Proprietary mame Manufacturer Tiare Wer Manygeneics AApnacane HC] Cafe abs yea HCl _ Ata Pharacetcl Lidocaine HCL Many goers ‘piscine HCI Cae abs Ghrcspan Septodent Cocaine He) rw che Rylcane HEI Asa Pharmac! Locane HC Many generis ‘phacaine HC) Cae ae preipan Sepoont {Getocae HCI Noval Chemical ylcane Hel haa Pharmacia Proprietary same Monutactree Wephacaiw HO) Many aera rstocrine HCL Ca Labs Exbocae HEI Cook Wate Labs (fennel Novo! Chamseal Pelocane HC) ta Momnsceuea! Seondonet HOI Septodont Mephacine HEI Many genres ‘rctocsine HCL Cae Lae freee HC! Novo Chena Pokenne NCL Ata Pharmaceutical CCbocae HCI Cook Wate Late atoocane HT Cooke Wie Libs Seandonest Ba Sept Spel Percent anesthetic _Vasoconstrctor Pevcent Tocal aestetic Vasoconstriction 3 tpinepine "30,000 Epinephrine omer Ven000' "20000 Enineivine 1200 000 Epinepvine 100,000 Duration of analgesia Taipak 3 safe tive: Sette 3 toshe Pulp in Saft: tose Duration of analgesia Palpat 20% ‘0 ein svrage (20min ‘0 an oc) Saft ts 2 10 Sh awesge 01090 ‘min verage ‘Shvowrage Papal 45 to Saft tse: 2 ‘thw alps 60 rin Saft tise Manufacturers “ali 2a oie ae 30 Beng one tie Son max 500 Manufacaeors ao (i) eg Son ‘ne 400 eg Soe ‘este nn 400 eg Sone Aoi ang Sone ‘bso eS Twol__p Authors am on) ‘aig om ‘nce 300 hg 20m Anche mat 300 aang om ‘Ao authors ao (ma) Wang Doe Abia aa 20 Absoite hy 20 aig 201Percent Proprietary local Duration of Author's and Tame,” Manufacturer anesthetic Vasoconstrctor analgesia manufacturer's MRD (mg) hanes Pain Ava Pamacewteal— + ——Pulpak 10min Cg tration 2a so minock ‘Abie max: 400 Zhe nouatery 2a dire anet Fome Asa Phamcutil Fnnnephane Rapa 6010 sh 200.000 90 min 22hy soft sue: 3 ‘Ae mae 400 ‘Authors and uraiton of manatectarers Manulacturer Yvexoconstrctoe analgesia MRD (mg) Septedent iploephine Papas we Ate ih, 205 Gtactine DS Heats abs "200000 hmin Nolte ma $00 sei ue 2 Chien a, 2.3 Sonex st Seodont—=S«~S*S*«CRine lp No AE 7h, 3.2 Uivacine eects ts i000 75min ovohte mat 500 ss Fotte sot tiive:3 Cher 2:40 Proprietary Percent local ‘Authors and frame,” Manufacturer anesthetic Vatoconstrctor rmaratecturer’s MRD (70) Waring HET Cookie labs «OS Teinephine Ppa 90 to Tig Tegan wom oie saree: ‘At an 0 Div. upto ‘2he pore Proprietary Toca ame Manuiecturer __anestnetie__Vasoconstictor 5 Epinephrine Yao mm enge 3.65 sone Ato Abolte ma 40 ShawneHANDBOOK OF LOCAL ANESTHESIAHANDBOOK OF LOCAL ANESTHESIA FOURTH EDITION STANLEY F. MALAMED, D.D.S. i Professor and Chair, Section of Anesthesia and Medicine University of Southem California School of Dentistry Los Angeles, California Original drawings by Susan B, Cliford, R.D.H., Ed.D. with 346 itustrations NA MosbyNA Mosby TF A Tons Meroe o Compan ce Prose a Sutter Dom Lig Developmental ator: Mets Sb Fron aca ‘Compt pectatn Chine 1 Pa a cla Nee Meanactariay Menage Wis A Wane, Ags sere No pa of hs pao ey be repre tncany Ceci mechanical. punicapyigsrecordng eerie, whoo Fermin wo shtocop oh ty trl personal me pe teller taco her cs need wn he Capi Caance Cntr p> Sided ht be fne vo Fp per ple 1 er pape wal eet He ‘Copii leans Came? One es, Ses BA OI Thy ease i ted arity iyi i te tn {Comps y sty etn Pandan, Papi Fring by Yon Hela Pes Lary of Congress Catala Publication Data ncn: hppa vefrence a Unde. ‘vanes in deny, 2 Lal anesthe IMIS T Anchen Dent. 2 Anestesiol a noah Loa pamalagy AO 40 MES 19] mom ors9n7 654To Beverly, Heather, Jennifer, and jeremySankey Malan las lacisd his considerable now edge and encnwes here to develop an uptodate Haribo of tocatAncatnese (eal anesesia. wide fy ame metal of pain conte in denuste, continues to Deateeptes by mow pricabiers with matter fessthi not ona vestament vo safety ad etezey Bor als an indication uf our complacency and reluc face to lon for even moe ffecupe and safer materials tn echoes ‘This handhokcsefly explores and teaches mesons ‘tar catance yo lea snesthests pactices wile ser lngthe eae spect hazard errors that may Pre doe bn nine and naj compteations.Adeapcesinall Ispecs of he scence ad technology of anesthe have fen not aad he tus practioner wi heretic rt {ene reading ofthis Rando il so become moe ‘hideor that loc anesthe ere pale prepaadon FOREWORD to achieve optimal efeets The atraumatic injection tkyerves an receives special considecation Dt Mulameds hook Apprepnate pelican pharm Colic preparations thar accompany Toca aneshest IMiinistetion Bei achieve maxial ellecuveness and ih rsiacon fr bah the dents and de patient ‘Mader acceptance of dental weatmeat a he ered ius targe meas tothe eecom from pain that ca) testes alfes Ax “Nonacath” becime&Hoaslok frond entsiryprewe aways pata sage ae FRecame an important Heal and esthetic service [Rdvances in all pises of focal anesthetic practice cot state coating proses. Mates, mets and teh figues have andsigone pronouneed changes and ar ‘ant our renewed attention Norma Trleger DMD, MD.Publication of this Zourth edition of the Handbook of ime of considerably height ened interest in the field of anesthesiology in dentistry Interest among students, both those still in dental school and those practicing dentistry, is intense. Attendance at continuing education seminars on this subject has increased sharply over the past 5 years, Why has this occurred? Local anesthesia is, arguably, tbe technique that has allowed dentistry 10 become what i is today—enabling, dentistry fo be inmnsformed from a mere trade to a high ly regarded profession. Preventing pain associated with, dental eare is the goal of all who practice in this profes- on, as well as the strong desire ofall of our patients. Yet e with which pain control can be obtained, the occasional problem docs intrude, Problems include the inability 10 anesthetize certain patients or certain teeth, a patient’s inherent fear of receiving shots’ of local anesthetic drugs, and those local and sys temic complications that are associated with the admin \strition of intraoral local anesthetics. Many reasons exist for these problems, including biological variation in response to drugs, anatomical differences among, patients, and, significant sn relation to intraoral