is the only depolarizing agent in clinical use today. No other muscle relaxant has been manufactured that compares as favorably to SCh in onset and duration of action, with a manageable side-effect profile. Mechanism of Action SCh looks like acetylcholine (ACh) in structure. As a matter of fact, SCh is actually two ACh molecules joined together. Fig (Morgan, E., Mikhail, M. & Murray, M. Clinical Anesthesiology. 2002, p.184.) As a result of its structural similarity to ACh, SCh is able to mimic ACh at nicotinic receptors. It binds to the alpha subunits of the ACh receptor, causing depolarization of the postjunctional membrane. SCh, unlike ACh, is not metabolized by acetylcholinesterase (AChE) at the neuromuscular junction (NMJ). As a result, it continues to bind to the alpha subunits of the ACh receptor, rendering the site inactive to subsequence ACh release. This sustained depolarization causes muscle paralysis. Both alpha subunits must be occupied by a SCh molecule for this to occur. Depolarizing muscle relaxants act as ACh receptor agonists. The depolarizing block is also referred to as a noncompetitive or Phase I block. [Depolarizing Agents = ACh Receptor Agonists = Noncompetitive Block = Phase I Block] Basic Pharmacokinetic Properties Quick onset related to its low lipid solubility Shortest duration of action of any muscle relaxant. Brief duration is due to rapid hydrolysis by plasma cholinesterase (pseudocholinesterase or butyrylcholinesterase) before reaching the NMJ. Only a small fraction of administered SCh will reach the NMJ and cause paralysis, as most is metabolized by plasma cholinesterase. Metabolized to succinylmonocholine, which maintains 1/20 th to 1/80 th the potency of SCh. This active metabolite is quickly broken down to succinic acid and choline by pseudocholinesterase. 119

125 Peripheral Nerve Stimulator Commonly utilized patterns of electrical stimulation applied clinically to assess depth of neuromuscular blockage include: Twitch A single pulse of msec in Hz. Train-of-Four A series of four twitches in two a 2 Hz frequency. Double Burst A series of two tetanic stimuli bursts: 3 at 50 Hz, then 2 at 50 Hz. Tetany A sustained stimulus of Hz lasting five seconds. Posttetanic Count A sustained stimulus of Hz lasting five seconds followed by a single 1 Hz twitch. Phase I Blockade Characteristics 1. Dose related decrease in twitch height 2. No fade to train of four 3. No fade to tetany 4. No post-tetanic potentiation 5. Fasciculations Normal 6. Augmentation of blockade with administration of an anticholinesterase agent Depolarizing **Clinical Relevance** SCh will be prolonged in the presence of an anticholinesterase agent such as Neostigmine. This is the result of inhibition of pseudocholinesterase. Clinically, this can be seen when SCh is administered after reversal of a nondepolarizing (NDP) block with Neostigmine. This may occur as a result of a post-extubation laryngospasm that requires the administration of SCh. If a full re-intubating dose of SCh is administered, it is likely that the duration of action of SCh will be prolonged extensively (up to 60 minutes in some cases) in this scenario. Phase 2 Blockade ( Conversion Block ) Characteristics of this block are similar to those seen when a NDP muscle relaxant is used. This block is caused by the administration of an excess dose of SCh (>4mg/kg) and results in a prolonged block. It is proposed that this conversion to a block that illustrates fade is a result of ionic and conformational changes that accompany prolonged muscle depolarization. Characteristics of a Phase 2 Block 1. Dose related decrease in twitch height 2. Fade to train of four 3. Fade to tetany 4. Some post-tetanic potentiation 5. **Antagonized by anticholinesterases** FADE Note: This block is caused by the administration of SCh, but unlike a Phase I block, it CAN be antagonized by Neostigmine. Important to remember this!! 120

126 Fig. 10-2: (Morgan, E., Mikhail, M., & Murray, M. Clinical Anesthesiology, 2002, p.182.) Major Side Effects and Clinical Considerations Cardiovascular SCh stimulates all ACh receptors, including preganglionic autonomic receptors. Unpredictable CV responses may include increased or decrease heart rate and blood pressure. The response elicited is very much dependent upon pre-existing factors as well as the autonomic tone of the patient. (See Figure 10-3) or HR & BP related to preganglionic autonomic stimulation. Succinylmonocholine stimulates cholinergic receptors in the SA node causing bradycardia. 1. Bradycardia is more common in children with the first dose. 2. Bradycardia is common in adults after the second dose. **Clinical Application** As a result of these CV effects, atropine IM or IV is often administered prophylactically with the first dose of SCh in children, and is always administered if a second dose is required. In adults, Atropine or Glycopyrrolate is usually given IV if a second dose of Succinylcholine is needed for intubation. Fasciculations The onset of SCh is often accompanied by visible motor unit contractions called fasciculations. This is caused by the sudden release of ACh, as the receptor depolarizes. Fasciculations are associated with a variety of physiologic responses to include: Increased intragastric, intracranial, and intraocular pressure Myalgias Hyperkalemia 121

127 Defasciculation Technique This phenomenon can be prevented or minimized by administering a small dose of a NDP muscle relaxant (usually 10% of the intubating dose) with presynaptic activity, 3-5 minutes prior to SCh. (Figure 10-3) CNS Autonomic Nervous System Somatic N.S. Parasympathetic N.S. Sympathetic N.S. ACh (SCh) ACh ACh (SCh) Skeletal Muscle Cholinergic Adrenergic ACh (SCh) Effector Organs NE ACh = Acetylcholine NE = Norepinephrine Effector Organs = smooth muscle, glands, cardiac tissue. 122

128 Mechanism of Action of Defasciculation Presumably the small dose of NDP is just enough to bind to some ACh alpha subunits to prevent a dramatic depolarization when SCh arrives. Hence, defasciculations are minimized. **Be aware that defasciculation may prolong the onset time of SCh, as now SCh has to find other receptors that are not bound by the prior dose of NDP. **Clinical Application** A slightly prolonged onset when defasciculation has occurred is usually not an issue, and increasing the initial dose of SCh can minimize this effect. There are many more benefits in defasciculating, as many of the adverse physiologic effects caused by fasciculations are avoided. Common defasciculating agents include Curare, Rocuronium, and Vecuronium. Of these, Curare is the most reliable, as it has the highest affinity for presynaptic ACh receptors. Neurological SCh is associated with increased CBF and ICP, primarily related to the fasciculatory effects of this drug rather than a direct effect. Attenuation of these effects can be accomplished by: 1. Prior hyperventilation 2. Lidocaine IV prior to intubation 3. Pretreatment with a NDP muscle relaxant Hyperkalemia SCh depolarization can result in the release of potassium enough to raise serum levels by 0.5 meq/l. Hyperkalemia resulting in cardiac arrest has been well documented in the literature. Major risk factors attributing to SCh-induced hyperkalemia include: 1. Underlying myopathies, (especially undiagnosed) such as Duchenne s muscular dystrophy. 2. Massive trauma (greatest risk > 72 hours from injury) 3. Burn injury (greatest risk > 24 hours from injury) 4. Denervation injuries (spinal cord) 5. Upper motor neuron disorders (Guillain-Barre ) 6. Prolonged immobilization Etiology of SCh-Induced Hyperkalemia In patients with crush or burn injuries, serum potassium levels are usually high as a result of significant muscle injury (rhabdomyolysis), which worsens with the administration of SCh. In patients with myopathies, denervation injuries, or prolonged immobilization where muscle atrophy has occurred, the mechanism of SCh-induced hyperkalemia is related to up-regulation of extrajunctional ACh receptors. This occurs as a compensatory mechanism related to lack of use of the muscle. The patient develops an increased density of receptors, which precipitates widespread depolarization and hyperkalemia. **Clinical Note** In patients with recent burn, denervation, or crush injuries, the window of safety for the administration of SCh is often debated clinically. As a guideline for these patients, a generally accepted time frame for safe administration of SCh is less than 24 hours from time of injury. 123

129 In children, many case reports have been documented in the literature of SCh-induced hyperkalemia leading to cardiac arrest and death, generally associated with undiagnosed myopathies. As a result it is now considered contraindicated to use SCh for routine management of children, typically less than ten years old. Extrajunctional Receptors Extrajunctional Receptors Fig. 10-4: (Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 1999, p.187 with modification.) Myalgias Muscle pain from SCh administration is most common in females and large, muscular men postoperatively. Defasciculation may help prevent this occurrence, but this is clinically inconsistent. When there are no contraindications to defasciculation, it is prudent to do so. Elevated Intragastric Pressure SCh causes abdominal wall fasciculations which intragastric pressure. SCh also causes in lower esophageal sphincter tone. **Clinical Note** The increase in intragastric pressure is offset by the increase in esophageal sphincter tone, and is also minimized by defasciculation. If cricoid pressure is also applied, patients are generally NOT at increased risk of aspiration when SCh is used. Elevated Intraocular Pressure (IOP) The striated muscle of the eye contains a high density of motor end-plates that will cause transient increases in IOP when depolarization occurs from SCh administration. SCh should be used with caution in patients with eye trauma. It is recommended to defasciculate prior to SCh administration in these patients to minimize the rise in IOP. There are no case reports in the literature of exacerbated eye injury from SCh administration when defasciculation was utilized. 124

130 Elevated Intracranial Pressure (ICP) SCh increases CBF and ICP (as stated previously) Attenuation of these effects can be accomplished by: 1. Prior hyperventilation 2. Lidocaine IV prior to intubation 3. Pretreatment with a NDP muscle relaxant Malignant Hyperthermia (MH) SUCCINYLCHOLINE IS A TRIGGERING AGENT FOR MH. SCh should be avoided in all patients with a history of MH. Masseter muscle rigidity following SCh administration may be an initial sign of MH. Inappropriate dosing of SCh can also result in insufficient relaxation of the masseter muscle. The distinction between the two must be made clinically, and often involves following the patient closely for further signs of MH, as well as converting the anesthesia to a nontriggering technique. Atypical Plasma Cholinesterase (Pseudocholinesterase) Involves a genetic defect in the production of plasma cholinesterase Incidence is approximately 1:3200 patients Results in prolonged duration of action of SCh, as well as other drugs that are metabolized by plasma cholinesterase, such as Mivacurium. **Clinical Application** Typically, the presence of atypical enzyme is not discovered until after the administration of SCh. When SCh is administered to an otherwise healthy patient and extended flaccid paralysis results, EXPECT ATYPICAL ENZYME. These patients may be paralyzed for three or more hours. These patients should have a plasma cholinesterase level drawn as well as a dibucaine panel. Dibucaine Number Dibucaine is an amide local anesthetic that inhibits the activity of normal plasma cholinesterase enzyme by approximately 80%. It is used to reflect the quality of plasma cholinesterase, NOT the quantity. (Refer to Table 10-2) Atypical Plasma Cholinesterase & The Dibucaine Number Genetic Variant Dibucaine Value Response to SCh Frequency None 80 Normal 96% Heterozygous Moderately Prolonged 1:480 Homozygous 20 Greatly Prolonged (6-8 hours) 1:3200 Table 10-2: (Partially reproduced from Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 1999, p. 192.) 125

131 Other Clinical Considerations: Use with caution in patients with low plasma cholinesterase levels. These patients will likely develop a prolonged paralysis. At risk patients include: 1. Severe liver disease 2. Burns 3. Cancer 4. Pregnancy 5. Patients receiving Neostigmine, Echothiophate, Cyclophosphamide ** Patients receiving Echothiophate eye drops should discontinue this drug four weeks prior to surgery. Advantages Succinylcholine Disadvantages Quick Onset Phase II Conversion Block Short Duration Bradycardia * Increased LES tone Increased Intracranial Pressure * Increased Intragastric Pressure * Increased Intraocular Pressure * Myalgias * Hyperkalemia Malignant Hyperthermia Atypical Pseudocholinesterase Organ-Dependent Metabolism and Excretion * Possibly prevented or minimized with defasciculation Table 10-3 Reversal of SCh Block SCh is NOT metabolized by acetylcholinesterase at the NMJ. SCh block reversal is the result of diffusion of SCh away from the NMJ, where it is metabolized quickly by pseudocholinesterase. Primary Clinical Use SCh is primarily used to provide relaxation of the vocal cords and pharyngeal/laryngeal musculature for intubation. Component of rapid sequence inductions Rapid securing of an emergency airway Suspected difficult airway ***REMEMBER, SCh HAS NO ANALGESIC, AMNESTIC, OR SEDATIVE PROPERTIES!! 126

132 NONDEPOLARIZING NEUROMUSCULAR BLOCKERS There are many NDP muscle relaxants in clinical use today (Refer to Table 10-1). Many of them have unique characteristics that the anesthesia provider must be aware of. The following section will focus primarily on the unique differences between these agents, and their clinical application in anesthesia. Mechanism of Action NDP muscle relaxants are incapable of inducing a conformational change in the ACh receptor, as their large structures to not resemble ACh (Refer to Figure 10-5). They are capable of competing with ACh for receptor sites, and will block ACh from causing an action potential. NDP are competitive antagonists to ACh. NDP prevent depolarization. NDP do not cause fasciculations [Nondepolarizing Agents =ACh Receptor Antagonists = Competitive Block] Structural Implications Steroidal Compounds = Vagolytic Properties, Cleaner Side-Effect Profile Benzyl isoquinolines = Histamine Release * Refer to Table 10-1 & Table

133 Chemical Structures of Neuromuscular Blockers Fig. 10-5: (Morgan, E., Mikhail, M., & Murray, M. Clinical Anesthesiology, 2002, p.184.) See how big they are???? 128

134 Nondepolarizing Block Characteristics FADE 1. Dose related decrease in twitch height 2. Fade to train of four 3. Fade to tetany 4. Post-tetanic potentiation 5. No fasciculations 6. Antagonism of blockade with administration of an anticholinesterase Fig. 10-6: (Morgan, E., Mikhail, M., & Murray, M. Clinical Anesthesiology, 2002, p.182 with modification.) Long-Acting Nondepolarizing Muscle Relaxants Pancuronium Bromide (Pavulon) Structure Steroid ring resembling ACh. Not similar enough to cause channel opening Elimination Limited metabolism in the liver Excretion is primarily renal (40%) and biliary (10%) 129

135 Side Effects & Clinical Concerns Block prolongation and slowed elimination can occur with renal failure. Modest blockade of cardiac muscarinic receptors give this drug atropine-like CV properties. Hypertension and tachycardia can occur, with a 10-15% increase in baseline HR, MAP, and CO. Use cautiously in presence of coronary artery disease, or any other pathology where tachycardia is unwanted. Potential for dysrhythmias related to increased release of catecholamines. USE CAUTIOUSLY IN THE PRESENCE OF TCA S AND HALOTHANE! Clinical Uses Skeletal muscle paralysis for surgical procedures of a long duration. Muscle relaxant of choice to offset the vagotonic properties of other drugs, such as opioids, or intrinsic baseline bradycardias. **Clinical Application** Often for longer procedures in patients with low resting heart rates, Pavulon will be chosen for its vagolytic properties. It is used in many cardiac inductions to offset opioid-induced bradycardia. Pavulon is also very cheap and maintains a long shelf life. (up to 18 months with refrigeration) **Ideal muscle relaxant for deployment. Doxacurium (Nuromax) Structure Benzyl isoquinoline compound Structurally similar to Mivacurium and Atracurium Elimination Primary route of elimination is renal Small amount of hydrolysis by plasma cholinesterase Side Effects and Clinical Concerns Use cautiously in presence of renal failure. Be prepared for ultra-long muscle paralysis up to 3 hrs. It is the longest acting muscle relaxant used clinically. Very clean CV profile Clinical Used Used when an extensively prolonged duration of muscle relaxation is desired without CV side effects. 130

136 Structure Steroidal compound similar to Pavulon Pipecuronium (Arduan) Elimination Elimination is dependent upon excretion, which is primarily renal (70%). Side Effects and Clinical Concerns Use cautiously in the presence of renal failure. Similar to Nuromax in its long duration of action devoid of major CV side effects. Clinical Use Used when a prolonged duration of muscle relaxation is desired without CV side effects. Duration is not as long as Nuromax. Intermediate-Acting Nondepolarizing Muscle Relaxants Atracurium (Tracrium) Structure Benzyl isoquinoline compound that possesses unique characteristics of degradation. Elimination Over 90% is metabolized in the body. Less than 10 % is excreted unchanged (biliary and renal). **Metabolism is independent of hepatic or renal function. Processes of metabolism: 1. Ester Hydrolysis by nonspecific esterases, NOT acetylcholinesterase or pseudocholinesterase. 2. Hofmann Elimination: Refers to spontaneous chemical breakdown at physiologic ph and temperature. (Non-enzymatic) Side Effects and Clinical Concerns Cardiovascular Triggers the release of histamine. Hypotension and tachycardia may result. Minimized by slow rate of injection, and dosage administration < 0.5mg/kg. Bronchospasm Induced by histamine release. Avoid in asthmatic patients. Laudanosine Toxicity Laudanosine is a metabolite of Atracurium (Atc) that can cause increased CNS excitation. Avoid in patients who are predisposed to seizure activity. 131

