Local anaesthetic agents can be defined as drugs that are used clinically to produce reversible inhibition of excita-tion and conducexcita-tion in peripheral nerve fibres and nerve endings, and thus produce the loss of sensation in a cir-cumscribed area of the body. Many agents with differ-ent chemical structures, including chlorpromazine, pro-pranolol and pethidine, that are primarily used for other purposes, have local anaesthetic properties. Only a small number of tertiary amines (esters or amides) are com-monly used to induce local anaesthesia. Some of these may also be used as antiarrhythmic agents and have occa-sionally been used as anticonvulsants.
History of local anaesthetics
It has been recognized for many years that some natu-rally occurring substances can produce local or generalized changes in sensory appreciation and motor power. During his voyages of discovery in the eighteenth century, Cap-tain James Cook tasted ‘puffer fish’ in the South Seas and graphically described its subjective effects on the nervous system. It is now recognized that these phenomena were due to tetrodotoxin poisoning. This substance is present in octopi, salamanders, newts and amphibia, as well as the Japanese puffer fish (Spheroides spengleri), and is probably produced by microbial biosynthesis. An unrelated series of biotoxins (the saxitoxins) are produced by the dinoflag-ellates (flagellated unicellular organisms which contami-nate shellfish). Although both tetrodotoxin and saxitoxin are extremely potent substances, they are relatively polar compounds that do not readily penetrate cell membranes.
Consequently, they are not used as local anaesthetics and are of no clinical importance.
The naturally occurring alkaloid cocaine was the first local anaesthetic used in clinical practice. It is derived from a shrub (Erythroxylon coca) that grows in the foothills of the Andes, and for many centuries its leaves were chewed by Peruvian Indians for its mood elevating and stimulant properties. Pure cocaine was first isolated by Niemann in
1860, who confirmed its effects on sensation, and its phar-macological actions were studied by Von Anrep between 1870 and 1880. The drug was introduced into clinical prac-tice by Freud and K¨oller in 1884. Sigmund Freud used cocaine in an attempt to treat a morphine-dependent col-league, but converted him into a cocaine addict. He also took cocaine himself for a period of 10 years (while he was writing ‘The Interpretation of Dreams’). Karl K¨oller1 initially used cocaine to produce corneal anaesthesia in ex-perimental animals and rapidly appreciated its potential advantages. He introduced it into ophthalmological prac-tice as a surface anaesthetic, and its use for infiltration, conduction and spinal anaesthesia soon followed.
Unfortunately, its potential for producing drug depen-dence was not initially appreciated. Nevertheless, by 1890, its dangers were well recognized, and a search began for newer and safer drugs. Procaine, the first synthetic local anaesthetic, was introduced by Einhorn in 1905. Many other synthetic local anaesthetic esters were subsequently investigated. Most of these have now been discarded and are solely of historical interest. However, the local anaes-thetic ester tetracaine is still widely used to produce topical anaesthesia.
An important milestone occurred in 1943 when lido-caine was synthesized by Lofgren and subsequently intro-duced into anaesthetic practice. This aminoacylamide was the prototype of a new group of local anaesthetic drugs.
Since the advent of lidocaine, other amides have been in-troduced, some of which have been developed as single stereoisomers with significant clinical advantages.
Local anaesthetic agents that are currently used in the UK are
Esters:
Cocaine Procaine
1An apocryphal story suggests that the enthusiasm of Karl K¨oller for cocaine anaesthesia led to the use of the soubriquet ‘Coca K¨oller’
by his friends and acquaintances, which was subsequently translit-erated and employed in a rather different context.
Principles and Practice of Pharmacology for Anaesthetists, Fifth Edition T.N. Calvey and N.E. Williams 149
© 2008 Norman Calvey and Norton Williams. ISBN: 978-1-405-15727-8
Tetracaine Amides:
Articaine Lidocaine Mepivacaine Prilocaine Bupivacaine Ropivacaine Levobupivacaine
Articaine and mepivacaine are only used in dental practice and are not considered in detail in this chapter. Etidocaine is an extremely potent amide anaesthetic, which has been used clinically in many countries (but not the UK). Some local anaesthetics (lidocaine and bupivacaine) have also been used experimentally as liposomal preparations2in order to prolong the duration of local anaesthesia and reduce systemic toxicity.
