PHARMACOLOGY OF LOCAL ANAESTHETIC AGENTS

Transcription

1 Br. J. Anaesth. (1986), 58, PHARMACOLOGY OF LOCAL ANAESTHETIC AGENTS B. G. COVINO Local anaesthetic drugs are chemical compounds the primary pharmacological activity of which involves inhibition of the excitation conduction process in peripheral nerves. In common with many of the early therapeutic agents, the first local anaesthetic agent, cocaine, was a naturally occurring alkaloid that had been isolated from the leaves of the Erythroxylin coca bush which was indigenous to South America. The introduction of cocaine to clinical practice has been attributed to Roller, who described the topical anaesthetic properties of this agent for ophthalmological use in However, both the anaesthetic and QMS stimulant activities of cocaine were recognized by the South American natives for many years before Roller's presentation. Procaine was synthesized by Einhorn in 1905 and represented the first injectable agent of clinical value for the production of local anaesthesia. Following the introduction of procaine, numerous compounds of similar chemical structure were developed. Amethocaine (tetracaine, USP) and chloroprocaine are the procainelike agents which have persisted to this day, as clinically useful local anaesthetics. In 1943, Lofgren synthesized lignocaine (lidocaine, USP) which represented a new chemical class of local anaesthetic compounds. Whereas the procaine-like drugs are ester derivatives of para-aminobenzoic acid, lignocaine is an amide derivative of diethylamino acetic acid. Since the advent of lignocaine, many other amide substances such as mepivacaine, prilocaine, bupivacaine and etidocaine have been introduced to clinical practice as local anaesthetic agents each with its own pharmacological profile. STRUCTURE-ACTIVITY RELATIONSHIP OF LOCAL ANAESTHETIC AGENTS Chemical compounds that demonstrate local anaesthetic activity usually possess an aromatic BENJAMIN G. COVINO, PH.D., MJ)., Departments of Anesthesia, Harvard Medical School and Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115, U.S.A. and an amine group separated by an intermediate chain (table I). The clinically useful local anaesthetic agents fall essentially into one of two chemically distinct groups. Those agents which possess an ester link between the aromatic portion and the intermediate chain are referred to as amino esters and include procaine, chloroprocaine and amethocaine. Local anaesthetics with an amide link between the aromatic end and the intermediate chain are referred to as amino amides and include lignocaine, mepivacaine, prilocaine, bupivacaine and etidocaine. The basic difference between the ester and amide compounds resides in their chemical stability. Esters are hydrolysed easily and are relatively unstable in solution. On the other hand, amides are much more stable. In the body, the amino esters are hydrolysed in plasma by the enzyme cholinesterase, whereas the amide compounds undergo enzymatic degradation in the liver. Para-aminobenzoic acid is one of the metabolites formed from the hydrolysis of ester type compounds, and this substance is capable of inducing allergic type reactions in a small percentage of patients. The amino amides, however, are not metabolized to para-aminobenzoic acid and reports of allergic reactions to these agents are extremely rare. The properties of the various local anaesthetic agents which are clinically important include potency, speed of onset and duration of anaesthetic activity. The clinical profile of the individual agents is essentially determined by the physicochemical characteristics of the various compounds, which in turn are dependent on their chemical structure. The physicochemical properties which influence anaesthetic activity are lipid solubility, protein binding, and pk a. Minor changes in molecular structure have dramatic effects on these properties (table I). Potency Lipid solubility appears to be the primary determinant of intrinsic anaesthetic potency. Consideration of the biochemical composition of the nerve membrane provides a logical explanation

2 TABLE I. Chemical structure, physicochemical properties, and pharmacological properties of local anaesthetic agents Slow 1 Short Slow 8 Long Agent PhygiochemicaJ properties Chemical configuration Pharmacological properties Molecular Protein Aromatic Intermediate Amine weight pk Partition binding Relative lipophilic chain hydrophilic (base) (25 C) coefficient (%) Onset potency Duration Esters Procaine Amethocaine H-Ni H COOCH 2CH 2 -N COOCHgCHg-N CH, CH 3 Chloroprocaine Amides Prilocaine COOCH,CH-- N ^C Cl 2 Hg.CH, H NHCOCH N I VC,H, CH, CH, Lignocaine (Q)-NHCOCH., -N CH 3 C 2 H 5 Mepivacaine Bupivacaine Etidocaine CH, CH, NHCO CH, CH, och, on NHCOCH -N C 4 H CH, C 3 H 3 n 7 Fast 1 Short Fast Moderate Fast Moderate Fast Moderate Moderate 8 Long Fast 6 Long

3 PHARMACOLOGY OF LOCAL ANAESTHETIC AGENTS D Etidocaine Bupivacaine Etidocaine 27.5 Bupivacaine Lignocaine PrUocaine Mepivacaine in vitro Relative potency Lignocaine I Pribcaine Mepivacaine i i in vivo Relative potency FIG. 1. Relationship of lipid solubility (partition coefficient) to in vitro and in vivo anaesthetic potency. for the relationship between lipid solubility and anaesthetic potency. The nerve membrane is basically a lipoprotein matrix. The axolemma consists of 90% lipids and 10% proteins. As a result, chemical compounds which are highly lipophilic tend to penetrate the nerve membrane more easily, such that less molecules are required for conduction blockade, resulting in enhanced potency. In vitro studies on isolated nerves show a correlation between the partition coefficient of local anaesthetics and the minimum concentration (C mln ) required for conduction blockade (Truant and Takman, 1959; Gissen, Covino and Gregus, 1980; Wildsmith et al., 1985). For example, among the amino amides, mepivacaine and prilocaine are the least lipid soluble and weakest amide agents, while etidocaine is the most lipophilic and the most potent local anaesthetic (fig. 1). A similar relationship between lipid solubility and potency exists among the ester type drugs. Procaine is the least lipid soluble and the weakest agent, while amethocaine is the most lipophilic and the most potent ester type drug. In vivo studies in man indicate that the correlation between lipid solubility and anaesthetic potency is not as precise as in an isolated nerve (fig. 1). Lignocaine is approximately twice as potent as prilocaine and mepivacaine in an isolated preparation but, in man, little difference in anaesthetic potency is apparent between these three agents (Covino and Vassallo, 1976). Similarly, etidocaine is more potent than bupivacaine in an isolated nerve while, clinically, etidocaine is less active than bupivacaine (Scott et al., 1980). The difference between in vitro and in vivo results is believed to be related to the vasodilator or tissue redistribution properties of the various local anaesthetics. For example, lignocaine causes a greater degree of vasodilatation than either mepivacaine or prilocaine, resulting in a more rapid vascular absorption of lignocaine such that fewer molecules of lignocaine are available for neural blockade in vivo. The extremely high lipid solubility of etidocaine results in a greater uptake of this agent by adipose tissue such as in the extradural space, which again results in fewer etidocaine molecules available for neural blockade compared with bupivacaine. Duration of anaesthesia The duration of anaesthesia is primarily related to the degree of protein binding of the various local anaesthetics. Conduction blockade is believed to occur following the interaction of local anaesthetics with a protein receptor located within the sodium channel of the nerve membrane. Chemical compounds which possess a greater affinity for and bind morefirmlyto the receptor site remain within the channel for a longer period of time, resulting in a prolonged duration of conduction blockade. Most of the information regarding the protein binding of local anaesthetics has been obtained from studies involving the binding of these agents to plasma proteins. It is assumed that a relationship exists between the plasma protein binding of local anaesthetics and the degree ofbinding to membrane proteins. In vitro studies have demonstrated that agents such as procaine which are poorly protein bound are washed out rapidly from isolated nerves, whereas drugs such as amethocaine, bupivacaine and etidocaine are removed at an extremely slow rate (fig. 2) (Truant and Takman, 1959; Gissen, Covino and Gregus, 1980; Wildsmith et al., 1985). In vivo studies, including clinical investigations in man, have confirmed the relationship between protein binding of local anaesthetics and their duration of action. For example, procaine produces a duration of brachial plexus blockade of

