UNIFORMED SERVICES UNIVERSITY

of the Health Sciences

NURSE ANESTHESIA PROGRAM

ANESTHESIA PHARMACOLOGY NOTESET

2009 REVISION

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. Determines the intensity of the drugs effect with time e. 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

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Dose of drug administered

PHARMACOKINETICS

ABSORPTION
Drug concentration in systemic circulation

DISTRIBUTION REDISTRIBUTION

Drug in tissues of distribution

ELIMINATION
Drug metabolized or excreted
Drug concentration at site of action

PHARMACODYNAMICS
Pharmacologic Effect Clinical Response Toxicity Efficacy

Fig. 1-1: (Katzung, Bertram G., Basic & Clinical Pharmacology, 10th Ed., 2007, figure 3-1 with modification.)

Absorption
Many factors affect systemic absorption of drugs. Some of the most important factors are listed below. 1. 2. 3. 4. 5. Route of administration Drug properties (solubility) Circulation to site of absorption Local tissue conditions Area of absorbing surface

**Absorption does NOT occur with intravenously administered drugs.

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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 preparation. 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 enter the portal venous blood and pass through the liver before entering the systemic circulation for delivery to tissue receptors (Fig. 1-2). 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 80-320 mg / IV 0.5-3.0 mg)

Fig 1-2: (Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 4th Ed. 2006, p 9.)

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 non-ionized, highly lipidsoluble 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

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Transcutaneous/Transdermal Administration
Commonly used to administer medications in patch form, such as Nitroglycerin, Scopolamine, Clonidine, and opioids (Duragesic/Fentanyl) 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. Ex: Succinylcholine can be given IM under the tongue or submentally into the glossal region. Disadvantages: 1. High local concentration deposited into muscle mass can cause tissue damage. 2. Rate limiting factor includes local blood flow. 3. Drugs must be in aqueous solution to be readily and predictably absorbed.

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 Tylenol, 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.

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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 and epidural Depodur. Disadvantages: 1. Requires expertise in the technique of administration 2. Requires use of larger volumes of drug to elicit clinical effect. 3. Adverse systemic drug effects.

Routes of Administration for Drug Delivery

ROUTE Sublingual (SL) Oral (PO) Stomach Duodenum Jejunum, Ileum Rectal Intranasal Intratracheal Transcutaneous Subcutaneous Intramuscular (IM) Intravenous (IV) Intrathecal Epidural Inhalational Intraorbital Intraarticular Lungs Orbit (eye) Joint Muscle Venous Trachea, Bronchi Skin Colon 1-3 4.8-8.2 7.5-8.0 7.0-7.5 TISSUE LOCAL pH FIRST PASS EFFECT No (SVC) Yes Yes Yes Yes/No (~ 50%) No No No No No No No No No No No

Table 1-1: (Produced from information in Miller, R.D. Anesthesia. 2005, Chapter 2 & Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 2006, Chapter 1.)

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Impact of Circulation on Absorption

Blood flow to the site can greatly affect the rate of absorption of a drug.

Vasodilation (heat, rubbing) Increased rate of absorption Vasoconstriction (hypothermia) Decreased rate of absorption

Body Tissue Composition and Relative Blood Flow (Average 70 kg adult)

% Cardiac Output Perfusion (ml/min/100 g)

Tissue Group

Organ/Tissue

% Body Mass

Central Compartments

VRG (Vessel Rich)

Muscle Group Fat Group VPG (Vessel Poor)

Lungs Heart 10 Brain Liver Kidney Peripheral Compartments Skeletal Muscle 50 Skin Adipose Bone Cartilage 20 20

75

75

19 6 <1

3 3 0

Table 1-2: (Produced from information in Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 2006, p 10, Nagelhout, J.J. Nurse Anesthesia. 2005, p 67)

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 (alveolar blood flow equals cardiac output), and GI tract (primarily the small intestine).

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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 (solubility of aqueous and organic solvents) Lipid solubility Molecular weight pKa, pH and Blood flow Patient age, sex, temp, pathology

Dose-Response Curves
Refers to the relationship between increasing doses of a drug and the ensuing changes in pharmacological effects. Four Aspects of the dose-response curve (Figure 1-3): Potency dose required to produce a given effect in 50% of patients i.e. ED50 Slope rate of increase in effect as the dose is increased o Usually between 20%-80% of the maximal effect Efficacy maximum effect of the drug Variability the difference in the potency, efficacy, and slope between different patients o Curve shifts right or left for different patients

Fig 1-3: (Barash, P.G. Clinical Anesthesia. 5th Ed. 2006, p. 263, with modifications.)

Drug-Receptor Interactions
Agonists Drugs that bind to receptors and produce a maximal effect (curve A) o Ex: Succinylcholine, morphine Partial Agonists Drugs that are not capable of producing the maximal effect at any dose (curve C) o Ex: Meptazinol Antagonists Drugs that bind to receptors without producing any effects Competitive Antagonists Drug binds reversibly to receptors, but can be overcome by large amounts of agonists (curves A -agonist and B-antagonist) o Ex: Rocuronium Noncompetitive Antagonists Drug binds irreversibly to receptors, same as decreasing the number of receptors, slope and maximal effect, cannot be overcome by large amounts of agonists (curves A and C) o Ex: Phenoxybenzamine

Fig 1-4: (Barash, P.G. Clinical Anesthesia. 5th Ed. 2006, p. 265.)

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DISTRIBUTION
Major Determinants Blood flow (see table 1-2) Concentration gradient (administered dose) Drug physical/chemical properties Blood-brain barrier

Volume of Distribution (Vd)

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. Vd 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. Vd reflects the ratio of drug in extraplasmic spaces (tissue) relative to the plasma space.

Mathematical calculation:

Vd

Dose of drug Plasma concentration before elimination

Vd 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 Drugs with a large Vd Low plasma concentration Low availability for elimination Drugs with a small Vd High plasma concentration High availability for elimination

** 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 Vd. 2. Vecuronium is a large, poorly soluble compound that stays primarily in the central compartment. Its Vd is said to be very small, and is similar to extracellular fluid. ** The smallest Vd 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 5.5 13 42 L L L L

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Vss = Sum of the Vd of all compartments at steady state or equilibrium.

Vd of some commonly used drugs in anesthesia

Fig. 1-5: (Barash, P.G. Clinical Anesthesia. 5th Ed. 2006, p. 260)

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 initial distribution from the central compartment to the peripheral tissues. c. Slope is especially steep for highly lipid soluble drugs. 2. Elimination Phase (Beta Phase) a. Represents a gradual decline (plateau phase) in drug plasma concentration, as the drug is redistributed back into the central compartment. b. Reflects elimination by renal and hepatic clearance mechanisms. c. Used to determine the elimination half-life of drugs.

(Alpha Phase)

(Beta Phase)

Fig. 1-6: (Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 4th Ed. 2006, p.6 with modification.)

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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. 1-7: Hypothetical redistribution model of a single IV bolus injection of 250 mg Sodium Thiopental 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 Propofol. 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. Fetal pH < maternal pH Basic drugs (opioids/local anesthetics) become more ionized in the fetus Higher drug concentration in fetal than maternal blood i.e. ion trapping.

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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. It increases the drugs polarity and prepares for phase II reactions Major Phase I reactions o Oxidation o Reduction o Hydrolysis

Phase II Reactions + POLAR + SUBSTRATE

ENDOGENOUS COMPOUND

EXCRETABLE HYDROPHILIC SUBSTANCE

PHASE II - THINK CONJUGATION 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 Phase II Reactions

Excretable Hydrophilic Substances

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MAJOR BIOTRANSFORMATION REACTIONS

Phase I OXIDATION N-dealkylation O-dealkylation Side chain Hydroxylation N-Hydroxylation N-Oxidation S-Oxidation Oxidative Deamination Desulfuration Dehalogenation N-demethylation O-demethylation REDUCTION Azoreduction Nitroreduction HYDROLYSIS Ester hydrolysis Amide hydrolysis Phase II CONJUGATION Glucuronide Conjugation Glycine Conjugation Sulfur Conjugation Methylation Amino Acid Conjugation Acetate Conjugation

Table 1-3: (Produced from information in Barash, P.G., Cullen, B.F., & Stoelting, R.K. Clinical Anesthesia. 2006, Chapter 11, & Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 2006, Chapter 1.)

Major Anesthesia Drugs & Principle Metabolic Pathways

Inhaled Agents Halothane Morphine Fentanyl Sufentanil Alfentanil Remifentanil Demerol Sodium Thiopental Propofol Etomidate Ketamine Midazolam Ester Local Anesthetics Amide Local Anesthetics Succinylcholine Pancuronium, Vecuronium Atracurium Rocuronium Cis-atracurium Mivacurium Neostigmine Glycopyrrolate Oxidative metabolism (Cytochrome-P-450) Oxidative and reductive metabolism Glucuronidation N-demethylation N-dealkylation, O-demethylation N-dealkylation Nonspecific plasma esterases (major) N-dealkylation (minor) Demethylation, Hydrolysis Hydroxylation, Desulfuration Desulfuration, Glucuronidation Ester Hydrolysis in liver and plasma Demethylation, Hydroxylation, Glucuronidation Hydroxylation, Glucuronidation Hydrolysis by plasma cholinesterase Hydrolysis, dealkylation Plasma cholinesterase hydrolysis Deacetylation Hofmann Elimination, Nonspecific esterase metabolism Biliary and renal excretion Hofmann Elimination Plasma cholinesterase hydrolysis Hydroxylation, Renal excretion Renal excretion

Table 1-4: (Produced from information in Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 4th Ed. 2006, Chapters 2-10.)

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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 CP-450 system. A variety of factors can alter the C-P-450 system, leading to induction (acceleration/ stimulation) or inhibition of enzyme activity. Major factors are listed below:
Cytochrome-P-450 Inhibition Organ Dysfunction Cimetidine Acute alcohol ingestion

Cytochrome-P-450 Induction Barbiturates Phenytoin Rifampin Macrolide antibiotics (Erythromycin) Imidazole antifungal agents Corticosteroids Carbamazepine Chronic alcohol ingestion Smoking

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, gall bladder, and kidney.

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. Liver failure has minimal effect on clearance. o Hepatic blood flow Rate of clearance 2. If the hepatic extraction ratio is low (<0.3), drug clearance will depend primarily on enzymatic metabolism. Liver failure has a large effect on clearance. o Enzyme Activity (liver failure) Rate of Clearance o Protein Binding Rate of Clearance

**High Hepatic Extraction = Perfusion-dependent elimination = High clearance drugs **Low Hepatic Extraction = Capacity-dependent elimination

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Classification of Drugs according to Hepatic Extraction Ratios

Low Diazepam Lorazepam Methadone Phenytoin Rocuronium Theophylline Thiopental Intermediate Alfentanil Methohexital Midazolam Vecuronium High Bupivacaine Diltiazem Fentanyl Ketamine Lidocaine Meperidine Morphine Naloxone Propofol Sufentanil

Table 1-5: (Barash, P.G., Clinical Anesthesia. 5th Ed. 2006, p. 252 with modification.)

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. o Example: Rocuronium

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. o Drug bound to proteins is not filtered. o Even if none of the drug were bound to proteins only 20% can be removed by GFR. Renal secretion is often used to actively transport protein-bound drugs across the tubular lumen for elimination. Renal reabsorption is often used for more lipophilic drugs that can easily cross the cell membrane of the renal tubular epithelium and thus are not eliminated. o Drugs that are highly ionized will not be reabsorbed and thus are eliminated. Urine pH is very important i.e. weak acids are excreted rapidly in alkaline urine. Drugs with significant renal excretion: Aminoglycosides, atenolol, cephalosporins, edrophonium, neostigmine, pancuronium, and penicillins.

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Fig 1-8: Overall Process of Drug Distribution and Elimination

Tissue Compartments Blood

Drug Effect Redistribution

Blood

C-P-450 Hepatic Biotransformation

Hydrophilic Excretable Metabolites

Unchanged Drug Excretion

Bile

GI Tract

Blood

Kidneys

Protein Bound Drug

Hydrophilic Metabolites Filtration (Glomerulus) Renal Tubular Lumen

Lipophilic Metabolites

Renal Secretion (Distal Renal Tubule)

Renal Reabsorption (Proximal Renal Tubule) Excretion from the body

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Elimination Kinetics
First-Order Kinetics
The fraction of drug in the body removed over time remains constant. The absolute amount or concentration of drug removed over time is directly proportional to the amount of drug in the body. High Concentration of drug High Elimination of drug Example: 50% of remaining plasma concentration of drug will be eliminated per hour.

log plot

Conc
linear plot

Time
(Fig 1-9) Zero-Order Kinetics
The fraction of drug in the body removed over time varies. The absolute amount or concentration of drug removed over time is constant, and does not change with the amount of drug in the body. Example: No matter how much drug was administered only 5 mg will be eliminated per hour.

log plot

Conc

linear plot

(Fig 1-10)

Time

The graphs above illustrate a hypothetical drug exhibiting both first-order (Fig 1-9) and zero-order (Fig 1-10) elimination kinetics in a one-compartment model. Notice that both the linear and logarithmic plots are represented.

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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)

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 = 0.693 k
** Elimination half time is directly proportional to Vd, and indirectly proportional to drug clearance. ** Any factor that alters Vd 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
0 1 2 3 4 5 6

Fraction of Initial Drug Remaining

1 1/8 1/16 1/32 1/64

Percent of Initial Amount Eliminated

0 50 75 87.5 93.8 96.9 98.4

Table 1-6: (Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 4th Ed., 2006, p.7.)

**Approximately five elimination half times are needed for near complete elimination of the drug. **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.)

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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 Zero-order metabolism

50
First-order metabolism

Low

Dose of drug

High

Fig 1-11: (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 1-11 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 (Vd), and elimination half-times (T).

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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 Vd
Cl

(Fig 1-12)

Ke

Vd = Volume of distribution Ke = First-order elimination rate constant Cl = Clearance Assumptions:

1. 2. 3. 4. 5. The body is a single compartment. Drug distribution is instantaneous. There are no concentration gradients. Concentration decreases only by elimination from the compartment. Prior to elimination, the amount of drug present is equal to the amount of drug injected. Therefore;

Vd

_________ dose of drug__ ______ 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 1-13)

Fig 1-13: (Barash, P.G. Clinical Anesthesia. 5th Ed., 2006, p.260 with modification.)

The slope of the log plot is equal to the first-order elimination rate constant (Ke).

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Key Relationships:
1. Clearance (Cl) is equal to the product of the elimination rate constant and the volume of distribution.

Cl = Ke X Vd
2. The elimination half-life is equal to the product of the Vd and the constant 0.693 divided by the Cl.

T = 0.693 X Vd Cl Key Concepts:

The important conclusions to draw from these equations are: 1. There exists a mathematical relationship between Cl, Vd, Ke, and T1/2. 2. The greater the Vd, the longer the T. (and vise versa) 3. The greater the Cl, the shorter the T. (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.

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.

Two Compartments
Drug Administered

Ka
Vd Peripheral Compartment

Vd Central Compartment

(Fig 1-14)

Kb Ke
Ka = Rate constant from central compartment Kb = Rate constant from peripheral compartment Ke = First-order elimination rate constant

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A hypothetical drug with two-compartment, first-order kinetics would display a concentration versus time logarithmic curve as shown below. (Fig 1-15)

Fig 1-15: (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 Vd 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 Slow Peripheral Compartment (Fat group)

Rapid Peripheral Compartment (Vessel-rich tissue, muscle tissue)

Ka
Central Compartment

Kc

Kb

Ke

Kd
(Fig 1-16)

Ka = rate constant from central to rapid peripheral compartment Kb = rate constant from rapid peripheral to central compartment Kc = rate constant from central to slow peripheral compartment Kd = rate constant from slow peripheral to central compartment Ke = first-order elimination rate constant

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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 1-17)

Rapid distribution

Slower distribution

Elimination

Fig 1-17: (Miller, Ronald D., Anesthesia. 6th Ed., 2005, p. 82 with modification.)

In this model (Fig 1-17), 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 vessel-rich 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.

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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.

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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 Vd 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, manufacturers recommendations are to use the patients 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.

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 Vd. 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).

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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 i.e. Thiopental/Propofol) 2. Alpha-1-acid glycoprotein (basic drugs i.e. morphine) 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. 2. 3. 4. 5. 6. Renal Failure or Nephrotic Syndrome Liver Disease Malabsorption Surgery/Stress Burns Elderly 7. Trauma 8. Malnutrition 9. Dilution by I.V. fluids 10. Congenital Analbuminemia 11. Pregnancy 12. Cancer

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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. Daltons 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 (Pbr). 4. Brain partial pressure (Pbr) = anesthetic effect ** Ultimate brain partial pressure is affected by a variety of factors. (Fig 2-1)

Vaporizer

Anesthesia Machine

Lungs

Brain
Fig: 2-1

Other Tissues

Blood

*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.

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General Definition

FA = the concentration of the anesthetic in the alveoli FI = the inspired concentration of the anesthetic FA/ FI = the ratio of alveolar concentration to inspired concentration. At equilibrium, this value equals one.
FA/FI ratio is expressed as a curve relative to time. Anesthetic agents can be compared based upon their FA/FI Curves

FA/FI Curves

Fig 2-2 (Morgan, E., Mikhail, M. & Murray, M. Clinical Anesthesiology. 2002, p.131.)

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General Concepts Blood: Gas Partition Coefficient 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 Methoxyflurane Halothane Enflurane Isoflurane Nitrous Oxide Desflurane Sevoflurane

Blood:Gas Brain:Blood Muscle:Blood Partition Partition Partition Coefficient Coefficient Coefficient 12 2.54 1.90 1.46 0.46 0.42 0.69 2 1.9 1.5 1.6 1.1 1.3 1.7 1.3 3.4 1.7 2.9 1.2 2.0 3.1

Fat:Blood Partition Coefficient 48.8 51.1 36.2 44.9 2.3 27.2 47.5

Oil:Gas Partition Coefficient 970 224 98 98 1.4 18.7 55

Table 2-1: (Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 2006, p. 27 with modification.)

Highly Soluble
Methoxyflurane

Intermediate Solubility
Halothane Enflurane Isoflurane

Poorly Soluble
Nitrous Oxide Desflurane 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.

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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 FA/FI curve and the quicker the agent will reach an FA/FI ratio of one.

** Refer to Figure 2-2. In observing this graph, notice how nitrous oxide has the fastest rate of rise compared to the other agents for two reasons. The administered concentration of nitrous oxide can be up to 70% as opposed to Desflurane which is administered at 6-8%. It is also poorly soluble, 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 PA. Other common abbreviations are listed below:

PI = Inhaled Partial Pressure PA = Alveolar Partial Pressure Pa = Arterial Partial Pressure Pbr = 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 PA and Pbr, in that PA eventually mirrors Pbr. As a result the following conclusion can be made.

PA can be used as an indirect measurement of anesthetic partial pressure at the brain. March 2009 29 Petty/Tilley

**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 Characteristics of Anesthesia Breathing System Functional Residual Capacity

Factors Affecting Transfer From Alveoli to Blood:

Blood-Gas Partition Coefficient Cardiac Output Alveolar-to-Venous Partial Pressure Difference

Factors Affecting Transfer From Blood to Brain:

Brain-Blood Partition Coefficient Cerebral Blood Flow Arterial-to-Venous Partial Pressure Difference

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 FA/FI curve is quicker, as FA approaches FI.

% gas delivered = PA = Pbr

This is also known as the concentration effect.

**Clinical Application**
This concept is frequently used with pediatric inductions, where the initial % agent delivered is much higher (concentration) 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.

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Alveolar Ventilation (VA)

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

** VA is the most important factor for Pbr. It is more important than changes in cardiac output.

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 PA. Three primary factors are: Volume of the external 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) **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. **Remember, the oxygen flush valve bypasses the vaporizer.

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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 FA/FI curve B:G coefficient = solubility = rate of rise of FA/FI curve

For agents that are highly soluble, a larger amount of the drug must be absorbed into the blood and vessel-rich tissues, before Pa = PA, and brain equilibrium is achieved.

Cardiac Output
Cardiac output = pulmonary blood flow Pulmonary blood flow determines PA, as more or less anesthetic agent is carried away from the lungs. ** A change in cardiac output affects primarily the rate of increase of PA 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 PA

cardiac output = tissue uptake = PA cardiac output = tissue uptake = PA **In agents that are less soluble (Nitrous Oxide, Sevoflurane, Desflurane), the rate of increase of PA is rapid regardless of changes in cardiac output, so they are less affected by 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 FA/FI 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.

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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 FA with FI.

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 20-32 hours. In other words, assuming a continuous administration of a constant volumes % of volatile agent, it would take 20-32 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 PA.

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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 PA approaches PI. 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 concentration effect is the primary reason that nitrous oxide has the fastest rise in the FA/FI curve. Remember that the administered concentration for nitrous oxide is up to 70% and the concentration for Desflurane is 6-8%. Also remember that the B:G partition coefficient is greater for nitrous oxide (0.46) as compared to Desflurane (0.42) so this cant be the primary reason.

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 PA 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, via the concentrating effect, of the second gas in a smaller lung volume accelerates the PA 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. 2006, p.25 with modification.)

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**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.

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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 = 7.5 min =

15 L 2 L/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

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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 Substance X = 1.89% Two time constants (15 min) = 0.86 X 3% = 2.58% Substance X = 3%

2 L/min Capacity = 15 L Substance X = 2.58%

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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 CO2 absorber. The volume of this system is typically 7 L. (3-L bag, 2-L CO2 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

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In the example above, the capacity of the system = 7 L, the flow through the system = 0.5 L/min

Time constant = 14 min =

7L 0.5 L/min 7L 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%

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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 Isoflurane = 0.76%

Two time constants (28 min) = 0.86 X 1.2% = 1.03%

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 Isoflurane = 1.14%

Four time constants (56 min) = 0.98 X 1.2% = 1.18%

1.2% Isoflurane Fresh Gas Flow = 0.5 L/min

Capacity = 7 L Isoflurane = 1.18% Petty/Tilley

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Now lets 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 7L 6 L/min 7L 6 L/min

Time constant = 1.2 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%

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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 Isoflurane = 1.03%

Three time constants (3.6 min) = 0.95 X 1.2% = 1.14%

1.2% Isoflurane Fresh Gas Flow = 6 L/min

Capacity = 7 L Isoflurane = 1.14%

Four time constants (4.8 min) = 0.98 X 1.2% = 1.18%

1.2% Isoflurane

Fresh Gas Flow = 6 L/min

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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 FA/FI 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 Tissue blood flow

Partition coefficient

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 Two Time Constants Three Time Constants Four Time Constants

= = = =

63% change (in FA/FI ratio) 86% change 95% change 98% change

Lets look at a hypothetical application of time constants in the context of inhaled anesthetics and tissue compartments: Tissue/Blood Flow Per 100 ml of Tissue 100 ml/min 3 ml/min 100 ml/min 2 ml/min Tissue/Blood Partition Coefficient 1 1 2 50 Time Constant (Minutes) 1 33 2 2500

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

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** 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 % Body Mass 9 50 19 Liters/70 kg 6 33 14 % Cardiac 75 18 7

Output * Liters/Min

VPG 22 12 0 0

1.0 0.4 * Cardiac Output = 5.4 Liters/Min

4.0

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 patients 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 patients 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

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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% - 0.76% = 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% - 1.03% = 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% - 1.14% = 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% - 1.14% = 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 ED50 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.

