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Home , Anesthesiology, Anesthetic, Cyclopropane, Etomidate, General anaesthesia, Levobupivacaine

Chapter 16

Anesthetic Agents: General and Local T IMOTHY J. MAHER

Drugs Covered in This Chapter Inhaled general anesthetics • • • Ether • • • • Thiopental • • Local anesthetics • • • • • • • • • • • • • Intravenous general anesthetics • Dibucaine • • • • Abbreviations BTX, GABA, g-aminobutyric acid NO, CNS, central HBr, hydrobromic acid NMDA, N-methyl-D-aspartate

COCl2, phosgene HCl, hydrochloric acid PABA, p-aminobenzoic acid EEG, electroencephalograph MAC, minimum alveolar concentration PCP, EMLA, Eutectic Mixture of a Local Na/K-ATPase, -potassium STX, adenosine triphosphatase TTX,

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SCENARIO Paul Arpino, R.Ph. CDL is a 70-year-old obese man scheduled for carpal tunnel sur- During the preoperative assessment before the scheduled day of gery. A review of his medical file indicates a history of obstruc- , the team discovers that CDL has an undefined tive and benign prostatic hypertrophy (BPH). CDL to procaine (Novocain) and that he experienced severe blistering sleeps with a continuous positive pressure airway device and his after a dental procedure many years ago and was told he cannot BPH is treated with tamsulosin, 0.4 mg daily. Given that patients receive “ like Novocain again.” with sleep apnea are at high risk for respiratory depression, the clinical team decides that a peripheral would be a (The reader is directed to the clinical solution and chemical analy- better alternative to both neuraxial and general . sis of this case at the end of the chapter).

INTRODUCTION nitrous oxide at a public demonstration of “laughing .” One of the volunteers, a clerk named Anesthesia, defi ned as a loss of sensation with or with- Samuel Cooley, injured his leg while under the infl uence out loss of , can be effectively achieved with of this gas and appeared to experience no . The next a wide range of drugs with very diverse chemical struc- day, Wells inhaled the gas himself and, with the aid of a tures. The list of such compounds includes not only the colleague, had one of his own teeth extracted without classic anesthetic agents, such as the general and local any sensation of pain. Wells then began routinely using anesthetics, but also many (CNS) nitrous oxide for dental procedures in his own practice. , such as , / (bar- In 1845, he attempted to demonstrate the anesthetic biturates and ), , and effects of nitrous oxide at the Massachusetts General relaxants. Although various mechanisms in Boston. This demonstration was considered of action are attributed to these agents, ultimately they all to be a failure, however, because the patient cried out produce their anesthetic actions by interfering with con- in the middle of the procedure. Following this unfortu- duction in sensory and sometimes also motor nate incident, the use of nitrous oxide was minimal until neurons. Many of these agents are routinely used today it resurfaced in dental practice during the mid-1860s, in clinical practice to facilitate surgical and medical pro- when it was combined with and made available cedures. This chapter will focus on those agents typically in steel cylinders. This gas is still commonly used today, classifi ed as “general” and “local” anesthetics. especially in combination with other anesthetic and anal- gesic agents. GENERAL ANESTHETICS The general anesthetic that gained greatest popularity shortly after the failed demonstration of Wells was diethyl Prior to the mid-1800s, pain-producing surgical and ether. William Morton, a Boston , was familiar at dental procedures typically were undertaken without the time with the use of nitrous oxide by Wells. He also the aid of effective anesthetic agents. Chemical methods had heard of the interesting effects of and available at the time included intoxication with ethanol, began to experiment on animals and himself with this hashish (), or , whereas physical meth- volatile liquid. In 1846, he was allowed an opportunity ods included packing a limb in ice, creating ischemic to demonstrate the anesthetic actions of diethyl ether at, conditions with tourniquets, inducing again, the Massachusetts General Hospital. In the famed by a blow to the head, or the most common technique, “Ether Dome,” which still stands today, Morton admin- employing strong-armed assistants to hold down the help- istered diethyl ether with a specially designed delivery less patient during the entire painful surgical procedure. device to the nervous patient, and the surgical proce- Additionally, at this time, many practicing had dure was performed without apparent pain. Following been erroneously taught that pain was a requirement for this demonstration, word of its success spread quickly, effective healing; therefore, the observation of a patient and soon, dental and medical practices throughout the in terrible pain was viewed as part of the normal healing United States and Europe were employing diethyl ether process. These factors, along with the lack of knowledge as a general anesthetic agent. Today, diethyl ether is no regarding aseptic techniques or the availability of suit- longer used in procedures because of its toxicity and able -fi ghting agents, made surgical procedures dangerous physical properties (e.g., it is fl ammable and a last resort approach to treating . explosive!). There have been many accounts of the fi rst dem- Other general anesthetic agents that enjoyed early pop- onstration by the Hartford dentist Horace Wells of the ularity were and . Chloroform use of nitrous oxide as a general anesthetic for surgery vapor depresses the CNS of a patient, allowing a doctor in 1844. Wells fi rst observed the anesthetic actions of to perform various otherwise painful surgical procedures.

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CLINICAL SIGNIFICANCE

Anesthetics are a structurally of new agents is aimed at reducing adverse reactions, main- diverse class of that taining optimal physiologic conditions during procedures, and enable clinicians to perform sur- minimizing postoperative complications related to the proce- gery and other noxious procedures. dure itself. The study of medicinal chemistry gives us hope Understanding the essential components of for future treatment options, and knowledge of structure- the anesthetic state (i.e., immobilization, analgesia, and ) activity relationships fosters the development of new medi- as well as the medicinal chemistry of the various anesthetic agents cations and administration techniques. New generations of allows the clinician to optimize to meet patient specific drugs are being created by modifying the structures of exist- needs. The patient undergoing a minimally invasive ambulatory ing compounds to improve the side effect and pharmacoki- surgical procedure may only require a with adjunc- netic profiles. Clinicians will have to stay up to date with new tive pain control. Alternatively, patients undergoing a major surgi- developments in anesthesia practices, the molecular actions of cal procedure may require general anesthesia with several different anesthetics, and the pharmacokinetic properties of the drugs classes of anesthetics as well as several adjunctive medications to to provide the best therapeutic outcomes for patients. counteract deleterious emergence reactions related to the anesthet- ics. In both cases, a thorough understanding of the basic chemical Paul Arpino, RPh properties of the drugs and their respective mechanisms of action Harvard will prove invaluable to making appropriate clinical decisions. Department of Pharmacy The practice of anesthesia is typically not considered to be Massachusetts General Hospital therapeutic; therefore, the practice as well as the development Boston, MA

In 1847, the Scottish obstetrician and Gillespie subsequently further subdivided these fi rst used chloroform for general anesthesia during child- stages (Fig. 16.1), as described in the following sections. birth. The use of chloroform during surgery expanded rapidly thereafter in Europe. In the United States, chlo- Stage 1: Analgesia roform replaced diethyl ether as an anesthetic at the Characterized by a mild depression of higher cortical beginning of the 20th century; however, it was quickly aban- neurons, this stage is suitable for minor surgical pro- doned due to its cardio and CNS toxicity. Cyclopropane cedures that do not require signifi cant neuromuscular is a with anesthetic properties like diethyl relaxation. Depression of thalamic centers probably ether, except it is also explosive and is no longer used. As accounts for the observed analgesia, because many of the described later in this chapter, the inhalational general neuronal systems that mediate pain sensation traverse anesthetic agents used today are typically through this anatomic area. Some general anesthetic and halogenated ethers (Cl, Br, or F); nitrous oxide is the agents do not possess signifi cant activity, but exception. Table 16.1 lists the characteristics of the “ideal” they all produce a loss of consciousness that, in turn, can general anesthetic agent. Unfortunately, the agent that produce some degree of insensitivity to painful stimuli. fulfi lls all these characteristics is currently unknown. TABLE 16.1 Characteristics of the Ideal General Anesthetic Agent Stages of General Anesthesia The ideal general anesthetic state is characterized by a Rapid and pleasant induction of surgical anesthesia loss of all sensations and includes analgesia and muscle Rapid and pleasant withdrawal from surgical anesthesia relaxation. Neuronal depression in specifi c areas of the CNS is believed to be largely responsible for such an Adequate relaxation of skeletal muscles anesthetic state. The areas involved include many corti- Potent enough to permit adequate oxygen supply in mixture cal regions that are represented by excitatory pyramidal cells and inhibitory/excitatory stellate cells. Excitation Wide margin of safety of the pyramidal cells helps to maintain consciousness, Nontoxic whereas the degree of inhibition or excitation of stellate cells determines the overall activity level of the pyrami- Absence of adverse effects dal cells with which they synapse. As the concentration Nonflammable/nonexplosive of the anesthetic agent increases in the brain, the degree Chemically compatible with anesthetic devices of overall neuronal depression also increases, resulting in progressively deeper stages of anesthesia. Based on Nonreactive observations using diethyl ether, Guedel in 1920 origi- Inexpensive nally described this progression as four distinct stages,

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to prevent apnea, pressure to prevent Awake Stage 1:Analgesia Awake , and rate to prevent (a state of *Analgesia (depends on ) no cardiac electrical activity). *Amnesia * Modern General Anesthetic Agents Although these stages have been described for diethyl ether, an anesthetic agent no longer used today. Some of Stage 2: today’s clinically useful general anesthetic agents fail to follow this described pattern of anesthetic progression. *Excitement *Delirium Some attempts have been made to correlate changes *Combative behavior in the electroencephalograph (EEG) with the depth of anesthesia. Most of these studies, however, have failed

Deepening anesthesia to yield a reliable predictor for anesthesiologists to use.

Recoveryt from anesthesia Recoveryt Additionally, concomitant drugs used as preanesthetic Stage 3:Surgical Anesthesia agents can alter the EEG while not altering the depth *Unconsciousness of anesthesia. Rather than describing specifi c stages or *Regular respiration using EEG patterns, a number of useful signs that more *Decreasing eye movement accurately refl ect the depth of anesthesia for most of the anesthetic agents are currently used. When during the initial period of anesthetic administration a patient has Commence Surgery irregular respiratory depth and rate, is still swallowing, Surgery Completed Stage 4:Respiratory and blinks the eyes when the eyelashes are touched, the desired surgical stage of anesthesia likely has not been *Medullary depression reached. However, when a loss of the eyelash refl ex * *Cardiac depression and arrest occurs along with rhythmic , however, a level *No eye movement of adequate surgical anesthesia has generally begun. If a patient at this stage exhibits elevations in , FIGURE 16.1 Stages of general anesthesia. increased respiration rate, or increased jaw tension when a surgical incision is attempted, the subject is considered to be “light” and typically requires additional anesthe- Stage 2: Delirium sia to facilitate further surgical manipulations. These responses decrease further—until they are abolished— As depression of inhibitory neurons in the CNS pro- as the depth of anesthesia progresses. By gresses, especially in the (a network of refl exes, blood pressure, and respiration rate and depth, neurons in the ), a resultant excitation of corti- today’s anesthesiologist is capable of effectively maintain- cal motor neurons leads to signifi cant involuntary muscle ing an appropriate depth of surgical anesthesia without activity, such as urination, delirium, uncontrolled skeletal producing unwanted medullary depression. muscular movements, and increased , blood pressure, and respiration. These paradoxical responses are caused by suppression of inhibitory neurons that normally Pharmacokinetic Principles of Volatile Anesthetics function to closely regulate such neuronal activity. Ideally, The production and maintenance of the anesthetic state an anesthetic agent should produce little or no excitatory is believed by most to be dependent on the concentra- phase. Together, stages 1 and 2 comprise the induction tion, or partial pressure, of the anesthetic agent in yet period, which ideally should be of short duration. unknown areas of the brain. Obviously, the concentra- tion of the anesthetic agent in the gas mixture admin- Stage 3: Surgical Anesthesia istered, as well as the rate and depth of respiration of This stage is divided into four planes characterized by the patient, will infl uence the rate of anesthesia induc- increasing CNS depression: fi rst, loss of spinal refl exes; tion. The rate at which delivery of anesthetic agents to second, decreased skeletal muscle refl exes; third, paraly- these sites occurs is dependent on their physicochemical sis of ; and fourth, loss of most muscle properties, particularly their solubility in lipid and blood tone. Stage 3 is also characterized by regular breathing, (Fig. 16.2). a loss of many refl exes, and roving eyeball movements. Administration of Volatile Anesthetics Stage 4: Respiratory Paralysis The administration of gaseous or volatile liquid anesthet- Characterized by respiratory and vasomotor paralysis, this ics involves a number of sophisticated devices that have stage represents an overdose or toxic level that should be been refi ned over the years to aid the anesthesiologist avoided. Normally, this stage is never reached, because in carefully controlling the amount of anesthetic deliv- the anesthesiologist is careful to monitor abdominal ered to the patient while minimizing the exposure of the

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FIGURE 16.2 Dynamic equilibria existing during the state of anesthesia.

surgical personnel to these agents. Early systems used a more soluble in the blood (have a low blood/gas parti- gauze pad in a mask placed over the nose and mouth tion coeffi cient, Fig. 16.2) will require a longer time to of the patient. The anesthesiologist would then put achieve saturation of the blood–brain compartment. In drops of the volatile anesthetic on the gauze pad, and such cases, the time for induction will be prolonged. On as the patient breathed, the anesthetic was delivered to the other hand, an anesthetic that is poorly soluble in the lungs. This procedure was somewhat effective, but it blood (has a high blood/gas partition coeffi cient, Fig. allowed little or no control over the amount of anesthetic 16.2) will quickly saturate the blood compartment and and oxygen delivered to the patient. Thus, the anesthetic then rapidly enter the tissues to produce a short induc- agent not inhaled was allowed to evaporate into the sur- tion period. Similarly, agents with high blood/gas parti- rounding area in the surgical suite and posed a signifi cant tion coeffi cients will require a longer time for recovery risk to the surgical personnel. Today, fl owmeters, vapor- from anesthesia. The solubility of an agent in the blood is izers, and absorber devices are routinely available, allow- usually expressed as the blood/gas partition coeffi cient, ing precise determination and control of the amount of which is the ratio of the concentration of anesthetic in volatile anesthetic, oxygen, and adminis- blood to that in the gas phase at equilibrium (Table 16.2). tered while preventing signifi cant exposure to workers. These values correspond well with the oil/gas partition Typically, oxygen is bubbled through a volatile anesthetic coeffi cient, which is easier to determine experimentally. liquid, and the resultant gas mixture is delivered to the The blood/gas partition coeffi cient can be very high patient for continual . Many of these devices (e.g., 12) for soluble agents, such as methoxyfl urane, and are described in greater detail elsewhere (1). extremely low (e.g., 0.47) for poorly soluble agents, such The inhaled anesthetic concentration is controlled by as nitrous oxide. the anesthesiologist, who can either increase or decrease The solubility of the anesthetic in tissue is expressed this concentration depending on the observed depth of as the tissue/blood partition coeffi cient. Because the anesthesia. Eventually, with continued administration, concentration of the anesthetic in the brain is probably the concentration of anesthetic in the bronchiolar alveoli of most interest, the brain/blood partition coeffi cient reaches equilibrium with that in the inspired gas mixture is more useful. Because the solubility of the anesthetic (Fig. 16.2). Transfer from the alveolar space to the blood in tissues is essentially equal to that in blood, the proceeds quickly, and depending on the concentrations tissue/blood or brain/blood partition coeffi cient is typi- of anesthetic used and its physiochemical characteristics, cally close to a value of 1. In fatty tissues, however, the equilibrium with the arterial blood is achieved. However, partition coeffi cient can be much larger due to lipid solu- before appreciable amounts of anesthetic agent dissolved bility. The rate of blood fl ow to a particular will also in the blood will enter the brain, the blood must be satu- infl uence the rate at which anesthetics reach their sites of rated with the anesthetic. Therefore, anesthetics that are action. The brain, , and kidneys have relatively high

