Summary

Clinical Pharmacokinetics 4: 241-278 (1979) 0312-5963/79/0500-0241/$09.50/0 ADIS Press Australasia Pty ltd. All rights reserved.

Clinical Pharmacokinetics of Local Anaesthetics 1

G.T. Tucker and L.E. Mather Department of Therapeutics, University of Sheffield, Sheffield, and Department of Anaesthesia and Intensive Care, Flinders Medical Centre, Adelaide

The introduction qf the new long acting local anaesthetics, bupivacaine and etidocaine, has stimulated an expansion Qf interest in regional anaesthesia, particularly for obstetrical ap-plications and pain therapy.

Systemic toxicity following injection of local anaesthetics occurs albeit infrequently, and tentative correlations have been made between the onset of eNS and cardiovascular effects and circulating drug concentrations in both adults and neonates. Amongst other factors, interpreta-tion of these relationships depends upon blood distribution and plasma bindingQf the agents, sampling sites and acid-base balance.

The disposition kinetics and placental transfer Qf the amide type agents have been well characterised. In adults their clearance is almost entirely hepatic but in neonates an increase in the renal component is, in part, a reflection of the immaturity of some of the enzymes respons-ible for their metabolism. Ester type agents are rapidly hydrolysed by plasma pseudocholin-esterase and this has led /0 a preference for chloroprocaine in some obstetric procedures.

Major determinants Qf the systemic absorption Qf the agents after perineural administration include their physicochemical and vasoactive properties, perfusion and tissue binding at the site of injection and whether or not adrenaline has been added. In respect of blood drug concentra-tions achieved after various regional anaesthetic procedures, the margin of systemic safety ap-pears to favour bupivacaine and etidocaine compared to shorter acting analogues stich as lig-nocaine and mepivacaine. The time course of local anaesthetic remaining at the site of injection has been calculated following intravenous regional anaesthesia and peridural block. This has allowed prediction of the local and systemic accumulation of the drugs following continued dosage.

Blood concentrations Qf local anaesthetics after perineural injection are not closely related to age, weight or pregnancy but may be influenced by diseases associated with haemodynamic changes and by other drugs given at or around the time of regional blockade.

This paper is dedicated to Professor John J. Bonica on the occasion of his retirement as Chairman, Department of Anesthesiology, University of Washington, Without him, regional anaesthesia surely would have progressed but not nearly so effectively.

Clinical Pharmacokinetics of Local Anaesthetics

Local anaesthetics and regional anaesthesia are widely used in surgical, obstetric and dental patients. When properly administered the various agent~ and techniques are effective and safe, with significant ad-vantages over general anaesthesia (Bonica, 1971). They are also finding increasing application in the control of postoperative pain and in the diagnosis and therapy of chronic pain. As with other drugs, an un-derstanding of the pharmacokinetics of local anaes-thetics contributes to the selection of the best agent and its optimal dose for each particular clinical indica-tion.

1. Major Agents

Modern regional anaesthesia is practised with a relatively small armamentarium of agents. These can be divided into esters of the procaine type and amides of the lignocaine (lidocaine) type; their structures and some salient physicochemical and biological proper-ties are summarised in table I. Of the compounds listed, bupivacaine (Marcaine) and lignocaine (Xylo-caine) are currently the most widely used in anaes-thetic practice. The former is especially popular for providing peridural2 analgesia during labour and vaginal delivery, owing to its relatively long duration of action and an ability to produce a marked differen-tial blockade favouring sensory rather than motor loss. Etidocaine (Duranest) is a new long acting analogue but a tendency to produce a differential motor block may confine its use to surgical anaes-thesia (Lofstrom, 1975). Prilocaine (Citanest) has fallen out of favour for peridural anaesthesia because of methaemoglobinaemia associated with high doses, although a relatively low propensity for CNS toxicity commends it for some peripheral nerve blocks (Wildsmith et aI., 1977).

Of the ester compounds, procaine is now largely relegated to use as an inmtration agent; tetracaine

2 The terms peridural, epidural and extradural ar~ synony-mous.

242

Glossary of symbols

A-V Arterio-venous V Apparent initial dilution volume Vd,;s Apparent volume of distribution at steady-

state of equilibrium Vd Apparent volume of distribution from ex-

trapolation of terminal decay slope VB Blood volume tl/2 rapid Rapid half-life t1/2 inter Intermediate half -life tl /2 slow Slow or terminal half-life CI Total body clearance E Estimated hepatic extraction ratio fB Free fraction of drug in blood fp Free fraction of drug in plasma ft Free fraction of drug in extravascular space fu Fraction excreted unchanged in urine tl/2 x Rapid absorption half-life tl/2'~ Slow absorption half-life

(amethocaine) [Pontocaine], in common with cocaine and benzocaine, is restricted to topical application, although some centres still use it as a spinal anaes-thetic; while chloroprocaine (Nesacaine) has lately been resurrected for obstetric applications following reports of fetal morbidity associated with paracervical injection of more toxic agents such as mepivacaine (Carbocaine) [Freeman and Arnold, 1975].

2. Blood Concentrations of Local Anaesthetics and Systemic Effects

Analysis of the systemic absorption and disposi-tion kinetics of local anaesthetics is of value in assess-ing their safety since their presence in the circulation can be associated with unwanted effects, mediated principally through the central nervous and car-diovascular systems. Adverse reactions are usually due to rapid inadvertent intravenous injection of nor-

Table

I. S

truct

ure-

activ

ity re

latio

nshi

ps o

f clin

ical

ly use

d lo

cal a

na

est

hetic

s (co

mpile

d fro

m T

ucke

r, 19

75a;

Cov

ino

and

Vass

allo

, 19

76; M

athe

r, unpu

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oed

data

Q

1979

) :j' (i' 9!.

Agen

t St

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ure

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Parti

tion

Prot

ein

Equi

-effe

ctiv

eb

Appr

oxim

ateb

Con

vulsi

ve d

ose

'1J

:T

(at 25

C)

coe

ffici

ent

bind

ing

an

ae

sthe

tic

an

ae

sthe

tic

(mg/

kg)

'" 3

(%)

con

cen

trat

ion

dura

tion

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"

(%)

(min)

m

on

key

cat

0 ~

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ne

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-8.

7 0.