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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 (N2O) 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 Pbr and therefore is also a reflection of MAC concentration delivered.

1 MAC = ED50 1.3 MAC = ED95 0.3-0.4 MAC = MAC Awake (50% of patients will wake up in this MAC range for all
agents)

Inhalation Agents & Comparative MAC Information Agent N20 Halothane Enflurane Isoflurane Desflurane Sevoflurane MAC in 100% oxygen 104 0.75 1.6 1.1 6.6 1.8 MAC in 70% N20 ------0.29 0.65 0.5 2.8 0.66 Oil:Gas Partition Coefficient 1.4 224 98 98 18 55

Table 2-4 (Produced from information in Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 4th Ed. 2006, 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.

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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 Cocaine Hypernatremia Hyperthermia Increased circulating catecholamines Young age Factors Decreasing MAC Requirements Addition of N2O Hypothermia Pregnancy (possibly r/t progesterone) Older age Catecholamine depletion MAP < 50 mm Hg Acute alcohol ingestion or opioid use Premedications (opioids, anxiolytics) PaO2 < 38 mm Hg Lithium Factors Having No Impact On MAC Duration of Anesthesia Gender pH (unless CSF pH changes) PaCO2 between 15-95 mm Hg PaO2 > 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. 2. 3. 4. 5. All exhaled gases are rebreathed, except carbon dioxide. The CO2 absorber neutralizes all carbon dioxide. Exhaled gases are not scavenged. Adjustable pressure-limiting valve is completely closed. Low total fresh gas flows are utilized.

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Determining Fresh Gas Flows:

Must be equal to amount of gas taken up by the patients 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 = 150-250 cc/min]

For most adults, a fresh gas flow of 500-600 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-bellows 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 for surgeries greater than 2 hours. 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 25-100 cc/min. Modern anesthesia machines dont 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, CO2 canisters, Breathing Bag, Patients 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.

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Deployment Application FACTS:

Supplies of compressed gases are limited. Ventilators are user selectable between oxygen driven and air driven (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.

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CHAPTER 3 Basic Concepts Related To General Anesthesia

Stages of Anesthesia
Stage I: Analgesia/Amnesia (Clouding)
Begins with the induction of anesthesia and continues until the patient loses consciousness. The sensation of pain is not absent or lowered 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/Excitement)

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

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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 intercostals 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/Overdose)

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. 2. 3. 4. 5. 6. Assessment of eyelash reflex Presence of swallowing Assessment of depth and quality of respirations Assessment of position of eyes and size of pupils Tightness of jaw muscles 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.

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Theoretical Basis of General Anesthesia

Believe it or not, we dont 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 agents 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 + 0.5 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 dont 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 patients temperature does not make them more sensitive to anesthetics.

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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.

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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: http://www.udmercy.edu/crna/agm/mathweb.htm 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/H20 0.73 mm Hg = 1 cm/H20 760 mm Hg x 14.7 psi / 760 mm Hg = 14.7 psi 1 atmosphere = 760 mm Hg = 760 torr = 14.7 psi = 100 kPa
Temperature

F = [(C X 9)/5] + 32 C = [(F 32) X5]/9 Kelvin = C + 273 *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.

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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, 100.0 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
1:1000 1:10,000 1:100,000 1:200,000 1:400,000
Table 4-1

mg/cc
1 0.1 0.01 0.005 0.0025

mcg/cc
1000 100 10 5 2.5

** Frequently you will need to use these values to calculate epinephrine doses for peripheral 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 1/16th % Bupivacaine, you know that by dividing 1 by 16, this also equals 0.0625%. 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 0.625 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 %
1/4 1/8 1/10 1/16 1/25 1/32
Table 4-2

Decimal %
0.25 0.125 0.1 0.0625 0.04 0.03125

mg/cc
2.5 1.25 1 0.625 0.4 0.3125

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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 mcg/kg/min of that drug. Using the following formula, this can be quickly calculated.

1 mcg/kg/min = kg wt X 60 = cc/hr to be dialed into IMEDD pump mcg/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 mcg/kg/min. How are you going to do that??? Well, you need to know the concentration of NTG on hand as well as the patients weight. You have 50 mg of NTG in 250 cc of volume, and your patient weighs 80kg. Using the above formula, 1mcg/kg/min = 80 X 60 = 4800 = 24 cc/hr 50,000/250 200

** In other words, in order to provide 1 mcg/kg/min of NTG, you need to run an infusion of 24 cc/hr for this patient. If we want 2 mcg/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, and Nitroglycerin. 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.

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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 (5500-7500)
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) Initial Filling pressure (psi)

(known liters full) (total liter flow)

So you have 800/1900 X 660 15 = 18.5 minutes ** You have 18.5 minutes before your tank runs out. Work quickly!!

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CHAPTER 5 Physics Applied To Anesthesia

So, you didnt 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.

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Physics of Gases P = Pressure V = Volume T = Temperature Daltons 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. PT = P1 + P2 + P3 * The partial pressures are additive because the partial pressure of one gas is independent of the partial pressure of another.

The General Gas Laws Boyles 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-Lussacs Law
At constant volume, pressure varies directly with temperature. P1 = P2 T1 T2

P
G = Guy-Lussacs Law

B= Boyles Law

V
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 Boyles law, the relationship is indirect; in Charles and Guy-Lussacs law, the relationship is direct.

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Avogadros Principle
Equal volumes of different ideal gases at equal temperatures contain the same number of molecules.

Avogadros Number = 6.02 X 1023 molecules in 1 mole of gas * 1 mole of gas occupies 22.4 L Ideal Gas Law
Combination of Boyles law, Charles law, and Avogadros hypothesis. P1V1 = P2V2 T1 T2

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 Grahams 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

Henrys 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

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Poiseuilles 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 () and length (l). Flow = (Pr4)/(8l) 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.

Ficks 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 4. Solubility of the molecules 2. Tissue thickness 5. Molecular size and weight 3. Concentration gradient 6. Electrical charge

**Clinical Application**
CO2 (44) and O2 (32) are about the same molecular weight but CO2 is much more soluble in blood. CO2 therefore diffuses about 20 times faster than O2. Carbon monoxide (CO) is very soluble in blood as compared to O2. 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 N2O. 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 Bernoullis 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 ** This theory assumes a non-viscous, frictionless system with no resistance to fluid flow, where the total energy of the system is constant.

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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 Bernoullis 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 Bernoullis 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
15 Fig: 5-2
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.
Needle Valve

Entrained Gas

Driving Gas

Mixture

Fig: 5-3 Ventilating Bronchoscope

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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

Ohms Law
Basic principle of electricity. Forms the basis for the physiologic equation BP = CO X SVR Electromotive force (volts) = current (amperes) X Resistance (ohms) or E = I X R

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 SwanGanz 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.

Law of LaPlace
LaPlaces law states that if surface tension is constant, pressure would increase as radius decreases. P = T/r

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Law/Principle
Beer/Lambert Law Bernoullis Principle (Venturi Effect) Charles Law Daltons Law Fick Principle Grahams Law Henrys Law Joule-Thompson Effect Law of LaPlace Ohms Law

Clinical Application
Pulse Oximetry and Capnometry Entrainment of air with the jet ventilator Nebulizer/Venturi Oxygen mask 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 Expansion of an LMA cuff during autoclave sterilization Calculation of the partial pressure of a gas if the % concentration is known Calculation of cardiac output Expansion of closed spaces with the administration of N2O (Pneumothorax/Tympanic membrane/GI tract/ETT) Concentration Effect Second Gas Effect Diffusion Hypoxia Explains diffusion in relation to substance size as well as solubility When the temperature of a closed cylinder increases, cylinder pressure also increases and vice versa Explains diffusion in relation to its molecular weight/density Smaller substances diffuse in greater quantities. At high O2 flow rates, the flow tube is wider and gas flow is a function of density Calculation of the amount of dissolved O2 and CO2 in the blood As a cylinder of compressed gas empties, the cylinder cools ARDS causes smaller alveoli to empty into larger ones resulting in Atelectasis Dilated ventricles generate greater wall tension than smaller ventricles Calculation of Systemic Vascular Resistance 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

Boyles Law

Ficks Law of Diffusion

Gay-Lussacs Law

Poiseuilles Law

Table 5-1

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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 dont 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 N2O and Halothane, are derived from modifying diethyl ether.

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Fluorinated

Isomers

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

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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). Lets 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 (N20)

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

N2O is 34X more diffusible than nitrogen (BG: PC 0.46 vs. 0.014) Implications: Passage of N20 into air-filled cavities such as the intestines, blebs, existing pneumothorax. Passage of N20 into non-compliant cavities such as the middle ear and cerebral ventricles.

**Clinical Implication**
Because N20 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. 75% N2O doubles a pneumothorax in 10 min and triples it in 30 minutes. 2. N2O must be turned off in procedures involving the middle ear where a tympanic patch is used. 3. N2O will displace nitrogen out of the balloon at the end of your ET. For long cases, the pressure in the balloon must be frequently checked and adjusted to prevent tracheal mucosal damage. 4. Air-filled cuffs of pulmonary artery catheters can expand and cause damage via increased pressure in the pulmonary artery.

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Diffusion Hypoxia
This concept related to N2O occurs with abrupt discontinuation of this gas. Because N2O 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 N20 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 N2O 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 N2O 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 = 2.54)

**Intermediate solubility + high potency = rapid onset and relatively recovery from anesthesia.

Boiling Point Vapor Pressure BG: PC MAC % % Metabolized

50.2 C 244mmHg 2.54 0.75 15-20

Table 6-1: (Produced from information obtained in Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 4th Ed. 2006, 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.

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Enflurane (Ethrane)
Halogenated methyl ethyl ether Clear, nonflammable liquid at room temperature Pungent, ethereal odor High potency (MAC = 1.6) Intermediate solubility (BG: PC = 1.90)

** Intermediate solubility + High potency = rapid onset and relative recovery from anesthesia.

Boiling Point Vapor Pressure BG: PC MAC % % Metabolized

56.5C 172 mmHg 1.90 1.6 2

Table 6-2: (Produced from information obtained in Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 4th Ed. 2006, 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 = 1.46)

** Intermediate solubility + high potency = rapid onset and relative recovery from anesthesia

Boiling Point Vapor Pressure BG: PC MAC % % Metabolized

48.5C 240 mmHg 1.46 1.1 0.2

Table 6-3: (Produced from information obtained in Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 4th Ed. 2006, Chapter 2.)

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1. Isoflurane is characterized by extreme physical stability 2. There is no detectable deterioration after five years of storage or exposure to sunlight. 3. Isoflurane is an isomer of Enflurane (mirror images)

Enflurane

Isoflurane

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

58.5C 170 mmHg 0.69 1.8 3-5

Table 6-5: (Produced from information obtained in Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 4th Ed. 2006, 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.

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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 N2O

** Low potency + poor solubility results in rapid inductions and emergence, but requires more agent.

Boiling Point Vapor Pressure BG: PC MAC % % Metabolized

23.5C 669 mmHg 0.42 6.6 0.02

Table 6-4: (Produced from information obtained in Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 2006, 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 4. Desflurane produces the highest carbon monoxide concentration.
Desfluranes 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.

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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% N20
------0.29 0.65 0.5 2.8 0.66

Vapor Pressure mmHg @ 20 C

39,000 244 172 240 669 170

B:G Coefficient
0.46 2.54 1.90 1.46 0.42 0.69

% Met

Boiling Point (C)

-88.5 50.2 56.5 48.5 23.5 58.5

Pungency
__

N20 Halothane (Fluothane) Enflurane (Ethrane) Isoflurane (Forane) Desflurane (Suprane) Sevoflurane (Ultane)

104 0.75 1.6 1.1 6.6 1.8

Trace 12-25 2 0.2 0.02 3-5

__ + + ++ __

Table 6-6: (Partially reproduced from information in Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 4th Ed. 2006, Chapter 2.)

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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 (CMRO2), 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 PaC02 < 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.
Fig 6-3: (Duke, J. Anesthesia Secrets. 3rd Ed., 2006, p. 480.)

Cerebral Blood Flow (CBF)

All inhaled agents produced a dose-dependent increase in cerebral blood flow during normocapnia. Increased cerebral vasodilation Decreased cerebral vascular resistance Decreased CMRO2 (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 > N2O)

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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.

Fig 6-4: (Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 4th Ed, 2006, p. 48.)

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 vasodilation

** Potency ranking related to increases in ICP (H > E > I = D = S > N2O) **Clinical Application**
Hyperventilation to a PaCO2 < 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 CO2 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

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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. Sevoflurane increases heart rate only at concentrations of > 1.5 MAC, whereas isoflurane and desflurane tend to increase heart rate at lower concentrations. **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.

Fig 6-5: (Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 4th Ed, 2006, p.52.)

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, N2O is contraindicated, as increases in PVR may increase RL shunting, causing arterial hypoxemia.

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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, Pancuronium, 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 Epi to the following: Halothane 1-2 mcg/kg per 30 minutes All other volatile agent 4 mcg/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.

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)

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Ventilatory Response To Carbon Dioxide

All volatile agents produce a dose-dependent increase in PaCO2 and a decrease in the response to CO2. It takes a higher CO2 level to stimulate respirations. ** The PETCO2 ventilation response curve shifts downward and to the right (Fig 6-6).

Fig 6-6: Morgan, E., Mikhail, M. & Murray, M. Clinical Anesthesiology. 2006, p.569.)

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 6-7)

Fig 6-7: Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 4th Ed. 2006, p.61.

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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 PO2 of < 30 mm Hg to drive ventilations under general anesthesia.

Airway Resistance
All volatile agents produce a dose-dependent decrease in airway resistance. All volatile agents dilate bronchioles. Halothane is the 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 Halothane Isoflurane Sevoflurane Desflurane Hepatotoxicity
Post-operative liver dysfunction has been associated with most volatile agents; however Halothane has been the most implicated.

Portal Vein Flow

Hepatic Artery Flow

Drug Clearance No change No change No change

Liver Enzymes Slight No change No change No change

Table 6-7: (Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 1999, Chapter 2.)

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

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**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 FIO2 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 FIO2 > 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.

Bone Marrow Function

Nitrous oxide is unique among the inhaled anesthetics in its ability to irreversibly oxidize vitamin B12 and inactivate the enzyme methionine synthase, an enzyme that controls interrelations between vitamin B12 and folic acid metabolism. Methionine synthase is required for DNA synthesis, assembly of myelin sheath and methyl substitutions in neurotransmitters. High doses of nitrous oxide may result in anemia and polyneuropathy.

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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) ** N20 does not relax skeletal muscle.

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 N2O 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.

Deployment Considerations
UPAC Vaporizer and volatile anesthetics Pneumonics to live by: **HI SE (like the drink Hi-C) Halothane and Isoflurane have a high vapor pressure (244 & 240) Sevoflurane and Enflurane have a low vapor pressure (170 & 172) ** So if you are using a UPAC and only have the Halothane & Enflurane disks, you can use the Halothane disk for Isoflurane and the Enflurane disk for Sevoflurane. Just remember they have different potencies so you would have to dial it appropriately. Hi Lo Hi if you put Isoflurane (High vapor pressure) in a Sevoflurane (Low vapor pressure) vaporizer, you will give a higher than expected amount of volatile anesthetic i.e. Isoflurane. Lo Hi Lo if you put Sevoflurane (Low vapor pressure) in an Isoflurane (High vapor pressure) vaporizer, you will give a lower than expected amount of volatile anesthetic i.e. Sevoflurane. Remember: It doesnt matter what flows, if you have flows at all, are used while administering Sevoflurane via a UPAC because there is no soda lime being used with this draw-over vaporizer.

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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.

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THE BARBITURATES

Fig 7-1: (Morgan, E., Mikhail, M. & Murray, M. Clinical Anesthesiology. 2006, p. 185.)

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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 1930s and has proven to be a safe, reliable induction drug over time.

**Induction Dose = 3-6 mg/kg IV

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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) Thiopentals ability to protect the brain is related to its direct effects on cerebral dynamics. These effects include: 1. Drug induced cerebrovascular vasoconstriction. This leads to cerebral blood flow (CBF). Subsequent intracranial pressure (ICP). 2. Decreased cerebral metabolic oxygen consumption (CMRO2).

Physiologic Effects
Central Nervous System
Decreases CBF, ICP, and CMRO2 Protective effects on the brain Considered to be coupled

Cardiovascular
Mild, transient blood pressure reductions in normovolemic patients related to peripheral vasodilation 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 inhibits spasm) b. Papaverine (inject into the artery with 40-80 mg) c. Heparin (intravenous heparization to prevent thrombosis) d. Phentolamine (Regitine) (local infiltration around the artery) 3. Stellate ganglion or brachial plexus block to relieve vasoconstriction

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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 (subtype of glutamate receptor), opioid, 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 (1/5 (20%) to 1/3 (30%) as potent as ketamine)

Clearance
Renal clearance mechanisms. Less than 4% of this drug is recovered unchanged in urine.

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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) o Ketamine 1-2 mg/kg IV or 3-5 mg/kg IM+(Robinul 0.005 mg/kg + Versed 0.05 mg/kg) IM/IV Analgesia for painful procedures

Induction of Anesthesia
Effective IV and IM for the induction of anesthesia. Consciousness is lost in 30-60 seconds after IV, and 2-4 minutes after IM administration. **Induction Dose = 1-2.5 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 especially in OB. 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 0.005 mg/kg IV/IM) Intense bronchodilating properties related to its sympathomimetic properties.

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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. o Visual, auditory illusions o Confusion o 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 o Preoperative Midazolam administration (0.05 mg/kg IV/IM) o Avoidance of Atropine and Droperidol, as they have central properties that may be synergistic o Recovery in a quiet, calm environment

Etomidate (Amidate)
Etomidate is a 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. Weak Base unlike Thiopental

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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 = 0.1- 0.4 mg/kg IV Physiologic Effects Central Nervous System
Potent direct cerebral vasoconstrictor, which decreases CBF and CMRO2 by up to 45%. This is GREAT for patients with ICP. o Considered to be coupled. 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.

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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 as a result of subcortical disinhibition. 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. Weak Acid like Thiopental

Metabolism
Rapid metabolism by the liver creates inactive, water-soluble metabolites. No evidence of impaired metabolism with liver dysfunction.

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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 = 1- 2.5 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 CMRO2 . o Considered to be coupled. Myoclonus 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, due to decreased baroreceptor reflex. 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)

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Allergic Reactions
Propofol has allergic potential related to its phenyl nucleus and di-isopropyl side chain. Anaphylaxis has been reported. Generic propofol contains sodium metabisulphite, which is contraindicated in patients with sulphite 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.

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 1-2% 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 10-20 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.

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Common Intravenous Agents and Dosages

Agent Generic Name
Thiopental Propofol Etomidate Ketamine

Trade Name
Pentothal Diprivan Amidate Ketalar

Induction Dose (IV) mg/kg

3-6 1-2.5 0.1-0.4 1-2.5

Induction Dose (IM) mg/kg

NA NA NA 5-10

Maintenance Dose (IV) mcg/kg/min

NA 50-200 NA NA

Sedative Dose (IV)

0.5-1.5 mg/kg 25-100 mcg/kg/min NA 0.25-1 mg/kg

Sedative Dose (IM) mg/kg

NA NA NA 2.5-5

Table 7-1: (Produced from information in Omoigui, S. Anesthesia Drug Handbook. 1999, p. 1-502.)

Intravenous Agents & Comparative Pharmacokinetic Properties

Agent Propofol Thiopental Etomidate Ketamine Elimination Half-Times (hrs) 0.5-1.5 11-12 2-5 2-3 Volume of Distribution (liters/kg) 3.5-4.5 2.5 2.2-4.5 2.5-3.5 Clearance (cc/kg/min) 30-60 3.4 10-20 16-18 Systemic Blood Pressure No change Heart Rate No change

Table 7-2: (Produced from information in Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 2006, p.131, 156.)

Intravenous Agents & Comparative Neurophysiologic Effects **Effects are Coupled Agent
Thiopental Propofol Etomidate Ketamine

CMRO2

CBF

ICP

CMRO2 = Cerebral Metabolic Oxygen Requirement CBF = Cerebral Blood Flow ICP = Intracranial Pressure
Table 7-3: (Morgan, E., Mikhail, M. & Murray, M. Clinical Anesthesiology. 2006, p. 200 with modifications.)

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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). Types of Analgesia Spinal - I dont hurt Supraspinal I hurt but I dont care

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Endogenous Opioid Receptors

Mu-1 Analgesia Spinal Supraspinal Euphoria Major Effects Hypothermia Miosis Bradycardia Urinary Retention Endorphins Agonists Morphine Synthetic opioids Antagonists Naloxone Naltrexone Nalmefene Endorphins Morphine Synthetic opioids Naloxone Naltrexone Nalmefene Naloxone Naltrexone Nalmefene Naloxone Naltrexone Nalmefene Naloxone Naltrexone Nalmefene Dynorphins Meperidine Mu-2 Spinal analgesia Ventilatory Depression Physical Dependence Constipation Kappa Delta Sigma Dysphoria Analgesia Analgesia Spinal Spinal Supraspinal Supraspinal Ventilatory Stimulation Ventilatory Dysphoria Hypertonia Depression Miosis Tachycardia Physical Dependence Sedation Constipation Urinary Retention Enkephalins Ketamine??

Table 8-1: (Produced from information in Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 2006, p.89 & 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 Duramorph, 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.

**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, especially if a lipid soluble opioid is administered.

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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. Early depression (within two hours) usually occurs with fentanyl or sufentanil and is most likely due to systemic absorption of the lipid soluble opioid. Delayed depression (6-12 hours) usually occurs with the cephalad migration of hydrophilic opioids such as morphine (Duramorph) in the CSF. It primarily reflects interaction of the opioid with receptors found in the ventral medulla. This is less of a problem with lipophilic opioids which usually diffuse out of the CSF into the bloodstream instead of migrating cephalad. DepoDur After the administration into the epidural space, morphine sulfate is released from the multivesicular liposomes over time so respiratory depression can occur for up to 48 hours. o DO NOT administer DepoDur in the subarachnoid space

**Ventilatory depression generally has not occurred with epidural or intrathecal morphine administration after 24 hours. Factors increasing the risk of ventilatory depression include: Advanced age Low lipid solubility of opioids (morphine is hydrophilic and hence more of a Concomitant IV opioid administration concern) Increased intrathoracic pressures High opioid dose Ventilatory depression can be successfully treated with IV or IM Naloxone, usually titrated to effect.

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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 (Hydrophilic) 2. High degree of protein binding 3. High degree of ionization at physiologic pH Primary metabolic pathway is conjugation in the liver. Unlike Fentanyl and sufentanil it has no pulmonary first pass uptake. **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) Epidural administration as a bolus (DepoDur) 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 hydromorphone

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

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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. It is also similar to local anesthetics in structure. When administered intrathecally, it blocks sodium channels to a degree comparable with Lidocaine.