TABLE 16.2 Partition Coefficients, MACs, and of Some General Anesthetics

Anesthetics Partition Coefficients at 37°C MAC (vol %)a % Metabolism

Oil/Gas Blood/Gas Without N2O With N2O (%) MAC-Awake (Vol %)

Methoxyflurane 970 12 0.16 0.07 (56) — 50

Halothane 224 2.3 0.77 0.29 (66) 0.4 20

Enflurane 99 1.9 91.7 0.60 (70) 0.4 2.4

Isoflurane 97 1.4 1.15 0.50 (70) 0.4 0.17

Sevoflurane (2) 53 0.60 1.71 0.66 (64) 0.6 4–6

Desflurane (3) 19 0.42 6.0 2.83 (60) 2.4 0.02

Nitrous oxide 1.4 0.47 104 — 60 None

aMAC = minimum alveolar concentration, expressed as volume %, that is required to produce immobility in respect to a standard surgical incision in 50% of middle-aged humans.

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blood fl ows, whereas skeletal muscle at rest and fat tissues TABLE 16.3 Factors That May Alter MAC have relatively poor blood fl ows and would be expected to accumulate less of the anesthetic agent. Increase MAC Increased levels in CNS Reversal of the anesthetic state and recovery requires Hypernatremia a reduction in the concentration of the anesthetic in the brain. This is achieved by stopping the delivery of the Decrease MAC Decreased catecholamine levels in CNS anesthetic through the lungs. As the patient continues Ingestion Hyponatremia to breathe, the anesthetic is continually removed, which Hypotension favors from the brain to the blood, to the alve- Lidocaine Lithium oli, and fi nally, to the expired air. The rate at which this Increased age occurs generally parallels that of induction, because the solubility of an agent in the brain and in the blood deter- No effect on MAC Plasma potassium mines how quickly these compartments will return to Gender a preanesthetic state. The main route of elimination is via the expired air, which can be mostly captured by gas- Duration of anesthesia scavenging devices with absorbers, but some metabolism of these agents does take place (discussed below).

Minimum Alveolar Concentration The minimum alveolar concentration (MAC) is defi ned responses to verbal commands are lost in 50% of the as the concentration at 1 atmosphere of anesthetic in the patients tested. At this concentration, amnesia and a loss alveoli that is required to produce immobility in 50% of of awareness are evident, and the patient is said to be in adult patients subjected to a standard surgical incision. A a state of hypnosis. The MAC-Awake occurs at concentra- further increase to 1.3 MAC will frequently cause immo- tions signifi cantly lower (e.g., 50% to 75% lower) than bility in 99% of patients. At equilibrium, the concentra- those required for surgical anesthesia. tion (or partial pressure) of an anesthetic in the alveoli is equal to that in the brain, and it is this concentration Theories About the Mechanisms of Anesthesia in the brain that most closely refl ects the concentration Meyer-Overton Theory at the site responsible for the anesthetic actions. Thus, In the early 1900s, Hans Meyer and Charles Overton sug- the MAC is often used as a measure of the potency of gested that the potency of a substance as an anesthetic was individual anesthetic agents. The MAC of many of the directly related to its lipid solubility, or oil/gas partition volatile and gaseous anesthetics in use today is shown in coeffi cient (Table 16.2) (3–5). This has commonly been Table 16.2. referred to as the “unitary theory of anesthesia.” They When anesthetic agents are used in combination, the used , octanol, and other “membrane-like” lipids MACs for inhaled anesthetics are simply additive. For to determine the lipid solubility of the agents available at instance, the anesthetic depth achieved with 0.5 MAC that time. Compounds with high lipid solubility required of enfl urane plus 0.5 MAC of nitrous oxide is equiva- lower concentrations (i.e., lower MAC) to produce anes- lent to that produced by 1.0 MAC of either agent alone. thesia. It was later postulated that the interaction of the The combination of two anesthetics is a very common anesthetic molecules with a hydrophobic portion of the practice, because this technique allows for a reduction in nerve membrane caused a distortion of the nerve mem- the patient exposure to any one of the individual agents, brane near the channels that conducted Na+, those that thereby decreasing the likelihood of adverse reactions. mediated the fast action potentials and neuronal cell fi r- Many factors infl uence the MAC via a number of dif- ing. The presence of this critical volume of anesthetic ferent mechanisms (Table 16.3). Factors that have been dissolved within the membrane caused the membrane to shown to increase the MAC for many volatile anesthet- “bloat” and cause a “squeezing in” on the Na+ channel ics include elevated in the CNS follow- to interfere with Na+ conductance and normal neuronal ing pharmacologic treatments, hypernatremia, and depolarization. In support of this theory, it was found hyperthermia. Factors known to decrease MAC include that at high pressures (40 to 100 atmospheres), the anes- ethanol ingestion, clonidine, lithium, lidocaine, centrally thetic actions of many of these agents could be partially administered opioids, and drugs that decrease central reversed, presumably by compressing membranes back catecholamine levels. Additionally, hyponatremia, hypo- to their original conformation. Arguing against this tension, hypothermia, hypoxia, increasing age, and preg- theory, however, is the fi nding that not all highly lipid- nancy have also been shown to decrease MAC. Plasma soluble substances are capable of producing anesthesia. potassium, hypertension, gender, and the duration of Additionally, more recent work involving protein–drug anesthesia typically generally have minimal to no effect interactions has seriously challenged this theory. Today, on the MAC (2). more than 150 years after the fi rst demonstration of the Another term, the “MAC-Awake,” is used to describe use of a volatile anesthetic agent, most theories about the the concentration of anesthetic at which appropriate mechanisms of anesthesia suggest that multiple selective

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lipid–protein membrane interactions, involving numer- curves observed, 2) the stereochemical requirements of ous types, are responsible for the anesthesia various anesthetics, 3) the fi nding that increasing the produced and that no reason exists to believe that all molecular weight and corresponding lipid solubility of anesthetic agents need to produce their effects via identi- an anesthetic can actually decrease or abolish anesthetic cal actions. Thus, a single molecular target for anesthetic activity, and 4) the fi nding that specifi c ion channels and actions is no longer required (6). receptor systems are required for most of the observed effects of the anesthetics. What appears Stereochemical Aspects to be emerging as a central theme for the mechanism of The volatile anesthetics isofl urane, desfl urane, enfl urane, action of general anesthetics involves the interaction of and halothane each contain an asymmetric carbon and, the anesthetics with receptors that allosterically modulate thus, can exist as (+)- or (−)-. Although all of the activity of ion channels (e.g., chloride and potassium) the commercially available preparations are racemates, or with the directly (e.g., sodium). Many some researchers have been able to determine the anes- other mechanisms are also emerging to help explain the thetic properties of individual enantiomers. The (+)-enan- mechanisms of action of the general anesthetics. tiomer of isofl urane is at least 50% more potent as an anesthetic in the rat than is the (−)- (7). In that CHLORIDE CHANNEL The ion channel that has received the study, the MAC values were 1.06% and 1.62% for the (+)- most investigative attention is that for chloride (Fig. 16.3).

and (−)-enantiomers, respectively. In another study, how- Both the g-aminobutyric acidA (GABAA) and the glycineA ever, the potency of the individual isofl urane enantiomers (-sensitive) receptors are -gated ion chan- to depress myocardial activity was not found to be different, nels and linked to chloride channels that normally mediate suggesting possible involvement of mechanisms dissimi- inhibitory responses within the CNS. Halothane, isofl u- lar from those responsible for producing anesthesia (8). rane, and other volatile anesthetics are capable of inhibit- These fi ndings argue against the original and simple lipid- ing the synaptic destruction of GABA, thereby increasing solubility theory of anesthesia, and they support a more the GABAergic neurotransmission, which typically is complex mechanism, probably likely involvement of pro- inhibitory in nature (10). Studies have also demonstrated teins in the form of receptor–anesthetic interactions (9). the ability of these anesthetics to enhance the binding of GABA or other allosteric modulators within the GABA Ion Channel and Protein Receptor Hypotheses receptor complex (11). In one such study, (+)-isofl urane More recently, investigators have determined the effects was signifi cantly more potent than the (−)-enantiomer of anesthetics on a number of protein receptors within at enhancing GABAergic function (12). The volatile the CNS. Features that support the likelihood of an inter- anesthetics, and many of the intravenous general anes-

action with a protein include 1) the steep dose–response thetic agents, bind to discrete cavities within the GABAA

EXTRACELLULAR FLUID

Benzodiazepines GABA Barbituates

Cl-

INTRACELLULAR FLUID

FIGURE 16.3 The GABAA receptor controls the chloride ion channel. GABA binds to its receptor, opening the chloride ion channel and resulting in hyperpolarization of the . Benzodiazepines and can produce anesthesia by allosterically enhancing GABA opening of chloride channels, which are located at inhibitory synapses on pyramidal cells.

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receptor complex to enhance GABA neurotransmission N-methyl-d-aspartate (NMDA) receptor complex. When

(13,14). Studies using mutant chimeric GABAA receptors activated by the excitatory amino acid neurotransmitter, have identifi ed a specifi c binding site for general anes- glutamate, an increase in the conductance to Na+ occurs thetics located between transmembrane segments 2 and that promotes neuronal depolarization (Fig. 16.4) (19). 3 (15). At therapeutic concentrations, just about all of the Compounds known to stimulate NMDA receptors are inhalational general anesthetics are capable of enhancing typically capable of increasing alertness and of acting as GABAergic function, whereas at considerably higher con- convulsants, whereas pharmacologic agents that act as centrations, many also can act directly as GABA mimetics antagonists at this site are usually , anticonvulsants, (16). Recent studies have demonstrated an effect of these and anesthetics (e.g., ketamine). Halothane

agents not only on the synaptic GABAA receptor function has been demonstrated to specifi cally antagonize the that mediates phasic neuronal responses but also on those glutamate-stimulated depolarization of neurons (20),

extrasynaptic GABAA receptors that mediate tonic neuro- whereas isofl urane has been shown to decrease glutamate nal activity (17). Other specifi c anesthetic agents can alter release and enhance its removal from the synaptic cleft

GABAA receptor function via different mechanisms. For (21). Glutamate acting at NMDA and other non-NMDA instance, propofol, an intravenous general anesthetic, receptors within the CNS is probably one of the most

appears to slow the desensitization of the GABAA recep- important excitatory inputs that supports consciousness. tor during bouts of rapid, repetitive activation at inhibi- It is not surprising that the general anesthetics would act tory synapses (18). Most of these agents also potentiate by altering neurotransmission in this system (22). Others the actions of , the other important inhibitory have reported an interaction of general anesthetics with amino acid neurotransmitter (16). The combination of the neuronal nicotinic receptor–linked Na+ GABAergic and potentiation by the general channel (23). Voltage-gated Na+ channels in small, nonmy- anesthetics probably accounts for the vast majority of the elinated hippocampal also appear to be inhibited by observed activity of the inhalational agents as well as that general anesthetics, such as isofl urane (24). of the barbiturates. POTASSIUM CHANNELS Potassium ion channels have also SODIUM CHANNELS One channel that has received much been suggested as a site for general anesthetic agents. attention regarding the mediation of drug-induced anes- Increasing K+ conductance normally functions to main- thetic actions is the ligand-gated Na+ channel within the tain the polarized state of neurons and to assist in the

EXTRACELLULAR FLUID

Glutamate + or K NMDA NO Glycine Ketamine blocks

Mg+2

Ca+2 Na+ NO INTRACELLULAR FLUID Calmodulin Nitric oxide synthase and NO Guanylyl cyclase and cyclic GMP Response FIGURE 16.4 Glutamate or NMDA receptors in the CNS. Binding of (glutamate or NMDA) opens the channel, allowing K+ to flow outward to extracellular fluid and sodium and ions to flow into the nerve cells. Increased intracellular fluid calcium ion concentration triggers a cascade that produces a response and liberates the retrograde neuronal messenger nitric oxide (NO). Ketamine can produce anesthesia by blocking these NMDA-controlled channels, which are located at excitatory synapses on pyramidal cells (3). Glycine acts as a positive at the NMDA receptor.

