Clinical Pharmacokinetics 3: 177-201 (1978) © ADIS Press 1978
Clinical Pharmacokinetics of Lignocaine NL Benowitz and W. Meister Clinical Pharmacology Unit of the Medical Service, San Francisco General Hospital Medical Center, and the Department of Medicine and the Cardiovascular Research Institute, University of California, San Francisco, California
Summary
Lignocaine is widely used as a local anaesthetic and antiarrhythmic drug. It is commonly administered to patients with acute myocardial infarction as prophylaxis for ventricular fibrillation, although its efficacy in preventing primary ventricular fibrillation is still debated. Toxicity, sometimes with serious clinical consequence, is not uncommon and is usually related to overdosage. Blood lignocaine concentrations correlate roughly with antiarrhythmic and toxic effects and might be useful as an end point for monitoring prophylactiC therapy. Administration of lignocaine as a local anaesthetic may result in blood lignocaine concentration in the antiarrhythmic or even toxic ranges. Expected peak levels for various routes of local anaesthesia are tabulated so that 'safe' total doses can be calculated. Intramuscular injection of high doses results in sustained therapeutic levels but is often associated with early minor toxicity. Lignocaine is eliminated primarily by hepatic metabolism, which appears to be limited by liver perfusion. Active metabolites may contribute to therapeutic and/or toxic effects. Disease states such as cardiacfai/ure or drugs that alter hepatic blood flow may significantly affect lignocaine clearance. Pharmacokinetic studies in man show wide variability in drug disposition between patients, even when cardiac and hepatic status is considered, making specific dosing recommendations a problem. With intravenous injection, multicompartment kinetics is observed, with an initial rapid decline phase and initial decline in antiarrhythmic activity due to redistribution. With constant infusion, steady state concentrations of lignocaine are seen after 3 to 4 hours in normal sUQjects and after 8 to /0 hours in patients with myocardial infarction without circulatory insufficiency. In patients with cardiac failure, blood lignocaine concentration may continue to rise for 24 to 48 hours. In the presence of cardiac failure, decreased volumes of distribution and clearance require reduction in loading and maintenance doses. Lignocaine clearance is reduced in patients ,with liver disease and appears to be a sensitive index of liver dysfunction. A dOSing. algorithm for treatment of patients with myocardial infarction is presented.
Clinical Pharmacokinetics of lignocaine
Lignocaine is widely used as a local anaesthetic and as an antiarrhythmic drug. Although considered a safe drug by most clinicians, occurrence of clinically important adverse effects is not uncommon. This review will attempt to: (I) outline the rationale for and the importance of clinical pharmacokinetics of lignocaine; (2) review the evidence for a blood lignocaine concentration-response relationship; (3) update concepts of pharmacokinetics and of physiological influences on the pharmacokinetics of lignocaine; (4) review relevant pharmacokinetic data obtained in man in disease states; and (5) synthesise available data in a dosing algorithm.
1. Importance a/Clinical Pharmacokinetics 0/ Lignocaine The use of blood lignocaine concentrations or the application of pharmacokinetically designed dosing regimens has 2 major functions: to optimise potential therapeutic benefit and to minimise the risk of toxicity. In this section we will discuss some of the benefits and risks of lignocaine administration in patients with acute myocardial infarction and some of the reasons why pharmacokinetic considerations might -improve the balance -between benefits and risks.