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 (i.e. NO basal rate PCA) 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 and by its agonist effect at alpha2 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 75-125 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.

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Short duration of action of a single, small to moderate dose represents rapid redistribution out of the central compartment, NOT metabolism. **Significant first-pass pulmonary uptake** of about 75% of the initial dose Metabolism is primarily hepatic conjugation. Its elimination half-time is longer than morphines, despite its short duration of action. This is because the lungs serve as a large, inactive reservoir for Fentanyl, and its volume of distribution (Vd) 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 750-1000 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 alpha1-acid glycoproteins, contributes to a smaller Vd 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 Vd .

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 Vd. Primary hepatic metabolism and urinary excretion

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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 75-100 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 Vd 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 Vd, 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). Labor management for the parturient with no neuraxial analgesia via PCA bolus: 0.2-0.6 mcg/kg over < 20 sec with a lock out of every 2 minutes. Basal rate administration has been researched but can result in respiratory depression and fetal bradycardia/decelerations.

**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.

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Comparative Pharmacokinetic Properties of the Opioids Amount of % NonSpeed of Opioid Protein Vd ionized Elimination Binding Morphine + +++ ++ ++ Meperidine ++ ++++ + + Fentanyl +++ ++++ + + Sufentanil ++++ ++ ++ ++ Alfentanil ++++ + ++++ +++ Remifentanil +++ + +++ ++++

Clearance Rate ++ ++ ++ + + ++++

Table 8-2: (Produced from information in Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 2006, p.93. & Nagelhout, J. J. Nurse Anesthesia. 2005, p. 152.)*

*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 Fentanyls context-sensitive half-time significantly increases after about two hours compared to all other opioids. This can be attributed to fentanyls 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.

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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 venodilation, 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 venodilation, as well as histamine-release. **Morphine/hydromorphone do 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. ( contractility) Tachycardia may result from the atropine-like properties of Meperidine. **Meperidine in combination with MAO-Is 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 vasodilation. **Clinical Note** All opioids are used cautiously in patients with altered intracranial pressure. If they are used in this scenario, close monitoring of PaCO2 is required to ensure that hypercarbia does not result.

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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 CO2 ventilatory response curve is shifted downward and to the right (just like with volatile agents). 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 (40-100 mcg 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. 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.

Cutaneous

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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 (wooden chest). This rigidity can be prevented or minimized with administration of a muscle relaxant. (Sufentanil > Fentanyl) 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 30-40 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.

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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 1520 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.

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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 30-45 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 MCG/KG TITRATED TO DESIRED EFFECT.

Side Effects and Other Considerations

This drug reverses analgesia !! With slow titration (20-40 mcg increments - diluted down to 40 mcg/cc), respiratory depression can be reversed while sparing analgesia. o It comes in 0.4 mg/cc concentration. DO NOT just draw up a cc and give it. 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!!!!

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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
Meperidine (Demerol) Morphine (Astromorph, Duramorph, DepoDur) Hydromorphone (Dilaudid) Fentanyl (Sublimaze) Sufentanil (Sufenta) Alfentanil (Alfenta) Remifentanil (Ultiva)
Table 8-3: (Partially reproduced from information in Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 2006, p. 88.)

Mixed AgonistsAntagonists
Butorphanol (Stadol) Nalbuphine (Nubain) Pentazocine (Talwin) Buprenorphine (Buprenex) Nalorphine (Nalline)

Pure Antagonists
Naloxone (Narcan) Nalmefene (Revex) Naltrexone (Trexan) (Oral only)

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Potency Ranking of Common Opioids

Meperidine (Demerol) Morphine (Astromorph, Duramorph, DepoDur) Nalbuphine (Nubain) Butorphanol (Stadol) Hydromorphone (Dilaudid) Alfentanil (Alfenta) Fentanyl (Sublimaze) Remifentanil (Ultiva) Sufentanil (Sufenta)
Table 8-4
*

0.1 1 1 3-7 8 10 100 - 125 100 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
Fentanyl Sufentanil Duramorph DepoDur Hydromorphone (Dilaudid) Meperidine

Epidural Dose
Bolus: 1-2 mcg/kg (50-100 mcg) Infusion: 0.5-0.7 mcg/kg/hr (25-60 mcg/hr) Bolus: 0.2-0.7 mcg/kg (10-50 mcg) Infusion: 0.1-0.6 mcg/kg/hr (5-30 mcg/hr) Bolus: 40-100 mcg/kg (2-5 mg) Infusion: 2-20 mcg/kg/hr (0.1- 1 mg/hr) Bolus: 10-15 mg with 5-10 cc of MPF NS Infusion: Contraindicated Bolus: 20-40 mcg/kg (1-2 mg) Infusion: 2-3.5 mcg/kg/hr (0.15-0.3 mg/hr) Bolus: 1-2 mg/kg (25-50 mg) Infusion: 0.2-0.4 mg/kg/hr (5-20 mg/hr)

Intrathecal Dose
Bolus: 0.1-0.4 mcg/kg (5-25 mcg) Bolus: 0.02-0.08 mcg/kg (1-10 mcg) Bolus: 4-20 mcg/kg (200-300 mcg) Contraindicated Bolus: 2-4 mcg/kg (0.1-0.2 mg) Bolus: 0.2-1 mg/kg (10-50 mg)

*Table 8-5: (Produced from information in Omoigui, S. Anesthesia Drug Handbook. 1999, p. 1-502.)

* Please note that bolus injections of opioids into the epidural space should be diluted with 10cc of preservative-free normal saline or local anesthetic (except DepoDur). March 2009 107 Petty/Tilley

Common Intravenous Opioid Dosing Regimens

Agent Meperidine Morphine Hydromorphone Fentanyl Alfentanil Sufentanil Remifentanil 5-40 mcg/kg 50-300 mcg/kg 2-10 mcg/kg 0.5-1 mcg/kg 0.025-0.25 mcg/kg/min 0.5-15 mcg/kg/min 0.1-0.5 mcg/kg/hr 0.25-0.4 mcg/kg/min Induction Dose Maintenance Infusion Postoperative Dose 0.5-2 mg/kg 0.03-0.15 mg/kg 0.01-0.04 mg/kg

Table 8-6: (Produced from information in Omoigui, S. Anesthesia Drug Handbook. 1999, p. 1-502 & GlaxoWellcome package insert for Remifentanil, 2001)

DepoDur Administration Rules (Morphine Sulfate extended-release liposome injection) Dos Donts
Keep refrigerated but dont freeze Administer only in the lumbar epidural region Observe/monitor for respiratory depression for 48 post administration Mix with 5-10 cc of preservative-free normal saline Reduce the dose for elderly and debilitated patients Do Not vigorously shake the vial Do Not use an in-line filter or filter needle Do Not administer any other medication including local anesthetics, before, during or after injection Do Not administer IV, ITN, SQ, IM Do Not give within 15 minutes of giving test dose **Most providers inject directly through the epidural needle and do not administer a test dose

Table 8-7: (Produced from information in Endo Pharmaceuticals package insert for DepoDur, 2006)

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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. 2. 3. 4. 5. Production of amnesia Minimal cardiovascular or respiratory depression Anticonvulsant properties Skeletal muscle relaxant (centrally) Anxiolysis and sedation

Commonly used BNZ are listed in the table below. Generic Name Diazepam Midazolam Lorazepam Chlordiazepoxide Clonazepam Flurazepam Temazepam Triazolam
Table 9-1

Trade Name Valium/Diazac 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.

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Chloride Channel

Fig. 9-1 (Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 4th Ed. 2006, p. 141.)

Fig. 9-2 (Richter, JJ. Anesthesiology, 1981; 54: 66-72)

**The GABAA 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.

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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 > 4. 3. 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. 4th Ed. 2006, p.143 with modification.)

Pharmacokinetic Highlights
This drug rarely burns 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 (burns). 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 0.5-1 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.

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**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, CMRO2, 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)

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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 VD 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

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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.

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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 45-90 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, CMRO2, 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 0.2 1 mg* (4-20 mcg/kg) Max Single Dose 1 mg Max Total Hourly Dose 3 mg Infusion 30-60 mcg/min (0.5 -1 mcg/kg/min)

* 0.2 mg/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. 362-364.)

**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.

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Comparative Pharmacokinetics of Benzodiazepines

Agent
Diazepam Midazolam Lorazepam

Potency Rating
1 3-4 5

Protein Binding (%)

98 98 98

Elimination Half Life (hrs)

20-40 2-4 10-20

Clearance (ml/kg/min)
0.2-0.5 6-8 0.7-1.0

Table 9-3: (Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 4th Ed. 2006, p 143.)

Common Midazolam Dosing Regimens

Premed Bolus for Conscious Sedation
0.5-5 mg (0.025-0.1 mg/kg)

Infusion for Conscious Sedation

1-15 mg/hr (20-300 mcg/kg/hr)

Induction
50-350 mcg/kg

IV IM PO Intranasal Rectal

Adult 1-5 mg Titrate to effect 2.5-10 mg (0.05-0.2 mg/kg) 20-40 mg ** (0.5-1 mg/kg) 0.2-0.3 mg/kg 15-20 mg diluted in 5cc NS (0.3-0.35 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.573-576.)

** 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.

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Chapter 10 Neuromuscular Blocking Drugs

Neuromuscular blocking drugs have only been used clinically in anesthesia since the early 1940s, 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 Depolarizers
Succinylcholine (Anectine, Quelicin) Ultra-short

DURATION

Nondepolarizers STEROIDAL
Pancuronium (Pavulon) Pipecuronium (Arduan) Vecuronium (Norcuron) Rocuronium (Zemuron) Long Long Intermediate Intermediate

BENZYL ISOQUINOLINE
d-Tubocurarine (Curare) Doxacurium (Nuromax) Atracurium (Tracrium) Cisatracurium (Nimbex) Mivacurium (Mivacron) Long Long Intermediate Intermediate Short

Table 10-1: (Partially reproduced from Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 2006, p. 209.)

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.

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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. 10-1 (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 in the bloodstream. SCh is NOT metabolized in the cleft. It must diffuse away from the NMJ down its concentration gradient for metabolism to occur. Metabolized to succinylmonocholine, which maintains 1/20th to 1/80th the potency of SCh. This active metabolite is quickly broken down to succinic acid and choline by pseudocholinesterase.

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Peripheral Nerve Stimulator

Commonly utilized patterns of electrical stimulation applied clinically to assess depth of neuromuscular blockage include:

Twitch A single pulse of 0.1-0.2 msec in duration @ 0.1-1 Hz. Train-of-Four A series of four twitches in two seconds @ 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 50-100 Hz lasting five seconds. Posttetanic Count A sustained stimulus of 50-100 Hz lasting five seconds followed by a 3 sec pause followed by a single 1 Hz twitch.

Phase I Blockade Characteristics

1. 2. 3. 4. 5. 6.

Normal

Depolarizing

Dose related decrease in twitch height No fade to train of four No fade to tetany No post-tetanic potentiation Fasciculations Augmentation of blockade with administration of an anticholinesterase agent

**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 II 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 (>4 mg/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 II Block

1. 2. 3. 4. 5. Dose related decrease in twitch height Fade to train of four Fade to tetany Some post-tetanic potentiation **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!!

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Fig. 10-2: (Morgan, E., Mikhail, M., & Murray, M. Clinical Anesthesiology, 2006, p.210.)

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 Fig. 10-3) or HR & BP related to preganglionic autonomic stimulation and postganglionic parasympathetic 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

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(Fig. 10-3)

CNS
Somatic N.S.

Autonomic Nervous System

Sympathetic N.S. Parasympathetic N.S.

ACh
(SUX)

(SCh)

ACh

ACh

(SCh) (SCh)

Skeletal Muscle

ACh
Cholinergic Adrenergic

NE

Effector Organs

ACh = Acetylcholine NE = Norepinephrine Effector Organs = smooth muscle, glands, cardiac tissue

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Figure 10-4: (Kier, L. The Chemistry of Drugs for Nurse Anesthetists, 2004. P 103 with modifications.)

What occurs at the synapse or ganglion? See Figure 10-4

1. Neurotransmitter (Acetylcholine) is synthesized in the presynaptic vesicle 2. Calcium enters the cell causing the vesicle to fuse to the membrane and neurotransmitter is released into the synapse 3. Neurotransmitter travels across the synapse to the postsynaptic cell 4. Neurotransmitter binds at the postsynaptic receptor 5. Signal transduction occurs resulting in an intracellular postsynaptic effect 6. Metabolizing enzymes (acetylcholinesterase) in the synapse degrade the neurotransmitter 7. Degraded neurotransmitter (choline) is taken up by the presynaptic cell 8. Unmetabolized neurotransmitter is taken up by the presynaptic cell by reuptake transporters

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.

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.

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**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 Duchennes 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 nicotinic 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. 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.

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Extrajunctional Receptors

Extrajunctional Receptors

Fig. 10-5: (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. SCh causes abdominal wall fasciculations which intragastric pressure. SCh also causes in lower esophageal sphincter tone.

Elevated Intragastric Pressure

**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. 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

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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
None Heterozygous Homozygous

Dibucaine Value
80 60 20

Response to SCh
Normal Moderately Prolonged Greatly Prolonged (6-8 hours)

Frequency
96% 1:480 1:3200

Table 10-2: (Partially reproduced from Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 2006, p. 219.)

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.

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Succinylcholine
Advantages
Quick Onset Short Duration Increased LES tone

Disadvantages
Phase II Conversion Block Bradycardia* 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!!

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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 10-8.

Chemical Structures of Neuromuscular Blockers

Fig. 10-6: (Morgan, E., Mikhail, M., & Murray, M. Clinical Anesthesiology, 2002, p.184.)

See how big they are????

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Nondepolarizing Block Characteristics

1. 2. 3. 4. 5. 6.

FADE

Dose related decrease in twitch height Fade to train of four Fade to tetany Post-tetanic potentiation No fasciculations Antagonism of blockade with administration of an anticholinesterase

Fig. 10-7: (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%)

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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 TCAS 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.

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Pipecuronium (Arduan)
Structure
Steroidal compound similar to Pavulon

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.

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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. 132) 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%).

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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 0.9-1.2 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 ED95), 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.

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Short-Acting Nondepolarizing Muscle Relaxants Mivacurium (Mivacron)

Structure
Benzyl isoquinoline compound

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 20-30 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 60-90 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!!

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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 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.

**Clinical Note**

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.

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Drugs Altering Neuromuscular Blocking Response Drug

Antibiotics Anticonvulsants Antidysrhythmics Antihypertensives Cholinesterase Inhibitors Dantrolene Furosemide (Lasix) Inhalation Agents Local Anesthetics Lithium Magnesium Sulfate
1

Effect on SCh
Unknown Unknown or

Effect on NDP
or Unknown

Comments
Aminoglycosides1 Polymyxin, Clindamycin Lincomycin, Tetracycline Phenytoin, Carbamazepine Quinidine, Calcium Channel Blockers, Lidocaine, Procainamide Trimethaphan, Nitroglycerin Neostigmine, Pyridostigmine, Edrophonium, Echothiophate Dose dependent Smaller doses = Larger doses = S = D = I = E >> H 2 High doses only Prolongs onset and duration of SCh Pre-eclampsia and eclampsia

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, 2006, p.213 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
Hypersensitivity Hypersensitivity Resistance Resistance Hypersensitivity Resistance Normal or Slight Resistance Hypersensitivity Hypersensitivity Resistance Amyotrophic Lateral Sclerosis Contracture (ALS) Autoimmune Disorders1 Hypersensitivity Burn Injury Hyerkalemia Cerebral Palsy Slightly Sensitive Guillain-Barre Syndrome Hyperkalemia Hemiplegia Hyperkalemia Muscle Denervation Hyperkalemia and Contracture Muscular Dystrophy Hyperkalemia and Malignant (Duchennes) Hyperthermia Myasthenia Gravis Resistance Severe Chronic Infection Hyperkalemia 1 Systemic Lupus Erythematosus, Polymyositis 2 Tetanus, Botulism

Table 10-5: (Morgan, E., Mikhail, M., & Murray, M. Clinical Anesthesiology, 2002, p.190 with modification.)

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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 associated with a NDP or Phase II block. Fade to TOF is used clinically to assess the depth of paralysis.

Number of TOF Twitches 0 1 2 3 4

Table 10-6

% Receptors Occupied By Muscle Relaxant >95 90 80 75 < 75

% Receptors Free Of Muscle Relaxant 0 10 20 25 > 25

**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

Succinylcholine

Dosage (mg/kg)

Peak (Minutes)
1 2-6 3-5 3-5 3-9 3-5 3-5 1-3 5 1-3

Duration (Minutes)
4-6 30-90 40-60 45-120 30-160 20-35 25-40 15-150 60 6-16

Adult: 1 Neonates/Infants: 2-3 Children: 1-2 D-Tubocurare L 0.3-0.6 (Curare) M 0.05-0.3 Pancuronium L 0.04-0.1 (Pavulon) M 0.01-0.05 Pipecuronium L 0.07-0.085 (Arduan) M 0.01-0.04 Doxacurium L 0.05-0.08 (Nuromax) M 0.005-0.04 Atracurium L 0.3-0.5 (Tracrium) M 0.1-0.2 Vecuronium L 0.08-0.1 (Norcuron) M 0.01-0.05 Rocuronium L 0.6-1.2 (Zemuron) M 0.10-0.20 Cisatracurium L 0.2 (Nimbex) M 0.03 Mivacurium L 0.15-0.2 (Mivacron) M 0.01-0.1 L = Loading Dose M = Maintenance Dose

Table 10-7: (Produced from information in Omoigui, S. Anesthesia Drug Handbook, 1999, p. 1-502.)

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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.

Summary Table of Muscle Relaxant Properties

Drug
Succinylcholine (Anectine) D-Tubocurare (Curare) Pancuronium (Pavulon) Pipecuronium (Arduan) Doxacurium (Nuromax) Atracurium (Tracrium) Vecuronium (Norcuron) Rocuronium (Zemuron) Cisatracurium (Nimbex) Mivacurium (Mivacron)

Histamine Release
+

Vagal Blockade
+

Primary Elimination (Metabolism/Excretion)

Plasma cholinesterase

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

+++ None None None ++ None None None ++ + Mild Effect

None ++ None None None None + None None

Renal excretion 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 Hofmann Elimination Plasma cholinesterase

++ Moderate Effect +++ Marked Effect

Table 10-8: (Produced from information in Stoelting, R.K. (1999), Chapter 8 & Morgan, E., Mikhail, M., & Murray, M. Clinical Anesthesiology, 2002, Chapter 9.)

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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)

(Fig. 11-1)

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Cholinergic Receptor Types

Receptor
Nicotinic Muscarinic

Location
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

Agonist
Nicotine Acetylcholine Succinylcholine Muscarine Acetylcholine Succinylcholine

Antagonist
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 RBCs 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.

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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. 2. 3. 4. Acetylation (REVERSIBLE binding of AChE to ACh, as described above) Electrostatic Attachment (REVERSIBLE) Carbamylation (REVERSIBLE) Phosphorylation (IRREVERSIBLE)

Clinically Used Anticholinesterase Agents:

1. 2. 3. 4. Edrophonium (Tensilon) Neostigmine (Prostigmine) Pyridostigmine (Mestinon) Physostigmine (Antilirium)

Fig: 11-3: (Morgan, E., Mikhail, M., & Murray, M. Clinical Anesthesiology, 2002, p.203.)

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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)

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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 20-30 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 20-30 minutes.

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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 20-30 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.

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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 BNZs 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)

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Major Pharmacokinetic Principles of Anticholinesterases

Speed of onset varies with each agent.

Edrophonium = Rapid Neostigmine = Intermediate Pyridostigmine = Delayed

Duration of action ranges between 20-80 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 4060 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 agents structural components.

Physostigmine = Tertiary Amine = Highly Lipid Soluble = Crosses BBB Organophosphates = Highly Lipid Soluble = Cross BBB All Others = Quaternary Amine = Poorly Lipid Soluble = Cant 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.

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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
Cardiovascular Pulmonary Cerebral Gastrointestinal Genitourinary Eyes Skeletal Muscle * Physostigmine only

Physiologic Effect
Bradycardia, Dysrhythmias Bronchospasm, Secretions Excitation, Delirium * Nausea, Vomiting, Secretions Incontinence Constricted Contraction, Fasciculations

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.

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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 11-3. 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

Common Anticholinesterase Anticholinesterase Dose Neostigmine Pyridostigmine Edrophonium Physostigmine 0.04-0.08 mg/kg 0.1-0.4 mg/kg 0.5-1 mg/kg 0.01-0.03 mg/kg Recommended Anticholinergic Glycopyrrolate Glycopyrrolate Atropine Not needed Usual Dose of Anticholinergic per mg of Anticholinesterase 0.2 mg 0.05 mg 0.014 mg Not applicable

Table 11-3: (Morgan, E., Mikhail, M. & Murray, M. Clinical Anesthesiology. 2006, p. 234 with modification.)

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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. 2. 3. 4. 5. 6. 7. Sustained head lift for > 5 seconds Sustained hand grip Effective cough Vital capacity breaths of > 15 cc/kg. Negative inspiratory force of at least 40 cm H20 pressure Sustained tetany to 50-100 Hz for > 5 seconds Full TOF without fade

Comparison of Tests Of Neuromuscular Function

Clinical Test
Tidal Volume Train-Of-Four (TOF) Vital Capacity Breaths Tetanic Stimulation (50 Hz) Double-burst Stimulation **Sustained Head Lift/Hand grip
rd

Estimated % of Receptors Occupied

80 70-75 70 70 60-70 50

Table 11-4: (Nagelhout, J.J. Nurse Anesthesia. 3 Ed. 2005, p. 188 with modification).

**Sustained head lift or sustained strong hand grip are the most reliable clinical indicator of degree of residual muscle relaxation.

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Neuromuscular Transmission Monitoring

Nerve Monitored
Muscle stimulated

Ulnar
Adductor Pollicis Thumb adduction Negative lead medial aspect of the forearm 2 cm proximal to the wrist with Positive lead 2-5 cm distal On Emergence

Facial
Orbicularis Oculi Orbicularis Oris Negative lead lateral and below the lateral canthus of the eye with Positive lead 2 cm above & lateral to the lateral canthus On Induction

Posterior Tibial
Great Toe Plantar Flexion Negative lead behind the medial malleolus, anterior to the Achilles tendon with Positive lead more proximal On Emergence

Peroneal
Foot Dorsiflexion Lateral to the neck of the fibula with the negative lead more distal Not determined

Electrode Placement

Best Time to Utilize

Table 11-5: (Produced from information in Dorsch, J.A. Understanding Anesthesia Equipment. 1999, p. 858-863 and Miller, R. D. Anesthesia. 2006, 1557).

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)

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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. (Fig. 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.

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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 bronchodilation 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)

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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 = 45-60 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)

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Glycopyrrolate (Robinul)
Physical Structure
Glycopyrrolate is a quaternary amine that has minimal ability to 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 = 30-45 minutes; PO = 60 minutes Duration for vagal blockade is 2-3 hours; antisialogogue effect 7 hours.

