Anesthesia Considerations for the Oral and Maxillofacial Surgeon

By Matthew Mizukawa, Samuel J. McKenna and Luis G. Vega

Although office-based anesthesia administration has been essential in the evolution of outpatient surgery, it is becoming more complex as people live longer and with more comorbid diseases. The purpose of this book is to strengthen the margin of safety of office-based anesthesia administration by helping practitioners determine whether the patients they treat are good candidates for office-based anesthesia. This book is organized into three sections. The first section provides a review of the principles of anesthesia, including the pharmacology of anesthetic agents, local anesthesia, patient monitoring, preoperative evaluation, the airway, and management of emergencies and complications. The major organ systems of the body are reviewed in section two, and the most common comorbid conditions that affect these systems are described in terms of their pathophysiology, diagnosis, management, and anesthesia-related considerations. Section three reviews patient groups that warrant special consideration in the administration of office-based anesthesia, such as geriatric, pediatric, pregnant, and obese patients. Spiral-bound and featuring tabs for quick and easy reference, this important book belongs on the shelf of every clinician who provides anesthesia in the office setting.

• Language: English
• Publisher: Quintessence Publishing Co, Inc
• Release date: Oct 1, 2019
• ISBN: 9780867158847

Book preview

The pharmacologic effects of drugs are determined by pharmacokinetic and pharmacodynamic principles. Pharmacokinetics describes the absorption, distribution, metabolism, and excretion of the drug. Pharmacodynamics describes the interaction of the drug with the target receptor and the subsequent effect on an organ, tissue, or system. Understanding the pharmacokinetic and pharmacodynamic properties of each anesthetic agent is essential to predict the patient’s response.

Pharmacokinetics

When a drug is administered to a patient to produce a systemic effect, the drug undergoes four pharmacokinetic processes: absorption, distribution, metabolism, and excretion.

Absorption is the process of movement of the drug from the site of administration into the bloodstream. Although many routes of administration are available, common routes utilized in office-based anesthesia include intravenous, oral, intramuscular, intraosseous, transmucosal, transcutaneous, inhaled, and intranasal. If the drug is administered intravenously (directly into the bloodstream), the process of absorption and its potential variability is avoided. Drugs administered by other routes of administration must be absorbed from the site of administration into the bloodstream. Most drug absorption occurs by passive diffusion based on Fick’s law of diffusion:

where K is the partition coefficient; A, the surface area (diffusional area); D, the diffusion coefficient; C1, the extracellular concentration; C2, the intracellular concentration; and h, the thickness of the membrane (diffusional distance).

Lipophilic drugs in their un-ionized form generally have higher partition and diffusion coefficients, which favors absorption. Blood flow away from the absorption site maintains the concentration gradient and promotes drug absorption. Thinner, well-perfused membranes (eg, vascular mucosa) favor absorption. Additionally, the greater the surface area to which the drug is administered or exposed, the more absorption will occur. The bioavailability of a drug, or the fraction of the dose administered that reaches systemic circulation, can vary among the nonintravenous routes of administration. For example, when a drug is administered orally, only a fraction of the initial dose may survive the acid and digestive enzymes of the stomach and/or the first-pass metabolism across the gastric mucosa and the portal circulation from the duodenum through the liver. Consequently, only a portion of the initial dose administered may reach the central nervous system to elicit an effect. An advantage of oral dosing, however, is the ease of administration compared with more invasive routes, such as intramuscular, intraosseous, and intravenous.

Intramuscular administration and intraosseous administration are efficient because exposure of a drug to well-perfused muscle and bone tissue results in rapid absorption into the venous circulation. These routes also avoid initial metabolism of the drug in the digestive system, so smaller doses are often required to achieve the same effect than would be required with oral administration.

Bronchial inhaled administration is rapid. When drug is inhaled, it is absorbed into the pulmonary venous circulation and then transported to the left heart and subsequently to the systemic circulation, including the central nervous system. Three main factors affect absorption of gases into the blood: relative solubility of the drug in blood and gas, cardiac output, and the gradient of alveolar partial pressure to venous partial pressure.

Solubility of the anesthetic agent is determined by the blood/gas partition coefficient. This coefficient indicates the relative capacity of blood and gas to hold the drug. For example, isoflurane has a blood/gas coefficient of 1.4, which means that, at equilibrium, blood holds 1.4 times the amount of isoflurane that gas does. Desflurane has a blood/gas coefficient of 0.45, which means that, at equilibrium, more of the drug stays in the alveoli in the gas phase than enters the blood.

Cardiac output, defined as the product of heart rate and stroke volume, describes the movement of blood through the circulation. Cardiac output is required to push blood through the pulmonary circulation to maintain the gradient of partial pressure required for absorption. The more blood that passes through the pulmonary circulation, the more drug can be absorbed and carried back to the heart. If stasis of blood occurs in the pulmonary circulation, the blood will become saturated and unable to absorb any more of the drug.

The gradient of alveolar and venous partial pressures of the drug also affects absorption. This gradient is driven by delivery and unloading of the drug in brain, muscle, fat, and other tissues, creating a pressure difference. Tissue uptake of the anesthetic agent is essential in creating this gradient.

Distribution describes the movement of a drug to and from the bloodstream and extravascular sites. For most drugs, the site of action is outside the bloodstream. For the drug to reach the site of action and elicit a pharmacologic response, it must distribute from the bloodstream through the capillary and other phospholipid bilayer membranes to the target tissue or organ. Factors that influence distribution and extravascular migration of the drug include the size of the drug molecule, the degree of protein binding, the lipophilicity of the drug, and the pKa of the drug.

Drug molecules with small molecular weight generally diffuse passively across most biologic membranes. Because general anesthetics, sedatives, and opioid analgesics elicit their pharmacologic effect in the central nervous system, they must penetrate the tight junctions of the highly lipophilic blood-brain barrier. Small drug molecules that can squeeze between the tight junctions of blood vessels and the blood-brain barrier diffuse more readily into the central nervous system than larger drug molecules do.

The binding of drugs to plasma proteins, such as albumin or α1-acid glycoprotein, limits drug distribution because of the size of the protein-drug complex. In the case of drugs with lower protein binding, or as the protein binding of a drug decreases because of lower protein concentrations or displacement by other protein-bound drugs, a higher concentration of free drug is available to distribute extravascularly to peripheral sites. Because the concentration of plasma proteins influences distribution, many elderly patients who have decreased serum protein concentrations can have increased free drug concentrations; therefore, for a drug to achieve the same effect in these patients as it would have in younger adult patients, a markedly lower dose may be required.