137 Temperature and ph Sensitivity Atc metabolism is dependent upon temperature and ph conditions. Marked prolonged drug effect may be seen in patients who are hypothermic or acidotic. Chemical Incompatibility Precipitates out of solution in an alkaline environment. Atc is incompatible with Thiopental and should not be mixed in the same IV line simultaneously. **Clinical Use** Atc is used in patients who are not predisposed to bronchospastic disorders where a moderate duration of muscle relaxation is required. Often used when hepatic or renal dysfunction is present. With the advent of Cis-Atracurium, the clinical use of Atc is declining due to its side effect profile. Cis-Atracurium (Nimbex) Structure Benzyl isoquinoline compound that is an isomer of Atc. Elimination Organ-independent Hofmann elimination, similar to Atc. Unlike Atc, it is NOT metabolized by nonspecific esterases. Side Effects and Clinical Concerns Laudanosine toxicity, chemical incompatibilities, and temperature/ph sensitivity are a concern, similar to Atc. (See p. 131) Unlike Atc, it does NOT cause the release of histamine, even in large doses. Clean side effect profile **Clinical Use** Muscle relaxant of choice for use in patients with hepatic or renal disorders. Generally selected over Atc for its clean side effect profile. Miscellaneous Requires refrigeration Must be used within 21 days when stored at room temperature Rocuronium Bromide (Zemuron) Structure Steroidal analogue of Vecuronium Structural changes provide a rapid onset of action Elimination No metabolism occurs with Rocuronium Excretion is primarily biliary (50%) and renal (30%). 132

138 Side Effects and Clinical Concerns Slight vagolytic properties may lead to unwanted tachycardia. Duration of action is prolonged with hepatic disease. Use cautiously and reduce dosage by at least 50%. Very stable side effect profile Quickest onset of action of all nondepolarizers Onset of action is similar to SCh in an intubating dose of mg/kg. **Clinical Use** Commonly used muscle relaxant to provide paralysis of intermediate duration. Suitable for rapid sequence inductions when SCh is contraindicated. **Remember, although onset is comparable to SCh in larger doses (3-4X ED 95 ), the duration of action is significantly longer. Miscellaneous Requires refrigeration Must be used within 30 days at room temperature Along with Vecuronium, it is the most popular NDP used today. Vecuronium Bromide (Norcuron) Structure Steroidal compound similar to Pavulon, but without a quaternary methyl group. This structural change alters the side effect profile immensely. Elimination Primarily excreted unchanged in the bile (40%) Secondary renal excretion of unchanged drug and metabolite (30%) Metabolized in the liver to a small extent Side Effects and Clinical Concerns No significant CV effects are seen, even at large doses Reduce dose in presence of liver disease **Clinical Use** Used when a moderate duration of muscle relaxation is desired without CV side effects. Infusion in the ICU for intubated and sedated patients. Miscellaneous Supplied as a powder that requires reconstitution. Stable for 24 hours after dilution. Discard after 24 hours. **Ideal muscle relaxant for deployment related to long shelf life in the powder form and stable side effect profile. 133

139 Short-Acting Nondepolarizing Muscle Relaxants Structure Benzyl isoquinoline compound Mivacurium (Mivacron) Elimination Mivacron, like SCh, is metabolized primarily by pseudocholinesterase. Minimal metabolism by acetylcholinesterase. Side Effects and Clinical Concerns Release of histamine is equivalent to Atc. Histamine release may result in decreased MAP and tachycardia. **Cardiovascular effects are minimized by a slow injection over one minute and an administered dose of <0.15 mg/kg. Duration of action is significantly prolonged in the presence of atypical pseudocholinesterase. Clinical Uses Used when muscle relaxation is needed for a short duration of action (i.e. tonsillectomy), and SCh is not desired, or is contraindicated. Duration of action is minutes. Miscellaneous Children may exhibit a faster onset and shorter duration of action. Mivacron has a shelf life of about 18 months at room temperature. RELATED CONCEPTS Priming Dose This is a technique utilized to speed the onset of nondepolarizing muscle relaxants. It involves the administration of 10-15% of the intubating dose 5 minutes prior to induction. Priming Dose = 10-15% of Intubating Dose of NDP = Defasciculating Dose Theory Enough receptors will be occupied that speed of onset will be increased significantly when the balance of the intubating dose is given. Clinically Speed of onset of short and intermediate acting NDP can be as little as seconds with the priming technique. Precautions The priming dose may cause dyspnea, dysphagia, or apnea in susceptible patients, including those with limited pulmonary reserve (i.e. severe COPD), or underlying neuromuscular dysfunction (i.e. myasthenia gravis). Use with caution in these patients or not at all!! 134

140 Major Factors Causing Altered Responses to NDP Muscle Relaxants Temperature Temp = Prolonged metabolism and excretion of NDP muscle relaxants. ** Recall that the metabolism of Atc and Cis-Atc is temperature dependent. Acid Base Balance ph = Prolonged blockade of NDP muscle relaxants. **Clinical Note** Hypoventilation in an emerging patient may prolong recovery from NDP drugs. ** Recall that the metabolism of Atc and Cis-Atc is also ph dependent. Electrolyte Abnormalities Augmentation of a NDP block is observed with the following abnormalities: 1. Hypokalemia 2. Hypocalcemia 3. Hypermagnesemia **Clinical Note** The duration of action of all muscle relaxants in pre-eclamptic patients treated with Mg +2 is often significantly prolonged. Usual doses should be decreased by about 50% in these patients. Age Neonates and infants illustrate sensitivity to NDP muscle relaxants, due primarily to an immature neuromuscular junction. **Clinical Note** This is the exact OPPOSITE for SCh, which usually requires about twice the dose in infants compared to adults. This is primarily related to the increased extracellular fluid volume in infants. Remember, SCh is highly water soluble, and redistributes into the extracellular space rapidly. Specific Drug Interactions There are many drugs that will alter the clinical response of muscle relaxants. The mechanism of action for many is not well understood, but can affect the NMJ prejuctionally, postjunctionally, or have a direct affect on the muscle fiber. 135

141 Drugs Altering Neuromuscular Blocking Response Drug Effect on SCh Effect on NDP Comments Antibiotics Aminoglycosides 1 Anticonvulsants Unknown Phenytoin, Carbamazepine Antidysrhythmics Quinidine, Calcium Channel Blockers, Lidocaine, Procainamide Antihypertensives Trimethaphan, Nitroglycerin Cholinesterase Inhibitors Neostigmine, Pyridostigmine, Edrophonium, Echothiophate Dantrolene Unknown Furosemide (Lasix) or or Dose dependent Smaller doses = Larger doses = Inhalation Agents S = D = I = E >> H 2 Local Anesthetics Lithium Unknown Prolongs onset and duration of SCh Magnesium Sulfate Pre-eclampsia and eclampsia 1 Includes Gentamicin, Amikacin, Kanamycin, Streptomycin, Tobramycin 2 Sevoflurane, Desflurane, Isoflurane, Enflurane, Halothane = Potentiates muscle relaxation = Antagonizes muscle relaxation Table 10-4: (Morgan, E., Mikhail, M., & Murray, M. Clinical Anesthesiology, 2002, p.185 with modification.) Concurrent Diseases or Physiologic States Many underlying neurological or muscular diseases have a profound effect on the clinical response of all muscle relaxants. Some of the major disease states and clinical effects are listed below. Disease States Causing Altered Responses to Muscle Relaxants Disease Response To SCh Response to NDP Amyotrophic Lateral Sclerosis Contracture Hypersensitivity (ALS) Autoimmune Disorders 1 Hypersensitivity Hypersensitivity Burn Injury Hyerkalemia Resistance Cerebral Palsy Slightly Sensitive Resistance Guillain-Barre Syndrome Hyperkalemia Hypersensitivity Hemiplegia Hyperkalemia Resistance Muscle Denervation Hyperkalemia and Contracture Normal or Slight Resistance Muscular Dystrophy Hyperkalemia and Malignant Hypersensitivity (Duchenne s) Hyperthermia Myasthenia Gravis Resistance Hypersensitivity Severe Chronic Infection Hyperkalemia Resistance 1 Systemic Lupus Erythematosus, Polymyositis 2 Tetanus, Botulism Table 10-5: (Morgan, E., Mikhail, M., & Murray, M. Clinical Anesthesiology, 2002, p.190 with modification.) 136

142 Assessment of Depth of Paralysis Paralysis caused by NDP muscle relaxants is characterized by the occurrence of fade to trainof-four (TOF), as well as sustained tetany. Fade describes a gradual diminished response during prolonged or repeated electrical stimulation. Fade is only associated with a NDP block. Fade to TOF is used clinically to assess the depth of paralysis. Number of TOF Twitches % Receptors Occupied % Receptors Free Of By Muscle Relaxant Muscle Relaxant 0 > < 75 > 25 Table 10-6 **Clinical Application** Dosing and reversal of NDP muscle relaxants relies on the correlation between number of TOF twitches and depth of paralysis. Reversal of a NDP block cannot successfully occur until at least one twitch returns in a TOF stimulation. Common Dosing Regimens For Muscle Relaxants Drug Dosage (mg/kg) Peak (Minutes) Succinylcholine Adult: 1 Neonates/Infants: 2-3 Children: 1-2 D-Tubocurare L (Curare) M Pancuronium L (Pavulon) M Pipecuronium L (Arduan) M Doxacurium L (Nuromax) M Atracurium L (Tracrium) M Vecuronium L (Norcuron) M Rocuronium L (Zemuron) M Cisatracurium L 0.2 (Nimbex) M 0.03 Mivacurium L (Mivacron) M L = Loading Dose M = Maintenance Dose Duration (Minutes) Table 10-7: (Produced from information in Omoigui, S. Anesthesia Drug Handbook, 1999, p ) 137

143 Reversal of Nondepolarizing Muscle Relaxants Clinically, NDP blocks are competitive blocks that often require reversal agents to terminate the muscle paralysis. Reversal agents used to antagonize NDP blocks are termed anticholinesterase agents. (Chapter 11). All NDP blocks will fatigue with time without a reversal agent if no other paralytic agents have been administered. Anticholinesterase agents are used clinically to hasten the reversal process. Drug Succinylcholine (Anectine) D-Tubocurare (Curare) Pancuronium (Pavulon) Pipecuronium (Arduan) Doxacurium (Nuromax) Atracurium (Tracrium) Vecuronium (Norcuron) Rocuronium (Zemuron) Cisatracurium (Nimbex) Mivacurium (Mivacron) Summary Table of Muscle Relaxant Properties Histamine Release Vagal Blockade Primary Elimination (Metabolism/Excretion) + + Plasma cholinesterase +++ None Renal excretion None ++ None None None None ++ None None None None + Primary renal excretion (40%) Primary renal excretion (70%) Some plasma hydrolysis Primary renal excretion Ester hydrolysis Hofmann Elimination Biliary excretion (40%) Renal excretion (30%) Some hepatic metabolism Biliary excretion (50%) Renal excretion (>30%) No metabolism occurs None None Hofmann Elimination ++ None Plasma cholinesterase + Mild Effect ++ Moderate Effect +++ Marked Effect Special Concerns MH Atypical Enzyme Bradycardia Hyperkalemia Asthma Best defasciculator Renal Failure Vagolytic TCA and Halothane Renal Failure Renal Failure Longest Acting MR Renal Failure Organ Independent Asthma Laudanosine Toxicity Hepatic Disease Powder form Hepatic Disease Shortest Onset Time Requires refrigeration Organ Independent Laudanosine Toxicity Requires refrigeration Asthma Atypical Enzyme Tachycardia, MAP Table 10-8: (Produced from information in Stoelting, R.K. (1999), Chapter 8 & Morgan, E., Mikhail, M., & Murray, M. Clinical Anesthesiology, 2002, Chapter 9.) ** Remember, all of the nondepolarizing blocking drugs are large, highly ionized quaternary ammonium compounds that are poorly lipid soluble. They do not cross the blood: brain barrier. 138

144 Chapter 11 Anticholinesterase Drugs Anticholinesterase drugs are a group of drugs primarily used in anesthesia to reverse muscle paralysis caused by nondepolarizing muscle relaxants. Review of Acetylcholine Receptors ACh is the primary neurotransmitter found throughout the entire central nervous system. The ACh receptor is divided into either the nicotinic or muscarinic receptor, based upon its reaction with either nicotine or muscarine. (Figure 11-1) Nicotinic Receptors All autonomic ganglia Skeletal muscle Muscarinic Receptors Glands Smooth Muscle Heart Nicotinic Nicotinic Muscarinic ACH (Sweat Glands) (Figure: 11-1) 139

145 Cholinergic Receptor Types Receptor Location Agonist Antagonist Nicotinic Muscarinic Sympathetic Autonomic Ganglia Parasympathetic Autonomic Ganglia Skeletal Muscle Lacrimal, Salivary, Gastric Glands (PNS) Sweat glands (SNS) Smooth Muscle Bronchial Gastrointestinal Bladder Blood Vessels Heart SA node AV node Nicotine Acetylcholine Muscarine Acetylcholine Nondepolarizers Anticholinergics Atropine Scopolamine Glycopyrrolate Table 11-1: (Morgan, E., Mikhail, M., & Murray, M. Clinical Anesthesiology, 2002, p.200 with modification.) Review of Cholinesterase Enzymes Acetylcholinesterase (AChE, True Cholinesterase) Produced in the membranes of RBC s and all cholinergic synapses in the central and peripheral nervous system. Enzyme responsible for the breakdown of acetylcholine (ACh). Butyrylcholinesterase (BuChE, Pseudocholinesterase, Plasma Cholinesterase) Produced in the liver Found in the liver, plasma, kidney, and intestine Enzyme responsible for hydrolysis of succinylcholine (SCh) Acetylcholine/Acetylcholinesterase Relationship Acetylcholinesterase (AChE) is responsible for the breakdown of acetylcholine (ACh) everywhere that this neurotransmitter is present. AChE consists of an anionic and esteratic site that compliments the ACh substrate in such a way that physical binding occurs through acetylation. This physical binding inactivates ACh. Acetylation of ACh substrate Fig: 11-2: (Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 1999, p.226.) AChE Anionic Site (Negative Charge) binds to the quaternary nitrogen of ACh. AChE Esteratic Site (Positive Charge) is oriented with the ester linkage of ACh. 140

146 KEY POINTS: 1. Propagation of an action potential depends on ACh binding to nicotinic cholinergic receptors at the NMJ. 2. Nondepolarizing muscle relaxants (NDP) compete with ACh for these binding sites, blocking transmission of an action potential. 3. Block reversal depends on diffusion, redistribution, metabolism, and excretion of the NDP relaxant. 4. We can pharmacologically reverse a nondepolarizing block by administering an anticholinesterase drug. Mechanism of Action of Anticholinesterase Drugs All anticholinesterase drugs inactivate AChE by physically binding to this enzyme. As a result, ACh builds up at the NMJ, competitively displacing the NDP muscle relaxant from the cholinergic receptor. Anticholinesterase drugs are classified according to the type of bond they establish with AChE. Types of Bonds: 1. Acetylation (REVERSIBLE binding of AChE to ACh, as described above) 2. Electrostatic Attachment (REVERSIBLE) 3. Carbamylation (REVERSIBLE) 4. Phosphorylation (IRREVERSIBLE) Clinically Used Anticholinesterase Agents: 1. Edrophonium (Tensilon) 2. Neostigmine (Prostigmine) 3. Pyridostigmine (Mestinon) 4. Physostigmine (Antilirium) Fig: 11-3: (Morgan, E., Mikhail, M., & Murray, M. Clinical Anesthesiology, 2002, p.203.) 141

147 Reversible Anticholinesterase Drugs All of the anticholinesterase drugs that we use clinically to reverse NDP muscle relaxants form reversible bonds with AChE. These would include Edrophonium, Neostigmine, Pyridostigmine, and Physostigmine. Edrophonium (Tensilon) Structure Large quaternary amine lacking a carbamyl group; poorly lipid soluble. Binding Characteristics Reversible bond Electrostatic attachment to the anionic component of AChE. Further stabilization by hydrogen binding at the esteratic site. (Fig. 11-3) Weak bond with quickest onset and shortest duration of effect. Edrophonium (Electrostatic Attachment) Fig: 11-4: (Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 1999, p.225.) Other Major Characteristics Least muscarinic side effects of all the anticholinesterase drugs. Primary site of action is presynaptic. Primary Clinical Uses Used in ER/ICU to differentiate between myasthenic and cholinergic crisis. It is preferred because of its quick onset and short duration. Quick reversal of shorter-acting NDP muscle relaxants. Evaluation of a Phase II block from SCh. **Clinical Note** Edrophonium is NOT recommended for reversal of intermediate and long-acting MR due to its short duration of action. (Short clinical effect) 142