local anes thetic administration, fear and anxiety: ‘The importance of clinically adequate pain control during dental treatment is highlighted by the fact that it is not possible to safely complete treatment in the n-control. Most. if not all, practicing den- tists have faced the vexing problem of the inability 10 provide complete anesthesia to a patient. Though th can occur anywhere in the oral cavity; itis almost a given that this problem occurs most often in mandibular molars. In the absence of complete anesthesia, tt is ofte times not possible to complete the planned dental pro- cedure, Additionally, and of even greater importance, treatment in the absence of adcquitte pain control is responsible for the development of a significant number of the medical emergencies that occur in dental practice Matsuura demonstrates that of 22% of emergencies developing during dental treatment, 67% occur either during the extraction of a tooth or during pulpal extir- Local Anesthesia comes at despite the ust absence of PREFACE pation—two procedures where achieving profound puk pal anesthesia is, on occasion, difficult ' Additionally, 54.9% of all of the emergencies reported in Matsuurt’s studly develop either during the injection or within the first 5 minutes after local anesthetic administration. The vast majority of these emergencies are related 10 the stress of receiving the injection (psychogenically induced emergencies) or 10 the uptake of the drug into the cardiovascular sy "Another reason for the increase in interest in the field of dental pain control is the continual introduction of new rechniques, devices, and drugs. Ibis the expectation of their designers that these innovations represent an improvement on the drugs or devices that preceded them: a drug that when infiltrated on the maxillary buc- cal surface will diffuse palatally, providing, palatal anes- thesia withour the need for a palatal injection; devices that can help to make the administration of focal anes thetics on the palate (or elsewhere) absolutely atraumat- ic: techniques that will Uo away with the need for local anesthesia entirely! Try though we might,and as close as we may Come in some cases,a pantcea for pain control in dentistry has yet to be developed. New drugs. devices, and techniques are discussed in Chapter 19. Yet some new devices seem destined to succeed, One example, in my opinion, is the so-called “safety” syringe. Needle-stick injury with a contaminated needle is « significant fear of health professionals, Syringe/needic devices with which it is virtually impossible to stick oneself or an auxiliary spear to have a place in the pain control armamentark ‘um in dentistry, Several such devices, whieh have recent ly been introduced are discussed in Chapter 5 Vechniques for intraoral anesthesia, especially in the jlibie, have evolved to the point where today a den- tist has available six techniques for pain contiol. These include the tead 1 nerve block (NB), the menta/incisive NB, the Gow-Gates mandibular NB, the Vazirani-Akinosi mandibular NB, the periodontal Ii ment (PDI) injection, and intraosseous anesthesia, Many Of these techniques did not exist, or were aot used, by most dentists as recently as 20 years ago. Today an increasing number of dentist's have many or all of these em of the patient jonal inferior al xi ——ee el techniques available for clinical use, thereby diminishing the number of patients in whom i: is difficult or impos: sible to achieve profound mandibular pulpal anesthesia Despite all of the efforts at improving local anesthesia in dentistry, "the more things change, the more they stay the same.” In this fourth edition of the Handbook of Local Anesthesia, those basic concepts that are essential to the safe and effective practice of local anesthesia in dentistry, well known and well established for more than, 449 years, continue to be emphasized, Without knowledge and understanding of these concepts, the field of local mnesthesia and pain control in dentistry is fraught with, peril, and the likelihood of therapeutic misilvencure is sreatly increased, So this fourth edition contains both the “golden oldies” and the best of the exciting innovations and tech: niques that promise to make dental pain control both more effective and safer As always, there are a number of people whom I must acknowledge, for without their assistance, which took ‘many and varied forms, publication of this fourth edition of he Handbook of Local Anesibesta would not have been ‘sart with the models, Drs. Gabriel Aslanian, “Tmavsky, who sat and endured possible Lm Kenneth Leopold,and Gr many hours of hot lights and needle sticks to provide the new photographs included in this edition, Thanks, too, to severil of the manufacturers of local anesthetic drugs and devices in North Americx: Astra Pharmaceutical Products, +h, Kodak, Hoechst Pharmaceuticals, Novocol, Safety Syringes, and Septodont, for their assistance in preparing the chapters on local anesthetic drugs and armamentari- lum, [also wish to thank Melba Steube from Mosby- Year Book, who has had the task of dealing with an oftentimes lazy, frequently hard-to-reach, author, Her perseverance has paid off with this fine fourth edition, Finally, wish to thank the many, many members of my profession of dentistry, who have provided me with weit. ten and verbal input regarding prior editions of this text: book. A good many of their suggestions for addition deletions, and corrections have been incorporated into this new text. Thank you all! Stantey F. Matamed REFERENCE |. Matsuura: Analysis of systemic complications al dk dental restment in Japan, Aracsthesta Prog 4X45)‘the teearment modes and dhe indetions and tose drug Handbook of Loca esti ase been reimmendes ta the medical erature. Unless specially indicated dru cowes are those ecommend forsale patients “The package insert foreach drug shoul Be curate Jor use an Janes ax approved bythe FDA Because la reo sige change, ts adsl to keep abrewse of revi! recommendations paticuley those concerning ew csPART ONE 1 2 PART TWO. onan PART