Lipophilicity, described by the octanol/water partition coefficient, promotes the movement of a drug across membranes, particularly lipophilic barriers, such as the blood-brain barrier. Lipophilic drugs have a high affinity for fatty tissue, into which they distribute more slowly than they do into highly perfused organs and tissues. This high affinity for and slower distribution into fat creates a drug reservoir that results in redistribution of the drug into and out of the blood and central nervous system over time, which can prolong the drug’s action.

As determined by the Henderson-Hasselbalch equation, drugs in the un-ionized form favor movement across membranes. Because many general anesthetic agents are basic, a pKa below or approaching 7.4 means that more of the drug will be un-ionized at physiologic pH. For the barbiturate anesthetics and propofol, which are acidic, a pKa above or approaching 7.4 means that more of the drug will be un-ionized at physiologic pH.

Pharmacokinetic models view the body as compartments in relationship to the bloodstream. The bloodstream and the organs and tissues that are immediately perfused are considered the central compartment. The tissues and organs into which drugs distribute more slowly are considered peripheral compartments (Fig 1-1). In the two-compartment model, the distribution of drug to and from the blood and perfused tissues and organs results in a rapid decline in concentration in the bloodstream in the distribution phase, followed by a slower decline in drug concentration in the bloodstream caused by metabolism and excretion of the drug (the elimination phase). In the two-compartment model, the half-life of the drug in the distribution phase, α, is always much shorter than the half-life in the elimination phase, β, and is generally more predictive of the duration of the drug’s effects in the perfused organs, such as the central nervous system. For drugs that subsequently distribute into less well-perfused tissues or organs, such as muscle or fat, the deeper peripheral compartment may be considered a third compartment. Distribution of the drug into and out of this deeper peripheral compartment frequently creates a drug reservoir that can result in prolonged redistribution and effect of the drug. The extent of distribution of the drug from the bloodstream to extravascular sites is described by the apparent volume of distribution, Vd. Therefore, lipophilic drugs with a higher Vd are more extensively distributed outside the bloodstream than hydrophilic drugs with a smaller Vd are. Because Vd is directly related to half-life, drugs with a larger Vd have a longer half-life, described in the equation t½ = 0.693Vd / Cl.

Fig 1-1 Diagram depicting the pharmacokinetic journey of drugs from their site of administration to their ultimate clearance from the body.

Metabolism describes the conversion of active drug to inactive metabolites that can be excreted from the body. Although some drugs are metabolized outside the liver, drug clearance is generally accomplished primarily by means of biotransformation or metabolism in the liver and excretion by the kidneys and to a lesser degree in bile. The primary purpose of hepatic biotransformation is to produce polar metabolites that can be excreted by the kidneys. Because general anesthetic agents, sedatives, and opioid analgesics are lipophilic molecules, they must be metabolized by the liver and undergo biotransformation into water-soluble metabolites that can be excreted by the kidneys or in bile. Hepatic metabolic processes are classified as phase I or phase II. Phase I consists of oxidative/reductive metabolic processes that generally produce polar metabolites that are excreted by the kidneys. Cytochrome P450 enzymes, the largest group of phase I enzymes, are susceptible to induction and inhibition drug interactions, and their function decreases with aging. Phase II consists of conjugative metabolic processes that are generally employed when phase I metabolism does not produce sufficiently polar metabolites. Of the phase II processes, glucuronidation is of greatest relevance to the metabolism of general anesthetic agents, sedatives, and opioid analgesics because glucuronide metabolites often undergo biliary excretion and subsequently are enterohepatically recirculated from the gastrointestinal tract into the bloodstream. Enterohepatic recirculation of glucuronide metabolites occurs when gastrointestinal flora cleave the glucuronide conjugate from the drug or drug metabolite molecule and the active drug or drug metabolite is reabsorbed from the gastrointestinal tract through the hepatic portal vein into systemic circulation. The processes of enterohepatic recirculation of glucuronide metabolites and the redistribution of lipophilic drugs into and out of the central nervous system contribute to the variable and prolonged effects of several general anesthetic agents, sedatives, and opioid analgesics.

Renal excretion of polar metabolites of general anesthetic agents, sedatives, and opioid analgesics generally has little impact on their effect in patients. If a renally excreted metabolite has pharmacologic activity, alterations in renal function can result in adverse effects.

Considerations of inhaled anesthetics

For inhaled anesthetics, potency is described in terms of minimum alveolar concentration (MAC). The concentration of an inhaled anesthetic that prevents movement in response to surgical stimulation in 50% of patients is defined as the MAC of that anesthetic agent. MACawake is a fraction of the MAC that indicates the alveolar concentration of anesthetic agent at which suppression of verbal response and memory formation is achieved. Inhaled anesthetic agents behave as gases do, not as liquids do. As they distribute between tissues, or between blood and gas, equilibrium is reached when the partial pressure of anesthetic gas is equal in the two tissues or between the blood and gas. At equilibrium, the concentrations differ because of differences in solubility in those tissues or physiologic environments, resulting in unique blood/gas, brain/blood, and fat/blood partition coefficients. These ratios demonstrate that inhaled anesthetic agents are more soluble in some tissues, such as fat, than in others, such as blood, and that the different agents have a range of solubility within each tissue or physiologic environment (Table 1-1). For inhaled anesthetics that are not very soluble in blood or fat, such as nitrous oxide, equilibrium is achieved quickly. For an agent that is more soluble in fat, such as halothane, equilibrium is achieved more slowly because fat represents a large anesthetic reservoir that is poorly perfused and therefore fills slowly.

Table 1-1 Properties of common inhaled anesthetic agents

An important consideration is the speed of anesthetic induction. Anesthesia occurs when the partial pressure of the anesthetic agent in the brain is equal to or greater than the MAC of that anesthetic. Because the brain is highly perfused, the partial pressure of the anesthetic in the brain becomes equal to the partial pressure in alveolar gas and blood within several minutes. Therefore, anesthesia is achieved shortly after alveolar partial pressure reaches the MAC. For anesthetic agents that are highly soluble in blood and other tissues, the partial pressure will rise more slowly. This limitation on the speed of induction can be overcome by delivering higher inspired partial pressure of the anesthetic agent.