4 704 BRITISH JOURNAL OF ANAESTHESIA 120r 20 E 80 o 15 c s I 4 0 Pnxane Prilocaino Amethocane Buptvacaine = Lignocaine ' Amethocane Procaine Washout (min) FIG. 2. Relationship of protein binding to the rate of washout (that is, recovery from block) from an isolated nerve. 100r <D Procame LignocaiTe Mepivacane Amethocane (?) Bupivacaine Duration of anaesthesia (h) FIG. 3. Relationship of protein binding of various local anaesthetics to the duration of brachial plexus blockade min, while approximately 10 h of anaesthesia has been reported following the use of bupivacaine or etidocaine for brachial plexus blockade (fig. 3) (Scott and Cousins, 1980). Speed of onset The onset of conduction block in isolated nerves is determined primarily by the pk & of the individual agents, that is, the ph at which the ionized and non-ionized forms of the chemical compound are present in equal amounts. Since the uncharged form of the local anaesthetic agent is primarily responsible for diffusion across the nerve sheath and nerve membrane (Ritchie, Ritchie and Greengard, 1965), th& onset of action will be related directly to the amount of drug which exists in the base form (fig. 4). The percentage of a specific local anaesthetic drug, which is present in the base form when injected to tissue of ph 7.4, is inversely proportional to the 10 p* a Un-tonized {%) FIG. 4. Relationship of onset of anaesthesia of various local anaesthetic agents to their pat, and percentage of drug in un-ionized form. pk a of that agent. For example, mepivacaine, lignocaine, prilocaine and etidocaine possess a pk & of approximately 7.7. When these agents are injected to tissue at a ph of 7.4, approximately 65 % of these drugs exist in the ionized form and 35 % in the non-ionized base form. On the other hand, amethocaine possesses a pk a of 8.6 and only 5 % is present in the non-ionized form at a tissue ph of 7.4, while 95 % exists in the charged cationic form. The pk a of bupivacaine is 8.1, which means that 15 % of this agent is present in the non-ionized form at a tissue ph of 7.4, and 85 % exists in the charged cationic form. Therefore, lignocaine, mepivacaine, prilocaine and etidocaine show a rapid onset of action, whereas procaine and amethocaine, with a high pk^, have a slow onset time (fig. 4). Bupivacaine occupies an intermediate position in terms of pk a and latency of blockade: The anaesthetic characteristics of various chemical compounds in vivo are dependent in part on other miscellaneous considerations. The onset of action may be altered by the rate of diffusion through non-nervous tissue. For example, lignocaine and prilocaine possess a similar pk & and similar onset of action in an isolated nerve. However, in vivo studies suggest that prilocaine may be somewhat slower in onset than lignocaine. This difference may be related to an enhanced ability of lignocaine to diffuse through non-nervous tissue. More important, however, is the concentration of local anaesthetic agent used. For example, 0.25 % bupivacaine possesses a rather slow onset of action; however, increasing the concentration to 0.75% results in a significant decrease in the latency of anaesthetic activity. The rapid onset