THREE THE DRUGS Neurophysiology, 2 Pharmacology of local anesthetics, 24 Pharmacology of vasoconstrictors, 37 Clinical action of specific agents, 49 THE ARMAMENTARIUM The syringe, 76 The needle, 85 The cartridge, 91 Additional armamentarium, 100 Preparation of the armamentarium, 103 TECHNIQUES OF REGIONAL ANESTHESIA IN DENTISTRY Physical and psychological evaluation, 116 CONTENTS 11 Basic injection technique, 132 12. Anatomical considerations, 143 13. Techniques of maxillary anesthesia, 160 14 Techniques of mandibular anesthesia, 193 15 Supplemental injection techniques, 220 16 Local anesthetic considerations in dental specialties, 232 part FouR COMPLICATIONS, QUESTIONS, AND FUTURE TRENDS 17 Local complications, 246 18 — Systemic complications, 259 19 Future trends in pain control, 287 20 Questions, 303HANDBOOK OF LOCAL ANESTHESIANeurophysiology Pharmacology of local anesthetics Pharmacology of vasoconstrictors Clinical action of specific agentsPART one The drugs |n the first section of this book the pharmacological and clinical proper- ties of the classes of drugs known as local anesthetics (Chapter 2) and vasoconstrictors (Chapter 3) are discussed. Knowledge of the pharmaco- logical and clinical properties of these drugs, by all persons permitted to administer them, is absolutely essential for their safe use and for a better understanding of those potentially life-threatening systemic reactions asso- ciated with their administration. Emphasis is placed on those local anes- thetic drug combinations currently used in anesthesia in dentistry (Chapter 4). Chapter 1 provides background for an understanding of how local anes- thetics work to block nerve conduction and thus prevent pain from being experienced. The anatomy and physiology of normal neurons and nerve conduction are reviewed as a background for the discussion, which, in subsequent chapters, takes up the pharmacology and clinical actions of various specific agents.DESIRABLE PROPERTIES OF LOCAL ANESTHETICS Local anesthesia has been defined as 1 1oss of sensation ina circumscribed area of the body caused by a depres- sion of excitation in nerve endings or an inhibition of the ‘conduction process in peripheral nerves.! An important feature of local anesthesia is that it produces this 1oss of sensation without inducing & loss of consciousness. In this one major atea local anesthesia differs dramatically from general anesthesis, ‘There are many methods of inducing local anesthesia, some of which follow: |. Mechanical trauma . Low temperature . Anoxia Chemical irritants Neurolytic agents such as aleohol and phenol Chemical agents such as local anesthetics aways However, only those methods or substances ura induce a transient and completely reversible ate of ane thesia are used in clinical practice The following are those properties deemed most desirable for a local anesthetie 1, Ie should not be irritating to the tissue to which itis, applied. 2. It should not cause any permanent alteration of nerve structure, 3. Its systemic toxicity should be low: 4, It must he effective regardless of whether itis inject ced into the tissue or applied locally 19 mucous mem- branes. 5. The time of onset of anesthesia should be as short as possible, 6, The duration of action must be long enough to per mit completion of the procedure yet not so long as to require an extended recovery, ‘Most local anesihietics discussed in this section meet the first to criteria: they are (relatively) nonirritating 1 tissmes and completely woersfole, Of paramount impor tance is systemic toxicity, since all injectable and most topical local anesthetics are eventually absorbed feom their site of administration into the cardiovascular system. ‘Therefore the potential toxicity of a drug is an important factor in its selection tor use as a local anesthetic. Toxicity. varies greatly among the local anesthetics currently in use. Toxicity is discussed more thoroughly in Chapter 2. Although it isa desirable characteristic, not alloca anes thetics in clinical use today meet the critesion of being effective regardless of whether the drug ts injected or applied topically, Several of the more potent injectable local anesthetics (procaine, mepivacaine) prove to be ret atively ineffective when applied topically to mucous membrane, To be effective as topical anesthetics, these Ccrugs must be applied in concentrations that prove to be locally irritating to tissues and increase the risk of sys temic toxicity: Dyclonine, a potent topical anesthetic, is, ‘not administered by injection because of its tissueirritat. ing properties, Lidocaine and tetructine, on the other hand, are both effective anesthetics when administered ll el ereby injection or topical application in clinically accey concentrations, The last factors, rapid onset of action and adequate duration of clinical action, are met quite satis- factorily by most of the clinically effective local anesthet- jes in use today, Clinical duration of action does vary con- among drugs and also among different prepari- tions of the same drug. The duration of anesthesia requied to complete a procedure will be « major considh cerition in the selection of a local a In addition to these qualities, Bennett? lists other desirable properties of an ideal local anesthetic: 7, It should have a potency suff plete anesthesia without the cemirated solutions. 