The elimination of an inhaled anesthetic mimics in reverse the process of uptake. For anesthetic agents with low solubility in blood and tissue, recovery is independent of the duration of anesthetic administration and should mirror the speed of induction. For anesthetic agents with high blood and tissue solubility, accumulation in the fat prevents blood and alveolar partial pressures from rapidly declining, and recovery depends on the duration of anesthetic administration. Patients will be arousable when alveolar partial pressures reach MACawake.

Considerations of parenteral anesthetics

Parenteral anesthetics are small lipophilic compounds that quickly partition into the highly perfused and lipophilic tissues of the central nervous system, where they rapidly produce anesthesia. After a single intravenous bolus, anesthetic concentrations in the bloodstream decline rapidly as the anesthetic distributes into the central nervous system. Anesthetic concentrations in the central nervous system then fall rapidly as the anesthetic redistributes from the central nervous system back into the blood, where it either is transported to and metabolized by the liver or diffuses into viscera and muscle and subsequently into poorly perfused adipose tissue. The termination of the anesthetic effect primarily results from redistribution of the anesthetic agent from the central nervous system, not metabolism. Therefore, the duration of the anesthetic effect after a single dose often depends more on the distribution half-life (α) than on the elimination half-life (β) of the anesthetic agent. After administration of multiple doses or prolonged infusion of a parenteral anesthetic agent, its lipophilic properties (resulting in its accumulation in fatty tissue) and elimination half-life (reflecting the metabolic clearance) are more predictive of the duration of effect. The physicochemical and pharmacokinetic properties of common parenterally administered general anesthetic agents are provided in Table 1-2.

Table 1-2 Properties of common parenterally administered general anesthetic agents

NM, not measurable.

Clinical drug efficacy and safety

The efficacy of a drug refers to its ability to elicit a specific physiologic effect. Efficacy is generally expressed in terms of the maximum effect of a drug, compared with the maximum effect of another. For example, if drug A elicits a greater effect than drug B does, despite the dose given, then drug A is said to have greater efficacy.¹ The potency of intravenous anesthetic agents is more difficult to measure and is defined as the amount of a drug required to elicit a certain effect. In comparing two anesthetic agents, if one agent produces the desired effect with 10 mg and the other agent requires 100 mg to produce the same effect, the first agent is more potent. Potency can be easily illustrated in a typical dose-response curve (Fig 1-2).

Fig 1-2 Dose-response curves demonstrating potency of two drugs. Drug A is more potent than drug B because it achieves the desired response at a smaller dose. Although the efficacy (maximum effect) of the two drugs is the same, the leftward shift of the dose-response curve of drug A indicates greater potency.

The safety of drugs is expressed in terms of effective doses and lethal doses. The median effective dose (ED50) is the free plasma concentration at equilibrium that produces a specific response in 50% of patients. In anesthesia, the desired response is lack of response to surgical stimulation. The median lethal dose (LD50) is the dose that results in death in 50% of patients. The therapeutic index of a drug is equal to the ratio LD50:ED50; the greater the ratio, the safer the drug. In other words, the greater the difference between ED50 and LD50, the less likely it is that administration of the drug at effective doses will result in death.

Pharmacodynamics

Pharmacodynamics is defined as the study of the biochemical and physiologic effects of drugs and the mechanism of their actions, including the correlation of their action and effect with their chemical structure. For a substance to produce an effect, it must bind to a receptor within the body. Several types of receptors have naturally occurring ligands, or molecules that bind to them. Drugs may be agonists or antagonists for these receptors, thereby producing effects within the body that influence the potency and efficacy of the drug.

Ligands

A ligand is any molecule that binds to a receptor. Ligands can be endogenous, such as antibodies, hormones, and neurotransmitters, or they can be exogenous, such as the vast spectrum of drugs available for therapeutic use. Drugs can be classified as agonists, which have excitatory or inhibitory effects, or antagonists. Agonistic drugs are designed to elicit effects similar to those of endogenous agonists, whereas antagonists are molecules that prevent an agonist from binding to a receptor, thus blocking its effect. Antagonists can be further characterized as competitive or noncompetitive. A competitive antagonist competes with an agonist and reversibly binds to a receptor. A noncompetitive antagonist irreversibly binds to a receptor and permanently blocks the agonist action until new receptors can be generated. At the neuromuscular junction, acetylcholine mediates muscle contraction by reversibly binding to the postsynaptic nicotinic acetylcholine receptor. Atracurium (a non-depolarizing neuromuscular blocking drug) is an example of a competitive antagonist. Botulinum toxin is an example of a noncompetitive antagonist. Some drugs, classified as inverse agonist or superantagonist, decrease receptor response to less than that which occurs in the absence of the agonist. This scenario can occur because some receptors are in an activated state in the absence of an agonist, creating a baseline effect.²

Receptors

Receptors are present in the cell membrane and intracellularly. Receptors in the cell membrane include membrane receptors, voltage-gated ion channels, and ligand-gated ion channels. These receptors interact with water-soluble ligands that do not readily cross the hydrophobic lipid bilayer.

Guanine nucleotide–binding proteins (G proteins) are membrane-associated, heterotrimeric proteins composed of α, β, and γ subunits.³,⁴ The G protein–coupled receptor (GPCR) superfamily of proteins provide the primary mechanism by which cells detect changes in the external environment and present this information intracellularly.⁵ Binding of an extracellular agonist to a GPCR induces a change in conformation of the receptor. The activated receptor promotes the exchange of bound guanosine diphosphate (GDP) for guanosine triphosphate (GTP) on the G protein α subunit. GTP binding changes the conformation of switch regions within the α subunit, allowing the bound inactive trimeric G protein to be released from the receptor and to dissociate into an active α subunit (GTP-bound) and a β/γ dimer.⁶ The α subunit and the β/γ dimer then activate distinct downstream effectors, such as adenylyl cyclase, phosphodiesterases, phospholipase C, and ion channels. These effectors regulate the intracellular concentrations of secondary messengers, including cyclic adenosine monophosphate (cAMP), diacylglycerol, and sodium and calcium cations.⁷ The result is a physiologic response caused by downstream regulation of gene transcription. Hydrolysis of α subunit–bound GTP to GDP allows the α and β/γ subunits to reassociate and bind to the receptor, terminating the signal.⁶ Stimuli to which GPCRs are known to respond include neurotransmitters, neuropeptides, light, gustatory compounds, odors, hormones, and glycoproteins. Examples of GPCRs include (1) presynaptic α2-adrenergic receptors, which cause inhibition of voltage-dependent calcium channels and decrease the release of norepinephrine,⁸ and (2) opioid receptors, which prevent calcium influx into presynaptic terminals and reduce glutaminergic excitatory transmission.⁹

