Pharmacokinetics of local anaesthetics

8 Pharmacokinetics of local anaesthetics G. RICHARD ARTHUR BENJAMIN G. COVINO

Local anaesthetics are applied directly to their site of action such that the major interest, from a pharmacokinetic point of view, concerns how rapidly these agents are absorbed from their site of injection and how rapidly they are removed from the circulation. The inadvertent intravenous injection of a local anaesthetic is the usual cause of a toxic reaction. In addition, adverse systemic effects may occur following the extravascular administration of an excessive dose or following rapid systemic absorption from highly vascular tissues. A knowledge of the absorption and elimination of these agents is helpful in understanding why these reactions occur and avoiding the possibility of systemic toxicity. ABSORPTION The rate at which a local anaesthetic agent is absorbed from the site of injection is related to the site of injection, the dose of local anaesthetic administered, the co-administration of vasoconstrictor agents, and the pharmacological profile of the drug. Injection site The vascularity at the various injection sites will clearly affect the rate of absorption following different local and regional anaesthetic techniques. If equal doses of a local anaesthetic are injected, the highest circulating concentrations occur after intercostal nerve blockade, followed by administration into the paracervical area, caudal canal, lumbar epidural space, the brachial plexus and sciatic femoral areas and subcutaneous tissue (Figure 1). The rapid absorption and relatively high local anaesthetic concentrations resulting from intercostal nerve blockade are attributable not only to the vascularity of the intercostal space but also to the large number of injections required to perform this procedure, which will increase the vascular surface area to which the drug is exposed. Similarly, the greater vascularity of the paracervical area and caudal canal, as compared with the lumbar epidural space, would explain the higher blood concentrations following these regional anaesthetic techniques. Mayumi et al (1983) reported no significant Bailli&e's Clinical Anaesthesiology-Vol. 5, No. 3, December 1991 ISBN 0-7020-1526-1

635 Copyright 9 1991, by Bailli6re Tindall All rights of reproduction in any form reserved

636

G . R . ARTHUR AND B. G. COVINO 7

INTERCOSTAL

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difference in peak lignocaine concentrations in three groups of patients receiving 200 mg lignocaine for cervical, thoracic or lumbar epidural anaesthesia. However, mean concentrations in the lumbar epidural group were lower than those in the other groups throughout the initial 30 min of sampling. The large amounts of adipose tissue in the lumbar epidural space may act as a depot for these agents, and will tend to retard vascular absorption. The decreased vascularity and the presence of varying amounts of adipose tissue in the region of the brachial plexus and subcutaneous tissue may account for the rather slow absorption of local anaesthetics in these areas. The various techniques employed for brachial plexus blockade have no effect on resulting anaesthetic concentrations in blood. Maclean et al (1988) reported no significant differences between the concentrations of pritocaine following interscalene, subclavian perivascular or axillary approaches to the brachial plexus. The rate of absorption of lignocaine and bupivacaine administered intrathecally is significantly slower than that following epidural administration (Burm, 1989). This may suggest that diffusion of local anaesthetics from cerebrospinal fluid across the dura mater into the epidural space is required before significant vascular absorption of intrathecally administered agents Occurs.

Intravenous regional anaesthesia (Bier's block) represents a unique situation since the drug is administered intravenously into a tourniquetoccluded limb. In the absence of circulation through the limb, drug is absorbed by tissue surrounding the venous network. Once the tourniquet is released and the blood supply restored to the limb, the drug rapidly gains access to the general circulation. A great differential exists between the

P H A R M A C O K I N E T I C S OF L O C A L A N A E S T H E T I C S

637

concentration of drug in the blood draining the blocked limb and the contralateral limb (Tucker and Boas, 1971; Evans et al, 1974; Table 1) due to uptake of local anaesthetic by the lung (Tucker and Boas, 1971). The peak blood concentration of lignocaine decreases as the tourniquet time is increased from 15 to 45 min (Table 1). Cyclic deflation and reinflation of the tourniquet in an attempt to reduce lignocaine concentrations has met with limited success (Sukhani et al, 1989). Prilocaine offers the greatest margin of safety for this regional anaesthetic procedure as it produces the lowest circulating concentrations and is the least toxic of the amide agents (Bader et al, 1987). Various sites of topical local anaesthetic application also result in differences in absorption and potential toxicity. In general, local anaesthetics are absorbed more rapidly following intratracheal administration than intranasal installation or administration into the urethra and urinary bladder, due in part to differences in vascularity of the sites and the type of anaesthetic solutions utilized. Arterial concentrations approaching 6 txg/ml have been reported following laryngeal spraying of lignocaine at a dose of 4 mg/kg (Eyres et al, 1983b). Venous plasma concentrations of lignocaine of approximately 3.5 txg/ml and 1.5 ixg/ml have been reported following the endotracheal administration of 200 and 100 mg lignocaine, respectively (Chu et al, 1975; Scott et al, 1976). Moreover, the blood concentrations of lignocaine are significantly higher following endotracheal administration in artificially ventilated patients than in spontaneously breathing patients (Scott et al, 1976). As indicated above, the formulation of topically applied local anaesthetics may affect their absorption and subsequent blood concentration. For example, the intranasal administration of an aerosol formulation of lignocaine produced a peak plasma concentration of 0.8 tzg/ml compared with 0.5 ~g/ml when lignocaine was administered in the form of a gel (Efthimiau et al, 1982). However, the peak concentration actually occurred more rapidly following the use of the gel preparation (34 min) compared with the aerosol (46 min). EMLA cream, which is an oil in water emulsion containing lignocaine and prilocaine ( 5 % ) in the base form, has provided a means of producing cutaneous anaesthesia with local anaesthetics. Resultant peak drug concentrations are very low (lignocaine 0.075 txg/ml; prilocaine 0.025 txg/ml) (Evers et al, 1985). Even after prolonged application over large surface areas for skin grafting, concentrations of lignocaine reached 1.1 ixg/ml and prilocaine concentrations were only 0.2 p~g/ml (Ohlsen et al, 1985). The variability in the rate of absorption as a function of the injection site renders meaningless the concept of a single maximum dose for a specific local anaesthetic. For example, lignocaine concentrations of 5 txg/ml are believed to be associated with initial signs of central nervous system toxicity. Based on the rate of vascular absorption from different injection sites, the maximum dose of lignocaine should be approximately 300 mg for intercostal nerve blocks, 500 mg for lumbar epidural anaesthesia, 600 mg for brachial plexus blocks, and more than 1000 mg for subcutaneous infiltration (Scott, 1989). Clearly the practice of establishing a maximum recommended dose of