8, It should be relatively free from producing allergic reactions, 9. Ic should be stable in solution and readily undergo biotransformation in the body: 10, It should either he sterile or be capable of being sterilized by heat without deterioration, cient to give com of harmful con- ‘The local anesthetics in use today, although they do hot satisfy all of these criteria, do meet the majority of them. Rescarch is continuing in an effort to produce newer crugs that possess « maximum of desirable factors and a minimum of negative ones, FUNDAMENTALS OF IMPULSE GENERATION AND TRANSMISSION The discovery in the late 1800s of a group of chemicals with the ability to prevent pain without inducing a loss fof consciousness was one of the major steps in the advancement of the medicil and cenial professions, Medical and dental procedures could, For the first time, be carried out easily and in the that is virtually taken for granted by contempd ical and dental professionals and their patients. The concept hehind the actions of local anesthetics is simple: they prevent both the generation and the con nerve impulse, In effect, local anesthetics set up a chemical roadblock between the source of the impulse (e.g..the scalpel incision in soft tissues) and the jorted impulse, prevented from reaching the beain, is not, therefore, interpreted as pain by the patient How; in fact, do local anesthetics, the most commonly used drugs in dentistry, function to abolish or prevent pain? ‘The following is a discussion of current theories secking fo explain the mode of action of local anesthe ic drugs. To understand the mode of action of local anes- thetics better however, the reader must have an aequain: tance with the fiandamentals of nerve conduction; thus review of the relevant characteristics and properties of nerve anatomy and physiology follows dbsence of pain, y mec Neurophysiology CHAPTER 1 3 The Neuron The neuron or nerve cell is the structural unit of the ner- yous system. It is able (© transmit messages herween the ceniral nervous system (CNS) and al! parts of the body. There are two basic types of ncuron: the sensory (aifer ent) and the motor (efferent). The basic structure of these Wwo neuronal types differs significantly (Fig. L4). Sensory neurons that are capable of transmitting the sensation of pain consist of three major portions.> The dendritic zone, which is composed of an arborization of free nerve endings, is the most distal segment of the sen- sory neuron, These free nerve endings respond to stimu- lation produced in the tissues in which they le, provol- 1g an impulse that is transmitted centrally along the axon. The axon is a thin cablelike structure that may be quite long (the giant squid axon has been measured at 100 to 200 em). At its mesial Cor central) end there js an arborization similar to that seen in the dendritic zone. However, in this case the arborizations form synapses: swith various nuclei in the CNS 10 distribute incoming, (sensory) impulses to their appropriate sites within the ENS for interpretation. The cell body, o soma, is the third part of the neuron. In the sensory neuron described here, the cell body is located at a distance from the axon, or the main pathway of impulse transmission in this Terminal arborization Schwann call axon Nel of Ranvier Freenere Derchiie one fencing Fig, 1-1 Sensory neuson innervating the oil mucosa. The relative length of the axon in this diagram i foreshortened by 4 fictor of 5000. CErom Justak JT, Yagieta JA’ Regional anes: thesia of the oral cavity, Sf Louis, 1981, Mosby-Year Book)4 PART ONE The Drugs nerve. The cell body of the sensory nerve is therefore not involved in the process of impulse transmission, its pri mary function being to provide the vital metabolic sup port for the entire neuron Nerve cells that conduct impulses from the CNS peripherally are termed motor neurons and are struc toraly different irom the sensory neurons just described their cell body ts interposed between the axo1 the dendrites, In motor neurons the cell body not only an integral component of the impulse transmission sys- 10 provides metabolic support for the cell The Axon ‘The single nerve fiber—the axon—is a long cylinder of neural cytoplasm (axoplasm) encased in a thin sheath— the nerve membrane, of axolemma, Nerve cells have a cell body and a nucleus, as do all other cells; however, nerve cells differ from other cells in that nerve cells have an axonal process from which the cell body may be a considerable distance, ‘The axoplssm, a gelatinous. sub- stance, ly separated from extracellular Nuids by at contine uous nerve membrane In some nerves this membrane is itself covered by an insulating lipid-rich layer of myelin, werve excitability Current thinking holds that sensory tributable 10 changes devel: and conduction are both Polar croup Noapolar group ig. 1-2 A, Configuration of «biological membrane B, Heterogeneous lipoprotein membrane as suggested by Singer and Nicolson.’ (From Covino BG, Vassalo HG Local anesthetics: mechanisms of action and clinical use, New York, 1976, Grune & Stration, Used by permission.) nd oping within the nerve membrane. The cell body the axoplasm are not essential for nerve conduction, ‘They are important, however: the metabolic support of the membrane is probably derived from the axoplasm, ‘The nerve (cell) membrine itself is approximately 70 to 80 A thick. (An angstrom unit is 1/10,000 of a mierom- eter Figure 1-2 represents a currently acceptable con- guration. All biologic membranes are organized to CL) block the diffusion of oluble molecules; 2) be selectively permeable to certain molecules via special ized pores or channels; and (3) transduce information by 11 or physical pro stimulation by neurotransmitiers or hormones (chemi cal) or light, vibrations, or pressure (physical). The membrane is described as a flexible nonstretchable Structure consisting of two layers of lipid molecules (ilipid layer of phospholipids) and associated proteins, lipids, and carbohydrates. The lipids are oriented with, their hydrophilic (polar) ends facing the outer surface and the hydrophobic (nonpolar) ends projecting to the middle of the 1nembrane (Fig, 1-2, ). Proteins ase visual ed as the primary ongnizational elements of mem branes (Fig, 12, £).5 Proteins are classified as transport proteins (channels, carriers, or pumps) and receptor sites, Channel proteins are thought to be continuous pores through the membrane, allowing some ions (Nat K+, Ca*¥) to flow passively, whereas other channels are gated” permitting ion flow only when the gate is open”! ‘The nerve membrane lies at the interface between the exteicellular fluid and axoplasm. It sepa: rates highly diverse ionic concentrations within the axon, from those outside. The resting nerve membrane