1.1 Lignocaine Prophylaxis in Acute Myocardial Infarction Lignocaine is widely used in the treatment of acute myocardial infarction, mainly in an attempt to prevent ventricular fibrillation. Primary ventricular fibrillation occurs in I to II % of patients with acute myocardial infarction (Bigger et aI., 1977). Initially, Lown et al. (I967) recommended an approach in which lignocaine was administered after the appearance of so-called warning arrhythmias. This practice continues in many coronary care units. The relevance of warning arrhythmias has recently been questioned. When examined prospectively, such ar-
178
rhythmias occurred willi llie same frequency (approximately 60 %) in those patients who developed ventricular fibrillation as in those who did not (EISherif et al., 1976; Lie et al., 1975). Thus, if lignocaine is to be given prophylactically, it appears that all patients admitted to a coronary care unit, irrespective of 'warning' arrhythmias, should be treated. In lliis situation there is not always a clinical end point such as suppression of premature ventricular contractions. The therapeutic utility oflignocaine prophylaxis is still debated (Anonymous, 1975; Anonymous, 1976; Halkin, 1974). One controlled study (Lie et aI., 1974) and a large uncontrolled study (Wyman and Hammersmith, 1974) reported efficacy in preventing ventricular fibrillation in acute myocardial infarction patients. Several ollier trials failed to show benefit (Bennett et aI., 1970; Bleifeld et al., 1973; Chopra et aI., 1971; Church and Biern, 1972). Lignocaine doses were higher in the Lie et al. (I 974) trial than in most of the unsuccessful trials. Adequacy of dose may be a critical factor in success of prophylactic therapy (Bigger et aI., 1977). It appears from the above that in prophylactic use lignocaine is often administered: (I) to a large number of patients of whom only a small fraction will benefit (and even that benefit is debated), (2) willi out a good clinical end point ",ith respect to dosing, and (3) in a situation in which relatively high -dO~eSapPearto -be necessary for efficacy.
1.2 Lignocaine Toxicity
1.2.1 Adverse Effects on the Central Nervous System The most frequent aqverse effects of lignocaine involve the central nervous system. Even with conservative doses, drowsiness, dizziness, paraesthesiae, and euphoria commonly occur (Foldes et aI., 1960; Koppanyi, 1962). Typical symptoms with higher doses include confusion, agitation, dysarthria, vertigo, visual disturbances, tinnitus, and nausea. Sweating, muscle tremor, or fasciculations may occur. Manifestations of severe toxicity of the nervous
Clinical Pharmacokinetics of Lignocaine
system include psychosis, seizures, respiratory depression, and coma (see section 1.2.4). In a recent survey, 6 of 12 life-threatening and 25 of 35 nonlifethreatening adverse reactions to intravenous lignocaine involved the central nervous system (Pfeifer et al.,1976).
/.2.2 Adverse Electrophysiological Effects on the Heart Adverse electrophysiological effects on the heart are uncommon but may be serious. Anecdotal reports describe sinus standstill, complete atrioventricular (A-V) heart block, accelerated ventricular rate during atrial flutter or fibrillation, and ventricular dysrhythmias (Cheng and Wadhwa, 1973; Jeresaty et aI., 1972; Klein et al., 1975; Marriott and Bieza, 1972; Nevins, 1973; Sinatra and Jeresaty, 1977). Electrophysiological effects in patients have been investigated in 3 studies. In 10 patients without conduction disturbances, rapid injection of lignocaine (I to 2mg/kg body weight) had no effect on A-V or intraveritricular conduction as studied by His bundle electrogram (Rosen et aI., 1970). In another study of 21 patients with various intraventricular conduction abnormalities and premature ventricular contractions, a bolus of 50 to 100mg lignocaine was administered intravenously (Gupta et aI., 1974). Complete heart block developed in 2 patients and cardiac standstill in another. In a contrasting study, infusion of 6mg/kg body weight in 22 minutes to 10 patients with bundle branch block had no effect on the His bundle recordings, with peak serum lignocaine levels ranging between 3.3 and 11.0Jlg/ml (Kunkel et aI., 1974). Potentially of great clinical importance is the report. by Geddes et al. (I 972) that lignocaine may increase the frequency of premature ventricular contractions in the early phase of acute myocardial infarction.
1.2.3 Adverse Effects on the Circulatory System In most clinical studies, clinically relevant changes in circulatory dynamics have not been observed after
179
administration of lignocaine (Binnion et al., 1969; Cullhed, 1969; Grossman et aI., 1969; Harrison et al., 1963; Klein et aI., 1968; Rahimtoola et aI., 1971; Schumacher et aI., 1968). After a relatively large bolus injection of 2mg/kg body weight to 12 patients with acute myocardial infarction, a transient increase in pulmonary artery diastolic pressure of approximately 20 % occurred, whereas all other circulatory measures were unchanged; an infusion of I to 3.5mg/minute, however, did not produce any changes (Jewitt, I 971). Reports of a negative inotropic action with therapeutic doses of lignocaine remain inconclusive because of the use of nonspecific noninvasive methods (Boudolas et aI., 1977) or concomitant anaesthesia (Harrison et aI., 1963).