5 PHARMACOLOGY OF LOCAL ANAESTHETIC AGENTS 705 time of chloroprocaine in vivo may be related in part to improved diffusion through non-nervous tissue, but also to the use of a 3 % concentration of this agent. The p/c a of chloroprocaine is approximately 9 and its onset of action in isolated nerves is relatively slow. However, the low systemic toxicity of this agent allows the use of high concentrations. Therefore, the rapid onset time in vivo of chloroprocaine may be related simply to the large number of molecules placed in the vicinity of peripheral nerves. The effect of local anaesthetic agents on the vasculature at the site of injection also influences the in vivo potency and duration of action of these compounds. Absorption of local anaesthetic agents from the region of injection decreases the number of molecules available for diffusion to the receptor site in the nerve membrane. Factors which increase the absorption decrease the apparent anaesthetic potency and duration of action of a specific compound. All local anaesthetics, with the exception of cocaine, exhibit a ' biphasic effect on vascular smooth muscle. At extremely low concentrations they cause enhanced activity of vascular smooth muscle, leading to vasoconstriction, while, in the concentrations commonly used for regional anaesthesia, they tend to be vasodilators. The relative degree of vasodilatation produced by different local anaesthetic drugs can affect their potency and duration of action. This can be demonstrated by comparing the in vitro and in vivo activity of different agents. For example, in vitro studies of lignocaine and mepivacaine have shown that lignocaine is significantly more potent than the latter on an isolated nerve, while the duration of conduction blockade is similar. However, in vivo studies have shown little difference in their relative anaesthetic potency and, indeed, the duration of action of mepivacaine is somewhat longer than that of lignocaine. These differences appear to be related to a greater degree of vasodilatation produced by lignocaine. Addition of a vasoconstrictor agent such as adrenaline (epinephrine, USP) to solutions of both lignocaine and mepivacaine eliminates the difference in duration of the two compounds, which again suggests that the greater vasodilator activity of lignocaine is responsible for the difference in anaesthetic duration observed between the plain solutions. The only agent which produces a state of vasoconstriction at clinically useful concentrations is cocaine, the vasoconstrictor action of which is not directly related to the agent itself, but is an indirect action. Cocaine possesses the ability to prevent the re-uptake of noradrenaline (norepinephrine, USP) by storage granules, which results in a state of vasoconstriction. In summary, the pharmacological activity of local anaesthetic agents is related primarily to their physicochemical properties. However, the activity of these agents in vivo may be altered by other actions which are essentially unrelated to their physicochemical properties. On the basis of anaesthetic activity in man, the various agents may be classified as follows: (1) Agents of low anaesthetic potency and short duration of action: procaine and chloroprocaine. (2) Agents of intermediate anaesthetic potency and duration of action: lignocaine, mepivacaine and prilocaine. (3) Agents of high anaesthetic potency and prolonged duration of action: amethocaine, bupivacaine and etidocaine. In terms of latency, chloroprocaine, lignocaine, mepivacaine, prilocaine and etidocaine possess a relatively rapid onset of action. Bupivacaine is intermediate in terms of onset of anaesthesia, while procaine and amethocaine demonstrate a long latency period. Differential blockade In addition to the anaesthetic properties described above, one other important clinical consideration is the ability of local anaesthetic agents to cause a differential blockade of sensory and motor fibres. The intrathecal administration of varying concentrations of procaine has been utilized to provide a differential blockade of sensory, sympathetic and motor fibres. However, it has been extremely difficult to produce sensory anaesthesia sufficient for surgery without a significant impairment of motor function. Bupivacaine was the first agent which showed a relative specificity for sensory fibres such that adequate sensory analgesia without profound inhibition of motor fibres could be achieved for surgical, obstetric and acute and chronic pain therapy regardless of the regional anaesthetic technique used. Bupivacaine and etidocaine, which are the two local anaesthetic agents most recently introduced to clinical practice, provide an interesting contrast in terms of their differential sensory/motor blocking activity, although they are both potent long acting anaesthetic agents (fig. 5) (Scott et al., 1980). For example, bupivacaine is widely used

6 BRITISH JOURNAL OF ANAESTHESIA 706 Bupivacaine Etidocaine 100 Sensory block 0 Motor block Concentration (%) FIG. 5. Comparative sensory/motor blockade of bupivacaine and etidocaine following extradural administration. extradurally for both surgical and obstetric procedures and relief of pain after operation as a result of its ability to provide adequate sensory analgesia with minimal blockade of motor fibres, particularly when used as a 0.25% or 0.5% solution. Thus, the patient in labour can be rendered pain free and still be able to move her legs, which is one of the primary reasons why this agent has enjoyed popularity for continuous extradural blockade during labour. Increasing the concentration of bupivacaine to 0.75 % increases the depth of both sensory and motor blockade, while also shortening latency and producing a more prolonged duration of anaesthesia. On the other hand, etidocaine shows little separation between sensory and motor blockade. In order to achieve adequate extradural sensory anaesthesia, 1.5% concentrations of etidocaine are usually required. At these concentrations, etidocaine has an extremely rapid onset of action and a prolonged duration of anaesthesia. However, sensory anaesthesia is associated with a profound degree of motor blockade. Thus, etidocaine is a valuable agent, particularly for extradural blockade in surgical situations where maximum neuromuscular blockade is desirable, since it combines a rapid onset, prolonged duration, and satisfactory quality of anaesthesia, with profound motor blockade. However, this marked effect on motor function renders etidocaine of limited value for obstetric analgesia and postoperative pain relief. The factors responsible for the differential sensory/motor separation associated with bupiva- caine are not precisely known. Studies on isolated nerves have shown that, at low concentrations, bupivacaine initially blocks unmyelinated C fibres followed, at a later time, by a block of myelinated A fibres (Gissen, Covino and Gregus, 1982). On the other hand, etidocaine blocks both A and C fibres at approximately the same rate. The slow blockade of A fibres by bupivacaine is believed to be attributable to the relatively high pka of this agent, such that fewer uncharged molecules are available to penetrate the diffusion barriers surrounding large A fibres. In vivo, the combination of the slow diffusion of bupivacaine and its absorption by the vasculature in the region of drug administration may result in a situation in which the number of bupivacaine molecules which ultimately penetrate the membrane of the large motor A fibres is insufficient to cause conduction blockade. The lack of diffusion barriers around the small sensory C fibres allows a sufficient number of bupivacaine molecules to reach the receptor sites in the C fibre membrane to cause sensory anaesthesia. Thus, bupivacaine may possess the optimal pka and lipid solubility characteristics required for differential sensory/motor blockade. FACTORS INFLUENCING ANAESTHETIC ACTIVITY Although the inherent pharmacological properties of the various local anaesthetic agents basically determine their anaesthetic profile, other factors may also influence the quality of regional anaesthesia. These include dose of local anaesthetic