148 Neostigmine (Prostigmine) Structure A dimethylcarbamate and large quaternary amine that is poorly lipid soluble. Binding Characteristics Reversible bond Formation of a carbamyl-ester complex at the esteratic site of AChE. Carbamyl-ester bond half-time is approximately minutes. Neostigmine (Carbamyl-Ester Complex) Fig: 11-5: (Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 1999, p. 225.) Other Major Characteristics Muscarinic side effects are prominent. Primary site of action is postsynaptic. Over 50% is excreted unchanged in urine. Use cautiously with renal failure. Primary Clinical Uses Used in conjunction with an anticholinergic for antagonism of a NDP block. **Clinical Note** Neostigmine is the most common anticholinesterase reversal agent used in the OR. Pyridostigmine (Mestinon) Structure A dimethylcarbamate, a large quaternary amine that is poorly lipid soluble. Binding Characteristics Reversible bond Formation of a carbamyl-ester complex at the esteratic site of AChE. Carbamyl-ester bond half-time is approximately minutes. 143

149 Pyridostigmine (Carbamyl-Ester Complex) Fig: 11-6: (Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 1999, p. 225.) Other Major Characteristics Muscarinic side effects are prominent, but less than Neostigmine. Primary site of action is postsynaptic. Duration of action is the longest of all anticholinesterases. Over 75% is excreted unchanged in urine. Use cautiously with renal failure. Primary Clinical Uses Used in conjunction with an anticholinergic for antagonism of a NDP block. Less commonly used than Neostigmine, as its onset of action is delayed. Physostigmine (Antilirium) Structure A monomethylcarbamate, a tertiary amine that is highly lipid soluble. Binding Characteristics Reversible bond Formation of a carbamyl-ester complex at the esteratic site of AChE. Carbamyl-ester bond half-time is approximately minutes. Physostigmine (Carbamyl-Ester Complex) Fig: 11-7: (Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 1999, p. 225.) Other Major Characteristics Only anticholinesterase that crosses the blood:brain barrier (BBB), as the quaternary amine is replaced by a smaller tertiary amine in structure. Primary site of action is postsynaptic. Penetration across the BBB increases central ACh levels. Peripheral muscarinic side effects are prominent. Poor choice for reversal of NDP blocks related to its central cholinergic effects. 144

150 Primary Clinical Uses Treatment of Central Anticholinergic Syndrome (See Chapter 12) caused by anticholinergic overdose. Less commonly used to reverse delirium and depression associated with BNZ s and volatile agents. Irreversible Anticholinesterase Drugs Organophosphates Structure Varies, but all are lipid soluble compounds that readily cross lipid membranes. Binding Characteristics Irreversible bond Formation of a phosphorylate complex at the esteratic site of AChE. **Can last for several weeks. ** Synthesis of new AChE enzyme is required for normal activity to resume. Echothiophate (Phosphorylate Complex) Fig: 11-8: (Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 1999, p. 225.) Other Major Characteristics Substances that establish a phosphorylated bond with AChE include: 1. Echothiophate eye drops 2. Certain insecticides (Parathion, Malathion) 3. Nerve agents (Soman, Saran, Tabum) **Clinical Note** Echothiophate is the only organophosphate AChE drug used clinically!! KNOW THIS!!!!!! Aside from synthesis of new enzyme, organophosphate compounds can be physically removed from AChE by administering reactivators such as Hydroxylamine, Pralidoxime, or Obidoxime. (See Chapter 13) 145

151 Major Pharmacokinetic Principles of Anticholinesterases Speed of onset varies with each agent. Edrophonium = Rapid Neostigmine = Intermediate Pyridostigmine = Delayed Duration of action ranges between minutes, with Edrophonium having the shortest duration relative to clinical effect, and Pyridostigmine having the longest. **Clinical Note** Various textbooks will state that the duration of action of Edrophonium is similar to Neostigmine. Clinically, the duration of action of Edrophonium is only 5-20 minutes compared to Neostigmine at minutes. (Omoigui, S., 1995) This is why Edrophonium is not a commonly used reversal agent in the O.R. Lipid solubility is affected by each agent s structural components. Physostigmine = Tertiary Amine = Highly Lipid Soluble = Crosses BBB Organophosphates = Highly Lipid Soluble = Cross BBB All Others = Quaternary Amine = Poorly Lipid Soluble = Can t Cross BBB Clearance of anticholinesterase agents relies heavily on the kidney (50-75%) Major Pharmacologic Effects of Anticholinesterases The pharmacologic effects of these drugs are predictable and reflect the accumulation of ACh at muscarinic and nicotinic cholinergic receptors. Sometimes the effects elicited are desirable. Most of the time in anesthesia the effects are not desirable, and attempts are made to minimize them in a variety of ways. Cardiovascular Accumulation of ACh at muscarinic receptors in the heart, blood vessels, autonomic ganglia, and postganglionic cholinergic nerve endings can result in: *Bradycardia (most common) Hypotension Dysrhythmias, Asystole Pulmonary Muscarinic stimulation can precipitate smooth muscle contraction in the lungs, causing bronchospasm, and increased respiratory tract secretions. Cerebral Physostigmine crosses the BBB and can precipitate extreme agitation and delirium from its effects on nicotinic and muscarinic receptor sites. 146

152 Gastrointestinal Stimulation of muscarinic receptors can result in: Esophageal, gastric, and intestinal peristalsis leading to nausea, vomiting, and incontinence. Excessive salivation from stimulation of glandular secretions. Genitourinary Bladder tone may result in incontinence. **Clinical Note** All of the above side effects in bold are characteristics of a patient who has nerve agent poisoning as well. Organ System Effects of Anticholinesterases Organ System Physiologic Effect Cardiovascular Bradycardia, Dysrhythmias Pulmonary Bronchospasm, Secretions Cerebral Excitation, Delirium * Gastrointestinal Nausea, Vomiting, Secretions Genitourinary Incontinence Eyes Constricted Skeletal Muscle Contraction, Fasciculations * Physostigmine only Table 11-2: (Produced from information in Morgan, E., Mikhail, M. & Murray, M. Clinical Anesthesiology. 2002, p. 202 and Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. Chapter 9.) Antagonism of Non-Depolarizing Neuromuscular Blocks Key Points: 1. In the O.R., NDP blocks are antagonized (reversed) by the administration of anticholinesterase drugs. 2. The antagonism occurs as a result of the physical binding of these drugs to AChE. 3. The result is accumulation of ACh at the neuromuscular junction. 4. The effect is competitive removal of the NDP muscle relaxant from the ACh receptor. This process results in unwanted clinical side effects that are primarily muscarinic in nature. In order to minimize these effects, anticholinesterase agents are given concurrently with anticholinergic (antimuscarinic) agents. 147

153 Mixing Anticholinergics With Anticholinesterase Drugs Key Points: 1. All anticholinesterase agents have different pharmacokinetic profiles related to onset and duration of action. 2. All anticholinergic agents have different pharmacokinetic profiles related to onset and duration of action. 3. The goal is to match the appropriate anticholinergic agent with the appropriate anticholinesterase agent to mirror the time course of muscarinic stimulation. 4. The result is antagonism of AChE and block reversal, with minimal muscarinic side effects. Commonly Used Anticholinergics For Block Reversal Atropine Glycopyrrolate The preferred anticholinergic to be used with each anticholinesterase drug is reflected in Table Remember that the recommended anticholinergic is chosen because its pharmacokinetic profile closely mirrors the particular anticholinesterase it is matched with. The result is minimal muscarinic side effects. (Table 11-2) **The better you can mirror the pharmacokinetic profile of an anticholinesterase with an anticholinergic, the fewer side effects you will have. **The choice of anticholinesterase determines the choice of anticholinergic. Commonly Used Anticholinergic/Anticholinesterase Pairings Anticholinesterase Common Anticholinesterase Dose Recommended Anticholinergic Usual Dose of Anticholinergic per mg of Anticholinesterase Neostigmine mg/kg Glycopyrrolate 0.2 mg Pyridostigmine mg/kg Glycopyrrolate 0.05 mg Edrophonium mg/kg Atropine mg Physostigmine mg/kg Not needed Not applicable Table 11-3: (Morgan, E., Mikhail, M. & Murray, M. Clinical Anesthesiology. 2002, p. 204 with modification.) 148

154 Reversal Process Key Points: 1. Muscarinic side effects may still occur, despite administration of an anticholinergic agent. 2. Always give reversal agents slowly over 1-2 minutes to minimize these effects. (Especially cardiovascular and pulmonary) 3. NEVER reverse a nondepolarizing block unless there is at least one twitch present with TOF stimulation. 4. NEVER reverse a depolarizing block. (SCh) 5. Neostigmine and Glycopyrrolate can be mixed in the same syringe and administered simultaneously. 6. Atropine is generally drawn in a separate syringe and administered first. After an initial rise in heart rate is detected, the Edrophonium dose is administered. This is done to minimize cholinergic effects, as Edrophonium has a slightly quicker onset time compared to Atropine. Assessment of Recovery From Neuromuscular Blockade It is critical to assess adequate recovery from NMBers prior to extubation to avoid hypoventilation, hypoxia, and apnea requiring re-intubation. Major clinical criteria utilized to assess adequate block recovery include: 1. Sustained head lift for > 5 seconds 2. Sustained hand grip 3. Effective cough 4. Vital capacity breaths of > 15 cc/kg. 5. Negative inspiratory force of at least 40 cm H 2 0 pressure 6. Sustained tetany to Hz for > 5 seconds 7. Full TOF without fade Comparison of Tests Of Neuromuscular Function Clinical Test Estimated % of Receptors Occupied Tidal Volume 80 Train-Of-Four (TOF) Vital Capacity Breaths 70 Tetanic Stimulation (50 Hz) 70 Double-burst Stimulation **Sustained Head Lift 50 Table 11-4: (Nagelhout, J.J. Nurse Anesthesia. 2001, p. 195 with modification). **Sustained head lift is the most reliable clinical indicator of degree of residual muscle relaxation. 149

155 Factors Affecting Block Reversibility 1. Depth of block at time of reversal Deep paralysis usually takes longer to reverse. 2. Dose of anticholinesterase administered Sub-optimal dosing can prolong reversal. 3. Duration of neuromuscular blocker used Longer acting muscle relaxants should be antagonized with a full reversal dose. 4. Patient temperature Hypothermia prolongs the onset of reversal agents. Cold patients take longer to reverse and are more susceptible to re-paralysis after reversal as they approach normothermia. Reversal should only occur in a normothermic patient. 5. Acid-Base Status Respiratory acidosis prolongs the reversal process. Metabolic alkalosis prolongs the reversal process. 6. Electrolyte Abnormalities Hyperkalemia prolongs the reversal process. Hypermagnesemia prolongs the reversal process. 7. Other Drugs Drugs that are synergistic with NDP muscle relaxants will also cause a delay in the reversal process. (See Chapter 10) 150

156 CHAPTER 12 Anticholinergic Drugs Anticholinergic drugs are cholinergic antagonists. Recall, in Chapter 10 we discussed another type of cholinergic antagonist (ACh receptor antagonist) in the nondepolarizing muscle relaxants. KEY POINTS: Nondepolarizing muscle relaxants are cholinergic antagonists, specifically at nicotinic receptors in skeletal muscle. ** NDP relaxants = Nicotinic Cholinergic Antagonist ** Anticholinergic agents are cholinergic antagonists, primarily at postganglionic muscarinic receptors in the parasympathetic nervous system. (Figure 11-1) Anticholinergics can be referred to as antimuscarinics. ** Anticholinergics = Muscarinic Cholinergic Antagonists ** Mechanism of Action Anticholinergic drugs physically bind to the ACh receptor. This competitively blocks the ability of ACh to bind to its receptor. The result is the inability of ACh to cause a response at the receptor, specifically muscarinic receptors located in the heart, smooth muscle, and glands. Structural Components Anticholinergics = Aromatic Acid + Organic Base The ester linkage that is formed is important for effective binding of the anticholinergic to the ACh receptor. Commonly used anticholinergics in anesthesia include: 1. Atropine 2. Glycopyrrolate 3. Scopolamine The selection of a particular anticholinergic agent is driven by the pharmacologic and physiologic differences that exist between these drugs, as well as the desired clinical effect. 151

157 Figure 12-1: (Morgan, E., Mikhail, M. & Murray, M. Clinical Anesthesiology. 2002, p.208.) Pharmacologic Considerations of Anticholinergics Cardiovascular Anticholinergics block muscarinic receptors in the SA node of the heart causing tachycardia. They exert little or no effect on ventricular function or vascular resistance. Very useful in the treatment of vagally-induced bradycardia caused by peritoneal stimulation, baroreceptor reflex, and oculocardiac reflex. Pulmonary Anticholinergics inhibit respiratory tract secretions. This drying effect is also termed antisialogogue effect. Anticholinergics cause relaxation of bronchial smooth muscle. 1. Ipatropium bromide is a derivative of Atropine available in metered-dose or nebulized form. 2. More effective than beta-agonists in producing bronchodilatation in COPD patients. Cerebral Tertiary amines that cross the blood:brain barrier may cause central effects ranging from excitation to hallucinations. Anticholinergics most commonly associated with central effects are Scopolamine and Atropine. (Scopolamine >> Atropine) Specific antagonism of central effects can be achieved with Physostigmine. (See Central Anticholinergic Syndrome) 152

158 Gastrointestinal Greatly decreased salivary secretion (Scopolamine most effective) Decreased gastric secretions in larger doses Delayed gastric emptying related to peristalsis Decreased lower esophageal sphincter pressure Ophthalmic Pupillary dilation (mydriasis) Cycloplegia (lack of lens accommodation) May cause blurred vision and increased intraocular pressure Genitourinary Decreased ureteral and bladder tone Leads to urinary hesitancy and retention Thermoregulatory Anticholinergics inhibit sweating This may lead to a rise in body temperature. **Special Note** Referring to Figure 11-1, note that muscarinic receptors are present in the sympathetic nervous system in sweat glands. With this exception, all other muscarinic receptors are found at postganglionic parasympathetic sites. Atropine Sulfate (Atropine) Physical Structure Atropine is a tertiary amine that readily crosses lipid bilayers, to include the blood: brain barrier. Basic Pharmacokinetics Oral absorption is unpredictable; therefore the IM or IV route is preferred. Onset IV = seconds; IM = 5-40 minutes. Duration for vagal blockade is 1-2 hours; antisialogogue effect 4 hours. Clinical Considerations Quickest and most potent anticholinergic for treating bradyarrhythmias. Antisialogogue properties are the weakest of all anticholinergics. Cautious use in the presence of coronary artery disease, as atropine-induced tachycardia increases myocardial oxygen demand. Primary Clinical Uses Treatment or prevention of bradycardia in the O.R. 1. Vagally-mediated (OCR, peritoneal stimulation, etc ) 2. Direct effect of volatile agents, especially with pediatric inhalation inductions 3. Neuraxial-induced bradycardia Reversal of neuromuscular blockade in conjunction with Edrophonium Adjunct treatment of bronchospasm (Ipatropium Bromide) 153

159 Glycopyrrolate (Robinul) Physical Structure Glycopyrrolate is a quaternary amine that does NOT cross the BBB. Basic Pharmacokinetics Common routes of administration include IV and IM. Less commonly, Glycopyrrolate can be given PO, usually diluted in 3-5 cc of apple juice. Onset IV = < 1 minute; IM = minutes; PO = 60 minutes Duration for vagal blockade is 2-3 hours; antisialogogue effect 7 hours. Clinical Considerations Only anticholinergic that does NOT cross the BBB; therefore it elicits no central effects. Very potent antisialogogue Will increase heart rate, but less effectively than Atropine Primary Clinical Uses Drying agent for prep of anticipated difficult airway Treatment or prevention of mild bradycardia in O.R. Often administered prior to a repeat dose of SCh Reversal of neuromuscular blockage in conjunction with Neostigmine Often given in conjunction with Ketamine to minimize salivation Scopolamine Hydrobromide (Scopolamine) Physical Structure Scopolamine is a tertiary amine that readily crosses the BBB. Basic Pharmacokinetics Common route of delivery include PO, IV, IM, and transdermal (TD) patch. Onset IV = immediate; IM/PO/TD = 30 minutes Duration varies depending on route of delivery. o IV 2 hours o IM/PO 4-6 hours o TD 72 hours Clinical Considerations Strongest sedative and amnestic properties related to central effects. Antisialogogue effect is equipotent to Glycopyrrolate, but is rarely used due to central effects. Least effect on heart rate. Primary Clinical Uses Used as a premedication for its sedative and amnestic properties Used as an antiemetic agent in a transdermal patch Used intraoperatively for amnesia (less common) 154