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Dosage In general, a linear relationship exists between blood concentrations of local anaesthetics and the total dose administered at a given site (Figure 2). The peak blood concentration of local anaesthetics appears to be related to the total dose in milligrams rather than the volume or concentration injected. For example, when equal doses of various agents were administered epidurally in varying volumes and concentrations, no significant effect on the resultant peak blood concentrations was noted (Figure 3) (Scott et al, 1972; Lund et al, 1975). On the other hand, peak mepivacaine concentrations were greater when a 2% solution was employed compared with a 1% solution for intercostal and caudal blocks, although the total dosage was constant (Tucker et al, 1972). This was attributed to a greater tissue binding of mepivacaine since the larger volume of the 1% solution would tend to spread over a more extensive surface area.

Vasoconstrictor agents Vasoconstrictor agents are usually added to local anaesthetic solutions in an effort to decrease the rate of absorption and thereby reduce the potential for systemic toxicity and also to prolong the duration of regional anaesthesia. 9 9 9 X

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641

PHARMACOKINETICS OF LOCAL ANAESTHETICS

Epinephrine 1:200 000 (5 ixg/ml) is usually added to various local anaesthetic solutions intended for major regional anaesthetic procedures such as epidural blockade. A 1:80000 solution of epinephrine did not cause a significantly greater reduction in the peak plasma concentration of lignocaine than a 1:200 000 solution (Braid and Scott, 1965). AG ENT/DOSE BUPIVACAINE150 mg

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Figure 3. Peak local anaesthetic concentrations following epidural administration of different local anaesthetics. The same dose of each drug was administered using different volumes and concentrations of drug. Adapted from Scott et al (1972), Lund et al (1975), and Wilkinson and Lund (1970).

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Figure 4. Effect of epinephrine on peak local anaesthetic concentrations after brachial plexus block. Values in parentheses indicate the percentage reduction of peak concentrations with epinephrine. Adapted from Wildsmith et al (1977).

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G. R. ARTHUR AND B. G. COVINO

The ability of epinephrine to significantly reduce the peak blood concentration of local anaesthetic is dependent on the site of injection and the particular agent employed. For example, epinephrine will significantly decrease the peak blood concentration of lignocaine, prilocaine, bupivacaine and etidocaine following brachial plexus blockade (Figure 4) (Wildsmith et al, 1977). However, following epidura! administration epinephrine appears to exert little effect on the peak plasma concentration of etidocaine, bupivacaine and prilocaine (Wilkinson and Lund, 1970; Scott et al, 1972; Lund et al, 1975) while significantly reducing the peak blood concentrations of lignocaine and mepivacaine (Figure 5). Using a canine epidural model, Arthur et al (1988) reported minimal effects of epinephrine at reducing peak concentrations of bupivacaine or ropivacaine. These variable epinephrine effects are probably due to differences in rates of tissue distribution, inherent vasodilator activities and lipid solubilities. With regard to spinal anaesthesia, epinephrine and phenylephrine can significantly prolong the anaesthetic duration of tetracaine (Armstrong et al, 1983) but not the duration of bupivacaine or lignocaine (Chambers et al, 1981, 1982). Epinephrine has been shown to reduce the systemic absorption of lignocaine following subarachnoid administration in humans (Axelsson and Widman, 1981), but the absorption of lignocaine or bupivacaine was not reduced in dogs (Ravindran et al, 1983; Feldman et al, 1984) or monkeys (Denson et al, 1982). These conflicting results may be related to the differential effect of the various local anaesthetics on spinal cord blood flow. For example, tetracaine has been reported to increase, while bupivacaine has been reported to decrease, spinal cord blood flow (Kozody et al, 1985a, 1985b). [] [] E

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643

PHARMACOKINETICS OF LOCAL ANAESTHETICS

Pharmacological agents A comparison of the three local anaesthetic agents of equivalent potency reveals that lignocaine and mepivacaine show similar peak plasma drug concentrations while those of prilocaine are significantly lower following epidural and brachial plexus administration (Lund and Covino, 1967; Wildsmith et al, 1977). These differences may he due to the more rapid elimination rate and lower vasodilator potential of prilocaine. A similar comparison of the two more potent local anaesthetics reveals that peak plasma concentrations of etidocaine are generally lower than those of bupivacaine after epidural (Lund et al, 1973) and interscalene (Wildsmith et al, 1977) block. Etidocaine, which is highly lipid soluble, may be taken up by adipose tissue to a much greater extent than bupivacaine. Etidocaine is also cleared more rapidly from the blood than bupivacaine by both metabolism and tissue redistribution (Tucker and Mather, 1975). DISTRIBUTION OF LOCAL ANAESTHETICS Once the local anaesthetic has been absorbed from the site of injection, blood drug concentrations will be governed not only by metabolism and excretion but also by tissue redistribution. Local anaesthetic concentrations are measured either in arterial or venous whole blood, plasma or serum samples (Table 1). Tucker and Mather (1975) demonstrated significantly higher arterial than venous concentrations of local anaesthetics agents following epidural administration due to the tissue uptake between arterial and venous sampling sites. Plasma concentrations of lignocaine and etidocaine are also greater than their equivalent whole blood concentrations, due to differences in serum protein binding (Table 2). For pharmacokinetic purposes, it is more relevant to report whole blood concentrations, because they represent more precisely the amount of drug being delivered to an organ (Rowland and Tozer, 1989). It is also important to remember that local anaesthetic agents

Table 2, Physicochemical properties of local anaesthetic agents relevant to their disposition in

the body.