1.2.4 Serious and Fatal Adverse Effects In a recent survey (Pfeifer et al., 1976), 12 of 47 adverse reactions attributed to lignocaine were considered life-threatening, including respiratory depression, coma, grand mal seizures, heart block, cardiac arrest, hypotension, and combinations of these reactions. 8 of the 12 patients subsequently died, although the authors were reluctant to attribute the deaths to adverse reactions to lignocaine. Adverse reactions appeared to be more frequent in older patients and in patients with acute myocardial infarction, congestive heart failure, or low body weight. When dos.es were reported, they appeared to be in the commonly recommended range. The patients were not treated in a coronary care unit. Accidental overdosage would be more likely to occur and less likely to be detected in its minor stage on a general medical ward. Unfortunately, blood lignocaine conCentrations were not measured in this study. In a survey of anaesthetic use of lignocaine in 1962,9 deaths were reported (Deacock and Simpson, 1964). The doses in these fatal caSes ranged from 300mg (in a 4 year old child) to 3000mg with various routes of administration. Convulsions occurred in 7 patients, circulatory collapse in 3, cardiac arrest in 2 and respiratory failure in 2 of these 9 cases; 4 other fatalities were not described in detail. In all cases the
Clinical Pharmacokinetics of Lignocaine
dosage was unusually high by current standards. Grimes and Cates (1976) reported 4 deaths after paracervicai biock anaesthesia with an unusually high dose of lignocaine; in 2 cases the postmortem blood lignocaine concentration was estimated and found to be 9 and 5J.lg/ml. In summary, lignocaine used as an anaesthetic or antiarrhythmic agent can cause serious adverse effects and even death. Allergy is extremely rare (Strunin, 1975). In most cases, overdosage appears to be responsible. If serious adverse effects were heralded by manifestations of minor toxicity, the latter might be useful as a dosing end point. Although administering lignocaine to the point of minor toxicity has been recommended (Alderman et aI., 1974), the mere fact that serious adverse effects do occur demonstrates that minor toxicity in lignocaine therapy can be absent, neglected, or, probably most frequently, obscured by disease processes or concomitant drug therapy.
2. Blood Lignocaine Concentration-Response Relationship A range of blood lignocaine concentrations that would guarantee efficacy and rninimise--toxicitywould be helpful in planning treatment regimens. A prerequisite of clinically useful blood lignocaine concentration measurements and/ or of pharmacokinetically designed dosage regimens is the demonstration of a blood lignocaine concentration-response relationship.
2.1 Experimental Electrophysiology and Blood Lignocaine Concentration Response The cardiac electrophysiological effects of lignocaine and the mechanisms of its antiarrhythmic activity have been reviewed recently (Rosen et aI., 1975). Most investigators have studied the electrophysiologiCal effects of lignocaine in isolated cardiac muscle preparations, but the relevance of the ob-
180
served dose-response relationship to Lhe intact organism is unclear. Rosen et ai. (I 976) recently reported a promising experimental preparation in which blood from an intact and anaesthetised animal perfuses an isolated cardiac muscle preparation obtained from another animal. Blood levels in the intact animal can therefore be related to electrophysiological effects in the isolated muscle. They found a blood lignocaine concentration-related reduction in action potential amplitude and duration, in effective refractory period, and in membrane responsiveness at blood lignocaine concentrations ranging from I to I O)lg/ mg, which is comparable with the commonly quoted therapeutic range in man. Disease states can influence the electrophysiological effects of lignocaine and might disturb the blood lignocaine concentration-response relationship in animal experiments. For example, lignocaine delayed activation and prolonged the effective refractory period to a much greater extent in ischaemic than in normal myocardium (Kupersmith et aI., 1975). Similarly, the drug markedly increased the threshold stimulation current of ischaemic tissue, whereas no such effect occurred in normal myocardium (Hondeghem, 1976).