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repolarization of neurons following their stimulation- agents to be introduced as a general anesthetic, has high induced depolarization (Fig. 16.5). Thus, enhancing potency with signifi cant analgesic and neuromuscular the activity of certain K+ channels would be expected to relaxing effects. This agent is extremely fl ammable, and result in a decreased likelihood of neuronal excitation. when mixed with air, oxygen, or nitrous oxide, is explo- + A novel, anesthetic-sensitive K current [IK(an)] has been sive. Induction with diethyl ether is very slow; signifi cant identifi ed that is stereoselectively activated by isofl u- time is spent progressing through the delirium stage. rane (25). Mice with a targeted deletion of the TREK-1 Irritation of the by diethyl ether can lead two-pore-domain K+ channel show signifi cantly reduced to excessive bronchial secretions, complicating adequate sensitivity to general anesthetics compared to wild-type ventilation. In addition to its unpleasant induction and

controls (26). Additionally, certain a2-adrenoceptor ago- adverse effects, recovery is similarly prolonged and can nists (e.g., ) when injected produce an be accompanied by vomiting. These pharmacologic and anesthetic state that is mediated by a G protein–coupled physical characteristics of diethyl ether have limited the receptor that allosterically modulates K+ channels. These utility of this anesthetic in humans. responses can be antagonized by pertussis toxin and 4-aminopyridine, agents that inactivate G proteins and SHORT-CHAIN HYDROCARBONS Many of the short-chain block K+ channels, respectively, lending further support , , and are capable of producing an to the role of this ion channel (27). Similarly, G protein– anesthetic state when administered to patients. Potency mediated mechanisms appear to be involved with the generally increases as chain length increases. However, action of via the m- receptor (Fig. 16.5). because of their fl ammability and increased propensity to cause cardiovascular toxicity, these nonsubstituted CH3 NH2 H3C H CH hydrocarbons are not useful as anesthetic agents. N 3

N N HLOROFORM H C Another of the earlier anesthetic agents to be Dexmedetomidine 4-Aminopyridine used was chloroform (CHCl3). This halogenated hydro- carbon was fi rst offi cially used in the United States in 1847; Halogenated Hydrocarbons and Ethers however, its toxicity seriously limited its utility. The addi- tion of halogens to the hydrocarbon backbone increases Historical Aspects potency and , as well as decreases fl ammability. ETHER The useful volatile anesthetics, with the excep- Similar effects are also observed with such substitutions on tion of nitrous oxide, are halogenated hydrocarbons ethers. As an anesthetic agent, chloroform is very potent and ethers. Diethyl ether (Fig. 16.6), one of the fi rst and possesses signifi cant analgesic and neuromuscular

EXTRACELLULAR FLUID

μ α - 2-adrenoceptor K+

α α

GDP GDP

K+

INTRACELLULAR FLUID

FIGURE 16.5 Morphine and a2-agonists activate their respective G proteins, which hyperpolarize neurons by lowering intracellular fluid K+ ion concentration.

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F Br Cl F F F Cl F F C C Cl H C C O C H F C C O C H TABLE 16.4 Relative Flammability of “Nonflammable” F H F F F F H F Anesthetics

Halothane Enflurane Isoflurane Halothane Enflurane Isoflurane (%) (%) (%)

MFC of agent in 30% 4.75 5.75 7.0 F O with remaining F C F F 2 F H F Cl F H atmosphere N O F C C O C H H C C O C H H COC H 2 F F F Cl F H F C F H MAC of agent given 0.28 0.65 0.46 F in above atmosphere Methoxyflurane Desflurane Sevoflurane MAC in humans in 0.75 .68 1.15

the absence of N2O

H H H H MFC/MAC in N2O 17 8.9 15.2 NNO H C C O C C H H H H H MFC, minimum flammable concentration; MAC, minimum effective alveolar concentration Nitrous oxide Diethylether Cyclopropane

FIGURE 16.6 General anesthetics. are formed by reaction of the anesthetic agent with the basic substances such as soda lime, used as carbon diox- ide absorbents during anesthesia. This reaction results relaxing activity. Chloroform, a known carcinogen, has in the conversion of halothane to 2-bromo-2-chloro- the disadvantage of being both hepatotoxic and neph- 1,1-difl uoroethylene, sevofl urane to 2-(fl uoromethoxy)- rotoxic, in addition to producing adverse cardiovascular 1,1,3,3,3-pentafl uoro-1- (Compound A), and effects, such as and severe hypotension. As desfl urane, isofl urane, and enfl urane to carbon mon- a result of these toxicities, chloroform has an unaccept- oxide. Compound A forms a S-conjugate, able that prohibits its use in anesthesia. which undergoes to cysteine S-conjugates and Two other halogenated compounds that found limited bioactivation of the cysteine S-conjugates by renal cyste- use in the mid-1900s included and fl u- ine conjugate b-lyase to give nephrotoxic metabolites. roxene. Neither of these agents is used today. Knowledge regarding the infl uence of the halogen substitutions on HALOTHANE Halothane (Fig. 16.6) was introduced into the potency and fl ammability of hydrocarbons and ethers, medical practice in the United States in 1956 as a non- however, signifi cantly contributed to our understanding fl ammable, nonexplosive, halogenated volatile anesthetic of the structure–activity relationship of volatile anesthetics that is usually mixed with air or oxygen. The presence of and the eventual design of substantially improved agents.

FLAMMABILITY The occurrence of fi res in operating rooms is of great concern to all participants in the surgical pro- TABLE 16.5 Physicochemical Properties of Clinically cedure. Although the introduction of “nonfl ammable” Useful Volatile Anesthetics agents, such as halothane, enfl urane, and isofl urane, has substantially decreased this hazard, such fi res still occur. Generic Name (Trade Name) Boiling Chemically and Structure Point (°C) Stablea Three essential ingredients are required for any combus- tion: 1) an ignition source (e.g., a laser), 2) a combustible Desflurane (Suprane) 23.5 Yes

material (e.g., gauze, drapes, or rubber tubes), and 3) F2HC–O–CHF–CF3 an oxidizing agent (e.g., oxygen or nitrous oxide). Many Enflurane (Ethrane) 56.5 Yes substances are fl ammable in pure oxygen, nitrous oxide, F2HC–O–CF2–CHFCl or mixtures, but not air. Certain substances are fl amma- ble in nitrous oxide at concentrations that are too low to Halothane (Fluothane) 50.2 No F C–CHBrCl permit ignition in pure oxygen (28). The concentrations 2 required for combustion, as indicated in Table 16.4, are Isoflurane (Forane) 48.5 Yes F HC–O–CHCl-CF higher than those generally encountered, except possi- 2 3 bly during induction. Methoxyflurane (Penthrane) 104.7 No

H2C–O–CF2–CHCl2 Clinically Useful Inhalation Agents Nitrous oxide N2O –*8.0 Yes Fluorinated Hydrocarbons Sevoflurane (Ultane) 58.5 No The structure, physical properties and partition coef- (CF ) CH–O–CH F fi cients of the volatile anesthetics are given in Tables 3 2 2 16.2 and 16.5, respectively. Toxic degradation products aIndicates stability to soda lime, ultraviolet light, and common metals.

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the carbon–halogen bonds contributes to its nonfl amma- delivery devices, which might account for some slowing bility, volatility, and high lipid solubility (blood/gas parti- of the induction onset and recovery. Approximately 20% tion coeffi cient = 2.3). This clear liquid with a sweet odor of an administered dose is metabolized, which accounts, was developed based on predictions that its halogenated in part, for the increased hepatotoxicity observed with structure would provide chemical stability, an intermedi- this agent (Fig. 16.7). ate blood solubility, and signifi cant anesthetic potency. Halothane is the only useful volatile anesthetic possess- ENFLURANE Enfl urane (Fig. 16.6) was introduced into ing a bromine atom, which has been suggested to con- medical practice in the United States in 1973 and is a tribute to its potency. Similarly, the addition of fl uorine clear, colorless, nonfl ammable liquid with a mild, sweet atoms, of which halothane has three, contributes to its odor. Although relatively stable chemically, enfl urane increased potency, volatility, and relative chemical stabil- does not attack aluminum, copper, iron, or brass and is ity of the hydrocarbon skeleton (Table 16.5). soluble in rubber, which can prolong induction/recov- Halothane produces rapid onset and recovery from ery times, as seen with halothane (Table 16.5). Enfl urane anesthesia with high potency when used alone or in has an intermediate solubility in blood (blood/gas par- combination with nitrous oxide. Most metals, with the tition coeffi cient = 1.9) and signifi cant potency. Most exception of chromium, nickel, and titanium, are easily of its pharmacologic properties are similar to those of tarnished by halothane. Although halothane is relatively halothane, although there can be slightly less , stable, it is subject to spontaneous oxidative decompo- vomiting, arrhythmias, and postoperative shivering than sition to hydrochloric acid (HCl), hydrobromic acid observed with halothane. High concentrations of enfl u-

(HBr), and phosgene (COCl2). For this reason, it comes rane, however, are more likely to produce convulsions in dark, amber glass containers with added as a and circulatory depression. Enfl urane also relaxes the to minimize decomposition. Halothane can uterus and, thus, should not be used as an anesthetic dur- permeate into the rubber components of the anesthetic ing labor. Metabolism via CYP2E1 accounts for 2% of an

** -HF O O CF3 CFH O CF2OH + [O] F F F F3C H CF COOH O 3 Desflurane: CHF2 F -F- CF3 O ** CHF2 CHF OH + F C O 2 F3C F H2O 3 OH

O -F- -HCl O Enflurane: F2HC CF2CHClF F HC CF CClFOH F CHF2OCF2COOH O 2 O 2 F2HC CF2

CF3CBrClOH CF3COCl CF3COOH

Halothane: CF3CHBrCl +e-/-Br- Minor pathway Cl - O O O -F -2F- O O CF3CH2Cl CF3 C Cl CF2=CHCl HC C OH HO CCOH + HOCH C OH +e- -Cl- 2

-HCl O ** O F3C CHCl O CF2OH + [O] Cl F F F3C H Isoflurane: CHF2 F3C O O CF3COOH Cl ** -Cl- CHF2 CHF OH F C O 2 + F3C Cl H2O 3 OH

-HF -F- CHCl2CF2OCH2OH H2CO + CHCl2COF CHCl2COOH H2O Methoxyflurane: Cl2HC CF2 O CH3 O O -HCl -Cl- -2F- HOCCl2CF2OCH3 CH3OCF2COCl CH3OCF2COOH HO C C OH H2O -

Sevoflurane: (CF 3)2CHOCH2F (CF 3)2CHOCHFOH (CF 3)2CHOH + F + CO2

*Data from references 28 and 29. ** - - Decomposition of unstable intermediates: CF2O2F + CO2 ;2F CHF2OH + HCOOH ; FIGURE 16.7 Proposed metabolites of fluorinated anesthetics.

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inhaled dose and includes metabolism to form a fl uoride of desfl urane is close to room temperature, a specially ion and fl uoromethoxydifl uoroacetic acid (Fig. 16.7) designed, heated vaporizer is used to deliver the anes- (30). During recovery, enfl urane leaves the fatty tissues thetic with appropriate concentrations of oxygen either rapidly and, therefore, is not available for a prolonged alone or in combination with nitrous oxide. Recovery period of time for signifi cant metabolism to proceed. from the anesthetic state is also rapid, being approxi- mately twice as rapid as that with isofl urane. Because ISOFLURANE Isofl urane (Fig. 16.6) was introduced in the of the rapid induction and recovery associated with United States in 1981 and is a potent anesthetic agent desfl urane, this anesthetic has gained popularity in with many similarities to its isomer enfl urane (potent, outpatient surgical procedures. Desfl urane is rather pun- nonfl ammable, and intermediate blood solubility; with gent, so patients often are induced with an intravenous blood/gas partition coeffi cient = 1.4). However, it does anesthetic agent and then maintained with desfl urane. produce signifi cantly fewer cardiovascular effects than Desfl urane is not metabolized to any great extent and, enfl urane and can be used safely with epinephrine with- therefore, has not been associated with hepatotoxicity out a concern for production. Isofl urane has or nephrotoxicity (31). Metabolites, mostly trifl uoroac- a more pungent odor than halothane and, thus, can cause etate, account for less than 0.02% of the administered irritation to the throat and respiratory tract, triggering dose (Fig. 16.7). Although desfl urane can react with soda coughing and . To overcome this prob- lime or Baralyme to form carbon monoxide, no reports lem, it is often supplemented with intravenous agents. of adverse outcomes in patients have appeared. Less than 0.2% of an administered dose is metabolized, mostly to fl uoride and trifl uoroacetic acid (Fig. 16.7). As SEVOFLURANE Sevofl urane (Fig. 16.6) is a nonfl ammable, discussed below, some minimal potential for hepatotoxic- nonirritating, pleasant-odored volatile anesthetic avail- ity is associated with a trifl uoroacetyl halide metabolite. able for use in the United States. Similar to desfl urane A comparative assessment of the volatile anesthetic in many of its pharmacologic actions, except sevofl urane properties of enfl urane, halothane, and isofl urane is which has low blood solubility (blood/gas partition coef- shown in Table 16.6. fi cient = 0.60), higher potency, and the advantage of not being irritating to the respiratory tract. Induction and DESFLURANE Desfl urane (Fig. 16.6) was introduced in recovery are rapid. Sevofl urane undergoes signifi cantly the United States in 1992 and is a pungent, volatile more metabolism (CYP2E1) than desfl urane, however, agent that is nonfl ammable and noncorrosive to metals. and as much as 3% of an administered dose can be recov- With poor blood solubility (blood/gas partition coeffi - ered as hexafl uoroisopropanol (Fig. 16.7). Some fl uoride cient = 0.42), similar to that of nitrous oxide, desfl urane ion can also be produced, but the incidence of nephro- rapidly induces anesthesia. Because the toxicity or hepatotoxicity appears low, especially when used infrequently for short periods of time. There have been concerns regarding the reactivity of sevofl urane with soda lime or Baralyme, in which a potentially toxic olefi n TABLE 16.6 Comparative Assessment of Enflurane byproduct termed “Compound A” (2-(fl uoromethoxy)- (E), Halothane (H), and Isoflurane (I) 1,1,3,3,3-pentafl uoro-1-propene) can be formed. With appropriate precautions, however, sevofl urane can be Property Superior Intermediate Inferior used safely in both children and adults. Stability I = E — H METHOXYFLURANE Methoxyfl urane (Fig. 16.6) is seldom Blood solubility I E H used because of its propensity to cause renal toxicity. It Pungency H I E is the most potent of the agents discussed here, and it has high solubility in blood (blood/gas partition coeffi - Respiratory depression H I E cient = 12). Induction and recovery would be expected to Circulatory depression I H E be slow. Chemically, it is rather unstable, and as much as 50% of an administered dose can be metabolized. Toxic Induction of arrhythmias I E H metabolites signifi cantly limit its utility as a general anes- Muscle relaxation I = E — H thetic (Fig. 16.7). Increased intracranial IE H pressure/cerebral blood flow TOXICITY OF FLUORINATED GENERAL ANESTHETICS Although few signs of toxicity usually are observed during the short- activity H = E — E term, infrequent administration of general anesthetics, Metabolism I E H a few well-defi ned toxic effects have been noted. For instance, halothane and methoxyfl urane are known to Toxicity I E H produce hepatotoxicity and nephrotoxicity, respectively. Adapted from Wade JC, Stevens WC. Isoflurane: an anesthetic for the eighties? Both of these toxic reactions are believed to result from Anesth Analg 1981;60:666–682; with permission. highly reactive metabolites of the parent compound.