Voltage-gated ion channels are charged water-filled pores composed of several proteins that span the membrane. Ion pairs between positive and negative charges help stabilize these channels. Changes in membrane potential cause a conformational change in the central pore, with rearrangement of ion pairs that results in increased permeability of the ion specific to that channel. Examples of voltage-gated channels include (1) voltage-gated sodium channels, which are responsible for depolarization and for creation and propagation of action potential; (2) voltage-gated potassium channels, which are responsible for repolarization; (3) voltage-gated calcium channels, which link muscle excitation with contraction and neuronal excitation with release of neurotransmitters; (4) hyperpolarization-activated cyclic nucleotide-gated channels, which are permeable to potassium and sodium and function as pacemaking channels in the heart; and (5) voltage-gated proton channels, which open with depolarization and are strongly pH sensitive, allowing protons to leave the cell.¹⁰

A ligand-gated ion channel is a combination of a receptor protein and an ion channel. Binding of certain molecules to this ionotropic receptor directly alters the membrane potential by causing a conformational change in the channel protein. This change results in the opening of the channel and flux of ions across the cell membrane. Examples of ligand-gated ion channels include (1) anion-permeable γ-aminobutyric acid (GABAA) receptor, which causes intracellular flux of chloride ions, resulting in hyperpolarization of the membrane potential; (2) anion-permeable glycine receptor (GlyR), the activity of which is similar to that of GABAA receptor; (3) cation-permeable nicotinic acetylcholine receptor, which causes sodium and potassium influx, resulting in depolarization; (4) cation-permeable ionotropic glutamate-gated receptors, which cause sodium, potassium, and calcium flux, resulting in depolarization; and (5) two-pore-domain potassium channels, which cause potassium influx, resulting in hyperpolarization at the presynaptic and postsynaptic levels.¹⁰

Central Nervous System Regulation

General anesthetics work by causing a decrease in central nervous system activity, reportedly as a result of stimulation of inhibitory neurotransmitters and inhibition of excitatory neurotransmitters. This section gives a pertinent overview of this complex topic and presents the major modulators of the central nervous system, including inhibitory neurotransmitters, excitatory neurotransmitters, and intracellular signaling.

Inhibitory neurotransmitters

γ-aminobutyric acid receptor

GABA receptor is an inhibitory receptor found within the central nervous system. The most abundant inhibitory neurotransmitter receptor in the brain, it is found in high concentrations in the thalamus and cerebral cortex. It is a heteromeric transmembrane protein.¹¹ The subtype that has been widely studied is the GABAA receptor. The receptor is composed of five subunits. Stimulation of the GABAA receptor allows for the flux of chloride ion through the ionophore, causing hyperpolarization and a decrease in excitatory neurotransmission.¹¹ Binding sites for benzodiazepines, barbiturates, and neurosteroids have been identified.¹²,¹³ Volatile anesthetics and ethanol appear to bind at the neurosteroid site.

Transient inhibitory postsynaptic currents (IPSCs) are generated by the stimulation of GABAergic receptors located in high concentration at the postsynaptic terminals of excitatory neurons. GABAergic drugs, including general anesthetics, sedatives, and anxiolytics, enhance the blockade of fast excitatory impulses by the generation of IPSCs.¹⁴ GABAergic drugs also have other mechanisms of action, including potentiation of GABA, direct stimulation of the GABA receptor, and desensitization of non-postsynaptic receptors for GABA. GABAergic drugs potentiate the binding of GABA to the GABA receptor by means of allosteric modulation of the GABA receptor that can increase the receptor’s affinity for GABA.¹⁵ Desensitization allows for prolonged binding.

Glycine

Glycine is an inhibitory neurotransmitter. Its receptor, GlyR, has five known subunits and is highly expressed in the spinal cord and brainstem. Alanine, taurine, serine, and proline can bind to this receptor and cause inhibition but are less potent. GlyR is blocked by the plant alkaloid strychnine, which in high concentrations can cause muscular contractions and tetany. Glycine has properties similar to GABA, and binding of glycine to GlyR leads to an increase in the conductance of chlorine through glycine-gated channels, causing hyperpolarization of the neuronal membrane, which results in antagonism of other depolarization stimuli.¹⁶ The volatile anesthetics and ethanol have effects at this receptor.¹⁷ Of note, glycine has also been identified in the forebrain, where it has been shown to function as a co-agonist at the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor.¹⁸,¹⁹

Epinephrine/norepinephrine

The presynaptic α2-adrenergic receptor is present throughout the central nervous system. Three subtypes of the α2 receptor have been identified. The α2A receptor has been identified in high concentration in the locus ceruleus and brain stem.²⁰ α2-adrenergic receptor agonist causes activation of potassium channels, allowing for efflux of potassium and inhibition of calcium entry into the calcium channels of neuronal cells and resulting in hyperpolarization of the neuronal membrane and decreased activity.²¹ Stimulation of the presynaptic α2A receptor demonstrates sedative-hypnotic and analgesic effects. Dexmedetomidine is a highly selective and potent α2 agonist. The primary site of action of α2-adrenergic receptor agonist is the locus ceruleus, not the cerebral cortex. The unusual subcortical form of dexmedetomidine-induced sedation is characterized by an easy and quick arousal, resembling awakening from natural sleep.²²

Potassium

Two-pore-domain potassium channels, also known as potassium leak channels, are transmembrane potassium-selective ionic pores that are constitutively open at rest and are central to neural function.²³ They are voltage-independent and are thought to provide background modulation of neuronal excitability.²⁴ The TASK and TREK potassium leak channels serve to influence both resting membrane potential and the repolarization phase of the action potential. Human TREK-1 is highly expressed in the brain, where it is particularly abundant in GABA-containing interneurons of the caudate nucleus and putamen. TREK-1 is also expressed in the prefrontal cortex, hippocampus, hypothalamus, midbrain serotonergic neurons of the dorsal raphe nucleus, and sensory neurons of the dorsal root ganglia. Activation of these TREK-1 channels by volatile anesthetics hyperpolarizes the membrane and suppresses the generation of action potential.²⁵

Opioid neuropeptides

The identified opioid receptors and their endogenous opioid peptides have been well characterized. Actions of exogenous agonists at these receptors include analgesia, depression of respiratory function, decreased gastrointestinal motility, and sedation. Ketamine has been shown to interact with μ receptors and contribute to analgesia and respiratory depression. The analgesic effects of nitrous oxide are attributable in part to the release of endogenous opioid peptides in the periaqueductal gray (Table 1-3).