160 Comparative Characteristics of Anticholinergics Characteristic Atropine Glycopyrrolate Scopolamine Tachycardia Bronchodilatation Antisialogogue Sedation + None +++ Crosses BBB YES NO YES + Minimal Effect ++ Moderate Effect +++ Marked Effect Table 12-1: (Partially reproduced from information in Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 1999, p. 239.) A = Atropine G = Glycopyrrolate S = Scopolamine Tachycardia Bronchodilatation Antisialogogue Sedative A > G > S A = G > S S > G > A S > A > G Cautious Use of Anticholinergics 1. Cardiovascular disease 2. Narrow-angled glaucoma 3. Urinary bladder neck obstruction 4. Intestinal or pyloric obstruction Dose Continuum of Side Effects: Low Dose High Dose SECRETORY EYES & HEART SMOOTH MUSCLE GI SECRETIONS CNS sweating mydriasis tone secretions excitation salivation cycloplegia (LES, bladder, delirium bronchial tachycardia bronchial, etc) depression secretions Central Anticholinergic Syndrome Hot as a hare Dry as a bone Red as a beet Blind as a bat Mad as a hatter 155

161 Central Anticholinergic Syndrome (Toxicity) Etiology Syndrome associated with the tertiary amines that cross the BBB, specifically Scopolamine, and to a lesser extent Atropine Usually occurs with excessive or repeated dosing of these drugs Syndrome results from the central antagonism of ACh Symptoms Hot, red, dry skin Facial and chest rash Blurred vision Photophobia Agitation, restlessness, hallucinations, delirium HOT, DRY, RED, BLIND, MAD = Anticholinergic Effects Treatment Physostigmine ug/kg IV (only anticholinesterase that crosses BBB) **All other anticholinesterase agents are ineffective. 156

162 Sarin Poisoning on Tokyo Subway CHAPTER 13 Nerve Agent Exposure and Treatment MARCH 20, 1995, terrorists released sarin, an organophosphate (OP) nerve agent at several points in the Tokyo subway system, killing 11 and injuring more than 5,500 people Nerve agent exposure is no longer just a war-time worry. It is a very real threat in our own homes and on our own streets. As a military anesthesia provider, the probability of having to recognize and treat nerve agent exposure is very possible, whether at home or in a deployed environment. It is critical that four major areas related to nerve agents are completely understood by the anesthesia provider. 1. Mechanism of Action 2. Physiologic Affects 3. Pretreatment and Treatment 4. Anesthetic Implications General Facts About Nerve Agents They are organophosphate anticholinesterases (Chapter 11) that are clear, colorless, and either odorless or faintly sweetish smelling. Extreme potency and lethality Readily absorbed via ingestion, inhalation, or transdermal. Common Nerve Agents Name Year Made Lethal Dose Breathing Lethal Dose Skin (mg - min/m 3 ) (mg) Tabun (GA) ,000-1,700 Sarin (GB) ,000-1,700 Soman (GD) VX Other less common nerve agents include GE, GF, VE, VG, and VM. Table 13-1: (Produced from information in Medical Management of Chemical Casualties Handbook. 1995, p ) Breathing a lethal dose can kill in 15 minutes. A lethal dose on the skin can kill in only 1-2 minutes. To get an idea of how deadly these chemicals are, YOU DO THE MATH! *1 kilogram = 1000 mg = 2.2 lbs. *1 gram = 1000 mg = lbs. *10 mg = lbs. (Amount of VX that is deadly) This is about as much as a single grain of rice weighs!!! Get the picture? 157

163 Mechanism of Action Nerve agents, similar to Echothiophate and some insecticides, irreversibly bind to all types of AChE, forming a phosphorylate complex at the esteratic site. ACh rapidly builds up at ALL cholinergic receptor sites (muscarinic and nicotinic) causing a cholinergic crisis. Death results from CV collapse and respiratory paralysis due to extremely high levels of ACh. Physiologic Effects of Nerve Agent Poisoning (Cholinergic) Nicotinic Effects (MTWHF) Mydriasis Tachycardia Weakness/Paralysis Hypertension/Hyperglycemia Fasciculations Muscarinic Effects (SLUDE or DUMBELS) Salivation Lacrimation Urination Defecation Emesis Diarrhea Urinary incontinence Miosis (blurred vision) Bronchospasm/Bradycardia Emesis Lacrimation Salivation/Sweating CNS Effects Grand mal seizures Unconsciousness Apnea Hyperthermia (Rhabdomyolysis) Death Type of physiologic effects elicited is dependent upon route and amount of nerve agent exposure. **Severe systemic effects indicate a 70-80% AChE inhibition. Inhibition could last 45 days or longer!! Treatment of Nerve Agent Exposure Three major drugs used in the treatment of nerve agent exposure include: 1. Atropine 2. Pralidoxime Chloride 3. Diazepam 158

164 **Atropine** Atropine is the most important component of antidotal therapy. All other components are ineffective unless Atropine is given quickly and initially. Extremely effective at blocking peripheral muscarinic receptor sites from the effects of ACh. Not as effective in blocking nicotinic effects. (only in high doses) Blocks central effects to some degree, as Atropine is a tertiary amine that crosses the BBB. DOSE 2 mg initially, mg over 3 hours for severe toxicity. **Pralidoxime Chloride (2-PAM Cl)** 2-PAM is not effective unless Atropine has been given initially! 2-PAM is an oxime that physically attaches to the nerve agent that is bound to AChE, and breaks the agent-enzyme bond to restore normal enzymatic activity. Effective only at nicotinic receptors, allowing for return of normal skeletal muscle function. DOSE 600 mg initially, 1-2 grams over minutes if needed. 2-PAM must be given before aging of the nerve agent-enzyme complex has occurred. Aging Biochemical process by which the agent-enzyme complex becomes refractory to oxime reactivation. The process of aging can take 5 minutes to 24 hours depending upon the type of nerve agent used. **Clinical Note** Most nerve agents age over hours, so the likelihood of successful oxime treatment is great. However, Soman (GD) exposure produces an agent-enzyme complex that ages within 2 minutes. With Soman, Pralidoxime treatment is ineffective. **Diazepam** Diazepam is ineffective unless Atropine has been given first. Given to reduce brain damage caused by prolonged seizure activity. DOSE Diazepam 5-10 mg IV/IM 159

165 Current Field Doctrine In wartime scenarios, military personnel entering an area considered to be a high threat for chemical warfare are issued 3 MARK I Kits. One MARK 1 Kit contains: Atropine 2 mg auto injector Pralidoxime 600 mg auto injector In addition, personnel are issued one auto injector of Diazepam 10 mg for a buddy to administer if necessary. Diazepam should be administered with the three MARK I s when the casualty s condition warrants the use of three MARK I s at the same time. This would suggest severe toxicity, and convulsive activity is eminent. Pyridostigmine (Mestinon) Pretreatment Key Points: Pyridostigmine binds to AChE enzyme in the same fashion as nerve agents, EXCEPT it forms a carbamyl-ester complex that is reversible. (Chapter 11) While the AChE enzyme is carbamylated, the active site is protected from attack by other compounds, such as nerve agents. Carbamylation only lasts for several hours, as opposed to phosphorylation (nerve agents) that lasts for several days to weeks, and requires new enzyme synthesis. After several hours, decarbamylation occurs, and AChE becomes completely functional again. **Applied to a battlefield scenario, Pyridostigmine is used as a pretreatment adjunct to Atropine and 2-PAM to decrease the likelihood of nerve agent toxicity with acute exposure. DOSE 30 mg every 8 hours. (Blister packs contain twenty-one 30mg tablets). This dosage range carbamylates (protects) 20-40% of the AChE enzyme. Remember: 1. Pyridostigmine is not an antidote. It is ineffective in protecting AChE if taken after nerve agent exposure 2. When Pyridostigmine pretreatment is used in combination with the MARK I treatment kit for nerve agent exposure, survivability increases significantly. 3. Pyridostigmine pretreatment is useless unless Atropine is given at the onset of a cholinergic crisis. 160

166 Anesthesia Implications of Nerve Agent Exposure & Pyridostigmine Pretreatment When a casualty requires anesthesia in a battlefield scenario, circumstances may exist where the patient has been taking Pyridostigmine prophylactically, and/or has been exposed to nerve agents. In this scenario, it is critical that the anesthesia provider have a full understanding of the interaction of nerve agents and/or Pyridostigmine pretreatment with anesthesia management. Nerve agent exposure and Pyridostigmine pretreatment both create scenarios where there is an acute decrease in available AChE enzyme, leading to increased circulating amounts of ACh and related cholinergic symptoms. Reported Side Effects From Pyridostigmine Pretreatment Effect % Incidence Gastrointestinal (cramps, N/V) > 50 Urinary urgency and frequency 5-30 Diarrhea, salivation, visual changes > 10 Headache, rhinorrhea, diaphoresis, Tingling of extremities < 5 Table 13-2: Produced from information in Medical Management of Chemical Casualties Handbook. 1995, p ) Overall Anesthetic Management Principles Increased incidence of N/V increases the risk of aspiration and may require the use of gastric preps and rapid sequence intubations. Increased incidence of diarrhea and diaphoresis may present a severely hypovolemic patient that requires fluid resuscitation and induction with drugs that support overall hemodynamics, such as Etomidate or Ketamine. Increased oral and bronchial secretions make these patients prone to laryngospasm and bronchospasm. Use of an antisialogogue may be of benefit. Major Pharmacological Considerations If anticholinergics are used, a larger than normal dose is required for therapeutic effect. Increased levels of ACh compete with anticholinergics for ACh receptor sites. Dose of Anticholinergics Thiopental should be avoided related to its ability to precipitate bronchospastic activity in susceptible patients or under light anesthesia. These effects would be synergistic with already increased levels of ACh, making bronchospasm more likely. Ketamine increases secretions and sensitizes the larynx, making the possibility of laryngospasm more likely. Avoid Ketamine and Thiopental 161

167 **Clinical Note** It must be noted here that both Ketamine and Thiopental can be used safely. If Etomidate or Propofol were available, these would be better choices. If not, administer an adequate anticholinergic dose prior to Ketamine or Thiopental to help avoid these side effects. Remember, you will need an increased dose of anticholinergic. Depolarizing muscle relaxants (SCh) rely on pseudocholinesterase for metabolism and inactivation of therapeutic effect. Patients who have decreased levels of AChE as well as pseudocholinestase would be expected to have a prolonged response to SCh. Prolonged Response To Depolarizing Muscle Relaxants Nondepolarizing (NDP) muscle relaxants compete with ACh for receptor sites. In this scenario, increased circulating levels of ACh would antagonize a NDP block. These patients illustrate a resistance to NDP muscle relaxants, and an increased dose is usually required. Resistance To Nondepolarizing Muscle Relaxants **Clinical Note** Although patients may illustrate a resistance to NDP muscle relaxants, requiring larger administered doses, dosing for block reversal follows the standard dosing regimen. This is because the ratio of NDP:ACh is still the same as in a normal patient. The amount to block is more; the amount to antagonize is the same!! 162

168 Keeping It All In Perspective What Binds To The ACh Receptor?? ACh Nondepolarizing Muscle Relaxants ACh Receptor Depolarizing Muscle Relaxants Anticholinergics What Binds To Acetylcholinesterase?? Reversible Anticholinesterases ACh (Acetylation) 1. Electrostatic bond Edrophonium 2. Carbamylation Neostigmine Pyridostigmine Physostigmine AChE Irreversible Anticholinesterases 1. Phosphorylation Echothiophate Nerve Agents Insecticides 163

169 CHAPTER 14 Local Anesthetics Local anesthetics are drugs that reversibly inhibit the conduction of electrical impulse along nerve fibers. The degree of inhibition is influenced by the anatomy of the nerve being blocked, local tissue conditions, and the physicochemical properties of the local anesthetic agent. Desirable Properties Short onset Moderate duration of action Quick recovery Non-irritating to tissues Low systemic toxicity (high therapeutic index) **Therapeutic Index** Dose producing undesired effects divided by the lowest dose producing desired effect. (reflects margin of safety) High Therapeutic Index = Low Systemic Toxicity = High Safety Margin Basic Properties of Local Anesthetics Weakly basic amines Poorly water soluble Prepared as water-soluble HCL salts that are strongly acidic (ph < 6) Commercially prepared local anesthetics containing epinephrine often have sodium bisulfite added to lower ph to 4, as epinephrine is unstable in an alkaline ph. Structure of Local Anesthetics The core structure of all local anesthetics consists of three major components: 1. Lipophilic group Usually a benzene ring 2. Hydrophilic group Can be either a tertiary or a quaternary amine 3. Intermediate chain Contains an ester or amide group Figure 14-1: (Nagelhout, J.J. & Zaglaniczny, K.L. Nurse Anesthesia. 2001, p. 140) The type of linkage at the intermediate chain defines the type of local anesthetic as an ester or an amide, and determines metabolism and allergic potential. 164

170 Mechanism of Action Local anesthetics produce their effect by blocking sodium (Na + ) channels inside the neuronal membrane. This blockage prevents an increase in sodium permeability during an action potential, resulting in negation of electrical conduction. Two forms of local anesthetics: 1. Free base form (B) = Lipophilic unionized fraction 2. Cationic form (BH + ) = Hydrophilic ionized fraction Figure 14-2: (Mycek, Mary J. Lippincott s Illustrated Reviews: Pharmacology. 2000, p. 5 with modification) Free Base Form (B) = Unionized Lipophilic = Uncharged Form ** Determines onset of action Cationic Form (BH + ) = Ionized = Charged Form ** Determines block duration Both forms are involved in the process of nerve conduction block. Theory of nerve blockade 1. Local anesthetic is injected into an area with a local ph. 2. The local ph determines the % ionized and % unionized drug form. 3. The unionized form crosses the lipid bilayer of the nerve. 4. Once inside the nerve, the charged, ionized form binds to the Na + channel to decrease permeability of this ion into the cell. 5. Action potential is blocked. ** It is fortunate that intracellular ph is about 7.0, for this results in conversion of the unionized drug to its cationic, active form. REMEMBER THIS!! 165

171 Relationship of pk a to ph pk a defines the ph at which the amount of ionized and unionized drug fraction is equal. Local anesthetics with a pk a closer to physiologic ph (7.4) will have a quicker onset related to an increased unionized drug fraction. **Clinical Application ** Knowing the pk a of the drug you are using (fixed), as well as the ph of the tissue into which it is injected, you can determine the amount of unionized drug form available to cross the nerve membrane. You also need to remember this equation: log [cation]/[base] = pk a ph Clinical Example of Using pk a To Determine Onset: What proportion of Bupivacaine is available in the unionized form when injected into tissue with a ph of 6.8?? RECALL: log [cation]/[base] = pk a ph 1. Log [cation] / [base] = Log [cation] / [base] = Log 20 = 1.3 * 4. Therefore, Log [20]/Log [1] = This is 20 parts cation to 1 part base for a total of 21 parts. 6. % cation = 20/21 X 100 = 95% % base = 1/21 X 100% = 5% ** You will need a log table or calculator with an inverse log function to calculate this step. Remember common log relationships are: log 1 = 0 log 10 = 1 log 100 = 2 log 1000 = 3 From the above calculations, we can say that injecting Bupivacaine into local tissue with a ph of 6.8 (acidotic) makes only 5% of free base drug available for diffusion across the nerve membrane. This is a mathematical picture of why local anesthetics injected into acidotic, infected tissue work very slowly, or not at all. 166

172 Types of Local Anesthetics 1. Amino Esters (Ester link) 2. Amino Amides (Amide link) The two groups of local anesthetics are distinctly different in their metabolism and allergic potential. Ester Local Anesthetics Metabolized in the plasma by pseudocholinesterase. EXCEPTION is Cocaine, which is an ester that is mostly metabolized by plasma esterases, secondarily by the liver, and some is excreted unchanged in the urine. Duration of action may be prolonged with atypical pseudocholinesterase and pregnancy ( enzyme). Ester hydrolysis results in the formation of para-amino benzoic acid (PABA), which may bind to other compounds in the body to form haptens, which have allergic potential. Amide Local Anesthetics Metabolized by amidases (hepatocytes) and microsomal enzymes in the liver. Duration of action may be prolonged with liver disease. Amides may be manufactured with PABA added as a preservative. Since PABA has allergic potential, it should be avoided in patients who have an allergy to local anesthetics. Amide local anesthetics are not broken down to PABA. **Clinical Note** A true allergy to local anesthetics is RARE, especially to amides. Often patients will say they had an allergic reaction to Novacaine at the dentist, and will describe symptoms related more to intravascular injection rather than allergic reaction. When a patient does have a true allergy to local anesthetics, it is usually to the PABA, and it is best to use an amide local anesthetic without PABA. Commonly Used Local Anesthetics Esters pk a Amides pk a 2-Chloroprocaine (Nesacaine) 9.0 Bupivacaine (Marcaine) 8.1 Cocaine 8.7 Dibucaine (Nupercaine) 8.8 Procaine (Novocaine) 8.9 Etidocaine (Duranest) 7.7 Tetracaine (Pontocaine) 8.2 Lidocaine (Xylocaine) 7.8 Benzocaine (Americaine) None Mepivacaine (Carbocaine) 7.6 Prilocaine (Citanest) 7.8 Ropivacaine (Naropin) 8.1 Table 14-1: (Produced from information in Morgan, E. Clinical Anesthesiology. 2002, p ) **If you memorize the generic names of the esters, they all have just one i. All of the other local anesthetic then are amides that have two i s. 167