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Overall, however, the therapeutic ratio for most of the potential to produce damage to the renal tubular cells. general anesthetics approaches 4:1 (32). Of the fl uorinated anesthetics, methoxyfl urane is the only agent commonly associated with nephrotoxicity. Hepatotoxicity Hepatitis caused by halothane occurs Methoxyfl urane is metabolized (Fig. 16.7) to produce in 1 in 20,000 patients exposed to this anesthetic and is plasma fl uoride ion levels in excess of the threshold value thought to result from the binding of a reactive free radi- for renal damage of 40 mmol/L. Others, such as sevofl u- cal metabolite to liver tissue (Fig. 16.7). The resultant rane, have only very rarely been associated with nephro- abnormal molecular product in the liver is viewed by the toxicity—and then usually in patients with severe renal as a foreign substance (i.e., an antigen), compromise. Plasma levels of fl uoride only reach 15 to 20 which then sensitizes cells to produce antibodies. Some mmol/L following 2.5 MAC-hour exposure to enfl urane have suggested that the trifl uoroacetyl halide metabo- (33). The rates of metabolic defl uorination of the useful lite is responsible for the initiation of halothane hepa- anesthetic agents are as follows: methoxyfl urane > enfl u- titis. Interestingly, both enfl urane and isofl urane can be rane = sevofl urane > isofl urane > desfl urane = halothane. metabolized to the acylated halides and produce a similar immune-mediated syndrome, although to a much lesser Low-level Chronic Exposure Typically, patients are extent. Additionally, there appears to be cross-reactivity exposed to greater-than-MAC concentrations of the vola- among these three agents, because the antigen formed tile anesthetics for limited periods of time, such as a num- is similar enough in structure to elicit the immune sys- ber of hours during a surgical procedure, and not for tem response. Some investigations have suggested that a extended periods of time (e.g., days or weeks). Because genetic susceptibility factor could be responsible, in part, surgical and dental personnel, however, can be exposed for this serious form of hepatitis. to low levels of the general anesthetics for prolonged peri- Halothane also can produce another form of hepato- ods over many years or even decades, the ability of such toxicity. This is a self-limiting hepatic dysfunction char- agents to produce chronic toxicity is of paramount con- acterized by elevated liver transaminase , which cern. Although the occupational exposure to these agents probably results from impaired oxygenation of the hepa- has been minimized with improved waste gas–scavenging tocytes during exposure to this anesthetic. Isofl urane and devices, some epidemiologic studies have demonstrated enfl urane have also been reported to produce a similar increased levels of spontaneous , congenital elevation of liver enzymes, although to a lesser extent birth defects in offspring, and increased rates of certain than halothane. cancers in chronically exposed medical personnel (34).

Malignant Hyperthermia This rare (1 in 15,000 anes- Nitrous Oxide

thetic uses) but potentially fatal associated Commonly called “laughing gas,” nitrous oxide (N2O) is with the use of certain anesthetics (e.g., halothane) is a gas at room temperature, the least potent of the inha- characterized by a rapid rise in core body temperature lation anesthetics used today and poor blood solubility associated with hypermetabolic reactions in the skeletal (blood/gas partition coeffi cient = 0.47) (Table 16.5). muscle of genetically susceptible subjects. Such individu- With an MAC value in excess of 105%, this colorless, als appear to have an autosomal dominant–mediated tasteless, and odorless to slightly sweet-smelling gas is not defect in the Ca2+-release channel commonly referred normally capable of producing surgical anesthesia when to as the ryanodine receptor. The large amounts of heat administered alone. The MAC for nitrous oxide has been generated, massive increase in oxygen consumption, demonstrated to be between 105% and 140% and, thus, and production of carbon dioxide can quickly lead to cannot achieve surgical anesthesia under conditions at death or permanent neurologic damage unless appro- standard barometric pressure. To demonstrate that the priate supportive treatment, including rapid cooling, MAC was greater than 100%, Bert in 1879 used a mixture 100% oxygen, and control of acidosis, is promptly initi- of 85% nitrous oxide with oxygen at 1.2 atmospheres in a ated. The administration of the skeletal pressurized chamber. Only at this elevated pressure could , which blocks release of Ca2+ from the sar- an MAC adequate for surgical anesthesia be achieved. coplasmic reticulum, reduces muscle rigidity and heat Decreasing the oxygen content of a nitrous oxide mix- production, which signifi cantly improves the prognosis ture to values less than 20% to allow an increase in the of the patient. Besides the fl uorinated volatile anesthet- concentration of nitrous oxide to greater than 80% can ics, some depolarizing neuromuscular blocking agents be dangerous, because hypoxia would be expected to (e.g., succinylcholine) and some neuroleptics (e.g., halo- result. Thus, when administered alone, nitrous oxide peridol) are also reportedly associated with similar malig- fi nds utility as an anesthetic agent during certain pro- nant hyperthermic syndromes, although the underlying cedures (e.g., dental) in which full surgical anesthesia mechanism mediating these can differ somewhat from is not required. Most commonly, however, nitrous oxide those associated with the general anesthetics. is used in combination with other general anesthetics, because it is capable of decreasing the concentration of Nephrotoxicity Fluorinated anesthetics that undergo the added anesthetic required to produce an adequate metabolism to form inorganic fl uoride ion have the depth of anesthesia for surgical procedures.

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Although no fi rm underlying mechanisms have been rapidly via hepatic conversion to its glucuronide and sul- demonstrated, some authors have suggested that irrevers- fate conjugates, with less than 0.3% excreted unchanged.

ible oxidation of the cobalt atom in B12 by nitrous Because this agent produces a rapid induction and recov- oxide can lead to inactivation of enzymes dependent on ery and is infrequently associated with episodes of vomit- this vitamin, with resultant metabolic aberrations. Such ing, propofol has found utility as an anesthetic agent in examples have included methionine synthetase and thy- outpatient surgical environments. midylate synthetase, which are essential in the synthetic pathways leading to the production of myelin and thy- Fospropofol midine, respectively. Should these enzymes be impaired Due to its water solubility, the phosphate during the sensitive periods of in utero development, the of propofol (Lusedra), fospropofol, avoids the potential for malformations can unfortunately be realized. formulation concerns described earlier for propofol. All To date, no studies have been able to demonstrate conclu- of the pharmacodynamic effects of fospropofol are attrib- sively that low-level exposure to nitrous oxide is associated uted to propofol, which is liberated following hydrolytic with a meaningful disruption of crucial metabolic func- metabolism by serum alkaline phosphatases. Typical dos- tions to produce the above-described toxicity; however, ing is 6.5 mg/kg, with supplemental doses of 1.6 mg/kg measures including improved waste gas–scavenging sys- as needed. While and phosphate are also tems should be taken to minimize exposure of personnel. released by this metabolic conversion, the levels of these compounds do not increase to levels beyond those nor- mally found endogenously and thus do not pose any Clinically Useful Intravenous General Anesthetic toxicity concerns, except perhaps in overdose situations. Agents Due to its requirement for conversion to the active propo- Propofol fol, the onset of fospropofol is delayed (4 to 10 minutes) when compared to that for propofol (30 to 60 seconds) and has a prolonged duration of anesthetic action. Na O Na Ketamine P O O O Cl Cl CH3 OH CH3 CH3 O CH3 O O H3C C C CH3 H3C CH C CH3 H H H N CH3 NH2 H

Propofol Fospropofol Ketamine

One of the most commonly used parenteral anesthetics Ketamine hydrochloride is an injectable, very potent, used in the United States is propofol (Diprivan). Used rapidly acting anesthetic agent. As with propofol, its dura- intravenously, propofol is not chemically related to the tion of anesthetic activity is also relatively short (10 to barbiturates or other intravenous anesthetics. Propofol 25 minutes). Ketamine does not relax skeletal muscles appears to act via enhancing GABAergic neurotransmis- and, therefore, can only be used alone in procedures of

sion within the CNS. This occurs most likely at the GABAA short duration that do not require muscle relaxation. receptor complex, but at a site distinct from where the Recovery from anesthesia can be accompanied by “emer- benzodiazepines bind. Because of its poor water solubil- gence delirium,” which is characterized by visual, auditory, ity (partition coeffi cient ∼6,200), propofol is formulated and confusional . Disturbing dreams and halluci- as a 1% or 2% emulsion with , egg , nations can occur up to 24 hours after the administration and . Sodium metabisulfi te (an antioxidant) or of ketamine. Its elimination half-life is 2 to 3 hours, and ethylenediaminetetraacetic acid (metal chelating agent) its volume of distribution is 2 to 3 L/kg. Ketamine has an is also included in the parenteral dosage form for stabil- oral of less than 16%. Termination of the ity. Because of the likelihood of bacterial contamination acute action of ketamine is largely a result of its redis- of open containers, propofol should be either adminis- tribution from the brain into other tissue; however, the tered or discarded shortly after sterility seals are broken. formation of the glucuronide conjugate and metabolism Following intravenous administration of a dose of 2.0 to in the liver to a number of metabolites does occur. One 2.5 mg/kg, a state of hypnosis is achieved within 30 to of these metabolites of interest, norketamine, is formed 60 seconds, which lasts for approximately 5 to 10 minutes. via the action of CYP2B6. This N-demethylated deriva- A longer anesthetic state can be achieved by additional tive retains signifi cant activity at the NMDA receptor and propofol dosing or, as typically is the case, maintenance can account for some of the longer-lasting effects of this with a volatile anesthetic agent. Blood pressure and heart anesthetic agent. Eventual conversion of norketamine to rate usually are decreased following propofol admin- hydroxylated metabolites and subsequent conjugation istration. Propofol is highly bound to plasma proteins leads to metabolites that can be renally eliminated. Less (approximately 98%). Metabolism of propofol proceeds than 4% of a dose is excreted unchanged in the .

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Ketamine is capable of producing a “dissociative” anes- Ultrashort-Acting Barbiturates thesia, which is characterized by EEG changes indicating CH3 a dissociation between the thalamocortical and limbic sys- CH3 H3C tems (35). These neuronal systems, which normally are O O associated with one another, help to maintain the neuro- nal connections required for consciousness. When disas- HN N sociated, the subject will appear to be cataleptic, with the S Na eyes open in a slow, nystagmic gaze (oscillating movement of the eyeball) (1). A potent analgesic and amnesic effect Thiopental is produced, as is an increase in muscle tone in some areas. Although patients can appear to be awake, they are inca- Thiopental, an ultrashort-acting (partition pable of communicating and do not remember the event coeffi cient ∼390), is used intravenously to produce a or the people around them. Blood pressure and heart rate rapid unconsciousness for surgical and basal anesthesia. usually are increased following ketamine administration. This agent is used initially to induce anesthesia, which Ketamine appears to act similarly to phencyclidine then can be maintained during the surgical procedure (PCP; also known as Angel Dust), which acts as an antago- with a general anesthetic agent. The induction typically nist within the cationic channel of the NMDA receptor is very rapid and pleasant. (The ultrashort-acting barbitu- complex (36). By preventing the fl ow of cations through rates are discussed in Chapter 15.) this channel, ketamine prevents neuronal activation, which normally is required for the conscious state. The analgesic activity of ketamine, however, is more likely the LOCAL ANESTHETICS result of an interaction with an opioid receptor or the less Local anesthetic agents are drugs that, when given either well-understood non-opioid sigma receptor. Other studies topically or administered directly into a localized area, have suggested a possible involvement of recep- produce a state of by reversibly blocking tors and muscarinic receptors (37). Ketamine, like PCP, nerve conductances that transmit the sensations of pain has a signifi cant potential for abuse. from this localized area to the brain. Unlike the anes- Etomidate thesia produced by general anesthetics, the anesthesia produced by local anesthetics is without loss of conscious- ness or impairment of vital central cardiorespiratory (R) H3C functions. Local anesthetics block nerve conductance by O binding to selective sites on the Na+ channels in the excit- N + O able membranes, thereby reducing Na passage (i.e., con- N ductance) through the pores and, thus, interfere with the generation of action potentials. Although local anes- R-Etomidate thetics decrease the excitability of nerve membranes, they do not affect the neuron’s resting potential. Local Etomidate is the ester of a carboxylated , with anesthetics, in contrast to analgesic compounds, do not interact with the pain receptors or inhibit the release or a partition coeffi cient of 2,000 and a weak base pKa of 4.5, that is available as the R-(+)-isomer solubilized in the of pain mediators. 35% for intravenous in addi- tion to being available for rectal administration. It is a The Discovery of Local Anesthetics potent, short-acting agent (<3 minutes) with- As with many modern drugs, the initial leads for the design out analgesic activity and with a rapid . of clinically useful local anesthetics originated from nat- This agent is useful for the induction of anesthesia in ural sources. As early as 1532, the anesthetic properties hemodynamically unstable patients prone to hypoten- of leaves (Erythroxylon coca Lam) became known to sion because of hypovolemia, coronary artery disease, or Europeans from the natives of Peru, who chewed the cardiomyopathies. Recovery is similarly rapid following leaves for a general feeling of well-being and to reduce discontinuance of the drug. Etomidate is hydrolyzed by hunger. Saliva from chewing the leaves was often used by hepatic to the corresponding inactive carbox- the natives to relieve painful wounds. The active principle ylic acid, with subsequent renal and biliary ter- of the coca leaf, however, was not discovered until 1860 minating its action. Its apparent elimination half-life is by Niemann, who obtained a crystalline alkaloid from approximately 5 to 6 hours, with a volume of distribution the leaves, to which he gave the name cocaine, and who of 5 to 7 L/kg. Changes in hepatic blood fl ow or hepatic noted the anesthetic effect on the tongue (see Fig. 16.8 metabolism will have only moderate effects on etomidate for structure of cocaine). Although Moréno y Maiz in disposition. Concerns regarding the ability of etomidate 1868 fi rst asked the question of whether cocaine could to precipitate myoclonic jerks and inhibit adrenal be used as a local anesthetic, Von Anrep in 1880, after synthesis have been reported. many animal experiments, recommended that cocaine

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COOH Carbomethoxy Group Although the intrinsic potency of procaine was low and its duration of action relatively short compared with that of cocaine, it was found that these defi ciencies could CH3 be remedied when procaine was combined with a vaso- N COOCH3 CH N 3 constrictor, such as epinephrine. Vasoconstrictor agents Hydrolysis COOH O reduce the local blood supply and, thereby, prolong the residence time of the local anesthetic at the injection site. H OH O Following the introduction of procaine, hundreds of H Tropine Moiety Benzoyl structurally related analogs were prepared and their local Ecgonine Group anesthetic properties examined in an attempt to identify Cocaine agents with enhanced potency and duration of action CH3OH compared to the weak and short-acting procaine. Among these compounds, tetracaine remains the most potent, FIGURE 16.8 Structures of cocaine and its hydrolysis products. long-acting, ester-type local anesthetic agent, which is used in spinal anesthesia.