2.2 Clinical Studies and Blood Lignocaine Concentration Response The minimal blood lignocaine concentrations effective in suppressing premature ventricular contractions range from 0.6 to 2.0J.lg/ml (Benowitz, 1974; Gianelly et aI., 1967; Kunkel et aI., 1974; Schwartz et aI., 1974; Sheridan et aI., 1977; Singh and Kocot, 1976). Some patients, however, require much higher concentrations (up to I O.O)lg/ mO or may develop toxicity of the central nervous system before the antiarrhythmic effect is achieved (Alderman et aI., 1974). The study by Lie et a!. (I 974) provides some data about blood lignocaine concentrations that are effective in preventing ventricular fibrillation in acute myocardial infarction patients. Patients were given a bolus of 100mg followed by infusion of 3mg/ minute.
Clinical Pharmacokinetics of Lignocaine
Blood lignocaine concentration ranged from 1.5 to 6.5pg/ml (mean ± SD:3.5 ± O.9pg/ml). However, the samples were obtained within 6 hours after initiation of infusion. It is likely that most patients had a higher blood lignocaine concentration later during the infusion (see section 3.2.3).
2.3 Toxicity and Blood Lignocaine Concentration
181
lignocaine concentrations and the data of Lie et aI. (J 974) for minimal presumably effective blood ligno-
caine concentrations, we define blood lignocaine concentrations from 1.5 to S.Sllg/ml as the therapeutic range for purposes of pharmacokinetic planning.
3. Pharmacokinetics of Lignocaine (general considera lions)
In general, subjective toxic effects of lignocaine on the central nervous system occur at blood lignocaine 3.1 Absorption in Local concentrations of 3 to Spg/ml and objective adverse Anaesthesia manifestations, including muscular irritability, convulsions and coma, appear at blood lignocaine concentrations of 6 to IOpg/ml (Benowitz, 1974; After administration as a local anaesthetic agent, Gianelly et al., 1967). Unfortunately the survey of systemic absorption of lignocaine may result in blood lignocaine toxicity by Pfeifer et al. (t 976) did not re- lignocaine concentrations in the usual antiarrhythmic port blood lignocaine concentrations. Similarly, most or even toxic ranges. Because avoidance of systemic of the reported clinical trials do not indicate the blood toxicity is of concern, the absorption characteristics, lignocaine concentrations in the patients with adverse particularly peak concentrations and time of peak effects. concentrations, have been tabulated (table O. As In the study by Alderman et al. (t 974), in which reviewed by Covino (t 972), absorption depends on large dose infusions were administered, all 3 patients the site of injection and whether or not a vasoconwith blood lignocaine concentrations over 811g/ ml strictor is added. developed adverse effects. In another study, 7 of 12 From data published by Scott et aI. (I972, 1976), patients with an average peak blood lignocaine con- we calculated peak venous plasma concentrations of centration of 6.S ± 2.1 pg/ml (mean ± SEM) lignocaine expected after administration of IOOmg after an intradeltoid injection of 6mg/kg body weight dose of lignocaine by the following routes: endotrahad minor toxic effects (Zener et aI., 1973). After an cheal (paralysed patients) and intercostal, I. 611g / mIl intramuscular dose of 4mg/kg body weight (mean IOOmg; subcutaneous vaginal, I.2pg/ml/lOOmg; blood lignocaine concentration 2.5pg/mI), only 2 of epidural, 1.1 pg/ml/ IOOmg; endotracheal (spontane12 patients complained of minor central nervous ously breathing patients), 1.0pg/ mIl I OOmg; and system symptoms. There are data suggesting that subcutaneous abdominal, O.Spg/ml/l OOmg. Absorption rate appears to relate to vascularity of metabolites contribute to toxicity, especially in the presence of other disease states (see section 3.3.3). Ac- the particular tissues. Absorption of adrenaline cumulation of metabolites in disease states, as well as (epinephrine) reduces local blood flow and decreases the disease state itself, complicates the blood ligno- peak concentrations, irrespective of the site of administration. The peak levels achieved by local anaescaine concentration-toxicity relationship. In summary, there is considerable overlap of thesia in any site appear to be linearly related to the therapeutic and toxic blood lignocaine concentration dose administered. Thus the maximal 'safe' dose ranges. A major consideration in using lignocaine could be approximated for various routes of adprophylactically has to be minimising major toxicity. ministration from these data and from data in Using conservative estimates of minimal toxic blood table I.