7 PHARMACOLOGY OF LOCAL ANAESTHETIC AGENTS T 250 1= 200 to ^ XX) Dose (mg) FIG. 6. Effect of dose of extradural eudocaine on onset, frequency and duration of anaesthesia. administered; addition of a vasoconstrictor to the local anaesthetic solution; site of administration; carbonation of local anaesthetics; addition of dextran; mixtures of local anaesthetics. Dosage of local anaesthetic solutions The mass of drug administered influences the onset, depth and duration of anaesthesia (fig. 6). As the dose of local anaesthetic is increased, the frequency of satisfactory anaesthesia and the duration of anaesthesia increase and the time to onset of anaesthesia decreases. In general, the dose of local anaesthetic administered can be increased by administering either a larger volume of a less concentrated solution, or a smaller volume of a more concentrated solution. However, in clinical practice, an increase in dose is achieved usually by using a more concentrated solution of the specific agent. For example, a dose-response study involving the use of bupivacaine for extradural analgesia in obstetrics has shown that increasing the concentration from 0.125% to 0.5% while maintaining the same volume of injectate (10 ml) resulted in a decreased latency, improved incidence of satisfactory analgesia and an increased duration of sensory analgesia (Littlewood et al., 1979). A similar study involving the use of bupivacaine for surgical anaesthesia has also demonstrated that increasing the concentration from 0.5 % to 0.75 % with a concomitant increase in dose from approximately 100 mg to 150 mg produced a more rapid onset and prolonged duration of sensory anaesthesia (Scott et al., 1980). In addition, the frequency of satisfactory sensory anaesthesia was increased and the depth of motor blockade was enhanced. The relative influence of volume, concentration and dose was demonstrated in a study in which prilocaine 600 mg administered extradurally either as 30 ml of a 2 % solution or 20 ml of 3 % solution, was evaluated (Crawford, 1964). No difference in onset, adequacy or duration of anaesthesia and onset, depth and duration of motor blockade was observed, despite differences in volume and concentration of anaesthetic solution used, since the dose was maintained constant. The volume of anaesthetic solution administered may influence the spread of anaesthesia. For example, 30 ml of 1 % lignocaine administered to the extradural space was shown to produce a level of anaesthesia which was 4.3 dermatomes higher than that achieved when 10 ml of 3 % lignocaine was used (Erdimir, Soper and Sweet, 1965). Thus, except for the possible effect on the spread of anaesthesia, the primary qualities of regional anaesthesia namely, onset, depth and duration of blockade are related to the mass of drug injected, that is, the product of volume and concentration. Addition of a vasoconstrictor to local anaesthetic solutions Vasoconstrictors, particularly adrenaline, are frequently added to local anaesthetic solutions. The decrease in the rate of vascular absorption which results from the addition of adrenaline allows more anaesthetic molecules to reach the nerve membrane and thereby improves the depth and duration of anaesthesia. Local anaesthetic solutions usually contain a 1: (5 ug ml" 1 ) concentration of adrenaline. This concentration

8 708 BRITISH JOURNAL OF ANAESTHESIA I T Ametho Ametha Ametho. adreno.2mg phen. 2.0mg FIG. 7. Effect of adrenaline (adren.) (epinephrine, USP) and phenylephrine (phen.) on the duration of spinal anaesthesia produced by amethocaine (Ametho.) (tetracaine, USP). has been reported to provide an optimal degree of vasoconstriction when used with lignocaine for extradural or intercostal use (Braid and Scott, 1965). Little information is available concerning the optimum concentration of adrenaline when it is used with other local anaesthetic agents. Other vasoconstrictor agents such as noradrenaline and phenylephrine have also been used as additives to solutions of local anaesthetics. Regional blood now studies indicate that adrenaline is more effective as a vasoconstrictor than noradrenaline when combined with local anaesthetic agents (Dhuner and Lewis, 1966). Phenylephrine has been reported to produce the greatest prolongation of spinal anaesthesia when combined with amethocaine (Meagher, Moore and DeVries, 1966). However, more recent studies conducted under double-blind conditions indicated that, at equipment doses, no differences existed between the ability of adrenaline and phenylephrine to prolong the duration of spinal anaesthesia produced by amethocaine (fig. 7) (Conception et al., 1984). Differences exist in terms of the effect of adrenaline on prolonging the duration of action of various local anaesthetic agents (fig. 8). For example, procaine, lignocaine and mepivacaine benefit greatly from the addition of adrenaline in terms of prolonging the duration of infiltration anaesthesia, peripheral nerve blocks and extradural blockade (Gramling, Ellis and Volpitto, 1964; Albert and Lofstrom, 1965; Bromage, 1965a; Swerdlow and Jones, 1970). The duration of action of prilocaine, bupivacaine and etidocaine is also prolonged by the addition of adrenaline Brachial plexus block L Lignocaine M- Mepivacaine P- Pnlocaine E-Etidocaine B-Bupivacaine Extradural block FIG. 8. Percent increase in anaesthetic duration of various local anaesthetic agents resulting from the addition of adrenaline. when these agents are used for infiltration and peripheral nerve blocks (Albert and Lofstrom, 1965; Swerdlow and Jones, 1970). However, the duration of action of these agents is not markedly affected by adrenaline following extradural blockade (Bromage, 1965a; Keir, 1974; Buckley et al., 1978). The decreased vasodilator action of prilocaine compared with lignocaine is believed to be responsible for the reduced effect of added adrenaline to solutions of prilocaine. In the case of bupivacaine and etidocaine, the high lipid solubility of these agents may be responsible for the diminished effect of adrenaline. These agents are taken up substantially by extradural fat and then released slowly, which contributes to their prolonged duration of action. However, the interaction of adrenaline and the long-acting agents, such as bupivacaine, is dependent on the concentration of drug used. For example, in extradural blockade for labour, the frequency and duration of adequate analgesia was improved when adrenaline 1: was added to % and 0.25 % bupivacaine (Crawford, 1964). However, the addition of adrenaline to 0.5% and 0.75% bupivacaine was not associated with a significant improvement in