be used clinically as a local anesthetic. The fi rst report O O N(CH3)2 of successful surgical use of cocaine appeared in 1884 by O OCH2CH3 Koller, an Austrian ophthalmologist. This discovery led C4H9HN H2N to the rapid development of new local anesthetic agents Tetracaine Benzocaine and anesthetic techniques (38). Cocaine dependence (or ) is psychologi- cal dependency on the regular use of cocaine. The use The agent benzocaine was synthe- of cocaine, depending on the severity, can cause mood sized by Ritsert in 1890 and found to have good anes- swings, paranoia, , psychosis, high blood pres- thetizing properties and low toxicity. However, due to its sure, , panic attacks, cognitive impairments, limited water solubility, except at low pH values as a result and drastic changes in the personality that can lead to of the lack of a basic aliphatic amino group, the prepara- aggressive, compulsive, criminal, and/or erratic behaviors. tion of pharmaceutically acceptable parenteral solutions The symptoms of cocaine withdrawal range from moder- could not be achieved. ate to severe: dysphoria, depression, anxiety, psychological O and physical weakness, pain, and compulsive craving. CH3 N(C2H5)2 Although the structure of cocaine was not known until N N(CH3)2 H 1924, many attempts were made to prepare new analogs of N H CH cocaine that lacked its addicting liability and other thera- 3 Isogramine Lidocaine peutic shortcomings, such as allergic reactions, tissue irrita- tions, and poor stability in aqueous solution. Also, cocaine is easily decomposed to hydrolysis products, ecgonine and The serendipitous discovery of the local anesthetic benzoic acid, when the solution is sterilized (Fig. 16.8). activity of another natural alkaloidal product, isogra- mine, in 1935 by von Euler and Erdtman was the next CH3 major turning point in the development of clinically use- N O ful local anesthetic agents. This observation led to the N(C H ) O 2 5 2 O synthesis of lidocaine (Xylocaine) by Löfgren in 1946;

H2N lidocaine was the fi rst nonirritating, amide-type local H O anesthetic agent with good local anesthetic properties yet Benzoyltropine Procaine less prone to allergenic reactions than procaine analogs, and was found to be stabile in aqueous solution due to its When the chemical structure of ecgonine became more stable amide functionality. Structurally, lidocaine known, the preparation of active compounds containing can be viewed as an open-chain analog of isogramine the ecgonine nucleus accelerated. It was soon realized and, thus, is a bioisosteric analog of isogramine. that a variety of benzoyl of amino , includ- Since the discovery of lidocaine in the 1940s, much ing benzoyltropine, exhibited strong local anesthetic more progress has been achieved in the fi elds of neuro- properties without any of cocaine’s addiction liability. and neuropharmacology than in the synthesis Thus, removal of the 2-carbomethoxy group from cocaine of local anesthetics by medicinal chemists. Most of this also abolished its addiction liability. This discovery even- research has signifi cantly increased our understanding tually led to the synthesis of procaine in 1905 (known as of how nerve conduction occurs and how compounds Novocain), which then became the prototype for local interact with the neuronal membranes to produce local anesthetics for nearly half a century, largely because it anesthesia. It should be noted, however, that although lacked the severe local and systemic toxicities of cocaine. a number of current clinically useful local anesthetic

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agents have been introduced into the market, the ideal as a result of electrochemical changes in the Na+ and local anesthetic drug has, unfortunately, not yet been K+ potential across the neuronal membrane. Such neu- realized. rons are bundled together into a cable-like structure and wrapped in a connective tissue sheath (the peri- Characteristics of an Ideal Local Anesthetic neurium), called a nerve. Within a nerve, each The ideal local anesthetic should produce reversible is wrapped by a layer of connective tissue called the blockade of sensory neurons with a minimal effect on endoneurium. Finally, the entire nerve is wrapped in a the motor neurons. It also should possess a rapid onset, layer of connective tissue called the epineurium (much have a suffi cient duration of action for the completion of like an electrical cable of wires wrapped with a plastic major surgical procedures without any systemic toxicity, casing), as shown in Figure 16.9. (39). A nerve pro- and be easily sterilized and not inordinately expensive vides a common pathway for the transmission of elec- (Table 16.7). Hopefully through further structure– trochemical impulses. Thus, each nerve is a cord-like activity relationship studies, particularly with regard to structure that contains groups of neurons in small bun- their selective actions on the voltage-gated Na+ chan- dles. The cell bodies of the sensory neurons are found nels, the ideal local anesthetic agent can be realized. at the point at which the nerve enters the vertebrae Additional leads for the design of ideal local anesthetics and can be seen as enlargements on the nerve bundles could also come from a more systematic metabolic and (spinal or dorsal root ganglion). The cell bodies (ante- toxicity study of currently available agents. To under- rior horn cell) of the motor neurons are found within stand the chemical aspects of local anesthetics and, the gray matter of the . thus, to provide a proper background for practical uses Figures 16.9 and 16.10 also illustrate that each axon of these compounds, it is necessary to have a working has its own membranous covering, the endoneurium knowledge of basic neuroanatomy and electrophysiology (often called the nerve membrane), which is tightly of the nervous system. surrounded by a myelin sheath of the Schwann cell. The myelin sheath is not continuous along the fi ber, Neuroanatomy and Electrophysiology of the with intermittent gaps or interruptions at the nodes of Nervous System Ranvier, which serve to facilitate neuronal conduction. Neuroanatomy Electrophysiology of Nerve Membrane Sensory neurons (afferent neurons) transmit sen- RESTING POTENTIAL Most nerves have a resting membrane sory electrochemical impulses from sensory endings potential (unstimulated or polarized state) of approxi- (receptors) in the and other sensory organs mately −70 to −90 mV as a result of a slight imbalance toward the CNS (i.e., brain and spinal cord) where the of electrolyte ions (e.g., sodium, potassium, calcium, information is processed. On the other hand, motor , and chloride) across the nerve membranes, neurons (efferent neurons) transmit electrochemical between the intracellular cytoplasm and the extracellular impulses from the CNS toward motor endings or other fl uid (40). In the polarized state, the nerve membrane is target (effector) cells that, when stimulated, produce a somewhat impermeable to Na+ as seen by the low intra- response such as contraction of muscle or stimulation/ cellular Na+ concentration, whereas K+ fl ows in and out inhibition of sweat glands or exocrine glands. The of the cell with greater ease, indicating that the neuronal transmission of a nerve impulse along an axon occurs membrane is highly permeable to K+. A high K+ concen- tration is retained intracellularly by the attractive forces

TABLE 16.7 Characteristics of the Ideal Local Anesthetic Agent

Produces a reversible blockade

Selective for sensory neurons with no effect on motor neurons

Rapid onset

Sufficient duration of action

Chemically stable when sterilized

No systemic toxicity

Wide margin of safety

Compatible with other coadministered drugs

Absence of adverse effects FIGURE 16.9 Diagram showing the various parts of a peripheral nerve. (Adapted from Ham AW. Histology, 6th Ed. Philadelphia: JB Inexpensive Lippincott, 1969:524, with permission.)

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mV

+60 +40

+20 1 msec 0

FIGURE 16.10 Single myelinated nerve fiber. -20 -40 Threshold provided by the negatively charged intracellular protein -60 Resting potential molecules. Thus, the predominant intracellular cations -80 are K+ (∼110 to 170 mmol/L), and the predominant extracellular cations are Na+ (∼140 mmol/L) and chlo- ride (∼110 mmol/L). Because changes in the intracellular or extracellular K + Sodium pump K concentration of K would be expected to markedly alter Na+/K+-ATPase the resting membrane potential, electrophysiologists (inside) modeled the excitable cell as if it were an electrochemi- Nerve membrane cal, or Nernst, cell. Thus, the resting potential for K+ can

be determined by the familiar Nernst equation: (outside) ATP c-AMP Na + + Na E = −RT/zF ln [K ]i/[K ]o FIGURE 16.11 Relationship between membrane in which E = membrane potential, intracellular minus and ionic flux across the nerve membrane. extracellular; R = gas constant; T = temperature; z = ion + valence; F = Faraday’s constant; [K ]i = activity of intracel- lular K+; and [K+] = activity of extracellular K+. o by which intracellular Na+ could be rapidly transported ACTION POTENTIAL In most cells, action potentials are tran- (effl uxed) from inside the membrane to the outside sient transmembrane depolarizations that result from the extracellular fl uid and extracellular K+ could be trans- infl ux of Na+ through a brief opening of the voltage-gated ported (infl uxed) from extracellular fl uid to inside the Na+ channels upon excitation of the cell (40). The trans- membrane. This is accomplished by the “sodium pump,” membrane potential during an action potential changes which requires energy from the splitting of adenosine from −70 to approximately +40 mV (a total net change of triphosphate by sodium-potassium adenosine triphos- 110 mV) (depolarized state) and then promptly returns phatase (Na/K-ATPase) to adenosine monophosphate. to the resting (polarized state) potential; the entire event This pump transports three Na+ to the outside of the typically lasts approximately 1 millisecond (Fig. 16.11). membrane for every two K+ that enter the inside of the An action potential is capable of traveling long distances membrane. along the neuron because open Na+ gates stimulate neighboring Na+ gates to open. THRESHOLD The voltage necessary to change localized The transmembrane potential for Na+ at the peak of electrochemical differences into a propagated action its action potential can be predicted from the Nernst potential is called the threshold voltage, which is closely equation by substituting appropriate Na+ concentrations related to the stimulus duration—the longer the stimu- for those of K+. Thus, it appears that the excitable nerve lus, the lower the threshold voltage. An electrical stimu- membrane can be transformed from a potassium elec- lus of less than a certain voltage can only result in local trode to a sodium electrode during the active process electrochemical changes and cannot elicit a propagated (41). action potential. As the cell approaches its peak action potential, the membrane permeability to Na+ again decreases (Na+ REFRACTORINESS A state of absolute refractoriness (i.e., inactivation). If no other event occurred, this cell would complete inexcitability) occurs immediately after an slowly return to its resting potential, but the cell again impulse has been propagated, and no stimulus, no mat- becomes highly permeable to K+, allowing K+ to fl ow out ter how strong or long, can produce an excited state. into extracellular fl uid and quickly restore the mem- Shortly thereafter, the axon becomes relatively refrac- brane potential (repolarization). After an action poten- tory; it responds with a propagated impulse only to tial, the cell would therefore be left with a small increase stimulation that is greater than the normal thresh- in Na+ and a decrease in K+. To explain how the nerve old. The length of the refractory period is affected is restored to its original electrolyte composition at the by the frequency of stimulation and by many drugs resting potential, it is necessary to postulate a mechanism (Fig. 16.12).

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Nobel Prize in 1991 for physiology and for their work on ion channels with these (50).

OH OH OH H H OH H OH N N A OH OH N N O H2N H2N H H OH OH O O HO HO O OH (Lactone form) (Hemiacetal form) B Tetrodotoxin (TTX) FIGURE 16.12 Impulse propagation. (A) The wave of depolariza- O H3C tion passes down the nerve, followed by a wave of refractoriness. N H H2N O CH2 H3C O (B) The wave of refractoriness is followed by a wave of repolariza- H H H CH tion. (Adapted from De Jong RH, Freund FG. Physiology of periph- N N HO O 3 NH2 N CH3 eral nerve and local anesthesia. Int Anesthesiol Clin 1970;8:35–53, N H2N N H with permission.) OH O OH O HO H Saxitoxin (STX) Batrachotoxin CONDUCTANCE VELOCITY AND NODAL CONDUCTION The con- ductance velocity is the velocity at which an impulse is Recent mapping of receptor binding sites within the conducted along the nerve and is proportional to the channel protein for lipid-soluble neurotoxins, such as diameter of the axon. Because longitudinal resistance is batrachotoxin (BTX), and for local anesthetics using inversely proportional to cross-sectional area, impulses are site-directed mutagenesis has provided further insight conducted faster in large-diameter axons. The squid giant regarding these channels (49). For example, mammalian axon, used in many neurophysiology investigations, is voltage-gated Na+ channels contain one large a-subunit unmyelinated and exceptionally large (∼500 to 1,000 mm); and one or two smaller b-subunits (15). The primary therefore, impulses are conducted rapidly along the axon. structure of the a-subunit is composed of four homolo- However, contraction of the mantle of a squid, which this gous domains (D1 to D4), each with six transmembrane axon controls, is an uncomplicated procedure that does segments (S1 to S6) and a hydrophobic loop thought to not require a complex sensorimotor feedback system. dip into the membrane to align the aqueous pore into a Perhaps during evolution, vertebrates developed a com- pseudotetrameric arrangement (Fig. 16.13) (47–49). plicated input–output system of many axons collected in Furthermore, the voltage sensor for activation gating bundles, as shown in Figure 16.9. and the structure for fast inactivation gating have been Conduction along these neurons would be slow if delineated to involve the positively charged S4 segments they were not insulated with a myelin coat of connective of each domain (also known as the ion selectivity fi lter, tissue, interrupted at intervals by the nodes of Ranvier, which contains positively charged amino acid residues). where electrical current enters and exits. These ionic fl uxes occurring at the nodes allow the electrical impulse to jump along the axon from node to node much faster S6S2 S6 S2 than could occur in an unmyelinated axon (42). S4 S4 S5S3S1 S5 S3 S1

SODIUM CHANNEL The voltage-gated Na+ channels are dis- DIII DIV crete, membrane-bound glycoproteins that mediate Na+ permeability and, thus, are responsible for the genera- tion of action potentials in skeletal muscle, nerve, and Pore cardiac tissues (43–50). Our understanding of the struc- DIII DIV tural domains and binding sites on voltage-gated Na+ channels has evolved considerably since the fi rst cloning Hydrophobic Loop and expression studies of the channel protein by Noda (43). The channel gating kinetics have been extensively + studied with the use of selective blockers of Na channels, DII DI such as tetrodotoxin (TTX) and saxitoxin (STX), and by site-directed mutagenesis (49). Both TTX and STX bind FIGURE 16.13 A schematic representation of the a subunit of stoichiometrically to the outer opening of the channels the and the pore-forming unit. (From Anger T, and are detected with patch-clamp electrophysiologic Madge DJ, Mulla M, et al. Medicinal chemistry of neuronal voltage- techniques on the cut-open squid giant axon (50). Neher gated sodium channel blockers. J Med Chem 2001;44:115–137, and Sakmann, two German scientists, were awarded the with permission.)

