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 the intensity of the drug’s effect with time 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 Response
Clinical 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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PHARMACOKINETICS
Dose of drug administered
ABSORPTION Drug concentration in systemic circulation
DISTRIBUTION
Drug in tissues of distribution
REDISTRIBUTION ELIMINATION Drug metabolized or excreted Drug concentration at site of action
PHARMACODYNAMICS Pharmacologic Effect
Clinical Response
Toxicity
Efficacy th
Fig. 1-1: (Katzung, Bertram G., Basic & Clinical Pharmacology, 10 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 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 r eceptors (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)
th
Fig 1-2: (Stoelting, R.K. Pharmacology & Physiology in Anesthetic Anesthetic Practice. 4 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 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 pai n 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. March 2009
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Intrathecal Administration Frequently used route of drug delivery for local anesthetics and narcotics. This route all ows 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
TISSUE
Sublingual (SL) Oral (PO)
Rectal
FIRST PASS EFFECT
LOCAL pH
No (SVC) Stomach
1-3
Yes
Duodenum
4.8-8.2
Yes
Jejunum, Ileum
7.5-8.0
Yes
Colon
7.0-7.5
Yes/No (~ 50%)
Intranasal
No
Intratracheal
Trachea, Bronchi
No
Transcutaneous
Skin
No
Subcutaneous
No
Intramuscular (IM)
Muscle
No
Intravenous (IV)
Venous
No
Intrathecal
No
Epidural
No
Inhalational
Lungs
No
Intraorbital
Orbit (eye)
No
Intraarticular
Joint
No
Table 1-1: (Produced from information in Miller, R.D. Anesthesia. 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)
Tissue Group
Organ/Tissue
% Body Mass
% Cardiac Output
Perfusion (ml/min/100 g)
75
75
Central Compartments
Lungs Heart Brain Liver Kidney
VRG (Vessel Rich)
10
Peripheral Compartments Muscle Group
Skeletal Muscle Skin
50
19
3
Fat Group
Adipose
20
6
3
VPG (Vessel Poor)
Bone Cartilage
20
<1
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
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) Ex : Meptazinol o • 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) Ex: Rocuronium o • 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 March 2009
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Fig 1-3: (Barash, P.G. Clinical Anesthesia. th 5 Ed. 2006, p. 263, with modifications.)
Fig 1-4: (Barash, P.G. Clinical Anesthesia. th 5 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 (V d ) This is a phrase that is often used in anesthesia to describe drugs, and is a concept that should be conceptually understood by the anesthesia provider.
• • •
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 Lipid solubility o Plasma protein binding o 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 V d for a drug is the plasma volume. (See table below)
Body compartment
Volume (70 kg)
Blood plasma Blood volume Extracellular water Total Body Water
3.5 5.5 13 42
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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
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Fig. 1-5: (Barash, P.G. Clinical Anesthesia. 5 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)
th
Fig. 1-6: (Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 4 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
250 mg Thiopental
PLASMA
BRAIN
Anesthetic Effect
250 mg Thiopental PLASMA
REDISTRIBUTION
Patient Awakens
0 MG PLASMA 200 MG MU SCLE 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 drug’s polarity and prepares for phase II reactions Major Phase I reactions Oxidation o Reduction o Hydrolysis o
Phase II Reactions ++ POLAR SUBSTRATE
• • •
EXCRETABLE HYDROPHILIC SUBSTANCE
ENDOGENOUS COMPOUND
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
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MAJOR BIOTRANSFORMATION REACTIONS Phase I OXIDATION
Phase II CONJUGATION
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
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: 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: o
• •
Cytochrome-P-450 Induction
Cytochrome-P-450 Inhibition
Barbiturates Phenytoin Rifampin Macrolide antibiotics (Erythromycin) Imidazole antifungal agents Corticosteroids Carbamazepine Chronic alcohol ingestion Smoking
Organ Dysfunction Cimetidine Acute alcohol ingestion
Drug Excretion Recall that the primary processes of elimination of drugs from the body involve enzymatic pathways primarily in the liver, as well as specific organ clearance mechanisms. Clearance (Cl) refers to the volume of plasma cleared of drug per unit of time . The three primary
organs involved with drug clearance include the liver, 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. ↓ Hepatic blood flow → ↓ Rate of clearance o 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
Intermediate
High
Diazepam Lorazepam Methadone Phenytoin Rocuronium Theophylline Thiopental
Alfentanil Methohexital Midazolam Vecuronium
Bupivacaine Diltiazem Fentanyl Ketamine Lidocaine Meperidine Morphine Naloxone Propofol Sufentanil
th
Table 1-5: (Barash, P.G., Clinical Anesthesia. 5 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. Example: Rocuronium o 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. 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. o • 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
Drug Effect
Tissue Compartments
Blood Redistribution
Blood
C-P-450 Hepatic Biotransformation
Hydrophilic Excretable Metabolites
Unchanged Drug Excretion
Bile
GI Tract
Blood
Kidneys
Protein Bound Drug
Renal Secretion (Distal Renal Tubule)
Hydrophilic Metabolites Filtration (Glomerulus) Renal Tubular Lumen
Lipophilic Metabolites
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
(Fig 1-10)
linear plot
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 ½) • To simplify this concept, pharmacokinetic processes are described in terms of half-times, as opposed to rate constants. • By definition, elimination half-time is the time that it takes for 50% of the plasma concentration of a drug to decline during the elimination phase. • By definition, elimination half-time is also the time required for the concentration to change by a factor of two. • The relationship that exists between rate constant and half-time is expressed by the following formula.
T½ = 0.693 k ** Elimination half time is directly proportional to V d, and indirectly proportional to drug clearance.
** Any factor that alters V d or hepatic or renal clearance, will also alter elimination half time. **The half-time of any first-order kinetic process, including drug absorption, distribution, and elimination, can be calculated. Clinically, the elimination half-time of all drugs used in anesthesia is
known, and is derived using a known rate constant established experimentally.
Comparison of Half Times to Drug Elimination: Number of Half-Times
Fraction of Initial Drug Remaining
Percent of Initial Amount Eliminated
0 1 2 3 4 5 6
1 ½ ¼ 1/8 1/16 1/32 1/64
0 50 75 87.5 93.8 96.9 98.4
th
Table 1-6: (Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 4 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, let’s 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
0
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 dru g 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 (T½).
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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
(Fig 1-12)
Vd Cl
K e
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)
th
Fig 1-13: (Barash, P.G. Clinical Anesthesia. 5 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.
T½ = 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 ½. (and vise versa) 3. The greater the Cl, the shorter the T ½. (and vise versa)
Two-Compartment Model • This model illustrates simple kinetic concepts that more accurately portray drug behavior, compared to the one-compartment model. The two-compartment model can be used to illustrate basic concepts of kinetics that can be applied to more complex, multi-compartment models.
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
Vd Peripheral Compartment
K a
Vd Central Compartment
(Fig 1-14)
K b K e 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
Rapid Peripheral Compartment
(Vessel-rich tissue, muscle tissue)
K a
K c Central Compartment
K b
K e
K a = rate constant from central to rapid peripheral compartment K b = rate constant from rapid peripheral to central compartment K c = rate constant from central to slow peripheral compartment K d = rate constant from slow peripheral to central compartment K e = first-order elimination rate constant
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Slow Peripheral Compartment (Fat group)
K d (Fig 1-16)
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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
th
Fig 1-17: (Miller, Ronald D., Anesthesia. 6 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 pr edicting 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, manufacturer’s recommendations are to use the patient’s IBW to calculate initial drug dosing. (Wellcome package insert) 2) The administration of Rocuronium using ABW to patients who were at least 30% or more above IBW was not associated with significant differences in onset, d uration, 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). March 2009
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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
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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. • Dalton’s Law of Partial Pressures → States that the sum of the partial pressures of the gases in a mixture will equal the total partial pressure of the mixture.
2. All anesthetic gases must overcome a partial pressure gradient to exert an effect. 3. The goal of inhaled anesthesia is to obtain a constant brain partial pressure (P br). 4. Brain partial pressure (P br ) = anesthetic effect
** Ultimate brain partial pressure is affected by a variety of factors. (Fig 2-1)
Vaporizer
Brain
Anesthesia Machine
Lungs
Other Tissues
Blood
Fig: 2-1
*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, let’s start with some general definition. March 2009
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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. • F A/FI ratio is expressed as a curve relative to time. • Anesthetic agents can be compared based upon their “F A/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
Blood:Gas Partition Coefficient
Brain:Blood Partition Coefficient
Muscle:Blood Partition Coefficient
Fat:Blood Partition Coefficient
Oil:Gas Partition Coefficient
Methoxyflurane
12
2
1.3
48.8
970
Halothane
2.54
1.9
3.4
51.1
224
Enflurane
1.90
1.5
1.7
36.2
98
Isoflurane
1.46
1.6
2.9
44.9
98
Nitrous Oxide
0.46
1.1
1.2
2.3
1.4
Desflurane
0.42
1.3
2.0
27.2
18.7
Sevoflurane
0.69
1.7
3.1
47.5
55
Table 2-1: (Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 2006, p. 27 with modification.)
Highly Soluble
Intermediate Solubility
Poorly Soluble
Methoxyflurane
Halothane Enflurane Isoflurane
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 F A /FI curve and the quicker the agent will reach an F A /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 P A. 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 P A and Pbr , in that P A 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
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**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. Let’s see how.
Inspired Gas Concentration This is basically what you have dialed in on your vaporizer (% delivered gas). Initially, a high % concentration is needed to offset the effects of tissue uptake. As a result, the rate of induction is accelerated, and the rate of rise of the F A/FI curve is quicker, as F A 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 (V A) Increased minute ventilation (MV) leads to accelerated u ptake 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 P A. 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. March 2009
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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 F A /FI curve
•
↓ B:G coefficient = ↓ solubility = ↑ rate of rise of F A /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 = P A, and brain equilibrium is achieved.
Cardiac Output Cardiac output = pulmonary blood flow Pulmonary blood flow determines P A, as more or less anesthetic agent is carried away from the lungs. ** A change in cardiac output affects primarily the rate of increase of P A in the soluble agents. Increased cardiac output results in more rapid uptake of agent into the tissue (esp. more soluble agents such as Methoxyflurane, Halothane, and Isoflurane) and results in a slower increase in P A ↑ cardiac output = ↑ tissue uptake = ↓ PA ↓ cardiac output = ↓ tissue uptake = ↑ PA
**In agents that are less soluble (Nitrous Oxide, Sevoflurane, Desflurane), the rate of increase of P A is rapid regardless of changes in cardiac output, 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 F A/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 F A 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 P A.
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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 P A 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 F A/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 can’t 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 P A of a concurrently administered “second gas” (a volatile agent). For example, referring to the graph below, we can see that the lung is initially filled with a total of 100 parts of gas (A). As 50% of the Nitrous Oxide is quickly taken up into the blood (40 parts), this leaves only 60 parts left in the lung. As a result, the remaining second gas is now concentrated in a smaller lung volume, resulting in an increased concentration of the second gas from 1% to 1.7%. This increased concentration, via the “concentrating effect”, of the second gas in a smaller lung volume accelerates the P A of the second gas.
1/60 = 1.7 %
19/60 = 31.7%
40/60 = 66.7%
Fig. 2-3 (Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 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 u tilized 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, let’s 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. March 2009
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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, let’s apply this concept to anesthesia.