9 PHARMACOLOGY OF LOCAL ANAESTHETIC AGENTS 709 the frequency of satisfactory extradural blockade in obstetric or surgical patients (Littlewood et al., 1979; Sinclair and Scott, 1984). The profoundness of motor blockade is enhanced following the extradural administration of adrenaline-containing solutions of bupivacaine and etidocaine (Sinclair and Scott, 1984). The differential effect of adrenaline in terms of prolonging the duration of action of local anaesthetic agents is most apparent in the subarachnoid space. Adrenaline significantly extends the duration of spinal anaesthesia when combined with amethocaine (Armstrong, Littlewood and Chambers, 1983; Conception et al., 1984). However, the duration of effective surgical anaesthesia is not markedly enhanced when solutions of lignocaine or bupivacaine with adrenaline are administered intrathecally (Chambers et al., 1981; Chambers, Littlewood and Scott, 1982). Site of injection The site of administration of local anaesthetic agents influences their anaesthetic profile. Although local anaesthetics are frequently classified as agents of short, moderate or long duration with a slow or rapid onset of action, these general properties are influenced by the type of procedure performed. For example, amethocaine is usuallv considered an agent of slow onset and long duration. However, the onset of action of this drug is quite rapid (approximately 3 min) when administered intrathecally, while the duration of spinal anaesthesia with amethocaine is only 2-3 h (Concepcion et al., 1984). In terms of latency, the most rapid onset of action occurs following the intrathecal or subcutaneous administration of local anaesthetics, while the slowest onset times are observed during the performance of brachial plexus blocks (Covino and Bush, 1975). With regard to the duration of anaesthesia, an agent such as bupivacaine possesses a duration of surgical anaesthesia of approximately 4 h when administered to the extradural space. However, when bupivacaine is administered for brachial plexus blockade, the duration of anaesthesia averages 10 h. Differences in the onset and duration of anaesthesia depending on the site of injection result in part from the particular anatomy of the area of injection, the variation in the rate of vascular absorption, and the amount of drug used for various types of regional anaesthesia. In the case of spinal anaesthesia, the lack of a nerve sheath around the spinal cord and the deposition of the local anaesthetic solution in the immediate vicinity of the spinal cord are responsible for the rapid onset of action. On the other hand, the relatively small amount of drug used for spinal anaesthesia probably accounts for the relatively short duration of action associated with this particular technique. In the case of brachial plexus blockade, the onset of anaesthesia is slow as a result of the fact that the anaesthetic agent is usually deposited at some distance from the nerve roots, and therefore time for diffusion to the nerve membrane is required before signs of anaesthesia are apparent. The long duration of brachial plexus blockade observed with most local anaesthetics, but in particular the longer acting agents, is probably related to the decreased rate of vascular absorption from that site, and also the larger doses of drug commonly used for this regional anaesthetic technique. Carbonation of local anaesthetics Carbonation of local anaesthetic solutions has been attempted in an effort to improve the onset and depth of anaesthesia. In isolated nerve preparations, carbon dioxide will enhance the diffusion of local anaesthetics through nerve sheaths resulting in a more rapid onset (fig. 9) and a decrease in the minimum concentration (C mln ) of local anaesthetic required for conduction blockade (Catchlove, 1972; Gissen, Covino and Gregus, (min) 10 - CD * o - - HCI CO2 HCI CO2 0.25Z Q5Z Bupivacaine Bupivacaine FIG. 9. Onset time of conduction block in an isolated nerve following exposure to bupivacaine hydrochloride and carbonated bupivacaine.

10 710 BRITISH JOURNAL OF ANAESTHESIA 1985). The diffusion of carbon dioxide through the nerve membrane decreases the axoplasmic ph. The lower ph increases the intracellular concentration of the cationic form of the local anaesthetic, which represents the active form that binds to a receptor in the sodium channel. In addition, the local anaesthetic cation does not readily diffuse through membranes, so that the drug remains entrapped within the axoplasm, a situation referred to as ion trapping. The enhanced formation of the local anaesthetic cation and the process of ion trapping are believed responsible for the more rapid onset and more profound degree of conduction block. A number of clinical studies have been carried out with carbonated solutions of lignocaine. The initial investigations in man reported that lignocaine carbonate solutions demonstrated a more rapid onset of brachial plexus and extradural blockade compared with the use of lignocaine hydrochloride solutions (Bromage, 1965b, 1970). However, more recent double-blind studies have failed to demonstrate a significantly more rapid onset of action when lignocaine carbonate was compared with lignocaine hydrochloride for extradural blockade (Morrison, 1981; Cole et al., 1985). In theory an agent such as bupivacaine which has a relatively slow onset of action should benefit greatly from the use of a carbonated solution and it has been reported that bupivacaine-carbon dioxide is associated with a more rapid onset of action in man (Eckstein et al., 1978). However, double-blind studies in which bupivacaine carbonate was compared with bupivacaine hydrochloride for brachial plexus or extradural blockade, have failed to confirm these earlier reports of a significantly shorter onset of action of the carbonated solution (Brown et al., 1980; McClure and Scon, 1981). Thus, at the present time, it is not certain whether carbonation of local anaesthetic solutions imparts any advantage to the various local anaesthetic agents in terms of onset of block when used under clinical conditions, although the depth of anaesthesia may be improved. The discrepancy between in vitro and in vivo studies suggests that the injected carbon dioxide is rapidly buffered in vivo such that the intracellular ph is not sufficiently altered and significantly increased concentrations of the cationic form of the local anaesthetic are not achieved to produce a more rapid onset of anaesthesia. Attempts have been made to improve the onset of conduction blockade by the addition of sodium bicarbonate to local anaesthetic solutions immediately before injection (Galindo, Schou and Witcher, 1981; Hilgier, 1985). Theoretically, sodium bicarbonate may increase the ph of the local anaesthetic solution, which in turn increases the amount of drug in the uncharged base form. Thus, the rate of diffusion across the nerve sheath and nerve membrane should be enhanced, resulting in a more rapid onset of anaesthesia. Several clinical studies have been carried out in which the addition of sodium bicarbonate to solutions of bupivacaine did appear to produce a significant decrease in the latency of brachial plexus blockade (Galindo, Schou and Witcher, 1981, Hilgier, 1985). In addition, it has also been reported that the duration of anaesthesia was prolonged by increasing the ph of the local anaesthetic solution (Hilgier, 1985). Addition of dextran Various attempts have been made to prolong the duration of anaesthesia by incorporating dextran into local anaesthetic solutions (Loder, 1960; Rosenblatt and Fung, 1979). Discrepancies exist with regard to the effectiveness of dextran in prolonging the duration of regional anaesthesia. In one controlled clinical study, prolonged durations of anaesthesia were observed in some individual patients, but the mean duration of intercostal nerve blockade was not significantly altered when solutions of bupivacaine with and without dextran were compared (Bridenbaugh, 1978). It has been suggested that the difference in results obtained by various investigators may be related to the ph of the dextran solution used. Dextran solutions with a ph of 8.0 significantly prolonged the duration of bupivacaine-induced coccygeal nerve blocks in rats, whereas the duration of block was not altered when dextran with a ph of was added to bupivacaine (Rosenblatt and Fung, 1980). These results indicate that alkalinization of the anaesthetic solution may be responsible for prolonged conduction blockade, rather than the dextran itself. Mixtures of local anaesthetics The use of mixtures of local anaesthetics for regional anaesthesia has become relatively popular in recent years. The basis for this practice is to compensate for the short duration of action of