Structure and function of nerve fibres Structure
Peripheral nerves consist of the dendrites and axons of sensory and/or motor nerves, which are bound together and surrounded by connective tissue. Layers of longitu-dinally arranged collagen surround individual nerve fi-bres (the endoneurium) or groups of nerve fifi-bres (the perineurium). An outer connective tissue sheath (the epineurium) surrounds the nerve trunk and carries its blood vessels and lymphatics. Each nerve fibre is con-nected with a central cell body from which it receives its metabolic and nutritional requirements and is surrounded by a sheath of Schwann cell cytoplasm.
Unmyelinated fibres are usually enclosed in groups by the sheath of a single Schwann cell (which may be up to 0.5 mm long), which is in contact with the cytoplasm of adjacent Schwann cells. In contrast, each myelinated fibre is enclosed by the cytoplasm of a single Schwann cell, with its phospholipid cell membrane wound spirally around the fibre to form the myelin sheath (Fig. 9.1). Between individual Schwann cells the myelin sheath is absent, and the resultant junctions between adjacent cells are known as the nodes of Ranvier. The internodal distance is related to the size of the Schwann cells and the diameter of the nerve fibres. In large myelinated nerves, the internodal distance may be 1–2 mm.
2Liposomes are vesicles with a diameter of 50 nm–10m; they consist of an aqueous phase surrounded by a phospholipid bilayer.
Drugs can be incorporated in either the lipid or the aqueous phase.
Fig. 9.1 Diagram showing transverse section of (a) myelinated nerve fibres and (b) unmyelinated nerve fibres. a, axon or dendrite; m, myelin sheath; sn, nucleus of Schwann cell.
Individual nerve fibres consist of a central core (the neu-roplasm), which is enclosed by a limiting cell membrane (the neurilemma). The neuroplasm contains mitochon-dria, microtubules and neurofilaments, which are required for normal nutrition and metabolism. In contrast, the neurilemma is a characteristic phospholipid membrane and contains integral proteins (Fig. 1.1). Some of these proteins contain pores or ion channels, which play an im-portant role in neuronal function.
Physiology
In the inactive state, there is a difference in potential of 60–90 mV across the neurilemma, i.e. the inside is elec-tronegative relative to the outside. This potential differ-ence (the resting potential) mainly reflects the selective permeability of the neurilemma to K+. In resting con-ditions, the membrane is impermeable to Na+, but K+ can slowly diffuse from the neuroplasm. This process is opposed by the negative charge on intracellular proteins, which tends to prevent K+diffusion. The balance between these two forces represents the resting membrane poten-tial, an electrochemical gradient which is closely related to the ratio K+i/K+o (Fig. 9.2).
During activity, characteristic changes occur in the membrane potential. Initially, there is a slow phase of de-polarization as the cell becomes progressively less neg-ative. When the threshold potential (about−50 mV) is reached, there is a rapid and transient depolarization to approximately+25 mV, followed by a return to the rest-ing value (repolarization). These changes are referred to as the action potential and occur within 1–2 milliseconds (Fig. 9.3).
The ability to generate an action potential depends on the presence of voltage-sensitive Na+channels in the
Local Anaesthetics 151
ATPase Nai+ Ki+
Nao+ Ko+
Neuroplasm
Extracellular fluid
−Protein −
Fig. 9.2 The origin of the resting membrane potential. The enzyme Na+/K+ATPase maintains a high internal K+ concentration (K+i) and a high external Na+concentration (Nao+). In the resting state, the membrane is effectively impermeable to Na+( ), although K+can passively diffuse from the neuroplasm to extracellular fluid ( ). The tendency for K+to leave the fibre is opposed by the ionic charges on intracellular proteins (−protein−), giving rise to the resting membrane potential.