Table 1-3 Receptor-drug interactions

Excitatory neurotransmitters

Glutamate

Glutamate and aspartate are the main excitatory neurotransmitters in the central nervous system. The three classes of glutamate receptors are NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainic acid.²⁶ Stimulation of the NMDA receptor plays an extensive role in the memory and learning areas of the hippocampus. These NMDA receptors are found in large concentrations in central respiratory control centers. Activation of the NMDA receptor requires binding of glutamate or aspartate for activation. For efficient opening of ion channels, the NMDA receptor requires the binding of glycine or D-serine as a co-agonist.²⁷,²⁸ The organization of the glutamate receptor subtypes suggests that they have both ionotropic and metabotropic receptor families.²⁹ All glutamate receptors are highly permeable to sodium and potassium, and the NMDA receptor is also highly permeable to calcium.³⁰ Binding of glutamate to the glutamate receptor will increase the probability of channel opening and enhance neurotransmission by increasing conductance of sodium and in some cases calcium. Stimulation of these receptors causes fast excitatory postsynaptic currents. NMDA receptor antagonists, such as ketamine and nitrous oxide, block this excitation.³¹ Metabotropic glutamate receptors provide another level of response through their links with the phosphoinositide and cyclic nucleotide (cAMP) second messenger systems.³² Metabotropic glutamate receptors are coupled to signal transduction pathways via G proteins, producing alterations in intracellular second messengers and generating slower synaptic responses.

Acetylcholine

Nicotinic and muscarinic acetylcholine receptors (AChRs) are found throughout the body.³³ Nicotinic AChRs are formed by the association of five subunits, each contributing to the pore lining. AChRs can be divided into two main families: muscular and neuronal.³³ Stimulation of the nicotinic and muscarinic AChRs is complex and can be inhibitory or excitatory.³⁴–³⁶ The AChR is a nonspecific cation channel and is activated in conscious awareness and rapid eye movement sleep. Cholinergic defects of the central nervous system are associated with disturbances in conscious awareness, hallucinations, and some degenerative brain diseases.³⁷ AChRs are inhibited by volatile and intravenous anesthetics.³⁶ Ketamine is a strong inhibitor of nicotinic AChR. Physostigmine, a cholinesterase inhibitor, raises the concentration of acetylcholine within the acetylcholine synaptic cleft and is used to treat delirium after general anesthesia.

Intracellular signaling

Multiple anesthetics have been shown to affect G protein activation. Halothane, isoflurane, enflurane, and sevoflurane all inhibit GTP–GDP exchange and enhance dissociation of one of the nonhydrolyzable GTP analogs. GPCR agonists, such as μ opioid and α2-adrenergic receptors, can affect anesthetic sensitivity, reducing MAC.

Conclusion

Knowledge of basic pharmacologic principles gives the clinician an understanding of the characteristics of anesthetic agents that make them suitable for use in clinical practice. A deeper appreciation can be achieved through an understanding of the neurotransmitters and receptors in the central nervous system and how anesthetic agents interact with these receptors. The overview of clinically relevant basic principles of anesthesia in this chapter provides the clinician with a foundation for the topics presented in later chapters of this book.

References

1. Griffin CE III, Kaye AM, Bueno FR, Kaye AD. Benzodiazepine pharmacology and central nervous system-mediated effects. Ochsner J 2013;13:214–223.

2. Milano CA, Allen LF, Rockman HA, et al. Enhanced myocardial function in transgenic mice overexpressing the beta 2-adrenergic receptor. Science 1994;264(5158):582–586.

3. Preininger AM, Hamm HE. G protein signaling: Insights from new structures. Sci STKE 2004;2004(218):re3.

4. Hurowitz EH, Melnyk JM, Chen YJ, Kouros-Mehr H, Simon MI, Shizuya H. Genomic characterization of the human heterotrimeric G protein alpha, beta, and gamma subunit genes. DNA Res 2000;7:111–120.

5. Gether U. Uncovering molecular mechanisms involved in activation of G protein-coupled receptors. Endocr Rev 2000;21:90–113.

6. Svoboda P, Teisinger J, Novotný J, et al. Biochemistry of transmembrane signaling mediated by trimeric G proteins. Physiol Res 2004;53(suppl 1):S141–S152.

7. Landry Y, Gies JP. Heterotrimeric G proteins control diverse pathways of transmembrane signaling, a base for drug discovery. Mini Rev Med Chem 2002;2:361–372.

8. Qin K, Sethi PR, Lambert NA. Abundance and stability of complexes containing inactive G protein-coupled receptors and G proteins. FASEB J 2008;22:2920–2927.

9. Standifer KM, Pasternak GW. G proteins and opioid receptor-mediated signalling. Cell Signal 1997;9:237–248.

10. Camerino DC, Tricarico D, Desaphy JF. Ion channel pharmacology. Neurotherapeutics 2007;4:184–198.

11. Garcia PS, Kolesky SE, Jenkins A. General anesthetic actions on GABA(A) receptors. Curr Neuropharmacol 2010;8:2–9.

12. Study RE, Barker JL. Diazepam and (--)-pentobarbital: Fluctuation analysis reveals different mechanisms for potentiation of gamma-aminobutyric acid responses in cultured central neurons. Proc Natl Acad Sci U S A 1981;78:7180–7184.

13. Skolnick P, Moncada V, Barker JL, Paul SM. Pentobarbital: Dual actions to increase brain benzodiazepine receptor affinity. Science 1981;211(4489):1448–1450.