Agent

Ratio of whole blood: plasma concentrations*

Serum protein binding (%)?

Partition coefficient~

pKa~:

Relative vasodilator activityw

Prilocaine Lignocaine Mepivacaine Etidocaine Bupivacaine Ropivacaine

i .0 0.84 0.92 0.58 0.73 0.69

40 70 75 95 95 95

25 43 21 800 346 115

8.0 8.2 7.9 8.1 8.2 8.2

0.5 1.0 0.8 2.5 2.5 --

* Tucker and Mather (1979); Lee et al (1989); ? G. R. Arthur, unpublished data; ~: Strichartz et al (1990); w Blair (1975).

644

G. R. ARTHURAND B. G. COVINO

are usually p r e p a r e d in the form of hydrochloride salts, while blood concentrations are usually expressed as micrograms of drug base per millilitre of fluid. The difference between the molecular weight of the base and hydrochloride form of the amide agents is greater than 10%, which can introduce a large error in the calculation of pharmacokinetic data. Local anaesthetic agents are distributed in all body tissues but concentrations vary between tissues. For example, the m o r e highly perfused tissues such as the lung and kidney have higher bupivacaine concentations than the less well perfused tissues such as muscle and fat (Sjostrand and Widman, 1973). Studies in rats after intramuscular injection ( A k e r m a n et al, 1966a) showed that the highest concentrations of lignocaine and prilocaine are present in the lung, followed by the kidney, spleen, brain, heart and liver. Significantly higher concentrations of prilocaine as c o m p a r e d with lignocaine are found in the lung. Studies in sheep have indicated similar distribution patterns for bupivacaine, etidocaine and lignocaine, although a comparison of tissue: plasma concentration ratios revealed lower values for lignocaine in heart, lung and liver (Morishima et al, 1985).

P H A R M A C O K I N E T I C CONSIDERATIONS

In an attempt to simplify the derivation of pharmacokinetic data for local anaesthetic agents, the use of non-compartmental analysis has been proposed (Tucker, 1984). Clearance of amide agents is essentially related to hepatic metabolism of these agents since only a very small amount of the parent c o m p o u n d is excreted unchanged in the urine (Table 3). Clearance of the ester-type agents is dependent on plasma pseudocholinesterase activity. Although clearance and volume of distribution are frequently expressed with respect to body-weight, the correlation between bodyweight and local anaesthetic pharmacokinetic data is poor. H o w e v e r , for comparison between adults and children or between human and animal data, this m e t h o d of expressing pharmacokinetic data may be useful. Table 3. Pharmacokinetic data obtained after intravenous infusion in humans with respect to

arterial blood concentrations, with the exception of prilocaine (which is with respect to venous plasma concentrations) and ropivacaine (which is with respect to venous blood). From Arthur et al, 1979; Tucker and Mather, 1979; Lee et al, 1989. Prilocaine Lignocaine Mepivacaine Bupivacaine Etidocaine Ropivacaine tv2z(min) 93 Vd ss (litres) 261 Clearance rate 2.84 (1/min) Estimated hepatic > 100? extraction (%) Renal excretion 1 (%)*

96 91 0.95

114 84 0.78

162 73 0.58

162 134 1.11

111 59 0.73

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P H A R M A C O K I N E T I C S OF L O C A L A N A E S T H E T I C S

645

The data presented in Table 3 have been determined following intravenous infusion of various amide-type local anaesthetic agents into healthy male volunteers (Arthur et al, 1979; Tucker and Mather, 1979; Lee et al, 1989). Prilocaine and lignocaine were found to have the shortest half-life of elimination, while etidocaine and bupivacaine demonstrate the longest half-lives of elimination. Mepivacaine and ropivacaine have intermediate values. A comparison of the volume of distribution with the serum protein binding, lipid solubility and pKa of the various local anaesthetics (see Table 2) indicates that no precise relationship exists between any of these physicochemical properties and the corresponding values for volume of distribution. For example, etidocaine, which has the highest partition coefficient, has a large volume of distribution as might be expected. However, the volume of distribution for prilocaine is two times greater than for etidocaine although it has a partition coefficient which is over 30 times smaller. In terms of serum protein binding, bupivacaine, ropivacaine and etidocaine are the most highly protein-bound local anaesthetics, and yet etidocaine has an extremely high volume of distribution whereas bupivacaine and ropivacaine have a low volume of distribution. Differences in pKa could also affect the tissue uptake and distribution of the various agents since it is the un-ionized form of the drug that diffuses most readily through cell membranes. However, the amide-type local anaesthetics have similar pKas, indicating that at a physiological pH the ratio of un-ionized to ionized drug would be similar for all of these agents. Thus, the molecular structure of the various local anaesthetics, their partition coefficients, pKa and serum (and tissue) protein binding characteristics are probably all involved in the pharmacokinetic profile of these drugs, with no single chemical or physical property governing their uptake, distribution or clearance. The urinary excretion of unchanged amide local anaesthetics is very low, suggesting that clearance is mainly due to hepatic blood flow and hepatic extraction (Table 3). Prilocaine is the only amide-type local anaesthetic which has a clearance value in excess of hepatic blood flow, suggesting some degree of extrahepatic metabolism. In vitro studies have shown some metabolism of prilocaine in lung and kidneys (Arthur, 1981; Akerman et al, 1966a). Studies in anaesthetized dogs have also shown that extrahepatic metabolism of prilocaine does occur (Arthur, 1981). Studies in human volunteers (Wiklund 1977a, 1977b) have shown that the hepatic extraction of bupivacaine is less than that of lignocaine and etidocaine following intravenous infusions.