bas an \ce about 50 times greater than that oF ar and extracellular fluids, thus preventing, jum, potassium, and chloride ions jon geadients. When « nerve impule passes, however, electrical conductivity of the nerve membrane increases approximately a hundred: fold. This increase in conductivity permits the passage of sodium and potassium ions along their concentration gradients through the nerve membrine. It is the move- ment of these ions that provides the immediate source of energy for impulse conduction along the nerve. Some nerve fibers are covered by an insulating lipid layer of myelin, In vertebrates, myelinated nerve fibers nelude all but the smallest of axony (Table 1-1) Ke«! nerve fibers (Fig. 13) are enclosed in spirally ceptors responsive ta chemi electrical resist the iniracel the passage of s0% down their concentea fers of lipoprotein myelin sheaths, which are chwann cell Although pri- wrapped li actually a specialized form of marily (75%) lipid, the myelin sheath also conrains some protein (20%) and carbohydrate (5%).” Each myelinated nerve fiber is enclosed in its own myelin sheath. The out- ermost layer of myelin consists of the Schwann cell cyto: plasm and its nucleus. There are constrictions located at regular intervals (approximately every 0.5 to 3 mm)— Neurophysiology CHAPTER 1 5. [SSIADTRTEYRIP ise tenanteic of reper Ne ERE Classification Characteristic A-alpha Abeta Agamma Adelta 8 Myelin +e " + y = = Diameter (pir) 12 10 20 51012 Sio12 1104 103 05101 Conduction velocity (msec) 70 10 120 30 ta70 30%0 70 12930 148 12 met time ‘ s 4 3 1 2 Functon Motor, muscle Touch, pressure Touch, metor—*ain, temperature, Preganglionic Pair temperature, ropvioception —_proprieception proprioception pressure pro: autonomic itch, pressure pproceptien (ympathete) —_postgangioni actinty sympathetic axctiviy Fig. 1-3 Structure of a myctinated nerve Lontis, 1994, Mosby Year Book.) Axoplesm Aolenma Nucleus of Schwann ell ‘Asoplasm Arolenma se 1-4 structure of an unmyelinated nerve fiber fiber (Fron de Jong RH: Local anesth Node of Rarvier along the myelinated nerve fiber. These are nodes of Ranvier, and they form a gap between two adjoining Schwann cells and their myelin spirals.® At these nodes the nerve membrane is exposed directly 10 the extracel. Jular medium, Unmyclinated nerve bers (Fig, 1-1) are also surround ed by a Schwann cell sheath. Groups of unmyelinated nerve fibers share the same sheath. The insulating prop~ criies of the myelin sheath enable a myelinated nerve to conduct impulses at a much faster rate than an unnyeli- nated nerve of equal size can. Physiology of the Peripheral Nerves The function of 4 nerve is to carry messages from one part of the body to another These messages inthe form Drelectrical action potentials are called émputses. Acton potentials are transient membrane depoiarizations that esl from a bret increase in the permeability of the membrane to sodium, an ustlly also fo increase in the peemeabily to potassim,? Impulses ae6 PART ONE The Drugs initiated by chemical, thermal, mechanical, or elect stimuli Once an impulse is initiated by a stimulus in any par ticular nerve fiber, the amplitude and shape of that npulse remain constant, regardless OF changes in the quality of the stimulus oF is strength, The impulse remains constant without losing strength as it passes loag the nerve because the energy used for its propa: from energy that is released by the tial gation is derive nerve fiber along its length and not solely from the stimulus. de Jong has described impulse conduc being like the active progress of a spark along a fuse of gunpowder. ! Once fit, the fuse burns steadily along its length, one burning segment providing the energy required (0 ignite its neighbor. Such ‘s the situation with, impulse propagation along a nerve Electrophysiology of Nerve Conduction The following is a description of electrical events that impulse. Subsequent sections describe the precise anisms for each of these steps Step A nerve possesses a resting potential (Fig. 5, Step 1). "this is 4 negative electrical potential of ~70 mV that exists across the nerve membrane, produced by differing concentrations of ions on either side of the a nerve during the conduction of an ech. Sep ‘Axoplosm Step 3 ‘membrane (Table 1-2). The interior of the nerve is nega tive in relation to the exterior, Step 2 A stimulus excites the nerve, leading to the following sequence of events An initial phase of slow depolarization, The electrica potential within the nerve becomes slightly I tive (Fig. 1-5, Step 2, A), b.When the filling electrical potential reaches a critical level, an extremely rapid phase of depolarization results. This is termed threshold potential, or firing tresbotit (iy, 1-5, Step 2, BD, .This phase of rapid depotartzation ves sal of the electrical pot brane (Fig. 1-5, Step 2, ©. The interior of the nerve is now electrically positive in relation to the exterior. An, electrical potential of +40 0 son the interior of the nerve eell,!! al across the nerve men Step 3 Following these steps of depoheization, repolarization occurs (Fig, 1-5, Step 3). The electeical potential nerve cell relative to outside until the original resting potential of ~70 mV i ieved, The entire process (Steps 2 and 3) requires 1 mil lisecond (msec); depolarization (Step 2) takes 0.3 msec; repolarization (Step 3) takes 0.7 msec ive inside the Nowe mambrine Normal -70m¥ (esting potential) Fring = 50 to ~60 mV [low depolerizetion to hreshold potenil) Potential "20 (iopid depolarization Repolarization ~60t0 ~ 90 mV Fig. 1-5 step /, Resting potential, rep 2, A and 6, Slow depotarization to threshold. step 2,6, Rapid depolarization. Step 3, RepolaElectrochemistry of Nerve Conduction The preceding sequence of events depends on two important factors: (1) the concentrations of electrolytes in the axoplasm interior of the nerve cell Inlar fluids and (2) the permeability of the nerve mem: brane to sodium and potassium ions, ‘Table 1-2 shows the differing concentrations of ions found within nerve cells and in the extracellular