First, let’s 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, let’s 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 =
7L 0.5 L/min
14 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, let’s 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
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Now let’s increase the fresh gas flow to 6 L/min. The capacity of the system is still 7 L. Time constant =
Time constant =
1.2 min =
Capacity of system Flow through system
7L 6 L/min 7L 6 L/min
**The time constant for this system is 1.2 minutes. What does that tell you? It tells you the system will reach 63% equilibrium in 1.2 minutes, 86% equilibrium in 2.4 minutes, etc. (See the table below) The Amount of Change at the End of Each Time Constant for an Anesthesia Machine With a Capacity of 7 L and a Fresh Gas Flow of 6 L/min One time constant = 63% change = 1.2 min Two time constants = 86% change = 2.4 min Three time constants = 95% change = 3.6 min Four time constants = 98% change = 4.8 min Let’s again set the vaporizer concentration of Isoflurane to 1.2%. Using the information we no w 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
Capacity = 7 L Isoflurane = 1.18%
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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 F A/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
X
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
Let’s 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 e ach 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** Let’s 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
4.0
1.0
0.4
VPG 22 12 0 0
* Cardiac Output = 5.4 Liters/Min Table 2-3 (Eger, E. “The Distinguished Professor Program I”. 1994, Figure 27.)
In this scenario, we have a patient that is 70 kg, and a calculated cardiac output of 5.4 Liters/Minute. We are administering Isoflurane with a known Brain:Blood partition coefficient of 1.6 (Refer to Table 2-1). You are wondering how much time it will take for Isoflurane to equilibrate to 98% with the brain…?? Using the known values from the above table, the brain falls under the VRG:
(6 liters
4 liters/min X 1.6) = 2.4 minutes for one time constant (63% change)
Therefore, to calculate a 98% change (four time constants) you simply multiply 2.4 minutes X 4 to give you a total time of 9.6 minutes. In other words, it will take 9.6 minutes for Isoflurane to equilibrate 98% with the brain using Isoflurane. To take the example further, assume the concentration of Isoflurane in this patient’s brain is 1.2%. The Isoflurane is quickly and completely discontinued (we have so far looked at wash-in, now we are looking at washout!) . How long will it take for the concentration of Isoflurane to decrease in this patient’s brain? Assume same cardiac output and weight information (Table 2-3). Starting concentration in brain is 1.2%. Time constant for this example is 2.4 minutes, as we calculated above.
Time 0 = Discontinue Isoflurane
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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 = ED 50 1.3 MAC = ED 95 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
MAC in 100% oxygen
MAC in 70% N20
Oil:Gas Partition Coefficient
N20
104
-------
1.4
Halothane
0.75
0.29
224
Enflurane
1.6
0.65
98
Isoflurane
1.1
0.5
98
Desflurane
6.6
2.8
18
Sevoflurane
1.8
0.66
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 pa rameters of the patient during surgery.
Closed-Circuit Anesthesia Closed circuit anesthesia is synonymous with total rebreathing system . The goal of this type of anesthesia is to add only enough oxygen and anesthetic vapor to the breathing circuit to exactly match patient consumption, thereby maintaining a constant circuit volume and a constant expired oxygen concentration.
Characteristics: 1. All exhaled gases are rebreathed, except carbon dioxide. 2. The CO2 absorber neutralizes all carbon dioxide. 3. Exhaled gases are not scavenged. 4. Adjustable pressure-limiting valve is completely closed. 5. Low total fresh gas flows are utilized. March 2009
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Determining Fresh Gas Flows: • Must be equal to amount of gas taken up by the patient’s lungs.
[Oxygen Consumption = 3-5 cc/kg/min] •
Must replace gas sampled from the circuit for analysis, if it is not returned to the circuit. (Generally it is scavenged off)
[Gas Sampling = 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-bellow’s height is unchanged. Constant expired oxygen concentration is assessed via the gas analyzer.
Sevoflurane is contraindicated for use in closed-circuit anesthesia. Recall that it requires flows of at least two liters per minute 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 don’t allow oxygen delivery less than 150cc/min. 4. Huge discrepancies exist between delivered concentration (vaporizer dial) and alveolar concentration. • Dilutional Effect → Approximately 10 liters of deadspace gas exists in a circle system. (Tubing, CO2 canisters, Breathing Bag, Patient’s FRC) • “Priming” Technique → Filling the circuit after induction with high % concentration of volatile agent may help to overcome this dilutional effect. 5. Small circuit leaks can significantly alter % oxygen and agent delivery. 6. Requires more vigilance.
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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 eyebal l” 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 don’t really know how inhalation agents really work to depress the central nervous system. To date, no one theory exists to completely explain the mechanism of action of inhalation agents. There are many postulations as you might guess, and here are some of the most popular regarding mechanism of action.
*Meyer-Overton Theory* There is a relatively consistent correlation between an agent’s oil: gas partition coefficient, i.e. lipid solubility and potency. Therefore, a hydrophobic site is implicated. Anesthesia results when a critical number of molecules occupy a hydrophobic region of the membrane. *This theory implies that it is the number of molecules present, and not the type that is most important in eliciting a therapeutic effect. This would suggest that different inhaled agents are additive, resulting in a summated effect. (0.5 MAC + 0.5 MAC = 1 MAC)
Volume Expansion or Membrane Fluidity Theory This theory holds that when a critical number of anesthetic molecules enter the lip id membrane, expansion of the membrane occurs resulting in altered cell membrane function. Pitfalls: 1. Increasing temperature causes an increase in membrane volume expansion, which should reduce MAC, but the opposite is true. 2. Some highly lipid soluble compounds expand membranes, but don’t have any anesthetic action.
Lateral Phase Separation This theory suggests that in the normal lipid membrane there are phase separations, such that there are areas of solid-gel protein alternating with areas of liquid-crystalline protein. Inhalation agents increase phase transition temperatures, resulting in greater fluid areas of the membrane. This causes the membrane around a protein channel to remain in the fluid state, allowing the channel to stay open. Pitfalls: 1. Temperature elevations increase membrane fluidity, but result in an increased MAC requirement. 2. Temperature decreases cause an increase in the gel state in the membrane, but result in a decreased MAC requirement. 3. We know that increasing the patient’s temperature does not make them more sensitive to anesthetics.
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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/H 20 0.73 mm Hg = 1 cm/H 20 760 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 = [(ºC X 9)/5] + 32 °C = [(ºF – 32) X5]/9 ºKelvin = 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
mg/cc
mcg/cc
1:1000 1:10,000 1:100,000 1:200,000 1:400,000
1 0.1 0.01 0.005 0.0025
1000 100 10 5 2.5
Table 4-1 ** 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 %
Decimal %
mg/cc
1/4 1/8 1/10 1/16 1/25 1/32
0.25 0.125 0.1 0.0625 0.04 0.03125
2.5 1.25 1 0.625 0.4 0.3125
Table 4-2
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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 patient’s 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)
X
(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 didn’t want to be a physicist, you wanted to be an anesthetist? Well, unfortunately there are many physical concepts applied to anesthesia that you need to be understand, from the drugs you use to the monitors you apply. This chapter will highlight some important definitions and concepts that are critical to understand in anesthesia.
Important Definitions
Molecular Theory of Matter Matter is made up of minute particles called molecules, which exist in various phases of aggregation (solid, liquid, gas).
Kinetic Theory of Matter Molecules are in constant random motion and maintain a degree of attraction between them called van der Waals forces.
Vapor Pressure: The pressure exerted by a vapor in an enclosed space. **All volatile agents exist in a liquid state at room temperature, but are very near their boiling points. Vapor pressure is independent of atmospheric pressure, and dependent only upon the physical characteristics of the vapor and temperature.
Saturated Vapor Pressure The partial pressure exerted by a vapor above a liquid at equilibrium in a closed container. All volatile liquids have a saturated vapor pressure in their enclosed bottles.
Boiling Point The temperature at which the vapor pressure of a gas is equal to atmospheric pressure. ** At higher elevations, boiling point is lower as atmospheric pressure is lower (660 mm Hg in Denver)
Latent Heat of Vaporization The amount of heat in calories required to vaporize 1 gram of liquid. As molecules leave the liquid, kinetic energy is also removed resulting in cooling of the liquid with vaporization.
Specific Heat The amount of heat in calories needed to increase the temperature of 1 gram of a substance by 1° C.
Critical Temperature The temperature above which a gas cannot be liquefied regardless of how much pressure is applied.
Critical Pressure The vapor pressure of a gas at its critical temperature.
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Physics of Gases P = Pressure V = Volume T = Temperature
Dalton’s Law of Partial Pressures The total pressure exerted by a mixture of gases is equal to the sum of the partial pressures of each gas constituting the mixture. 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
Boyle’s Law At constant temperature, the pressure exerted by a gas is indirectly proportional to the volume. P1V1=P2V2
Charles’ Law At constant pressure, the volume of a definite quantity of gas is directly proportional to the temperature. V1 = V2 T1 T2
Guy-Lussac’s Law At constant volume, pressure varies directly with temperature. P1 = P2 T1 T2
B= Boyle’s Law
P
V
G = Guy-Lussac’s Law
C = Charles’ Law
“Could this guy possibly be a violinist”
T The simple diagram above can help you remember what variable is held constant with which law. The letter that lies across from the law describes the variable held constant. In Boyle’s law, the relationship is indirect; in Charles’ and Guy-Lussac’s law, the relationship is direct. March 2009
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Avogadro’s Principle Equal volumes of different ideal gases at equal temperatures contain the same number of molecules.
Avogadro’s Number = 6.02 X 10 23 molecules in 1 mole of gas * 1 mole of gas occupies 22.4 L
Ideal Gas Law Combination of Boyle’s law, Charles’ law, and Avogadro’s hypothesis. P1V1 = P2V2 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
Graham’s Law The rate of diffusion of a gas is inversely proportional to the square root of its molecular weight. **Lighter gases diffuse quicker than heavier gases. •O2, CO2, He, H •Anesthetic vapors
Henry’s Law At any given temperature, the solubility of a gas in a liquid is directly proportional to the pressure of the gas above the liquid at equilibrium. Another way to say this is the amount of gas absorbed by a liquid is directly proportional to the partial pressure of gas in contact with the liquid.
pressure = pressure =
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Poiseuille’s Law Defines the relationship between pressure and the flow of fluid through a tube. Factors affecting movement of fluid through a tube are length, diameter, pressure, and viscosity. The rate of discharge through a tube is directly proportional to its radius (r) and pressure (P) , but inversely proportional to its viscosity ( η) and length (l). Flow = ( Pr 4)/(8 l) 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 pre ssures as much.
Fick’s Law Describes the diffusion of gases through tissues such that of tissue is dependent on: 1. Tissue area 2. Tissue thickness 3. Concentration gradient
the rate of transfer of a gas through a sheet 4. Solubility of the molecules 5. Molecular size and weight 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 Bernoulli’s Theorem (How pressure and velocity interact) The lateral pressure energy of a fluid flowing through a tube of varying diameters is least at the point of greatest constriction and speed is the greatest. At the widest diameter, lateral pressure energy is greatest, and speed is the least. The total energy of the system is constant.
• •
The same volume of fluid must pass through all portion of a tube. Flow will be faster through the constricted portions, and slower in wider portions.
Wider Diameter = Narrow Diameter =
Lateral Wall Pressure = Lateral Wall Pressure =
Speed 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 Bernoulli’s theorem, it should also exert less pressure. High Velocity Low Pressure
Low Velocity High Pressure
Low Velocity High Pressure
Fig: 5-1 Venturi Tube Venturi Principle This principle represents an extension of Bernoulli’s work on the relationship between velocity of flow and lateral pressure. It states that to restore the lateral pressure of a fluid that has flowed through a constriction to its pre-constriction magnitude, there must exist a gradual passage dilation immediately distal to the constriction, with an angle of divergence not exceeding 15°.
Flow 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.
Entrained Gas
Needle Valve
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
Ohm’s 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 p rinciple. 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 a nd vapors use this concept, such as our gas analyzers.