14. Maconochie DJ, Zempel JM, Steinbach JH. How quickly can GABAA receptors open? Neuron 1994;12:61–71.

15. Olsen RW, Li GD. GABA(A) receptors as molecular targets of general anesthetics: Identification of binding sites provides clues to allosteric modulation. Can J Anaesth 2011;58:206–215.

16. Betz H, Becker CM. The mammalian glycine receptor: Biology and structure of a neuronal chloride channel protein. Neurochem Int 1988;13:137–146.

17. Sonner JM, Antognini JF, Dutton RC, et al. Inhaled anesthetics and immobility: Mechanisms, mysteries, and minimum alveolar anesthetic concentration. Anesth Analg 2003;97:718–740.

18. Furukawa H, Singh SK, Mancusso R, Gouaux E. Subunit arrangement and function in NMDA receptors. Nature 2005;438(7065):185–192.

19. Kleckner NW, Dingledine R. Requirement for glycine in activation of NMDA-receptors expressed in Xenopus oocytes. Science 1988;241(4867):835–837.

20. Chiu TH, Chen MJ, Yang YR, Yang JJ, Tang FI. Action of dexmedetomidine on rat locus coeruleus neurones: Intracellular recording in vitro. Eur J Pharmacol 1995;285:261–268.

21. Khan ZP, Ferguson CN, Jones RM. Alpha-2 and imidazoline receptor agonists: Their pharmacology and therapeutic role. Anaesthesia 1999;54:146–165.

22. Arcangeli A, D’Alò C, Gaspari R. Dexmedetomidine use in general anaesthesia. Curr Drug Targets 2009;10:687–695.

23. Lesage F. Pharmacology of neuronal background potassium channels. Neuropharmacology 2003;44:1–7.

24. Franks NP. General anaesthesia: From molecular targets to neuronal pathways of sleep and arousal. Nat Rev Neurosci 2008;9:370–386.

25. Westphalen RI, Krivitski M, Amarosa A, Guy N, Hemmings HC Jr. Reduced inhibition of cortical glutamate and GABA release by halothane in mice lacking the K + channel, TREK-1. Br J Pharmacol 2007;152:939–945.

26. Dingledine R, Borges K, Bowie D, Traynelis SF. The glutamate receptor ion channels. Pharmacol Rev 1999;51:7–61.

27. Chen PE, Geballe MT, Stansfeld PJ, et al. Structural features of the glutamate binding site in recombinant NR1/NR2A N-methyl-D-aspartate receptors determined by site-directed mutagenesis and molecular modeling. Mol Pharmacol 2005;67:1470–1484.

28. Wolosker H. D-serine regulation of NMDA receptor activity. Sci STKE 2006;2006(356):pe41.

29. Aramori I, Nakanishi S. Signal transduction and pharmacological characteristics of a metabotropic glutamate receptor, mGluR1, in transfected CHO cells. Neuron 1992;8:757–765.

30. Paoletti P, Neyton J. NMDA receptor subunits: Function and pharmacology. Curr Opin Pharmacol 2007;7:39–47.

31. de Sousa SL, Dickinson R, Lieb WR, Franks NP. Contrasting synaptic actions of the inhalational general anesthetics isoflurane and xenon. Anesthesiology 2000;92:1055–1066.

32. Schoepp DD, Conn PJ. Metabotropic glutamate receptors in brain function and pathology. Trends Pharmacol Sci 1993;14:13–20.

33. Vizi ES, Lendvai B. Side effects of nondepolarizing muscle relaxants: Relationship to their antinicotinic and antimuscarinic actions. Pharmacol Ther 1997;73:75–89.

34. Flood P, Ramirez-Latorre J, Role L. Alpha 4 beta 2 neuronal nicotinic acetylcholine receptors in the central nervous system are inhibited by isoflurane and propofol, but alpha 7-type nicotinic acetylcholine receptors are unaffected. Anesthesiology 1997;86:859–865.

35. Radcliffe KA, Dani JA. Nicotinic stimulation produces multiple forms of increased glutamatergic synaptic transmission. J Neurosci 1998;18:7075–7083.

36. Franks NP, Lieb WR. Molecular and cellular mechanisms of general anaesthesia. Nature 1994;367(6464):607–614.

37. Ji D, Lape R, Dani JA. Timing and location of nicotinic activity enhances or depresses hippocampal synaptic plasticity. Neuron 2001; 31:131–141.

Anesthesia administered via an intravenous (IV) route is the mainstay of office-based anesthesia and is a reliable, safe mode of anesthesia care. Myriad drugs are utilized in the office setting, all of which have unique pharmacologic characteristics and profiles. Thorough knowledge of these characteristics and how they influence the utility or contraindication of these drugs is critical in safely and efficiently administering IV anesthesia in patients with comorbid disease. This chapter reviews the classes of drugs used in IV anesthesia and includes the mechanism of action, dosing, time of onset, duration of effect, and pros and cons of commonly used drugs in each class. The reader should keep in mind that these profiles assume a balanced technique including multiple IV agents, unless otherwise specified.

Three receptors in the body, when modulated by agents discussed in this chapter, produce the anesthetic effects of anxiolysis, sedation, hypnosis, amnesia, and analgesia. These receptors are the γ-aminobutyric acid (GABA), N-methyl-D-aspartate (NMDA), and α2-adrenergic receptors. Opioids have no hypnotic or amnestic effects, but they provide analgesia and potentiate the effects of GABA agonists.

Benzodiazepines

GABA is the chief inhibitory neurotransmitter of the central nervous system. Benzodiazepines are GABA agonists and bind to the α and γ subunits of the anion-permeable GABA (GABAA) receptor. This binding enhances the affinity of the GABA receptor to GABA, causing an influx of chloride ion intracellularly, hyperpolarizing the postsynaptic nerve, and inhibiting action potential formation. The GABA α1 subunit accounts for the anticonvulsant, sedative, and amnestic effects, whereas the α2 subunit accounts for the anxiolytic and muscle relaxant effects.¹ Three benzodiazepines are commonly used clinically: midazolam, diazepam, and lorazepam. In office-based anesthesia, midazolam is the chief player because of its kinetic and safety profiles, and diazepam may have clinical relevance. Lorazepam has no utility in office-based anesthesia.

Midazolam

Midazolam (Versed, Roche) is the most widely used benzodiazepine in office-based anesthesia. In a balanced technique, midazolam is dosed at 0.05 to 0.15 mg/kg, titrated to effect. Its time of onset is approximately 30 to 60 seconds, and duration is approximately 20 to 30 minutes, depending on the dose. Amnesia associated with midazolam tends to be more profound than amnesia associated with diazepam, which is a major advantage (Box 2-1).