11 PHARMACOLOGY OF LOCAL ANAESTHETIC AGENTS 711 certain agents such as chloroprocaine or lignocaine and the long latency of other agents such as amethocaine and bupivacaine. The combination of lignocaine or mepivacaine and amethocaine was commonly used in some centres before the advent of bupivacaine and etidocaine as long duration anaesthetics. Since the slow onset of amethocaine for peripheral nerve blocks and extradural anaesthesia was clinically unacceptable, the addition of lignocaine or mepivacaine provided a local anaesthetic solution which afforded a relatively rapid onset of action and prolonged duration of anaesthesia. Recently, mixtures of chloroprocaine and bupivacaine have been used in an effort to produce a local anaesthetic solution with a rapid onset and long duration of action. The low systemic toxicity of chloroprocaine afforded an additional advantage to such a mixture. However, the use of a chloroprocaine-bupivacaine mixture has produced contradictory results. It was originally reported that a mixture of chloroprocaine and bupivacaine did result in a short latency and prolonged duration of bracbial plexus blockade (Cunningham and Kaplan, 1974). However, subsequent studies indicated that the duration of extradural anaesthesia produced by a mixture of chloroprocaine-bupivacaine was significantly shorter than that obtained with solutions of bupivacaine alone (Cohen and Thurlow, 1979). This reduced duration has been attributed in part to a decrease in ph, since chloroprocaine solutions have a ph of approximately 3.0 (Galindo and Witcher, 1980). Reduction in ph decreases the amount of bupivacaine available in the uncharged base form, which may reduce the number of molecules able to penetrate the nerve sheath. In addition, data from isolated nerve studies suggest that a metabolite of chloroprocaine may inhibit the binding of bupivacaine to membrane receptor sites (Corke, Carlson and Dettbarn, 1984). At the present time there do not appear to be any clinically significant advantages to the use of mixtures of local anaesthetic agents. Etidocaine and bupivacaine provide clinically acceptable onsets of action and prolonged durations of anaesthesia. In addition, the use of catheter techniques for extradural anaesthesia and also for brachial plexus blockade make it possible to administer repeated injection of the rapidly acting agents such as chloroprocaine or lignocaine which provide an anaesthetic duration of indefinite length. SPECIFIC LOCAL ANAESTHETIC AGENTS (table II) Amino ester agents Cocaine. This compound, which was isolated from the Erythroxylin coca bush, was the first agent successfully used for the production of clinical local anaesthesia. The relatively high potential for systemic toxicity and the addiction liabilities associated with its use resulted in the abandonment of this agent for most regional anaesthetic techniques. However, cocaine is an excellent topical anaesthetic agent and is the only local anaesthetic that produces vasoconstriction at clinically useful concentrations. As a result, it is still used to anaesthetize and constrict the nasal mucosa before nasotracheal intubation. It is also used frequently by otolaryngologists during nasal surgery because of its topical anaesthetic and vasoconstrictor properties. Procaine. This was the first synthetic compound successfully used for regional anaesthesia. However, procaine is a relatively weak local anaesthetic with a slow onset and short duration of action. The relatively low potency and rapid hydrolysis of this agent is responsible for the low systemic toxicity of procaine. On the other hand, procaine is hydrolysed to para-aminobenzoic acid, which is responsible for the allergic reactions associated with the repeated use of this drug. At present, procaine is primarily used for infiltration anaesthesia and diagnostic differential spinal blocks. Recently, a combination of procaine and amethocaine has been used for spinal anaesthesia in obstetric patients (Chantigian et al., 1984). Chloroprocaine. Chloroprocaine is characterized by a rapid onset of action, a short duration, and low systemic toxicity. Although the potency of this agent is relatively low, it may be used in a concentration of 3%, because of its systemic safety. The duration of action of chloroprocaine is approximately min. This agent is used primarily for extradural analgesia and anaesthesia in obstetrics because of its rapid onset and low systemic toxicity in mother and fetus. However, frequent injections are required in order to provide adequate pain relief during labour. Often, extradural analgesia is established in the pregnant patient with chloroprocaine, following which a longer acting agent such as bupivacaine is used. The extradural use of chloroprocaine may have declined somewhat as a result of reports of

12 712 BRITISH JOURNAL OF ANAESTHESIA TABLE II. Clinical use of local anaesthetic agents Agents Amino Esters Cocaine Procaine Chloroprocaine Amethocaine (tetracaine, USP) Amino Amides Lignocaine (lidocaine, USP) Mepivacaine Prilocaine Bupivacaine Etidocaine Miscellaneous Cinchocaine (dibucaine, USP) Benzocaine Primary clinicnl uses Topical Infiltration Spinal Peripheral nerve blocks Obstetric extradural blocks Spinal anaesthesia Infiltration I.v. regional anaesthesia Peripheral nerve block Surgical and obstetric extradural blocks Spinal anaesthesia Topical Infiltration Peripheral nerve blocks Surgical extradural blocks Infiltration I.v. regional anaesthesia Peripheral nerve blocks Surgical extradural blocks Infiltration Peripheral nerve blocks Obstetric and surgical extradural blocks Spinal anaesthesia Infiltration Peripheral nerve blocks Surgical extradural blocks Spinal anaesthesia Topical Comments Limited use because of addictive potential T.imitrd use because of slow onset, short duration, allergic potential Fast onset, short duration, low systemic toxicity I.imitrd use except for spinal anaesthesia because of slow onset, high systemic toxicity Most versatile agent Similar to lignocaine Methaemoglobinaemia at high doses Least systemic toxicity of amide agents Sensory/motor separation Profound motor block Use limited to spinal anaesthesia Use limited to topical anaesthesia prolonged sensory/motor deficits following the accidental subarachnoid injection of this agent (Ravindran et al., 1980; Resiner, Hochman and Plumer, 1980). Chloroprocaine has also proven of value for peripheral nerve blocks and extradural anaesthesia when the duration of surgery is not expected to exceed min. Thus, this drug is useful for ambulatory surgical procedures performed under regional anaesthesia. Chloroprocaine has also been mixed with other agents such as bupivacaine or amethocaine in order to provide a rapid onset and prolonged duration of anaesthesia. However, as discussed previously, such mixtures may not result in the long duration of anaesthesia usually associated with bupivacaine. Amethocaine. This agent is primarily used for spinal anaesthesia. It may be used as an isobaric, hypobaric or hyperbaric solution for spinal blockade, although hyperbaric solutions of amethocaine are probably used most commonly. It provides a relatively rapid onset of spinal anaesthesia approximately 3 5 min excellent qualities of sensory anaesthesia and a profound block of motor function. Plain solutions of amethocaine provide an average duration of spinal anaesthesia of 2 3 h, while the addition of