Law of LaPlace LaPlace’s 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 Bernoulli’s Principle (Venturi Effect)
Clinical Application
• • • • •
Boyle’s Law
• Charles’ Law Dalton’s Law Fick Principle
Fick’s Law of Diffusion
Gay-Lussac’s Law
• • • • • • • • • •
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 N 2O (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
Graham’s Law
•
Henry’s Law
• Calculation of the amount of dissolved O2 and CO2 in the blood
Joule-Thompson Effect
• As a cylinder of compressed gas empties, the cylinder cools • ARDS causes smaller alveoli to empty into larger ones resulting
Law of LaPlace
•
Ohm’s Law
• • • • • •
Poiseuille’s Law
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
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 don’t have carbon. (Nitrous Oxide) “Inhaled Agent ” refers to ALL of the gases including Nitrous Oxide. “Volatile Agent ” refers to all of the gases except Nitrous Oxide. All of the inhaled agents available today, with the exception of 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). Let’s look a bit closer now at the different physical and chemical properties of each of these drugs.
Physical and Chemical Properties of Inhaled Agents The physical and chemical properties of anesthetic agents are described according to the following parameter. • Chemical structure • Boiling point • Vapor pressure • Blood/gas partition coefficient • MAC • Amount metabolized
Nitrous Oxide (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
50.2 °C 244mmHg
BG: PC
2.54
MAC %
0.75
% Metabolized
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
56.5°C
Vapor Pressure
172 mmHg
BG: PC
1.90
MAC %
1.6
% Metabolized
2
Table 6-2: (Produced from information obtained in Stoelting, R.K. Pharmacology & Physiology in Anesthetic th
Practice. 4 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
48.5°C
Vapor Pressure
240 mmHg
BG: PC
1.46
MAC %
1.1
% Metabolized
0.2
Table 6-3: (Produced from information obtained in Stoelting, R.K. Pharmacology & Physiology in Anesthetic th
Practice. 4 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
58.5°C
Vapor Pressure
170 mmHg
BG: PC
0.69
MAC %
1.8
% Metabolized
3-5
Table 6-5: (Produced from information obtained in Stoelting, R.K. Pharmacology & th
Physiology in Anesthetic Practice. 4 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 N 2O
** Low potency + poor solubility results in rapid inductions and emergence, but requires more agent.
Boiling Point
23.5°C
Vapor Pressure
669 mmHg
BG: PC
0.42
MAC %
6.6
% Metabolized
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. Desflurane’s “Special Needs”
Desflurane has an extremely high vapor pressure. As a result, it needs a special vaporizer that can heat the liquid in a controlled fashion, providing for a more regulated gas concentration.
Ohmeda Tec 6 Vaporizer This is a special vaporizer designed specifically for Desflurane that contains a reservoir where the liquid is heated to a fixed temperature, giving a fixed vapor pressure (39 degrees and 1500 mm Hg vapor pressure). No fresh gas flows through the sump; instead, the Desflurane gas joins the FGF exiting the vaporizer. March 2009
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Fig 6-2: (The Ohmeda Tec 6 Vaporizer Product Guide. 1992, p. 11.)
CHEMICAL AND PHYSICAL PROPERTIES OF INHALED AGENTS Vapor Pressure mmHg @ 20 C
B:G Coefficient
% Met
Boiling Point ( C)
Agent
MAC
MAC in 70% N20
N20
104
-------
39,000
0.46
Trace
-88.5
Halothane (Fluothane)
0.75
0.29
244
2.54
12-25
50.2
__
Enflurane (Ethrane)
1.6
0.65
172
1.90
2
56.5
+
Isoflurane (Forane)
1.1
0.5
240
1.46
0.2
48.5
+
Desflurane (Suprane)
6.6
2.8
669
0.42
0.02
23.5
++
Sevoflurane (Ultane)
1.8
0.66
170
0.69
3-5
58.5
__
Pungency
Table 6-6: (Partially reproduced from information in Stoelting, R.K. Pharmacology & Physiology in th Anesthetic Practice. 4 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. r
Fig 6-3: (Duke, J. Anesthesia Secrets. 3 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.
th
Fig 6-4: (Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 4 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 CO 2 are totally separate mechanisms.
Cardiovascular Effects This section will compare the inhaled agents and their effects on myocardial contractility, mean arterial blood pressure (MAP), heart rate (HR), cardiac output (CO), arrhythmogenicity, and coronary blood flow.
Myocardial Contractility All inhaled agents are direct cardiac depressants that elicit a dose-dependent depression of myocardial contractility. **Potency ranking related to myocardial depression
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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.
th
Fig 6-5: (Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 4 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 R →L shunting, causing arterial hypoxemia. March 2009
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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 P aCO2 and a decrease in the response to CO 2. It takes a higher CO 2 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)
th
Fig 6-7: Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 4 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 PO 2 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
Portal Vein Flow
Hepatic Artery Flow
Drug Clearance
Halothane
Liver Enzymes Slight
Isoflurane
No change
No change
Sevoflurane
No change
No change
Desflurane
No change
No change
Table 6-7: (Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 1999, Chapter 2.)
Hepatotoxicity Post-operative liver dysfunction has been associated with most volatile agents; however Halothane has been the most implicated. Halothane Hepatotoxicity Two forms of Halothane hepatotoxicity have been observed.
Mild, self-limiting post-operative hepatotoxicity
• • •
Nausea, lethargy, fever, minor increases in liver enzymes 20% incidence Most likely due to alterations in hepatic blood flow
Halothane Hepatitis
• • •
Massive hepatic necrosis 1:10-30,000 incidence Most likely immune-mediated
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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) ** N 20 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 h ave 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 doesn’t 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. March 2009
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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. 2. 3. 4.
Methohexital Phenobarbital Pentobarbital 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 1930’s 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) Thiopental’s 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 CMRO 2 • 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 e vidence 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) Ketamine 1-2 mg/kg IV or 3-5 mg/kg IM+(Robinul 0.005 mg/kg + Versed 0.05 mg/kg) IM/IV o • 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 **Induct ion 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. h yperventilation. • 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. lun gs. • 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 Confusion o o Delirium **Remember, Ketamine is a phencyclidine derivative similar to PCP, so this phenomenon is not surprising.
• • •
Incidence is 5-30% Dose-dependent occurrence occurrence at > 2mg/kg 2mg/kg Prevention Preoperative Midazolam administration (0.05 mg/kg IV/IM) o Avoidance of Atropine and Droperidol, as they have central properties that may be o synergistic Recovery in a quiet, calm environment o
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 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 March 2009
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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 CMRO 2 by up to 45%. This is GREAT for patients with ↑ ICP. Considered to be “coupled”. o • 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. March 2009
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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 equip otent 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) March 2009
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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. March 2009
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Common Intravenous Agents and Dosages Trade Name
Induction Dose (IV) mg/kg
Induction Dose (IM) mg/kg
Maintenance Dose (IV) mcg/kg/min
Sedative Dose (IV)
Sedative Dose (IM) mg/kg
Thiopental
Pentothal
3-6
NA
NA
0.5-1.5 mg/kg
NA
Propofol
Diprivan
1-2.5
NA
50-200
25-100 mcg/kg/min
NA
Etomidate
Amidate
0.1-0.4
NA
NA
NA
NA
Ketamine
Ketalar
1-2.5
5-10
NA
0.25-1 mg/kg
2.5-5
Agent Generic Name
Table 7-1: (Produced from information in Omoigui, S. Anesthesia Drug Handbook. 1999, p. 1-502.)
Intravenous Agents & Comparative Pharmacokinetic Properties Agent
Elimination Half-Times (hrs)
Volume of Distribution (liters/kg)
Clearance (cc/kg/min)
Propofol
0.5-1.5
3.5-4.5
30-60
Thiopental
11-12
2.5
3.4
Etomidate
2-5
2.2-4.5
10-20
Ketamine
2-3
2.5-3.5
16-18
Systemic Blood Pressure
Heart Rate
No change
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
CMRO2
CBF
ICP
Thiopental Propofol Etomidate Ketamine 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 don’t hurt” • Supraspinal – “I hurt but I don’t care”
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Endogenous Opioid Receptors Mu-1 Analgesia • Spinal • Supraspinal
Mu-2 Spinal analgesia Ventilatory Depression
Euphoria Major Effects
Agonists
Antagonists
Hypothermia
Physical Dependence
Miosis
Constipation
Kappa Delta Sigma Analgesia Analgesia Dysphoria • Spinal • Spinal • Supraspinal • Supraspinal Ventilatory Stimulation Dysphoria Ventilatory Hypertonia Depression Miosis Tachycardia Physical Sedation Dependence
Bradycardia
Constipation
Urinary Retention
Urinary Retention
Endorphins
Endorphins
Dynorphins
Morphine
Morphine
Meperidine
Synthetic opioids
Synthetic opioids
Naloxone Naltrexone Nalmefene
Naloxone Naltrexone Nalmefene
Naloxone Naltrexone Nalmefene
Enkephalins
Ketamine??
Naloxone Naltrexone Nalmefene
Naloxone Naltrexone Nalmefene
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 r eliable, and weaker analgesia, which may not be any more advantageous than IV administration, especially if a lipid soluble opioid is administered. March 2009
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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. DO NOT administer DepoDur in the subarachnoid space o
**Ventilatory depression generally has not occurred with epidural or intrathecal morphine administration after 24 hours. Factors increasing the risk of ventilatory depression in clude: • Low lipid solubility of opioids (morphine • Advanced age 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 an d 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 March 2009
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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. March 2009
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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 morphine’s, despite its short duration of action. This is because the lungs serve as a large, inactive reservoir for Fentanyl, and its volume of distribution (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 March 2009
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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 o ther 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 Opioid Morphine Meperidine Fentanyl Sufentanil Alfentanil Remifentanil
Amount of Protein Binding + ++ +++ ++++ ++++ +++
Vd
% Nonionized
Speed of Elimination
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 du ration to the time required for a 50% decrease in plasma opioid concentration. A comparison of these curves can provide valuable information regarding the pharmacokinetic properties of these drugs. For example, notice that Fentanyl’s context-sensitive half-time significantly increases after about two hours compared to all other opioids. This can be attributed to fentanyl’s large volume of distribution, and saturation of inactive tissue sites, such as the lung. In contrast, the context-sensitive half-time for Remifentanil is the same regardle ss 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-I’s can produce excitation, convulsions, hyperthermia, and hypertensive crisis, possibly related to its vagolytic properties. Synthetic Opioids (Fentanyl, Sufentanil, Alfentanil, Remifentanil) • Bradycardia may result from a direct depression of the SA node. This effect is more prominent than with morphine, and could result in decreased cardiac output and decreased blood pressure. • Overall hemodynamic stability is observed. • No histamine release, even in high doses • DO NOT sensitize the heart to catecholamines or cause significant depression of myocardial contractility
Neurological Meperidine • Causes mydriasis. (All other opioids induce miosis.) • May increase intracranial pressure (ICP) related to its tachycardic properties, which could lead to increased cerebral blood flow (CBF). • CNS stimulant properties related to normeperidine metabolites. Heart Rate = CBF =
ICP
All Other Opioids • Cause a dose-dependent miosis • Slightly decrease or have no effect on CBF or ICP with normocarbia • Opioids may increase CBF indirectly by causing a dose-dependent respiratory depression and hypercarbia, which leads to cerebral 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. March 2009
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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 b e 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. Cutaneous
• •
Morphine and Hydromorphone cause histamine release, which leads to dilation of
cutaneous blood vessels. This leads to flushing of the face, neck and chest, as well as itching and redness usually around the injection site. Other opioids can cause itching, but the mechanism is not well understood. It does NOT appear to be related to histamine release, however.
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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 an d 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. March 2009
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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
Mixed AgonistsAntagonists
Pure Antagonists
Meperidine (Demerol)
Butorphanol (Stadol)
Naloxone (Narcan)
Morphine (Astromorph, Duramorph, DepoDur)
Nalbuphine (Nubain)
Nalmefene (Revex)
Hydromorphone (Dilaudid)
Pentazocine (Talwin)
Naltrexone (Trexan) (Oral only)
Fentanyl (Sublimaze)
Buprenorphine (Buprenex)
Sufentanil (Sufenta)
Nalorphine (Nalline)
Alfentanil (Alfenta) Remifentanil (Ultiva) Table 8-3: (Partially reproduced from information in Stoelting, R.K. Pharmacology & Physiology in Anesthetic
Practice. 2006, p. 88.)