173 Pharmacokinetic Profile of Local Anesthetics The specific clinical characteristics of local anesthetics are determined by four primary factors. # 1 LIPID SOLUBILITY The free base, lipid soluble fraction is what penetrates the nerve. The higher the lipid solubility, the more potent the local anesthetic. **Lipid Solubility = Potency** #2 PROTEIN BINDING Local anesthetics that are poorly protein bound have a shorter duration. Local anesthetics that are highly protein bound have a longer duration. Local blood flow washes the local anesthetic from the protein receptor site, so if it clings on stronger, it elicits its effect longer. **Protein Binding = Duration of Action** #3 pka The free base, lipid soluble, unionized fraction is what penetrates the nerve. The drugs pk a determines unionized drug fraction available. The amount of unionized drug determines onset time. o Lidocaine pk a = 7.8 = 25% unionized & 75% ionized o Tetracaine pk a = 8.2 = 7% unionized & 93% ionized The closer the drugs pk a is to physiologic ph, the quicker the onset. o Remember, local anesthetics are basic drugs. **pk a = Speed of onset** #4 INTRINSIC VASODILATOR ACTIVITY All local anesthetics EXCEPT Cocaine and Ropivacaine, possess the ability to cause vasodilatation in the area they are injected, increasing blood flow to that area. As a result, local anesthetics that possess more vasodilatory properties increase their own absorption into the central circulation. The end result is less drug available at the receptor site to elicit an effect. Increased intrinsic vasodilator properties = decreased potency and duration. **Intrinsic Vasodilator Activity = Potency and Duration of Action** Categories of Local Anesthetics Group 1: Low Potency, Short Duration Group 2: Intermediate Potency, Intermediate Duration Group 3: High Potency, Long Duration 168

174 Characteristic Low Potency Short Duration Local Anesthetic Characteristics Drug Relative Potency Onset Duration (min) Procaine 1 Slow Chloroprocaine 1 Fast Intermediate Potency Intermediate Duration Mepivacaine 2 Fast Prilocaine 2 Fast Lidocaine 2 Fast High Potency Long Duration Tetracaine 8 Slow Ropivacaine 10 Slow Bupivacaine 9 Intermediate Etidocaine 6 Fast Table 14-2: (Produced from Nagelhout, J.J. Nurse Anesthesia. 2001, p. 142 with modification.) Local Anesthetic Disposition Absorption Distribution Metabolism Excretion Primary Factors Affecting Absorption of Local Anesthetics Site of Injection The rate of systemic absorption is proportionate to the vascularity of the site of injection. The higher the vascularity, the quicker the absorption. **Blood > Intratracheal > Intercostal > Caudal > Epidural > Brachial Plexus > Sciatic > Subcutaneous B- I- I- C- E- P- S (good way to remember order) Dosage This refers to total dose used, which is [concentration X volume]. Addition of a Vasoconstrictor Adding a vasoconstrictor into a mixture with a local anesthetic, such as Epinephrine or less commonly Neosynephrine, decreases absorption of the local anesthetic into the blood. Vasoconstrictors = Decreased Absorption = Decreased Systemic Toxicity This results in prolonged duration of action. **Vasoconstrictors are primarily used to decrease systemic toxicity!! 169

175 Specific Drug Characteristics Lipid solubility, protein binding, pk a, and intrinsic vasodilator properties of each drug will affect their absorption into the bloodstream. Also, local anesthetics such as Lidocaine and Bupivacaine are subject to first-pass pulmonary extraction, limiting the amount of drug reaching the central circulation. Distribution of Local Anesthetics Local anesthetics rapidly distribute throughout total body water after they reach the bloodstream. Re-distribution half - time (T 1/2 alpha) is very quick related to equilibration with vessel-rich tissue. Elimination half - time (T 1/2 beta) is slower related to distribution to less perfused tissue, metabolism, and excretion. Metabolism and Excretion All local anesthetics are eliminated by conversion to more polar compounds and removal by the kidney. Metabolic pathways vary based on chemical classification. ESTERS Pseudocholinesterase hydrolysis = FAST AMIDES Multiple biotransformation pathways in the liver Hepatic disease prolongs amide metabolism more than esters. Renal disease usually does not have a significant effect on local anesthetics. Local Anesthetic Toxicity All local anesthetics are essentially depressant drugs. The symptoms that are clinically elicited with toxicity range from excitatory to inhibitory, and are dosedependent, as well as drug-specific. **Toxicity primarily involves the CNS and CV system. Initial symptoms involve excitation of the CNS, as inhibitory pathways in the limbic system and cortex are depressed. Premonitory CNS Symptoms Circumoral Numbness* Metallic Taste Lightheadedness Dizziness Blurred Vision Tinnitus Disorientation Shivering Muscle Twitching Tonic/Clonic Seizures Classic Later (Figure 14-3). Bovill, J. G. Clinical Pharmacology for Anaesthetists. 1999, p.166. * Numbness of the tongue and circumoral tissue is the earliest sign of toxicity. During this stage, CV symptoms involve tachycardia and hypertension related to the CNS excitatory effects. 170

176 Later symptoms involve depression of the CNS, as both inhibitory and excitatory pathways are blocked. Late CNS Symptoms Drowsiness Slurred Speech Termination of seizure activity Unconsciousness Apnea Later symptoms involving the CV system are the result of direct depression of cardiac and vascular smooth muscle, leading to a decrease in myocardial electrical activity, conduction rate, and force of contractions. Late CV Symptoms Bradycardia Hypotension Dysrhythmias Asystole Progressive Stages of Local Anesthesia Toxicity 1. CNS Excitation 2. CV Excitation 3. CNS Depression 4. CV Depression 5. Death **Rapid injection of extremely high levels of local anesthetics can progress to CV and CNS collapse without initial excitatory signs. Treatment of Local Anesthesia Toxicity The range of symptoms that the patient elicits dictates various treatment protocols. 1. Initial Premonitory CNS Symptoms Stop injection if applicable Apply 100% oxygen. Oxygen raises the seizure threshold. Have patient hyperventilate. Hypocarbia raises the seizure threshold. Administer an anticonvulsant, such as Midazolam or Thiopental. These drugs are readily available, and also raise the seizure threshold. CALL FOR HELP! Prepare for the next stage 2. Progressive Symptoms of CNS Stimulation Convulsions can be treated with incremental boluses of Midazolam, Thiopental, or Propofol. Assist ventilations if needed Intubate if unable to ventilate 3. Symptoms of CNS Depression Maintain airway and oxygenation Control ventilation 4. Symptoms of CV Depression Administer vasopressor support CPR 171

177 **Clinical Note** It is not uncommon for seizure activity to return as blood levels of the local anesthetic fall and excitatory CNS symptoms reoccur. The highest risk in anesthesia of encountering the above is associated with intra-arterial injection of local anesthetics for an axillary block. Avoidance of systemic toxicity begins with the anesthesia provider. Some helpful tips include: Lidocaine Bupivacaine Ropivacaine 2-Chloroprocaine Mepivacaine Tetracaine Benzocaine Cocaine Table 14-3 Careful placement of axillary needle with use of constant aspiration. Minimal pressure on the axillary artery so that you can get a reliable blood return if intravascular. Diligent assessment of the patient and monitors. Oxygen and Midazolam up front before the procedure to help raise the seizure threshold. Always use Epinephrine in your mixtures as a vascular marker. When in doubt as to placement, STOP and reassess!! If you get tachycardia, or any of the initial CNS signs, STOP the injection. Remember the more drug, the more likely the progression of symptoms. Avoid Bupivacaine, as this local anesthetic is highly lipid soluble, and has a strong affinity for cardiac muscle. A toxic dose may result in refractory cardiac arrest. Commonly Used Local Anesthetics Local Anesthetic Primary Clinical Use Primary Clinical Uses of Local Anesthetics Intravenous, Infiltration, Topical, Neuraxial Blocks, Bier Blocks, Nerve Blocks Infiltration, Neuraxial Blocks, Peripheral Nerve Blocks Infiltration, Neuraxial Blocks, Peripheral Nerve Blocks Epidural Blocks, Nerve Blocks Axillary, Peripheral Nerve Blocks Spinal, Axillary Blocks Topical Spray Topical Liquid Topical Anesthesia Local anesthetics are applied topically to the mucous membranes of the nose, mouth, pulmonary tree, esophagus, and genitourinary tract. 1-4% Lidocaine nebulized, gel, viscous, and liquid forms. 1-5% Cocaine liquid form applied topically to the nose to decrease bleeding. 172

178 Local Infiltration Injection of local anesthetics into tissues to block pain. Often Epinephrine is added to increase the duration of action. Epinephrine almost doubles the duration of action of most local anesthetics. Epinephrine should NOT be added to local anesthetics injected around end-arteries in the fingers, nose, toes, ears, and penis. Commonly used local anesthetics for infiltration include: 0.5% - 1% Lidocaine 0.125% - 0.5% Bupivacaine Nerve Block Anesthesia Injection of local anesthetics around single nerves or a plexus of nerves can provide anesthesia for a large area. Common nerve blocks include digital blocks, ankle blocks, axillary blocks, lumbar plexus and sciatic blocks, popliteal block, interscalene blocks, superior laryngeal nerve (SLN) blocks, retrobulbar blocks (RBBB), and recurrent laryngeal nerve (RLN) blocks. Commonly used local anesthetics for nerve blocks include: 2-Chloroprocaine 2-3% (brachial plexus and ankle blocks) Lidocaine 0.5-2% (all peripheral nerve blocks) Lidocaine 4% (SLN, RLN) Bupivacaine 0.25% - 0.5% (all peripheral nerve blocks) Mepivacaine 1-2% (all peripheral nerve blocks) Ropivacaine % (peripheral nerve blocks) Spinal Anesthesia Common agents used for spinal anesthesia include Tetracaine, Bupivacaine, and Lidocaine supplied in standard concentrations. Tetracaine comes as a hyperbaric solution of 0.1% or 0.2% in 6% dextrose, an isobaric solution of 1%, or a lyophilized powder of 20 mg that can be diluted with sterile water to make a hypobaric solution. Bupivacaine for spinal use comes as a hyperbaric mixture of 0.75% in 8.25% dextrose. Lidocaine for spinal use also comes as a hyperbaric mixture of 5.0% in 7.5% dextrose. Epidural Anesthesia Almost all local anesthetics can be used for epidural anesthesia. The agent selected is primarily based upon onset and duration of action desired. The concentration selected is primarily based upon desired clinical effect of sensory loss only, or sensory and motor loss. Common agents selected for intraoperative anesthesia include: Lidocaine 1-2% Bupivacaine % Ropivacaine % 2-Chloroprocaine 2-3% **Expect sensory and motor block in these concentrations. 173

179 Common agents selected for epidural analgesia for labor or postoperative pain management include: % % Bupivacaine % Lidocaine 0.1% Ropivacaine **Expect sensory block with mild to no motor block. Adding Sodium Bicarbonate to Local Anesthetics The addition of sodium bicarbonate to local anesthetic solutions appears to speed the onset of action. This process of alkalization increases the % of unionized drug available to cross the nerve membrane, thus speeding onset of action. Commonly used dosing is 1 meq Bicarbonate to 10 cc of local anesthetic. (Except Bupivacaine = 0.1 meq Bicarbonate to 10 cc of local anesthetic) This technique is used clinically with brachial plexus and epidural blocks. Ineffective in acidotic infected tissue. REMEMBER: **Bicarbonate = Quicker onset time **Epinephrine = Less systemic toxicity = Prolonged duration of action Individual Drug Highlights Cocaine Unique Only local anesthetic metabolized by two pathways (pseudocholinesterase and the liver). Causes vasoconstriction (All other local anesthetics, except Ropivacaine, cause vasodilatation). 1. Blocks the reuptake of Norepinephrine and Epinephrine resulting in vasoconstriction. 2. May cause hypertension, tachycardia, and dysrhythmias. 3. Use cautiously in presence of volatile agents, TCA, Pancuronium, Epinephrine, and Ketamine. (Avoid if possible) Used in anesthesia for its vasoconstricting properties when applied to the nasal mucosa. 2-Chloroprocaine Odd Duck Quickest onset and shortest duration of action of all local anesthetics. Possesses the highest pk a of all local anesthetics, but the quickest onset. Recall this is the exact opposite of what we should see. The low systemic toxicity of this agent allows the use of high concentrations (3%), which may decrease onset time by virtue of more molecules being deposited in the area at once. Very popular for use in obstetrics related to its high concentration, quick onset and short duration of action. Used as supplementation for a spotty epidural block, or to dose for perineal pain associated with delivery. 174

180 Tetracaine Manufactured as a lyophilized powder that requires dilution, as well as a hyperbaric solution premixed with dextrose. Commonly used in a hypobaric spinal mixture for perineal cases. Longest duration of action of all spinal agents. Lidocaine Higher margin of safety compared to Bupivacaine. It takes three times more Lidocaine to cause CV collapse than it does to cause convulsions. Lidocaine is safer than Bupivacaine if injected intra-arterial, due to its high CV/CNS toxicity ratio. Spinal Lidocaine in standard hyperbaric concentration of 5% has been associated with cauda equina syndrome and permanent neurologic damage. 1. Do not used 5% Lidocaine through a continuous spinal catheter. 2. Use 5% Lidocaine cautiously for procedures involving the high lithotomy position, where perfusion of the cauda equina may be compromised and the nerves may be more vulnerable. 3. Recommended to dilute the dose administered with equal volumes of CSF prior to injection. 4. Use lowest lumbar level possible for injection (L4-L5 preferred). Only local anesthetic agent given intravenously on a routine basis in the O.R. to blunt the adrenergic response to intubation, and minimize burning on injection from Propofol. Bupivacaine Small therapeutic window Margin of safety is low. This means there is a small dose window between therapeutic dose and toxic dose. Toxicity often results in refractory cardiac arrest. Concentrations > 0.5% are not recommended in obstetrics for epidural use. Not recommended for bier blocks or trans-arterial axillary blocks. Ropivacaine It differs from Bupivacaine in that it is an S-stereoisomer and has a propyl instead of a butyl. Similar to Bupivacaine in onset and duration of action. It is slightly less potent. It is less cardiotoxic than Bupivacaine. In equipotent dosing, Ropivacaine causes less motor block, with equipotent sensory block. Favored in obstetric anesthesia as part of a walking epidural for pain management, as pain is controlled and motor function is spared. Levobupivacaine It is THE S-enantiomer of bupivacaine. Similar to Bupivacaine in onset, duration of action and relative potency. It is less cardiotoxic than Bupivacaine with similar dosing and available concentrations. Concentrations > 0.5% are not recommended in obstetrics for epidural use. 175

181 Prilocaine Can cause methemoglobinemia in a dose-dependent fashion, with incidence occurring in dosing > 600 mg epidurally. Spontaneous recovery occurs in 2-3 hours from discontinuation. Avoid in obstetrics, as 10% fetal hemoglobin can be converted to methemoglobin, causing neonatal hypoxia. Avoid in patients with severe anemia or heart failure. Acute treatment = methylene blue A commonly used dermal anesthetic, EMLA cream, consists of a 1:1 mixture of 5% lidocaine and 5% prilocaine. 1. Remember: It must be applied 1 hour prior to IV attempt. Differential Conduction Blockade There are different nerve fibers in the body, which vary according to size, myelin protection, and function. When nerve fibers are blocked, the physiologic response elicited is dependent upon these characteristics. Nerve Fiber Characteristics (Neuraxial Anesthesia) Fiber Type Size (microns) Function B 0.25 Preganglionic Autonomic C* 0.5 Temperature, Dull Pain A-delta 0.5 Temperature, Sharp Pain A-gamma 0.75 Muscle Spindle, Muscle Tone A-beta 0.75 Light Pressure, Touch A-alpha 1.0 Somatic Motor, Proprioception * Unmyelinated Fibers Table 14-4: (Partially reproduced from Morgan, E. Clinical Anesthesiology. 2002, p. 260.) Order of Blockade Smaller nerve fibers are more vulnerable to blockade in lower concentrations of local anesthetics. As concentration is increased, larger nerve fibers are blocked. The order of loss is as follows: 1. Autonomic regulation 2. Temperature (especially to cold) 3. Dull pain 4. Sharp pain 5. Touch 6. Deep pressure 7. Proprioception 8. Somatic muscle function Low Local Anesthetic Concentration High Local Anesthetic Concentration 176