Clinical Considerations
Only anticholinergic that has minimal ability to cross the BBB; therefore it elicits no central nervous system 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)

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Comparative Characteristics of Anticholinergics

Characteristic
Tachycardia Bronchodilation Antisialogogue Sedation Mydriasis + Minimal Effect

Atropine
+++ ++ + + +

Glycopyrrolate
++ ++ ++ None None +++ Marked Effect

Scopolamine
+ + +++ +++ +++

++ Moderate Effect

Table 12-1: (Partially reproduced from information in Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 2006, p. 268.)

A = Atropine Tachycardia A>G>S

1. 2. 3. 4.

G = Glycopyrrolate Bronchodilation A=G>S

S = Scopolamine Sedative S>A>G

Antisialogogue S>G>A

Cautious Use of Anticholinergics

Cardiovascular disease Narrow-angled glaucoma Urinary bladder neck obstruction Intestinal or pyloric obstruction

Dose Continuum of Side Effects:

Low Dose ----------------------------------------------------------------------------------High Dose SECRETORY
sweating salivation bronchial secretions

EYES & HEART

mydriasis cycloplegia tachycardia

SMOOTH MUSCLE
tone (LES, bladder, bronchial, etc)

GI SECRETIONS
secretions

CNS
excitation delirium depression

Central Anticholinergic Syndrome

Hot as a hare Dry as a bone Red as a beet Blind as a bat Mad as a hatter March 2009 154 Petty/Tilley

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 15-60 ug/kg IV (only anticholinesterase that crosses BBB)

**All other anticholinesterase agents are ineffective.

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CHAPTER 13 Nerve Agent Exposure and Treatment

Sarin Poisoning on Tokyo Subway 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

Lethal Dose Breathing Lethal Dose Skin 3 (mg - min/m ) (mg) 1936 150-400 1,000-1,700 Tabun (GA) 1938 75-100 1,000-1,700 Sarin (GB) 1944 35-50 50-100 Soman (GD) 1952 10 6-10 VX Other less common nerve agents include GE, GF, VE, VG, and VM. Name Year Made
Table 13-1: (Produced from information in Medical Management of Chemical Casualties Handbook. 1995, p. 17-44.)

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 = 0.0022 lbs. *10 mg = 0.00022 lbs. (Amount of VX that is deadly) This is about as much as a single grain of rice weighs!!! Get the picture? March 2009 156 Petty/Tilley

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

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**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, 15-20 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 30-60 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

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Current Field Doctrine

In wartime scenarios, military personnel entering an area considered to be a high threat for chemical warfare are issued either 3 MARK I Kits or 3 Duodote injectors. One MARK 1 Kit contains 2 injectors: Atropine 2 mg auto injector Pralidoxime 600 mg auto injector One Duodote contains 1 injector: Atropine 2.1 mg/0.7 cc and Pralidoxime 600 mg/2 cc auto injector administered sequentially with one needle/injection

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 Is/Duodotes when the casualtys condition warrants the use of three MARK Is/Duodotes 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.

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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/Duodote for nerve agent exposure, survivability increases significantly. 3. Pyridostigmine pretreatment is useless unless Atropine is given at the onset of a cholinergic crisis.

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
Gastrointestinal (cramps, N/V) Urinary urgency and frequency Diarrhea, salivation, visual changes Headache, rhinorrhea, diaphoresis, Tingling of extremities

% Incidence
> 50 5-30 > 10 <5

Table 13-2: Produced from information in Medical Management of Chemical Casualties Handbook. 1995, p. 17- 46.)

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.

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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 **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!!

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Keeping It All In Perspective

What Binds To The ACh Receptor??
ACh
ACh Receptor

Nondepolarizing Muscle Relaxants

Depolarizing Muscle Relaxants

Anticholinergics

What Binds To Acetylcholinesterase??

Reversible Anticholinesterases 1. Electrostatic bond Edrophonium 2. Carbamylation Neostigmine Pyridostigmine Physostigmine

ACh (Acetylation)

AChE

Irreversible Anticholinesterases 1. Phosphorylation Echothiophate Nerve Agents Insecticides

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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.

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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

Mechanism of Action

Figure 14-2: (Mycek, Mary J. Lippincotts 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!! March 2009 164 Petty/Tilley

Relationship of pKa to pH
pKa defines the pH at which the amount of ionized and unionized drug fraction is equal. Local anesthetics with a pKa closer to physiologic pH (7.4) will have a quicker onset related to an increased unionized drug fraction.

**Clinical Application **
Knowing the pKa 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] = pka pH

Clinical Example of Using pka 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] = pka pH
1. Log [cation] / [base] = 8.1 - 6.8 2. Log [cation] / [base] = 1.3 3. Log20 = 1.3 * 4. Therefore, Log [20]/Log [1] = 1.3 5. 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: log1 log10 log100 log1000 =0 =1 =2 =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.

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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 cholinesterases, secondarily by the liver, and some is excreted unchanged in the urine. Duration of action may be prolonged with atypical pseudocholinesterase and pregnancy ( enzyme). Hydrolysis by cholinesterase enzyme 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
2-Chloroprocaine (Nesacaine) Cocaine Procaine (Novocaine) Tetracaine (Pontocaine) Benzocaine (Americaine) Remember: CCPT like captain

pKa
9.0 8.7 8.9 8.2 None

Amides
Bupivacaine (Marcaine) Dibucaine (Nupercaine) Etidocaine (Duranest) Lidocaine (Xylocaine) Mepivacaine (Carbocaine) Prilocaine (Citanest) Ropivacaine (Naropin)

pKa
8.1 8.8 7.7 7.8 7.6 7.8 8.1

Table 14-1: (Produced from information in Morgan, E. Clinical Anesthesiology. 2006, p. 267-268.)

**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.

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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 pKa determines unionized drug fraction available. The amount of unionized drug determines onset time. o Lidocaine pKa = 7.8 = 25% unionized & 75% ionized o Tetracaine pKa = 8.2 = 7% unionized & 93% ionized The closer the drugs pKa is to physiologic pH, the quicker the onset. o Remember, local anesthetics are basic drugs.

**pKa = Speed of onset** #4 INTRINSIC VASODILATOR ACTIVITY

All local anesthetics EXCEPT Cocaine and Ropivacaine, possess the ability to cause vasodilation in the area they are injected, increasing blood flow to that area. O Epinephrine is only utilized as a vascular marker with Ropivacaine. 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

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Local Anesthetic Characteristics

Characteristic
Low Potency Short Duration

Drug
Procaine 2-Chloroprocaine

Relative Potency
1 1 2 2 2 8 10 9 6
rd

Onset
Slow Fast Fast Fast Fast Slow Slow Intermediate Fast

Duration (min)
60-90 30-60 120-240 120-240 90-200 180-600 180-600 180-600 180-600

Intermediate Potency Intermediate Duration

Mepivacaine Prilocaine Lidocaine

High Potency Long Duration

Tetracaine Ropivacaine Bupivacaine Etidocaine

Table 14-2: (Produced from Nagelhout, J.J. Nurse Anesthesia. 3 Ed. 2005, p. 132 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) (Femoral is similar to Sciatic) 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!!

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Specific Drug Characteristics

Lipid solubility, protein binding, pKa, 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 (T1/2 alpha) is very quick related to equilibration with vessel-rich tissue. Elimination half - time (T1/2 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 with 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.

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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. 2. 3. 4. 5. CNS Excitation CV Excitation CNS Depression CV Depression Death

**Rapid injection of extremely high levels of local anesthetics can progress to CV and CNS collapse without initial excitatory signs. Remember: Some patients dont read the book.

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 **Clinical Note** It is not uncommon for seizure activity to return as blood levels of the local anesthetic fall and excitatory CNS symptoms reoccur.

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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: 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
Lidocaine Bupivacaine Ropivacaine 2-Chloroprocaine Mepivacaine Tetracaine Benzocaine Cocaine
Table 14-3

Primary Clinical Use

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

Primary Clinical Uses of Local Anesthetics

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.

Local Infiltration
Injection of local anesthetics into tissues to block pain. Often Epinephrine is added to increase the duration of action. Remember: Lidocaine and epinephrine solutions become unstable if mixed too early. So mix it just prior to administration. 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.

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Commonly used local anesthetics for infiltration include: 0.5% - 1% Lidocaine 0.125% - 0.5% Bupivacaine 0.25% - 0.5% Ropivacaine Shortcut for quickly calculating dose of Bupivacaine the surgeon can inject/infiltrate Bupivacaine 0.5%: give half the patients kg weight in cc i.e. 60 kg pt = 30 cc injection Bupivacaine 0.25%: give the patients kg weight in cc i.e. 60 kg pt = 60 cc injection

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, femoral nerve, 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 0.2-0.75% (all 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. Bupivacaine for spinal use also comes as an isobaric mixture of 0.5%-0.75% in NS. 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/analgesia include: Lidocaine 1-2% Bupivacaine 0.25-0.5% Ropivacaine 0.2-0.5% 2-Chloroprocaine 2-3% **Expect sensory and motor block in these concentrations. Common agents selected for epidural analgesia for labor or postoperative pain management include: 0.0625% - 0.125% Bupivacaine 0.25-1% Lidocaine 0.1%-0.25% Ropivacaine **Expect sensory block with mild to no motor block.

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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 or Ropivacaine = 0.1 mEq Bicarbonate to 20 cc of local anesthetic because they precipitate) 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 vasodilation). 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 pKa 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.

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. Can be mixed with other faster onset, shorter acting local anesthetics to increase duration

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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 use 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 contraindicated 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. No longer on the market.

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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
B C* A-delta A-gamma A-beta A-alpha * Unmyelinated Fibers

Size (microns)
0.25 0.5 0.5 0.75 0.75 1.0

Function
Preganglionic Autonomic Temperature, Dull Pain Temperature, Sharp Pain Muscle Spindle, Muscle Tone Light Pressure, Touch Somatic Motor, Proprioception

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. 2. 3. 4. 5. 6. 7. 8.

Autonomic regulation Temperature (especially to cold) Dull pain Sharp pain Touch Deep pressure Proprioception Somatic muscle function

Low Local Anesthetic Concentration

High Local Anesthetic Concentration

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**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 cant 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.

Local Anesthetics Single Injection Dose

Agent Maximum Dose With Epinephrine (mg/kg) Maximum Dose Without Epinephrine (mg/kg) Maximum Single Dose (Total mg)

Bupivacaine 3.2 2.5 225 0.25-0.5% Levobupivacaine 3.2 2.5 225 0.25-0.5% Ropivacaine 3.5 3 250 0.2-0.5% 2-Chloroprocaine 14 11 1000 2-3% Mepivacaine 7 4 500 1-2% Lidocaine 7 4 500 1-2% Tetracaine 3 1-2 200 1-1.5% Table 14-5*: (Nagelhout, J.J. Nurse Anesthesia. 3rd Ed. 2005, p. 140 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 pKas and pHs. Usually this is not a problem, but some unpredictability has been reported with 2-Chloroprocaine, probably related to its high pKa.

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Suggested Spinal Anesthetic Concentrations

Tetracaine 1% T-6 Level C-Section Height Dose Height Dose (inches) (mg) (inches) (mg) 65 7 60 5 66 8 61 5.5 67 9 62 6 68 10 63 6.5 69 11 64 7 70 12 65 7.5 71 13 66 8 72 14 67 8.5 73 15 68 9 74 16 69 9.5 75 16 70 10 5% Lidocaine / 7.5 % Glucose T-4 Level C-Section Height Dose Height Dose (inches) (mg) (inches) (mg) 60 50 < 65 50 61 55 66 55 62 60 67 60 63 65 68 65 64 70 69 70 65 75 70 75 66 80 71 80 67 85 72 85 68 90 73 90 69 95 74 95 70 100 75 100

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 7.5 -15 mg dependent upon desired block level relative to height. Patients commonly receive 10.5 -15 mg of Bupivacaine for most surgical procedures without much difficulty. However, be careful injecting more than 12 mg in patients who are 5 3 or less, especially in parturient. Injecting Bupivacaine in the sitting position will consistently decrease the risk of unwanted cephalad spread.

Common Axillary Block Mixtures

** 1.5% Mepivacaine + Epinephrine 1:200,000 (40cc) 20 cc 2% Mepivacaine + 20cc 1% Mepivacaine + 0.2 cc Epinephrine (1:1000) **1.75% Mepivacaine + Epinephrine 1:200,000 + 60 mg Tetracaine (40cc) 30 cc 2% Mepivacaine + 10 cc NS + 0.2 cc Epi (1:1000) + 3 vials of Tetracaine (20 mg/vial)

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Common Epidural Infusion Mixtures **0.125% (1/8th) Bupivacaine + 2 ug/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% (1/8th) Bupivacaine + 4 ug/cc Fentanyl 250cc NS - 62cc NS + 42cc 0.75% Bupivacaine + 20cc Fentanyl **0.1% (1/10th) Bupivacaine + 2 ug/cc Fentanyl 250cc NS - 44cc NS + 34cc 0.75% Bupivacaine + 10cc Fentanyl **0.1% (1/10th) Bupivacaine + 4 ug/cc Fentanyl 250cc NS - 54cc NS + 34cc 0.75% Bupivacaine + 20cc Fentanyl **0.1% (1/10th) Bupivacaine + 10 ug/cc Hydromorphone 250cc NS - 54cc NS + 34cc 0.75% Bupivacaine + 1.25 cc Hydromorphone **0.0625% (1/16th) Bupivacaine + 4 ug/cc Fentanyl 250cc NS - 50cc NS + 30cc 0.5% Bupivacaine + 20cc Fentanyl **0.0625% (1/16th) Bupivacaine + 40 ug/cc Duramorph 250cc NS - 40cc NS + 30cc 0.5% Bupivacaine + 10cc Duramorph **0.2% (1/5th) Ropivacaine + 4 ug/cc Fentanyl (labor epidural) 250cc NS - 70cc NS + 50cc 1% Ropivacaine + 20cc Fentanyl **0.75% (3/4) Ropivacaine + 2 ug/cc Fentanyl (surgical anesthesia) 250cc NS 197.5cc NS + 187.5cc 1% Ropivacaine + 10cc Fentanyl

NOTE: Consider the addition of Fentanyl, Duramorph, Hydromorphone or Sufentanil to the admixture on a case by case basis. It is not always the best method of pain management. For instance, patients with multiple traumatic injuries may also need to receive PCA/IV/IM narcotics in addition to the epidural analgesia. Generally, it is deemed unsafe to administer PCA/IV/IM narcotics concurrently with epidural narcotics.

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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 patients 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

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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 alpha1, beta1, and beta2 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 MAOIs 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.

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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.

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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. Johns 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/MAOIs Unpredictable clinical responses to direct and indirect-acting sympathomimetic drugs (Neosynephrine, Ephedrine). Recommend discontinuation at least 5 days prior to surgery.

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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.

Most Commonly Used Herbal Medicines

Herb
Echinacea Ephedra Garlic Ginkgo biloba Ginseng Kava St. Johns Wort

Perioperative Concerns
Counteracts immune suppressive therapy Hepatotoxicity Causes immune suppression long term. Increased heart rate and blood pressure Myocardial infarction Dysrhythmias Bleeding from inhibition of platelets Bleeding from inhibition of platelets Bleeding from platelet inhibition Bleeding from coagulation cascade inhibition Hypoglycemia Increased sedative effects of anesthetics Liver enzyme induction leading to increased drug metabolism. Interaction with sympathomimetic drugs Potentiation of anesthesia drugs Acute withdrawal symptoms

Perioperative Recommendations
D/C as soon as possible

D/C at least 24 hours prior Avoid MAOIs D/C at least 7 days prior D/C at least 36 hours prior D/C at least 7 days prior 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 weeks If not possible, continue up to day of surgery. Petty/Tilley

Valerian

Table 15-1: (Produced from information in Morgan, E., Mikhail, M. Clinical Anesthesiology. 2002, p.7.)

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Herbal Medicines With Coagulation Effects

Herb
Alfalfa Capsicum Celery Chamomile Fenugreek Feverfew Fish oil Garlic Ginger Gingko biloba Ginseng Horseradish Kava Kava Licorice Passionflower Red Clover Vitamin E

Effect
Contains coumarins Contains coumarins Inhibits platelet aggregation Contains coumarins Contains coumarins Contains coumarins Inhibits platelet aggregation Decreases platelet adhesion and aggregation Decreases plasma viscosity Increases clotting time Inhibits platelet aggregation Inhibits platelet function Inhibits platelet function Lowers fibrinogen levels Decreases plasma viscosity Inhibits platelet aggregation Contains coumarins Contains coumarins Decreases platelet aggregation Contains coumarins Contains coumarins Contains coumarins 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 Black Cohosh Capsicum Celery Ephedra Fenugreek Garlic Ginger Ginseng Goldenseal Hawthorn Horseradish Licorice St. Johns Wort Effect Decreased Increased Decreased Marked Increase Decreased Decreased Variable Variable Increased Decreased Decreased Increased Variable

Table 15-3: (Norred, C., Use of complementary and alternative medicines by surgical patients. AANA J, 2000; 68 (1): 16, with modification.)

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Herbal Medicines With Sedative Effects

Celery Chamomile Ginseng Goldenrod Hops Kava Kava Passionflower St. Johns 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 Ephedra Fenugreek Ginger Ginseng Goldenseal Hawthorn Licorice Lobelia Bradycardia, Peripheral Vasodilation Palpitations, Arrhythmias Increased Heart Rate Bradycardia, Positive Inotrope Tachycardia, Positive Inotrope Cardiac Stimulant Increase Coronary Blood Flow Arrhythmias Digitalis Potentiation Arrhythmias Tachycardia

Table 15-5: (Norred, C., Use of complementary and alternative medicines by surgical patients. AANA J, 2000; 68 (1): 16, with modification.)

Herbal Medicines With Electrolyte Effects

Herb
Aloe Chromium Fenugreek Figwort Ginseng Goldenseal Licorice Rauwolfia

Effect
Hypokalemia Hypoglycemia Hypoglycemia Hypoglycemia Hypoglycemia Hypernatremia Increased Serum Osmolality Hypernatremia Hypokalemia Hypernatremia

Table 15-6: (Produced from information in Skidmore-Roth, L. Mosbys Handbook of Herbs & Natural Supplements, 2001, p.864-72.)

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Internet Resources For Herbal Information American Botanical Council www.herbalgram.org American Holistic Nurses Association www.ahna.org Center for Food Safety and Applied Nutrition Food and Drug Administration www.cfsan.fda.gov Herb Research Foundation www.herbs.org HerbMed www.herbmed.org National Center for Complimentary and Alternative Medicines, NIH http://nccam.nih.gov Office of Dietary Supplements, National Institutes of Health, NIH http://odp.od.nih.gov U.S. Pharmacopia www.usp.org

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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.

Patient Factors Increasing PONV

Factor
Age Gender Anxiety Menstruation Weight Concomitant Disease Patient History

Description
16 years and younger Females, pregnancy -adrenergic mechanism (Epinephrine & Norepinephrine) Luteal phase of cycle (3rd and 4th week) Obesity Gastroparesis (Diabetes, GERD, Bowel Obstruction), Increased ICP Previous history of PONV, Motion sickness, Migraines, Non-smokers, Food Intake

Procedural Factors Increasing PONV

Gynecological Ophthalmic ENT Laparoscopic Intraabdominal Dental/Oral Testicular Duration of anesthesia Type of Anesthesia Peritoneal and organ retraction Centrally mediated Blood in mouth, stomach CO2 Insufflation Peritoneal and organ retraction Blood in mouth, stomach Vagally mediated

Anesthetic Factors Increasing PONV

Increased exposure Narcotics Volatile Agents Nitrous Oxide Anticholinesterases Etomidate Barbiturates

PACU Factors Increasing PONV

Pain Treatment of pain Movement Oral intake Hypotension Parasympathetic? Mu-2 agonism Vestibular Gastroparesis 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.)

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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

Fig. 16-1: (Kovac, A., Antiemetic Use in Postoperative Nausea and Vomiting, Drugs, 2000; 59 (2): 213-243.)

Midbrain Neurochemical Emetogenic Receptor Locations

Midbrain Location
Area Postrema

Receptorsa

Opioid Dopamine (D2) Serotonin (5-HT3) Enkephalin Chemoreceptor Trigger Zone Opioid Dopamine (D2) Enkephalin Nucleus of Solitary Tract Histamine (H1) 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): 213-243 with modification.)

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Factors Influencing Nausea and Vomiting

Sensory input (pain, smell, sight) Higher Cortical Centers Memory, fear, anticipation
NK1 Antagonist
Histamine Antagonists Muscarinic Antagonists Dopamine Antagonists Benzodiazepines Propofol

Chemotherapy Anesthetics Opioids

Chemoreceptor Trigger Zone (area postrema) 4th Ventricle

Sphincter Modulators 5HT3 Antagonists
ve er

Vomiting Center Medulla

Vomiting Reflex
ag us N

Histamine Antagonists Muscarinic Antagonists

ia V

Chemotherapy Surgery Radiotherapy

Gastroprokinetic Agents

Stomach Small Intestines

Labyrinths Vestibular Apparatus CN VIII

Surgery Motion

Neuronal Pathways Factors which can cause PONV

Sites of action of drugs

NK1 Antagonist

Figure 16-2. http://www.nauseaandvomiting.co.uk/NAVRES001-3-PONV.htm#B8 with modification

Classification
Anticholinergics Antimuscarinics Antihistamines Substituted Benzamides Benzodiazepines Butyrophenones Isopropylphenol Phenothiazines 5-HT3 receptor antagonists Steroids

Antiemetic Drugs
Atropine Scopolamine Diphenhydramine (Benadryl) Hydroxyzine (Vistaril) Metoclopramide (Reglan) Lorazepam (Ativan) Midazolam (Versed) Droperidol (Inapsine) Haloperidol (Haldol) Propofol Promethazine (Phenergan) Prochlorperazine (Compazine) Chlorpromazine (Thorazine) Ondansetron (Zofran) Dolasetron (Anzemet) Granisetron (Kytril) Dexamethasone (Decadron) Methylprednisolone (Solumedrol)

Receptor
Acetylcholine (Vestibular apparatus) Muscarinic Acetylcholine (Vestibular apparatus) Histamine H1 Dopamine D2 Antagonist Gastroprokinetic/Sphincter modulator Anxiolytic decrease plasma levels of catecholamines Alpha1 blocker (Hypotension) GABA blocker (Sedation) Dopamine D2 Blocker Unknown, probably not anti-dopaminergic Alpha1 blocker (Hypotension) Dopamine D2 Blocker Histamine H1 Blocker 5-HT3 (Serotonin) (Area Postrema and abdominal vagal afferents) Unknown, many hypotheses

Substance P/ NK1 (Central Nervous System and gut) Aprepitant (Emend) Neurokinin 1 NK1 Does not work at the CTZ receptor antagonists Table 16-3: (Kovac, A., Antiemetic Use in Postoperative Nausea and Vomiting, Drugs, 2000; 59 (2): 213-243 with modification.)