Diazepam

Diazepam (Valium, Roche) was widely used for IV anesthesia before the emergence of midazolam. Diazepam can be used in a balanced technique with a dose of 5 to 20 mg, which has a slightly slower time of onset than midazolam at 30 to 45 seconds and has a duration of 60 to 120 minutes, depending on the dose (Box 2-2).

Flumazenil

Flumazenil (Romazicon, Roche) is a competitive antagonist of the GABA receptor. Its affinity for the receptor is much higher than that of other benzodiazepines, such as midazolam and diazepam. When it binds the receptor, flumazenil has minimal effect on the nerve and its transmission. Flumazenil has no intrinsic ability to displace an agonist from the receptor, but rather exerts its effect by quickly binding the receptor after an agonist dissociates. It can be used to reverse overdosing of any benzodiazepine. In office-based anesthesia, it is generally given to reverse the effects of benzodiazepine after inadvertent overdosing or to counteract prolonged effects after the procedure is completed. It is given in 0.2 mg IV doses every 2 minutes, up to a 3-mg total dose, until the desired effect is achieved. It has a rapid onset, with clinical manifestations occurring within approximately 1 minute, and a short duration of approximately 30 minutes. Patients should be monitored for at least 30 minutes after dosing to make sure resedation does not occur, particularly with longer-acting benzodiazepines (Box 2-3).

Barbiturates

Barbiturates are agonists for the GABAA receptor, although studies have also shown modulation of the NMDA receptor.¹ Barbiturates bind to the GABA receptor and directly cause chloride ion influx, hyperpolarization of the nerve, and inhibition of transmission. Barbiturates include thiobarbiturates and oxybarbiturates. Methohexital is an oxybarbiturate that was widely used before the introduction of propofol. A dose-dependent drop in blood pressure and an associated reflex tachycardia are often seen with administration of barbiturates. Although these effects are typically tolerated well by healthy individuals, caution should be used in patients with hypovolemia or a compromised ability to compensate for this drop in blood pressure. Apnea can occur with large doses of barbiturate, and dose-dependent respiratory depression is seen with smaller doses. Barbiturates are contraindicated in patients with a diagnosis of acute intermittent porphyria.

Thiopental

Thiopental was the main thiobarbiturate used in anesthesia and was also used in lethal injections, but it is not currently manufactured or available for use. A 3- to 4-mg/kg dose will rapidly induce general anesthesia in 15 to 30 seconds and has a duration of approximately 20 to 30 minutes. It has a weaker hypnotic effect than other agents and can potentiate or trigger status asthmaticus.¹

Methohexital

Methohexital succeeded thiopental as an IV anesthetic induction agent. It has a very rapid onset, 10 to 30 seconds, with a 1- to 1.5-mg/kg induction dose. Its duration is approximately 5 to 7 minutes, making it attractive for use in office-based anesthesia (Box 2-4).

Propofol

Propofol is an alkyl phenol that is currently the most widely used IV anesthetic induction agent. Its mechanism of action is thought to be modulation of the β subunit of the GABAA receptor, causing hyperpolarization of the nerve. Studies also show effects on the α and γ subunits, as well as some effect on the α2-adrenergic and NMDA receptors.¹ An induction dose of 2 mg/kg will produce unconsciousness in 20 to 30 seconds, with a duration of approximately 5 to 10 minutes. When propofol is used in a balanced IV technique, boluses of 20 to 30 mg can be administered incrementally until the desired level of anesthesia is achieved. An infusion of 30 to 100 μg/kg per minute can be used, depending on the other medications used and the age and health of the patient. It is a potent respiratory depressant and will cause apnea with an induction dose. A dose-dependent 10% to 40% drop in blood pressure can be seen, with relatively little change in the heart rate because of the depressive effect on the heart and the baroreflex.¹ It is highly lipid soluble and comes in a formulation with soybean oil, glycerol, and lecithin, a purified egg phospholipid. Propofol has been shown to be safe in most patients with egg allergies because the allergen is usually albumin (yolk), not lecithin (egg white).² Propofol is metabolized in the liver and, to a lesser degree, in the lungs, resulting in largely inactive metabolites that are excreted by the kidneys. Propofol infusion syndrome, characterized by bradycardia, asystole, metabolic acidosis, rhabdomyolysis, hyperlipidemia, and enlarged liver, is extremely rare during short procedures in the office setting¹ (Box 2-5).

Ketamine

Ketamine is a phencyclidine derivative that produces general anesthesia rapidly. Its anesthetic effects are the result of inhibition of the NMDA receptor. Its analgesic effects are thought to be the result of binding of opioid receptors. Unlike many other IV agents used in anesthesia, it is a potent analgesic and causes minimal cardiovascular and respiratory depression (Box 2-6). Overall, its effects are largely sympathomimetic, except for an increase in secretions and salivation. It is said to produce dissociative or cataleptic anesthesia, characterized by unconsciousness, eyes remaining open with nystagmus, and some preservation of protective reflexes, such as cough, swallowing, and corneal reflexes.¹ These effects are the result of disruption of the afferent sensory stimulation of higher cortical centers in the brain. A 2-mg/kg induction dose has an onset of 20 to 30 seconds and duration of 20 to 30 minutes. However, when ketamine is used in a balanced technique, the dose may be decreased to 0.5 mg/kg and given in small boluses, similar to the administration of propofol. Intramuscular dosing generally starts at a dose of 2 to 4 mg/kg with a 5-minute onset and will last approximately 20 minutes, depending on the dose.⁴

Opioids

Opioids are a class of drug characterized by the production of analgesia, but they have many other physiologic effects that must be appreciated by the anesthesia provider. The effects of opioids are modulated by the μ, δ, and κ opioid receptors. The μ receptor will cause analgesia, respiratory depression, gastroparesis, decreased gastrointestinal function, and sedation. μ receptors can be classified as μ1, μ2, and μ3 receptors. The δ receptor produces analgesia. The κ receptor produces analgesia, decreased gastrointestinal motility, and sedation. μ and κ receptors, found in the spinal cord and brain, provide analgesia by blocking afferent nociceptor impulse transmission from the spinal cord to the brain, as well as blocking pain centers in the brain.