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Potency Ranking of Common Opioids Meperidine (Demerol)
0.1
Morphine (Astromorph, Duramorph, DepoDur)
1
Nalbuphine (Nubain)
1
Butorphanol (Stadol)
3-7
Hydromorphone (Dilaudid)
8
Alfentanil (Alfenta)
10
Fentanyl (Sublimaze)
100 - 125
Remifentanil (Ultiva)
100
Sufentanil (Sufenta)
1000
Table 8-4
*
*The table above reflects relative potencies of commonly used opioids relative to Morphine, which is given a potency of one. For instance, Fentanyl has a potency of 100, which means it is 100 times more potent than Morphine. Meperidine is one tenth as potent as Morphine, etc.
Common Neuraxial Opioid Dosing Opioid
Epidural Dose
Fentanyl
Bolus : 1-2 mcg/kg (50-100 mcg) Infusion : 0.5-0.7 mcg/kg/hr (25-60 mcg/hr)
Bolus: 0.1-0.4 mcg/kg (5-25 mcg)
Sufentanil
Bolus: 0.2-0.7 mcg/kg (10-50 mcg) Infusion: 0.1-0.6 mcg/kg/hr (5-30 mcg/hr)
Bolus: 0.02-0.08 mcg/kg (1-10 mcg)
Duramorph
Bolus: 40-100 mcg/kg (2-5 mg) Infusion: 2-20 mcg/kg/hr (0.1- 1 mg/hr)
Bolus: 4-20 mcg/kg (200-300 mcg)
Bolus: 10-15 mg with 5-10 cc of MPF NS Infusion: Contraindicated
Contraindicated
Bolus: 20-40 mcg/kg (1-2 mg) Infusion: 2-3.5 mcg/kg/hr (0.15-0.3 mg/hr)
Bolus: 2-4 mcg/kg (0.1-0.2 mg)
Bolus: 1-2 mg/kg (25-50 mg) Infusion: 0.2-0.4 mg/kg/hr (5-20 mg/hr)
Bolus: 0.2-1 mg/kg (10-50 mg)
DepoDur Hydromorphone (Dilaudid) Meperidine
Intrathecal Dose
*Table 8-5: (Produced from information in Omoigui, S. Anesthesia Drug Handbook. 1999, p. 1-502.)
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Common Intravenous Opioid Dosing Regimens Induction Dose
Agent
Maintenance Infusion
Postoperative Dose
Meperidine
0.5-2 mg/kg
Morphine
0.03-0.15 mg/kg
Hydromorphone
0.01-0.04 mg/kg
Fentanyl
5-40 mcg/kg
0.025-0.25 mcg/kg/min
Alfentanil
50-300 mcg/kg
0.5-15 mcg/kg/min
Sufentanil
2-10 mcg/kg
0.1-0.5 mcg/kg/hr
Remifentanil
0.5-1 mcg/kg
0.25-0.4 mcg/kg/min
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) Do’s Keep refrigerated but don’t 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
Don’ts 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
Trade Name
Diazepam Midazolam Lorazepam Chlordiazepoxide Clonazepam Flurazepam Temazepam Triazolam
Valium/Diazac Versed Ativan Librium Klonopin Dalmane Restoril Halcion
Table 9-1
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
th
Fig. 9-1 (Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 4 Ed. 2006, p. 141.)
Fig. 9-2 (Richter, JJ. Anesthesiology, 1981; 54: 66-72)
**The GABA A receptor is found predominately on postsynaptic nerve endings in the CNS. It contains specific binding sites for BNZ, barbiturates, as well as alcohol, which explains the synergistic effects that these drugs have when used in combination.
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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
th
Fig. 9-3: (Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 4 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. Let’s take a look at how it achieves this reversal. Mechanism of Action Flumazenil is a specific BNZ antagonist, with a very h igh 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
Max Single Dose
Max Total Hourly Dose
Infusion
0.2 – 1 mg* (4-20 mcg/kg)
1 mg
3 mg
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
Potency Rating
Protein Binding (%)
Elimination Half Life (hrs)
Clearance (ml/kg/min)
Diazepam
1
98
20-40
0.2-0.5
Midazolam
3-4
98
2-4
6-8
Lorazepam
5
98
10-20
0.7-1.0 th
Table 9-3: (Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 4 Ed. 2006, p 143.)
Common Midazolam Dosing Regimens Premed
Bolus for Conscious Sedation
Infusion for Conscious Sedation
Induction
IV
Adult 1-5 mg Titrate to effect
0.5-5 mg (0.025-0.1 mg/kg)
1-15 mg/hr (20-300 mcg/kg/hr)
50-350 mcg/kg
IM
2.5-10 mg (0.05-0.2 mg/kg)
PO
20-40 mg ** (0.5-1 mg/kg)
Intranasal
0.2-0.3 mg/kg
Rectal
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 1940’s, when d-Tubocurarine (Curare) was used to provide muscle relaxation for general anesthesia. Since this time, many neuromuscular blockers (NMB) have been developed for clinical use in anesthesia, becoming commonplace in their administration for a variety of general anesthetics. Neuromuscular blockers are also known as muscle relaxants, and are generally categorized according to duration of action or mechanism of action. When described according to duration of action, they are referred to as ultra-short acting, short acting, intermediate acting, and long acting. When described by mechanism of action, they are referred to as depolarizing or nondepolarizing agents. Further delineation can be made with the nondepolarizing agents, as they are further categorized according to structure as either benzyl isoquinoline or aminosteroid compounds. (See Table 10-1 below)
Classification of Neuromuscular Blocking Drugs AGENT
DURATION Depolarizers
Succinylcholine (Anectine, Quelicin)
Ultra-short
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. March 2009
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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 gra dient 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. March 2009
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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.
“FADE”
Dose related decrease in twitch height Fade to train of four Fade to tetany Some post-tetanic potentiation **Antagonized by anticholinesterases**
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 March 2009
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(Fig. 10-3)
CNS
Autonomic Nervous System Sympathetic N.S.
Somatic N.S. Parasympathetic N.S.
ACh
(SCh)
(SUX)
ACh
ACh
(SCh)
Skeletal Muscle
ACh Cholinergic
(SCh)
NE
Effector Organs
Adrenergic 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 Duchenne’s muscular dystrophy. 2. Massive trauma (greatest risk > 72 hours from injury) 3. Burn injury (greatest risk > 24 hours from injury) 4. Denervation injuries (spinal cord) 5. Upper motor neuron disorders (Guillain-Barre’) 6. Prolonged immobilization
Etiology of SCh-Induced Hyperkalemia In patients with crush or burn injuries, serum potassium levels are usually high as a result of significant muscle injury (rhabdomyolysis), which worsens with the administration of SCh. In patients with myopathies, denervation injuries, or p rolonged 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.
Elevated Intragastric Pressure • SCh causes abdominal wall fasciculations which ↑ intragastric pressure. • SCh also causes ↑ in lower esophageal sphincter tone.
**Clinical Note** The increase in intragastric pressure is offset by the increase in esophageal sphincter tone, and is also minimized by defasciculation. If cricoid pressure is also applied, patients are generally NOT at increased risk of aspiration when SCh is used.
Elevated Intraocular Pressure (IOP) • The striated muscle of the eye contains a high density of motor end-plates that will cause transient increases in IOP when depolarization occurs from SCh administration. • SCh should be used with caution in patients with eye trauma. It is recommended to defasciculate prior to SCh administration in these patients to minimize the rise in IOP. There are no case reports in the literature of exacerbated eye injury from SCh administration when defasciculation was utilized.
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
Dibucaine Value
Response to SCh
Frequency
None
80
Normal
96%
Heterozygous
60
Moderately Prolonged
1:480
Homozygous
20
Greatly Prolonged (6-8 hours)
1:3200
Table 10-2: (Partially reproduced from Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 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. March 2009
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Succinylcholine Advantages
Disadvantages
Quick Onset Short Duration Increased LES tone
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???? March 2009
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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 TCA’S AND HALOTHANE! Clinical Uses • Skeletal muscle paralysis for surgical procedures of a long duration. • Muscle relaxant of choice to offset the vagotonic properties of other drugs, such as opioids, or intrinsic baseline bradycardias.
**Clinical Application** Often for longer procedures in patients with low resting heart rates, Pavulon will be chosen for its vagolytic properties. It is used in many cardiac inductions to offset opioid-induced bradycardia. Pavulon is also very cheap and maintains a long shelf life. (up to 18 months with refrigeration) **Ideal muscle relaxant for deployment.
Doxacurium (Nuromax) Structure • Benzyl isoquinoline compound • Structurally similar to Mivacurium and Atracurium Elimination • Primary route of elimination is renal • Small amount of hydrolysis by plasma cholinesterase Side Effects and Clinical Concerns • Use cautiously in presence of renal failure. • Be prepared for ultra-long muscle paralysis up to 3 hrs. It is the longest acting muscle relaxant used clinically. • Very clean CV profile Clinical Used • Used when an extensively prolonged duration of muscle relaxation is desired without CV side effects.
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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 para lysis 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: abnormalities: 1. Hypokalemia 2. Hypocalcemia 3. Hypermagnesemia
**Clinical Note**
The duration of action of all muscle relaxants in pre-eclamptic patients treated with Mg+2 is often significantly prolonged. Usual doses should be decreased by about 50% in these patients.
Age Neonates and infants illustrate ↑ sensitivity to NDP muscle relaxants, due primarily to an immature neuromuscular junction.
**Clinical Note** This is the exact OPPOSITE for SCh, which usually requires about twice the dose in infants compared to adults. This is primarily related to the increased extracellular fluid volume in infants. Remember, SCh is highly water soluble, and redistributes into the extracellular space rapidly.
Specific Drug Interactions There are many drugs that will alter the clinical response of muscle relaxants. The mechanism of action for many is not well understood, but can affect the NMJ prejuctionally, postjunctionally, or have a direct affect on the muscle fiber.
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Drugs Altering Neuromuscular Blocking Response Drug
Effect on SCh
Effect on NDP
Antibiotics
↑
↑
Anticonvulsants
Unknown
↓
Antidysrhythmics
↑
↑
Antihypertensives
↑
↑
Cholinesterase Inhibitors
↑↑
↓↓
Dantrolene
Unknown
↑
Furosemide (Lasix)
↑or ↓
↑or ↓
Inhalation Agents Local Anesthetics
↑ ↑
↑ ↑
Lithium
↑
Unknown
Magnesium Sulfate
↑
↑
1
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 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 (Duchenne’s) Hyperthermia Myasthenia Gravis Resistance Severe Chronic Infection Hyperkalemia 1 Systemic Lupus Erythematosus, Polymyositis 2 Tetanus, Botulism
Response to NDP Hypersensitivity Hypersensitivity Resistance Resistance Hypersensitivity Resistance Normal or Slight Resistance Hypersensitivity Hypersensitivity Resistance
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
% Receptors Occupied By Muscle Relaxant
% Receptors Free Of Muscle Relaxant
0 1 2 3 4
>95 90 80 75 < 75
0 10 20 25 > 25
Table 10-6
**Clinical Application** Dosing and reversal of NDP muscle relaxants relies on the correlation between number of TOF
twitches and depth of paralysis. Reversal of a NDP block cannot successfully occur until at least one twitch returns in a TOF stimulation.
Common Dosing Regimens For Muscle Relaxants Drug
Dosage (mg/kg)
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
Peak (Minutes)
Duration (Minutes)
1
4-6
2-6
30-90
3-5
40-60
3-5
45-120
3-9
30-160
3-5
20-35
3-5
25-40
1-3
15-150
5
60
1-3
6-16
Succinylcholine
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
Histamine Release
Vagal Blockade
Primary Elimination (Metabolism/Excretion)
Succinylcholine (Anectine)
+
+
Plasma cholinesterase
D-Tubocurare (Curare)
+++
None
Renal excretion
Pancuronium (Pavulon)
None
++
Primary renal excretion (40%)
None
None
None
None
++
None
Pipecuronium (Arduan) Doxacurium (Nuromax) Atracurium (Tracrium) Vecuronium (Norcuron)
None
None
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
Rocuronium (Zemuron)
None
+
Cisatracurium (Nimbex)
None
None
Hofmann Elimination
Mivacurium (Mivacron)
++
None
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
+ Mild Effect ++ 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.)