14

3 So

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r- 0

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-@

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aine

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02

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50

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, CD

(J>

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Clinical Pharmacokinetics of Local Anaesthetics

mal extravascular doses intended for neural blockade, administration into highly vascular areas, or the ex-travascular injection of an excessive dose. The inci-dence of serious local anaesthetic induced reactions is unknown but probably very low. For example, a review of the world literature on peridural anaes-thesia in 1969 revealed a 0.2 % frequency of toxicity in more than 60,000 cases (Dawkins, 1969). Occa-sionally however, toxic CNS ;esponses to very small doses (less than 50mg) of local anaesthetics occur. Such reactions should not be confused with the infre-quent allergic response to ester-type agents since they may represent true pharmacological overdose result-ing from an inadvertent intra-arterial injection. Thus, Aldrete et aJ. (I 977, 1978) have shown that the in-troduction of local anaesthetics under pressure into the lingual, brachial or femoral artery of baboons and the facial artery of dogs can produce a retrograde flow permitting direct access of high concentrations of drug to the cerebral circulation.

A somewhat similar explanation has been pro-posed to account for a relationship observed between fetal bradycardia and excessive fetal to maternal blood concentration ratios of mepivacaine after paracervical block. This phenomenon was rationalised by the hy-pothesis that drug diffuses J;apidly into the uterine ar-teries close to the site of injection resulting in the delivery of high drug concentrations directly to the placenta (Asling 1970; Steffenson et ai., 1970).

2.1 CNS Toxicity

Intravenous tolerance studies have shown that the dose of a local anaesthetic required to elicit pre-con-vulsive signs and symptoms in healthy, unpremedi-cated men and frank convulsions in animals is directly related to the anaesthetic potency of the com-pound (Covino and Vassallo, 1976; table I). Attempts have also been made to define plasma concentrations of the agents associated with onset of CNS toxicity. Data from short term intravenous infusion studies in man are collated in table II, although comparisons are complicated by variability in endpoints, assay

244

methods, sampling sites and infusion rates. Observa-tions in patients receiving lignocaine by more prolonged infusion for suppression of ventricular dysrhythmias support the generalisation that subjec-tive effects of this agent are associated with plasma concentrations of 3 to 5)Jg/ ml and that objective signs appear at 6 to IO)Jg/ml (Benowitz and Meister, 1978). Animal experiments (Munson et aI., 1972, 1975; Malagodi etaI., 1977; BlumeretaI., 1973; 10r-feldt et aI., 1968) suggest that plasma concentrations of the agents accompanying convulsions may be 2- to 3-fold greater than those related to the onset of less severe objective manifestations of CNS toxicity.

2.2 Cardiovascular Effects

In reviewing relationships between the anti-dysrhythmic effect of lignocaine and its blood con-centration, Benowitz and Meister (I 978) pointed out that in this therapeutic context, clinically relevant changes in circulatory dynamics have not been ob-served. Nevertheless, most of the commonly used amide type agents have been shown to produce plasma concentration-related stimulation of the myocardium and pe.ripheral vasculature at non-toxic doses (Wiklund, 1977a,b; Mather et aI., 1979). At higher concentrations associated with CNS toxicity, these effects are replaced by depression of the myocar-dium and reduced peripheral vascular resistance lead-ing to hypotension and cardiac arrest. It is wortli remembering, however, that the concomitant ad-ministration of CNS depressant drugs, including some general anaesthetics, blocks the positive ino-tropic effect of local anaesthetics thereby lowering the threshold for cardiovascular depression below that for CNS toxicity (Blair, 1975). Furthermore, diazepam, which can prevent the CNS toxicity of local anaesthetics, does nothing for their adverse cir-culatory effects even though it may not make them worse (de long and Heavner, 1973). In the final analysis all cardiovascular actions of local anaes-thetics must be considered in relation to the indirect effects of conduction blockade of autonomic nerve

Tabl

e II.

Rel

atio

nshi

p be

twee

n pl

asm

a co

nce

ntra

tions

of l

ocal

an

ae

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afte

r int

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nous

adm

inis

tratio

n a

nd

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toxi

city

Agen

t A

utho

r

Pro-

Usub

iaga

et a

l. (19

66)

cain

e

Lign

o-Fo

ldes

et a

l. (19

60)

cain

e Jo

rfeld

t et a

l. (19

68)

Scot

t (197

5)

Mep

iva-

Jorfe

ldt e

t al.

(1968

) ca

ine

Bupi

va-

Jorfe

ldt e

t al.

(1968

) ca

ine

Mat

her e

t al.

(1971

b)

Scot

t (197

5) W

ilkun

d a

nd

Berli

ng-W

ahle

n (19

77)

Mat

her e

t al.

(1979

)

Etid

o-Sc

ott (1

975)

cain

e W

ilkun

d an

d Be

rlin-

Wah

len

(1977

) M

athe

r et a

l. (19

79)

Glo

ssar

y o

f sym

bols

M

M

axim

um

T =

Th

resh

old

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rial

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ric

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chro

mat

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phy

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f In

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sion

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ith s

ympt

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rate

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Clinical Pharmacokinetics of Local Anaesthetics

fibres that regulate cardiac and peripheral vascular function.

2.3 Fetal and Neonatal Toxicity

The clinical picture of acute fetal cardiovascular and CNS depression which sometimes follows obstetric regional anaesthesia has been reproduced in several animal models employing intravascular injec-tion oflocal anaesthetics (Ralston and Shnider, 1978). However, direct implication of the agent as a cause of this toxicity in humans in largely based upon studies with isolated denervated fetal hearts obtained after therapeutic abortion (Andersson et aI., 1970). Signifi-cant depression of these preparations, especially in the presence of acidosis, was noted with concentrations of mepivacaine that are commonly encountered in vivo. Limited evidence suggests that toxicity in the intact human fetus varies with the blood level of local anaesthetic. For example, umbilical venous blood levels in excess of 2.5~g/ ml of lignocaine and mepivacaine have been associated with overt depres-sion in neonates delivered from mothers receiving peridural injections of these agents (Shnider and Way, 1968; Morishima et aI., 1966). The lower toxic threshold compared to that seen in adults implied by these studies may be explained by differences in adult and fetal protein binding (see section 2.4. n.

An association between high fetal/maternal con-centration ratios of mepivacaine and fetal bradycardia after paracervical block has already been mentioned. However, this has not been a general finding as others have reported similar lignocaine concentrations in fetuses with and without significant reductions in heart rate (Liston et aI., 1973).