280 400 300-500 300-680
40-160. 40-160 ~ 200
EndolPPB EndoNeb
Epid Epid
Epid Epid
Extra Extra
Peri Peri
Chinn et al. (1977)
Bromage and Robson ( 1961)
Scott et al. ( 1972)
Mather et al. (1976)
Cannell et al. (1975)
a
Endo = endotracheal Endo IPPB = endotracheal intermittent positive pressure breathing Endo Neb = endotracheal nebuliser Epid = epidural Extra = extradural Peri = perioral SC(af) = subcutaneous (antecubital fossa)
+
400
51 51
Scott et al. (1972)
b
11 12
9
9
10 10
8
9 11
5 5
23 15
15 12
5 5
59 6h 5h
15
6 4
12
No. subj.
SeA = subcutaneous abdominal SCV = subcuianeous vaginal SI~ = selective! intercostal FI, = fluorometric BI: = blood GC = gas chromatography PI, = plasma Co = colourimetric
2
+
400
+
SCV SCV
2
Scott et al. (1972)
400
SC(af)
SCA SCA
+
+
+
+
Scott et al. (1972)
2 2
2
101
Adrenaline
Schwartz et al. (1974)
400
400
2 2
4 4
5 or
100 100 50
Endo Endo Endo
Scott et al. (1976)
4
400
Endo
Karvonen et al. (1976)
4
2mg/kg d .e
Endo Endo
Viegas and Stoelting (1975)
4
280-520 .
Endo
Bromage and Robson (1961)
Concentration (%)
Route"
Author
Dose (mg)
Table I. Pharmacokinetic data after administration of lignocaine for local anaesthesia
Pl,Co
c d d e f 9 h
Mean ± SO kg = kg body weight Arterial blood With lignocaine lubricant Aerosol Paralysed Spontaneous breathing SEM
6.48 ± 0.38 i 5.28 ± 0.36 i .'
15 20
15 15
± ±
0.43 i 0.36 i 4.91 2.50
1.95 ± 0.23 i 1.02 ± 0.15 i Pl,Co
30 15
0.49
PI, Co
120
",,10 30-60
12 25
GC,BI
0.16
0.4 ... 2.0 0.4 ... 1.5
GC, PI orBI
±
3.7'± 0.5 d 2.1 ± 0.4
GC,PI
20 15
20
± ±
3 4
18 ± 9 23 ± 8
4.32 ± 2.01 2.52 ± 1.23
BI, FI 0.24i 0.25 i
10
0.6 0.44
GC,PI
± ±
10
1.46 ± 0.43 0.96 ± 0.25 0.48 ± 0.25
PI,GC
4.27 2.95
20
1.39 ± 0.66 d
PI.GC 20 5
9-15 4-15
1.7 ± 0.2d 2.4 ± 0.3 d
GC,BI
5 ... 25
0.7 ... 10.0
FI, BI
Peake time (min)
Peake level ()Jg/ml)
Assayb
1.62 1.32.
1.23 0.63
0.49 0.26
0.25
0.93 0.53
1.07 0.74
==1 0.63
0.21 0.11
1.46 0.96 0.96
0.35
1.13
Peak serum drug level ()Jg/l00mg of dose)
s·
Q
00 N
co
Q)
"s·
0
to ::>
c
So
"'"
!:to
co
:l
Q)
3 "0Co
Q)
"C ::T
!!!.
o·
Clinical Pharmacokinetics of Lignocaine
183
3.2 Intramuscular Absorption
et aI., 1966; Sung and Truant, 1954; Thomson et aI., 1973).