13 PHARMACOLOGY OF LOCAL ANAESTHETIC AGENTS 713 adrenaline can extend the duration of anaesthesia to 4-6 h. Amethocaine is rarely used for other forms of regional anaesthesia as a result of its extremely slow onset of action and the potential for systemic toxic reactions when the larger doses required for other types of regional blockade are used. Amethocaine does possess excellent topical anaesthetic properties and solutions of this agent were commonly used for endotracheal surface anaesthesia. However, the absorption of amethocaine from the tracheo-bronchial area is extremely rapid, and several fatalities have been reported following the use of an endotracheal aerosol of amethocaine. Amino amide agents Lignocaim. Lignocaine was the first drug of the amino amide type to be introduced to clinical practice. This agent remains the most versatile and most commonly used local anaesthetic by virtue of its inherent potency, rapid onset, moderate duration of action and topical anaesthetic activity. Solutions of 0.5%, 1.0%, 1.5% and 2.0% lignocaine are available for infiltration, peripheral nerve blocks and extradural anaesthesia. In addition, 5% lignocaine with 7.5% glucose is widely used for spinal anaesthesia of min duration. Lignocaine is also used in ointment, jelly, viscous and aerosol preparations for a variety of topical anaesthetic procedures. Although the duration of action of lignocaine is approximately 1-2 h for various regional anaesthetic procedures, the addition of adrenaline significantly prolongs the duration of this agent. In addition, adrenaline decreases the rate of absorption of lignocaine which significantly decreases its potential for producing systemic toxic reactions. Mepivacaine. This agent is similar to lignocaine in terms of its anaesthetic profile. Mepivacaine may produce a profound depth of anaesthesia, with a relatively rapid onset and a moderate duration of action. This agent may be used for infiltration, peripheral nerve blocks and extradural anaesthesia in concentrations varying from 0.5 to 2.0 %. In some countries, 4 % hyperbaric solutions of mepivacaine are also available for spinal anaesthesia. Differences do exist between mepivacaine and lignocaine. Mepivacaine is not effective as a topical anaesthetic agent and so is less versatile than lignocaine. In addition, the metabolism of mepivacaine is markedly prolonged in the fetus and newborn, such that this agent is not usually used for obstetric anaesthesia. However, in adults, mepivacaine appears to be somewhat less toxic than lignocaine. In addition, the vasodilator activity of mepivacaine is less than that of lignocaine. Thus, mepivacaine provides a somewhat longer duration of anaesthesia than lignocaine when the two agents are used without adrenaline. The duration of action of mepivacaine may be prolonged significantly by the addition of a vasoconstrictor such as adrenaline. Prilocaine. The clinical profile of prilocaine is also similar to that of lignocaine. Prilocaine has a relatively rapid onset of action, while providing a moderate duration of anaesthesia and a profound depth of conduction blockade. This agent causes significantly less vasodilatation than lignocaine and so may be used without adrenaline. In general, the duration of prilocaine without adrenaline is similar to that of lignocaine with adrenaline. Thus, prilocaine is particularly useful in patients in whom adrenaline may be contraindicated. Prilocaine is useful for infiltration, peripheral nerve blockade, and extradural anaesthesia. Although prilocaine possesses topical anaesthetic activity, and can induce spinal anaesthesia of short duration, no specific formulations of this agent are available for topical or spinal anaesthesia. Prilocaine is the least toxic of the amino amide local anaesthetics. Thus, this agent is particularly useful for i.v. regional anaesthesia, since CNS toxic effects are rarely seen following tourniquet deflation, even when early accidental release of the tourniquet may occur. Forty millilitre of 0.5% prilocaine (200 mg) provides effective anaesthesia for hand surgery using the i.v. regional anaesthetic technique. The major deterrent to the use of prilocaine is related to the formation of methaemoglobinaemia with this drug (Lund and Cwik, 1965). This unusual side effect of prilocaine has essentially eliminated the use of this drug in obstetrics, although prilocaine has not been reported to cause any significant adverse effects in mother, fetus or newborn. However, the cyanotic appearance of newborns delivered of mothers who have received prilocaine for extradural anaesthesia during labour has resulted in sufficient confusion concerning the aetiology of the cyanosis, such that the obstetric use of this potentially valuable drug has been virtually abandoned.