Protein binding Differences exist in the serum protein binding of the various amide local anaesthetics. As serum concentrations of local anaesthetic increases, the protein binding decreases markedly (Figure 6). This was initially demonstrated for bupivacaine, mepivacaine and lignocaine over a concentration range of 0.5-20.0 ~Lg/ml (Tucker et al, 1970a). Local anaesthetics primarily bind to al-acid glycoprotein (AAG) and as the concentration of local

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anaesthetic in blood increases, AAG binding sites become saturated and a progressive decrease in the percentage of protein binding occurs. Local anaesthetics also bind to albumin which has a high capacity for binding but a low affinity for these agents, as opposed to A A G which has a low binding capacity and a high affinity for local anaesthetics (Denson et al, 1984a). Of the amide-type agents, prilocaine exhibits the least change in serum protein binding over a concentration range of 1-100 txg/ml (Figure 6). Unlike the other amide agents, which are tertiary amines, prilocaine is a secondary amine. Monoethylglycinexylidide(MEGX), which is the primary metabolite of lignocaine (Figure 7), is also a secondary amine and protein binding studies with MEGX have indicated that this compound also has a very limited capacity to bind to AAG (Drayer et al, 1983; Holtzman et al, 1983). It is possible that prilocaine may have a very low affinity for A A G and is bound primarily to serum albumin. Bound local anaesthetics are susceptible to interaction with other concomitantly administered drugs. For example, bupivacaine, disopyramide and quinidine increase the free fraction of lignocaine in serum, whereas several lignocaine metabolites, procainamide and propranolol, do not (McNamara et al, 1981). Sodium thiopentone and diazepam have no effect on the serum protein binding of bupivacaine (Arthur et al, 1984; Denson et al, 1984b) which is of importance since administration of these sedative-hypnotic agents to control the central nervous system toxicity of local anaesthetics should not increase the potential cardiac toxicity of a drug such as bupivacaine.

PHARMACOKINETICSOF LOCALANAESTHETICS

647

Acidosis and hypercarbia will decrease the protein binding and increase the free fraction of local anaesthetics in blood (Burney et al, 1978; McNamara et al, 1981; Denson et al, 1984a; Apfelbaum et al, 1985). On the other hand, serum A A G levels are elevated with cancer, trauma and myocardial infarction resulting in an increase in the protein binding of lignocaine (Routledge et al, 1981; Edwards et al, 1982; Jackson et al, 1982). It has been demonstrated that the protein binding of lignocaine and the A A G levels are higher in non-pregnant than in pregnant women, who in turn have significantly higher levels of bound lignocaine and A A G than newborns (Wood and Wood, 1981). A similar correlation has been observed between maternal and fetal A A G concentrations and serum bupivacaine binding (Mather and Thomas, 1978; Petersen et al, 1981). Considerable variability exists in fetal:maternal A A G concentration ratios (0.20-0.96), 3

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Table 4. Relationship between serum protein binding capacity and umbilical vein: maternal blood (UV:M) ratios of various local anaesthetic agents (protein binding values are for nonpregnant adults so values will likely be decreased in pregnant women). From Wood and Wood (1981).

Agent

Serum protein Maternal blood UV concentration bound (%) concentration (arterial Oxg/ml) UV:M or venous) (jxg/ml)

Prilocaine Lignocaine Mepivacaine Etidocaine Bupivacaine

40 70 75 95 95

1.0.1.5 1.2-3.5 2.9-6.9 0.25-1.3 0.31-0.75

1.1-1.5 0.8-1.8 1.9-4.9 0.07-0.45 0.10-0.27

ratio

1.0-1.2 0.52-0.69 0.69-0.71 0.14-0.35 0.17-0.52

which in turn can result in a correspondingly wide variability in fetal: maternal local anaesthetic concentration ratios, e.g. bupivacaine from 0.17 to 0.52 (Petersen et al, 1981). An inverse correlation exists between the protein binding capacity and umbilical:maternal blood concentration ratios (UV:M) (Table 4) which is believed to be due to the inability of fetal plasma to bind as much drug as maternal plasma (Tucker et al, 1970b). Thus, although the free drug concentration may be in equilibrium across the placenta, the total plasma concentration of maternal and fetal plasma may be different. Because placental transmission of local anaesthetics occurs by passive diffusion of free unionized drug, the maternal fetal blood concentration gradient determines the rate of diffusion. However, the equilibrium U V : M values are independent of the maternal blood concentration of local anaesthetic. For example, maternal lignocaine concentrations of 2.65 and 1.19 ixg/ml result in U V : M ratios of 0.69 and 0.63, and bupivacaine maternal concentrations of 0.75 and 0.31 are associated with UV:M ratios of 0.36 and 0.31 (Kileff et al, 1984; A b b o u d et al, 1982). No difference is believed to exist in the drug uptake by fetal and maternal tissues. Although lignocaine concentrations in the brain, heart and kidney are significantly lower in fetal sheep when compared with those of the mother (Pedersen et al, 1988), no significant difference exists in the tissue:plasma concentration ratios between mother and fetus except for the liver. The higher liver:plasma concentration ratio in the fetus may be related to the presence of immature enzyme systems. Local anaesthetic agents which are highly bound to plasma proteins in maternal blood demonstrate the lowest U V : M ratios. However, these agents have the greatest partition coefficients which probably results in greater tissue uptake. Thus, although the U V : M ratios differ considerably between the various local anaesthetic agents (Table 4), the amount of drug that diffuses across the placenta is probably relatively similar for all agents. Fetal acidosis will increase the amounts of local anaesthetic in blood and ultimately in tissue, a situation referred to as 'ion trapping'. Intravenous infusion of lactic acid into fetal sheep reduced the blood p H from 7.39 to 7.12, and the fetal arterial:maternal arterial bupivacaine concentration ratio was increased from 0.59 to 0.76 (Pickering et al, 1981). Morishima and

P H A R M A C O K I N E T I C S OF L O C A L A N A E S T H E T I C S

649

Covino (1981) reported that the dose of lignocaine necessary to produce fetal cardiac arrest was approximately four times lower in asphyxiated animals (pH 7.01), probably due to the reduced serum protein binding and tissue ion trapping of the local anaesthetics. METABOLISM AND EXCRETION Amino esters