** Remember, all of the nondepolarizing blocking drugs are large, highly ionized quaternary ammonium compounds that are poorly lipid soluble. They do not cross the blood: brain barrier or placenta.
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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)
Agonist Nicotine Acetylcholine Succinylcholine Muscarine Acetylcholine Succinylcholine
Smooth Muscle • Bronchial • Gastrointestinal • Bladder • Blood Vessels Heart • SA node • AV node
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 RBC’s and all cholinergic synapses in the central and
•
peripheral nervous system. Enzyme responsible for the breakdown of acetylcholine (ACh).
Butyrylcholinesterase → (BuChE, Pseudocholinesterase, Plasma Cholinesterase) • Produced in the liver • Found in the liver, plasma, kidney, and intestine • Enzyme responsible for hydrolysis of succinylcholine (SCh) Acetylcholine/Acetylcholinesterase Relationship Acetylcholinesterase (AChE) is responsible for the breakdown of acetylcholine (ACh) everywhere that this neurotransmitter is present. AChE consists of an anionic and esteratic site that compliments the ACh substrate in such a way that physical binding occurs through acetylation. This physical binding inactivates ACh.
Acetylation of ACh substrate
Fig: 11-2: (Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 1999, p.226.)
AChE Anionic Site (Negative Charge) binds to the quaternary nitrogen of ACh. AChE Esteratic Site (Positive Charge) is oriented with the ester linkage of ACh.
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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. Acetylation (REVERSIBLE binding of AChE to ACh, as described above) 2. Electrostatic Attachment (REVERSIBLE) 3. Carbamylation (REVERSIBLE) 4. Phosphorylation (IRREVERSIBLE) Clinically Used Anticholinesterase Agents: 1. Edrophonium (Tensilon) 2. Neostigmine (Prostigmine) 3. Pyridostigmine (Mestinon) 4. Physostigmine (Antilirium)
Fig: 11-3: (Morgan, E., Mikhail, M., & Murray, M. Clinical Anesthesiology, 2002, p.203.)
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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 BNZ’s and volatile agents.
Irreversible Anticholinesterase Drugs Organophosphates Structure Varies, but all are lipid soluble compounds that readily cross lipid membranes .
Binding Characteristics • Irreversible bond • Formation of a phosphorylate complex at the esteratic site of AChE. • **Can last for several weeks . ** • Synthesis of new AChE enzyme is required for normal activity to resume.
Echothiophate (Phosphorylate Complex)
Fig: 11-8: (Stoelting, R.K. Pharmacology & Physiology in Anesthetic Practice. 1999, p. 225.)
Other Major Characteristics • Substances that establish a phosphorylated bond with AChE include: 1. Echothiophate eye drops 2. Certain insecticides (Parathion, Malathion) 3. Nerve agents (Soman, Saran, Tabum)
**Clinical Note** Echothiophate is the only organophosphate AChE drug used clinically!!
KNOW THIS!!!!!!
•
Aside from synthesis of new enzyme, organophosphate compounds can be physically removed from AChE by administering reactivators such as Hydroxylamine, Pralidoxime , or Obidoxime. (See Chapter 13)
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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 agent’s structural components.
Physostigmine = Tertiary Amine = Highly Lipid Soluble = Crosses BBB Organophosphates = Highly Lipid Soluble = Cross BBB All Others = Quaternary Amine = Poorly Lipid Soluble = Can’t Cross BBB
•
Clearance of anticholinesterase agents relies heavily on the kidney (50-75%)
Major Pharmacologic Effects of Anticholinesterases The pharmacologic effects of these drugs are predictable and reflect the accumulation of ACh at muscarinic and nicotinic cholinergic receptors. Sometimes the effects elicited are desirable. Most of the time in anesthesia the effects are not desirable, and attempts are made to minimize them in a variety of ways.
Cardiovascular Accumulation of ACh at muscarinic receptors in the heart, blood vessels, autonomic ganglia, and postganglionic cholinergic nerve endings can result in:
• • •
*Bradycardia (most common)
Hypotension Dysrhythmias, Asystole
Pulmonary Muscarinic stimulation can precipitate smooth muscle contraction in the lungs, causing bronchospasm, and increased respiratory tract secretions. Cerebral Physostigmine crosses the BBB and can precipitate extreme agitation and delirium from its effects
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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 be cause its pharmacokinetic profile closely mirrors the particular anticholinesterase it is matched with. The result is minimal muscarinic side effects. (Table 11-2) **The better you can mirror the pharmacokinetic profile of an anticholinesterase with an anticholinergic, the fewer side effects you will have. **The choice of anticholinesterase determines the choice of anticholinergic.
Commonly Used Anticholinergic/Anticholinesterase Pairings
Anticholinesterase
Common Anticholinesterase Dose
Recommended Anticholinergic
Usual Dose of Anticholinergic per mg of Anticholinesterase
Neostigmine
0.04-0.08 mg/kg
Glycopyrrolate
0.2 mg
Pyridostigmine
0.1-0.4 mg/kg
Glycopyrrolate
0.05 mg
Edrophonium
0.5-1 mg/kg
Atropine
0.014 mg
Physostigmine
0.01-0.03 mg/kg
Not needed
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
Estimated % of Receptors Occupied
Tidal Volume
80
Train-Of-Four (TOF)
70-75
Vital Capacity Breaths
70
Tetanic Stimulation (50 Hz)
70
Double-burst Stimulation
60-70
**Sustained Head Lift/Hand grip
50 rd
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
Ulnar
Facial
Posterior Tibial
Peroneal
Muscle stimulated
Adductor Pollicis Thumb adduction
Great Toe Plantar Flexion
Foot Dorsiflexion
Electrode Placement
Negative lead medial aspect of the forearm 2 cm proximal to the wrist with Positive lead 2-5 cm distal
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
Negative lead behind the medial malleolus, anterior to the Achilles tendon with Positive lead more proximal
Lateral to the neck of the fibula with the negative lead more distal
On Emergence
Not determined
Best Time to Utilize
On Emergence
On Induction
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. IV → 2 hours o IM/PO → 4-6 hours o TD → 72 hours o 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
Atropine
Glycopyrrolate
Scopolamine
Tachycardia Bronchodilation Antisialogogue Sedation Mydriasis
+++ ++ + + +
++ ++ ++ None None
+ + +++ +++ +++
+ Minimal Effect
++ Moderate Effect
+++ Marked 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
G = Glycopyrrolate Bronchodilation A=G>S
S = Scopolamine
Antisialogogue S>G>A
Sedative S>A>G
Cautious Use of Anticholinergics 1. Cardiovascular disease 2. Narrow-angled glaucoma 3. Urinary bladder neck obstruction 4. Intestinal or pyloric obstruction
Dose Continuum of Side Effects: Low Dose ----------------------------------------------------------------------------------High Dose SECRETORY ↓ 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
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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) Sarin (GB) 1938 75-100 1,000-1,700 1944 35-50 50-100 Soman (GD) VX 1952 10 6-10 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
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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 I’s/Duodote’s when the casualty’s condition warrants the use of three MARK I’s/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
% Incidence
Gastrointestinal (cramps, N/V)
> 50
Urinary urgency and frequency
5-30
Diarrhea, salivation, visual changes
> 10
Headache, rhinorrhea, diaphoresis, Tingling of extremities
<5
Table 13-2: Produced from information in Medical Management of Chemical Casualties Handbook. 1995,
p. 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
Nondepolarizing Muscle Relaxants
ACh Receptor
Depolarizing Muscle Relaxants
Anticholinergics
What Binds To Acetylcholinesterase?? ACh (Acetylation)
Reversible Anticholinesterases
1. Electrostatic bond • Edrophonium 2. Carbamylation • Neostigmine • Pyridostigmine • Physostigmine
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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Mechanism of Action Local anesthetics produce their effect by blocking sodium (Na+) channels inside the neuronal membrane. This blockage prevents an increase in sodium permeability during an action potential, resulting in negation of electrical conduction. Two forms of local anesthetics: 1. Free base form (B) = Lipophilic unionized fraction 2. Cationic form (BH+) = Hydrophilic ionized fraction
Figure 14-2: (Mycek, Mary J. Lippincott’s Illustrated Reviews: Pharmacology. 2000, p. 5 with modification)
Free Base Form (B) = Unionized Lipophilic = Uncharged Form
** Determines onset of action Cationic Form (BH +) = Ionized = Charged Form ** Determines block duration
• •
Both forms are involved in the process of nerve conduction block. Theory of nerve blockade 1. Local anesthetic is injected into an area with a local pH. 2. The local pH determines the % ionized and % unionized drug form. 3. The unionized form crosses the lipid bilayer of the nerve. 4. Once inside the nerve, the charged, ionized form binds to the Na+ channel to decrease permeability of this ion into the cell. 5. Action potential is blocked.
** It is fortunate that intracellular pH is about 7.0, for this results in conversion of the unionized drug to its cationic, active form.
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Relationship of pK a 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] = pk a – 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
pKa
Amides
pKa
2-Chloroprocaine (Nesacaine) Cocaine Procaine (Novocaine) Tetracaine (Pontocaine) Benzocaine (Americaine) Remember: CCPT like captain
9.0 8.7 8.9 8.2 None
Bupivacaine (Marcaine) Dibucaine (Nupercaine) Etidocaine (Duranest) Lidocaine (Xylocaine) Mepivacaine (Carbocaine) Prilocaine (Citanest) Ropivacaine (Naropin)
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 o
•
Lidocaine pKa = 7.8 = 25% unionized & 75% ionized Tetracaine pKa = 8.2 = 7% unionized & 93% ionized
The closer the drugs pKa is to physiologic pH, the quicker the onset. Remember, local anesthetics are basic drugs. o
**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
Drug
Relative Potency
Onset
Duration (min)
Low Potency Short Duration
Procaine
1
Slow
60-90
2-Chloroprocaine
1
Fast
30-60
Mepivacaine
2
Fast
120-240
Prilocaine
2
Fast
120-240
Lidocaine
2
Fast
90-200
Tetracaine
8
Slow
180-600
Ropivacaine
10
Slow
180-600
Bupivacaine
9
Intermediate
180-600
Etidocaine
6
Fast
180-600
Intermediate Potency Intermediate Duration
High Potency Long Duration
rd
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 (T 1/2 beta) is slower related to distribution to less perfused tissue, metabolism, and excretion. Metabolism and Excretion • All local anesthetics are eliminated by conversion to more polar compounds and removal by the kidney. • Metabolic pathways vary based on chemical classification. ESTERS → Pseudocholinesterase hydrolysis = FAST AMIDES → Multiple biotransformation pathways in the liver • Hepatic disease prolongs amide metabolism more than 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
(Figure 14-3). Bovill, J. G. Clinical
Later
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. March 2009
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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 don’t 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. March 2009
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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
Primary Clinical Use Intravenous, Infiltration, Topical, Neuraxial Blocks, Bier Blocks, Nerve Blocks Infiltration, Neuraxial Blocks, Peripheral Nerve Blocks Infiltration, Neuraxial Blocks, Peripheral Nerve Blocks
2-Chloroprocaine
Epidural Blocks, Nerve Blocks
Mepivacaine
Axillary, Peripheral Nerve Blocks
Tetracaine
Spinal, Axillary Blocks
Benzocaine
Topical Spray
Cocaine
Topical Liquid
Table 14-3
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 patient’s kg weight in cc i.e. 60 kg pt = 30 cc injection • Bupivacaine 0.25%: give the patient’s 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. March 2009
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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
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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 can’t tell if alcohol pad is cold), followed by inability to feel sharp pain (needle prick). The patient may often complain that they feel that they have no idea where their limbs are (loss of proprioception), but this usually comes later. Often, the patient may not feel pain, but may still have the ability to move their limbs at incision.