182 **Clinical Application** Clinically, the order of nerve loss is clearly evident. During neuraxial anesthesia, the first indication that the block is working is usually a drop in blood pressure (autonomic block), followed by inability to differentiate temperature (patient can t tell if alcohol pad is cold), followed by inability to feel sharp pain (needle prick). The patient may often complain that they feel that they have no idea where their limbs are (loss of proprioception), but this usually comes later. Often, the patient may not feel pain, but may still have the ability to move their limbs at incision. The first nerves to be blocked are the last to recover in neuraxial anesthesia. Large A-alpha fibers are very difficult to block related to large size. Agent Local Anesthetics Single Injection Dose Maximum Dose With Epinephrine (mg/kg) Maximum Dose Without Epinephrine (mg/kg) Maximum Singe Dose (Total mg) Bupivacaine % Levobupivacaine % Ropivacaine % Chloroprocaine 2-3% Mepivacaine 1-2% Lidocaine 1-2% Tetracaine 1-1.5% Table 14-5*: (Nagelhout, J.J. Nurse Anesthesia. 2001, p. 149 with modification). *Please note there is some variability in the suggested dosing from one reference to another. These values serve only as a general guideline for administration. Note that the maximum dose for administration increases with the addition of epinephrine. Recall that the addition of epinephrine allows for decreased systemic toxicity related to slower absorption into the central circulation. This allows for the administration of a larger initial dose. When local anesthetics are combined together, unpredictable clinical responses may be observed related to mixing of different pka s and ph s. Usually this is not a problem, but some unpredictability has been reported with 2-Chloroprocaine, probably related to its high pka. 177

183 Suggested Spinal Anesthetic Concentrations Tetracaine 1% 5% Lidocaine / 7.5 % Glucose T-6 Level C-Section T-4 Level C-Section Height (inches) Dose (mg) Height (inches) Dose (mg) Height (inches) Dose (mg) Height (inches) Dose (mg) < Table 14-6 * *These values serve as a general guideline only. The actual dose utilized is left to the discretion of the anesthesia provider, and ultimate block height is influenced by other factors such as speed of injection and patient position. Other General Guidelines Bupivacaine is commonly used for spinal anesthesia, including C-sections. Bupivacaine is much more lipophilic than Lidocaine and therefore is more predictable regarding set-up, and less likely to float unpredictably cephalad in cerebrospinal fluid after injection. Bupivacaine is commonly dosed at mg dependent upon desired block level relative to height. Patients commonly receive mg of Bupivacaine for most surgical procedures without much difficulty. Injecting Bupivacaine in the sitting position will consistently decrease the risk of unwanted cephalad spread. Common Epidural Infusion Mixtures **0.125% (1/8 th ) Bupivacaine + 2ug/cc Fentanyl 250cc NS - 70cc NS + 60cc 0.5% Bupivacaine + 10cc Fentanyl 250cc NS - 52 cc NS + 42cc 0.75% Bupivacaine + 10cc Fentanyl **0.125% (1/8 th ) Bupivacaine + 4ug/cc Fentanyl 250cc NS - 62cc NS + 42cc 0.75% Bupivacaine + 20cc Fentanyl **0.1% (1/10 th ) Bupivacaine + 2 ug/cc Fentanyl 250cc NS - 44cc NS + 34cc 0.75% Bupivacaine + 10cc Fentanyl 178

184 **0.1% (1/10 th ) Bupivacaine + 4ug/cc Fentanyl 250cc NS - 54cc NS + 34cc 0.75% Bupivacaine + 20cc Fentanyl **0.0625% (1/16 th ) Bupivacaine + 4ug/cc Fentanyl 250cc NS - 50cc NS + 30cc 0.5% Bupivacaine + 20cc Fentanyl **0.0625% (1/16 th ) Bupivacaine + 40ug/cc Duramorph 250cc NS - 40cc NS + 30cc 0.5% Bupivacaine + 10cc Duramorph **0.2% (1/5 th ) Ropivacaine + 4ug/cc Fentanyl (labor epidural) 250cc NS - 70cc NS + 50cc 1% Ropivacaine + 20cc Fentanyl **0.75% (3/4) Ropivacaine + 2ug/cc Fentanyl (surgical anesthesia) 250cc NS 197.5cc NS cc 1% Ropivacaine + 10cc Fentanyl 179

185 CHAPTER 15 Herbal Medicine FACTS: The sale of herbal remedies exceeds $13 billion a year in the United States. Over 22% of patients undergoing surgery report herbal medicine use. Natural does not mean safe!! Most consumers are not fully aware of the risks involved with herbal medicine consumption. In fact, most people seem to think that because these medications are labeled as natural, that this must also mean safe. This is primarily due to lack of education and misleading advertising. Seven of ten herbal medicine users never tell their health care provider about herbal products they are taking. Herbal remedies are drugs with pharmacologic effects. The pharmacologic effects of concern widely vary with the specific herbal supplement. It is crucial for the anesthesia provider to understand the basic management of patients taking herbal supplements, and tailor the anesthesia plan accordingly. Anesthesia Management Concerns 1. Management begins with the preoperative interview. a. Routinely ask patients about herbal supplements when asking about medication use. b. List several of the most common herbs and those of most concern to anesthesia providers to help the patient recall their herbal supplement. c. Instruct patient to discontinue herbal supplements at least two to three weeks prior to elective surgery. (ASA recommendations) 2. If the surgical procedure is emergent, it is critical that the anesthesia provider understand specific clinical concerns for all herbal medicines. 3. For all surgical procedures, information obtained about the patient s use of herbal medicines should be shared with all members of the surgical team, to allow for a collective decision about continuing with the proposed surgical procedure. 4. It is critical that the surgeon understand anesthesia risks if the surgery proceeds on an emergency basis. 5. Patients have died in the O.R. from complications related to the use of herbal medicines. TAKE IT SERIOUSLY!! Major Anesthetic Implications 1. Coagulopathies 2. Electrolyte Abnormalities 3. Hemodynamic Changes 4. Sedative Effects 5. Cardiac Effects 6. Withdrawal Syndrome 7. Cytochrome P-450 induction 180

186 Commonly Used Herbal Supplements Over the past few years, eight of the most commonly used herbal supplements have been identified, primarily through sales data and a survey of the literature. For this reason, these supplements are presented below in greater detail than in the tables provided. 1. Echinacea (Purple Coneflower) Common Use A member of the daisy family, Echinacea is used for the prophylaxis and treatment of viral, fungal, and bacterial infections, especially of the upper respiratory tract. Pharmacological Effects Immunostimulatory effects with short term use Perioperative Concerns Risk of allergic reactions and rare anaphylaxis Immunosuppression can occur with use exceeding 8 weeks. Should be avoided in patients awaiting organ transplantation or pre-existing immunosuppression (i.e. AIDS). Possibly hepatoxic with long-term use Pharmacokinetic information is not available. Recommend discontinuation as soon as possible prior to surgery 2. Ephedra (Ma Huang) Common Uses Shrub native to central Asia. It is used to promote weight loss, increase energy, and treat respiratory tract conditions. (asthma, bronchitis) Pharmacological Effects Predominant active ingredient is ephedrine. Clinical effects include a dose-dependent increase in blood pressure and heart rate. Direct agonist of alpha 1, beta 1, and beta 2 adrenergic receptors Indirectly causes release of norepinephrine Perioperative Concerns Risk of myocardial ischemia and stroke Dysrhythmias with concomitant use of halothane Hemodynamic instability related to endogenous catecholamine depletion with long-term use. Avoid concurrent use of ephedra with MAOI s Discontinue at least 24 hours prior to surgery **Ma Hung has been associated with more than 22 deaths, as well as life-threatening hyperpyrexia, hypertension, and coma. 181

187 3. Garlic (Ajo) Clinical Use One of the most researched of the herbal medicines. It is a sulfur-containing compound that may decrease the risk of atherosclerosis by reducing blood pressure and lowering lipid and cholesterol levels. Pharmacological Effects One of the constituents of garlic, ajoene, irreversibly inhibits platelet aggregation. Garlic lowers blood pressure, primarily by decreasing pulmonary and systemic vascular resistance. This effect is thought to be weak, however. Perioperative Concerns Primary clinical concern is irreversible platelet inhibition, increasing the risk of bleeding intraoperatively Potentiates the effects of other platelet inhibitors such as Indomethacin and Dipyridamole Epidural hematomas have been reported associated with use of high-dose garlic. Discontinue at least 7 days prior to surgery 4. Ginkgo (Duckfoot Tree, Maidenhair Tree, Silver Apricot) Common Uses Derived from the leaf of Ginkgo biloba tree. Ginkgo may stabilize or improve cognitive performance (dementia), and has been used in the general population to treat peripheral vascular disease, vertigo, tinnitus, and erectile dysfunction. Pharmacological Effects Active compounds in Ginkgo include flavonoids and terpenoids, which appear to alter vasoregulation and inhibit platelet-activating factor. Perioperative Concerns: Increased risk of bleeding intraoperatively, especially when used in combination with other platelet-inhibiting drugs. Spontaneous intracranial bleeding has been reported. Recommend discontinuation of this drug at least 36 hours prior to surgery. 5. Ginseng (Tarter Root) Common Uses Several species are available, most commonly Asian, American, Chinese, and Korean. Ginseng is commonly labeled an adaptogen, since it protects the body against stress and restores homeostasis. Pharmacological Effects Underlying mechanism is similar to steroid hormones Ginseng can lower blood glucose levels. Inhibition of platelet aggregation, as well as the coagulation cascade may occur. 182

188 Perioperative Concerns Increased risk of bleeding, which may be irreversible as well as synergistic with other anticoagulants (Heparin, Warfarin). Increased risk of hypoglycemia related to drug effect compounded by a fasting state. May cause profound hypoglycemia when used in the presence of insulin or oral hypoglycemics. Recommend discontinuation at least seven days before surgery. 6. Kava (Awa, Kawa, Intoxicating Pepper) Common Uses Derived from the dry root of the pepper plant, it has been used as an anxiolytic and sedative. Pharmacological Effects Neuroprotective effects that include antiepileptic properties. Local anesthetic properties Effect elicited may be the result of an interaction with GABA. Perioperative Concerns Potentiation of sedative effects of anesthetic agents, especially benzodiazepines and barbiturates. Possible risk of acute withdrawal syndrome. Recommend discontinuation at least 24 hours prior to surgery. 7. St. John s Wort (Amber, Goatweed, Hardhay, Klamath Weed) Common Uses Common name for the flower Hypericum perforatum, it is used for the short-term treatment of mild-tomoderate depression. Studies suggest it is not useful for treating major depressive states. Pharmacological Effects Inhibits serotonin, norepinephrine, and dopamine reuptake by neurons Precipitates induction of the cytochrome P-450 system in the liver Perioperative Concerns Liver enzyme induction may affect metabolism of many drugs to include cyclosporines, Warfarin, steroids, protease inhibitors, benzodiazepines, and calcium channel blockers. Central serotonin excess syndrome may develop with concomitant use with other serotonin blockers (Zofran?). Unpredictable interaction with TCA/MAOI s Unpredictable clinical responses to direct and indirect-acting sympathomimetic drugs (Neosynephrine, Ephedrine). Recommend discontinuation at least 5 days prior to surgery. 183

189 8. Valerian (All Heal, Garden Heliotrope, Vandal Root) Common Uses Valerian is a perennial cultivated throughout the world that is used to treat nervous disorders such as anxiety, restlessness, and insomnia. Pharmacological Effects Dose-dependent sedation and hypnosis through modulation of GABA neurotransmission. Perioperative Concerns Potentiation of centrally acting anesthesia drugs, to include barbiturates, benzodiazepines, and opioids. Acute withdrawal symptoms may occur if discontinued abruptly. Recommend discontinuation as a taper over several weeks. If this is not feasible, then continue to the day of surgery. Withdrawal symptoms can be treated with benzodiazepines. Herb Echinacea Ephedra Most Commonly Used Herbal Medicines Perioperative Concerns Counteracts immune suppressive therapy Hepatotoxicity Causes immune suppression long term. Increased heart rate and blood pressure Myocardial infarction Dysrhythmias 184 Perioperative Recommendations D/C as soon as possible D/C at least 24 hours prior Avoid MAOI s Garlic Bleeding from inhibition of platelets D/C at least 7 days prior Ginkgo Bleeding from inhibition of platelets D/C at least 36 hours prior Ginseng Bleeding from platelet inhibition Bleeding from coagulation cascade inhibition Hypoglycemia D/C at least 7 days prior Kava St. John s Wort Increased sedative effects of anesthetics Liver enzyme induction leading to increased drug metabolism. Interaction with sympathomimetic drugs D/C at least 24 hours prior Cautious use of BNZ/BARBS D/C at least 5 days prior Cautious use with adrenergic drugs. D/C as a taper over several Valerian Potentiation of anesthesia drugs weeks Acute withdrawal symptoms If not possible, continue up to day of surgery. Table 15-1: (Produced from information in Morgan, E., Mikhail, M. Clinical Anesthesiology. 2002, p.7.)

190 Herbal Medicines With Coagulation Effects Herb Effect Alfalfa Contains coumarins Capsicum Contains coumarins Inhibits platelet aggregation Celery Contains coumarins Chamomile Contains coumarins Fenugreek Contains coumarins Feverfew Inhibits platelet aggregation Fish oil Decreases platelet adhesion and aggregation Garlic Decreases plasma viscosity Increases clotting time Inhibits platelet aggregation Ginger Inhibits platelet function Gingko Inhibits platelet function Lowers fibrinogen levels Decreases plasma viscosity Ginseng Inhibits platelet aggregation Contains coumarins Horseradish Contains coumarins Kava Kava Decreases platelet aggregation Licorice Contains coumarins Passionflower Contains coumarins Red Clover Contains coumarins Vitamin E Reduces platelet adhesion and aggregation Table 15-2: (Norred, C., Use of complementary and alternative medicines by surgical patients. AANA J, 2000; 68 (1): 15, with modification.) Herbal Medicines With Blood Pressure Effects Herb Effect Black Cohosh Decreased Capsicum Increased Celery Decreased Ephedra Marked Increase Fenugreek Decreased Garlic Decreased Ginger Variable Ginseng Variable Goldenseal Increased Hawthorn Decreased Horseradish Decreased Licorice Increased St. John s Wort Variable Table 15-3: (Norred, C., Use of complementary and alternative medicines by surgical patients. AANA J, 2000; 68 (1): 16, with modification.) 185

191 Herbal Medicines With Sedative Effects Celery Chamomile Ginseng Goldenrod Hops Kava Kava Passionflower St. John s Wort Valerian Table 15-4: (Norred, C., Use of complementary and alternative medicines by surgical patients. AANA J, 2000; 68 (1): 16, with modification.) Herbal Medicines With Cardiac Effects Herb Effect Black Cohosh Bradycardia, Peripheral Vasodilatation Ephedra Palpitations, Arrhythmias Fenugreek Increased Heart Rate Ginger Bradycardia, Positive Inotrope Ginseng Tachycardia, Positive Inotrope Goldenseal Cardiac Stimulant Increase Coronary Blood Flow Hawthorn Arrhythmias Digitalis Potentiation Licorice Arrhythmias Lobelia Tachycardia Table 15-5: (Norred, C., Use of complementary and alternative medicines by surgical patients. AANA J, 2000; 68 (1): 16, with modification.) Aloe Chromium Fenugreek Figwort Ginseng Goldenseal Licorice Herbal Medicines With Electrolyte Effects Herb Effect Hypokalemia Hypoglycemia Hypoglycemia Hypoglycemia Hypoglycemia Hypernatremia Increased Serum Osmolality Hypernatremia Hypokalemia Hypernatremia Rauwolfia Table 15-6: (Produced from information in Skidmore-Roth, L. Mosby s Handbook of Herbs & Natural Supplements, 2001, p ) 186

192 Internet Resources For Herbal Information American Botanical Council American Holistic Nurses Association Center for Food Safety and Applied Nutrition Food and Drug Administration Herb Research Foundation HerbMed National Center for Complimentary and Alternative Medicines, NIH Office of Dietary Supplements, National Institutes of Health, NIH U.S. Pharmacopia 187