Opioids, when administered alone, have little inotropism but can cause bradycardia by directly affecting the sinoatrial node.⁵ Because these effects are relatively weak, increased heart rate resulting from drops in blood pressure because of coadministration of drugs such as midazolam and propofol will trump the negative chronotropic effects of the opioids. Opioids also produce a dose-dependent respiratory depression, mainly caused by the μ receptor. This respiratory depression manifests as decreased ventilatory effort, blunting of ventilatory drive in response to hypercapnia, and blunting of the cough reflex. The latter can be useful in a patient with a hyperactive airway. Large doses of opioids can attenuate or prevent coughing resulting from substantial airway stimulation, such as endotracheal intubation or laryngeal mask airway placement. Opioids are said to be cardioprotective and are widely used in cardiothoracic surgery because of their ability to attenuate the sympathetic response to surgical stimulation and pain.⁵

Decreased gastrointestinal motility and delayed gastric emptying may compromise the nil per os (NPO, no oral intake) status of patients who have taken preanesthetic opioids. Patients who use opioids chronically may have clinically relevant volumes of gastric contents even after 6 hours without oral intake. Postoperative nausea and vomiting (PONV) is a common side effect of opioids because they directly stimulate the chemoreceptor trigger zone, resulting in nausea. Coadministration of ondansetron, promethazine, propofol, dexamethasone, and/or other antiemetic agents can help prevent PONV.

Miosis, or pupillary constriction, can also occur with opioid administration. It is caused by increased parasym-pathetic tone of the oculomotor nerve. Meperidine can attenuate postoperative shivering, although other opioids do not display this property. Pruritus often occurs with opioid administration. Although some opioids, such as morphine, codeine, and meperidine, have been shown to cause histamine release, non–histamine-releasing opioids are associated with pruritus as well. It is not uncommon for patients to scratch their nose on induction of anesthesia after administration of fentanyl. Interestingly, naloxone will alleviate the pruritus caused by opioids.

Relevant opioids in office-based outpatient anesthesia include fentanyl, remifentanil, and meperidine.

Fentanyl

Fentanyl is the most widely used opioid in office-based anesthesia because of its pharmacologic profile and low cost. At a dose of 1 µg/kg, fentanyl has an onset of 20 to 30 seconds and duration of 20 to 30 minutes, which is congruent with the duration of many outpatient oral surgery procedures. Though it has no intrinsic sedative or amnestic properties, it has a synergistic effect with midazolam and other sedatives/hypnotics when used in a balanced technique (Box 2-7).

Remifentanil

The opioid remifentanil is useful in IV anesthesia because of its ultra-short-acting properties. It is usually administered via infusion at a rate of 0.05 to 0.1 µg/kg per minute for deep sedation and at a rate of 0.05 to 2 µg/kg per minute for general anesthesia.⁶ It can be used in small bolus doses of 0.5 to 1 µg/kg, titrated to effect, similar to the administration of fentanyl. Remifentanil has a rapid onset and short duration. Its metabolism by plasma esterases results in recovery within minutes of the termination of dosing or discontinuation of infusion, regardless of the duration of infusion (Box 2-8).

Meperidine

Meperidine was the most widely used opioid before the introduction of fentanyl. A dose of 0.5 to 1 mg/kg, titrated to effect, has an onset of 3 minutes and duration of 30 to 45 minutes. Compared with fentanyl, it has substantial drawbacks. Fentanyl is approximately 1,000 times more potent than meperidine. Meperidine is chemically similar to atropine; therefore, although it is an antisialagogue, it produces tachycardia. Meperidine is associated with histamine release and must be used with caution in asthmatic patients. It has a very potent active metabolite, normeperidine, which is a central nervous system stimulant and can cause seizure activity. Normeperidine can have adverse reactions with monoamine oxidase inhibitors and amphetamines, leading to seizures, agitation, cardiovascular collapse, and serotonin syndrome⁷ (Box 2-9).

Naloxone

Naloxone is an opioid receptor antagonist. Although it acts on all opioid receptor subtypes, it has the greatest affinity for the μ receptor, which is responsible for analgesia and respiratory depression. Indications for its use include prolonged ventilatory depression, nausea, pruritus, and muscle rigidity associated with opioid use. It is given in a 0.4-mg dose and has an onset of 1 to 2 minutes and duration of 30 to 45 minutes. Administration can result in increased heart rate and blood pressure because of the reversal of analgesia and increased pain. Depending on the initial dose of opioid, the duration of action of the opioid may exceed the duration of naloxone. Therefore, patients should be monitored for at least 30 minutes after naloxone administration to ensure that respiratory depression does not recur (Box 2-10).

Etomidate

Etomidate is a GABA receptor agonist. It is dosed at 0.2 to 0.6 mg/kg for general anesthesia and 0.2 to 0.4 mg/kg for deep sedation, with an onset of 15 to 20 seconds and duration of 10 minutes. Because of its ability to induce general anesthesia with minimal cardiovascular and ventilatory changes, it is useful in patients who cannot tolerate the drop in blood pressure that is routinely seen with administration of other general anesthetic agents, such as propofol and methohexital, or the elevation in blood pressure and heart rate that is seen with ketamine. Because etomidate is associated with adrenal insufficiency after even a single dose, its use has declined rapidly. A body of research investigating its use in procedural sedation, particularly in the emergency department, may strengthen the indication for its use in office-based anesthesia. The emergency medicine literature has recently shown positive outcomes of the use of etomidate for procedural sedation in adults and children, with no substantial morbidity or mortality.⁸,⁹ These studies showed a statistically significant drop in adrenal function for up to 12 hours after a single dose of etomidate, although the results of the adrenocorticotropic hormone stimulation test remained within a normal limit.¹⁰ Furthermore, these patients were not observed to have significant intraoperative or postoperative hypotension.⁹ A separate study investigating the postoperative effect of a single dose of etomidate in cardiothoracic surgery showed no evidence associating etomidate exposure with significant hypotension, prolonged mechanical ventilation, longer hospital stay, or mortality.¹¹ Although etomidate could be better than other anesthetic agents for sedation of patients with substantial congestive heart failure or compromised cardiac reserve, such patients are poor candidates for in-office anesthesia and may be more safely treated in a surgical center or hospital operating room (Box 2-11).