•
The first nerves to be blocked are the last to recover in neuraxial anesthesia.
•
Large A-alpha fibers are very difficult to block related to large size.
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% rd Table 14-5*: (Nagelhout, J.J. Nurse Anesthesia. 3 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 pKa’s and pH’s. Usually this is not a problem, but some unpredictability has been reported with 2-Chloroprocaine, probably related to its high pKa.
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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 Table 14-6
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
*
*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% (1/10 th) Bupivacaine + 2 ug/cc Fentanyl • 250cc NS - 44cc NS + 34cc 0.75% Bupivacaine + 10cc Fentanyl **0.1% (1/10 th) Bupivacaine + 4 ug/cc Fentanyl • 250cc NS - 54cc NS + 34cc 0.75% Bupivacaine + 20cc Fentanyl **0.1% (1/10 th) Bupivacaine + 10 ug/cc Hydromorphone • 250cc NS - 54cc NS + 34cc 0.75% Bupivacaine + 1.25 cc Hydromorphone **0.0625% (1/16 th) Bupivacaine + 4 ug/cc Fentanyl • 250cc NS - 50cc NS + 30cc 0.5% Bupivacaine + 20cc Fentanyl **0.0625% (1/16 th) 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 patient’s use of herbal medicines should be shared with all members of the surgical team, to allow for a collective decision about continuing with the proposed surgical procedure. 4. It is critical that the surgeon understand anesthesia risks if the surgery proceeds on an emergency basis. 5. Patients have died in the O.R. from complications related to the use of herbal medicines. TAKE IT SERIOUSLY!!
Major Anesthetic Implications 1. 2. 3. 4. 5. 6. 7. 8.
Coagulopathies Electrolyte Abnormalities Hemodynamic Changes Sedative Effects Seizures Cardiac Effects Withdrawal Syndrome Cytochrome P-450 induction
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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 MAOI’s • Discontinue at least 24 hours prior to surgery **Ma Hung has been associated with more than 22 deaths, as well as life-threatening hyperpyrexia, hypertension, and coma.
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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. March 2009
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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. John’s Wort (Amber, Goatweed, Hardhay, Klamath Weed) Common Uses Common name for the flower Hypericum perforatum, it is used for the short-term treatment of mild-tomoderate depression. Studies suggest it is not useful for treating major depressive states.
Pharmacological Effects • Inhibits serotonin, norepinephrine, and dopamine reuptake by neurons • Precipitates induction of the cytochrome P-450 system in the liver Perioperative Concerns • Liver enzyme induction may affect metabolism of many drugs to include cyclosporines,
• • • •
Warfarin, steroids, protease inhibitors, benzodiazepines, and calcium channel bl ockers. Central serotonin excess syndrome may develop with concomitant use with other serotonin blockers (Zofran?). Unpredictable interaction with TCA/MAOI’s Unpredictable clinical responses to direct and indirect-acting sympathomimetic drugs (Neosynephrine, Ephedrine). Recommend discontinuation at least 5 days prior to surgery.
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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
Perioperative Concerns
Perioperative Recommendations
• Counteracts immune suppressive Echinacea
• • •
Ephedra Garlic Ginkgo biloba Ginseng
• • • • • • •
Kava
therapy Hepatotoxicity Causes immune suppression long term. Increased heart rate and blood pressure Myocardial infarction Dysrhythmias Bleeding from inhibition of platelet’s Bleeding from inhibition of platelet’s Bleeding from platelet inhibition Bleeding from coagulation cascade inhibition Hypoglycemia
• Increased sedative effects of anesthetics
• Liver enzyme induction leading to St. John’s Wort
Valerian
•
increased drug metabolism. Interaction with sympathomimetic drugs
• Potentiation of anesthesia drugs • Acute withdrawal symptoms
D/C as soon as possible
D/C at least 24 hours prior Avoid MAOI’s 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.
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. John’s 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. John’s Wort Valerian Table 15-4: (Norred, C., Use of complementary and alternative medicines by surgical patients. AANA J, 2000;
68 (1): 16, with modification.)
Herbal Medicines With Cardiac Effects Herb Black Cohosh Ephedra Fenugreek Ginger Ginseng Goldenseal
Effect 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
Hawthorn Licorice Lobelia
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. Mosby’s 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 a re 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 α-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
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 Duration of anesthesia Type of Anesthesia
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
Fourth Ventricle
Nucleus of the solitary tract
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
Receptors a
Opioid Area Postrema 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, 2 000; 59 (2): 213-243 with modification.)
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Factors Influencing Nausea and Vomiting Sensory input (pain, smell, sight)
Higher Cortical Centers
Memory, f ear, anticipation NK 1 Antagonist
Histamine Antagonists Muscarinic Antagonists Dopamine Antagonists
Chemotherapy Anesthetics Opioids
Chemoreceptor Trigger Zone (area postrema) 4th Ventricle Sphincter Modulators
Chemotherapy Surgery Radiotherapy
Benzodiazepines Propofol
Vomiting Center Medulla
Vomiting Reflex
5HT 3 Antagonists
v e e r N u s a g V i a V
Stomach Small Intestines
Histamine Antagonists Muscarinic Antagonists
Labyrinths Vestibular Apparatus CN VIII
Gastroprokinetic Agents
Surgery Motion
Neuronal Pathways
Factors which can cause PONV
NK 1 Antagonist
Sites of action of drugs
Figure 16-2. http://www.nauseaandvomiting.co.uk/NAVRES001-3-PONV.htm#B8 with modification
Classification
Antiemetic Drugs
Receptor
Anticholinergics Antimuscarinics
Atropine Scopolamine Diphenhydramine (Benadryl) Hydroxyzine (Vistaril)
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
Antihistamines Substituted Benzamides
Metoclopramide (Reglan)
Benzodiazepines
Lorazepam (Ativan) Midazolam (Versed)
Butyrophenones
Droperidol (Inapsine) Haloperidol (Haldol)
Isopropylphenol Phenothiazines 5-HT3 receptor antagonists Steroids
Propofol Promethazine (Phenergan) Prochlorperazine (Compazine) Chlorpromazine (Thorazine) Ondansetron (Zofran) Dolasetron (Anzemet) Granisetron (Kytril) Dexamethasone (Decadron) Methylprednisolone (Solumedrol)
5-HT3 (Serotonin) (Area Postrema and abdominal vagal afferents) Unknown, many hypotheses
Substance P/ NK1 (Central Nervous System and gut) Neurokinin 1 NK1 Aprepitant (Emend) 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 tablet’s (4, 8, 16 mg), orally disintegrating tablet’s (4 mg) Side Effects and Clinical Concerns • Headache if administered too quickly (<2 min) preoperatively • Dizziness, constipation, and diarrhea have been repo rted. • 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 can’t 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 µg/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 µg/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: ♦ Parkinson’s 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 ♦ Parkinson’s Disease, Epilepsy ♦ Pheochromocytoma Hypertensive crisis can occur if given to a patient with a pheochromocytoma. It increases catecholamine secretion by the tumor. • Use cautiously in children due to an increased risk for extrapyramidal reactions. **Clinical Use** • Most effective against opioid induced decreased GI motility d uring 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 prolo ng 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 Scóp 1.5 mg patch delivers 1.0 mg of scopolamine over 72 hours. ♦ Oral or IV administration of scopolamine would require large doses, resulting in undesirable side effects. IV scopolamine is utilized more often for its sedative properties. • The safety and effectiveness of Transderm Scóp in children has not been established. Side Effects and Clinical Concerns • Sedation, dry mouth, dizziness, urinary retention and blurred vision ♦ Can cause temporary dilation of the pupils and blurred vision if it comes in contact with the eyes • Confusion, anxiety • Central Anticholinergic Syndrome ♦ Treatment of choice is physostigmine 15-60 µg/kg IV. **Clinical Use** • Prevention of nausea and vomiting associated with motion sickness and recovery from anesthesia • Caution with: Narrow-angle glaucoma, intestinal obstruction, coronary heart disease • Atropine crosses the blood brain barrier but is used less often. • Glycopyrrolate is a quaternary amine so it is not effective as an antiemetic.
Antihistamines – H1-Receptor Antagonists Diphenhydramine (Benadryl) Structure • Is an ethanolamine with atropine-like activity used to treat allergic symptoms, vertigo/motion sickness, Parkinson’s, sedation, drug-induced extrapyramidal reactions, nausea and vomiting • Blocks histamine (H1) receptors in the nucleus of the solitary tract ♦ It DOES NOT block the release of histamine. • Blocks acetylcholine (ACh) receptors in the vestibular apparatus of the inner ear Elimination • Both excreted unchanged in the urine and metabolized in the liver. Pharmacokinetic Properties and Dosing • Dose: 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 March 2009
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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
Drug Scopolamine
Benzamides
Metoclopramide
Butyrophenones
Droperidol
Route IM, IV, Transderm Patch IM, IV PO PO IM IM, IV, PO IV IM, IV
Antihistamines
Diphenhydramine
5-HT3 receptor Antagonists
Ondansetron
PO
Hydroxyzine
IV Dolasetron
PO IV
NK1 Antagonist Phenothiazines
Steroids
Granisetron
IV
Aprepitant Promethazine
PO IM, IV, PO
Prochlorperazine Betamethasone
IV IM, PO IM
Dexamethasone
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 µg/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 µg/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
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
Mild to Mod Risk 1-2 factors present (20-40%)
Mod to High Risk 3-4 factors present (40-80%)
Any 1 of the following:
• • • •
Dexamethasone
•
Dexamethasone + 5-HT3 antagonist
•
Droperidol + 5-HT3 antagonist
Scopolamine Prochlorperazine 5-HT3 antagonist
Laparoscopy Strabismus ENT Breast surgery Gynecologic surgery
Very High Risk > 4 factors present (> 80%)
•
Combination antiemetics + TIVA with propofol
Figure 16-3: (Kovac, A., Antiemetic Use in Postoperative Nausea and Vomiting, Drugs, 2000; 59 (2):
213-243 with modification.)
Triad of Aspiration Pneumonitis Prophylaxis Aspiration pneumonitis (Mendelson's syndrome) is a chemicalinjury 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
•
Bronchospasm due to unopposed histamine effects of H 1-receptors on bronchial smooth muscle.
• •
Avoid in patients with acute porphyria because it can precipitate an attack.
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.
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.
• • • •
Bradycardia, hypotension or heart block can occur following rapid IV infusion.
Slurred speech, delirium and confusion occur more often with cimetidine than with ranitidine especially in the elderly patient. 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 March 2009
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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
Route
Dose
Onset
Duration
Cimetidine
PO IV
300-800 mg 300 mg
1-2 hours 15 min
4-8 hrs
Ranitidine
PO IV
150-300 mg 50 mg
1-2 hours 30 min
Bicitra
PO
15-30 ml
Metoclopramide
PO IV
10-20 mg 10-20 mg
Acidity
Volume
LES tone
↓↓↓
↓↓
No effect
10-12 hrs
↓↓↓
↓↓
No effect
5-10 min
30-60 min
↓↓↓
↑
No effect
30-60 min 3-5 min
1-2 hrs
No effect
↓↓
↑↑
↓↓ = Moderate decrease ↓↓↓ = Marked decrease ↑ = Slight increase ↑↑ = Moderate increase LES tone = Lower esophageal sphincter tone rd
Table 16-6 (Morgan, E., Mikhail, M., Murray, M. (2002). Clinical Anesthesiology. 3 Edition, New York: McGraw-
Hill, 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). Lippincott’s Illustrated nd Reviews: Pharmacology. 2 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
1
Inhibition of Norepinephrine release Inhibition of Insulin release Platelet aggregation Decreased Lipolysis Reduces sympathetic outflow, i.e. Sympatholytic
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 nd
Table 17-1: (Mycek, Mary J., et al. (2000). Lippincott’s Illustrated Reviews: Pharmacology. 2 Ed, p 60, with modification).