−75
−50
−25 0 25
0 0.5 1 1.5 2 2.5 3
Time (ms)
Transmembrane potential (mV) Ion conductance (ms cm−2)
−30
−15
Fig. 9.3 Changes in the transmembrane potential ( ), Na+ conductance ( ) and K+conductance ( ) during a nerve action potential.
membrane. During excitation, Na+ channels open and Na+rapidly diffuse across the neurilemma, causing the transient reversal in the membrane potential. After 1–2 milliseconds, K+slowly diffuses across the neurilemma, resulting in repolarization. During the refractory period, these ionic changes are reversed by the enzyme Na+/K+ ATPase in the membrane, which extrudes 3 Na+in ex-change for the entry of 2 K+.
Calcium ions are also present in the neuronal mem-brane and can affect the function of voltage-sensitive Na+ channels. In experimental conditions, the threshold po-tential required for Na+channel opening is reduced (i.e.
becomes more negative) when the local concentration of Ca2+decreases, although the resting membrane potential is unaltered.
In unmyelinated fibres, activation and depolarization produces a local flow of current in the neurilemma, which decreases the membrane potential of the adjacent nerve.
Voltage-sensitive Na+channels are activated and impulses are propagated along the nerve fibre. Retrograde conduc-tion cannot occur due to the rapid inactivaconduc-tion of Na+ channels in the wake of the impulse.
In contrast, in myelinated fibres current flows from one node of Ranvier to the immediate precedent and adja-cent node. Since the internodal distance may be 1–2 mm, saltatory3conduction in myelinated fibres is much more rapid (up to approximately 120 m s−1).
Molecular structure of sodium and potassium channels
In recent years, the detailed structure of Na+ and K+ channels in neuronal membranes has been clarified by biochemical, biophysical and molecular biological techniques.
Sodium channels
Voltage sensitive Na+channels are integral proteins that cross neuronal membranes and surround an aqueous pore (Fig. 1.1). Most Na+channels consist of three subunits (, 1 and2). The largest subunit (the unit) has a molecular weight of 260 kDa and consists of a single long peptide chain (1950 amino acids) containing four hy-drophobic regions (domains I–IV), which cross the mem-brane and symmetrically surround the pore (Fig. 9.4). The four domains are connected to each other by intracellular bridges.
Each domain consists of six membrane-spanning seg-ments (S1–S6). The S4 segment is a voltage sensor, and the short loop between S5 and S6 forms part of the lining of the outer pore of the channel. The intracellular bridge between two of the regions (III and IV) is the fast inactiva-tion gate. This gate is responsible for the rapid inactivainactiva-tion of Na+channels.
3Saltare: to leap, jump or skip.
Na+
Na+ I II III IV
Extracellular fluid
Neurilemma
Neuroplasm (a)
Extracellular fluid
Neurilemma
Neuroplasm (b)
S1 S2 S3 S4 S5 S6 +
+
Intracellular bridge
Fig. 9.4 (a) Structure of the-subunit of voltage-sensitive Na+channels in the neurilemma. The-subunit consists of a single long peptide chain containing four hydrophobic regions (I–IV), which cross the neuronal membrane. The four hydrophobic regions symmetrically surround the aqueous pore of the Na+channel; (b) The detailed structure of one of the hydrophobic regions.
Each region consists of six transmembrane segments (S1–S6), and S4 is a voltage sensor (+). The short loops between S5 and S6 form part of the lining of the Na+channel, and intracellular bridges connect S1 and S6 to adjacent regions. Local anaesthetics are believed to block the channel near tyrosine and phenylalanine residues in the S6 segment of region IV.
Potassium channels
Potassium channels are a large and heterogeneous group of membrane proteins. Many different types of K+channel have been recognized and serve a variety of physiological functions. Some K+channels are voltage-sensitive, while others respond to neurotransmitters, intracellular Ca2+ or ATP. They may or may not inactivate after membrane depolarization. Since the equilibrium potential for K+is
−100 mV, all open K+channels tend to cause neuronal repolarization and reduce membrane excitability.