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5-HT3 Receptor Antagonists

Ondansetron HCl (Zofran)
Structure Carbazalone derivative that is structurally similar to serotonin that selectively blocks 5-HT3 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-HT3 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 cant be given as you extubate the patient. Metabolized in the liver via hydroxylation and conjugation by cytochrome P-450 53% 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-HT3 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.

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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: 0.1 mg or 1 mg IV over 30-60 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: 0.1 mg or 1 mg IV over 30-60 seconds Dose: 40 g/kg IV administered over 30-60 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. 0.1 mg/ml vials do not contain the preservative benzyl alcohol. The 1 mg/ml vials do.

Butyrophenones
Droperidol (Inapsine)
Structure Structurally resembles phenothiazines with similar antiemetic effectiveness. Target receptors are Dopamine D2 receptors in the Chemoreceptor Trigger Zone (CTZ) in the area postrema. Interferes with the transmission of NE, serotonin, and GABA It is an alpha1 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: 0.625 2.5 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 g/kg IV for children

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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: Parkinsons Disease Prolonged QT interval Other side effects: Hypotension from Alpha1 receptor blockade Sedation from GABA blockade Utilized for preoperative sedation in preparation for an awake fiberoptic intubation Extrapyramidal reactions and dysphoria from Dopamine D2 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.

Substituted Benzamides
Metoclopramide (Reglan)
Structure Structurally resembles procainamide but lacks local anesthetic properties Acts centrally at receptors in the CTZ of the CNS as a dopamine (D2) 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 30-60 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: 10-20 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

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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 Parkinsons 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 10-20 cm H2O. 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.

Anticholinergics
Scopolamine
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.

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Pharmacokinetic Properties and Dosing Dose: Transderm Scp 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 Scp 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 15-60 g/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 H1-Receptor Antagonists

Diphenhydramine (Benadryl)
Structure Is an ethanolamine with atropine-like activity used to treat allergic symptoms, vertigo/motion sickness, Parkinsons, 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: 10-50 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 H2 vasodilation **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

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Phenothiazines
Promethazine (Phenergan) Prochlorperazine (Compazine)
Structure Has a tricyclic nucleus with an aliphatic side chain Blocks Dopamine (D2) 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: 12.5-25 mg IV Promethazine Dose: Child: 0.25-0.5 mg/kg IV Prochlorperazine Dose: Adult: 2.5-10 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 (D2) 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

Corticosteroids
Dexamethasone (Decadron)
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 4-4.5 hours. Onset is within a few minutes.

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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.

Substance P/Neurokinin 1 (NK1) Receptor Antagonist

Aprepitant (Emend)
Structure Selectively blocks Substance P/Neurokinin 1 receptors in the CNS and gut, with little or no effect on 5-HT3, dopamine, and corticosteroid receptors Elimination Elimination half-life is 9-13 hours Pharmacokinetic Properties and Dosing Dose: Adult: 40 mg po given 1-3 hours preop Dose: Child has not been evaluated in patients below 18 years of age Must be given preop. It cannot be used as a rescue drug for N/V. Side Effects and Clinical Concerns Induces CY3A4 and in doses > 40 mg has increased the plasma concentration of midazolam

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 N2O and anticholinesterase agents if possible 3. RSI 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. IV 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 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.

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Side Effects of Commonly Used Antiemetics

Sedation Extrapyramidal Symptoms Dysphoria Headache/Dizziness Dry mouth Hypotension Diphenhydramine, Hydroxyzine Droperidol Promethazine/Prochlorperazine Droperidol Metoclopramide Promethazine/Prochlorperazine Droperidol Scopolamine, Atropine Dolasetron Ondansetron Atropine, Scopolamine Diphenhydramine Hydroxyzine Droperidol Promethazine/Prochlorperazine

Table 16-4: (Kovac, A., Antiemetic Use in Postoperative Nausea and Vomiting, Drugs, 2000; 59 (2): 213-243 with modification.)

Dosing Guidelines for Antiemetic Medications

Class
Anticholinergics Antihistamines

Drug
Scopolamine Diphenhydramine Hydroxyzine

Route
IM, IV, Transderm Patch IM, IV PO PO IM IM, IV, PO IV IM, IV PO IV

Initial Dose
Adult: 0.2-0.65 mg Adult 1.5 mg (apply 4 hrs preop) Adult: 10-50 mg Adult: 25-50 mg Adult: 25-50 mg Adult: 25-100 mg Adult: 10-20 mg Child: 0.15 mg/kg (max 10 mg) Adult: 0.625-2.5 mg Child: 5.0 - 7.5 g/kg Adult: 8-16 mg Adult: 4 mg Child: 0.1 mg/kg (max 4 mg) Rescue Dose: 1 mg Adult: 100 mg Adult: 12.5 mg Child: 0.35 mg/kg (max 12.5) Adult: 0.1 mg - 1 mg Child: 40 g/kg (max 1 mg) Adult only: 40 mg Adult: 12.5-25 mg Child: 0.25-0.5 mg/kg Adult: 2.5-10mg Adult: 5-10 mg Adult: 12 mg

Frequency/Timing
q 6-8 hrs q 72 hrs q 2-4 hrs q 6-8 hrs q 6 hrs At start of anesthesia At end of surgery At start of anesthesia 1-2 hrs prior to anesthesia At start of anesthesia 1-2 hrs prior to anesthesia 15 min prior to end of anesthesia Prior to anesthesia or on extubation 1-3 hours preop q 4-8 hrs q 6-8 hrs q 3-4 hrs At start of anesthesia

Benzamides Butyrophenones 5-HT3 receptor Antagonists

Metoclopramide Droperidol Ondansetron

Dolasetron

PO IV

Granisetron NK1 Antagonist Phenothiazines Aprepitant Promethazine Prochlorperazine Steroids Betamethasone Dexamethasone

IV PO IM, IV, PO IV IM, PO IM IV

Adult: 4-10 mg At start of anesthesia Child: 0.1 mg/kg Table 16-5: (Kovac, A., Antiemetic Use in Postoperative Nausea and Vomiting, Drugs, 2000; 59 (2): 213-243 with modification.)

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Guidelines for Prophylactic Antiemetic Therapy

Patient Factors Surgical Factors

Female gender H/O PONV Nonsmoker Use of opioids

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-HT3 antagonist

Mod to High Risk 3-4 factors present (40-80%)

Very High Risk > 4 factors present (> 80%)

Dexamethasone + 5-HT3 antagonist Droperidol + 5-HT3 antagonist

Combination antiemetics + TIVA with propofol

Figure 16-3: (Kovac, A., Antiemetic Use in Postoperative Nausea and Vomiting, Drugs, 2000; 59 (2): 213-243 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. H2-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.

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H2-Receptor Antagonists
Ranitidine (Zantac)
Structure Competitively blocks H2-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 2.0-2.5 hours. Duration of action is 6-8 hours. Pharmacokinetic Properties and Dosing Dose: Adult: 50 mg in 50 cc of NS over 15-30 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 H2-receptors. Hypotension with rapid infusion due to peripheral vasodilation but it can also suppress histamine-induced peripheral vasodilation. Bronchospasm due to unopposed histamine effects of H1-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

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Cimetidine (Tagamet)
Structure Competitively inhibits histamine binding to H2-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 15-30 minutes every 6-8 hours Onset time of 15 minutes after infusion. Dose: Adult: 300-400 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 60-90 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 H1 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

Gastroprokinetic Agents
Metoclopramide (Reglan)
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

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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 15-30 cc given 15-30 minutes prior to induction Antacids lose their effectiveness within 30-60 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 Cimetidine Ranitidine Bicitra Metoclopramide Route PO IV PO IV PO PO IV Dose 300-800 mg 300 mg 150-300 mg 50 mg 15-30 ml 10-20 mg 10-20 mg Onset 1-2 hours 15 min 1-2 hours 30 min 5-10 min 30-60 min 3-5 min Duration 4-8 hrs 10-12 hrs 30-60 min 1-2 hrs Acidity No effect Volume LES tone No effect No effect 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. 3rd Edition, New York: McGrawHill, p 244 with modification.)

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Chapter 17 Adrenergic Drugs & Vasopressors

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). Lippincotts Illustrated Reviews: Pharmacology. 2nd Edition, pg 32).

Table 17-1. Major Effects Mediated by - and - Adrenoreceptors

1
Vasoconstriction Increased Peripheral resistance Increased Blood Pressure Bronchoconstriction Decreased nasal congestion Mydriasis Smooth muscle contraction of gut, uterus, and bladder

2
Inhibition of Norepinephrine release Inhibition of Insulin release Platelet aggregation Decreased Lipolysis Reduces sympathetic outflow, i.e. Sympatholytic

1
Tachycardia Chronotropy Increased Myocardial contractility Inotropy Increased conduction velocity - Dromotropy Increased Lipolysis

2
Vasodilation Slightly Decreased Peripheral resistance Induces hypokalemia drives K+ into the cells Bronchodilation Increased muscle and liver Glycogenolysis Increased Glucagon Smooth muscle relaxation of gut, uterus, and bladder

Table 17-1: (Mycek, Mary J., et al. (2000). Lippincotts Illustrated Reviews: Pharmacology. 2nd Ed, p 60, with modification).

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Figure 17-2: (Morgan, E., Mikhail, M. & Murray, M. (2002). Clinical Anesthesiology. 3rd 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.

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Figure 17-3: (Neal, M. J. (1995). Medical Pharmacology at a Glance. 2nd 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.

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Figure 17-4: (Mycek, Mary J., et al. (2000). Lippincotts Illustrated Reviews: Pharmacology. 2nd 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 (IP3) 5. REMOVAL OF NEUROTRANSMITTER Recaptured by uptake back into the neuron Diffuse out of synapse Metabolized to O-methylated derivatives by COMT

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Table 17-2. Classification and Comparison Pharmacology of Sympathomimetics

Airway Resistance Renal Blood Flow Receptors Stimulated Mechanism Of Action Cardiac Effects Continuous Infusion 1-20 g/min 4-16 g/min 1-20 g/kg/min 1-5 g/min 2-10 g/kg/min Not used Not used 20-50 g/min

Dysrhythmias

Alpha1

Alpha2

Beta1

Beta2

DA1

DA2

CO

Natural Catecholamines Epinephrine1 Norepinephrine Dopamine

1 1

HR

++ +++ ++

++ ++ ++

+++ ++ +

++ 0 +

0 0 +++

0 0 +++

Direct Direct Direct Indirect

++ +++

++ +

+++ + +

+++ +

MAP + +++ +

PVR

-NC NC

---+++

Synthetic Catecholamines Isoproterenol Dobutamine Synthetic Noncatecholamines Ephedrine Amphetamines Phenylephrine ++ ++ +++ ? ? + ++ + 0 + + 0 0 0 0 0 0 0 Indirect Direct Indirect Direct ++ + ++ + ++ + NC + ++ +++ ++ + +++ -NC NC ----0 0/+ 0 0 +++ +++ +++ + ? 0 ? 0 Direct Direct +++ +++ +++ + +++ -NC + --NC ++

CO = Cardiac Output PVR = Peripheral Vascular Resistance MAP = Mean Arterial Pressure ?, unknown; 0, none; +, Minimal increase; ++, Moderate increase; +++, Marked increase; -, Minimal decrease; --, Moderate decrease; ---, Marked decrease; NC, No change 1 The 1 effects of epinephrine, norepinephrine, and dopamine become more prominent at high doses. Table 17-2: (Stoelting, R.K. (1999). Pharmacology and Physiology in Anesthesia Practice. 3rd Edition, p 260. Morgan, E., Mikhail, M., Murray, M. (2002). Clinical Anesthesiology. 3rd Edition, p 216 with modification.)

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Sympathomimetics Natural Catecholamines

Epinephrine
Pharmacokinetic Properties Endogenous catecholamine that is synthesized from tyrosine in the adrenal medulla Direct acting agonist at 1, 2, 1, 2 Rapid onset, brief duration of action Rapidly metabolized in the GI tract and liver so the oral route is ineffective Administered IV, ET, SC, inhalation, or topically SC delayed onset systemic absorption is minimal due to injection site vasoconstriction Poor penetration into CNS due to its lipid insolubility but it can cause minor CNS disturbances Physiologic Effects Cardiovascular: Major site of action, Dose dependent Predominately 2 at 1-2 mcg/min Peripheral vasodilation (may see in diastolic BP) Relaxation of bronchial smooth muscle Predominately 1 at 4 mcg/min Contractility Positive Inotropic effect HR ( rate of spontaneous phase 4 depolarization) Positive Chronotropy (See Figure at right)

Clinical Picture with low to moderate doses of epinephrine Increased heart rate Increased force of cardiac contraction Decreased peripheral vascular resistance Increased systolic pressure Decreased diastolic pressure Widening pulse pressure
Predominately 1 > 1 at 10-20 g/min Vasoconstriction of skin, mucosa, and hepatorenal vasculature Respiratory: Powerful bronchodilation by acting directly on bronchial smooth muscle Renal: Decreases renal blood flow Metabolic effects Hyperglycemia Increases glycogenolysis in liver Beta2 effects Increases release of glucagon Beta2 effects Decreases release of insulin Alpha2 effects Hypokalemia drives potassium into skeletal muscle cells Lipolysis increases plasma concentration of cholesterol Coagulation accelerates due to increased activity of Factor V

Complications Cerebral hemorrhage (from increased BP) CNS disturbances (anxiety, fear, tension, headache and tremor) Coronary ischemia (inotropic/chronotropic effects increase myocardial oxygen demand) Pulmonary edema can be induced Ventricular dysrhythmias (potentiated by halothane)

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Indications ACLS ventricular fibrillation, asystole, PEA Asthma/Bronchospasm relieves dyspnea, increases tidal volume Decreases systemic absorption and prolongs duration and intensity of local anesthetics Utilize 1:100,000 (10 mcg/mL), 1:200,000 (5 mcg/mL), or 1:400,000 (2.5 mcg/mL) Temporizing treatment of hypotension (spinal anesthesia) Glaucoma topical treatment to decrease pressure in the eye **Clinical Application** During a general anesthetic the patient develops anaphylaxis following latex exposure. The cornerstone of treatment for anaphylaxis is epinephrine in the following dosages: 0.5-1.0 mcg/kg IV boluses (dilute 10 mcg/mL) SC - 10 mcg/kg (use 1:1000 solution) Infusion 2-4 mcg/min (1 mg in 250 mL of D5W [4 mcg/mL]) Epinephrine is an effective treatment of anaphylaxis due to three mechanisms: 1. Supports hemodynamics by increasing blood pressure 2. Provides bronchodilation 3. Prevents mast cell degranulation

Norepinephrine
Pharmacokinetic Properties Endogenous catecholamine that is released from postganglionic sympathetic nerve endings Direct acting agonist at 1, 2, 1 Lacks Beta2 adrenergic effects Rapid onset, brief duration of action Rapidly metabolized in the GI tract and liver so the oral route is ineffective Administered as an intravenous infusion and less commonly as a bolus IV bolus 0.1 mcg/kg 4 mg in 500 cc of D5W [8 mcg/mL] at a rate of 4-16 mcg/min Extravasation can cause tissue necrosis Physiologic Effects Cardiovascular Vasoconstriction Intense vasoconstriction of arterial and venous vessels due to alpha1 effects with no beta2 vasodilation Increases afterload Increases myocardial contractility Beta1 effects Baroreceptor reflex - bradycardia offsets Beta1 positive chronotropic effects

Clinical Picture with intravenous infusions of norepinephrine Reflex bradycardia Increased peripheral vascular resistance Increased systolic pressure Increased diastolic pressure

Respiratory: No bronchodilation, so inappropriate choice to treat asthma Renal significant decrease in renal blood flow Indications Refractory hypotension

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Dopamine
Pharmacokinetic Properties Important neurotransmitter in the CNS and peripheral nervous system Primarily a Direct acting agonist at 1, 2, 1, 2, DA1, DA2 Immediate metabolic precursor to norepinephrine Indirectly stimulates the release of endogenous norepinephrine minimal effect Does not cause as many dysrhythmias as epinephrine Dopamine1 receptors are located postsynaptically and mediate vasodilation of renal, mesenteric, coronary, and cerebral blood vessels Dopamine2 receptors are presynaptic and inhibit release of norepinephrine Rapid onset, brief duration of action Rapidly metabolized in the GI tract and liver so the oral route is ineffective Administered as an intravenous infusion due to its rapid metabolism 400 mg in 250 cc of D5W [1600 mcg/mL] at a rate of 1-20 mcg/kg/min All catecholamines must be dissolved in D5W to avoid the inactivation that may occur in alkaline solutions. Physiologic Effects Cardiovascular/Renal: Dose dependent Predominately DA1 at 1-3 mcg/kg/min Vasodilates the renal vasculature and promotes diuresis Predominately 1 at 2-10 mcg/kg/min Contractility Positive Inotropic effects HR ( rate of spontaneous phase 4 depolarization/slope) Positive Chronotropy Cardiac output and myocardial oxygen demand Predominately 1 > 1 at 10-20 mcg/kg/min Vasoconstriction of skin, mucosa, and hepatorenal vasculature Increases peripheral vascular resistance Decreases renal blood flow Hyperglycemia drug-induced inhibition of insulin secretion CNS minimal CNS effects Indications Shock with low systemic blood pressure and low urine output Improves cardiac output Supports blood pressure Maintains renal function Increases RBF, GFR, sodium excretion and urine output Complications Extravasation produces intense vasoconstriction Treat with Phentolamine 10 mg diluted into 10 mL, infiltrate around affected area Nausea and vomiting Hypertension Dysrhythmias

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Synthetic Catecholamines
Isoproterenol
Pharmacokinetic Properties Synthetic Direct acting agonist at 1, 2 Lacks alpha agonist effects at clinical doses Chemical Pacemaker Rapid onset, brief duration of action Uptake into postganglionic sympathetic nerve endings is minimal Absorbed systemically by sublingual mucosa or as an inhaled aerosol Metabolism in the liver by COMT is rapid Administered as an intravenous infusion 3 mg in 250 cc of D5W or NS [12 mcg/mL] at a rate of 1-5 mcg/min Physiologic Effects Cardiovascular: Beta1 adrenergic effects Contractility Positive Inotropic effects HR ( rate of spontaneous phase 4 depolarization/slope) Positive Chronotropy Beta2 adrenergic effects Vasodilation of skeletal muscle arterioles

Clinical Picture with intravenous infusions of isoproterenol Increased heart rate Increased myocardial contractility Increased cardiac output Significant Decreased peripheral vascular resistance Increased systolic pressure Markedly Decreased diastolic pressure

Respiratory: Prolonged bronchodilation Metabolic effects: Hyperglycemia and Lipolysis Indications Bronchodilator for asthmatics but better drugs are now available Atrioventricular block or cardiac arrest rarely used Decreased pulmonary vascular resistance in patients with pulmonary hypertension Complications Increased myocardial oxygen demand Decreased coronary blood flow and myocardial oxygen supply Adverse effects similar to Epinephrine Isoproterenol has largely been replaced with more selective beta agonist drugs

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Dobutamine
Pharmacokinetic Properties Synthetic, direct acting catecholamine, selective 1 adrenergic agonist Lacks alpha-adrenergic effects Rapidly metabolized so it must be administered as a continuous infusion 500 mg in 500cc of D5W (1 mg/mL) at a rate of 2-10 mcg/kg/min As with natural catecholamines, it MUST be mixed with D5W to avoid inactivation of the catecholamine that may occur in an alkaline solution. Physiologic Effects Cardiovascular: Increases cardiac output Minimal increase in heart rate Increases conduction velocity through the AV node not the SA node Minimal increase in systemic vascular resistance Causes Coronary vasodilation Renal: Does not activate dopaminergic receptors so no renal vasodilation Increases renal blood flow by increasing cardiac output Indications Used to improve cardiac output in congestive heart failure patients Ineffective in patients that require an increase in systemic vascular resistance because it lacks alpha vasoconstrictive effects Little change in heart rate Does not significantly elevate myocardial oxygen demand Complications oxygen Use cautiously in patients with atrial fibrillation Increased conduction velocity through the AV node can result in excessive increases in heart rate Adverse effects are similar to epinephrine.