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rd
Figure 17-2: (Morgan, E., Mikhail, M. & Murray, M. (2002). Clinical Anesthesiology. 3 Edition, p. 213)
Definition of Terms:
Sympathomimetic Drugs – drugs that mimic the actions of epinephrin e 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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nd
Figure 17-3: (Neal, M. J. (1995). Medical Pharmacology at a Glance. 2 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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nd
Figure 17-4: (Mycek, Mary J., et al. (2000). Lippincott’s Illustrated Reviews: Pharmacology. 2 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 March 2009
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Table 17-2. Classification and Comparison Pharmacology of Sympathomimetics Receptors Stimulated
1
2
a h p l A
a h p l A
++
++
+++
++
1
a t e B
2
a t e B
A D
A D
+++
++
0
0
++
0
0
1
2
f O m n s o i n i t a c h A c e M
Cardiac Effects s a i m h t y h r s y D
R V P
P A M
e c n a t s i s e R y a w r i A
w o l F d o o l B l a n e R
s u n o o u i n s i u t f n n o I C
O C
R H
Direct
++
++
+++
±
+
--
--
1-20 µg/min
0
Direct
-
-
+
+++
+++
NC
---
4-16 µg/min
+++
+
+
+
+
NC
+++
1-20 µg/kg/min
Natural Catecholamines
Epinephrine1 1
Norepinephrine
++
++
+
+
+++
+++
Direct Indirect
Isoproterenol
0
0
+++
+++
?
?
Direct
+++
+++
+++
--
±
---
-
1-5 µg/min
Dobutamine
0/+
0
+++
+
0
0
Direct
+++
+
±
NC
+
NC
++
2-10 µg/kg/min
Ephedrine
++
?
++
+
0
0
++
++
++
+
++
--
--
Not used
Amphetamines
++
?
+
+
0
0
Indirect Direct Indirect
+
+
+
++
+
NC
--
Not used
Phenylephrine
+++
+
0
0
0
0
Direct
-
-
NC
+++
+++
NC
---
20-50 µg/min
1
Dopamine
Synthetic Catecholamines
Synthetic Noncatecholamines
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 α1 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. 3 rd 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 α1, α2, β1, β2 ♦ 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 β2 at 1-2 mcg/min Peripheral vasodilation (may see ↓ in diastolic BP) Relaxation of bronchial smooth muscle • Predominately β1 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 α1 > β1 at 10-20 µg/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) March 2009
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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 α1, α2, β1 • 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 – Beta 1 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 March 2009
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Dopamine Pharmacokinetic Properties ♦ Important neurotransmitter in the CNS and peripheral nervous system ♦ Primarily a Direct acting agonist at α1, α2, β1, β2, 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 β1 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 α1 > β1 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 β1, β2 • 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 h ypertension 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 β1 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%) March 2009
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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 (β1) • Increases blood pressure (α1, β1) • 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 (β2), 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 α2 and β-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 Phenylephrine will further decrease the heart rate and cardiac output o o Administer ephedrine instead to these patients March 2009
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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 Willebrand’s 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 Willebrand’s 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 March 2009
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Additional Adrenergic Agonists Albuterol Pharmacokinetics and Physiologic Effects ♦ Selective β2 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 α2 agonist with a higher affinity for α2 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 α1 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 patient’s 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
Parasympathetic 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
↓ Heart rate ↓ Conduction velocity
Relaxation
Contraction
Decrease Decrease Contraction Relaxation
Increase Increase Relaxation Contraction
Contraction
Variable
Relaxation Contraction
Contraction Relaxation
Minimal effect Slight ↓ in contractility
Mydriasis Relaxation for far vision Glycogenolysis Gluconeogenesis
Miosis Contraction for near vision Glycogen synthesis
Increase
Marked increase
Constriction (alpha) Relaxation (beta) Constriction Constriction (alpha) Relaxation (beta) Constriction
Relaxation (?) Relaxation Relaxation Relaxation
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) Does not rely on β-adrenergic stimulation o Effectiveness is not altered by prior beta blockade o ♦ Onset: 5-15 minutes ♦ Metabolism: excreted unchanged by the kidneys Decrease dose with severe renal dysfunction o ♦ 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 Inotropy: Increases myocardial contractility (see Fig 17-6) with minimal increases in o 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) β Agonist (1st messenger) and β-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) Gα + 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) Phosphorylation→↑intracellular 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
nd
Fig 17-6: (Mycek, M.J., Harvey, R.A., Champe, P.C. Pharmacology. 2
Ed. 2000, p.161 with modifications.)
Figure 17-7. How Phosphodiesterase Drugs Cause Vasodilation
nd
Fig 17-7: (Mycek, M.J., Harvey, R.A., Champe, P.C. Pharmacology. 2
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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
th
Fig 17-8: Mogan, E., Mikhail, M. & Murray, M. (2006). Clinical Anesthesiology, 4 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
Systolic BP mm Hg
Diastolic BP mm Hg
< 120
and
< 80
Pre-hypertension
120-139
or
80-89
Stage 1 Hypertension
140-159
or
90-99
Stage 2 Hypertension
> 160
or
> 100
Table 18-1: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and
Treatment of High Blood Pressure, Dec 2003. 200 3. (Currently up for review)
Adrenergic Receptor Antagonists/Blockers
Fig 18-1: Mycek, M.J., Harvey, R.A., Champe, P.C. Pharmacology. 2
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nd
Ed. 2000, p.184.
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Table 18-2. Pharmacological Properties of Adrenergic Antagonists HR
Cardiac Output
Peripheral Vascular Resistance
MAP
Receptor Antagonized 1
2
1
2
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)
Esmolol
0
0
++
+ with ↑dose
↓↓
↓↓
Slight ↑ with High doses
↓
Labetalol
+
0
++
+
↓
↓
↓↓
↓↓
Hepatic
Metoprolol
0
0
++
+
↓↓
↓↓
Slight ↑
↓
Hepatic
Atenolol
0
0
++
+
↓↓
↓↓
Slight ↑
↓
Renal
Prazosin
++
0
0
0
NC
↓↓
↓↓
↓↓
Hepatic
♦ 6-15 mg/day po
Phentolamine
++
+
0
0
↑
↑
↓↓
↓↓
Hepatic
♦ 1-5 mg IV Bolus ♦ 0.3 mg/min
♦ 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
(10 mg in 100 mL D5W) Phenoxybenzamine
++
+
0
0
↑
↑
↓↓
↓↓
♦ ♦ ♦ ♦ ♦
Irreversible blockade
♦ 0.5-1.0 mg/kg po
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: • Sinus bradycardia • Overt heart failure • Tachycardia with concurrent • Cardiogenic shock 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 α-blockade and β-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 March 2009
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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 α-adrenergic blocker (α1 > α2) • 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 March 2009
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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 ♦ Raynaud’s 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 Raynaud’s 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: Braunwald’s Heart Disease: A Textbook of th
Cardiovascular Medicine. 7 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. AGT = Angiotensinogen o o Ang I = Angiotensin I Ang II = Angiotensin II o ♦ 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, 22
n
Ed., 2004.
TABLE 18.3 COMPARISON OF COMMON ARBs Losartan (Cozaar) Candesartan cilexetil (Atacand) Eprosartan (Teveten) Irbesartan (Avapro) Telmisartan (Micardis) Valsartan (Diovan) Olmesartan Medoxomil (Benicar)
Peak
Half-Life
Elimination
Active Metabolite
Oral Dose
1-3 hrs
6-9 hrs
Renal/Hepatic
Yes
25-100 mg/day
3-4 hrs
9 hrs
Renal/Biliary
Yes
4-32 mg/day
1-2 hrs 1.5-2 hrs 0.5-1 hr 2-4 hrs
5-9 hrs 11-15 hrs 24 hrs 9 hrs
Renal/Biliary Renal/Biliary Biliary Hepatic
No No No No
400-800 mg/day 150-300 mg/day 40-80 mg/day 80-320 mg/day
1.4-2.8 hrs
10-15 hrs
GI Tract
Yes
20-40 mg/day
Table 18-3: (Developed from information in Hardman, Joel. Goodman & Gilman’s The Pharmacological Basis of th
Therapeutics 11 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. What does this mean? Intractable intraoperative hypotension o 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 ↑ Release of Epinephrine and NE from the adrenal medulla o 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 Development of o 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 t
Fig 18-5: Katzung, Bertram. Basic & Clinical Pharmacology, 9 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 High circulating levels of Angiotensin II stimulate AT 2R and ↑ vasodilation o ♦ Decreases Sympathetic Nervous System (SNS) output ♦ Decreases blood cholesterol levels Indications ♦ Essential hypertension First line for patients with diabetes without renal insufficiency o ♦ 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 Verapamil (Calan)
Diltiazem (Cardiazem)
Nifedipine (Procardia)
Nicardipine (Cardene)
Phenylalkylamine
Benzothiazepine
Dihydropyridine
Dihydropyridine
Negative inotropic (contractility)
+
0/+
0
+
Negative chronotropic (heart rate)
+
0/+
0
0
Negative dromotropic (cardiac conduction velocity)
++++
+++
0
0
Coronary vasodilation
++
+++
++++
+++++
Systemic vasodilation
++
++
++++
++++
Bronchodilation
0/+
Class/Effect Subclass
0/+ th
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. 2
nd
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). Inhibits extracellular Ca++ from entering the “slow channels” o ♦ 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 metabolites→↓dose 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 µg/mL) in any solution except LR ♦ Dose: 250 µg boluses until BP is therapeutic → start infusion at 2-5 mg/hr up to 15 mg/hr max Oral dose is 20-40 mg every 8 hours o Physiologic Effects ♦ Cardiovascular Relaxation of coronary vascular smooth muscle → ↑ coronary blood flow o ↑ Myocardial oxygen delivery in patients with vasospastic angina Greatest of any calcium channel blocker o Relaxation of peripheral arteries with minimal venod ilating effects ↓ SVR → ↓ afterload → ↑ cardiac output, ↑ PCWP & ↑ ejection fraction Has minimal cardiodepressant effects with no effects on heart rate o Reflex tachycardia does not occur as frequently as with nitroprusside March 2009
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♦ Central Nervous System o
Increases cerebral blood flow (CBF) with minimal effects on ICP
Indications ♦ Intraoperative hypertension ↑ CBF but does not increase ICP to the extent that nitroprusside does o 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 Mediated by activation of ATP-sensitive potassium channels within the arterial o vasculature causing hyperpolarization and relaxation ♦ Direct vasodilation of arterioles with little effect on veins Does NOT interact with adrenergic or cholinergic receptors o ♦ Onset: IV: 5-20 minutes ♦ Duration: IV: 1-4 hours depends on acetylator status of patient ♦ Elimination: Hepatically acetylated →↓ dose with hepatic dz Increase dose in “fast acetylator” patients o ♦ 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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th
Fig. 18-7: (Katzung, Bertram G., Basic & Clinical Pharmacology, 8 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 Effects blocked by beta blockers – (See Fig 18-7) o ♦ 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 Autoimmune reactions o
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 1-2 mcg/kg bolus prior to direct laryngoscopy but can cause transient hypotension o March 2009
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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
th
Fig 18-9: Stoelting, R. K. Pharmacology & Physiology in Anesthetic Practice. 4 Ed., 2006, p 356.