fluids. Sgnificant differences exist for ions between their inte cellularand extracellular concentrations. These ionic grat dients differ because the nerve membrane exhibits sefee ive permeabitity: Resting State In its resting state the nerve memb + Slightly permeable to sodium ions (Na) + Freely permeable to potassium ions (K') ly permeable to chloride ions (CL Potassium remains within the axoplasm, despite its abilicy to clffuse freely through the nerve membrane and espite its concentration graiient (passive ciffusion ust: ally occurs froma region of greiter concentration to one Of lesser concentration), bectuse the negative charge of the nerve membra ions by electrostatic attraction Chloride remains outside the nerve membrine instead of moving along, its concentration gradient into the nerve cell because the opposing, nearly equal, elec trostatic influence (electrostatic gradient from inside to outside) forces outward migration. The net result is no itfusion of chloride through the membrane, Sodium migrates inwardly because both the conc tration (greater outside) and the electrostatic gradient (positive ion attracted by negative intracellular potential) fayor such migeation, Only the fuct that the resting nerve membrine is relatively impermeable 10 sodium prevents 1c restrains the positively charged massive influx of this ion, Membrane Excitation Depolarization Excitation of a nerve segment leads to an increase in permeability of the cell mem brane to sodium ions. This is accomplished by a transient widening of transmembrane ion channels suffic permit the unhindered passage of hydrated sodium ions (p.§). The rapid influx of sodium ions to the interior of the nerve cell causes a depolarization of the nerve mem Neurophysiology CHAPTER 1 7 brane from its resting level to its firing threshold of approximately —50 to ~60 mv (Fig. 15, Ste 2, A and B).!2 The firing threshold is actually the magnitude of the decrease in negative transmembrane potential that {s required 10 initiate an action potential ¢impulse). \ decrease in negative transmembrane potential of 15 mV (e,,from —70 to —55) is required to reach the fit ing threshold; voltage difference of less than 15 m¥ will hot initiate an impulse. Ina normal nerve the firi Mureshold remains constant. Exposure of the nerve to local anesthetic raises its firing threshold. Elevating the threshold -means that more sodium must pass through the membrane to decrease the negative trans: membrane potential oa level where depolarization will oceur. When firing threshold is reached, permeability of the membrane to sodium increases dramatically, and sodium ions rapidly enter the axoplasm. At the end of depolar: ization (the peak of the action potential), the electrical potential of the nerve is actually reversed; an electric potential of +40 mY exists (Fig. 15, Step 2 ©). The entice depolarizition process requires approximately 0.3 msec Repolarizatio ed when the membrane repolarizes, This is caused by the extinction Cinactivation”) of increased permeability to In many cells permeability to potassium also, es, resulting in the efflux of K, Jeading to a more n to its resting The action potential is termi sodint rapid membrane repolarization and ret potential (Fig. 1-5,Step 3). The movement of sodium ions into the cell during depolarization and the subsequent movement of potassi- um ions out of the cell during repolarization are passive (not requiring the expenditure of energy),since each ion moves along fis concentration gradient, Following the return of the membt 70 mY), a slight excess of sodium exists within the nerve cell, ne potential to its original level ula slight excess of potassium exists extr cellularly: A period of metaholie activity then begins Active transfer of sodium ions out of the cell occurs via the “sodium pump."An expenditure of energy is need- ‘ed to move sodium ions out of the nerve cell against their concentration gradient, this enesgy coming from the oxidative metabolism of adenosine triphosphate (ATP). The sume pumping mechanism is thought to be responsible for the active transport of potassium ions inio the cell against their concentration gradient. The entire process of repokarization requires 0.7 msec. (SEIS tact tone oT EEE, Intracellular extracellular Ratio fon (meq/t) (mEq/L (approximate) Potassium (K*) T1010 170 305 a7 Sodium (Ne*) 51010 140 4 Chionde (Cl) 51010 Ho unPART ONE The Drugs Closed Braceller plan Pag Fig, 16 Soxium charnet transtion poten fom Interior hctng tte copen) channel configusition assumes a tion the inactivated refractory channel reverts 10 the ready for the next seq editor: Principles of new nce. (From Siegelbawmn ely after a stimulus has initiated an action. potential, a nerve is unable, for a time, to respond to another stimulus, regardless of its strength, This, termed the absolute refractory period, and it lasts for about the duration of the main part of the action poten- ial, The absolute retractory period is followed by a rela. tive refractory pertod, during which anew impulse can be initiated but only by a stronger than normal stimulus, ‘The relative refiactory period continues to decrease until the normal level of excitability returns, at whicl point the nerve is ssid to be repolarized During depolarization the major proportion of ionic sodium channels are found in their “open” (O) state (thus permitting the rapid influx of Nit), This is followed by a slower deciine into a state of inactivation”) of the chan- nels to a nonconducting state. Intetivation Cemporarily converts the channels to a state irom which they cannot ‘open in response to depolarization (absolute refractory period). This inactivated state is slowly converted back, so the majority of ebannels are found in their closed (©) rest ing form when the membrane ty repokurized (70 mY), Upon depolarization the channels change configuration, first an open ion-conducting (O) state and then to an wough both Cand Immed inactive nonconeucting (I) state. Al states correspond to noncondueting channels, they differ in that depolarization can