193 CHAPTER 16 Gastrointestinal and Antiemetic Drugs Postoperative nausea and vomiting (PONV) and pain are major concerns for patients who are scheduled for inpatient as well as outpatient surgery. Using opioids during the postoperative period helps control pain but may contribute to PONV. The act of vomiting can also increase the incidence of pain. Patients with gastroparesis are challenging because they are at an increased risk for both aspiration pneumonitis and PONV. There are several risk factors for PONV, some of which you as the nurse anesthetist can control. Factor Age Gender Anxiety Menstruation Weight Concomitant Disease Patient History Gynecological Ophthalmic ENT Laparoscopic Intraabdominal Dental/Oral Testicular Patient Factors Increasing PONV Description 16 years and younger Females, pregnancy α-adrenergic mechanism (Epinephrine & Norepinephrine) Luteal phase of cycle (3 rd and 4 th week) Obesity Gastroparesis (Diabetes, GERD, Bowel Obstruction), Increased ICP Previous history of PONV, Motion sickness, Migraines, Non-smokers, Food Intake Procedural Factors Increasing PONV Peritoneal and organ retraction Centrally mediated Blood in mouth, stomach CO 2 Insufflation Peritoneal and organ retraction Blood in mouth, stomach Vagally mediated Anesthetic Factors Increasing PONV Duration of anesthesia Increased exposure Type of Anesthesia Narcotics Volatile Agents Nitrous Oxide Anticholinesterases Etomidate Barbiturates PACU Factors Increasing PONV Pain Parasympathetic? Treatment of pain Mu-2 agonism Movement Vestibular Oral intake Gastroparesis Hypotension Decreased central perfusion Parasympathetic? Dehydration Decreased central perfusion Table 16-1: (Kovac, A., Antiemetic Use in Postoperative Nausea and Vomiting, FCG Institute for Continuing Education, Oct 2002 with modification.) 188

194 Nausea and vomiting receptor areas in the brain Vomiting Center: Located in the lateral reticular formation of the medulla oblongata of the midbrainstem at the level of the dorsal motor nucleus of the vagus nerve. Vagal afferents from the GI tract can easily stimulate the vomiting center. Nucleus of the Solitary Tract: In close proximity to the vomiting center Area Postrema: located on the dorsal surface of the medulla oblongata at the caudal end of the fourth ventricle. Chemoreceptor Trigger Zone (CTZ): Located in the Area Postrema No Blood Brain Barrier so it easily detects emetic toxins in both the blood and CSF Glossopharyngeal (gagging) and vagal (GI tract) can directly stimulate this area & cause vomiting. Cerebellum Area Postrema and Chemoreceptor trigger zone Nucleus of the solitary tract Fourth Ventricle Vomiting Center Figure 16-1: (Kovac, A., Antiemetic Use in Postoperative Nausea and Vomiting, Drugs, 2000; 59 (2): ) Midbrain Neurochemical Emetogenic Receptor Locations Midbrain Location Receptors a Area Postrema Chemoreceptor Trigger Zone Opioid Dopamine (D 2 ) Serotonin (5-HT 3 ) Enkephalin Opioid Dopamine (D 2 ) Enkephalin Nucleus of Solitary Tract Histamine (H 1 ) Muscarinic/Cholinergic a The vomiting center is the coordinator for these receptors to initiate the vomiting reflex Table 16-2: (Kovac, A., Antiemetic Use in Postoperative Nausea and Vomiting, Drugs, 2000; 59 (2): with modification.) 189

195 Factors Influencing Nausea and Vomiting Sensory input (pain, smell, sight) Higher Cortical Centers Memory, fear, anticipation Histamine Antagonists Muscarinic Antagonists Dopamine Antagonists Benzodiazepines Propofol Chemotherapy Anesthetics Opioids Chemoreceptor Trigger Zone (area postrema) 4 th Ventricle Vomiting Center Medulla Vomiting Reflex Chemotherapy Surgery Radiotherapy Sphincter Modulators 5HT 3 Antagonists Stomach Small Intestines Via Vagus Nerve Labyrinths Vestibular Apparatus CN VIII Histamine Antagonists Muscarinic Antagonists Surgery Motion Gastroprokinetic Agents Neuronal Pathways Factors which can cause PONV Sites of action of drugs Figure with modification Classification Antiemetic Drugs Receptor Anticholinergics Antimuscarinics Atropine Scopolamine Acetylcholine (Vestibular apparatus) Muscarinic Antihistamines Diphenhydramine (Benadryl) Acetylcholine (Vestibular apparatus) Hydroxyzine (Vistaril) Histamine H 1 Substituted Dopamine D Metoclopramide (Reglan) 2 Antagonist Benzamides Gastroprokinetic/Sphincter modulator Benzodiazepines Lorazepam (Ativan) Anxiolytic decrease plasma levels of Midazolam (Versed) catecholamines Butyrophenones Alpha Droperidol (Inapsine) 1 blocker (Hypotension) GABA blocker (Sedation) Haloperidol (Haldol) Dopamine D 2 Blocker Isopropylphenol Propofol Unknown, probably not anti-dopaminergic Phenothiazines 5-HT 3 receptor antagonists Promethazine (Phenergan) Prochlorperazine (Compazine) Chlorpromazine (Thorazine) Ondansetron (Zofran) Dolasetron (Anzemet) Granisetron (Kytril) Alpha 1 blocker (Hypotension) Dopamine D 2 Blocker Histamine H 1 Blocker 5-HT 3 (Serotonin) (Area Postrema and abdominal vagal afferents) Dexamethasone (Decadron) Unknown, many hypotheses Steroids Methylprednisolone (Solumedrol) Table 16-3: (Kovac, A., Antiemetic Use in Postoperative Nausea and Vomiting, Drugs, 2000; 59 (2): with modification.) 190

196 5-HT 3 Receptor Antagonists Ondansetron HCl (Zofran) Structure Carbazalone derivative that is structurally similar to serotonin that selectively blocks 5-HT 3 receptors, with little or no effect on dopamine, histamine, adrenergic, or cholinergic receptors. Elimination Extensively metabolized in the liver via hydroxylation and conjugation by cytochrome P-450. Minimal renal elimination Mean elimination half-life is 4 hours with an onset time of < 30 minutes. Pharmacokinetic Properties and Dosing Activity is based on receptor binding, not kinetic parameters; therefore, once 5-HT3 receptors are saturated, repeat or higher doses do not increase the effect. Prophylactic Dose: 4 to 8 mg IV administered over 2-5 minutes every 4 hours for the adult 30 minutes prior to induction for prophylaxis 15 minutes prior to emergence for procedures lasting > 4 hours Dose: 0.10 mg/kg IV administered over 2-5 minutes every 4 hours for children < 40 kg Safety for children less than 2 years of age has not been established. Rescue Dose in the PACU with no prior ondansetron administration: 1 mg IV Available: Intravenous (2 mg/cc), PO tablets (4, 8, 16 mg), orally disintegrating tablets (4 mg) Side Effects and Clinical Concerns Headache if administered too quickly (<2 min) preoperatively Dizziness, constipation, and diarrhea have been reported. Rapid administration (<2 min) has been associated with severe bradycardia. Does not cause sedation, extrapyramidal signs or respiratory depression It has no gastroprokinetic or sphincter modulating properties unlike metoclopramide. **Clinical Use** Prophylaxis or treatment of postoperative nausea and vomiting 5-HT 3 receptor antagonists are more expensive than other classes of antiemetics. Dolasetron mesylate (Anzemet) Elimination Reduced to an active metabolite, hydrodolasetron, this is responsible for its antiemetic effect. It takes approximately 15 minutes so it can t be given as you extubate the patient. Metabolized in the liver via hydroxylation and conjugation by cytochrome P % of hydrodolasetron is excreted unchanged in the urine. Use caution with renal failure. Mean elimination half-life of hydrodolasetron is 8 hours with an onset time of < 30 minutes. Pharmacokinetic Properties and Dosing A 5-HT 3 receptor antagonist that is more potent than ondansetron. Prophylactic Adult Dose: 12.5 mg IV over 2-5 minutes given at the end of surgery Rescue Adult Dose for treatment postop: 12.5 mg IV over 2-5 minutes Dose: 0.35 mg/kg IV administered over 2-5 minutes every 8 hours for children < 35 kg. Safety for children less than 2 years of age has not been established. 191

197 Side Effects and Clinical Concerns Side effect profile similar to ondansetron However, dolasetron can cause QT prolongation. Use with caution in patients taking antiarrhythmics drugs, or those with prolonged QT syndrome, hypokalemia, or hypomagnesemia. Granisetron HCl (Kytril) Elimination Metabolized in the liver via N-demethylation and aromatic ring oxidation followed by conjugation mediated by cytochrome P-450. Metabolites are excreted, 49% - urine and 34% - feces. 12% is unchanged in the urine. Dosage adjustments for patients with renal or hepatic disease are unnecessary. Mean elimination half-life is 8 hours with an onset time of < 30 minutes. Pharmacokinetic Properties and Dosing Adult Dose: 1 mg IV over sec given at the beginning or the end of surgery Does not require reduction to an active metabolite. Can give immediately prior to extubation. Rescue Adult Dose for treatment postop: 1 mg IV over seconds Dose: 40 µg/kg IV administered over seconds for children < 35 kg Safety for children less than 2 years of age has not been established. Side Effects and Clinical Concerns Side effect profile similar to ondansetron. Droperidol (Inapsine) Butyrophenones Structure Structurally resembles phenothiazines with similar antiemetic effectiveness. Target receptors are Dopamine D 2 receptors in the Chemoreceptor Trigger Zone (CTZ) in the area postrema. Interferes with the transmission of NE, serotonin, and GABA It is an alpha 1 adrenergic blocker. Elimination Extensively metabolized in the liver relying predominately on hepatic blood flow. Mean elimination half-life is 104 minutes with an onset time of < 30 minutes. Prolonged CNS effects due to probable slow dissociation of the drug from receptors in the brain. Pharmacokinetic Properties and Dosing Dose: mg or 0.15 mg/kg IV given at the end of surgery for the adult Caution: Sedative properties may prolong emergence. Dose: 7.5 µg/kg IV for children 192

198 Side Effects and Clinical Concerns Black Box Warning - can cause QT prolongation, torsades de pointes, or fatal arrhythmias usually when administered in doses > 2.5 mg but case reports have shown that it can occur at lower doses. Current recommendation is ECG monitoring pre-op and 2-3 hrs after administration. Avoid: CHF, Bradycardia, Hypertrophy, Hypokalemia, Hypomagnesemia, Diuretic Use Contraindicated in patients with: Parkinson s Disease Prolonged QT interval Other side effects: Hypotension from Alpha 1 receptor blockade Sedation from GABA blockade Utilized for preoperative sedation in preparation for an awake fiberoptic intubation Extrapyramidal reactions and dysphoria from Dopamine D 2 receptor blockade Feeling of restlessness and doom **Clinical Use** Prophylaxis or treatment of postoperative nausea and vomiting perhaps more potent than Ondansetron Neuroleptanalgesia produces a state of analgesia, immobility and variable amnesia Innovar 50:1 combination of Fentanyl and Droperidol Neuroleptic Malignant Syndrome (NMS) Patients who have been receiving Haldol or Droperidol for an extended period of time may develop this syndrome. The presentation as well as the treatment of NMS is very similar to malignant hyperthermia. As the anesthesia provider, you may be consulted to help manage this patient. Metoclopramide (Reglan) Substituted Benzamides Structure Structurally resembles procainamide but lacks local anesthetic properties Acts centrally at receptors in the CTZ of the CNS as a dopamine (D 2 ) antagonist Acts peripherally at cholinergic receptors in the stomach, small intestines and lower esophageal sphincter as a cholinomimetic, i.e. enhances the stimulatory effects of acetylcholine. Elimination 85% is excreted in the urine, 50% of which is unchanged. Decrease the dose in patients with renal dysfunction Mean elimination half-life is 2-4 hours with an onset time of 3-5 min (IV) or min (oral) Short duration of action of 1-2 hours Pharmacokinetic Properties and Dosing Most effective if administered at the end of surgery or during the immediate postoperative period Dose: mg IV/IM/PO (0.25 mg/kg) - administered IV over 5 minutes for the adult 80% of orally administered metoclopramide is rapidly absorbed and systemically available Dose: 0.15 mg/kg IV administered over 5 minutes for children < 40 kg with caution 193

199 Side Effects and Clinical Concerns Rapid injection may cause abdominal cramping and increased risk for extrapyramidal signs Many providers administer Midazolam prior to metoclopramide injection. Hypotension, hypertension and dysrhythmias can occur so give cautiously to hypertensive patients. Extrapyramidal reactions, sedation and nervousness, can occur and are reversible. Contraindicated in patients with: Intestinal obstruction, GI perforation, GI hemorrhage Parkinson s Disease, Epilepsy Pheochromocytoma Hypertensive crisis can occur if given to a patient with a pheochromocytoma. It increases catecholamine secretion by the tumor. Use cautiously in children due to an increased risk for extrapyramidal reactions. **Clinical Use** Most effective against opioid induced decreased GI motility during the immediate postop period. Decreases preoperative gastric fluid volume by accelerating gastric emptying It does not decrease or affect the secretion of gastric acid or the ph of gastric fluid. Symptomatic treatment of GERD and Diabetic Gastroparesis by increasing lower esophageal sphincter tone by cm H 2 O. Drug Interactions MAO inhibitors can potentiate the hypertensive effects of metoclopramide. Antimuscarinic drugs such as atropine and glycopyrrolate block the GI effects of metoclopramide. Concurrent use of MAO inhibitors, tricyclic antidepressants, phenothiazines and butyrophenones increases the likelihood of extrapyramidal side effects. It inhibits plasma cholinesterase activity. In susceptible patients, it can prolong the effects of succinycholine, mivacurium, and ester local anesthetics. Scopolamine Anticholinergics Structure Refer to Chapter 12 for structure information Acts in the central nervous system (CNS) by blocking cholinergic transmission from the vestibular nuclei to higher centers in the CNS and from the reticular formation to the vomiting center Potent inhibitor of cholinergic CNS emetic receptors in the cerebral cortex and pons Decreases gastric acid secretion, gastrointestinal motility, and lower esophageal sphincter tone Elimination Extensively metabolized with minimal unchanged drug excreted in the urine Mean elimination half-life is 9 hours after the patch is removed. Must be applied 4 hours preoperative with a peak effect in less than 24 hours. The patient should keep the patch on for at least 24 hours postoperative. 194

200 Pharmacokinetic Properties and Dosing Dose: Transderm Scóp 1.5 mg patch delivers 1.0 mg of scopolamine over 72 hours. Oral or IV administration of scopolamine would require large doses, resulting in undesirable side effects. IV scopolamine is utilized more often for its sedative properties. The safety and effectiveness of Transderm Scóp in children has not been established. Side Effects and Clinical Concerns Sedation, dry mouth, dizziness, urinary retention and blurred vision Can cause temporary dilation of the pupils and blurred vision if it comes in contact with the eyes Confusion, anxiety Central Anticholinergic Syndrome Treatment of choice is physostigmine µg/kg IV. **Clinical Use** Prevention of nausea and vomiting associated with motion sickness and recovery from anesthesia Caution with: Narrow-angle glaucoma, intestinal obstruction, coronary heart disease Atropine crosses the blood brain barrier but is used less often. Glycopyrrolate is a quaternary amine so it is not effective as an antiemetic. Antihistamines H 1 -Receptor Antagonists Diphenhydramine (Benadryl) Structure Is an ethanolamine with atropine-like activity used to treat allergic symptoms, vertigo/motion sickness, Parkinson s, sedation, drug-induced extrapyramidal reactions, nausea and vomiting. Blocks histamine (H1) receptors in the nucleus of the solitary tract It DOES NOT block the release of histamine. Blocks acetylcholine (ACh) receptors in the vestibular apparatus of the inner ear Elimination Both excreted unchanged in the urine and metabolized in the liver. Pharmacokinetic Properties and Dosing Dose: mg IV over 1-2 minutes Onset time usually occurs within a few minutes. Side Effects and Clinical Concerns Sedation, dizziness and urinary retention Dry mouth and blurred vision due to anticholinergic effects Hypotension Unopposed H 2 vasodilatation **Clinical Use** Antiemetic of choice following middle ear surgery Prevention of nausea and vomiting associated with motion sickness Local anesthetic properties Sedative properties usually do not affect the respiratory drive but can potentiate other CNS depressants 195

201 Phenothiazines Promethazine (Phenergan) Prochlorperazine (Compazine) Structure Has a tricyclic nucleus with an aliphatic side chain Blocks Dopamine (D 2 ) in the CTZ with moderate antihistaminergic and anticholinergic actions Elimination Metabolized in the liver and its metabolites are excreted in the urine. Use caution in patients with liver failure. Elimination half-life is 9-16 hours. Duration of action after IV administration is 4-6 hours Pharmacokinetic Properties and Dosing Promethazine Dose: Adult: mg IV Promethazine Dose: Child: mg/kg IV Prochlorperazine Dose: Adult: mg IV & 5-10 mg IM/PO Neither is recommended for children under 2 years of age due to extrapyramidal reactions. Side Effects and Clinical Concerns Significant sedation that can prolong and intensify the effects of narcotics, general anesthetics and sedative-hypnotics. High incidence of extrapyramidal symptoms (D 2 ) Neuroleptic Malignant Syndrome (NMS) can occur especially with longer-term use. Treated with Bromocryptine. Drug induced hypotension should be treated with phenylephrine not with epinephrine. Caution: Phenergan ampules contain sulfites. Do Not administer to patients with a sulfite allergy. **Clinical Use** Prevention of nausea and vomiting associated with motion sickness Combination with narcotics pre/post-op Dexamethasone (Decadron) Corticosteroids Structure Synthetic steroid An anti-inflammatory and/or membrane stabilizing effect may play a role in the antiemetic action of corticosteroids. Prostaglandin inhibition has also been hypothesized. Elimination Elimination half-life is hours. Onset is within a few minutes. 196