Physiologic Effects ♦ Cardiovascular Causes peripheral vasodilation by direct action on venous and arteriolar smooth muscle o 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 Intracoronary steal of blood flow away from ischemic areas (already maximally dilated) o o ↓ Diastolic BP → ↓ Coronary Perfusion March 2009
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♦ Cerebral Blood Flow (CBF) 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) Peripheral vasodilation → ↓ BP → ↓ HPV → ↑ Shunt to poorly ventilated alveoli → ↓ PaO2 o ♦ Platelet Aggregation ↑ Intracellular cGMP inhibits platelet aggregation with infusion rates > 3 mcg/kg/min o o
Indications ♦ Intraoperative Hypertensive Emergencies Pheochromocytoma Resection o 1-2 mcg/kg IV as a rapid injection o ♦ Controlled Hypotension to reduce bleeding during surgery ♦ Aortic Aneurysm repair during cross clamping ♦ Cardiac Surgery during rewarming phase of cardiopulmonary bypass Especially with mitral or aortic regurgitation o ♦ Congestive Heart Failure Precautions/Complications ♦ Profound sympathetic activation with tachycardia, ↑ myocardial contractility & flushing Caution in patients with coronary artery disease o 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 a nd death o Patients with anemia and liver/renal impairment are at an increased risk for toxicity Usually only accumulates with infusions > 2 mcg/kg/min or infusions lasting > 24 hrs o • 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: ½ - 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 Does not spontaneously produce nitric oxide unlike SNP o
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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 Coronary vasodilator o ♦ 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 Nitrite metabolite of NTG → oxidation of the ferrous ion to the ferric state → Methgb o
Table 18-5. Comparative Pharmacology of Vasodilator Agents Hydralazine
Nitroprusside
Nitroglycerin
Organ Effects ↑↑↑ ↑↑ ↑ Heart Rate ↓↓ ↓↓↓ Preload 0 ↓↓↓ ↓↓↓ ↓↓ Afterload CBF, ICP ↑↑ ↑↑ ↑↑ Kinetics Onset 5-20 min 1 min 1 min Duration 1-4 hr 5-10 min 5-10 min Dose Bolus 5-20 mg 50-100 mcg 50-100 mcg Infusion (mcg/kg/min) 0.25-1.5 0.3-10 0.5-10 0, no change; ↑ increase (slight, moderate, marked); ↓ decrease (slight, moderate, marked) 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
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
Table 1
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
Amplitude
⇑
⇑
⇓ ⇓ ⇓ ⇑ ⇑ ⇓
0
0
⇑ 0 0
⇓ ⇓ ⇓
⇑
0
0
⇓
0
⇑ ⇑ ?/0
Precautionary Use With Increased Intracranial Pressure Drug Halothane Ketamine Meperidine Succinylcholine Table 3
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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
Halothane Ketamine Propofol Morphine Meperidine
Pure Opioid Antagonists (Naloxone, Nalmefene) Anticholinergics Succinylcholine Pancuronium Cocaine
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
Table 4
Precautionary Use With Asthma Drug All Histamine-Releasing Drugs (Table 5)
Comment Histamine is a mediator of bronchoconstriction
Favorable Drugs For Use With Asthma All Volatile Agents Ketamine Propofol Anticholinergics Table 5
Dose-dependent bronchodilation Bronchodilatory properties Bronchodilatory properties ↓ Airway resistance
Histamine-Releasing Drugs Thiopental Morphine Meperidine Curare Atracurium Mivacurium Succinylcholine Ester Local Anesthetics (PABA) Table 6 March 2009
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Precautionary Use With Liver Dysfunction Drug Lidocaine, Diazepam, Meperidine, Morphine Halothane
Phenobarbital Vecuronium, Rocuronium Succinylcholine Mivacurium Amide Local Anesthetics Table 7
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
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 Mivacurium
Comments Metabolized by pseudocholinesterase. Prolonged muscle paralysis may occur dependent upon genetic variant.
Ester Local Anesthetics
Prolonged duration of action.
Succinylcholine
Table 10
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Drugs Triggering Malignant Hyperthermia Drug All Volatile Anesthetics Succinylcholine
Comments Not nitrous oxide
Controversial Triggers of Malignant Hyperthermia Phenothiazines Curare
Best to avoid Best to avoid
Safe Drugs To Use With Malignant Hyperthermia Nitrous Oxide Local anesthetics Opioids Benzodiazepines Intravenous Induction Agents Anticholinergics Anticholinesterases Nondepolarizing Muscle Relaxants Droperidol Reglan Vasoactive Drugs Table 11
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No longer controversial Amides and esters are safe
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References Chapter 1 Pharmacokinetic Principles 1. Barash, P.G., 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 Principles of Clinical Pharmacology. In Paul Paul G. Barash, Bruce F. Cullen, & Robert K. Stoelting (Eds), Clinical Anesthesia. 4 th Edition, Philadelphia: Lippincott Williams & Wilkins, Chapter 11. 3. Katzung, Bertram Bertram G. (2007). Basic and Clinical Pharmacology. 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 Mary J., et al. (2000). Lippincott’s Illustrated Reviews: Pharmacology. 2nd Edition, Philadelphia: Lippincott Williams & Wilkins, Chapter 1. 6. Nagelhout, J.J. J.J. & Zaglaniczny, K.L. (2001). Nurse Anesthesia. 2nd Edition, Philadelphia: W.B. Saunders Company, Chapter 5. 7. Nagelhout, J.J. 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 Miller (Ed), Anesthesia. 5th Edition, New York: Churchill Livingstone, Chapter 2. 9. Stoelting, R.K. R.K. (1999). Pharmacology Pharmacology and Physiology in Anesthesia Practice. 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 Zajtchuck & R. Bellamy (Eds), Textbook of Military Medicine, Anesthesia and Perioperative Care of the Combat Casualty. Falls Church, VA: Office of the Surgeon General, Ge neral, Chapter 8. 2. Eger, E. (1994). Uptake Uptake and Distribution of Inhaled Inhaled Anesthetics. The Distinguished Distinguished Professor 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. R.K. (1999). Pharmacology Pharmacology and Physiology in Anesthesia Practice. Practice. 3rd Edition, Philadelphia: Lippincott Williams and Wilkins, Chapter 1. 7. Stoelting, R.K. R.K. (2006). Pharmacology Pharmacology and Physiology in Anesthesia Practice. 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. J.B. Lippincott and Co., Chapter 10. 2. Nagelhout, J.J. J.J. & Zaglaniczny, K.L. (2001). Nurse Anesthesia. 2nd Edition, Philadelphia: W.B. Saunders Company, Chapter 7. 3. Stoelting, R.K. R.K. (1991). Pharmacology Pharmacology and Physiology in Anesthesia Practice. Practice. 2nd Edition, Philadelphia: Lippincott Williams and Wilkins, Chapter 1 4. Stoelting, R.K. R.K. (1999). Pharmacology Pharmacology and Physiology in Anesthesia Practice. Practice. 3rd Edition, Philadelphia: Lippincott Williams and Wilkins, Chapter 1. 5. Stoelting, R.K. R.K. (2006). Pharmacology Pharmacology and Physiology in Anesthesia Practice. Practice. 4th Edition, Philadelphia: Lippincott Williams and Wilkins, Chapter 1.
Chapter 4 Basic Math in Anesthesia Pharmacology 1. Dosch, M. (2001). Clinical Mathematics. Mathematics. Retrieved from the World Wide Web at URL: http://www.udmercy.edu/crna/agm/mathweb.htm 2. Morgan, E., E., Mikhail, M., M., & Murray, M. (2002). Clinical Clinical Anesthesiology. Anesthesiology. 3rd Edition, New York: McGraw-Hill, Chapter 4. 3. Petty, C. (1995). Military Anesthesia Machines. In R. 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. J.J. & Zaglaniczny, K.L. (2001). Nurse Anesthesia. 2nd Edition, Philadelphia: W.B. Saunders Company, Chapter 4. 3. Nagelhout, J.J. J.J. & Zaglaniczny, K.L. (2005). Nurse Anesthesia. 3rd Edition, Philadelphia: W.B. Saunders Company, Chapter 14. 4. Parbrook, G.D., Davis, P.D., P.D., & Parbrook, E.O. (1990). Basic Physics and Measurements in rd Anaesthesia. 3 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 (Product Information Pamphlet), 11. 2. Chestnut, David David H. (2004). Obstetric Anesthesia: Principles and Practice. 3rd Edition, Philadelphia, Elsevier Mosby, pg 437. 3. Duke, James (2006). Anesthesia Anesthesia Secrets. Secrets. 3rd Edition, Philadelphia: Elsevier, Chapter 76. 4. Hardman, Joel G. (2001). Goodman & Gilman’s: Gilman’s: 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. W.B. Saunders Company, Chapter 18. 6. Stoelting, R.K. R.K. (1999). Pharmacology Pharmacology and Physiology in Anesthesia Practice. Practice. 3rd Edition, Philadelphia: Lippincott Williams and Wilkins, Chapter 2. 7. Stoelting, R.K. R.K. (2006). Pharmacology Pharmacology and Physiology in Anesthesia Practice. Practice. 4th Edition, Philadelphia: Lippincott Williams and Wilkins, Chapter 2. March 2009
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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. J.J. & Zaglaniczny, K.L. (2001). Nurse Anesthesia. 2nd Edition, Philadelphia: W.B. Saunders Company, Chapter 7. 4. Nagelhout, J.J. J.J. & Zaglaniczny, K.L. (2005). Nurse Anesthesia. 3rd Edition, Philadelphia: W.B. Saunders Company, Chapter 8. 5. Omoigui, S. (1999). Anesthesia Anesthesia Drug Handbook. 3rd Edition, Malden, Mass.: Blackwell Science Inc., 1-502. 6. Stoelting, R.K. R.K. (1991). Pharmacology Pharmacology and Physiology in Anesthesia Practice. Practice. 2nd Edition, Philadelphia: Lippincott Williams and Wilkins, Chapters 4, 6. 7. Stoelting, R.K. R.K. (1999). Pharmacology Pharmacology and Physiology in Anesthesia Practice. Practice. 3rd Edition, Philadelphia: Lippincott Williams and Wilkins, Chapters 4, 6. 8. Stoelting, R.K. R.K. (2006). Pharmacology Pharmacology and Physiology in Anesthesia Practice. Practice. 4th Edition, Philadelphia: Lippincott Williams and Wilkins, Chapters 4, 6.
Chapter 8 Opioids 1. Nagelhout, J.J. J.J. & Zaglaniczny, K.L. (2001). Nurse Anesthesia. 2nd Edition, Philadelphia: W.B. Saunders Company, Chapter 10. 2. Nagelhout, J.J. J.J. & Zaglaniczny, K.L. (2005). Nurse Anesthesia. 3rd Edition, Philadelphia: W.B. Saunders Company, Chapter 10. 3. Omoigui, S. (1999). Anesthesia Anesthesia Drug Handbook. 3rd Edition, Maden, Mass.: Blackwell Science Inc., p. 1-502. 4. Stoelting, R.K. R.K. (1991). Pharmacology Pharmacology and Physiology in Anesthesia Practice. Practice. 2nd Edition, Philadelphia: Lippincott Williams and Wilkins, Chapter 3. 5. Stoelting, R.K. R.K. (1999). Pharmacology Pharmacology and Physiology in Anesthesia Practice. Practice. 3rd Edition, Philadelphia: Lippincott Williams and Wilkins, Chapter 3. 6. Stoelting, R.K. R.K. (2006). Pharmacology Pharmacology and Physiology in Anesthesia Practice. 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. J.J. Current theories about the mechanisms of benzodiazepines and neuroleptic drugs. Anesthesiology, 1981; 54: 66-72. 3. Stoelting, R.K. R.K. (1987). Pharmacology Pharmacology and Physiology in Anesthesia Practice. Practice. Philadelphia: Lippincott Williams and Wilkins, Chapter 5. 4. Stoelting, R.K. R.K. (1999). Pharmacology Pharmacology and Physiology in Anesthesia Practice. Practice. 3rd Edition, Philadelphia: Lippincott Williams and Wilkins, Chapter 5. 5. Stoelting, R.K. R.K. (2006). Pharmacology Pharmacology and Physiology in Anesthesia Practice. 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. 2 nd 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. March 2009
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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). Lippincott’s 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). Mosby’s 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). Lippincott’s 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. 3 rd 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 & Gilman’s 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). Lippincott’s 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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