A number of studies have suggested that local anaesthetics may cause subtle neurobehavioural changes in newborn babies even when they are not overtly depressed as indicated by Apgar scores (Ralston and Shnider, 1978). In some of these reports the experimental design was inadequate to distinguish between effects of maternal neural blockade per se and any direct influence of the local anaesthetic; in-terpretation is also complicated by co-administration

246

of narcotic analgesics. However, the data of Scanlon et ai. (J 974) stand out as indicating that infants whose mothers had received continuous peridural analgesia employing lignocaine or mepivacaine for vaginal delivery showed significant impairment compared to a control group. In contrast, subsequent studies (Scanlon et aI., 1976) have shown that bupivacaine manifests none of these changes even when higher doses are used for Caesarian section (McGuiness et aI., 1978). Although there is no evidence at the pre-sent time that the neuro-behavioural changes seen with some agents are detrimental to the newborn (Tronick et aI., 1976), they do provide added stimulus to studies of the placental transfer and neonatal dis-position of local anaesthetics.

2.4 Interpretation of 'Blood Levels'

Interpretation of circulating concentrations of local anaesthetics and their possible relationship to Systemic effects should take account of the following factors:

2.4.1 Blood Distribution and Plasma Binding Figure I shows that plasma and whole blood drug

concentrations are not synonymous. The ratio of whole blood to plasma concentration (A) varies amongst the amide type agents being lowest for the longer acting analogues (table III). This, in turn, reflects differences in their binding to plasma proteins which hinders access to the red cell (Tucker et aI., 1970a; table I). Most of this binding is accounted for by association with high affinity-low capacity sites on !XI-acid glycoprotein (Mather and Thomas, 1978), which remains relatively unsaturated in the non-toxic range of plasma drug concentrations (fig. 2). Differ-ences in maternal and neonatal plasma binding of local anaesthetics (table IV) are probably related to lower !XI-acid glycoprotein concentrations in the latter (Mather and Thomas, I 978). Higher A values are also observed in infants (table III) consistent with a decreased plasma binding and their higher haema-tocrits.

Clinical Pharmacokinetics of Local Anaesthetics

E --....

'" '" '" .0 Cl :l.

E -....

'" '" '" .0 Cl :l.

E --'" '" '" .a Cl "-

1.5

1.0

0.5

0

1.0

0.5

0--0 Arterial plasma ---. Arterial blood 6-:..A Venous plasma

Etidocaine - Patients (n = 10), 20m I 1 % solution + Adrenaline (5pg!mil, injection time = 1 min.

Etidocaine - Volunteers (n = 10), 20ml 1 % solution + Adrenaline (5pg!mil, injection time = 2 min.

-----------

O~~~--~_r---------r--------~--------~

2.5

2.0

1.5

1.0

05

0

Lignocaine - Volunteers (n = 10), 20ml 2 % solution + Adrenaline (5)lg!mil, injection time = 2 min.

~,,~-r-.--------'---------~'-------' 30 60 120 180 240 Time in minutes

247

Fig. 1. Mean concentrations of etidocaine and lignocaine after peridural administration in patients (female, 21 to 52 years, 110 to 1781b., undergoing abdominal hysterectomy, started after 30min) and volunteers (male, 21 to 32 years, 159 to 200lb) [Tucker and Mather, 1975al.

Clinical Pharmacokinetics of Local Anaesthetics 248

Table III. Blood/plasma distribution of amide type local anaesthetics (mean SO)

Agent Author Normal Normal Pregnant Neonate adult male adu!t fema!e (at delivery)

Lignocaine Tucker and Mather (1975a) 0.840.OS and Tucker et al. (1977a) Moore et al. (197S) O.Sl a 0.05 1.09a 0.10

Mepivacaine Tucker and Mather (1975a) 0.92 0.04 and Tucker et al. (1977a) Moore et al. (197S) 1.03a 0.05 1.15a0.12

~0.95d Hook et al.( 1971) -O.SOc

Bupivacaine Tucker and Mather( 1975a) 0.730.05 and Tucker et al. (1977a) Tucker et al. (1970b) O.59 0.02 0.620.11

Etidocaine Tucker and Mather (1975a) 0.61 0.06 and Tucker et al. (1977a) Morgan et al. (1977) 0.55 a 0.03 0.64a.b O.OS O.72a0.10

Morgan et al. (197S) Prilocaine Hook et al. ( 1971)

a In vitro data.

O.950.lS

-1.12c

1.24 0.64

-1.16d

b Same figure reported for pregnant women at 35 to 37 weeks gestation. c Assuming an haematocrit of 45. d Assuming an haematocrit of 55.

Less extensive binding of local anaesthetics in cOrd compared to maternal plasma largely accounts for transplacental distribution gradients measured in ierms of iotal plasma drug concentrations. Allowing for ion-trapping and assuming that perfusion of the feto-placental unit is normal, concentrations of the unbound species appear to equilibrate rapidly across the placenta. In the amide series, an inverse relation-ship is observed between the extent of plasma binding and the umbilical cordi maternal concentration ratios for total drug in plasma. This ratio ranges from 0.1 to 0.4 for etidocaine and bupivacaine, 0.5 to 0.7 for lig-nocaine and mepivacaine and 1.0 to 1.2 for prilocaine (Tucker et aI., 1 970b; Mather et al., 1971 a; Thomas et ai., 1976a; Ralston and Shnider, 1978).

Clearly, any comparison of the relative toxicity of the different agents must be related to unbound rather

than to total blood or plasma drug concentrations (Tucker, 1975a). For example, calculations per-formed by the authors indicate that, in terms of free drug, the ratio of concentrations associated with toxi-city in adults/ average concentrations in cord plasma at delivery could be at least 2 times greater for bupivacaine than for lignocaine and mepivacaine. This would be consistent with greater neuro-behavioural deficits observed after maternal admini-stration of the latter agents.

Adequate information on the plasma binding and blood distribution of ester type agents is not available.

2.4.2 Sampling Site The large A-V difference in drug concentration

across the arm in normal subjects after peridural in-

Clinical Pharmacokinetics of Local Anaesthetics

jection of local anaesthetics (fig. I) may be explained by compensatory vasoconstriction in the upper limbs as a result of vasodilatation in the legs caused by lum: bar sympathetic blockade (Tucker and Mather, 1975a). In contrast, patients show much smaller A-V differences (fig. I) probably as a consequence of generalised vasodilatation by premedicants antagonis-ing the compensatory vasoconstriction due to the block (Murphy et ai., 1977). These findings have several implications for the interpretation of blood drug-effect relationships. Firstly, the site of blood sampling may influence superficial conclusions about the systemic absorption rate of the agents. Thus, venous, but not arterial, data suggest that uptake may be slower in unmedicated subjects compared to patients (fig. 0. Secondly, arterial concentrations might be better indicators of the time profile of drug concentrations at sites of toxicity in well perfused vital organs, particularly if venous samples are taken from a limb with impaired perfusion and minimal cutaneous vasodilatation, when drug input is rapid.