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The selective fi lter discriminates Na+ from other ions In general, compounds containing an amide linkage (i.e., Na+ passes through this pore approximately 12-fold have greater chemical hydrolytic stability than do the faster than does K+). Sodium channels open and close ester types. In this regard, an aqueous solution of an as they switch between several conformational states: the amino ester–type local anesthetic is more likely to hydro- resting/closed form (polarized nonconducting state), lyze under normal conditions and cannot withstand heat the open channel (depolarized conducting state), and sterilization as a result of base-catalyzed hydrolysis of the the inactivated form (polarized nonconducting state). ester. At resting potential, the Na+ channels are in a resting/ Local anesthetic activity usually increases with increas- closed polarized state and are impermeable to the pas- ing lipid solubility. Unfortunately, this increase in lipid sage of Na+. On activation, the channels undergo confor- solubility is often inversely related to water solubility. For mational changes to an open depolarized state, allowing this reason, a suitable parenteral dosage form might not the rapid infl ux of Na+ across the neuronal membrane. be available for these agents because of poor water sol- Thus, when the threshold potential is exceeded, most ubility under acceptable conditions. For example, ben- of the Na+ channels are in an open, or conducting, state. zocaine, which lacks a suffi ciently basic aliphatic amino At the peak of the action potential, the open channels group needed for salt formation, is insoluble in water at spontaneously convert to an inactivated polarized state neutral pH. Protonation of the aromatic amino group in

by the “sodium pump” (i.e., nonconducting and non- benzocaine results in a salt with a pKa of 2.78, which is too activatable), leading to a decrease in Na+ permeability. acidic and, therefore, unsuitable for use as a parenteral When a Na+ channel is in the inactivated polarized state, dosage form for injection. For this reason, benzocaine it cannot be opened without fi rst being transformed to and its closely related analog, , are used mostly the normal resting/closed form. in creams or ointments to provide topical anesthesia of accessible mucous membranes or skin for burns, cuts, or Therapeutic Considerations for Using Local infl amed mucous surfaces. Anesthetic Drugs Many attempts have been made to substitute oils, fats, Since the discovery of cocaine in 1880 as a surgical local or fl uid polymers for the aqueous vehicle commonly anesthetic, several thousand new compounds have been used in injectable local anesthetics. Unfortunately, the tested and found to produce anesthesia by blocking pharmacologic results of these experiments have been nerve conductance. Among these agents, approximately quite disappointing, often as a result of the undesirable 20 are currently clinically available in the United States toxicity of the nonaqueous vehicle. as local anesthetic preparations (Table 16.8). Table 16.9 The only commonly accepted organic additives to contains chemical structures of the different types of local anesthetics are vasoconstrictors, such as epineph- agents in current or recent use. rine and levonordefrin (a-methylnorepinephrine). These compounds often increase the frequency of suc- Pharmaceutical Preparations cessful anesthesia and, to a limited degree, increase the Local anesthetic agents generally are prepared in various duration of activity by reducing the rate of drug loss from dosage forms: aqueous solutions for parenteral injection, the injection site, by constricting arterioles that supply and creams and ointments for topical applications. Thus, blood to the area of the injection. The effect of these chemical stability and aqueous solubility become primary vasoconstrictors is less pronounced if the vasoconstrictors factors in the preparations of suitable pharmaceutical are added to a local anesthetic solution that is injected in dosage forms. an area that has profuse venous drainage but is remote from an arterial supply. By slowing the diffusion of the local anesthetic away from the targeted site of injection, WHAT ARE THE SOURCES OF THESE the exposure of other tissues in the body is likely mini- mized such that the local anesthetic never reaches high NEUROTOXINS? enough concentrations to produce unwanted toxicities. However, there is a fl ip slide to the benefi t of the use of TTX is a potent isolated from the ovaries and liver vasoconstrictors: A prolonged local anesthetic effect long of many marine species of Tetraodontidae, especially the after the surgical procedure is completed can lead to pro- Japanese fugu (or puffer fish). STX, produced by the marine longed numbness and inadvertent soft tissue damage due dinoflagellates, Gonyaulax catenella or Gonyaulax tamarensis, to mechanical irritation (e.g., biting one’s lip or tongue is found concentrated in certain bivalve shellfish (e.g., mussels and clams). Consumption of contaminated mussels or clams following dental procedures) as a result of the contin- causes paralytic shellfish poisoning, which is usually associated ued loss of pain sensations. Soft tissue injury to the lip in with toxic “red tide” environmental episodes in various coastal children 4 to 7 years of age following mandibular nerve regions. BTX, a cardiotoxic and neurotoxic steroid isolated block has been reported to be as high as 16%. Recently, originally from the poisonous dart frog, Phyllobates terribilis, an approach to reverse the vasoconstrictor-induced pro- is a lipid-soluble neurotoxin that is at least 10-fold more toxic longed anesthetic state has utilized phentolamine, an than TTX. a-adrenoceptor antagonist. Phentolamine mesylate in doses of 0.4 to 0.8 mg in adults and adolescents and 0.2

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TABLE 16.8 Clinically Available Local Anesthetics

Generic Name Trade Name Recommended Application

Articaine Septocaine, Septanest Parenteral (dental)

Benoxinate Mainly in

Benzocaine Americaine, Anbesol, Benzodent, Orajel, Oratect, Topical Rid-A-Pain, Hurricaine

Benzyl alcohol Topical, mainly in combination with pramoxine

Bupivacaine Marcaine, Sensorcaine Parenteral

Butamben Butesin Topical

Chloroprocaine Nesacaine Parenteral

Dibucaine Nupercainal, Topical

Dyclonine Sucrets Topical (mucosal only)

Etidocaine Duranest Parenteral

Ethyl chloride Extracutaneous, temperature decreasing

Eugenol Topical, especially in

Levobupivacaine Chirocaine Parenteral

Lidocaine Xylocaine, L-Caine, DermaFlex, Dilocaine, Lidoject, Parenteral, topical Lignocaine, Octocaine,

Mepivacaine Carbocaine, Polocaine, Isocaine Parenteral, topical

Menthol Chloraseptic lozenges, Dermoplast, Pramegel, Topical, mainly in combination with benzocaine or pramoxine Pontacaine ointment or tetracaine

Phenol Anbesol Topical, mainly in combination with benzocaine

Pramoxine Prax, Tronothane Topical

Prilocaine Citanest Parenteral, topical

Procaine Novocain Parenteral

Proparacaine Alcaine, Ophthaine, Ak-Taine Mainly in ophthalmology

Propoxycaine Blockaine, Ravocaine Parenteral

Ropivacaine Naropin Parenteral

Tetracaine Pontocaine, Amethocaine, Prax Parenteral, topical

to 0.4 mg in children reverses the and of the classic local anesthetic agents that can result in sig- allows for a more rapid diffusion of the local anesthetic nifi cant clinical advantages. from the injection site and a recovery of sensation (51). A Eutectic Mixture of a Local Anesthetic (EMLA) Administration of a local anesthetic in a carbonic acid– containing 2.5% lidocaine and 2.5% prilocaine carbon dioxide aqueous solution rather than the usual (or ) is used for the topical application of local solution of a hydrochloride salt appreciably improves anesthetic through the keratinized layer of the intact skin the time of onset and duration of action without causing to provide dermal or epidermal analgesia. This mode of increased local or systemic toxicity. administration allows the use of higher concentrations of Carbon dioxide is believed to potentiate the action local anesthetic with minimal local irritation and lower of local anesthetics by initial indirect depression of the systemic toxicity. The use of EMLA creams, especially axon, followed by diffusion trapping of the active form of those containing prilocaine, on mucous membranes the local anesthetic within the nerve. Use of the carbon- is not recommended, however, because of the faster ate salt appears to be one pharmaceutical modifi cation absorption of the drugs and, therefore, the increasing

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TABLE 16.9 Structures of Local Anesthetics

risk of systemic toxicity, such as , neuromuscular junctions and the CNS are more suscep- specifi cally with prilocaine (52). tible than the cardiovascular system to the toxic effects of local anesthetics. Toxicity and The actions on skeletal muscles tend to be transient The side effects and toxicity of local anesthetics seem to and reversible, whereas the CNS side effects can be more be related to their actions on other excitable membrane deleterious. The primary effect of the toxicity seems to proteins, such as in the Na+ and K+ channels in the heart, be convulsions, followed by severe CNS depression, par- the nicotinic acetylcholine receptors in the neuromuscu- ticularly of the respiratory and cardiovascular centers. lar junctions, and the nerve cells in the CNS. In general, This can be related to an initial depression of inhibitory

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neurons, such as GABAergic systems, causing convul- fl exibility and responsiveness to changes in electrical sions, followed by depression of other neurons, leading fi elds. to general depression of the CNS. The nonspecifi c membrane actions of local anesthet- The amino amide–type local anesthetics (i.e., lido- ics can be easily ruled out, because most clinically use- caine derivatives) are, in general, more likely to produce ful agents, in contrast to general anesthetics, possess a CNS side effects than the amino ester–type compounds defi ned set of structure–activity relationships. At much (procaine analog). However, it should be noted that the higher drug concentrations, local anesthetics also bind toxic effects observed depend heavily on the route and and block K+ channels. site of administration as well as on the lipid solubility and metabolic stability of a given local anesthetic mol- INTERACTION WITH PHOSPHOLIPIDS AND CALCIUM Calcium ecule. For example, most amide-type local anesthetics, exists in the membrane in a bound state. Many inves- such as lidocaine, are fi rst degraded via N-dealkylation tigators believe that the release of the bound calcium by hepatic enzymes (see Fig. 16.17). Unlike lidocaine, is the fi rst step in membrane depolarization and that however, the initial metabolic degradation of prilocaine this release leads to the changes in ionic permeability in humans is hydrolysis of the amide linkage to give described previously. It has been suggested that local o- and N-propylalanine. Formation of o-tolu- anesthetics displace the bound calcium from these sites idine and its metabolites can cause methemoglobin- and form more stable bonds, thereby inhibiting ionic emia in some patients (52). For this reason, prilocaine is fl uxes. The following evidence has been offered in sup- much more likely than other local anesthetics to cause port of this theory: Both calcium and local anesthetics methemoglobinemia. bind to phospholipids in vitro, reducing their fl exibil- In contrast, allergic reactions to local anesthetics, ity and responsiveness to changes in electrical fi elds although rare, are known to occur exclusively with p-ami- (56–58). Also, membrane excitability and instability nobenzoic acid (PABA) ester-type local anesthetics (53). increase in calcium-defi cient solutions. Local anesthet- Whether the formation of PABA upon ester hydrolysis is ics counteract this abnormal increase in excitability, solely responsible for this hypersensitivity remains to be and more local anesthetic is necessary to block excita- determined. However, the preservative compounds, such tion in calcium-poor solutions (59). Direct proof of this as methylparaben, used in the preparation of amide-type hypothesis, however, is lacking because of the diffi culty local anesthetics are metabolized to the PABA-like sub- in measuring temporal Ca2+ movements in vivo. It is stance, p-hydroxybenzoic acid. Thus, patients who are also possible that the aforementioned cause-and-effect allergic to amino ester–type local anesthetics should be relationship between intracellular free Ca2+ and mem- treated with a preservative-free amino amide–type local brane excitability is the result of an Na+–Ca2+ exchange anesthetic. reaction; that is, the infl ux of Na+ displaces the mem- Amide-type local anesthetics (e.g., procainamide brane-bound calcium, which leads to an increase of and lidocaine) also possess antiarrhythmic activity intracellular free Ca2+ and, thereby, increases cellular when given parenterally and at a subanesthetic dos- excitability. age. Although this action is likely an extension of Local anesthetics interact differently, however, with their effects on Na+ channels in cardiac tissues, some neuronal phospholipids with or without the presence of evidence suggests a distinctly different mechanism . Thus, the interactions of local anesthetics of action with respect to the modulation of channel with the cellular membranes actually may help to explain receptors and the location of binding sites for these some of the observed differences in toxicity of the indi- compounds (54,55). vidual local anesthetic agents (60).

Chemical and Pharmacodynamic Aspects of Local ACTION ON VOLTAGE-SENSITIVE SODIUM CHANNELS Anesthetics As mentioned, the voltage-sensitive Na+ channels are Mechanism of Action membrane-bound glycoproteins that mediate Na+ per- Local anesthetics act by decreasing the excitability meability. On excitation, these channels undergo con- of nerve cells without affecting the resting potential. formational changes from a closed to an open state, Because the action potential, or the ability of nerve cells thus allowing a rapid infl ux of sodium. The movement to be excited, is associated with the movement of Na+ of Na+ is blocked by the neurotoxins TTX and STX and across the nerve membranes, anything that interferes by local anesthetics (61). Most electrophysiologists and with the movement of these ions will interfere with cell neuropharmacologists now agree that the mechanism excitability. For this reason, many hypotheses have been of action of local anesthetics results primarily from suggested to explain how local anesthetics regulate the their binding to one or more sites within the Na+ chan- changes in Na+ permeability that underlie the nerve nels, thus blocking Na+ conductance (62). However, impulse. These hypotheses include direct action on ionic the exact location of these binding sites and whether channels that interfere with ionic fl uxes and interaction all local anesthetics interact with a common site remain with phospholipids and calcium that reduces membrane matters of dispute.