Synthetic Noncatecholamines
Ephedrine
Pharmacokinetic Properties Noncatecholamine that stimulates alpha- & beta-adrenergic receptors Indirect agonist properties Central nervous system stimulation Peripheral postsynaptic norepinephrine release Inhibition of norepinephrine reuptake Direct agonist properties Direct stimulation of adrenergic receptors Onset immediate with intravenous administration Longer duration of action than with catecholamines (10-60 minutes) Oral route is acceptable due to its resistance to GI tract MAO metabolism. IM acceptable local vasoconstriction is less than with epinephrine Elimination: Hepatic - (MAO); Renal - excreted unchanged in the urine (40%)

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 Dosing: Hypotension IV 5-25 mg (100-200 mcg/kg) - Max dose 150 mg IV IM 10-25 mg SC 25-50 mg Usually diluted to 5 or 10 mg/mL Bronchospasm - 5-20 mg IV/IM/SC Physiologic Effects Cardiovascular: Increases heart rate (1) Increases blood pressure (1, 1) Predominately by increasing myocardial contractility not by vasoconstriction Minimally decreases uterine blood flow ideal for obstetrical anesthesia

Clinical Picture with ephedrine Significantly Increases heart rate Increases myocardial contractility Increases cardiac output Minimally Increases peripheral vascular resistance Alpha1 effects offset by Beta2 effects Increased systolic pressure Increased diastolic pressure

CNS: Stimulates CNS (raises MAC requirement) Increases alertness, decreases fatigue and prevents sleep Respiratory: Bronchodilation (2), less potent than epinephrine or isoproterenol Tachyphylaxis may occur because ephedrine has a longer duration of action. Ephedrine is already occupying the receptor so you should expect a less intense systemic response with subsequent doses. So if the patient remains hypotensive after repeated dosing, you need to administer a direct acting sympathomimetic such as phenylephrine. Tachyphylaxis also occurs with depleted norepinephrine stores Indications Hypotension due to: Inhaled or intravenous anesthetics, i.e. following induction and prior to surgical incision Sympathetic nervous system blockade following regional anesthesia Precautions/Complications oxygen Use cautiously in patients with coronary artery disease Tachycardia increases myocardial oxygen demand and decreases myocardial oxygen supply, which can cause ischemia Use cautiously in patients with previous beta-blockade Alpha-adrenergic response is now unopposed so you may see vasoconstriction and bradycardia. Unpredictable vasopressor response Elderly Underlying chronic hypertension, tachyarrhythmias Not indicated in patients with depleted endogenous catecholamines Adverse effects are similar to epinephrine

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Phenylephrine (Neosynephrine)
Pharmacokinetic Properties Synthetic, direct acting noncatecholamine, primarily alpha1 adrenergic agonist Minimal beta-adrenergic agonist effects at clinical doses High doses may stimulate 2 and -adrenergic receptors Less potent but longer duration of action than norepinephrine 15-20 minute duration of action Elimination: Hepatic Administered as an intravenous bolus or as an infusion Supplied as 1% solution for injection, 10 mg/mL vial Usually dilated to 40 mcg/mL or 100 mcg/mL Adult: 40-100 mcg boluses Children: 1-2 mcg/kg 10 mg in 250 cc of NS [40 mcg/mL] at a rate of 20-50 mcg/min Infusion: 0.25 1.0 mcg/kg/min [100 mcg/mL], use with caution Tachyphylaxis will occur requiring increases in dosing Extravasation can cause tissue necrosis. Physiologic Effects Cardiovascular: Vasoconstrictor that increases systemic vascular resistance and arterial blood pressure Baroreceptor-mediated Reflex bradycardia Negative Chronotropic effects May reduce cardiac output Increases coronary artery blood flow

Clinical Picture with phenylephrine Decreased heart rate Increased peripheral vascular resistance Increased systolic pressure Increased diastolic pressure

CNS stimulation is minimal. Renal blood flow is decreased Indications Hypotension due to sympathetic nervous system blockade following regional anesthesia Increases blood pressure in patients with coronary artery disease and aortic stenosis Increases coronary artery blood flow without increasing the heart rate Used topically as a nasal decongestant or for mydriasis during eye surgery Prolongs spinal anesthesia when added to local anesthetic solutions Can be used to slow hemodynamically unstable supraventricular tachydysrhythmias Precautions/Complications oxygen Can cause bradyarrhythmias and heart block Use cautiously in pregnancy Can cause decreased uterine blood flow and fetal asphyxia Use cautiously in end organ anesthesia and in patients with congestive heart failure Pediatric asystole has occurred with nasal use Not indicated for spinal anesthesia hypotension with associated bradycardia o Phenylephrine will further decrease the heart rate and cardiac output o Administer ephedrine instead to these patients

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Arginine Vasopressin (Pitressin/ADH)

Pharmacokinetic Properties Nonadrenergic sympathomimetic without alpha or beta adrenergic effects Endogenous hormone is synthesized in the supraoptic and paraventricular nuclei of the hypothalamus and stored in the posterior pituitary (neurohypophysis) Low dose: Acts predominately on V2 receptors in the distal tubules and collecting duct V2 receptor G proteins adenylyl cyclase cAMP Protein Kinase A Phosphorylation water resorption High dose: Acts predominately on V1 receptors in vascular smooth muscle V1 receptor G proteins phospholipase C IP3 release of intracellular Ca++ Also increases extracellular Ca++ influx via an unknown mechanism Elimination Half-life: 10-20 minutes, IV (no need to redose during code) Metabolism: Hepatic, renal Administered as an intravenous bolus or as an infusion Supplied as 20 units per mL Cardiac Arrest: Vasopressin 40 units IV or 2-2.5 times IV dose endotracheally Intractable Hypotension: Vasopressin titrate 2 units IV up to 10 units slowly After bolus, start infusion at 2-8 Units/hr - depending on your bolus dose Shock - Infusion: 100 units in 500 mL D5W (0.1-0.4 units/min) or (30-120 mL/hr) Extravasation can cause tissue necrosis and gangrene. Physiologic Effects Cardiovascular High doses Direct vasoconstrictor that increases SVR and ABP (both systolic & diastolic pressure) Baroreceptor-mediated Reflex bradycardia May reduce cardiac output Decreases coronary artery blood flow due to selective coronary artery vasoconstriction Pulmonary Vascular Resistance (PVR) PVR by V1 receptor mediated release of nitric oxide vasodilation in the pulmonary vasculature Renal Low doses V2 receptors found on renal tubule cells mediate antidiuresis through increased water permeability and water resorption in the collecting tubules Blood coagulation Low doses (usually Desmopressin/DDAVP 0.3 mcg/kg IV) Activation of V2 receptors increases the circulating levels of Factor VIII and von Willebrands factor by increasing release of these factors from vascular endothelium Activation of V1 receptors stimulates platelet aggregation Indications Intractable hypotension due to chronic ACE inhibitor or Angiotensin II blocker use Hypotension that is refractory to epinephrine and norepinephrine Cardiac arrest due to ventricular fibrillation, pulseless V-tach or pulseless electrical activity Nasal Desmopressin treatment of Diabetes Insipidus IV Desmopressin treatment of von Willebrands disease Precautions/Complications oxygen May cause asystole and severe decreased cardiac output in doses > 0.4 units/min Can cause cardiac ischemia - use caution in patients with coronary artery disease Can cause bronchoconstriction Can cause water intoxication and hyponatremia

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Additional Adrenergic Agonists

Albuterol
Pharmacokinetics and Physiologic Effects Selective 2 agonist Preferred agent for treatment of acute bronchospasm due to asthma Maximal bronchodilatory effects in 30 minutes lasting for 3-4 hours Dose: MDI 100 mcg/puff, 2 puffs every 4-6 hours 2.5-5 mg (0.5-1.0 ml of 0.5% solution in 5 ml of NS) by nebulizer every 15 minutes Continuous nebs up to 15 mg/hr for two hours can be used in life-threatening asthma Precautions/Complications Tachycardia and hypokalemia may occur with large doses

Clonidine
Centrally acting selective partial alpha2 adrenergic agonist Dose: 0.2-0.3 mg orally or weekly transderm patch Decreases sympathetic nervous system output from CNS Decreases MAC by 50% - causes sedation Used to treat essential hypertension Minimizes withdrawal symptoms from opiates or benzodiazepines. Preservative-free preparation used epidurally or subarachnoid will produce analgesia Activation of postsynaptic alpha2 receptors in the substantia gelatinosa of the spinal cord 150-450 mcg will not cause respiratory depression, pruritis, or nausea and vomiting

Dexmedetomidine HCL (Precedex)

Pharmacokinetic Properties Centrally acting 2 agonist with a higher affinity for 2 adrenergic receptors than clonidine Redistribution half-life of 6 minutes Terminal Elimination half-life: 2 hours Total metabolism by C-P450 i.e. the liver with no unchanged drug in the urine Substantially excreted via the kidneys Physiologic Effects Sedation and analgesia with minimal respiratory depression Inhibits release of substance P in the Locus Ceruleus/spinal cord Decreases sympathetic nervous system activity Caution with DM, chronic HTN, elderly and hypovolemic patients Precautions/Complications Decrease the dose in patients with hepatic and renal dysfunction Can cause severe bradycardia/hypotension so it is contraindicated in patients with heart block Caution in patients with high vagal tone and limited reserve Infusion cannot exceed 24 hours Severe hypertension can occur with the loading dose due to 1 stimulation May have to decrease the loading dose. Some advocate no loading dose.

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Dosing Mix 200 mcg (1 vial) into 48 cc of NS (4 mcg/cc) for infusion It must always be placed on a pump. You will NEVER push this drug. In general, Precedex is initiated with a loading infusion of 1.0 mcg/kg over 10-30 minutes, followed by a maintenance infusion of 0.2-0.7 mcg/kg/hr. (Hospira package insert) Yes per hour-- NOT per minute 1. Start the infusion at 0.5-0.7 mcg/kg/hr (per package insert) Recently, I have began increasing the initial dose to 2 mcg/kg/hr until the patients heart rate decreases to 10-20% of preop and then turn the infusion down to 0.5-0.9 mcg/kg/hr. This gets the patient to a steady state precedex level without giving the standard loading dose with its inherent hypertensive effects. 2. Decrease to 0.3-0.5 mcg/kg/hr 30 minutes prior to extubation 3. Decrease to 0.2-0.4 mcg/kg/hr 10 minutes prior to extubation 4. Can either be turned off at emergence or continue into the ICU or PACU

Table 17-3. Responses evoked by autonomic nervous system stimulation

Sympathetic nervous system stimulation
Heart Sinoatrial node Atrioventricular node His-Purkinje system Ventricles Bronchial smooth muscle Gastrointestinal tract Motility Secretion Sphincters Gallbladder Uterus Urinary bladder Smooth muscle Sphincter Eye Radial muscle Sphincter muscle Ciliary muscle Liver Salivary gland secretion Arterioles Coronary Skin and mucosa Skeletal muscle Pulmonary Heart rate Conduction velocity Automaticity, Conduction velocity Contractility, Conduction velocity, Automaticity Relaxation Decrease Decrease Contraction Relaxation Contraction Relaxation Contraction Mydriasis Relaxation for far vision Glycogenolysis Gluconeogenesis Increase Constriction (alpha) Relaxation (beta) Constriction Constriction (alpha) Relaxation (beta) Constriction Miosis Contraction for near vision Glycogen synthesis Marked increase Relaxation (?) Relaxation Relaxation Relaxation Heart rate Conduction velocity Minimal effect Slight in contractility Contraction Increase Increase Relaxation Contraction Variable Contraction Relaxation

Parasympathetic nervous system stimulation

Table 17-3: (Stoelting, R. K. Pharmacology and Physiology in Anesthesia Practice. 2006 p. 697 with modification)

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Phosphodiesterase Inhibitors
Milrinone/Primacor
Pharmacokinetic Properties Non-catecholamine, nonadrenergic competitive inhibitor of phosphodiesterase (PDE III) o Does not rely on -adrenergic stimulation o Effectiveness is not altered by prior beta blockade Onset: 5-15 minutes Metabolism: excreted unchanged by the kidneys o Decrease dose with severe renal dysfunction Elimination half-time: 2.7 hours Concentrations Supplied 1 mg/mL (20 mL vial) (dilute - 20 mL in 80 mL D5W/NS 200 mcg/mL conc) Premixed bags come 200 mcg/mL (100 mL, 200 mL) Dosing Loading: 50 mcg/kg over 10 minutes Maintenance: 0.375-0.750 mcg/kg/min (standard dose=0.5 mcg/kg/min) for 12 hrs Physiologic Effects Inodilator due to positive inotropy and vasodilatory effects o Inotropy: Increases myocardial contractility (see Fig 17-6) with minimal increases in heart rate (chronotropy) and myocardial oxygen consumption Accelerates myocardial diastolic relaxation (lusitropic effects) Augments coronary perfusion o Vasodilation: Decreases peripheral/systemic vascular resistance (arterial & venous) and pulmonary vascular resistance (PVR) (see Fig 17-7) Decreases left ventricular end-diastolic pressure

Contractility & Afterload & PVR Cardiac Output & PCWP & CVP & PAP
Mechanism of Action 1) Agonist (1st messenger) and -adrenergic receptor bind receptor is activated a) Activated receptor binds to a complex of proteins the G proteins b) Alpha subunit of the G complex binds to GTP c) G + GTP binding activates the enzyme adenylyl cyclase d) Activated adenylyl cyclase converts ATP to Cyclic AMP (2nd messenger) e) Phosphodiesterase breaks down cAMP and terminates its action 2) cAMP activates protein kinase phosphorylates Ca++ channels 3) Phosphorylationintracellular Ca++ contractility 4) Phosphodiesterase inhibitors prevent the hydrolysis of cAMP and prolongs its actions (see Fig 17.6)

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Figure 17-6. How Phosphodiesterase Drugs Cause Positive Inotropy

G Proteins

Adenylyl Cyclase

Fig 17-6: (Mycek, M.J., Harvey, R.A., Champe, P.C. Pharmacology. 2nd Ed. 2000, p.161 with modifications.)

Figure 17-7. How Phosphodiesterase Drugs Cause Vasodilation

Fig 17-7: (Mycek, M.J., Harvey, R.A., Champe, P.C. Pharmacology. 2nd Ed. 2000, p.161 with modifications.)

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Indications Drug of choice in severe Congestive Heart Failure patients concurrently taking beta-blockers Treatment of Cardiogenic Shock Weaning from Cardiopulmonary Bypass (CPB) to increase cardiac output Additive inotropy when given in combination with dobutamine, epinephrine etc Precautions/Complications Loading dose should be given during CPB i.e. before weaning in patients with poor LV function Avoids a decrease in MAP and the need for inotropes during weaning Increases outflow obstruction in patients with hypertrophic subaortic stenosis SVT and ventricular dysrhythmias have occurred in high risk patient Ensure that ventricular rate controlled in atrial fibrillation/flutter before initiating Not recommended for use in acute myocardial infarction patients Adjust dose in patients with renal dysfunction

Ventricular Cardiac Action Potential

Drugs affecting Cardiac Action Potentials
Calcium channel blockers work on phase 2, the plateau phase in ventricular muscle fibers Lidocaine, verapamil, digoxin work on phase 4, spontaneous depolarization in SA Node fibers

Fig 17-8: Mogan, E., Mikhail, M. & Murray, M. (2006). Clinical Anesthesiology, 4th Ed., pp 416-417.

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Chapter 18
Antihypertensive Drugs
Hypertension is the most common cardiovascular disease. It is defined per the 7th JNCC as listed in Table 18-1. The overall opinion is to treat to a blood pressure of < 140/90 mm Hg or in patients with diabetes or chronic kidney disease to a blood pressure of < 130/80 mm Hg. This chapter will look at the various drugs used to treat systemic hypertension to include; adrenergic receptor antagonists, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, calcium channel blockers and vasodilators.

Table 18-1. BP Classifications

BP Classification
Normal Pre-hypertension Stage 1 Hypertension Stage 2 Hypertension

Systolic BP mm Hg
< 120 120-139 140-159 > 160 and or or or

Diastolic BP mm Hg
< 80 80-89 90-99 > 100

Table 18-1: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure, Dec 2003. (Currently up for review)

Adrenergic Receptor Antagonists/Blockers

Fig 18-1: Mycek, M.J., Harvey, R.A., Champe, P.C. Pharmacology. 2nd Ed. 2000, p.184.

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Table 18-2. Pharmacological Properties of Adrenergic Antagonists

Receptor Antagonized 1 Esmolol Labetalol 0 + 2 0 0 1 ++ ++ 2 + with dose + HR Cardiac Output Peripheral Vascular Resistance Slight with High doses MAP Metabolism Dosing

Plasma Esterases 0.5-2.0 mg/kg IV Bolus Renal excretion of 50-200 mcg/kg/min inactive metabolites (5 g in 500 mL) Hepatic 0.1-0.5 mg/kg IV Bolus Usual dose is 5 mg 5 mg q2 min X3 MI 1-5 mg q2 min for HR & BP 5 mg over 5 min X 2 IV 25-100 mg/day po 6-15 mg/day po 1-5 mg IV Bolus 0.3 mg/min (10 mg in 100 mL D5W) 0.5-1.0 mg/kg po

Metoprolol

++

Slight

Hepatic

Atenolol Prazosin Phentolamine Phenoxybenzamine

0 ++ ++ ++

0 0 + +

++ 0 0 0

+ 0 0 0

NC

Slight

Renal Hepatic Hepatic Irreversible blockade

HR = Heart Rate MAP = Mean Arterial Pressure NC = No change, 0 = no blockade, + = Minimal blockade, ++ = Moderate blockade = Minimal increase, = Moderate increase = Minimal decrease, = Moderate decrease Table 18-2: (Stoelting R. K. Pharmacology and Physiology in Anesthesia Practice. 2006. Chp 14. Morgan, E., Mikhail, M., Murray, M. Clinical Anesthesiology. 2006, pp. 250-252 with modification).

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Esmolol/Brevibloc
Pharmacokinetic Properties Cardioselective Beta1 antagonist Rapid onset of 1-2 minutes Peak effect: 5 minutes Ultra short acting due to rapid redistribution (2 min) Elimination half-life of 9 minutes Ester linkage is hydrolyzed by red blood cell or plasma esterases NOT the same as plasma cholinesterases 75% of the inactive acid metabolite is excreted in the urine Concentrations Supplied 10mg/mL injectable (found in anesthesia cart ready to administer) 250 mg/mL (dilution for infusion usually not found in the cart for safety reasons) Dosing IV Bolus 25 -100 mg (0.5-2.0 mg/kg) to attenuate perioperative cardiovascular responses Longer treatment: 0.5 mg/kg, followed by infusion of 50-200 mcg/kg/min (5 g in 500 mL) Physiologic Effects Cardiovascular: Reduces heart rate and to a lesser extent blood pressure Negative Chronotropic and Inotropic effects CNS: Lipid insoluble so minimal diffusion into the CNS Pain on injection can occur Indications Prevention of tachycardia and hypertension during anesthesia Frequently given during laryngoscopy on induction and during emergence from GA Slow the ventricular response in patients with atrial fibrillation Treatment of supraventricular tachyarrhythmias Precautions/Complications oxygen Avoid in patients with: Overt heart failure Sinus bradycardia Cardiogenic shock Tachycardia with concurrent hypovolemia 2nd or 3rd degree AV heart block Use cautiously in patients with COPD/Asthma Beta2 adrenergic blockade at high doses can cause increased airway resistance May mask symptoms of hypoglycemia in patients with diabetes mellitus Incompatible with sodium bicarbonate

Labetalol/Normodyne/Trandate
Pharmacokinetic Properties Unique selective alpha1- and nonselective beta1- and beta2 adrenergic antagonist Ratio of -blockade and -blockade is 1:7 for IV labetalol Onset: 2-5 minutes Peak effect: 5 minutes Elimination half-life: 5-8 hours Prolonged with liver disease

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 Concentration supplied: 5 mg/mL in multi-dose vials or 100-600 mg oral Dose: 0.1-0.5 mg/kg IV Usual initial dose is 5 mg Dose can be doubled and repeated at 10 min intervals to effect Physiologic Effects Cardiovascular Reduces peripheral vascular resistance and arterial blood pressure Heart rate and cardiac output are minimally reduced Advantage: Decreased blood pressure without reflex tachycardia CNS: Cerebral blood flow and intracranial pressures are unchanged. Indications Antihypertensive Deliberate hypotension to reduce surgical bleeding Control perioperative adrenergic responses Emergency treatment of severe hypertension caused by an epinephrine overdose during submucosal injection for oral surgery Reduces the tachycardic and vasoconstrictive effects of epinephrine and lowers the incidence of pulmonary edema Precautions/Complications May mask symptoms of hypoglycemia in patients with diabetes mellitus Bronchospasm has occurred in susceptible patients Orthostatic hypotension is common in the postoperative period Congestive heart failure, bradycardia and heart block are potential risks

Metoprolol/Lopressor
Pharmacokinetic Properties Competitive, cardiac selective Beta1-adrenergic receptor blocker Onset: 5 minutes Peak effect: 20 minutes Elimination half-life: 3-4 hours Prolonged with liver disease Concentration supplied: 1 mg/mL in 5 mL multi-dose vials or (25-100 mg) oral Dose: 1-5 mg IV for HTN or 5 mg every 2 minutes up to 15 mg for patient with acute MI Usual dose in the OR is 1-2 mg every 5-20 minutes up to 5 mg total dose Physiologic Effects Cardiovascular: Reduces heart rate and blood pressure (systolic & diastolic) Negative Chronotropic and Inotropic effects Does not exhibit any membrane stabilizing or intrinsic sympathomimetic activity CNS: Fatigue, dizziness, headaches (especially in patients on chronic po lopressor) Indications Antihypertensive Reduction of cardiovascular mortality after acute phase of a myocardial infarction Deliberate hypotension to reduce surgical bleeding Control perioperative adrenergic responses

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Precautions/Complications (see esmolol patient considerations) Acute withdrawal may cause rebound HR and BP May mask symptoms of hypoglycemia in patients with diabetes mellitus Bronchospasm has occurred in susceptible patients

Phentolamine/Regitine
Pharmacokinetic Properties Competitive, non-selective alpha-adrenergic blocker Onset: 2 minutes Duration: 10-15 minutes Dose: 1-5 mg IV bolus Packaged as a lyophilized powder (5 mg) Follow with infusion of 0.3 mg/min (10mg in 100 mL D5W = 100 mcg/ml) Physiologic Effects Cardiovascular Decreased blood pressure by peripheral vasodilation Alpha1 receptor blockade Direct action on vascular smooth muscle Prevents vasoconstriction of peripheral blood vessels by endogenous catecholamines Reverses the alpha agonist effects of epinephrine Blocks the alpha effects and leaves the vasodilating beta2 effects unopposed Reflex baroreceptor-mediated tachycardia Increased cardiac output and tachycardia Alpha2 receptor blockade permits enhanced release of norepinephrine CNS: Cerebral blood flow and intracranial pressure are generally maintained Indications Treatment of acute hypertensive emergencies usually associated with pheochromocytoma and autonomic hyperreflexia. Treatment of rebound hypertension Treatment of sloughing after extravasation of a barbiturate or sympathomimetic drugs Local Infiltration with Phentolamine 5-10 mg in 10 mL of NS Precautions/Complications Reflex tachycardia Postural hypotension Treat Phentolamine induced hypotension with norepinephrine Use cautiously in patients with ischemic heart disease Can cause cardiac dysrhythmias and angina Hyperperistalsis, abdominal pain, and diarrhea

Phenoxybenzamine
Pharmacokinetic Properties Noncompetitive, non-selective, irreversible -adrenergic blocker (1 > 2) The body must synthesize new adrenoreceptors, which takes 24 hours to overcome this block. Slow Onset: 60 minutes Must be structurally modified in the body to the active form

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 Elimination half-life: 24 hours Dose: 0.5-1.0 mg/kg orally Physiologic Effects Cardiovascular Prevents vasoconstriction of peripheral blood vessels by endogenous catecholamines Reverses the alpha agonist effects of epinephrine Blocks the alpha effects and leaves the vasodilating beta2 effects unopposed Reflex tachycardia caused by the decreased peripheral vascular resistance Increased cardiac output due to Alpha2 blockade Poor antihypertensive for treat of chronic hypertension Indications Control blood pressure in patients with pheochromocytoma Raynauds syndrome to decrease vasospasms Manage autonomic hyperreflexia Precautions/Complications Postural hypotension Nausea & vomiting, miosis, sedation and nasal stuffiness

Prazosin/Minipres
Pharmacokinetic Properties Selective, competitive, postsynaptic alpha1 antagonist Substantial first-pass hepatic metabolism Elimination half-time: 3 hours Prolonged with liver disease and congestive heart failure Physiologic Effects Decreases peripheral vascular resistance and blood pressure Relaxation of vascular smooth muscle (arterial and venous) No alpha2 blockade so the inhibition of norepinephrine release remains intact No reflex tachycardia No increase in renin activity Decreases venous return and cardiac output Decreases vascular tone in both resistance and capacitance vessels Indications Treatment of essential hypertension with less incidence of tachycardia Preoperative preparation for patients with pheochromocytoma Relieve vasospasms in patients with Raynauds phenomenon Precautions/Complications First dose: exaggerated hypotensive response may require a decreased initial dose to avoid syncope Exaggerated hypotensive response following epidural anesthesia can occur Dry mouth, nasal congestion and sexual dysfunction

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Angiotensin-Converting Enzyme Inhibitors (ACEI)

Enalaprilat/Enalapril/Vasotec
Pharmacokinetic Properties Enalapril (Vasotec) is the oral preparation. It is a prodrug that must be hydrolyzed in the liver to the active drug, Enalaprilat. Enalaprilat is the intravenous form utilized in the OR and for hypertensive crisis. Onset: 6-15 minutes Duration: 4-6 hours Elimination: Renal, dose with renal dysfunction Concentration supplied: 1.25 mg/ml (1-2 mL vials) Dose: 0.625-1.25 mg IV over 5 min every 6 hours Mechanism of Action 1) JG cells in the kidney are stimulated 2) Renin is secreted into the blood 3) Angiotensinogen is produced in the liver and is ubiquitous in the blood 4) Renin converts Angiotensinogen to Angiotensin I 5) Angiotensin I is converted by ACE in the lungs (Type I cells) to Angiotensin II 6) ACEI block the conversion of Angiotensin I to Angiotensin II
Fig 18-2: Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, 7th Ed., 2005.