Concentration gradients of the agents across the lungs may also have some bearing on the precipita-tion of toxic reactions after rapid intravenous input. Following cuff-release after intravenous regional anaesthesia with lignocaine Tucker and Boas (1971)

100

80

60

"C 40 c

~ (#. 20

0.1 0.4 I-'g base/ml plasma

249

observed considerably greater drug concentrations in the pulmonary artery than in a peripheral artery for up to I to 4 minutes, and suggested that the lung functions as a buffer protecting the brain and coron-ary circulation from high input drug concentrations.

Using indocyanine green as an intravascular marker, Bertler et al. (J 978) and Lofstrom (J 978) have extended these findings by showing that the con-centration difference is the result of both blood transit and lung uptake of lignocaine. They found an extrac-tion ratio of 0.8 to 0.9 without any appreciable release over at least 25 seconds, but there was also evidence that the lung binding sites may be readily saturated. Clinical implications of these findings in-clude the possibility of a reduced 'buffer' effect after a second injection owing to saturation of binding sites by the previous dose, competition for uptake by other amine drugs and impaired buffering in patients with large anatomical or physiological lung shunts. Preliminary studies indicate high lung uptake but more rapid release of lignocaine in patients with pneumonia and shocked lungs (Lofstrom, 1978).

2.4.3 Acid-base Balance Acid-base balance is also a determinant of circulat-

ing concentrations of local anaesthetics and of their

~";",(Ol Etidocaine (6) x

Lignocaine

2 5 10 20

Fig. 2. Plasma binding of anilide type local anaesthetics in adult human plasma (Tucker and Mather, 1975a).

Clinical Pharmacokinetics of Local Anaesthetics 250

Table IV. Free fraction of amide type local anaesthetics in maternal and neonatal plasma (mean SO)

Agent Author Maternal Neonate

at 35-37 weeks at delivery

Lignocaine Tucker et al. (1970b) 0.437 a 0.027 0.758 a 0.028 Bupivacaine Tucker et al. (1970b) 0.047 a 0.014 0.345a 0.022

Mather et al. (1971 a) 0.146 a 0.301 a Thomas et al. (1976a) 0.093 0.062 0.490 0.272

Etidocaine I\t\organ et al. (1977) 0.056 a 0.017 0.264a 0.143

a In vitro data.

systemic effects. This is not surprising in view of the proximity of the pKa values to the range of blood pH (table I).

Studies in animals have shown that both hyper-carbia and acidosis drastically lower the convulsive threshold of local anaesthetics (Englesson, 1974; Englesson and Grevsten, 1974) and elevate total plasma and tissue concentrations of 3H-bupivacaine (Sjostrand and Widman, 1973), while Burney et al. (\ 978) have reported an inverse relationship between hydrogen ion concentration and human plasma bind-ing of lignocaine. Further systematic studies are indi-cated to define the inter-relationships between acid-base status and the pharmacokinetics and toxicity of local anaesthetics. There are also important implica-tions for perinatal safety because fetal acidosis leads to ion-trapping of the agents across the placenta (Brown et aI., 1976; Biehl et aI., 1978). Since acidosis exacerbates the myocardial depressant effects of local anaesthetics (Andersson et aI., 1970), this could lead to a vicious cycle involving further acidosis and fetal concentration of drug.

3. DispOSition Kinetics

3.1 Amide Type Agents

3.1.1 Studies in Adults Tucker and Mather (t 97 Sa) have measured

arterial blood concentration-time profiles of 4 of the

principal agents after short intravenous infusions in healthy volunteers (fig. 3). Individual data were fitted to triexponential equations and the mean values of derived kinetic parameters are summarised in table V.

Total clearances vary in the order bupiva-caine < mepivacaine < lignocaine < etidocaine, show-ing no relationship to anaesthetic potency or to lipid solubility /protein binding characteristics.

As etidocaine may be only slightly less toxic than bupivacaine in terms of blood concentrations its 2-fold higher V dss and clearance values might confer a clinical advantage. In practice, however, this will often be negated since up to twice the dose of etido-caine may be needed to achieve the same degree of sensory blockade in many procedures (see Cousins et aI., 1978; Lund et aI., 1975; Stanton-Hicks et aI., 1976). Furthermore, as V values, unlike V dss values, of the 2 agents are similar, a rapid inadvertent intra-venous injection of etidocaine would not be signifi-cantly less dangerous than one of bupivacaine, especially if double the dose were used.

Clearance of all the agents can be equated almost entirely with metabolic clearance as renal excretion of the unchanged forms accounts for less than 1 to 5 % of the dose at normal urine pH values (Adjepon-Yamoah et aI., 1973; Mather et al., 1971 b; Reynolds, 1 971 a; Thomas and Memn, 1 972; Thomas et aI., 1976b; Mihaly et al., 1978; Moore et aI., 1978). In turn, metabolic clearance appears to be synonymous

Clinical Pharmacokinetics of Local Anaesthetics

with hepatic clearance since Tucker et aI., (J 977a) have shown good agreement between indirect esti-mates of hepatic extraction derived from intravenous data (table V) and estimates obtained by direct measurement of arterial and hepatic venous drug con-centrations. These authors also considered the effect of increases in hepatic blood flow induced by the agents on their own clearance. Etidocaine clearance is most dependent upon liver perfusion whereas that of bupivacaine should be more sensitive to changes in intrinsic hepatic function. In the event of a toxic reac-tion there is little one can do to enhance hepatic elimination of the agents except to support the cir-culation generally in an attempt to maintain liver per-fusion. Forced acid diuresis will promote renal excre-tion by increasing ionisation of the agents in tubular fluid and thereby inhibiting their reabsorption (Eriksson, 1966). However, even under these condi-tions it may not be possible to remove more than 5 to

5.0

1.0

0.5

0.1

u

251

20% of the dose via the kidney as hepatic clearance is so dominant.

An approximation of the relative mean tissue affinities of the agents may be derived using equation I (Gibaldi and McNamara, 1978).

fS'V T (Eq. I) Vdss-Vs

where fT = average fraction of unbound drug in the extravascular space, fB = free fraction of drug in blood, V T = tissue volume + total body water (400 - blood volume (60 and VB = blood volume (60.