14 714 BRITISH JOURNAL OF ANAESTHESIA Bupivacaine. This agent has probably had the greatest influence on the practice of regional anaesthesia since the introduction of lignocaine. Bupivacaine was the first local anaesthetic that combined the properties of an acceptable onset, long duration of action, profound conduction blockade, and significant separation of sensory anaesthesia and motor blockade. This agent is used in concentrations of %, 0.25%, 0.5%, and 0.75 % for various regional anaesthetic procedures, including infiltration, peripheral nerve blocks, extradural and spinal anaesthesia. Bupivacaine has not been used for topical anaesthesia. The average duration of surgical anaesthesia of bupivacaine varies approximately from 3 to 10 h. Its longest duration of action occurs when major peripheral nerve blocks such as brachial plexus blockade are performed. In these situations, average durations of effective surgical anaesthesia of h have been reported. In some patients, durations of brachial plexus block of 24 h have been observed, with complete recovery of sensation. The major advantage of bupivacaine appears to be in the area of obstetric analgesia for labour. In this situation, bupivacaine administered extradurally in concentrations varying from % to 0.5 % provides satisfactory pain relief for 2-3 h which significantly decreases the need for repeated injections in the pregnant patient. More importantly, adequate analgesia is usually achieved without significant motor blockade, so that the patient in labour is able to move her legs. This differential blockade of sensory and motor fibres is also the basis for the widespread use of bupivacaine for postoperative extradural analgesia and for certain chronic pain states. In recent years, bupivacaine has been used extensively for spinal anaesthesia (Chambers, Edstrom and Scott, 1981; Sheskey et al., 1983; Rocco et al., 1984). Isobaric and hyperbaric solutions of 0.5 % and 0.75 % bupivacaine have been investigated for a variety of surgical procedures performed under subarachnoid blockade. Onset of spinal anaesthesia with bupivacaine usually occurs within 5 min while the duration of surgical anaesthesia persists for 3-4 h. Comparative studies of bupivacaine and amethocaine suggest little difference between the two agents in terms of onset, spread and duration of spinal blockade. Several investigations have suggested that the frequency of satisfactory anaesthesia may be greater with bupivacaine compared with amethocaine. In addition, less hypotension is apparent following the intrathecal administration of bupivacaine, even in patients with an exaggerated spread of sensory anaesthesia. The degree of motor blockade is greater when isobaric solutions of bupivacaine are used in comparison with the use of the hyperbaric formulation. Etidocaine. Etidocaine, which is chemically related to lignocaine, is the latest local anaesthetic introduced for clinical use. This agent is characterized by very rapid onset, prolonged duration of action, and profound sensory and motor blockade. Etidocaine may be used for infiltration, peripheral nerve blockade and extradural anaesthesia. Although etidocaine and bupivacaine provide prolonged durations of anaesthesia, significant differences exist with regard to the anaesthetic profile of these two local anaesthetics. Etidocaine has a significantly more rapid onset of action than bupivacaine. In addition, concentrations of etidocaine which are required for adequate sensory anaesthesia produce profound motor blockade. As a result, etidocaine is primarily useful as an anaesthetic for surgical procedures in which neuromuscular blockade is required. Thus, this agent is of limited use for obstetric extradural analgesia and for postoperative pain relief, since it does not provide a differential blockade of sensory and motor fibres. It is possible to take advantage of the different pharmacological profiles of etidocaine and bupivacaine in certain clinical situations. For example, it is possible to initiate extradural blockade with 1.5% etidocaine for lower limb orthopaedic procedures, such as total hip replacements, and abdominal surgical procedures. Under these conditions etidocaine provides a rapid onset of action and a profound depth of anaesthesia and neuromuscular blockade. Supplementary intraoperative and postoperative anaesthesia is then provided by 0.5 % bupivacaine, which produces excellent sensory anaesthesia with minimal motor blockade. Miscellaneous Cinchocaine (dibucaine, USF). This agent is essentially used for spinal anaesthesia. It is most widely used as a spinal anaesthetic drug outside the U.S.A., while its use is rather limited within the U.S.A. Comparative studies of cinchocaine and amethocaine indicate that the former is more potent: 0.25% cinchocaine provides a depth of anaesthesia similar to that produced by 0.5% amethocaine (Rocco et al., 1982). The onset of

15 PHARMACOLOGY OF LOCAL ANAESTHETIC AGENTS 715 action of the two agents is similar, while the duration of anaesthesia is slightly longer with cinchocaine. In addition, the degree of hypotension and the profoundness of motor blockade was less in patients receiving intrathecal cinchocaine, compared with subjects in whom amethocaine was administered to the subarachnoid space, although the spread of sensory anaesthesia was similar in the two groups. Hyperbaric solutions of 0.25% and 0.5% cinchocaine with 5% glucose are commonly available in most countries. In addition, a pre-formulated hypobaric solution of % cinchocaine is also available. Benzocaine. This local anaesthetic is used exclusively for topical anaesthesia. It is available in a variety of proprietary and non-proprietary preparations. The most common forms used in an operating room setting are as aerosol solutions for endotracheal administration and an ointment for lubrication of endotracheal tubes. SUMMARY The most important clinical properties of local anaesthetic agents are potency, onset, duration of action and relative blockade of sensory and motor fibres. These qualities are related primarily to the physicochemical properties of the various compounds. In general, lipid solubility determines the relative intrinsic potency of the various agents, while protein binding influences the duration of anaesthesia and pk a is correlated with the onset of action. In general, the local anaesthetics for infiltration, peripheral nerve blockade, and extradural anaesthesia can be classified into three groups: (1) agents of low potency and short duration, for example procaine and chloroprocaine; (2) agents of moderate potency and duration, for example lignocaine, mepivacaine and prilocaine; and (3) agents of high potency and long duration, for example amethocaine, bupivacaine and etidocaine. These local anaesthetics also vary in terms of onset: chloroprocaine, lignocaine, mepivacaine, prilocaine and etidocaine have a rapid onset, while procaine, amethocaine and bupivacaine are characterized by a longer latency period. REFERENCES Albert, J., and Lofstrom, B. (1965). Bilateral ulnar nerve blocks for the evaluation of local anaesthetic agents. Acta Anatsthtsiol. Scand., 9, 203. Armstrong, I. R., Littlewood, D. G., and Chambers, W. A. (1983). Spinal anesthesia with tetracaine effect of added vasoconstrictor. Anesth. Analg., 62, 793. Braid, D. P., and Scott, D. B. (1965). The systemic absorption of local analgesic drugs. Br. J. Anaesth., 37, 394. Bridenbaugh, L. D. (1978). Does the addition of low molecular weight dextran prolong the duration of action of bupivacaine? Rig. Anesth., 3, 6. Bromage, P. R. (1965a). A comparison of the hydrochloride salts of Lignocaine and prilocaine for epidural analgesia. Br. J. Anaesth., 37, 753. (1965b). A comparison of the hydrochloride and carbon dioxide salts of lidocaine and prilocaine in epidural analgesia. Acta Anaesthesiol. Scand. (Suppl.), 16, 55. (1970). An evaluation of two new local anaesthetics for major conduction blockade. Can. Anaesth. Soc. J., 17, 557. Brown, D. T., Morrison, D. H., Covino, B. G., and Scon, D. B. (1980). Comparison of carbonated bupivacaine and bupivacaine hydrochloride for extradural anaesthesia. Br. J. Anaesth., 52, 419. Buckley, F. P., Littlewood, D. G., Covino, B. G., and Scott, D. B. (1978). Effects of adrenaline and the concentration of solution on extradural block with etidocaine. Br.J. Anaesth., 50, 171. Catchlove, R. F. H. (1972). The influence of CO, and ph on local anesthetic action. J. Pharmacol. Exp. Ther., 181, 291. Chambers, W. A., Edstrom, H. H., and Scott, D. B. (1981). Effect of baricity on spinal anesthesia with bupivacaine. Br. J. Anaesth., 53, 279. Littlewood, D. G., Logan, M. R., and Scott, D. B. (1981). 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