The ester-type local anaesthetics are essentially metabolized by hydrolysis in plasma by the enzyme pseudocholinesterase (Brodie et al, 1948). Chloroprocaine is hydrolysed most rapidly (4.7 txmol m1-1 h -1) while tetracaine is hydrolysed most slowly (0.3 txmol m1-1 h -1) (Foldes et al, 1965). Procaine is intermediate in terms of rate of hydrolysis (1.1 txmolm1-1 h-l). The half-life of elimination of procaine and chloroprocaine have been determined to be less than 1 min (DuSouich and Erill, 1977; O'Brien et al, 1979). A decrease in serum pseudocholinesterase activity to approximately 20% of normal values, due to phospholine iodide administration, does not significantly reduce the rate of chloroprocaine hydrolysis (Lanks and Sklar, 1980). Bupivacaine has been reported to inhibit the hydrolysis of ester-type agents (Lalka et al, 1978; Raj et al, 1980). The hydrolysis of procaine in plasma results in the formation of paraaminobenzoic acid and diethyl aminoethanol. Para-aminobenzoic acid is excreted in the urine either unchanged or as a conjugated product, with a total recovery over a 24-h period of approximately 80% of the administered dose of procaine. Less than 2% of the parent compound is excreted in the urine during this time period. Similar amounts of the primary metabolite of chloroprocaine, i.e. 2-chloro-4-aminobenzoic acid, have been recovered in the urine of humans. Amino amides

The amino amides are metabolized primarily in the liver (Tucker et al, 1977). The initial step involves dealkylation of the amine nitrogen (r~-dealkylation) (Boyes, 1975). This facilitates amide hydrolysis in the case of the tertiary amine-type compounds. Approximately 73% of a dose of lignocaine appears in the urine as 4-hydroxy-2,6-xylidine, accounting for a majority of the administered dose (Boyes, 1975) (Figure 7). Etidocaine, which is similar in structure to lignocaine, produces smaller amounts of 2,6-xylidine and 4-hydroxy-2,6-xylidine (less than 10%), suggesting that the formation of amide hydrolysis products is not as important in the metabolism of etidocaine (Vine et al, 1978). Larger amounts of 3- and 4hydroxyetidocaine have been found in urine. Prilocaine, which is a secondary amine, is primarily metabolized by amide hydrolysis to ortho-toluidine and N-propylamine. Ortho-toluidine is subsequently hydroxylated to 2-amino-3 (and -5)-hydroxytoluene. These metabolites of prilocaine are believed to be responsible for the occurrence of methaemoglobinaemia (Akerman et al, 1966b).

650

G. R. A R T H U R A N D B. G. COVINO

Mepivacaine, bupivacaine and ropivacaine are also related structurally. Mepivacaine appears to undergo initial N-demethylation, resulting in the formation of the N-dealkylated metabolite, 2-pipeocoloxylidine. In addition, 3- and 4-hydroxymepivacaine have been identified in urine, and approximately 50% of mepivacaine as its metabolites has been identified in human urine. Bupivacaine also undergoes N-debutylation with the resulting 2-pipeocoloxylidine accounting for 5% of the dose (Friedman et al, 1982). Initial animal studies with ropivacaine by Halldin and Elofsson (1988) indicate that aromatic hydroxylation followed by conjugation with glucuronic acid represents the major elimination pathway. The metabolic products of the amide local anaesthetics may have clinically significant implications as they possess toxic properties similar to, but less potent than, that of the parent compound. CLINICAL FACTORS AFFECTING PHARMACOKINETICS

Age Newborns are unable to metabolize mepivacaine as completely as adults (Meffin et al, 1973). For example, 43% of mepivacaine is excreted unchanged in the urine of premature neonates, compared with 3.5% in adults (Moore et al, 1978). The elimination half-life of mepivacaine is also significantly prolonged in the neonate, which suggests that the immature hepatic enzyme system in the newborn is unable to metabolize mepivacaine. Lignocaine was also reported to have a prolonged elimination half-life in neonates (Mihaly et al, 1978). Twenty per cent of lignocaine is excreted unchanged in the urine of these neonates compared with 4% in adults. Although the amount of unchanged drug found in the urine is quite different, the hepatic clearance of lignocaine appears to be similar in neonatal and adult groups. Monoethylglycinexylidide, the primary Ndealkylated metabolite of lignocaine, accounts for 20% of the administered dose of lignocaine in the neonate, compared with 5 % in adults. On the other hand, 4-hydroxy-2,6-xylidine represents 64% of the administered dose of lignocaine in adults compared with only 9% in neonates. A similar pattern of etidocaine metabolism in the neonate has also been reported (Morgan et al, 1978). Following intravenous administration of lignocaine to fetal lambs in utero, newborn lambs and adult sheep, very similar elimination half-lives are seen in fetal lambs (33 min) and non-pregnant adults (31 min) (Morishima et al, 1979). However, the elimination half-life of 51 min in the newborn lamb is greater than that in both adult sheep and fetal lambs. Total body clearance is also increased owing to a greater renal excretion of the parent compound in the newborn lamb. The elimination half-life of etidocaine is similar in newborn lambs and adult sheep, although the renal clearance rate of unchanged drug is increased in the lambs (Pedersen et al, 1982). These data suggest that the hepatic enzymatic activity responsible for amide hydrolysis and/or hydroxylation of lignocaine and etidocaine is diminished in the neonate compared with the adult.