Estimates of fT are 0.14 (lignocaine), 0.10 (mepi-vacaine), 0.03 (bupivacaine) and 0.02 (etidocaine), in-dicating that an increase in blood binding in the series is accompanied by a parallel increase in affinity for tissue components. Both forms of binding are more extensive for those compounds with greater lipid

Etidocaine Lignocaine Mepivacaine Bupivacaine

.~ 0.05

.&: 1il

"-'"

-',

.,

'" c:

'"

'"

" -'"

, -, '"

--~ ~~-(.) -..... ..9 O.OI-'-----.-----.-----r----T----T-----','

2 3 4 6 Hours

Fig. 3. Mean post-infusion whole blood concentrations of local anaesthetics. after constant rate intravenous infusion of 44.2mg (base equivalent) of each drug over 10 minutes. in male volunteer subjects (Tucker and Mather. 1975a).

Clinical Pharmacokinetics of Local Anaesthetics 252

Table V. Pharmacokinetic parameters' describing the disposition of some amide type local anaesthetics after intravenous in-jection in adult male subjectsd (Tucker and Mather. 1975a; Tucker et al . 1977a)

Parameter Lignocaine iviepivacaine BupivClGaine Etidocaine

Number of subjects 5 7 8e 8e Dose (mg salt) 200 100 75 75 Infusion period (min) 3 2 10 10 Sampling time (h) 3 4 6 6 V(L) 8.3 1.6 8.1 3.8 14 8 124 Vdss(L) 91 15 84 35 73 26 133 75 t 1/2 rapid (h) 0.016 0.003 0.012 0.007 0.045 0.030 0.036 0.010 t1/2 inter. (h) 0.16 0.03 0.120.04 0.48 0.19 0.31 0.09 t 1/2 slow (h) 1.6 0.3 1.90.8 2.7 1.3 2.7 1.1 CI (L/min) 0.95 0.21 0.780.25 0.58 0.23 1.11 0.34 Eb 0.65 0.52 0.38 0.74 fBe 0.36 0.22 0.07 0.09

a Specified with respect to arterial blood concentrations mean SO. b Estimated hepatic extraction ratio. c Subjects common to studies with both drugs. d Supine. e Free fraction in blood = fp/),.,

solubility and anaesthetic potency. Clearly, consider-able tissue localisation of all of the agents militates against their effective removal by haemodialysis.

Additional studies of the disposition kinetics of the amide agents are summarised as follows:

Lignocaine Results of other studies in normal subjects have

been reviewed by Benowitz and Meister (t 978). Although there is good agreement on the value of the terminal half-life, the estimates of average plasma clearance range from 0.54 to 1.44L/min. Benowitz and Meister (t 978) have also discussed literature on the effects of age, weight and disease (renal, liver and cardiac) on lignocaine disposition.

Mepivacaine Moore et al. (t 978) gave I.Smg/kg intravenous

doses over 1.5 minutes to 6 healthy male subjects and found longer terminal half-lives (mean 3.17h) and

lower blood clearances (mean 0.40L/min) than those reported by Tucker and Mather (t 97Sa) [table V]. A longer sampling time ( > 7h) than that employed by the latter may partly explain these differences. How-ever, analysis of mean data of Reynolds (t 971 a) for 3 subjects given SOmg and sampled over 8 hours indi-cates an average blood clearance of about 0.7 6L/ min, similar to that reported by Tucker and Mather (t 97Sa).

Bupivacaine and Etidocaine Scott et al. (t 973) measured venous plasma con-

centrations of both agents after 25 and SOmg intra-venous doses in a crossover experiment with 6 volun-teers. Like Tucker and Mather (197 5a) they described a 2-fold difference in the total volume of distribu-tion of agents, but reported significantly shorter ter-minal half-lives (mean 0.95h and 1.27h for etidocaine and bupivacaine, respectively). However, sampling was continued for only 3 hours.

Tabl

e VI

. Co

mpa

rison

of t

he d

ispo

sitio

n ki

netic

s o

f am

ide

type

loca

l an

ae

sthe

tics

in a

dults

an

d n

eo

na

tes

Para

met

er

ligno

cain

e M

epiv

acai

ne

adu

lt n

eo

na

te

adu

lt n

eo

na

te

t 1 /2

slo

w (h

) 1.

8a

3.2b

3.

2d

8.7d

( 1

.2-2

.2)

(3.0-3

.3)

(1.7-7

.9)

(6.2-1

2.2)

3c

9c

Vdss

' (L

/kg)

1.11

a

1.02

d (0.

58-1.

91)

(0.68

-1.52

) V

d' (L

/kg)

2.75

b 1.

71d

( 1.4

4-4.

99)

(1.14

-2.77

)

CI'

(ml!m

in!kg

) 9.

2a

10.2

b 5.

5d

2.3d

(5.

3-12.1

) (5.

1-19.0

) (2.

9-8.9)

(1.

7-3.1)

f u

0.01

9b

0.16

0b

0.03

8d

0.35

7d

(0.00

6-0.04

7) (0.

015-0

.313)

(0.02

1-0.05

7) (0.

197-0

.527)

,

Spec

ified

with

resp

ect t

o ve

no

us

plas

ma

con

cen

tratio

ns.

a

Row

land

et a

t.( 19

71).

b M

ihal

y e

t al.

(1978

). c

Brow

n e

t at.(1

975).

d

Moo

re e

t al.

(1978

). e

Tuck

er e

t al.

(1977

a).

Mag

no e

t ai.

(1976

). g

Cald

well

et a

i. (19

76).

h M

orga

n e

t al.

(197

8)-u

rine

data

.

Bupi

vaca

ine

adu

lt

2.7

1

.3e

Etid

ocai

ne

ne

on

ate

a

dult

ne

on

ate

8.1

2

.5f

2.6

1

.1e

6.42

2

.73h

18

69

Q or

(i.

!!!.

"U

:::

T Ql 3 Ql (") o ~ " ~ (i. III ~ b (") !!!. " Ql ~ ~ :::T ~ (i. III N (J1 w

Clinical Pharmacokinetics of Local Anaesthetics

A comparison of the total blood clearance of etido-caine in non-pregnant and pregnant women after peridural administration indicated no significant dif-ferences (\.02 0.34L/min vs 0.93 0.17L/min), although fp values were markedly higher in the latter during delivery (table IV) [Morgan et ai., 1977].

Pri/ocaine Although precise data are lacking, there is evi-

dence to suggest that the clearance of prilocaine is considerably greater than that of lignocaine (Er-riksson, 1966; Lund and Covino, 1967). Animal ex-periments implicate a contribution of extra-hepatic metabolism, particularly in the lung (Akerman et ai., 1966).