Physiologic Effects Overall: Preload & Afterload Decreases SVR without increasing heart rate cardiac output Promotes natriuresis by reducing aldosterone Blocks the breakdown of bradykinin, a potent vasodilator Stimulates synthesis of Prostaglandin & Prostacyclin Decreases Sympathetic Nervous System (SNS) output Decreases blood cholesterol levels Indications Intraoperative hypertension Essential hypertension o First line for patients with diabetes Congestive Heart Failure Mitral Regurgitation

Fig 18-3: Braunwalds Heart Disease: A Textbook of Cardiovascular Medicine. 7th Ed. 2005 with modification.

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Precautions/Complications Chronically ACEI treated patients can develop intractable intraoperative hypotension Hyperkalemia because of decreased aldosterone Renal failure classically occurs in patients with bilateral renal artery stenosis Angioedema infrequently occurs Contraindicated during 2nd and 3rd trimester - very tetratogenic Persistent dry cough in patients chronically treated due to bradykinin buildup

Angiotensin II Receptor Blockers/Inhibitors (ARB)

Losartan/Cozaar
Pharmacokinetic Properties Competitively inhibits Type 1 angiotensin II receptors (AT1R) without affecting ACE activity Fig 18.4 shows where various antihypertensive agents work. o AGT = Angiotensinogen o Ang I = Angiotensin I o Ang II = Angiotensin II Notice that AT1R not only aldosterone, SNS activation and vasoconstriction, but they are also responsible for cell growth, i.e. cardiac muscle hypertrophy. o These drugs are used in patients with CHF to decrease remodeling. See Table 18.3 for individual ARB properties for comparison
Fig 18-4: Goldman, E.: Cecil Textbook of Medicine, 22nd Ed., 2004.

TABLE 18.3 COMPARISON OF COMMON ARBs

Peak Losartan (Cozaar) Candesartan cilexetil (Atacand) Eprosartan (Teveten) Irbesartan (Avapro) Telmisartan (Micardis) Valsartan (Diovan) Olmesartan Medoxomil (Benicar) 1-3 hrs 3-4 hrs 1-2 hrs 1.5-2 hrs 0.5-1 hr 2-4 hrs 1.4-2.8 hrs Half-Life 6-9 hrs 9 hrs 5-9 hrs 11-15 hrs 24 hrs 9 hrs 10-15 hrs Elimination Renal/Hepatic Renal/Biliary Renal/Biliary Renal/Biliary Biliary Hepatic GI Tract Active Metabolite Yes Yes No No No No Yes Oral Dose 25-100 mg/day 4-32 mg/day 400-800 mg/day 150-300 mg/day 40-80 mg/day 80-320 mg/day 20-40 mg/day

Table 18-3: (Developed from information in Hardman, Joel. Goodman & Gilmans The Pharmacological Basis of Therapeutics 11th Ed. 2006. pp 832-833)

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 Losartan is the prototype ARB. Newer agents have a more insurmountable AT1 affinity which should result in a sustained blockade no matter the concentration of Angiotensin II in the blood or when doses of the drug are missed. This means that patients who take Micardis the day before surgery may still have a potent effect of the drug on the day of surgery. o What does this mean? Intractable intraoperative hypotension Effects of Angiotensin II Blood Pressure Effects 40 times more potent than norepinephrine (NE) Direct contraction of arteriolar vasculature No reflex bradycardia because it acts on the brain to reset the baroreceptor reflex to a higher pressure Stimulates autonomic ganglia o Release of Epinephrine and NE from the adrenal medulla o Adrenergic stimulation Release & uptake of NE at the nerve terminals Adrenal Cortex Effects Acts directly on the zona glomerulosa of the adrenal cortex to aldosterone Kidney Effects Causes renal vasoconstriction, proximal tubular sodium reabsorption, renin secretion Central Nervous System Effects Thirst and oral fluid intake Vasopressin (ADH) secretion from the posterior pituitary ACTH secretion from the anterior pituitary Cell Growth Effects Mitogenic (causes miosis) for vascular and cardiac muscle cells o Development of cardiovascular hypertrophy Mechanism of Action ACEI ACE affects both Angiotensin II formation and bradykinin degradation

ARB
ARBs only affect the AT1R and not the production of Angiotensin II ACE degrades bradykinin so no accumulation and no cough Angiotensin II in the blood can be greatly increased in patients treated with ARBs
Fig 18-5: Katzung, Bertram. Basic & Clinical Pharmacology, 9th Ed. 2006.

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Physiologic Effects Overall: Preload & Afterload Decreases SVR without increasing heart rate cardiac output Promotes natriuresis by reducing aldosterone AT2R are not blocked, responsible for vasodilation o High circulating levels of Angiotensin II stimulate AT2R and vasodilation Decreases Sympathetic Nervous System (SNS) output Decreases blood cholesterol levels Indications Essential hypertension o First line for patients with diabetes without renal insufficiency Congestive Heart Failure (usually in combination with an ACEI or diuretic) Precautions/Complications Chronically ARB treated patients can develop intractable intraoperative hypotension Hyperkalemia because of decreased aldosterone Renal failure classically occurs in patients with bilateral renal artery stenosis Angioedema rarely occurs Contraindicated during 2nd and 3rd trimester - very tetratogenic ARBs do not cause the persistent cough unlike patients treated with ACEI.

CALCIUM CHANNEL BLOCKERS

Calcium channel blockers inhibit the entrance of calcium ions into cardiac and smooth muscle cells to produce antianginal, antiarrhythmic and antihypertensive effects. The chemical subclass, dihydropyridines, has a greater ratio of vascular smooth muscle effects to cardiac effects than the non-dihydropyridines, i.e. phenylalkylamines and benzothiazepines.

TABLE 18-4. EFFECTS OF CALCIUM CHANNEL BLOCKERS

Class/Effect Subclass Negative inotropic (contractility) Negative chronotropic (heart rate) Negative dromotropic (cardiac conduction velocity) Coronary vasodilation Systemic vasodilation Bronchodilation Verapamil (Calan) Phenylalkylamine Diltiazem (Cardiazem) Benzothiazepine Nifedipine (Procardia) Dihydropyridine Nicardipine (Cardene) Dihydropyridine

+ + ++++ ++ ++ 0/+
th

0/+ 0/+ +++ +++ ++

0 0 0 ++++ ++++ 0/+

+ 0 0 +++++ ++++

Table 18-4: Barash, Paul. Clinical Anesthesia. 5 Ed, 2006. p 325 with modifications. Myocardial depression with volatile anesthetics

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Fig 18-6: Mycek, M.J., Harvey, R.A., Champe, P.C. Pharmacology. 2nd Ed. 2000, p.154 with modifications.

Nicardipine/Cardene
Pharmacokinetic Properties Binds to receptors on L-type voltage gated Ca++ channels during depolarization maintenance of channel in inactive (closed) state. (See Figure 18-6). o Inhibits extracellular Ca++ from entering the slow channels Most potent of the calcium channel blockers in smooth muscle vasculature relaxation Onset: 1-3 minutes with dose adjustments or boluses made every 5 minutes Duration: Up to 30 minutes after infusion is discontinued Elimination: Hepatic metabolism with renal excretion of metabolitesdose with hepatic dz Concentration supplied: 2.5 mg/mL (10 mL vial or 25 mg/vial) Dilution: 25 mg/100 mL (250 mcg/mL) or 25 mg/250 mL (100 g/mL) in any solution except LR Dose: 250 g boluses until BP is therapeutic start infusion at 2-5 mg/hr up to 15 mg/hr max o Oral dose is 20-40 mg every 8 hours Physiologic Effects Cardiovascular o Relaxation of coronary vascular smooth muscle coronary blood flow Myocardial oxygen delivery in patients with vasospastic angina Greatest of any calcium channel blocker o Relaxation of peripheral arteries with minimal venodilating effects SVR afterload cardiac output, PCWP & ejection fraction o Has minimal cardiodepressant effects with no effects on heart rate Reflex tachycardia does not occur as frequently as with nitroprusside

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 Central Nervous System o Increases cerebral blood flow (CBF) with minimal effects on ICP Indications Intraoperative hypertension o CBF but does not increase ICP to the extent that nitroprusside does Drug of choice for hypertension in patient undergoing craniotomy with ICP Essential hypertension (oral form) Chronic stable angina/Congestive Heart Failure (oral form) Precautions/Complications Recent intracranial hemorrhage (risk/benefit less of a problem than nipride for severe hypertension which could cause hemorrhage) Aortic stenosis because a decrease in afterload is contraindicated in patients with AS Peripheral edema due to venodilation and sodium reabsorption Potentiate/augment the effects of depolarizing and nondepolarizing muscle relaxants Decreased effectiveness of anti-cholinesterase drugs due to presynaptic ACh release May interfere with calcium mediated platelet function Dantrolene precaution: can cause hyperkalemia and cardiovascular collapse so invasive hemodynamic monitoring is compulsory

VASODILATORS
Hydralazine/Apresoline
Pharmacokinetic Properties Phthalazine derivative that activates guanylyl cyclase o Mediated by activation of ATP-sensitive potassium channels within the arterial vasculature causing hyperpolarization and relaxation Direct vasodilation of arterioles with little effect on veins o Does NOT interact with adrenergic or cholinergic receptors Onset: IV: 5-20 minutes Duration: IV: 1-4 hours depends on acetylator status of patient Elimination: Hepatically acetylated dose with hepatic dz o Increase dose in fast acetylator patients Concentration supplied: 20 mg/mL (1 mL vial) Dose: 5 mg boluses made every 15-20 minutes up to 20 mg max Physiologic Effects Preferentially dilates arteries over veins SVR without orthostatic hypotension May stimulate the release of norepinephrine and augment myocardial contractility Lowers pulmonary vascular resistance but the greater cardiac output increase can cause mild pulmonary hypertension Does not dilate the epicardial arteries and can cause angina Indications Intraoperative Hypertension Essential Severe Hypertension Pre-eclampsia Chronic Heart Failure

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Fig. 18-7: (Katzung, Bertram G., Basic & Clinical Pharmacology, 8th Ed., 2001, p 169.)

Precautions/Complications Profound sympathetic activation with tachycardia, myocardial contractility & flushing o Caution in patient with coronary artery disease o Chronically treated patients are usually given beta blockers in conjunction o Effects blocked by beta blockers (See Fig 18-7) Peripheral edema in patients chronically treated usually requiring a diuretic o Renin levels are increased, leading to sodium and water retention Effects blocked by diuretics (See Fig 18-7) o Nonsteroidal anti-inflammatory drugs decrease the vasodilatory effects Aplastic anemia and lupus-like syndrome occurs with high dosages and prolonged use o Autoimmune reactions

Sodium Nitroprusside/Nipride
Pharmacokinetic Direct-acting, nonselective peripheral vasodilator Onset: < 2 minutes Duration: 1-10 minutes requires a continuous infusion to maintain its effects Elimination: Cyanide ion production in blood thiocyanate in the liver excreted in the urine Concentration supplied: 25 mg/mL (2 mL vial) Dilution: 50 mg in 250 mL of D5W (200 mcg/mL) and protected from light with foil Dose: 0.3-0.5 mcg/kg/min in increments of 0.5 mcg/kg/min up to 10 mcg/kg/min max o 1-2 mcg/kg bolus prior to direct laryngoscopy but can cause transient hypotension

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Mechanism of Action 1. SNP interacts with oxyhemoglobin & dissociates methemoglobin & releases nitric oxide (NO) & cyanide 2. NO activates intracellular guanylyl cyclase cGMP 3. cGMP inhibits calcium entry into vascular smooth muscle cells Vasodilation 4. SNP is a prodrug because it spontaneously generates NO much like endothelial cells resulting in Vasodilation 5. Fig 18-8 illustrates how PDE-5 inhibitors such as sildenafil can potentiate nitrates and vasodilators
Fig 18-8: Access Medicine online

Metabolism of Sodium Nitroprusside (SNP) (See Figure 18-9) 1. SNP transfers electron to oxyhemoglobin (oxyhgb) to make methemoglobin (methgb) 2. SNP radical promptly breaks down to 5 cyanides (CN) & Nitric Oxide 3. One Cyanide + methemoglobin = cyanomethemoglobin 4. Remaining cyanide + rhodanese (liver) thiocyanate 5. Thiocyanate is excreted in the urine

Fig 18-9: Stoelting, R. K. Pharmacology & Physiology in Anesthetic Practice. 4th Ed., 2006, p 356.

Physiologic Effects Cardiovascular o Causes peripheral vasodilation by direct action on venous and arteriolar smooth muscle o Systemic vascular resistance (SVR/afterload) & venous return (preload) o SVR baroreceptor mediated HR & myocardial contractility (inotropy) o Afterload Left Ventricular Impedance inotropy Cardiac Output o BP Renal Blood Flow (RBF) Renin BP with discontinuation of SNP Pretreat with ATR1 blocker to decrease overshoot BP with d/c after prolonged use o Intracoronary steal of blood flow away from ischemic areas (already maximally dilated) o Diastolic BP Coronary Perfusion

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 Cerebral Blood Flow (CBF) o Vasodilation CBF & Cerebral Blood Volume ICP Negated by slowly BP over 5 minutes with concurrent hypocarbia & hyperoxia Negated if utilized after the dura has been surgically opened Greater increase than with nitroglycerin or nicardipine Hypoxic Pulmonary Vasoconstriction (HPV) o Peripheral vasodilation BP HPV Shunt to poorly ventilated alveoli PaO2 Platelet Aggregation o Intracellular cGMP inhibits platelet aggregation with infusion rates > 3 mcg/kg/min Indications Intraoperative Hypertensive Emergencies o Pheochromocytoma Resection o 1-2 mcg/kg IV as a rapid injection Controlled Hypotension to reduce bleeding during surgery Aortic Aneurysm repair during cross clamping Cardiac Surgery during rewarming phase of cardiopulmonary bypass o Especially with mitral or aortic regurgitation Congestive Heart Failure Precautions/Complications Profound sympathetic activation with tachycardia, myocardial contractility & flushing o Caution in patients with coronary artery disease o Nitroglycerin is usually preferred Avoid in patients with aortic stenosis or coarctation Infusion must be wrapped with foil to protect from light in order to prevent breakdown of the parent drug to cyanide Cyanide toxicity tachyphylaxis, metabolic acidosis, dysrhythmias, tachycardia, excessive hypotension, almond smell on breath, convulsions, coma and death o Patients with anemia and liver/renal impairment are at an increased risk for toxicity o Usually only accumulates with infusions > 2 mcg/kg/min or infusions lasting > 24 hrs Treatment: Sodium thiosulfate 150 mg/kg IV over 15 min Sulfur donor converts cyanide to thiocyanate

Nitroglycerin (NTG)
Pharmacokinetic Organic nitrate, acts principally on venous capacitance vessels and large coronary arteries Onset: Topical: 15-60 min; IV: immediate Duration: Topical 2-12 hours; IV: 3-5 min requires an infusion Elimination: Urine Concentration supplied: Ointment: 2%; IV: 5 mg/mL (10 mL vial) or 250 mL bottle-200 mcg/mL Dilution: 50 mg in 250 mL of D5W (200 mcg/mL) in glass bottle Dose: Ointment: - 1 inch; IV: 5 mcg/min; increase 5 mcg/min every 5 min up to 20 mcg/min, if no response increase 20 mcg/min up to 200 mcg/min max Mechanism of Action NTG Intracellular nitrites Nitric oxide cGMP Dephosphorylation of myosin light chain Vascular smooth muscle relaxation o Does not spontaneously produce nitric oxide unlike SNP

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Physiologic Effects Cardiovascular o Preferentially dilates peripheral veins Cardiac oxygen demand by decreasing preload Left and Right ventricular end-diastolic pressures Minimally increases heart rate o Dilates large coronary arteries Improves collateral flow to ischemic regions of the heart o Can cause systemic arterial vasodilation with increasing doses > 2 mcg/kg/min May modestly decrease afterload o Pulmonary vasodilation is similar to arterial vasodilation (doses > 2 mcg/kg/min) Reduces pulmonary hypertension Indications Intraoperative ischemia or unstable angina o Coronary vasodilator Hypertensive emergency (especially during cardiac surgery) Intraoperative controlled hypotension Cardiac failure (CHF) after acute myocardial infarction o Improves cardiac output, relieves pulmonary congestion & MRO2 Relaxes sphincter of Oddi during a spasm i.e. during Lap Chole Uterine relaxation for versions and removal of placental fragments: usual dose 50 mcg Precautions/Complications Caution with hypovolemia, hypotension and right ventricular infarction Hypertrophic cardiomyopathy may be worsened d/t contractility b/c of the BP Cerebral hemorrhage + NTG = ICP Concurrent use with phosphodiesterase-5 (PDE-5) inhibitors (sildenafil/Viagra) BP Tolerance can occur so titrate appropriately Remove NTG patch prior to defibrillation or MRI study Methemoglobinemia o Nitrite metabolite of NTG oxidation of the ferrous ion to the ferric state Methgb

Table 18-5. Comparative Pharmacology of Vasodilator Agents

Hydralazine Nitroprusside Organ Effects Heart Rate Preload 0 Afterload CBF, ICP Kinetics Onset 5-20 min 1 min Duration 1-4 hr 5-10 min Dose Bolus 5-20 mg 50-100 mcg Infusion (mcg/kg/min) 0.25-1.5 0.3-10 0, no change; increase (slight, moderate, marked); decrease (slight, moderate, marked) Nitroglycerin 1 min 5-10 min 50-100 mcg 0.5-10

Table 18-5: Morgan, E., Mikhail, M. & Murray, M. Clinical Anesthesiology. 2006, p.257.)

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Appendix 1

Miscellaneous Summative Tables

Precautionary Use With Seizure Disorders

Drug
Atracurium, Cis-atracurium Enflurane Etomidate Flumazenil Ketamine Meperidine Methohexital Table 1

Comments
Laudanosine metabolite CNS stimulant CNS stimulant Stimulates seizure foci. Avoid in focal epilepsy Status epilepticus Tonic/clonic movements Normeperidine metabolite CNS stimulant Epileptiform seizures following high doses

Drugs/Conditions Affecting Somatosensory Evoked Potentials Monitoring

Drug/Condition Inhalation agent N2O Thiopental Etomidate Ketamine Narcotics/Opioids Muscle relaxants Hypothermia Hyperthermia Hypoxia Hypocarbia Hypotension Table 2 Latency 0 ?/0 0 0 0 0 Amplitude 0 0

Precautionary Use With Increased Intracranial Pressure

Drug
Halothane Ketamine Meperidine Succinylcholine Table 3

Comment
Increases CBF the most HR and BP leads to CBF HR and BP leads to CBF Fasciculations may increase ICP

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Precautionary Use With Cardiovascular Disease

Drug
All Volatile Agents

Comments
C.O. and sensitize heart to catecholamines = dysrhythmias All HR except Halothane Greatest myocardial depression Tachycardia, Hypertension SBP, MAP, CO, SVR more than other induction drugs. Vasodilation leads to BP Tachycardia r/t atropine-like effects Only opioid with direct myocardial depressant effects Pain perception, leads to HR, BP, and dysrhythmias. HR Bradycardia from succinylmonocholine Atropine-like effects cause HR Blocks reuptake of NE, epinephrine causing HR, BP, dysrhythmias

Halothane Ketamine Propofol Morphine Meperidine

Pure Opioid Antagonists (Naloxone, Nalmefene) Anticholinergics Succinylcholine Pancuronium Cocaine Table 4

Precautionary Use With Asthma

Drug
All Histamine-Releasing Drugs (Table 5)

Comment
Histamine is a mediator of bronchoconstriction Dose-dependent bronchodilation Bronchodilatory properties Bronchodilatory properties Airway resistance

Favorable Drugs For Use With Asthma

All Volatile Agents Ketamine Propofol Anticholinergics Table 5

Histamine-Releasing Drugs
Thiopental Morphine Meperidine Curare Atracurium Mivacurium Succinylcholine Ester Local Anesthetics (PABA) Table 6 March 2009 237 Petty/Tilley

Precautionary Use With Liver Dysfunction

Drug
Lidocaine, Diazepam, Meperidine, Morphine Halothane

Comment
Prolonged elimination with cirrhosis Reductive metabolism Halothane hepatitis Relies on liver for 15-20% metabolism Enzyme induction Primary biliary excretion (40-50%) Severe disease prolongs duration r/t levels of pseudocholinesterase Metabolized in the liver

Phenobarbital Vecuronium, Rocuronium Succinylcholine Mivacurium Amide Local Anesthetics Table 7

Precautionary Use With Renal Dysfunction

Drug
Enflurane Sevoflurane Morphine, Meperidine Pancuronium, Doxacurium, Pipecuronium, Curare Table 8

Comment
Fluoride ion induced nephrotoxicity Formulation of Compound A nephrotoxin. Occurs with flow rates < 2 liters Prolonged duration Primary renal excretion

Drugs Associated With Increased Nausea

Drug
All Opioids Etomidate Naloxone Anticholinesterase Agents Table 9

Comment
Stimulate the nausea center centrally Mechanism unclear Occurs with abrupt reversal Cholinergic response

Drugs To Avoid With Atypical Pseudocholinesterase

Drug
Succinylcholine Mivacurium Ester Local Anesthetics Table 10

Comments
Metabolized by pseudocholinesterase. Prolonged muscle paralysis may occur dependent upon genetic variant. Prolonged duration of action.

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Drugs Triggering Malignant Hyperthermia

Drug
All Volatile Anesthetics Succinylcholine Phenothiazines Curare Nitrous Oxide Local anesthetics Opioids Benzodiazepines Intravenous Induction Agents Anticholinergics Anticholinesterases Nondepolarizing Muscle Relaxants Droperidol Reglan Vasoactive Drugs Table 11

Comments
Not nitrous oxide

Controversial Triggers of Malignant Hyperthermia

Best to avoid Best to avoid No longer controversial Amides and esters are safe

Safe Drugs To Use With Malignant Hyperthermia

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References
Chapter 1 Pharmacokinetic Principles
1. Barash, P.G., Cullen, B.F., & Stoelting, R.K. (2006). Clinical Anesthesia. 5th Ed. Philadelphia: J.B. Lippincott Williams & Wilkins, Chapter 11. 2. Hudson, Robert J. (2001). Basic Principles of Clinical Pharmacology. In Paul G. Barash, Bruce F. Cullen, & Robert K. Stoelting (Eds), Clinical Anesthesia. 4th Edition, Philadelphia: Lippincott Williams & Wilkins, Chapter 11. 3. Katzung, Bertram G. (2007). Basic and Clinical Pharmacology. 10th Edition, New York: Lange Medical Books/McGraw-Hill, Chapter 3. 4. Miller, R. (2005). Anesthesia. 6th Edition, Philadelphia: Elsevier, Chapter 3. 5. Mycek, Mary J., et al. (2000). Lippincotts Illustrated Reviews: Pharmacology. 2nd Edition, Philadelphia: Lippincott Williams & Wilkins, Chapter 1. 6. Nagelhout, J.J. & Zaglaniczny, K.L. (2001). Nurse Anesthesia. 2nd Edition, Philadelphia: W.B. Saunders Company, Chapter 5. 7. Nagelhout, J.J. & Zaglaniczny, K.L. (2005). Nurse Anesthesia. 3rd Edition, Philadelphia: W.B. Saunders Company, Chapter 5. 8. Schwinn, Debra A. and Shafer, Steven L. (2000). Basic Principles of Pharmacology Related to Anesthesia. In Ronald D. Miller (Ed), Anesthesia. 5th Edition, New York: Churchill Livingstone, Chapter 2. 9. Stoelting, R.K. (1999). Pharmacology and Physiology in Anesthesia Practice. 3rd Edition, Philadelphia: Lippincott Williams and Wilkins, Chapter 1. 10. Stoelting, R.K. (2006). Pharmacology and Physiology in Anesthesia Practice. 4th Edition, Philadelphia: Lippincott Williams and Wilkins, Chapter 1. 11. Woerlee, G.M. (1992). Kinetics and Dynamics of Intravenous Anesthetics. Kluwer Academic Publishers, 47.