202 Pharmacokinetic Properties and Dosing Dose: Adult: 4-10 mg Dose: Child: 0.1 mg/kg More effective antiemetic when given pre-induction Side Effects and Clinical Concerns The solution contains phosphate and causes flushing and perineal itching. A single dose does not appear to interfere with wound healing. Other Antiemetics Propofol Antiemetic properties may be due to a direct depressant affect at CTZ. Recent studies show that it is probably not due to anti-dopaminergic properties. Dose: 10 mg IV for postoperative nausea and vomiting. Short duration of action so be prepared to treat nausea with another agent. Basic Guidelines 1. Consider preoperative anxiolytics (Midazolam) to decrease the risk of PONV 2. Limit opioids (but keep patient comfortable); Avoid Nitrous oxide and anticholinesterase agents if possible 3. Rapid sequence induction with cricoid pressure, no mask ventilation (to minimize air entry into the stomach) 4. Use anesthetic agents that have a low PONV potential, i.e. Propofol, Sevoflurane 5. Avoid IV anesthetic agents that have a high PONV potential, i.e. Etomidate, Desflurane 6. Prophylactic antiemetics for PONV prone patients and procedures 7. NG/OG suction prior to extubation 8. Intravenous hydration of 20 ml/kg is recommended to prevent postoperative dizziness and nausea. 9. Maintain BP, avoid hypotension (consider Ephedrine IM/IV) 10. PONV management in the PACU a. Ensure: adequate pain control, hydration and oxygenation. b. Avoid: tight-fitting masks, rapid movements, overuse of oropharyngeal suctioning and oral airways. c. Antiemetic treatment PRN Use a combination of antiemetic medications acting at different receptor sites If the first antiemetic agent is not effective, then use a different antiemetic acting at a different midbrain emetic receptor site. Do not continue to use the same agent. 197

203 Side Effects of Commonly Used Antiemetics Sedation Diphenhydramine, Hydroxyzine Droperidol Promethazine/Prochlorperazine Extrapyramidal Symptoms Droperidol Metoclopramide Promethazine/Prochlorperazine Dysphoria Droperidol Scopolamine, Atropine Headache/Dizziness Dolasetron Ondansetron Dry mouth Atropine, Scopolamine Diphenhydramine Hydroxyzine Hypotension Droperidol Promethazine/Prochlorperazine Table 16-4: (Kovac, A., Antiemetic Use in Postoperative Nausea and Vomiting, Drugs, 2000; 59 (2): with modification.) Dosing Guidelines for Antiemetic Medications Class Drug Route Initial Dose Frequency/Timing Anticholinergics Scopolamine IM, IV, Transderm Adult: mg Adult 1.5 mg (apply 4 hrs q 6-8 hrs q 72 hrs Patch preop) Antihistamines Diphenhydramine IM, IV Adult: mg q 2-4 hrs PO Adult: mg q 6-8 hrs Hydroxyzine PO IM Adult: mg Adult: mg q 6 hrs At start of anesthesia Benzamides Metoclopramide IM, IV, PO Adult: mg At end of surgery IV Child: 0.15 mg/kg (max 10 mg) Butyrophenones Droperidol IM, IV Adult: mg Child: µg/kg At start of anesthesia 5-HT 3 receptor Antagonists Phenothiazines Steroids Ondansetron PO IV Adult: 8-16 mg Adult: 4 mg Child: 0.1 mg/kg (max 4 mg) Rescue Dose: 1 mg Adult: 100 mg 1-2 hrs prior to anesthesia At start of anesthesia Dolasetron PO 1-2 hrs prior to anesthesia IV Adult: 12.5 mg 15 min prior to end of Child: 0.35 mg/kg (max 12.5) anesthesia Granisetron IV Adult: 1 mg Prior to anesthesia or Child: 40 µg/kg (max 1 mg) on extubation Promethazine IM, IV, PO Adult: mg q 4-8 hrs Child: mg/kg q 6-8 hrs Prochlorperazine IV Adult: mg q 3-4 hrs IM, PO Adult: 5-10 mg Betamethasone IM Adult: 12 mg At start of anesthesia Dexamethasone IV Adult: 4-10 mg Child: 0.1 mg/kg At start of anesthesia Table 16-5: (Kovac, A., Antiemetic Use in Postoperative Nausea and Vomiting, Drugs, 2000; 59 (2): with modification.) 198

204 Guidelines for Prophylactic Antiemetic Therapy Patient Factors Female gender H/O PONV Nonsmoker Use of opioids Surgical Factors Laparoscopy Strabismus ENT Breast surgery Gynecologic surgery Mild to Mod Risk 1-2 factors present (20-40%) Any 1 of the following: Dexamethasone Scopolamine Prochlorperazine 5-HT 3 antagonist Mod to High Risk 3-4 factors present (40-80%) Dexamethasone + 5-HT 3 antagonist Droperidol + 5-HT 3 antagonist Very High Risk > 4 factors present (> 80%) Combination antiemetics + TIVA with propofol Figure 16-3: (Kovac, A., Antiemetic Use in Postoperative Nausea and Vomiting, Drugs, 2000; 59 (2): with modification.) Triad of Aspiration Pneumonitis Prophylaxis Aspiration pneumonitis (Mendelson's syndrome) is a chemical injury caused by the inhalation of sterile gastric contents. It is a recognized complication of general anesthesia, accounting for 10 to 30 percent of all deaths associated with anesthesia. To decrease the risk of aspiration pneumonitis, anesthesia providers commonly administer the following triad of drugs: 1. H 2 -Receptor Antagonists Ranitidine (Zantac) Cimetidine (Tagamet) 2. Gastroprokinetic Agents Metoclopramide (Reglan) 3. Nonparticulate Antacids Sodium citrate (Bicitra) Under no circumstances should the administration of these drugs preclude you as the anesthesia provider from adequately protecting the airway. A cuffed endotracheal tube inserted after a rapid sequence induction with cricoid pressure or following an awake fiberoptic intubation is the standard of care. 199

205 H 2 -Receptor Antagonists Ranitidine (Zantac) Structure Competitively blocks H 2 -receptors of acid-secreting parietal cells in the stomach so that secretion of hydrogen ions is decreased. It increases the ph of gastric fluid being produced. It DOES NOT increase the ph of the fluid already present in the stomach. Nonparticulate antacids are given to raise the ph of stomach contents. It DOES NOT decrease the formation or release of histamine. Elimination 50-70% is found unchanged in the urine. Use with caution in patients with renal failure. Elimination half-life is hours. Duration of action is 6-8 hours. Pharmacokinetic Properties and Dosing Dose: Adult: 50 mg in 50 cc of NS over minutes every 6-8 hours Onset time of 15 minutes after infusion. Dose: Adult: 150 mg at bedtime and two hours prior to surgery Bioavailability is approximately 50%. It has significant first-pass hepatic metabolism. Onset time of 30 minutes with peak effect at 1-3 hours Dose: Child: 2-4 mg/kg (max 50 mg) in 50 cc of NS every 6-8 hours Side Effects and Clinical Concerns Weak inhibitor of the cytochrome P-450 system Burning at the IV injection site can occur Headaches, sometimes severe, and diarrhea are common. Poorly penetrates the blood brain barrier so mental confusion is rarely observed. Bradycardia with rapid infusion due to blockade of cardiac H 2 -receptors. Hypotension with rapid infusion due to peripheral vasodilatation but it can also suppress histamine-induced peripheral vasodilatation. Bronchospasm due to unopposed histamine effects of H 1 -receptors on bronchial smooth muscle. Avoid in patients with acute porphyria because it can precipitate an attack. May potentiate succinylcholine-depolarizing blockade by its anticholinesterase effects. **Clinical Use** Decreases gastric acid production and raises gastric ph to reduce the risk of aspiration pneumonia It has no effect on gastric emptying time or lower esophageal sphincter tone. Peptic ulcer diseases, Gastroesophageal Reflux Disease (GERD), Hiatal Hernia 200

206 Cimetidine (Tagamet) Structure Competitively inhibits histamine binding to H 2 -receptors of parietal cells similar to ranitidine. It DOES NOT decrease the formation or release of histamine. Elimination 50-80% is found unchanged in the urine. Use with caution in patients with renal failure. Elimination half-life is 2.0 hours with a duration of action of 6-8 hours. Pharmacokinetic Properties and Dosing Dose: Adult: 300 mg in 50 cc of NS over minutes every 6-8 hours Onset time of 15 minutes after infusion. Dose: Adult: mg two hours prior to surgery Bioavailability is approximately 60%. So it has significant first-pass hepatic metabolism. Onset time of 45 minutes with a peak effect at minutes. Side Effects and Clinical Concerns Significant binding of cimetidine to the heme portion of the cytochrome P-450 oxidase system It competitively inhibits cytochrome P-450 enzyme activity, i.e. an Enzyme Inhibitor. Reduces the metabolism of propranolol, phenytoin, lidocaine, warfarin, labetalol and diazepam resulting in potential toxicity. Headaches, sometimes severe, and diarrhea are common. Slurred speech, delirium and confusion occur more often with cimetidine than with ranitidine especially in the elderly patient. Bradycardia, hypotension or heart block can occur following rapid IV infusion. Increases the neuromuscular blocking effects of depolarizing and nondepolarizing drugs. Higher incidence of granulocytopenia, thrombocytopenia, and aplastic anemia with cimetidine. Can cause bronchospasm due to unopposed H 1 mediated bronchoconstriction **Clinical Use** Decreases gastric acid production and raises gastric ph to reduce the risk of aspiration pneumonitis It has no effect on gastric emptying time or lower esophageal sphincter tone. Peptic ulcer diseases, Gastroesophageal Reflux Disease (GERD), Hiatal Hernia Metoclopramide (Reglan) Gastroprokinetic Agents Pharmacokinetic Properties and Clinical Concerns Administered as part of the gastric prep during the preoperative period. Caution: Rapid injection can cause severe abdominal cramping. It enhances the stimulatory effects of acetylcholine on intestinal smooth muscle which: 1. Increases lower esophageal sphincter tone. 2. Speeds gastric emptying which lowers gastric fluid volume. No effect on gastric secretions or the ph of gastric fluid. See Antiemetic section page 193 for more detailed information 201

207 Nonparticulate Antacids Sodium Citrate (Bicitra) Elimination Hepatic elimination Pharmacokinetic Properties and Dosing Non-particulate antacid containing sodium citrate and citric acid that neutralizes stomach acid Reacts with hydrogen ions in the gastric fluid to form water Dose: Adult: a single dose of cc given minutes prior to induction Antacids lose their effectiveness within minutes after ingestion so timing is critical. Repeat dosing of Bicitra, i.e. on the labor deck, can cause an extremely elevated gastric volume that can be more problematic than aspirating untreated gastric contents. Side Effects and Clinical Concerns Particulate antacids if aspirated can cause as much damage as untreated gastric contents. Giving Bicitra decreases the risk of aspiration pneumonitis; however the risk of aspiration is increased due to the increase in gastric volume. Nonparticulate antacids mix more completely with gastric fluid than do particulate antacids Many patients vomit soon after drinking Bicitra. Altering stomach ph can change the absorption and elimination of many drugs Ranitidine & cimetidine absorption is slowed. **Clinical Use** Gastroesophageal Reflux Disease (GERD), Hiatal Hernia, Full Stomach Pharmacology of Aspiration Pneumonitis Prophylaxis Drug Route Dose Onset Duration Acidity Volume LES tone Cimetidine PO IV mg 300 mg 1-2 hours 15 min 4-8 hrs No effect Ranitidine PO IV mg 50 mg 1-2 hours 30 min hrs No effect Bicitra PO ml 5-10 min min No effect Metoclopramide PO IV mg mg min 3-5 min 1-2 hrs No effect = Moderate decrease = Marked decrease = Slight increase = Moderate increase LES tone = Lower esophageal sphincter tone Table 16-6 (Morgan, E., Mikhail, M., Murray, M. (2002). Clinical Anesthesiology. 3 rd Edition, New York: McGraw- Hill, p 244 with modification.) 202

208 Chapter 17 Adrenergic Drugs Adrenergic nerves release norepinephrine as the neurotransmitter for the sympathetic nervous system. The sympathetic nervous system activates and prepares the body for vigorous muscular activity, stress, and emergencies. Adrenergic drugs stimulate the adrenergic nerves directly by mimicking the action of norepinephrine or indirectly by stimulating the release of norepinephrine. There are at least two adrenergic receptor sites (alpha and beta). Norepinephrine activates primarily alpha-receptors and epinephrine activates primarily beta-receptors, although it may also activate alphareceptors in high concentrations. Anesthetists administer drugs that evoke or antagonize physiologic responses similar to those produced by the sympathetic nervous system. Figure 17-1: (Mycek, Mary J., et al. (2000). Lippincott s Illustrated Reviews: Pharmacology. 2 nd Edition, pg 32). Table Major Effects Mediated by α- and β- Adrenoreceptors α 1 α 2 β 1 β 2 Vasoconstriction Inhibition of Tachycardia - Vasodilatation Norepinephrine release Chronotropy Increased Peripheral resistance Inhibition of Insulin release Increased Myocardial contractility Inotropy Slightly Decreased Peripheral resistance Increased Blood Pressure Platelet aggregation Increased conduction velocity - Dromotropy Induces hypokalemia drives K + into the cells Bronchoconstriction Decreased Lipolysis Increased Lipolysis Bronchodilatation Decreased nasal congestion Reduces sympathetic outflow, i.e. Sympatholytic Increased muscle and liver Glycogenolysis Mydriasis Increased Glucagon Smooth muscle contraction of gut, uterus, and bladder Smooth muscle relaxation of gut, uterus, and bladder Table 17-1: (Mycek, Mary J., et al. (2000). Lippincott s Illustrated Reviews: Pharmacology. 2 nd Edition, pg 60, with modification). 203

209 Figure 17-2: (Morgan, E., Mikhail, M. & Murray, M. (2002). Clinical Anesthesiology. 3 rd Edition, p. 213) Definition of Terms: Sympathomimetic Drugs drugs that mimic the actions of epinephrine or norepinephrine Sympatholytic Drugs drugs that reduce the sympathetic outflow Catecholamines sympathomimetic amine containing a 3,4-dihydroxybenzene group Typically potent, but short acting (IV) due to its metabolism by COMT & MAO Ineffective if administered orally Noncatecholamines lacks hydroxyl group on the 3,4 carbon position of the benzene ring Not inactivated by COMT, or MAO so have longer half-lives Can be given orally Direct acting agents bind to and activate receptors Indirect acting sympathomimetics displace norepinephrine from the storage vesicles of adrenergic nerves thereby increasing endogenous neurotransmitter activity. Mixed-action induces release of norepinephrine from presynaptic terminals and activates postsynaptic receptors. 204

210 Figure 17-3: (Neal, M. J. (1995). Medical Pharmacology at a Glance. 2 nd Edition, pg 24 with modification). Definition of Terms continued: Uptake 1 recaptures (reuptake) most of the released norepinephrine and is the main method of terminating the actions of norepinephrine following its release into the synaptic cleft. Uptake 2 - reuptake into smooth muscle cells, similar transport process in the tissues but is less selective and less easily saturated. Monoamine oxidase (MAO) & Catechol-O-methyltransferase (COMT) widely distributed enzymes that catabolize catecholamines. Not the major means of terminating norepinephrine. Adrenergic blockers and adrenoreceptor antagonists are considered sympatholytic agents. Tachyphylaxis loss of effect when exposure is prolonged or repeated Supersensitization occurs when up-regulation of receptors results in an exaggerated response. 205

211 Figure 17-4: (Mycek, Mary J., et al. (2000). Lippincott s Illustrated Reviews: Pharmacology. 2 nd Edition, pg 57). NOREPINEPHRINE 1. SYNTHESIS Tyrosine DOPA DOPA Dopamine 2. STORAGE Dopamine converted to norepinephrine (NE) in vesicles 3. RELEASE Action potential causes influx of Ca ++ Results in NE filled vesicles fusing with the cell membrane for release into the synapse 4. RECEPTOR BINDING NE diffuses across the synapse binds to postsynaptic receptors on effector organ, or presynaptic receptors on nerve ending Recognition of NE by receptors triggers a cascade of events, resulting in the formation of second messengers Cyclic adenosine monophosphate (camp) Phosphoinositide cycle (IP 3 ) 5. REMOVAL OF NEUROTRANSMITTER Recaptured by uptake back into the neuron Diffuse out of synapse Metabolized to O-methylated derivatives by COMT 206