3.1.2 Studies in Neonates Measurement of plasma concentrations and urin-

ary excretion rates of lignocaine and mepivacaine given subcutaneously to facilitate arterial catheterisa-tion in neonates indicated rapid absorption followed by monoexponential elimination over at least 24 hours(Mihalyetai., 1978; Mooreetai., 1978). Com-parison with data from adults showed a 2- to 3-fold prolongation of the terminal half-life of both agents related in part to a 2-fold increase in weight corrected volume of distribution (table VO. Lower plasma bind-ing in the infants possibly contributes to these find-ings. Mean plasma and blood clearances (based upon body weight) of mepivacaine were more than halved in neonates whereas those of lignocaine were similar to adult values. Renal excretion of both drugs was in-creased by a factor of 8 to 9 (table VI).

When clearances were divided into renal and hepatic components, renal clearance of both drugs was found to be significantly elevated in neonates whereas the hepatic clearance of mepivacaine, but not of lignocaine, was considerably reduced. The first ob-servation may be due to decreased protein binding in neonatal blood and decreased tubular reabsorption owing to higher urine flow rates and lower urinary pH in newborns. Less impairment of the hepatic clearance of lignocaine might be explained by a greater dependence on hepatic perfusion compared

254

with mepivacaine, the elimination of which should be more affected by the function of immature liver enzymes.

Estimates of the terminal elimination half-lives of lignocaine and mepivacaine in neonuyafter peri-dural administration to their mothers agree closely with those derived from direct injection (table VO and also support a preference for the use of ligno-caine. Half-lives of bupivacaine and etidocaine in the neonate after maternal peridural injection also indi-cate prolonged elimination in the newborn, although estimates for bupivacaine vary widely (Magno et ai., 1976; Caldwell et ai., 1976; Cooper et ai., 1977).

3.2 Ester Type Agents

In contrast to the amides, the ester agents are cleared in both plasma and in liver. The most striking feature of their hydrolysis by plasma pseudo-cholinesterase is its speed, in vitro half-lives in plasma from normal adults being less than 1 minute for chloroprocaine and procaine (table VII) and a little longer for tetracaine (Foldes et aI., 1965). Because of this it has been extremely difficult to detect these drugs in human blood after normal doses. For exam-ple, using a specific assay sensitive to 25ng/ml, Finster et ai. (J 973) found no chloroprocaine in whole blood samples after intravenous infusion of 250mg over 20 to 30 minutes in 3 volunteers. The clinical implication of this is that if a toxic level is at-tained, for example following an inadvertent intra-venous injection, the ensuing reaction should be relatively short lived. On the other hand, if the esterase becomes saturated or substrate-inhibited (Kalow, 1952) because of a very high concentration of drug, or if the enzyme is genetically atypical (Foldes et ai., 1965), then toxic reactions will be prolonged. The incidence of serious atypical pseudo-cholinesterase is about I in 2400 patients (Wylie and Churchill-Davidson, 1972) and one might expect to see toxic effects with large doses of ester type agents in these abnormal subjects. Various disease states have been shown to be accompanied by a prolonged in

Clinical Pharmacokinetics of Local Anaesthetics 255

Table VII. In vitro plasma t 1/25 of chloroprocaine and procaine (secs SO)

Author Normals Pregnant Liver Renal Pulmonary Heart Neonates disease disease disease failure

Chloroprocaine Finster et al. (1973) 21 2(M) 21 1 43 2 25 1 (F)

Procaine Reidenberg et al. (1972) 39 8 duSouich and Erill (1977) 436

M=Male. F= Female.

vitro half-life of procaine (table VII) but the clinical significance of this finding is not known. Even though the half-lives of the agents in cord plasma are twice as long as in maternal plasma (table VII), a rapid rate of hydrolysis in the mother should help to reduce placental transfer and intoxication of the fetus. This possibility has contributed to the recent revival of interest in chloroprocaine for obstetric procedures (Freeman and Arnold, 1975).

4. Metabolites

4.1 Amide Type Agents

Identification of the biotransformation products of these agents in human urine indicates 3 major sites of metabolic attack, namely aromatic hydroxylation, N-dealkylation and amide hydrolysis (table VIII).

Recent studies involving direct subcutaneous in-jection of the agents into neonates (table VIII) and peridural administration to mothers (Meffin et aI., 1973; Morgan et aI., 1978) have provided valuable information on the patency of these routes in the neo-nate. In summary it appears that, compared to adults, the capacity of the newborn to carry out direct aromatic hydroxylation is negligible; N-dealkylation is viable but further metabolism of the products of this reaction may be impaired; amide hydrolysis to form 2,6-xylidine seems similar but further hydrox-

138 54 84 50 8430 83 16 92 11

ylation of this compound may be reduced, although conjugation of the 4-hydroxy product is as efficient.

Boyes (I 975) and Tucker (I 97 5b) have reviewed limited data on the pharmacological activity and toxi-city of the various metabolites of the amide type agents. Monoethylglycinexylidide, glycinexylidide and the 4-hydroxy-product formed from lignocaine, pipecolylxylidide from mepivacaine and the mono-dealkylated products of etidocaine have all been measured in human plasma (Strong et aI., 1973; Halkin et aI., 1975; Blankenbaker et aI., 1975; Mor-gan et aI., 1977). Of these, there is only evidence that the first contributes to the effects of the parent drug in some patients. The possibility that other metabolites may be of clinical significance warrants further study.

Prilocaine is a special case in that methaemoglobin formation at high doses (> 600mg peridural) is directly related to metabolism of the parent drug to 0-toluidine and its subsequent hydroxylation. The fetus is at higher risk than the adult possibly owing to a relative deficiency in methaemoglobin reductase in erythrocytes. When necessary, methylene blue, 5mg/kg intravenously, is an immediate and effective antidote in both mother and infant (Ralston and Shnider, 1978).

4.2 Ester Type Agents

Some of the metabolites formed by the hydrolysis of the ester type agents have been measured in human

Tabl

e VI

II.

Rena

l exc

retio

n o

f am

ide

type

loca

l an

ae

sthe

tics

and

thei

r me

tabo

lites

(% d

ose)

Agen

t Un

chan

ged

Arom

atic

hyd

roxy

latio

n

3-hy

drox

y'

ligno

cain

e a

dult

1.9a

CD en :T ~ o

.en

N

Ul

OJ

Clinical Pharmacokinetics of Local Anaesthetics

plasma, for example para-aminobenzoic acid and diethylaminoethanol which are the products of pro-caine (Brodie et aI., 1948; Usubiaga et aI., 1966). Para-aminobenzoic acid and its substituted analogues, derived from other ester type agents, are probably responsible for allergic phenomena which sometimes follow injection of this group of local anaesthetics.