Intramuscular administration of lignocaine has been proposed for prehospital management of patients with acute myocardial infarction (Valentine et aI., 1974). Several studies have investigated the pharmacokinetics of lignocaine administered intramuscularly and are summarised in table II. Differences in absorption rate with different sites of injection have been observed. Absorption is more rapid after injection into the deltoid muscle (absorption half-life 11.7 minutes) than into the vastus lateralis and gluteus maximus (absorption half-life 25.7 minutes) [Meyer and Zelechowski, 197 J). On the average, injection of 200 to 300mg results in plasma levels of 1 to 3pg/ml for 10 to 120 minutes. Larger doses of 6mg/kg body weight (mean 455mg) effect persistent therapeutic levels of over 1.5pg/ mg for over 2 hours in most patients (Zener et aI., 1973). The average peak plasma concentrations of drug with the 6mg/kg body weight regimen is 6.5pg/minute (Zener et al., 1973); this produces minor toxicity of the central nervous system in many patients, but no major adverse effects have been reported. Another recommended method of effecting rapid therapeutic levels that persist for up to 2 hours is to inject lignocaine both intravenously (50 to 100mg) and intramuscularly (200 to 300mg) [Scott et aI., 1970b]. Dose-blood lignocaine concentration relationships must be considered in planning and evaluating trials of prehospital intramuscular lignocaine administration. 3.3 Elimination and 'First Pass' Metabolism 3.3.1 Renal Excretion Excretion of unchanged lignocaine by the kidney is a minor route of elimination. Lignocaine is a weak base (pKa 7.85), so that excretion is influenced by urinary pH (Eriksson and Granberg, 1965; Mather and Thomas, 1972). Maximal excretion in an acid urine is about 10% of the administered dose (Beckett
--- - - - - - - - -
-
-
--
-
3.3.2 Metabolism Lignocaine is predominantly metabolised by the liver. Hepatic metabolism of lignocaine has been studied extensively in animals and man (Beckett et al., 1966; Boyes and Keenaghan, 1971; Hollinger, 1960; Keenaghan and Boyes, 1972; Mather and Thomas, 1972; Sung and Truant, 1954; Thomson et aI., 1973). Rat microsomal enzyme preparations of liver demonstrate high affinity and rapid velocity of metabolism (Nyberg et aI., 1977). Drugs that induce (phenobarbitone) and inhibit (SKF-52S) hepatic microsomal enzymes have been shown to enhance or impair, respectively, lignocaine metabolism in animals (DiFazio and Brown, 1972; Lautt and Skelton, 1977). 3.3.3 Metabolites Two major metabolites, monoethylg1ycinexylidide (MEGX) and glycinexylidide (GX), are found in significant concentrations in the blood of patients receiving lignocaine therapeutically (Adjepon-Yamoah and Prescott, 1973; Collinsworth et aI., 1975; Halkin et aI., 1975; Prescott et al., 1976; Strong et aI., 1973; Strong et aI., 1975). These metabolites have been shown to have antiarrhythmic and convulsant activities in animals, with MEGX appearing to have potencies similar to lignocaine itself (Blumer et aI., 1973; Burney et aI., 1974; Smith and Duce, 1971). MEGX is metabolised by the liver and has an estimated terminal elimination half-life of 120 minutes, which is similar to that of lignocaine. Compared with lignocaine, GX is 10 to 26 % as potent an antiarrhythmic agent and is apparently a much less potent convulsant agent in animals (Blumer et a\., 1973; Burney et aI., 1974). GX is both metabolised and excreted by the kidney and, unlike lignocaine and MEGX, has a long elimination half-life of 10 hours in normal volunteers (Strong et al., 1975). Accumulation of metabolites during prolonged intravenous administration may account for the development of toxicity while blood lignocaine con-
----
200 300
4/kge
200
Bellet et al.
Meyer and Zelechowski ( 1971)
Sloman et al.
(1972)
Cohen etai.
(1972)
Bernstein et al.
(1971)
(1971)
200
200
200 200 200
Scott et al.
(1970)
Dose (mg)
A.uthor
6 8 9 10 8 9 10 6 8 10
5
10 10
2 2
2 2 4
(%)
Concentration
Buttocks
lateral thi9?