In many respects, K+channels have structural similar-ities with Na+channels. Most voltage-sensitive K+ chan-nels consist of four distinct subunits, each of which is equivalent to a single domain of the Na+channel. Voltage-sensitive K+channels also contain a sensor in the S4 seg-ment, and some of them slowly inactivate due to occlusion by the terminal region of each subunit.
Mode of action
Physicochemical factors
Most local anaesthetic agents are tertiary amine bases (B), which are administered as water-soluble hydrochlorides
(B.HCl). In this form, they readily dissolve to form acidic solutions:
B.HClBH++ Cl−
After injection into tissues, a proportion of the ionized basic form (BH+) is converted to the non-ionized basic form (B) at the pH of extracellular fluid:
BH++ HCO−3 B+ H2O+ CO2
Consequently, local anaesthetics are present in tissues in both an ionized form (BH+) and a non-ionized form (B). The relative proportions of the two forms depend on the difference between their dissociation constants (pKa
value)4and extracellular pH. Only the non-ionized form
4The dissociation constant or pKavalue of a local anaesthetic is defined by a modification of the Henderson–Hasselbalch equation:
pKa= pH + log10[BH+] [B]
and is equal to the pH at which the concentration of the ionized base (BH+) and the non-ionized base (B) are equal. It can be used to calculate the proportion of the two forms that are present in solution at different pH values (Table 9.1).
Local Anaesthetics 153
B.HCl
pH 7.4
B BH+
Channel blockade
BH+
BH+
Extracellular fluid
Neurilemma
Neuroplasm B
B
H+
H+ ME
Fig. 9.5 Mode and site of action of local anaesthetics in Na+channels. Local anaesthetics are administered as hydrochloride salts (B.HCl) which release the unionized base (B) in extracellular fluid. Only the unionized form B diffuses across the neurilemmal membrane, attracts H+in the neuroplasm, and then gains access to its site of action in the open Na+channel, causing its blockade.
The unionized form B can also directly diffuse to the Na+channel through the neurilemma, and attract H+in the Na+channel. It may also cause channel blockade by ‘membrane expansion’ (ME), i.e. by causing swelling of the lipoprotein membrane. Tetrodotoxin and saxitoxin directly block the Na+channel from the exterior of the membrane, close to the external pore.
(B) is lipid-soluble and can diffuse through the nerve sheath, perineuronal tissues, and the neurilemma to reach the neuroplasm, where it attracts H+and reverts to the cationic form (BH+).
Effects on sodium channels
In the ionized form BH+, local anaesthetics in the neu-roplasm enter the Na+channel from its inner aspect, and physically occlude the Na+channel from the inside. They are believed to interact with phenylalanine (1764) and tyrosine (1771) residues in the S6 segment of domain IV, which are approximately one third of the distance along the channel (Fig. 9.4). Local anaesthetics presum-ably block the Na+channel in a non-specific manner, since all tertiary bases with pKavalues between 7.5 and 9 appear to have some local anaesthetic activity. Since the diffusion of local anaesthetics (as BH+) through the inner pores of Na+channels is essential for them to reach their site of ac-tion, nerve blockade is often dependent on the frequency of stimulation (‘use-dependent blockade’ or ‘phasic blockade’).
Convincing evidence to support this rather complex mechanism of action (Fig. 9.5) was provided by
exper-iments in which lidocaine and its N-ethylated quater-nary derivative were applied to different sides of the neurilemma. Lidocaine produces local anaesthesia when applied to the inside or the outside of the neurilemma. In contrast, its quaternary derivative is only effective when applied to the inner aspect of the membrane.
Membrane expansion
Certain local anaesthetics (e.g. benzocaine) are only present in the body as uncharged tertiary bases and must therefore act in a rather different way. They are believed to cause conduction blockade by ‘membrane expansion’ (i.e.
by causing swelling of the lipoprotein matrix of the Na+ channel). To some extent, other local anaesthetics which are partly present in the neurilemma as the uncharged base (Fig. 9.5) may act in this manner.
Local anaesthesia is influenced by the availability of the free base (B), since this is the form that read-ily diffuses through connective tissue and crosses the neurilemma. Local anaesthetics are relatively inactive when injected into tissues with an acid pH (e.g. pyogenic abcesses). This is presumably due to the reduced avail-ability of the free base for diffusion, and to the more rapid
removal of local anaesthetic due to the increase in tissue vascularity.