5. Absorption

5.1 Determinants of Absorption

In man, measurements of the magnitude and time of peak concentrations of local anaesthetics in the peripheral circulation have been widely used to assess systemic uptake of the agents after administration for regional anaesthesia (tables IX-XIII). The expectation is that by relating these concentrations to those associated with toxicity (table 11), ceilings on dosage for each procedure can be established with greater confidence.

The most important determinants of systemic ab-sorption are the physicochemical and pharmacologi-cal properties of the agent itself, the site of injection, the dosage (concentration and volume) of the local anaesthetic and the presence or absence of a vaso-constrictor in the injected solution.

5.1.1 Particular Local Anaesthetic Agent Examination of the data in tables IX-XIII will

show that the increment in whole blood concentra-tion per I OOmg of dose varies considerably depending upon the agent. For example, after peridural injection without adrenaline the figure is about 0.9 to I.O)Jg for lignocaine and mepivacaine, slightly less for prilo-caine and about half as much for bupivacaine and etidocaine. Although differences in disposition kine-tics contribute, it appears that despite similar peak times net absorption of the long acting, more lipid soluble agents is slower (see section 5.2.2). This con-clusion is also supported by data of Reynolds (1971 b) who measured blood drug concentrations after peridural injection of a mixture of lignocaine, mepiva-caine and bupivacaine.

257

The vasoactivity of local anaesthetics at sites of in-jection might also influence their own absorption rates by modification oflocal blood flow (Blair, 1975; Aps and Reynolds, 1976). However, the probability that bupivacaine and etidocaine are most likely to pro-duce vasodilatation indicates that relatively prolonged absorption of these agents is more a function of local binding than of vascular activity.

Although bupivacaine and etidocaine are intrin-sically more toxic than shorter acting analogues, there is some evidence to suggest that their qlargins of safety may be greater after successful injection for regional anaesthesia. If toxic blood concentrations are set at 5)Jg/ml for lignocaine and mepivacaine and 1.5)Jg/ml for bupivacaine and etidocaine, and assum-ing maximum concentrations of 4 and O. 8)Jg/ ml after average peridural doses for surgical anaesthesia (400mg for lignocaine and mepivacaine, 150mg for bupivacaine and 200mg for etidocaine) then the ratio of toxic/ maximum concentration is about 1.9 for the long acting agents compared to about 1.25 for the others. This, again, is largely a reflection of differ-ences in absorption rates.

Using spectrophotometry, Raj et al. (\977) have recently reported peak chloroprocaine levels as high as 8.5)Jg/ml plasma after brachial plexus and peridural blocks with doses of 450 to 600mg. How-ever, the validity of these estimates requires confir-mation by a more specific assay.

5.1.2 Site oj Injection Vascularity and the presence of tissue and fat

capable of binding local anaesthetics are primary in-fluences on their rate of removal from sites of injec-tion. In general, and independent of the agent used, absorption rate decreases in the order: intercostal block > caudal block > peridural block > bra-chial plexus block > sciatic and femoral nerve block (tables IX-XIII). Although the peridural space is more vascular than the intercostal site, most of the blood vessels contained within it traverse rather than drain it, while large quantities of fat are able to se-quester local anaesthetics and delay their uptake. Cir-culating concentrations of the agents after intercostal

Tabl

e IX

. Sy

stem

ic u

ptak

e o

f lig

noca

ine

afte

r adm

inis

tratio

n fo

r re

gion

al a

na

est

hesi

a 'Q

s

A

utho

r R

oute

D

ose

Conc

en-

Adr

en-

No.

of

Assa

y Sa

mpl

ing

Max

imum

-Pe

ak-

Max

imum

,r !!!.

(mg)

trat

ion

alin

e su

bjects

si

te

con

cen

-tim

e co

nce

n-

" ~

(%

) tr

atio

n (m

in)

lratio

n 01

3 (!l

g!ml

) (!l

g!lo

omg

01

n

of d

ose)

0 Co

:J S

Thom

as e

t al.

(1969

) TS

(V)

400

9 GC

VP

0.

55

50

0.14

,r '"

(0.16

-1.00

) (30

-120)

S.

TS(P

) 40

0 6

0.47

77

0.

12

b (0.

24-0.

B2)

(30-15

0) n

!!!.

TS(E

) 10

00

5 0.

46

24

0.05

~

:J

(0.

20-0.

65)

(10-45

) 01

CD

~ ~ Br

omag

e a

nd

Rob

son

( 1961

) En

do.

2BO-

520

4 12

C

VB

0.7-

10.0

5-

25

I ~. Pe

lton

et a

l. (19

70)

Endo

. 3!

kg

10

13

GC

VB

2.2

-5

1.

05

AB

2.5

-2

1.

19

Chu

et a

l. (19

75)

Endo

. 20

0 4

6d

GC

VP

3.54

0.

76b

20e

1.77

Pa

tters

on e

t al.

(1975

) En

do.

1 BO-

3BQe

21

GC

VB

1.

90

26

0.62

(0.

5B-1B

.20)

(5-75

) Vi

egas

an

d St

oelti

ng (1

975)

Endo

. 2!

kg

4 6d

GC

AB

1.

7

0.2

5b

9-15

1.

21

2!kg

e 4

4d

2.4

0

.3b

4-15

1.

71

Curra

n e

t al.

(1975

) En

do.

300

10

5d,t

GC

VB

5.1

(1.9-B

.2)

10-1

5 1.

70

300

10

5d, 9

1.1

(0.4-

2.5)

10-2

0 0.

37

Smith

(197

6) En

do.

2!kg

4

30

GC

B 0.

1-2.

0h

Karv

onen

et a

l. (19

76)

Endo

. 40

0 4

15

GC

AB

1,39

0.6

6 20

e 0.

35

VB

1.07

0.5

4 20

e 0.

27

Scot

t et a

l. (19

76)

Endo

, 10

0 5

or

10

5d

GC

VP

1.46

0.

43

10

1.46

En

do.

100

6 0.

960

.25

20

0.96

En

do.

50

5 O

.4B

0.2

5 5

0.96

Ch

inn e

t al.

(1977

) En

do,

2BO

4 5i

GC

VP

0.

6 20

0.

21

Endo

, 40

0 4

5i

0.44

10

0.

11

Cann

ell e

t al.

(1975

) Pe

riora

l 40

-160

2

9 GC

VB

0.

4-2.

0 -1

0

40-1

60

2 +

11

VP

0.