Chapter 2 Uptake and Distribution

1. Baumgarten, Richard K, M.D. (1995). Closed-Circuit Anesthesia. In R. Zajtchuck & R. Bellamy (Eds), Textbook of Military Medicine, Anesthesia and Perioperative Care of the Combat Casualty. Falls Church, VA: Office of the Surgeon General, Chapter 8. 2. Eger, E. (1994). Uptake and Distribution of Inhaled Anesthetics. The Distinguished Professor Program I by Ohmeda, New Jersey, Section 5. 3. Eger, E. (2000). Uptake and Distribution. In R.D. Miller (Ed), Anesthesia. 5th Edition, Philadelphia: Churchill Livingstone, Chapter 4. 4. Morgan, E., Mikhail, M., Murray, M. (2002). Clinical Anesthesiology. 3rd Edition, New York: McGraw-Hill, Chapter 7. 5. Morgan, E., Mikhail, M., Murray, M. (2006). Clinical Anesthesiology. 4th Edition, New York: McGraw-Hill, Chapter 7. 6. Stoelting, R.K. (1999). Pharmacology and Physiology in Anesthesia Practice. 3rd Edition, Philadelphia: Lippincott Williams and Wilkins, Chapter 1. 7. Stoelting, R.K. (2006). Pharmacology and Physiology in Anesthesia Practice. 4th Edition, Philadelphia: Lippincott Williams and Wilkins, Chapter 1.

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Chapter 3 Basic Concepts Related to General Anesthesia

1. Barash, P.G., Cullen, B.F., & Stoelting, R.K. (1989). Clinical Anesthesia. Philadelphia: J.B. Lippincott and Co., Chapter 10. 2. Nagelhout, J.J. & Zaglaniczny, K.L. (2001). Nurse Anesthesia. 2nd Edition, Philadelphia: W.B. Saunders Company, Chapter 7. 3. Stoelting, R.K. (1991). Pharmacology and Physiology in Anesthesia Practice. 2nd Edition, Philadelphia: Lippincott Williams and Wilkins, Chapter 1 4. Stoelting, R.K. (1999). Pharmacology and Physiology in Anesthesia Practice. 3rd Edition, Philadelphia: Lippincott Williams and Wilkins, Chapter 1. 5. Stoelting, R.K. (2006). Pharmacology and Physiology in Anesthesia Practice. 4th Edition, Philadelphia: Lippincott Williams and Wilkins, Chapter 1.

Chapter 4 Basic Math in Anesthesia Pharmacology

1. Dosch, M. (2001). Clinical Mathematics. Retrieved from the World Wide Web at URL: http://www.udmercy.edu/crna/agm/mathweb.htm 2. Morgan, E., Mikhail, M., & Murray, M. (2002). Clinical Anesthesiology. 3rd Edition, New York: McGraw-Hill, Chapter 4. 3. Petty, C. (1995). Military Anesthesia Machines. In R. Zajtchuck & R. Bellamy (Eds), Textbook of Military Medicine, Anesthesia and Perioperative Care of the Combat Casualty. Falls Church, VA: Office of the Surgeon General, Chapter 7.

Chapter 5 Physics Applied To Anesthesia

1. Morgan, E., Mikhail, M., Murray, M. (2002). Clinical Anesthesiology. 3rd Edition, New York: McGraw - Hall, Chapter 2. 2. Nagelhout, J.J. & Zaglaniczny, K.L. (2001). Nurse Anesthesia. 2nd Edition, Philadelphia: W.B. Saunders Company, Chapter 4. 3. Nagelhout, J.J. & Zaglaniczny, K.L. (2005). Nurse Anesthesia. 3rd Edition, Philadelphia: W.B. Saunders Company, Chapter 14. 4. Parbrook, G.D., Davis, P.D., & Parbrook, E.O. (1990). Basic Physics and Measurements in Anaesthesia. 3rd Edition, Oxford: British Cataloguing in Publication Data, Chapter 2, 4.

Chapter 6 Inhaled Anesthetic Agents

1. Anaquest Inc. (1992). The Ohmeda Tec 6 Vaporizer. (Product Information Pamphlet), 11. 2. Chestnut, David H. (2004). Obstetric Anesthesia: Principles and Practice. 3rd Edition, Philadelphia, Elsevier Mosby, pg 437. 3. Duke, James (2006). Anesthesia Secrets. 3rd Edition, Philadelphia: Elsevier, Chapter 76. 4. Hardman, Joel G. (2001). Goodman & Gilmans: The Pharmacological Basis of Therapeutics. 10th Edition, New York: McGraw-Hill, pg 354. 5. Nagelhout, J.J. & Zaglaniczny, K.L. (1997). Nurse Anesthesia. Philadelphia: W.B. Saunders Company, Chapter 18. 6. Stoelting, R.K. (1999). Pharmacology and Physiology in Anesthesia Practice. 3rd Edition, Philadelphia: Lippincott Williams and Wilkins, Chapter 2. 7. Stoelting, R.K. (2006). Pharmacology and Physiology in Anesthesia Practice. 4th Edition, Philadelphia: Lippincott Williams and Wilkins, Chapter 2.

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Chapter 7 Intravenous Induction Agents

1. Morgan, E. Mikhail, M. & Murray, M. (2002). Clinical Anesthesiology. 3rd Edition, New York: McGraw-Hill, Chapter 8. 2. Morgan, E. Mikhail, M. & Murray, M. (2006). Clinical Anesthesiology. 4th Edition, New York: McGraw-Hill, Chapter 8. 3. Nagelhout, J.J. & Zaglaniczny, K.L. (2001). Nurse Anesthesia. 2nd Edition, Philadelphia: W.B. Saunders Company, Chapter 7. 4. Nagelhout, J.J. & Zaglaniczny, K.L. (2005). Nurse Anesthesia. 3rd Edition, Philadelphia: W.B. Saunders Company, Chapter 8. 5. Omoigui, S. (1999). Anesthesia Drug Handbook. 3rd Edition, Malden, Mass.: Blackwell Science Inc., 1-502. 6. Stoelting, R.K. (1991). Pharmacology and Physiology in Anesthesia Practice. 2nd Edition, Philadelphia: Lippincott Williams and Wilkins, Chapters 4, 6. 7. Stoelting, R.K. (1999). Pharmacology and Physiology in Anesthesia Practice. 3rd Edition, Philadelphia: Lippincott Williams and Wilkins, Chapters 4, 6. 8. Stoelting, R.K. (2006). Pharmacology and Physiology in Anesthesia Practice. 4th Edition, Philadelphia: Lippincott Williams and Wilkins, Chapters 4, 6.

Chapter 8 Opioids
1. Nagelhout, J.J. & Zaglaniczny, K.L. (2001). Nurse Anesthesia. 2nd Edition, Philadelphia: W.B. Saunders Company, Chapter 10. 2. Nagelhout, J.J. & Zaglaniczny, K.L. (2005). Nurse Anesthesia. 3rd Edition, Philadelphia: W.B. Saunders Company, Chapter 10. 3. Omoigui, S. (1999). Anesthesia Drug Handbook. 3rd Edition, Maden, Mass.: Blackwell Science Inc., p. 1-502. 4. Stoelting, R.K. (1991). Pharmacology and Physiology in Anesthesia Practice. 2nd Edition, Philadelphia: Lippincott Williams and Wilkins, Chapter 3. 5. Stoelting, R.K. (1999). Pharmacology and Physiology in Anesthesia Practice. 3rd Edition, Philadelphia: Lippincott Williams and Wilkins, Chapter 3. 6. Stoelting, R.K. (2006). Pharmacology and Physiology in Anesthesia Practice. 3rd Edition, Philadelphia: Lippincott Williams and Wilkins, Chapter 3.

Chapter 9 Benzodiazepines
1. Donnelly, A.J., Cunningham, F.E., Baughman, V.L., (2000). Anesthesiology & Critical Care Drug Handbook. 3rd Edition, Hudson, Ohio: Lexi-Comp, Inc., 362-364, 573-576. 2. Richter, J.J. Current theories about the mechanisms of benzodiazepines and neuroleptic drugs. Anesthesiology, 1981; 54: 66-72. 3. Stoelting, R.K. (1987). Pharmacology and Physiology in Anesthesia Practice. Philadelphia: Lippincott Williams and Wilkins, Chapter 5. 4. Stoelting, R.K. (1999). Pharmacology and Physiology in Anesthesia Practice. 3rd Edition, Philadelphia: Lippincott Williams and Wilkins, Chapter 5. 5. Stoelting, R.K. (2006). Pharmacology and Physiology in Anesthesia Practice. 4th Edition, Philadelphia: Lippincott Williams and Wilkins, Chapter 5.

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Chapter 10 Neuromuscular Blocking Drugs

1. Kier, L., Dowd, C. (2004). The Chemistry of Drugs for Nurse Anesthetists. 1st Edition, AANA Publishing, Inc. pp 103-104. 2. Morgan, E., Mikhail, M., & Murray, M. (2002). Clinical Anesthesiology. 3rd Edition, New York: McGraw-Hill, Chapter 9. 3. Morgan, E., Mikhail, M., & Murray, M. (2006). Clinical Anesthesiology. 4th Edition, New York: McGraw-Hill, Chapter 9. 4. Nagelhout, J.J. & Zaglaniczny, K.L. (2001). Nurse Anesthesia. 2nd Edition, Philadelphia: W.B. Saunders Company, Chapter 11. 5. Nagelhout, J.J. & Zaglaniczny, K.L. (2005). Nurse Anesthesia. 3rd Edition, Philadelphia: W.B. Saunders Company, Chapter 11. 6. Omoigui, S. (1999). Anesthesia Drug Handbook. 3rd Edition, Malden, Mass.: Blackwell Science Inc., 1-502. 7. Stoelting, R.K. (1999). Pharmacology and Physiology in Anesthesia Practice. 3rd Edition, Philadelphia: Lippincott Williams and Wilkins, Chapter 8. 8. Stoelting, R.K. (2006). Pharmacology and Physiology in Anesthesia Practice. 4th Edition, Philadelphia: Lippincott Williams and Wilkins, Chapter 8.

Chapter 11 Anticholinesterase Drugs

1. Barash, P.G., Cullen, B.F., & Stoelting, R.K. (2001). Clinical Anesthesia. Philadelphia: J.B. Lippincott Williams & Wilkins, Chapter 16. 2. Dorsch, J. A., Dorsch, S. E. (1999) Understanding Anesthesia Equipment.4th Edition, Philadelphia: Lippincott, pp 858-863. 3. Miller, R. (2005). Anesthesia. 6th Edition, Philadelphia: Elsevier, Chapter 39. 4. Morgan, E., Mikhail, M. & Murray, M. (2002). Clinical Anesthesiology. 3rd Edition, New York: Lange Medical Books/McGraw -Hill, Chapter 10. 5. Morgan, E., Mikhail, M. & Murray, M. (2006). Clinical Anesthesiology. 4th Edition, New York: Lange Medical Books/McGraw -Hill, Chapter 10. 6. Nagelhout, J.J. & Zaglaniczny, K.L. (2005). Nurse Anesthesia. 3rd Edition, Philadelphia: W.B. Saunders Company, Chapter 11. 7. Omoigui, S. (1999). Anesthesia Drug Handbook. 3rd Edition, Malden, Mass.: Blackwell Science Inc., 1-502. 8. Stoelting, R.K. (1999). Pharmacology and Physiology in Anesthesia Practice. 3rd Edition, Philadelphia: Lippincott Williams and Wilkins, Chapter 9. 9. Stoelting, R.K. (2006). Pharmacology and Physiology in Anesthesia Practice. 4th Edition, Philadelphia: Lippincott Williams and Wilkins, Chapter 9. 10. Stoelting, R.K. & Miller, R.D. (1989). Basics of Anesthesia. 2nd Edition, New York: Churchill Livingstone, Inc., Chapter 8.

Chapter 12 Anticholinergic Drugs

1. Morgan, E., Mikhail, M. & Murray, M. (2002). Clinical Anesthesiology. 3rd Edition, New York: Lange Medical Books/McGraw -Hill, Chapter 11. 2. Omoigui, S. (1999). Anesthesia Drug Handbook. 3rd Ed., Malden: Blackwell Science Inc., 1-502. 3. Stoelting, R.K. (1999). Pharmacology and Physiology in Anesthesia Practice. 3rd Edition, Philadelphia: Lippincott Williams and Wilkins, Chapter 10. 4. Stoelting, R.K. (2006). Pharmacology and Physiology in Anesthesia Practice. 4th Edition, Philadelphia: Lippincott Williams and Wilkins, Chapter 10.

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Chapter 13 Nerve Agent Exposure and Treatment

1. Baker, David J., Phil, M., D.M., FFARCS, & Rustick, J.M., MD. (1995). Anesthesia For Casualties of Chemical Warfare Agents. In R. Zajtchuck & R. Bellamy (Eds), Textbook of Military Medicine, Anesthesia and Perioperative Care of the Combat Casualty. Falls Church, VA: Office of the Surgeon General, Chapter 30. 2. Keeler, Jill R., LTC, AN. Interactions between nerve agent pretreatment and drugs commonly used in combat anesthesia. Military Medicine. November, 1991; 155: 527-533. 3. Medical Management of Chemical Casualties Handbook, (September, 1995), Chemical Casualty Care Office, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Grounds: Maryland, 17-44.

Chapter 14 Local Anesthetics

1. Bovill, J. G. & Howie, M. B. (1999). Clinical Pharmacology for Anaesthetists. London: W. B Saunders, p.166. 2. Morgan, E., Mikhail, M. & Murray, M. (2002). Clinical Anesthesiology. 3rd Edition, New York: Lange Medical Books/McGraw -Hill, Chapter 14. 3. Morgan, E., Mikhail, M. & Murray, M. (2006). Clinical Anesthesiology. 4th Edition, New York: Lange Medical Books/McGraw -Hill, Chapter 14. 4. Mycek, Mary J., et al. (2000). Lippincotts Illustrated Reviews: Pharmacology. 2nd Edition, Philadelphia: Lippincott Williams & Wilkins, Chapter 1. 5. Nagelhout, J.J. & Zaglaniczny, K.L. (2001). Nurse Anesthesia. 2nd Edition, Philadelphia: W.B. Saunders Company, Chapter 9. 6. Nagelhout, J.J. & Zaglaniczny, K.L. (2005). Nurse Anesthesia. 3rd Edition, Philadelphia: W.B. Saunders Company, Chapter 9. 7. Stoelting, R.K. (1999). Pharmacology and Physiology in Anesthesia Practice. 3rd Edition, Philadelphia: Lippincott Williams and Wilkins, Chapter 7. 8. Stoelting, R.K. (2006). Pharmacology and Physiology in Anesthesia Practice. 4th Edition, Philadelphia: Lippincott Williams and Wilkins, Chapter 7.

Chapter 15 Herbal Medicines

1. Ang-Lee, M., Moss, J., & Yuan, C. Herbal medicines and perioperative care. JAMA, 2001; 286 (2): 208-216. 2. Brumley, C. Herbs and the perioperative patient. AORN J, 2000; 72 (5): 785-796. 3. Hatcher, T. The proverbial herb. American Journal of Nursing 2001; 101(2): 36-42. 4. Lyons, T. Herbal medicines and possible anesthesia interactions. AANA J, 2002; 70(1): 47-51. 5. Murphy, JM. Preoperative considerations with herbal medicines. AORN J, 1999; 69(1): 173-5, 78, 80-3. 6. Norred, C. Use of complementary and alternative medicines by surgical patients. AANA J, 2000; 68 (1): 13-18. 7. Skidmore-Roth, L. (2001). Mosbys Handbook of Herbs & Natural Supplements. St. Louis: Mosby, Inc, 1-897. 8. Stoelting, R.K. (2006). Pharmacology and Physiology in Anesthesia Practice. 4th Edition, Philadelphia: Lippincott Williams and Wilkins, Chapter 34.

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Chapter 16 Gastrointestinal and Antiemetic Drugs

1. Katzung, Bertram G. (2001). Basic and Clinical Pharmacology. 8th Edition, New York: Lange Medical Books/McGraw-Hill, Chapters 16, 63. 2. Kovac, A., Antiemetic Use in Postoperative Nausea and Vomiting, Drugs, 2000; 59 (2): 213-243. 3. Morgan, E., Mikhail, M. & Murray, M. (2002). Clinical Anesthesiology. 3rd Edition, New York: Lange Medical Books/McGraw -Hill, Chapter 15. 4. Mycek, Mary J., et al. (2000). Lippincotts Illustrated Reviews: Pharmacology. 2nd Edition, Philadelphia: Lippincott Williams & Wilkins, Chapters 24, 40. 5. Omoigui, S. (1999). Anesthesia Drug Handbook. 3rd Edition, Maden, Mass.: Blackwell Science Inc., p. 1-502. 6. Postoperative Nausea and Vomiting. Retrieved from the World Wide Web at URL: http://www.nauseaandvomiting.co.uk/NAVRES001-3-PONV.htm#B8 7. Stoelting, R.K. (1999). Pharmacology and Physiology in Anesthesia Practice. 3rd Edition, Philadelphia: Lippincott Williams and Wilkins, pp 238-246, 373-376, 406-407, 447-450.

Chapter 17 Adrenergic Drugs and Vasopressors

1. Barash, P.G., Cullen, B.F., & Stoelting, R.K. (2006). Clinical Anesthesia. 5th Edition, Philadelphia: J.B. Lippincott Williams & Wilkins, Chapter 12. 2. Donnelly, A. J., et al. (2006). Anesthesiology & Critical Care Drug Handbook. 7th Edition, Hudson: Lexi-Comp, pp 370-372, 851-853, 1342-1345. 3. Evers, S. & Maze, M. (2004). Anesthetic Pharmacology. Philadelphia: Churchill Livingstone, Chapter 14, 34, 37, 41. 4. Hardman, J. G. & Limbird, L. E. (2001). Goodman & Gilmans The Pharmacological Basis of Therapeutics. 10th Edition, New York: McGraw-Hill, Chapters 10, 30, 31. 5. Katzung, Bertram G. (2001). Basic and Clinical Pharmacology. 8th Edition, New York: Lange Medical Books/McGraw-Hill, Chapters 9, 10, 11. 6. Morgan, E., Mikhail, M. & Murray, M. (2002). Clinical Anesthesiology. 3rd Edition, New York: Lange Medical Books/McGraw -Hill, Chapters 12, 13. 7. Morgan, E., Mikhail, M. & Murray, M. (2006). Clinical Anesthesiology. 4th Edition, New York: Lange Medical Books/McGraw -Hill, Chapters 12, 13, 19. 8. Mycek, Mary J., et al. (2000). Lippincotts Illustrated Reviews: Pharmacology. 2nd Edition, Philadelphia: Lippincott Williams & Wilkins, Chapters 6, 7. 9. Neal, M. J. (1995). Medical Pharmacology at a Glance. 2nd Edition, Cambridge: Blackwell Science, pg 24. 10. Omoigui, S. (1999). Anesthesia Drug Handbook. 3rd Edition, Maden, Mass.: Blackwell Science Inc., p. 1-502. 11. Stoelting, R.K. (1999). Pharmacology and Physiology in Anesthesia Practice. 3rd Edition, Philadelphia: Lippincott Williams and Wilkins, Chapters 12, 14, 15, 42. 12. Stoelting, R.K. (2006). Pharmacology and Physiology in Anesthesia Practice. 4th Edition, Philadelphia: Lippincott Williams and Wilkins, Chapters 12, 14, 15, 42.

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Chapter 18 Antihypertensive Drugs

1. Achenbach, S. et al. (2005) Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, 7th Edition, Philadelphia: Saunders Elsevier, Chapter 21. 2. Barash, P.G., Cullen, B.F., & Stoelting, R.K. (2006). Clinical Anesthesia. 5th Edition, Philadelphia: J.B. Lippincott Williams & Wilkins, Chapter 12, 30. 3. Donnelly, A. J., et al. (2006). Anesthesiology & Critical Care Drug Handbook. 7th Edition, Hudson: Lexi-Comp, pp 632-634, 778-781,918-920, 928-933. 4. Evers, S. & Maze, M. (2004). Anesthetic Pharmacology. Philadelphai: Churchill Livingstone, Chapter 34, 36, 38, 39. 5. Goldman, L. (2004). Cecil Textbook of Medicine. 22nd Edition, Philadelphia: Saunders Elsevier, Chapter 240. 6. Hardman, J. G. & Limbird, L. E. (2001). Goodman & Gilmans The Pharmacological Basis of Therapeutics. 10th Edition, New York: McGraw-Hill, Chapters 10, 32, 33, 34. 7. Katzung, Bertram G. (2001). Basic and Clinical Pharmacology. 8th Edition, New York: Lange Medical Books/McGraw-Hill, Chapters 11, 12, 13, 19. 8. Katzung, Bertram G. (2005). Basic and Clinical Pharmacology. 8th Edition, New York: Lange Medical Books/McGraw-Hill, Chapters 10, 11, 12, 13. 9. Morgan, E., Mikhail, M. & Murray, M. (2006). Clinical Anesthesiology. 4th Edition, New York: Lange Medical Books/McGraw -Hill, Chapters 12, 13. 10. Mycek, Mary J., et al. (2000). Lippincotts Illustrated Reviews: Pharmacology. 2nd Edition, Philadelphia: Lippincott Williams & Wilkins, Chapter 16, 19. 11. Nagelhout, J.J. & Zaglaniczny, K.L. (2005). Nurse Anesthesia. 3rd Edition, Philadelphia: W.B. Saunders Company, Chapter 12. 12. Stoelting, R.K. (2006). Pharmacology and Physiology in Anesthesia Practice. 4th Edition, Philadelphia: Lippincott Williams and Wilkins, Chapters 14, 15, 16, 18. 13. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure, Dec 2003.

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