P H A R M A C O K I N E T I C S OF L O C A L A N A E S T H E T I C S

651

Studies in children of varying age have revealed no correlation between the pharmacokinetic properties of bupivacaine and age or weight in children varying in age from 3 months to 16 years in whom intercostal nerve blocks were performed (Rothstein et al, 1986). However, the steady-state volume of distribution in this paediatric population is almost three times greater than that of adults. In addition, an increased clearance rate has been observed in this paediatric population. The elimination half-life of bupivacaine is identical in children and adults. Bricker et al (1989) reported similar results with bupivacaine for intercostal nerve blocks in patients aged 6 months or younger. The increased clearance rate in paediatric patients may be due to a relatively greater hepatic blood flow per kilogram of botiy-weight, while the larger volume of distribution may be attributable to a greater proportion of well-perfused tissues and lower amounts of body fat in children compared with adults. Studies in geriatric patients have shown that the peak blood concentrations of bupivacaine and lignocaine following caudal anaesthesia are similar in young adults and elderly patients (Freund et al, 1984). Similarly, little difference in the peak blood concentrations of bupivacaine was reported following spinal anaesthesia in young and old patients (Pitkanen et al, 1984). However, a prolonged half-life of elimination of lignocaine has been reported in elderly subjects (Abernethy and Greenblatt, 1983). Pregnancy

A significant increase in the clearance of lignocaine was observed in pregnant sheep (100 mlmin -1 kg -1) compared with the non-pregnant animal (44 mlmin -1 kg -1) (Santos et al, 1988) owing to the increased cardiac output and redistribution of blood flow to various organs during pregnancy. The volume of distribution is increased in pregnant animals (3.2 1/kg) compared with non-pregnant ewes (1.9 1/kg). However, the clearance rate of ropivacaine was reported to be reduced in pregnant animals (pregnant 22 mlmin -1 kg-1; non-pregnant 45 mlmin -1 kg -1) (Santos et al, 1990). This seems to be offset by a somewhat reduced volume of distribution in pregnant animals (pregnant 1.7 1/kg; non-pregnant 3.0 1/kg). Disease states

Since hepatic metabolism is the major route for the elimination of amino amide-type local anaesthetics in the body, a significant alteration in hepatic function would be expected markedly to alter the pharmacokinetics of these agents (Table 5). Individuals with active acute hepatitis show a significant prolongation in the elimination half-life of lignocaine (Williams et al, 1976), whereas little difference is observed in patients with chronic hepatitis and in healthy adults (Huet and Villeneuve, 1983). In cirrhotic patients, clearance of lignocaine is reduced from 19 ml rain- 1 kg- 1 to 7 mlmin- 1 kg- 1 , while the elimination half-life is prolonged from 84 to 228 min (Huet and Villeneuve, 1983). However, the volume of distribution remains unchanged. The hepatic extraction of lignocaine is decreased to 31% in the

652

G. R. ARTHUR AND B. G. COVINO Table 5. Influence of disease states on lignocaine pharmacokinetics. Normal range*

q/2z (rain)

Renal failure?

90--108 148 Va (IJkg) 1.3-2.2 1.9 Clearance rate 10.0-18.2 12.3 (ml min -1 kg -1)

Renal Heart disease~ failurew

Chronic Acute Cirrhosis[] hepatitis[[ hepatitis 82

77 1.2 13.7

228 2.1 7.3

312 2.9 6.7

84 2.4 19.4

160 3.1 13.0

t~/~z, elimination half-life. Vd, volume of distribution. * Range from all studies; t Collinsworth et al (1975); ~ Thomson et al (1973); w Cusson et al (1985); ][ Huet and Villeneuve (1983); 82Williams et al (1976).

cirrhotic group compared with a value of 64% in patients with chronic hepatitis. No correlation exists between hepatic blood flow and hepatic extraction of lignocaine in the cirrhotic group, suggesting that an alteration in hepatic enzyme function is of greater importance than changes in hepatic blood flow. Any change in hepatic blood flow will clearly alter the hepatic extraction and clearance rate of most amide-type local anaesthetics. For example, in patients with myocardial infarction in whom hepatic blood flow is reduced, the elimination half-life of lignocaine is prolonged and the clearance of this agent is decreased (Bax et al, 1980; Cusson et al, 1985). Renal failure does not markedly influence the pharmacokinetics of lignocaine but the rate of disappearance from plasma of glycinexylidine, a secondary metabolite, is markedly decreased (Coltinsworth et al, 1975). No change in the elimination half-life of monoethylglycinexylidide is found in patients with renal failure since this primary metabolite is cleared from plasma by the liver. Pulmonary status

A substantial amount of amide local anaesthetics is taken up by the lung. For example, 40% of lignocaine is removed by the lung during a single passage through the pulmonary tree of pigs following an intravenous injection of 0.5 mg/kg (Bertler et al, 1978). When the intravenous dose of lignocaine is increased to 2.0 mg/kg, the lung uptake decreases to less than 30% of the injected dose. Studies in humans indicate that at a dose of 0.5 mg/kg approximately 60% of lignocaine is extracted by the lung (Jorfeldt et al, 1979). General anaesthesia and decreased pulmonary function do not appear to affect the uptake of lignocaine by the lung (Jorfeldt et al, 1983). "However, an increase in pH results in a greater absorption of lignocaine by the lung (Post et al, 1979) while acidosis produces a decreased uptake by the lung (Post and Eriksdotter-Behm, 1982). Drug interactions A number of drugs may interfere with the pharmacokinetic properties of

653

PHARMACOKINETICS OF LOCAL ANAESTHETICS

local anaesthetics. Pretreatment with cimetidine will decrease the clearance rate and increase the elimination half-life of lignocaine (Feely et al, 1982; Wing et al, 1984) due to a reduction in hepatic blood flow produced by cimetidine. The volume of distribution of lignocaine is also decreased. Feely et al (1982) also reported that peak blood concentrations of lignocaine increased by 50% following prior treatment with cimetidine. Cimetidine fails to alter the peak blood concentrations of epiduralty administered lignocaine (Webb and Ward, 1983), but does prolong the elimination halflife. Cimetidine also does not influence the peak blood concentrations of lignocaine in pregnant patients (Flynn et al, 1989) and bupivacaine in healthy subjects (Pihlajamaki et al, 1988). Propranolol will prolong the elimination half-life and decrease the clearance of lignocaine, due in part to a reduction in hepatic blood flow (Ochs et al, 1980) and interaction with the same enzyme system responsible for the degradation of lignocaine (Conrad et al, 1983; Tucker et al, 1984). No significant difference in peak central venous blood concentration of bupivacaine was found following intercostal nerve blocks in patients with and without co-administration of various types of [3-receptor blocking drugs (Ponten et al, 1982). SUMMARY

1.