4-1.

5 30

-60

Schw

artz

et a

l. (19

74)

SC-,t

20

0 2

B GC

VB

0.

490

.16

120

0.25

Sc

ott e

t al.

(1972

) SC

A 40

0 2

10

C VP

1.

95

0.23

-3

0

0.49

40

0 2

+

10

1.02

0

,15

-1

5

0.26

SC

V 40

0 2

9 4.

91

0.43

-1

5

1.23

40

0 2

+

9 2.

500

,36

-1

5

0.62

N

t1

1 C

J)

Petri

e e

t al.

(1974

) PC

B 20

0 10

GC

VP

2.

08

0.09

b 10

1.

04

'Q

s

M

azze

an

d D

unba

r (196

6) BP

6.

2/kg

1.

5 7

GC

VP

2.5

0.

5 30

0.

50

1'f

+

~

(20-60

) "

:r

Raj e

t al.

(1977

) BP

40

0k

2 5

GC

VP

-3

.4

25

0.85

'" 3

400k

2

+

5 -2

.4

25

0.60

'"

"

Wild

smith

et a

l. (19

77)

BPp

450

2 5

GC

VP

4.51

15

1.

00

0 0-45

0 2

5 3.

62

20

0.80

"

+

(1) ~.

"

en

Scot

t et a

l. (19

72)

IC

400

8 C

VP

6.8

0.32

-1

5

1.70

S.

40

0 1

+1

12

5.28

0.

36

-2

0

1.32

..

0 "

400

1 +

m

10

4.87

0

.24

-1

0

1.22

~

40

0 2

11

6.48

0.3

8 -1

5

1.62

:t>

"

Brai

d a

nd

Scot

t (196

5) IC

40

0 4

13

C VP

8.

420

.26

-1

5

2.10

'"

(1)

~ (1) Br

omag

e a

nd

Rob

son

( 1961

) Pe

rid.

300-

500

2 15

C

VB

1.7-

9.4

5-35

I ~.

30

0-68

0 2

+

12

1.0-

4.4

12-4

0 M

azze

an

d Du

nbar

< 19

66)

Perid

. 5.

5/kg

1.

5 +

4

GC

VP

3.1

0.7

20-3

0 0.

79

Lund

an

d Cw

ik (1

966)

Perid

. 60

0 2

+

C VB

2.

72

1.26

3()C

0.

45

Scot

t et a

l. (19

72)

Perid

. 20

0 2

11

C VP

3.

300

.07

-1

5

1.65

40

0 2

23

4.27

0.2

4 -2

0

1.07

400

2 +

1 15

2.

95

0.29

-1

5

0.74

40

0 2

+m

13

3.

090

.38

-3

0

0.77

60

0 2

10

7.34

0

.37

-1

5

1.22

60

0 3

8 6.

31

0.26

-1

5

1.05

Br

aid

an

d Sc

ott (1

966)

Perid

. 70

0 2

9 C

VP

7.43

0

.23

-1

5

1.06

Ra

j et a

l. (19

77)

Perid

. 30

0k

2 6

GC

VP

3.5

25

1.17

30

Ck

2 +

8

-2

.6

25

0.75

M

athe

r et a

l. (19

76)

Perid

. 40

0 2

5 GC

AP

3.

7

0.5

12

3

0.93

40

0 2

+

5 2.

1

0.4

25

4 0.

53

Maz

ze a

nd

Dunb

ar<

1966

) Ga

ud.

6.6/

kg

1.5

+

4 GC

VP

1.

8

0.5

40

(10-6

0) 0.

42

For g

loss

ary o

f sym

bols

see

page

265

. '" ~

Tabl

e X.

Sys

tem

ic u

ptak

e o

f pril

ocai

ne a

fter a

dmin

istra

tion

for r

egion

al an

aest

hesia

Auth

or

Rout

e Do

se

Conc

en-

Adre

n-No

. of

Assa

y (m

g) tra

tion

aline

su

bjects

(%

)

Wild

smith

et a

l. ( 1

977)

BPp

450

1.5

5 GC

45

0 1.

5 +

5

Scot

t et a

l. (19

72)

IC

400

9 C

400

2 13

40

0 2

+1

16

400

2 +

m

10

Lund

and

Cwi

k(196

5) Pe

rid.

600

2 C

600

2 +

?

900

3 ?

900

3 +

Scot

t et a

l. (19

72)

Perid

. 20

0 2

8 C

400

2 31

40

0 2

+1

27

400

2 +

m

36

600

2 9

600

3 12

For g

loss

ary

of s

ymbo

ls se

e pa

ge 2

65.

Sam

plin

g M

axim

um"

Peak

" si

te

con

cen

-tim

e tra

tion

(min)

(I'

g/ml

l

VP

2.3

30

1.2

30

VP

5.09

0.2

5 -1

5

4.46

0.

27

-1

5

3.63

0

.21

-2

0

2.79

0.

22

-1

5

VB

3.68

2.

05

20c

1.75

0.

84

20<

5.23

2.

57

20c

3.25

1.

40

20<

VP

1.69

0.2

1 -1

5

2.67

0

.15

-1

5

2.21

0.

1O

-2

0

2.23

0.1

3 -2

0

4.47

0

.15

-2

0

4.90

0.2

5 -2

0

Max

imum

co

nce

n-

tratio

n (l'

g/l0

0mg

of d

ose)

0.51

0.

27

1.27

1.

11

0.91

0.

70

0.61

0.

29

0.58

0.

36

0.84

0.

67

0.55

0.

56

0.74

0.

82

'0

:j" Ir !!!. ., :::T '" 3 '" (") 0 1'- :0 CD I[ r 0 (") !!!. ;to :0 '" CD VI ~ ~ ('j" ,VI N (J) o

Table

XI.

Syst

emic

upt

ake

of m

epi

vaca

ine

afte

r adm

inis

tratio

n fo

r re

gion

al a

na

est

hesi

a

Aut

hor

Rou

te

Dos

e Co

ncen

-Ad

ren-

No.

of

Assa

y Sa

mpl

ing

Max

imum

" Pe

ak"

Max

imum

Q

(mg)

trat

ion

alin

e su

bjects

si

te

con

cen

-tim

e co

nce

n-

:;'

o

(%)

trat

ion

(min)

tr

atio

n 2!.

(p

g/mi

l (p

g/10

0mg

"U

~

of d

ose)

III :3 III n

Tera

mo

an

d Ra

jamak

i (197

1) PC

B 20

0 5

C VP

1.

86

30e

0.93

0 1