recruit channels to the con- ducting © state from € but aot from 1 Figure 16 describes the sodium channel transition stages.) Membrane Channels Discrete aqueous pores through the excitable nerve membrane, called sodium (or ion) channels, are molecu- Inactive ‘ages. Depolarization reverses resting, membrane xgative (/ejt) Wo interior positive (center), The channel proteins poncling conformational changes fom resting state (closed) to ion-con. e changes continue from open (center) 10 different —but still impermeable—state. With repolarizi tive (riebD, where nitial resting configuration def), SA, Koester F: lon channels, fn Kandel EX, science, ed 3, Norwalk, Conn, £991, Appleton-Lange.) lar structures that mediate its sodium pesmeability: A channel seems to be a lipoglycoprotein firmly situated in the membrane (Fig, 1-2). It consists of an aqueous pore spanning the membrane that is narrow enough at least at fone point to discrminate between sodium and other lons (Nav passes through 12 times more easily than K*. The channel also includes # porsion that changes config- tration in respoase t changes in membrane potential, thereby gating the passage of ions through the pore (C, 0,1 states described above). The presence of these chan- nels helps explain membrane permeability or imperme ability t certain ions, Sodium channels have an internat diameter of approximately 0.30.5 nm." 4 sodium jon is “thinner” than either a potassium or a chloride ion and should therefore diffuse freely down its ntration geudient through membrane channe's into the nerve cell, This does not occur, however, because all these ions atract water molecules and thus become hydrated, Hydrated sodium ions have a radius of 3.4 A, whieh is approximately 50% greater than the 2.2 A radius ‘of potassium and chloride ions, Sodium ions are there- fore too large to pass through the narrow channels when, ve is at rest (Fig, 1-7). Potassium and chloride ions. can pass through these channels, During depolarization, sodium ions readily pass through the nerve membrane because configurational changes that develop within the membrane produce a transient widening of these trans- membrane channels to a size adequate to allow the unhindered passage of sodium ions dowa their concen- tration gradient into the axoplasm (transformation from the C to the O configuration). This concept can be visu alized as the opening of a gate during depolarization thatExtracallvar Tid 5 © an Se pi meron Lipid membrone Acopleam Fig. 1-7 Membr nceve is at rest channels are par sinated soxdivn ions (Na+) a pass through channels, although potassium ions (K++) can pass dirough unimpeded. is partially occluding the channel in the resting me brane (C) (ig. 1). Recent evidence indicates that channel speeificty exists, in that Sodium channely differ from potassium channels. !5 Phe gates on the sodium channel are located near the external surface of the nerve membrane, where: fas those on the po chanel are located near the internal surface of the nerve membrine. Impulse Propagation Following the initiation of an action potential by a stim ulis the impulse must move along the surface of the ‘axon, Energy for impulse propagation isderived from the herve membrane in the folowing manner The stimulis disrupts the resting equilibrium of the nerve membrane; the (ransmemprane potential is reversed momentarily-the interior ofthe cel changing from negitive 10 positive, the exterior changing from positive to negative. Tis new clecirical equilihefum in thi segment of nerve produces local currents that begin flowing between the depolarized segment and the adi cent resting area These local currents flaw from positive ve extending for several millimeters along, the herve membrane. TAs result of this current flow the interior ofthe ad cent area becomes less negative andits exterior less pos itive, Transmembrane potential decreases, approaching firing threshold for depolarization. Wha transmembrane potential is decreased by 15 mV’ from resting potential firing threshold is reached and complete depolarization dccurs.The newly depolarized segment scts up local cr: CHAPTER 1 9 ae [V8 Fig, 1-8 Membrane channels are open; depolarization ‘occurs, Hydeated sodium ions (Vat) now piss unimpeded ‘through che sodium channel ‘ent esting membrane, and the entire process starts anew: Conditions in the segment that has just depolarized, retum nomnal following the absolute and relative refractory periods. Bee the wave of depolar ization can spread in only one direction, Backward (ret- rogracle) movement is prevented by the unexcitable, refractory sepment Impulse Spread "The propagated impulse travels along the nerve mem- brane toward the CNS. The spread of this impulse cliffers depending on whether or not a nerve is myelinated Unmyelinated Nerves An unmyelinated nerve fibe with a high-electrical resis rounding i fow-resistance conducting core of axoplasm, all of which is bathed in lowsresistance extricellular uid ‘The high-resistance cell membrane and low-resistance inteacethilar_and extracellular media produce a rapid decrease in the density of current within a short distance Of the depolarized segment. In areas immediately adja- cent to this depolarized segment, local current flow may be adequate to initiate depolarization in the resting membrane. Farther away it will prove to be inadequate to ichieve firing threshold. The spread of an impulse in an unmyelinated nerve fiber is therefore characterized ay a relatively slow for ward-crceping process (Fig. 19). Conduction rite in unmyelinated € fibers is 1.2 n/see compared with 14.8. fo 120 m/sec in myelinated A-alpha and Adelta fibers.!6 is basically a tong cylinder yee cell membrane sur10 PART ONE The Drugs Myelinated Nerves Impulse spread within myctinated nerves differs trom that in unmyelinated nerves because of the layer of inst lating matertal separating the intracellular and extracel lular charges. The farther apaet the charges, the smaller will be the current required to change the membrane Local currents can thus travel much farther ina myeli nated