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ACTION ON SODIUM CONDUCTANCE Local anesthetics block forms, this result again suggests that the onium ions are Na+ conductance by two possible modes of action: tonic required for binding to the channel receptors. Narahashi inhibition and phasic inhibition (63,64). Tonic inhibi- and Frazier (68) further estimated that approximately tion results from the binding of local anesthetics to non- 90% of the blocking actions of lidocaine can be attrib- activated closed Na+ channels and, thus, is independent uted to onium forms of the drug molecule, whereas only of channel activation. Phasic inhibition is accomplished approximately 10% can result from un-ionized molecule when local anesthetics bind to activated, open states and, perhaps, at a hydrophobic binding site other than (conducting) or to inactivated states (nonconducting) of the primary binding site. Benzocaine, because of its lack + the Na channels. Thus, it is not surprising that a greater of a basic group (pKa = 2.78), and other neutral phasic inhibition usually is obtained with repetitive depo- anesthetics, such as , have been suggested larization and is referred to as use-dependent blockade. to bind to this hydrophobic binding site. Two reasons have been suggested to explain this obser- In 1984, Hille (69) proposed a unifi ed theory involv- vation. First, channel inactivation during depolarization ing a single binding site in the Na+ channels for both increases the number of binding sites that normally are onium ions (protonated tertiary and quaternary inaccessible to local anesthetics at resting potential. Second, ammonium compounds) and un-ionized forms of local both the open and the inactivated channels possess bind- anesthetics. As depicted in Figure 16.14, a number of

ing sites with a higher affi nity; therefore, local anesthetics pathways are available, depending on the size, pKa, and bind more tightly and result in a more stable nerve block. lipid solubility of the drug molecules as well as the volt- Furthermore, it is generally agreed that most of the age and frequency-dependent modulation of the chan- clinically useful local anesthetics exert their actions by nel states, for a drug to reach its binding sites. Protonated binding to the inactivated forms of the channels and, anesthetic molecules [BH+] and quaternary ammonium thus, prevent their transition to the original resting state compounds reach their target sites via the hydrophilic (64). Because most of these drugs exhibit both tonic pathway externally (pathway b in Fig. 16.14), which is and phasic inhibitions, whether tonic and phasic block available only during channel activation. results from at the same or different The lipid-soluble anesthetic molecules, on the other sites remains unclear. hand, diffuse across the neuronal membrane in their un- ionized forms. They can interact with the same binding sites from either the hydrophilic pathway (pathway b′ in LOCAL ANESTHETICS BINDING TO SODIUM CHANNELS Most of the Fig. 16.14) on reprotonation to their onium ions [BH+] clinically useful local anesthetics are tertiary amines with or via the hydrophobic pathway (pathway a in Fig. 16.14) a pK of 7.0 to 9.0. Thus, under physiologic conditions, a in their un-ionized forms [B]. Benzocaine and other both protonated forms (onium ions) and the un-ionized, nonbasic local anesthetic molecules use this hydropho- molecular forms are available for binding to the channel bic pathway and, thus, bind in the hydrophobic domain proteins. In fact, the ratio between the onium ions [BH+] to produce their actions. Site-directed mutagenesis stud- and the un-ionized molecules [B] can be easily calcu- ies (70–73) suggest that local anesthetics bind to the lated based on the pH of the medium and the pK of the a hydrophobic amino acid residues near the center and drug molecule by the Henderson-Hasselbalch equation: the intracellular end of the S6 segment in the domain + pH = pKa − log [BH ]/[B] External membrane The effect of pH changes on the potency of local anes- thetics has been extensively investigated (65). Based on B + H BH b these studies, it was concluded that local anesthetics block TTX,STX binding site the action potential by fi rst penetrating the nerve mem- a brane in their un-ionized forms and then binding to a site within the channels in their onium forms. Perhaps the most selective direct support for this hypothesis comes from the experi- filter mental results of Narahashi et al. (66,67), who studied the B effects of internal and external perfusion of local anesthet- a ics (both tertiary amines and quaternary ammonium com- + pounds), at different pH values, on the Na conductance Local anesthetic binding site of the squid giant axon. The observation that both tertiary b' amines and quaternary ammonium compounds produce B + H BH greater nerve blockage when applied internally indicates an axoplasmic site of action for these compounds. Internal membrane Furthermore, only the tertiary amines exhibit a reduc- FIGURE 16.14 Model of a sodium channel, as suggested by Hille tion in their local anesthetic activities when the inter- (69), depicting a hydrophilic pathway (denoted by b and b′) and nal pH is raised from 7.0 to 8.0. Because the increase of a hydrophobic pathway (denoted by a) by which local anesthetics internal pH to 8.0 favors the existence of the un-ionized can reach their binding sites.

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D4, whereas the BTX receptor is within segment S6 in and appear to play an important role in the binding of domain D1 of the a subunit of the Na+ channels (Fig. local anesthetics to the channel proteins. Structural mod- 16.14) (49). ifi cation of this portion of the molecule has a profound effect on its physical and chemical properties, which in Structure–Activity Relationships turn alters its local anesthetic properties. A quick perusal of Table 16.9 reveals that many diverse In the amino ester series, an electron-donating sub- chemical structures possess local anesthetic proper- stituent in the ortho or para (or both) positions increases ties: (procaine analogs), amino amides local anesthetic potency. Such groups as an aromatic (lidocaine analogs), amino ethers (pramoxine), amino amino (procaine, chloroprocaine, and ), ketones (dyclonine), alcohols (benzyl alcohol and men- an alkylamino (tetracaine), or an alkoxy (proparacaine thol), and ( and ). Although it and propoxycaine) group contribute electron density would seem that there is no obvious structure–activity rela- to the aromatic ring by both resonance and inductive tionship among these agents, most of the clinically useful effects, thereby enhancing local anesthetic potency over

local anesthetics are tertiary amines with pKa values of 7.0 nonsubstituted analogs (e.g., ). to 9.0. These compounds exhibit their local anesthetic As illustrated in Figure 16.16, resonance is expected properties by virtue of the interactions of the onium ions to give rise to a zwitterionic form (i.e., the electrons with a selective binding site within the Na+ channels (Fig. from the amino group can be resonance delocalized 16.14). For this reason, any structural modifi cations that onto the carbonyl oxygen). Although neither drawn

alter the lipid solubility, pKa, and metabolic inactivation structure of procaine in Figure 16.16 can accurately have a pronounced effect on the ability of a drug mol- represent the structure of procaine when it interacts ecule to reach or interact with the hypothetical binding with the local anesthetic binding site, it is reasonable sites, thus modifying its local anesthetic properties. to assume that the greater the resemblance to the zwit- terionic form, the greater the affi nity for the binding LIPOPHILIC PORTION The lipophilic portion of the molecule site (i.e., binding from both the hydrophilic pathway is essential for local anesthetic activity. For most of the b′ and hydrophobic pathway a in Fig. 16.14). This is clinically useful local anesthetics, this portion of the particularly true for the affi nity of benzocaine for its molecule consists of either an aromatic group directly binding site, because it lacks a basic amine group. attached to a carbonyl function (the amino ester series) Therefore, it can only bind from the hydrophobic or a 2,6-dimethylphenyl group attached to a carbonyl pathway a. Thus, addition of any aromatic substitution function through an —NH— group (the amino amide that can enhance the formation of the resonance form series) (Fig. 16.15). Both groups are highly lipophilic through electron donation or inductive effects will produce more potent local anesthetic agents. Electron-

withdrawing groups, such as nitro (—NO2), reduce the O local anesthetic activity. H2N C O CH2 CH2 N(C2H5)2 Procaine O

H2N CH2 C O CH2 CH2 N(C2H5)2 CH3 O H N C CH N(C H ) 2 2 5 2 Lidocaine Insertion of a methylene group between the aromatic CH3 moiety and the carbonyl function as shown above in the procaine molecule, which prohibits the formation of the

C4H7O O CH2 CH2 CH2 N O Pramoxine zwitterionic form, has led to a procaine analog with greatly reduced anesthetic potency. This observation lends fur- ther support for the involvement of the resonance form O CH 3 H when an ester-type local anesthetic binds to the binding C OCH2 C N C3H7 Meprylcaine CH3

CH3 O H N C O C2H5 +H O C H N Bupivacaine 2 5 H2N N H2N N C4H9 O O C2H5 CH3 C2H5 -H H O

H2N C O CH2 CH3 Benzocaine

O Lipophilic Intermediate Hydrophilic O C H C2H5 portiion chain portion 2 5 H N N H2N N 2 C H C H O 2 5 O 2 5 H FIGURE 16.15 Structure–activity relationship comparison of local anesthetics. FIGURE 16.16 Possible zwitterionic forms for procaine.

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site. When an amino or an alkoxy group is attached to the reduces local anesthetic potency as a result of a reduction meta position of the aromatic ring, however, no resonance of onium ions under physiologic conditions. As men- delocalization of their electrons is possible. The addition tioned earlier, the onium ions are required for effective of this function only increases (alkoxy group) or binding of the amino amide–type local anesthetics to the decreases (amino group) the lipophilicity of the mole- channel binding sites.

cule (e.g., benoxinate, logDpH 7.4 = 3.19; and proparacaine, YDROPHILIC ORTION logDpH 7.4 = 2.05). H P Most clinically useful local anesthetics Furthermore, tetracaine is approximately 50-fold have a tertiary alkylamine, which readily forms water-solu- more potent than procaine. Experimentally, this increase ble salts with acids, and this portion is commonly in potency cannot be correlated solely with the 2,500- considered to be the hydrophilic portion of the molecule fold increase of lipid solubility by the n-butyl group (Fig. 16.9). The necessity of this portion of the molecule

(logDpH 7.4 = 2.73 vs. procaine logDpH 7.4 = −0.32). Perhaps for amino ester–type local anesthetics remains a matter part of this potentiation of local anesthetic activity can of debate. The strongest opposition for requiring a basic be attributed to the electron-releasing property of the amino group for local anesthetic action comes from the n-butyl group via the inductive effect, which indirectly observation that benzocaine, which lacks the basic ali- enhances the electron density of the p-amino group, phatic amine function, has potent local anesthetic activ- which in turn increases the formation of the zwitterionic ity. For this reason, it is often suggested that the tertiary form available for interaction with the binding site pro- amine function in procaine analogs is needed only for the teins via both the hydrophobic and the hydrophilic path- formation of water-soluble salts suitable for pharmaceuti- ways of the receptor. cal preparations. With the understanding of the voltage- Another important aspect of aromatic substitution activated Na+ channel and the possible mechanism of has been observed from structure–activity relationship action of local anesthetics previously discussed, however, studies. In the amino amides (lidocaine analogs), the it is quite conceivable that the onium ions produced by o,o′-dimethyl groups are required to provide suitable protonation of the tertiary amine group are also required protection from amide hydrolysis to ensure a desirable for binding in the voltage-gated Na+ channels (Fig. 16.14). duration of action. Similar conclusions can be made to From Table 16.9, the hydrophilic group in most of the rationalize the increase in the duration of action of pro- clinically useful drugs can be in the form of a secondary poxycaine by the o-propoxy group. The shorter duration or tertiary alkyl amine or part of a heterocycle of action, however, observed with chloroprocaine when (e.g., , , or morpholine). As men- compared with that of procaine can only be explained by tioned earlier, most of the clinically useful local anesthet-

the inductive effect of the o-chloro group, which pulls the ics have pKa values of 7.5 to 9.0. The effects of an alkyl electron density away from the carbonyl function, thus substituent on the pKa depend on the size, length, and making it more susceptible to nucleophilic attack by the hydrophobicity of the group; and thus, it is diffi cult to plasma . see a clear structure–activity relationship among these structures. It is generally accepted that local anesthetics NTERMEDIATE HAIN I C The intermediate chain almost always with higher lipid solubility and lower pKa values appear contains a short alkyl chain of one to three carbons in to exhibit more rapid onset and lower toxicity. length linked to the aromatic ring via several possible organic functional groups. The nature of this intermedi- ate chain determines the chemical stability of the drug, Are there any stereochemical requirements of local anes- which also infl uences the duration of action and relative thetic compounds when they interact with the Na+ channel toxicity. In general, amino amides are more resistant to binding sites? A number of clinically used local anesthet- metabolic hydrolysis than the amino esters and, thus, ics do contain a chiral center (i.e., bupivacaine, etido- have a longer duration of action. The placement of small caine, mepivacaine, and prilocaine) (Table 16.9), but in alkyl groups (i.e., branching), especially around the ester contrast to other classes of drugs (e.g., ), the function (e.g., meprylcaine) or the amide function (e.g., effect of optical isomerism on isolated nerve preparations bupivacaine, etidocaine, prilocaine, or ropivacaine), revealed a lack of stereospecifi city. In a few cases (e.g., also hinders - or amidase-catalyzed hydrolysis, prilocaine, bupivacaine, and etidocaine), however, small prolonging the duration of action (Fig. 16.15 and Table differences in the total pharmacologic profi le of optical 16.9). It should be mentioned, however, that prolonging isomers have been noted when administered in vivo (76– the duration of action of a compound usually increases 78). Whether these differences result from differences its systemic toxicities unless it is more selective toward the in uptake, distribution, and metabolism or from direct voltage-gated Na+ channel, as in the case of levobupiva- binding to the Na+ channel have not been determined. caine (74,75). When structural rigidity has been imposed on the mol- In the lidocaine series, lengthening of the alkyl chain ecule, however, as in the case of some aminoalkyl spirot- etralin succinimides (79), differences in local anesthetic from one to two or three increases the pKa of the terminal tertiary amino group from 7.7 to 9.0 or 9.5, respectively. potency of the enantiomers have been observed (range, Thus, lengthening of the intermediate chain effectively 1:2 to 1:10). Although these differences in enantiomers

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clearly are not as pronounced as those with other phar- The amino amide–type local anesthetics, however, are macologic agents, such as adrenergic antagonists or anti- metabolized primarily in the liver, involving CYP1A2 iso- drugs, steric requirements are necessary for zymes (84). A general metabolic scheme for lidocaine is effective interaction between a local anesthetic agent and shown in Figure 16.17. its proposed channel binding sites. Marked species variations occur in the quantitative urinary excretion of these metabolites. For example, O (CH2)n-NRR' N rats produce large quantities of the 3-hydroxy deriva- n = 2 to 4 tives of both lidocaine and monoethylglycinexylidide, O which are subsequently conjugated and recycled in the R and R' = alkyl or hydroxyethyl group bile. Signifi cant quantities of these two metabolites, how- N-Aminoalkyl spirotetralin ever, are not produced by guinea pigs, dogs, or humans. succinimides Therefore, it is unlikely that biliary excretion is a major pathway for excretion in humans. Species variability is Stereochemistry of the local anesthetics, however, important primarily when the acute and chronic tox- plays an important role in their observed toxicity and icity of nonester-type local anesthetic agents is being pharmacokinetic properties. For example, ropivacaine evaluated. and levobupivacaine, the only optically active local anes- Although the exact mechanism for the CNS toxicity of thetics currently being marketed, have considerably lidocaine remains unclear, the metabolic studies of lido- lower cardiac toxicities than their close structural analog, caine provide some insight for future studies. Of all the bupivacaine (80). Furthermore, the degree of separation metabolites of lidocaine, only monoethylglycinexylidide between motor and sensory blockade is more apparent (and not glycinexylidide) contributes to some of the CNS with ropivacaine and levobupivacaine relative to bupi- side effects of lidocaine. This observation suggests that vacaine at a lower end of the dosage scale (81). Thus, the toxicities of lidocaine are, perhaps, related to the the observed cardiac toxicity of bupivacaine has been attributed to the R-(+)-bupivacaine enantiomer (76–78). The exact mechanisms for this enantiomeric difference Conguates Conguates remain unknown. Longobardo and colleagues observed a stereoselective blockade on the cardiac hKv1.5 channels by the R-(+)-enantiomers of bupivacaine, ropivacaine, OH OH and mepivacaine (82,83). It should be noted that S-(−)- CH3 CH3 O O H bupivacaine, which is approved by the U.S. Food and N N N N Drug Administration and marketed under the name of H H CH3 CH3 Chirocaine, has even less CNS toxicity than ropivacaine. 3-Hydroxylidocaine 3-Hydroxylmonoethylglycinexylidide Metabolism of Local Anesthetics CYP1A2 An understanding of the metabolism of local anesthetics H CH3 CYP1A2 is important in clinical practice because the overall toxic- CH3 O CH3 ity of a drug depends not only on its uptake and tissue O O H distribution but also on how it is deactivated in vivo. The N N N N H N-dealkylation H amino ester–type local anesthetics are rapidly hydrolyzed CH3 (CYP1A2) CH3 by plasma (also known as pseudocholines- Lidocaine Monoethylglycinexylidide terase), which is widely distributed in body tissues. These CNS toxicities (CNS toxicities) compounds can therefore be metabolized in the blood, kidneys, and liver and, to a lesser extent, at the site of H CH3 administration. For example, both procaine and benzo- O

HO CH3 CH3 caine are easily hydrolyzed by cholinesterase into PABA CH3 and the corresponding N,N′-diethylaminoethyl alcohol. NH2 NH2 It is not surprising that potential drug interactions NH NH2 CH3 CH3 exist between the amino ester–type local anesthetics and H3C O other clinically important drugs, such as cholinesterase 2,6-Xylidine Glycinexylidide inhibitors or -like drugs (see (No CNS toxicity) Chapter 9). These compounds either inhibit or compete with local anesthetics for cholinesterases, therefore pro- longing local anesthetic activity and/or toxicity. Another CH3

potential drug interaction with clinical signifi cance can Conguates NH2 be envisioned between benzocaine and sulfonamides; COOH that is, the hydrolysis of benzocaine to PABA can antago- nize the antibacterial activity of sulfonamides. FIGURE 16.17 Metabolic scheme for lidocaine.