Carbonated solutions
Factors that increase the conversion of the free local anaes-thetic base (B) to the active form (BH+) in the neuroplasm increase the diffusion gradient and the concentration of BH+in the Na+channel. In these conditions, the speed of onset and the depth of local anaesthesia may be enhanced.
In isolated preparations, CO2rapidly diffuses across the neurilemma and decreases intracellular pH, enhancing the conversion of the tertiary base (B) to the active form (BH+).
Although carbonated solutions of local anaesthetics have been used to improve the speed of onset and quality of blockade, it is doubtful whether they have any advan-tages in clinical practice. When carbon dioxide diffuses across the neurilemma, it is rapidly buffered by intracel-lular proteins, so that changes in pH are minimal. In ad-dition, carbonated solutions are unstable, the local anaes-thetic may be precipitated and any added vasoconstrictor is more easily hydrolysed. Consequently, carbonated so-lutions of local anaesthetics are not widely used in current practice. Other agents (e.g. sodium bicarbonate, various dextrans) have also been added to local anaesthetic solu-tions, in order to modify the proportion of the free base that is present in solution and increase the intensity and duration of action.
Antiarrhythmic effects
Local anaesthetics produce their effects by blockade of Na+channels, and thus retard or prevent depolarization.
Similar effects may be produced in other excitable tissues, particularly in the heart. In atrial and ventricular muscle, the depolarization of myocardial cells from−80 mV to approximately +30 mV during phase 0 of the cardiac action potential is mainly due to the rapid influx of Na+. Local anaesthetics reduce Na+entry and the rate of depolarization of ventricular muscle, and some of them (e.g. lidocaine) have a recognized role as antiarrhythmic drugs (Chapter 15).
Effects on other ion channels
Local anaesthetics can also affect other ion channels (par-ticularly K+and Ca2+channels), although they have a reduced affinity at these sites. They do not usually modify the neuronal resting potential, except in extremely high concentrations. Similarly, they do not alter the threshold
potential required for impulse propagation, although the rates of depolarization and repolarization are decreased, and conduction velocity is diminished. Nevertheless, it is usually considered that the toxic effects of bupivacaine on the heart are partially related to its effects on K+and Ca2+ channels.
Effect on different sensory modalities During conduction blockade, different modalities may be affected to an unequal extent by local anaesthetics. The sensation of pain usually disappears before touch and pres-sure, while motor fibres may remain functional although sensory pathways are blocked. These differences may be partly related to the diameter of nerve fibres that mediate different sensations.
Small diameter unmyelinated C fibres are usually most susceptible to local anaesthetics, since they have a relatively large surface area, due to the absence of a myelin sheath. In contrast, myelinated fibres have a relatively small surface area, are only susceptible to blockade at the nodes of Ran-vier, and sequential blockade of 2–3 nodes may be required to interrupt impulse conduction. Since the internodal dis-tance is usually related to nerve fibre diameter, smaller A and A myelinated fibres are usually more susceptible than the larger (A) fibres. Consequently, pain (which is partly mediated by unmyelinated C fibres) is commonly blocked before touch and pressure (mediated by A and A fibres), which in turn are blocked before propriocep-tion and motor funcpropriocep-tion (which are dependent on A fibres).
Nevertheless, these considerations do not adequately explain several clinical observations. For instance, myeli-nated fibres of the A group, which conduct the sensation of fast or first pain, may be blocked before some nonmyeli-nated C fibres. This phenomenon may reflect the anatom-ical distribution of nerve fibres and their accessibility to drugs.
Physicochemical factors may also account for the dif-ferential effects of local anaesthetics on sensory and motor function. For instance, low concentrations of bupivacaine and ropivacaine may readily affect unmyelinated C fibres due to their high lipid-solubility. In contrast, they may not readily diffuse across myelinated A fibres and cause motor blockade (due to their relatively high pKavalue).