2. 3.

The blood concentration of local anaesthetic agents following regional anaesthesia is determined by the absorption, tissue redistribution, metabolism and excretion characteristics of the various agents (Figure 8). Absorption is related to the site of injection, dosage employed, use of vasoconstrictors and physicochemical profile of the specific agent. Local anaesthetics are distributed throughout all body tissues. In general, tissues with a high vascular perfusion (e.g. lung) absorb local anaesthetics most rapidly while tissues with a low vascular perfusion show a slower rate of uptake. Plasma protein binding influences the rate SITE OF INJECTION

I ABSORPTION

PLASMA

]~

BLOOD < iTRIBUT,O.

KIDNEY 5*/. "

PRO;EINBINDING

*

BODYTISSUE BODY WATER

I

! METABOLISM

TISSUE PROTEIN BINDING

, LIVER

Figure 8. Schematicrepresentation of the physiologicaldispositionof local anaesthetics.

654

4.

5.

6.

G. R. ARTHUR AND B. G. COVINO

of tissue uptake. Local anaesthetics are primarily bound to a-l-acid glycoproteins. The metabolism of local anaesthetics varies according to their chemical classification. The amino esters are hydrolysed in plasma by the enzyme cholinesterase while the amino amides are primarily metabolized in the liver by microsomal enzymes. Local anaesthetics and their metabolites are excreted primarily by the kidneys. Less than 5% of the parent compound is excreted in an unchanged form. The elimination of local anaesthetics is influenced by a variety of factors such as age, clinical status of the patient, and concomitant administration of other drugs. In general, neonates and geriatric patients eliminate local anaesthetics more slowly.

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vacaine: plasma local anesthetic concentration and extent of sensory spread in old and young patients. Anesth Analg 63: 1017-1020. Friedman GA, Rowlinson JC, DiFazio CA et al (1982) Evaluation of the analgesic effect and Urinary excretion of systemic bupivacaine in man. Anesth Analg 61: 23-27. Halldin MM & Elofsson S (1988) Metabolism and excretion of ropivacaine in animals. 11th European Workshop on Drug Metabolism. Konstanz, Germany, 1988, A.3.39. Holtzman JL, Krause E, Eckfeldt JH et al (1983) Comparison of the binding of monoethylglycylxylidide and lidocaine to human sera and purified human serum proteins. Fed Proc 42: 1175. Huet PM & Villeneuve JP (1983) Determinants of drug disposition in patients with cirrhosis. Hepatology 3: 913-918. Jackson PR, Tucker GT & Woods HF (1982) Altered plasma drug binding in cancer: role of alpha 1-acid glycoprotein and albumin. Clin Pharmacol Ther 32: 295-302. Jorfeldt L, Lewis DH, Lofstrom JB et al (1979) Lung uptake of lidocaine in healthy volunteers. Acta Anaesthesiol Scand 23: 567-574. Jorfeldt L, Lewis DH, Lofstrom JB et al (1983) Lung uptake of lidocaine in man as influenced by anaesthesia, mepivacaine infusion, or lung insufficiency. Acta Anaesthesiol Scand 27: 5-9. Kileff ME, James FM, Dewan DM et al (1984) Neonatal neurobehavioral responses after epidural anesthesia for cesarean section using lidocaine and bupivacaine. Anesth Analg 63: 413-417. Kozody R, Palahniuk RJ & Cumming MO (1985a) Spinal cord blood flow following subarachnoid tetracaine. Can Anaesth Soe J 32: 23-29. Kozody R, Ong B, Palahniuk RJ et al (1985b) Subarachnoid bupivacaine decreases spinal cord blood flow in dogs. Can Anaesth Soc J 32: 216-222. Lalka D, Vicuna N, Burrow SR et al (1978) Bupivacaine and other amide local anesthetics inhibit the hydrolysis of chloroprocaine by human serum. Anesth Analg 57: 534-539. Lanks KW & Sklar GS (1980) Pseudocholinesterase levels and rates of chloroprocaine hydrolysis in patients receiving adequate doses of phospholine iodide. Anesthesiology 52: 434~435. Lee A, Fagan D, Tucker GT et al (1989) Disposition kinetics of ropivacaine in humans. Anesth Analg 69: 736-738. Lund PC & Covino BG (1967) Distribution of local anesthetics in man following peridural anesthesia. J Clin Pharmacol 7: 324-329. Lund PC, Cwik JC & Pagdanganan RT (1973) Etidocaine--a new long-acting local anesthetic agent: a clinical evaluation. Anesth Analg 52: 482-494. Lund PC, Bush DF & Covino BG (1975) Determinants of etidocaine concentration in the blood. Anesthesiology 42: 497-503. Maclean D, Chambers WA, Tucker GT & Wildsmith JAW (1988) Plasma prilocaine concentrations after three techniques of brachial plexus blockade. Br J Anaesth 60: 136-139. McNamara P J, Slaughter RL, Pieper JA et al (1981) Factors influencing serum protein binding of lidocaine in humans. Anesth Analg 60: 395-400. Mather LE & Thomas J (1978) Bupivacaine binding to plasma protein fractions. J Pharm Pharmaco130: 653-654. Mather LE, Tucker GT, Murphy TM et al (1976) Effects of adding adrenaline to etidocaine and lignocaine in extradural anaesthesia. II Pharmacokinetics. Br J Anaesth 48: 989-993. Mayumi T, Dohi S & Takahashi T (1983) Plasma concentrations of lidocaine associated with cervical thoracic, and lumbar epidural anesthesia. Anesth Analg 62: 578-580. Meffin P, Long GJ & Thomas J (1973) Clearance and metabolism of mepivacaine in the human neonate. Clin Pharmacol Ther 14: 218-225. Mihaly GW, Moore RG, Thomas J e t al (1978) The pharmacokinetics of the anilide type local anaesthetics in neonates. I. Lignocaine. Eur J Clin Pharmacol 13: 143-152. Moore DC, Mather LE, Bridenbaugh LD et al (1976) Arterial and venous plasma levels of bupivacaine following epidural and intercostal nerve blocks. Anesthesiology 45: 39-45. Moore RG, Thomas J, Triggs EJ et al (1978) The pharmacokinetics and metabolism of the anilide local anesthetics in neonates. III. Mepivaeaine. EurJ Clin Pharmaco114: 203-212. Morgan DH, McQuillan D & Thomas J (1978) The pharmacokinetics and metabolism of the anilide type local anesthetics in neonates. II. Etidocaine. Eur J Clin Pharrnaeo113:365-371. Morishima HO & Covino BG (1981) Toxicity and distribution of lidocaine in nonasphyxiated and asphyxiated baboon fetuses. Anesthesiology 54: 182-186.