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removal of the N-ethyl groups of lidocaine after crossing prone to being infl uenced by induction or inhi- the blood–brain barrier. Support for this hypothesis can bition due to other coadministered medications (e.g., be obtained from the fact that reaction of a tryptophan cimetidine and barbiturates). derivative with formaldehyde under physiologic condi- tions gives rise to a b-carboline derivative, which is a CNS Common Agents Used for Local Anesthesia

convulsant (Fig. 16.18). Advances in the GABAA recep- Local anesthetics are widely used in many primary care tor– receptor–chloride ion channels and settings. Techniques for their administration in these set- their role in the mechanism of action of benzodiazepine tings include topical application, local infi ltration, fi eld anticonvulsants lends further support to this hypothesis block, and peripheral nerve block. Their use can be max- (i.e., many b-carbolines are inverse agonists at the benzo- imized by an understanding of their potencies, durations diazepine binding site). of action, routes of administration, and pharmacokinetic and side effect profi les. The generic name, trade name, CH3 O CH3 O and recommended application are given in Table 16.8, C N CH HN HN 3 and the chemical structures of these agents can be found NH2 H3C CH3 H3C COOCH3 in Table 16.9. Articaine Tolycaine Articaine (Table 16.9) has been widely used in dentistry since its U.S. Food and Drug Administration approval in To minimize these unwanted side effects of lido- 2000 due to its quick onset and short duration of action. caine, tocainide and tolycaine have been prepared The structure of articaine differs from the structures of and found to possess good local anesthetic activity all other amino amide–type local anesthetics in that it without any appreciable CNS side effects. Tocainide, contains the bioisosteric thiophene ring instead of a ben- which lacks the vulnerable N-ethyl group but has an zene ring and a carbomethoxy group. This renders the a- to prevent degradation of the primary molecule more lipophilic and, thus, makes it easier to amine group from amine oxidase, has desirable local cross lipoidal membranes. anesthetic properties. Tolycaine has an o-carbomethoxy Its local anesthetic potency is approximately 1.5-fold

substituted for one of the o-methyl groups of lidocaine. that of lidocaine, even though it has similar pKa (7.8) The carbomethoxy group is fairly stable in tissues but is and smaller log DpH 7.4 (1.65 vs. logDpH 7.4 of 2.26 for lido- rapidly hydrolyzed in the blood to the polar carboxyl- caine) and (76%) properties. ate group and, thus, is unable to cross the blood–brain Articaine is metabolized primarily by plasma cholines- barrier. terases because of the presence of an ester group and, For this reason, tolycaine lacks any CNS side effects, therefore, has a much shorter duration of action than even though it still contains the N-ethyl group. It should lidocaine (i.e., only approximately one-fourth that of be noted, however, that both tocainide and tolycaine are lidocaine). Articaine undergoes rapid hydrolysis of the primarily used clinically as antiarrhythmic agents. carbomethoxy group to give articainic acid, which is Furthermore, the metabolism of nonester-type drugs, eliminated either unchanged (75%) or as its glucuro- especially lidocaine derivatives, is also known to be more nides (25%). Compared with other short-acting, amino amide–type local anesthetics, such as mepivacaine, lido- caine, or prilocaine, articaine is said to be a much safer X COOR R' H drug for regional anesthesia and is the drug of choice for H N H + N 2 O dental procedures. H

Tryptophan derivative Acetaldehyde Benzocaine (e.g., serotonin) (R' = CH3) Benzocaine (Table 16.9) is used topically by itself or in combination with or phenol in nonprescription dosage forms such as gels, creams, ointments, lotions, aerosols, and lozenges to relieve pain or irritation caused by such conditions as , insect bites, , COOR teething, cold sores or canker sores in or around the mouth, and fever blisters. Benzocaine is a lipophilic local X N anesthetic agent with a short duration of action. N H R' Like most amino ester–type local anesthetics, it is -Carboline derivative easily hydrolyzed by plasma cholinesterase. However, (known CNS convulsants when because of its low pKa, it is un-ionized under most physi- R'= small alkyl groups) ologic conditions and, therefore, can only bind to the

FIGURE 16.18 Reaction of a tryptophan derivative with acetalde- lipid site in the sodium channel (logDpH 7.4 = 1.91) (Fig. hyde under physiologic conditions. 16.14). When administered topically to abraded skin, it

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can easily cross membranes into the systemic circulation with prilocaine or etidocaine as a eutectic mixture that to cause systemic toxicities. Furthermore, being a PABA is very popular with pediatric patients. The use of lido- derivative, it has similar allergenic properties to procaine caine–epinephrine mixtures should be avoided, however, and is contraindicated with sulfonamide antibacterial in the areas with limited vascular supply to prevent tis- agents. sue . Lidocaine is also frequently used as a class IB for the treatment of ventricular Bupivacaine and Levobupivacaine arrhythmias, both because it binds and inhibits Na+ chan- Bupivacaine hydrochloride (Table 16.8) is a race- nels in the cardiac muscle and because of its longer dura- mic mixture of the S-(−)- and R-(+)-enantiomers. tion of action than amino ester–type local anesthetics

Bupivacaine has higher lipid solubility (logDpH 7.4 = (Chapter 21). 2.54) and a much decreased rate of hepatic degra- CNS changes are the most frequently observed dation compared with lidocaine. For this reason, systemic toxicities of lidocaine. The initial manifesta- bupivacaine has signifi cantly greater tendency than tions are restlessness, vertigo, , slurred speech, lidocaine to produce cardiotoxicity. Because of its and eventually, . Subsequent manifestations greater affi nity for voltage-gated Na+ channels, the include CNS depression with a cessation of convul- R-(+)-enantiomer confers greater cardiotoxicity than sions and the onset of unconsciousness and respira- racemic bupivacaine. tory depression or . This biphasic effect It was not surprising to see the approval of levobupiva- occurs because local anesthetics initially block the caine, the S-(-)-enantiomer of (±)-bupivacaine, as the sec- inhibitory GABAergic pathways, resulting in stimula- ond optically active, amino amide–type local anesthetic tion, and eventually block both inhibitory and excit- for parenteral applications. Like ropivacaine, levobupiva- atory pathways (i.e., block the Na+ channels associated caine has a lower cardiotoxicity than bupivacaine, but it with the NMDA receptors, resulting in overall CNS also has a lower CNS toxicity than both ropivacaine and inhibition) (85). lidocaine. Lidocaine is extensively metabolized in the liver by Possible pathways for metabolism of bupivacaine CYP3A4 N-dealkylation and aromatic cata- include CYP1A2 aromatic 3-hydroxylation, CYP3A4 lyzed by CYP1A2 (Fig. 16.17). Lidocaine also possesses a N-dealkylation, and to a minor extent, the amide hydro- weak inhibitory activity toward the CYP1A2 isozymes and, lysis. Only the N-dealkylated product, however, has been therefore, can interfere with metabolism of other medi- identifi ed in urine after epidural or spinal anesthesia. cations (86).

Chloroprocaine Mepivacaine Chloroprocaine (Fig. 16.8) is a very short-acting, amino Mepivacaine hydrochloride (Fig. 16.8) is an amino ester–type local anesthetic used to provide regional amide–type local anesthetic agent widely used to provide anesthesia by infi ltration as well as by peripheral and regional analgesia and anesthesia by local infi ltration, central nerve block, including lumbar and caudal epi- peripheral nerve block, and epidural and caudal blocks. dural blocks. The presence of a chlorine atom ortho to The pharmacologic and toxicologic profi le of mepiva- the carbonyl of the ester function increases its lipophilic- caine is quite similar to that of lidocaine, except that

ity (logDpH 7.4 = 0.95) and its rate of hydrolysis by plasma mepivacaine is less lipophilic (logDpH 7.4 = 1.95) and has a cholinesterase at least threefold compared to procaine slightly longer duration of action but lacks the vasodila- and benzocaine. Thus, chloroprocaine can be used in tor activity of lidocaine. For this reason, it serves as an maternal and neonatal patients with minimal placental alternate choice for lidocaine when addition of epineph- passage of chloroprocaine. The lower plasma cholines- rine is not recommended in patients with hypertensive terase activity in the maternal epidural space must still . have suffi cient activity for degrading chloroprocaine Mepivacaine undergoes extensive hepatic metabo- and, thus, not allowing it to cross the placental barrier. lism catalyzed by CYP3A4 and CYP1A2, with only a small Like PABA, the hydrolysis product of chloroprocaine, percentage of the administered dosage (<10%) being 4-amino-2-chlorobenzoic acid, also inhibits the action excreted unchanged in the urine. The major metabolic of sulfonamides. Therefore, its use with sulfonamides biotransformations of mepivacaine are N-dealkylation should be avoided. (to give the N-demethylated compound 2′,6′-pipecolox- ylidide) and aromatic . These metabolites Lidocaine are excreted as their corresponding glucuronides. Lidocaine (Fig. 16.8) is the most commonly used amino amide–type local anesthetic. Lidocaine is very lipid solu- Ropivacaine

ble (logDpH 7.4 = 2.26) and, thus, has a more rapid onset S-Ropivacaine hydrochloride (Fig. 16.8) is the fi rst and a longer duration of action than most amino ester– optically active, amino amide–type local anesthetic type local anesthetics, such as procaine and tetracaine. marketed in recent years. It combines the anesthetic It can be administered parenterally (with or without epi- potency and long duration of action of (±)-bupivacaine nephrine) or topically either by itself or in combination with a side effect profi le intermediate between those of

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SCENARIO: OUTCOME AND ANALYSIS

Outcome The aminoalkyl side chain is not necessary for local anes- Paul Arpino thetic activity but is useful for forming water-soluble salts for parenteral administration. The para-amino phenyl substituent After consulting with the covering pharmacist and the hospital’s enhances local anesthetic effect by increasing the electron den- allergy specialist, the team decides to proceed with the type of sity of the carbonyl oxygen through electron induction. anesthesia and surgery as planned. On the day of the surgery, Ropivacaine is a local anesthetic developed from another CDL received the peripheral nerve block with ropivacaine and natural alkaloid, isogramine. Structure activity studies of isogra- required minimal adjunctive medications during the procedure. mine led to the development of the lidocaine class (anilides) of Postoperatively, CDL’s pain was well controlled and there was no local anesthetics. evidence of an allergic reaction. The lidocaine types of local anesthetics are bioisosteres of isogramine. The amino alkyl side chain serves to form water- Chemical Analysis soluble salts for parenteral administration. As anilides, these S. William Zito and Victoria Roche compounds have a longer duration of action compared with the Procaine is a local anesthetic developed from the investigation benzoic acid ester class, and the 2,6-dimethyls of the aromatic of cocaine analogs that were synthesized in an effort to enhance ring also serve to increase duration of action. the local anesthetic properties and reduce cocaine’s addiction This class of local anesthetics is less irritating upon injection and acute toxicity liability. Cocaine and procaine are benzoic and, most importantly for this case, have no cross– allergic sen- acid derivatives and both are known to cause allergic reactions. sitivity with the benzoic acid class of local anesthetics. General anesthesia must be avoided in this case because it suppresses H C 3 N upper airway muscle activity, and it may impair breathing O OCH3 C H C 2 5 O by allowing the airway to close. General anesthesia thus may N O increase the number of and duration of sleep apnea episodes of C2H5 O this patient. NH2 O Cocaine Procaine

CH CH3 3 C H O C2H5 O 3 7 N N N(CH3)2 N N C2H5 N H H H CH3 CH3

Isogramine Lidocaine Ropivacaine

CASE STUDY S. William Zito and Victoria Roche

BB is a 19-year-old pregnant woman in her second trimester. Until use general anesthesia using rapid induction and securing her air- now she has had an unremarkable pregnancy. However, today she way with a small cuffed endotracheal tube. The following three gen- presents to the complaining of 3 days of eral anesthetics are proposed. Which one would you recommend? right lower quadrant pain, , and persistent nausea and vomiting. A of BB revealed vital signs of blood Cl pressure, 127/68 mm Hg; heart rate, 86 beats per minute; respira- O F3C O tory rate, 18 breaths per minute, and a temperature of 97.5 °F. A diag- NNO CH2F * N CH3 CF nosis is made of acute and surgery is recommended. H 3 Preoperative testing showed slight leucocytosis with a white blood cell count of 12,000/mm3; her was 12.1 gm/dL, with 1 a hematocrit level of 34.9% and count of 306,000/mm3. 2 3 BB’s medical history was unexceptional; she has had no previous health issues and she is not taking any medications except for prena- 1. Conduct a thorough and mechanistic SAR analysis of the tal multivitamins, which contain folic acid and iron. She reports no three therapeutic options in the case. surgical history and that her parents have had operations for which, 2. Apply the chemical understanding gained from the SAR to her knowledge, there were no anesthetic sequelae. The surgical analysis to this patient’s specific needs to make a thera- expects the operation to take 45 minutes and plans to peutic recommendation.

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