Consequently, these drugs may possess the optimal physic-ochemical characteristics required for differential sensory and motor blockade.
Local Anaesthetics 155
Local anaesthetic preparations
Most local anaesthetics are bases that are almost insol-uble in water. Consequently, their hydrochloride salts, which are extremely water-soluble, are usually dissolved in saline to form acidic solutions (pH 4.0–6.5). Prepa-rations with added adrenaline often contain a reducing agent (e.g. sodium metabisulphite), in order to prevent the oxidation and enhance the stability of the vasocon-strictor. Some local anaesthetic preparations (particularly multidose vials) also incorporate a preservative/fungicide (e.g. methyl p-hydroxybenzoate). Most local anaesthetic solutions are extremely stable and usually have an effective shelf-life of more than 2 years.
Vasoconstrictors
Many local anaesthetics have vasodilator effects and are rapidly absorbed after local injection. Consequently, they are often used with added vasoconstrictors, which enhance their potency and prolong their duration of action. Vaso-constrictors also decrease the systemic toxicity and in-crease the safety margin of local anaesthetics by reducing their rate of absorption, which is mainly dependent on local blood flow. Nevertheless, the effectiveness of added vasoconstrictors is extremely variable. In most infiltration procedures and in conduction blockade, vasoconstrictors usually prolong and enhance local anaesthesia. In contrast, they may have little effect on the duration of extradural blockade.
Adrenaline is the most commonly used vasoconstric-tor and is added to local anaesthetic solutions in con-centrations ranging from 1 in 500,000 (2g mL−1) to 1 in 200,000 (5 g mL−1). Higher concentrations may have toxic effects on the cardiovascular system, periph-eral nerves and the spinal cord. In addition, vasocon-strictors must not be used with local anaesthetic solu-tions that are injected into digits or appendages, as they may induce ischaemic necrosis. Although other sympa-thomimetic drugs have been used as vasoconstrictors, adrenaline is more effective than phenylephrine or no-radrenaline in decreasing the rate of absorption of most local anaesthetics.
Vasoconstrictors in dentistry
Local anaesthetic preparations containing higher concen-trations of adrenaline (e.g. 1 in 80,000; 12.5g/mL) are commonly used in dental practice. Preparations contain-ing noradrenaline have been used in the past, but are now
avoided due to their pressor effects. Some solutions of prilocaine (3%) that are licensed for dental use contain the vasoconstrictor felypressin (0.03 i.u./mL). Felypressin is a noncatecholamine vasoconstrictor that is chemically related to vasopressin, the posterior pituitary hormone.
It is a synthetic octapeptide that only affects peripheral blood vessels and has no action on the heart. Although it produces less marked vasoconstriction than adrenaline, it may be useful for patients with ischaemic heart disease when the use of catecholamines is undesirable.
Chemical structure and physicochemical properties
All local anaesthetics have certain chemical features in common. They are almost all weak bases that are partially ionized at physiological pH values, and consist of an aro-matic lipophilic group, an intermediate ester (–CO.O–) or amide (–NH.CO–) chain, and a hydrophilic secondary or tertiary amine group. The intermediate chain is the basis of the usual classification of local anaesthetics into esters or amides.
There are important practical differences between these two groups of local anaesthetics. Esters are relatively un-stable in solution and are rapidly hydrolysed in the body by butyrylcholinesterase (BChE) as well as some other esterases. Para-aminobenzoic acid (PABA) is usually one of the hydrolytic products and is sometimes associated with allergic reactions. By contrast, amides are relatively stable in solution and are slowly broken down by ami-dases in the liver. In addition, hypersensitivity reactions to amide local anaesthetics are almost unknown. In the UK, tetracaine is the only ester currently used to produce local anaesthesia.
Physicochemical properties
The chemical structure and physicochemical characteris-tics of local anaesthecharacteris-tics affect their clinical properties. In particular, these are modified by
rLipid solubility
rProtein binding
rDissociation constant (pKavalue)
Lipid solubility
There is a close correlation between their lipid-solubility and anaesthetic potency (particularly in in vitro con-ditions). The lipid solubility of different anaesthetics