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Morishima HO, Finster M, Pedersen H et al (1979) Pharmacokinetics of lidocaine in fetal and neonatal lambs and adult sheep. Anesthesiology 50: 431-436. Morishima HO, Pedersen H, Finster M et al (1985) Bupivacaine toxicity in pregnant and nonpregnant ewes. Anesthesiology 63" 134-139. O'Brien JE, Abbey V, Hinsvark O et al (1979) Metabolism and measurement of chloroprocaine, an ester-type local anesthetic. J Pharm Sci 68: 75-78. Ochs HR, Carstens G & Greenblatt DJ (1980) Reduction in lidocaine clearance during continuous infusion and by coadministration of propranolol. N Engl J Med 303: 373-377. Ohlsen L, Englesson S & Evers H (1985) An anaesthetic lignocaine/prilocaine cream (EMLA) for epicutaneous application tested for cutting skin grafts. Scand J Plast Reconstr Surg 19: 201-209. Pedersen H, Morishima HO, Finster M e t al (1982) Pharmacokinetics of etidocaine in fetal and neonatal lambs and adult sheep. Anesth Analg 61: 104--108. Pedersen H, Santos AC, Morishima HO et al (1988) Does gestational age affect the pharmacokinetics and pharmacodynamics of lidocaine in mother and fetus. Anesthesiology 68: 367-372. Petersen MC, Moore RG, Nation RL et al (1981) Relationship between the transplacental gradients of bupivacaine and alpha 1-acid glycoprotein. Br J Clin Pharmaco112: 859-862. Pickering B, Biehl D & Meatherall R (1981) The effect of fetal acidosis on bupivacaine levels in utero. Can Anaesth Soc J 28: 544.549. Pihlajamaki KK, Lindberg RLP, Jantunen ME (1988) Lack of effect of cimetidine on the pharmacokinetics of bupivacaine in healthy subjects. Br J Clin Pharrnaco126: 403-406. Pitkanen M, Haapaniemi L, Tuominen M e t al (1984) Influence of age on spinal anaesthesia with isobaric 0.5% bupivacaine. Br J Anaesth 56" 279-284. Ponten J, Biber B, Henriksson BA et al (1982) Bupivacaine for intercostal nerve blockade in patients on long-term B-receptor blocking therapy. Acta Anaesthesiol Scand Suppl 76: 70--77. Post C & Eriksdotter-Behm K (1982) Dependence of lung uptake of lidocaine in vivo on blood pH. Acta PharmacoI Toxico151: 136-160. Post C, Andersson RG, Ryrfeldt A et al (1979) Physicochemical modification of lidocaine uptake in rat lung tissue. Acta Pharmacol Toxico144: 103-109. Raj PP, Ohlweiler D, Hitt BA et al (1980) Kinetics of local anesthetic esters and the effects of adjuvant drugs on 2-chloroprocaine hydrolysis. Anesthesiology 53: 30%314. Ravindran RS, Viegas OJ, Pantazis KL et al (1983) Serum lidocaine levels following spinal anesthesia with lidocaine and lidocaine and epinephrine in dogs. Anesth Analg 8: 6-9. Rothstein P, Arthur GR, Feldman HS et al (1986) Bupivacaine for intercostal nerve blocks in children: blood concentrations and pharmacokinetics. Anesth Analg 65: 625-632. Routledge PA, Shand DG, Barchowsky A et al (1981) Relationship between alpha 1-acid glycoprotein and lidocaine disposition in myocardial infarction. Clin Pharmacol Ther 30: 154-157. Rowland M & Tozer TN (1989) Clinical Pharmacokinetics. Concepts and Applications pp. 151-152. Philadelphia: Lea and Febiger. Santos AC, Pedersen H, Morishima HO et al (1988) Pharmacokinetics of lidocaine in nonpregnant and pregnant ewes. Anesth Analg 67: 1154.1158. Santos AC, Pedersen H, Sallusto JA et al (1990) Pharmacokinetics of ropivacaine in nonpregnant and pregnant ewes. Anesth Analg 71: 262-266. Scott DB (1989) 'Maximum recommended doses' of local anaesthetic drugs. Br J Anaesth 63: 373-376. Scott DB, Jebson PJR, Braid DP et al (1972) Factors affecting plasma levels of lignocaine and prilocaine. Br J Anaesth 44: 1040-1048. Scott DB, Littlewood DG, Covino BG et al (1976) Plasma lignocaine concentrations following endotracheal spraying with an aerosol. Br J Anaesth 48: 899-901. Sjostrand U & Widman B (1973) Distribution of bupivacaine in the rabbit under normal and acidotic conditions. Acta Anaesthesiol Scand 50: 1-24. Strichartz GR, Sanchez V, Arthur GR et al (1990) Fundamental properties of local anesthetics. II. Measured octanol:buffer partition coefficients and pK, values of clinically used drugs. Anesth Analg 71: 158-170. Sukhani R, Garcia CJ, Munhall RJ et al (1989) Lidocaine disposition following intravenous regional anesthesia with different tourniquet deflation techniques. Anesth Analg 68: 633-637.

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