nerve than in an unmyelinated nerve before becoming incapable of depolarizing the nerve mem- brane ahead of it Impulse conduction in myelinated nerves occurs by means of current leaps from node to node—a process termed saltatory conduction (Fig. 1-9) (saltare is the Latin verb “to leap’). This form of impulse conduction proves to be much faster and more energy efficient than that which is employed in unmyelinated nerves, The thickness of the myelin sheath Increases with increasing diameter of the axon. In addition, the dis: tance between adjacent nodes of Ranvier increases with greater axor Recause of these two tors, saltatory conduction is more capid in a thicker Saltatory conduction usually progresses from one node to the next in a stepwise manner. However, it c be demonstrited that the current flow at the next node still exceeds that necessary to reach the firing threshold of the nodal membrane. If conduction of an impulse is blocked at one node, the local current will skip over that node and prove adequate to raise the membrane poten Fig. 1-9 Saltatory propagation. Comparing impulse propagation in. nonmyetinated (upper) and nryetinated dower) axons. tn rnonmyclinated axons the impulse moves forward by sequential depot short adjoining membrane segments. De polarization in myelinated axons, on the dther hand, is discontinuous; the impulse leaps forward trom node (0 node. Note hhow muich farther ahead the impulbe is in the myetinared axon after four depolariz tion sequences, (From de Jong RI Local anesthetics, S¢ Louis, 1994, Mosby Year Book) lal at the next node 10 ity fring potential and produce depolarization. A minimum of perhaps 8 to 10 mm of nerve must be coyered by anesthetic solution to ensure thorough blockade.!7 MODE AND SITE OF ACTION OF LOCAL ANESTHETICS How and where do local anesthetics alter the processes of impulse generation and transmission? It is possible for local anesthetic agents to interfere with the excitation nerve membrane in one OF More Of Lhe f0} process in lowing ways: 1, Altering the basic resting potential of the nerve membrane Altering, the threshold potential ring level) 3. Decreasing the rate of depolarization 1. Prolonging the rate of repolarization It has been established that the primary effects of local anesthetics occur during the depolarization phase of the action potential." These effects include a decrease in the Fate of depolarization, particularly in the phase of slow depolarization, Because of this, cellular depolarization is not sufficient to reduce the membrane potential of a nerve fer to its firing level, and a propa gated action potential does not develop. There is 110 ge in the rate of repolarization. ‘accompanying chNeurophysiology CHAPTER 1 11 ; weer (RN} N, x Extracellulor, Extracellular ‘ ‘ 3 mn 2 Wwe 4 ae : fii af ef 3 g - 0 = - (RN 3 ; 5 i ; ere thle 11-10 Membrane Where Do Local Anesthetics Work? at which loc shiek the The nerve membrane i the sit fc agents exert their pharmacological actions. M: ries have been promulgated over the years to explain the mechanism of action of local snestheties, including the acetylcholine, calcium displacement, and surfic charge theories, The acetylcholine theory stated ti acetyicholine was involved in nerve conduction in addi- tion to its role as a neurotransmitter at nerve synapses." ‘There is no evidence that acetylcholine is involved in curl transmission along the body of the neuron, ‘The splacement theory.once quite popular, main- wrlocal anesthetic nerve block was produced by the displacement of calcium from some membrane site that controlled permeability to sodium.2” Evidence th varying the concentration of calclum ions bathing a nerve does not alfect local anesthetic potency has dimin ned the credibility of this theory. The surface charge (repulsion) theory proposed that local anesthetics acted by binding to the nerve membrane and changing, the eleeirical potential at the membrane surface.?! Cationic CRNH*) (p16) drug molecules were aligned at the mem brane-water intecface, and since some of the local anes thetic molecules carried a net positive charge, they made the clectrical potential at the membrane surface more positive, thus decreasing the excitability of the nerve by increasing the threshold potential. Current evidence indicates that the resting potential of the nerve men brane is unaltered by focal anesthetics (they do not become hyperpolarized) aml tha conventional local anesthetics act within the membrane channels eather expansion theory than at the membrane surface. Also the surface charge theory cannot explain the activity of uncharged anes thetic molecules in blocking nerve impulses (e.g, ber zoeaine). ‘Iwo other theories, membrane expansion and specif ic receptor, are given some credent Of the bwo, the specific receptor theory is moze widely he'd, ‘The membrane expansion theory states that loca anesthetic molecules diffuse to hydrophobic regions of excitable membranes, producing « general disturbance of the bulk membrane structure, expanding some critical region(s) in the membrane, and thus preventing an increase in the permeability to sodium tons.222% Local anesthetics that are highly lipid soluble can easily pene- trate the lipid portion of the cell membrane, producing a change in configuration of the lipoprotein matrix of the nerve membrane, This results in a decreased diameter of sodium channels, which leads to an inhibition of both sodium conductance and neural excitation Fig. 1-10). ‘The membrane expansion theory serves as a possible on for the local anesthetic activity of a drug such as benzocaine, which does not exist in cationic form yet still exhibits potent topical anesthetic activity. It has been demonstrated that nerve membranes do, in fact, expand and become more“Hluid’ when exposed to local anesthetics, However, there is no direct evidence that nerve conduction is emirely blocked by membrane expansion per se. ‘The specific receptor theory, the most favored today proposes that local ct by binding to specif: receptors on the sodium channel (Fig, 1-11)2# The nesthetics