Deltoid
Gluteus maximus
Deltoid
Deltoid Vastus lateralis
Vastus latenl/is
SitE:
Patient Patient Patient
10 10 10
5 7 7 16 5 4 10 3 7 5 Patient Patient Patient Patient Patient Patient Patient Patient Patient Patient
Patient
Patient Patient
5 10
14
AMI Patient Patient
Disorder"
8 9 9
No. subj.
Table II. Pharmacokinetic data after intramuscular administration of lignocaihe
Co or GC.BI
GC. Ser
GC.PI
GC. PI
GC.BI
GC. PI
Assayb
30 30 10 45 20
1.9 ± 0.3 d 2.7 ± 0.2d 2.65 2.02 2.3 ± 1.3
2.42 2.27 2.02 1.52 1.37 1.73 1.00 1.60 1.00 1.72
± ± ± ± ± ± ± ± ± ±
0.65 d O.72 d O.54d 0.23 d 0.39 d 0.34d 0.13 d 0.96 d 0.27d 0.74d
1.56 ± 0.29d
90
30
10 10 10 30 10 30 30 90
30
30 15 30
2.54 ± 0.35 d 2.47 ± 0.43 d 2.34 ± 0.30d
(Ilg/m/)
time (min)
average
Peak level
0.79 0.59 0.35 0.75 0.41 0.66 0.56 0.53 0.45 0.52
± ± ± ± ± ± ± ±
O.lld 0.09 d 0.20d 0.38d 0.07 d O.24d 0.14d O.26d,
± 0.21d
± O.30d
1.01 ± 0.12d
1.1 0: 0.4
1.1 1.2
0.8 :±: O.ld 1.5 :±: 0.3 d
1.28 ± O.20d 1.36 ± O.14d 0.95 ± 0.23 d
(Ilg/m/)
After 2 hours c average
co
"'"
,CD
:;'
0
If'"
~
If:
0
'"
'"3
:T
"'!l
9!.
Q :;'
cr
Deltoid Buttocks Deltoid Buttocks
4/kge
Zener et al. (1973)
c d e
b
N = 4
Mean ± SO SEM kg = kg body weight
AMI = acute myocardial infarction CHD = chronic heart disease CF = cardiac failure GC = gas chromatography PI = plasma BI = blood Ser = serum Co = Colourimetric
4.5/kg e
Singh and Kocot (1976)
a
4.5/kg e
Schwartz et al. (1974)
6/kge
Deltoid
Deltoid
Vastus
10
10
Deltoid
10
10
21
13
11
12
12
10
AMI
5AMI 4CF
3 AMI 4CF
14AMI 5CHD
AMI
Patient Patient
OA/kg"
7 10
Vastus lateralis Vastus lateralis
Pickering (1973)
10
4 10
7 7
Gluteus maximus Vastus lateralis Patient Patient
4
200 200 200 300
18 AMI
Ryden et al. (1972)
26 7CHD
10
250
Fehmers and Dunning (1972)
GC, BI
GC,BI
GC,81
GC,BI
GC, PI
10 30
10
2.9 ± 0.4 1.5 ± 0.2
2.18 ± 0.22d
0.5 0.3 2.0 0.2
± ± ± ± 15 15 5 30
2.5 1.5 6.4 2.2
10
30 45
1.57 ± 0.54 1.73 ± 0.29 3.11 ± 1.28
10 30
30
1.90 ± 1.01! 1.87 ± 0.60
2.2 ± 0.18d
0.2 0.3 0.1
0.2
0.81 ± 0.05 d
= 1.5
= 1.5
0.9 ± 0.9 ± 2.3 ± 1.2 ±
1.33 ± 0.31
0.67 ± 0.24 1.07 ± 0.30
0.58 ± 0.15 0.96 ± 0.41
=104
00
c.n
II·
cO'
.-
S.
en
o·
~
:>
III
0 "1;.
3
III
~
-c
e!.
o·
:i"
Q
Clinical Pharmacokinetics of lignocaine
186
centrations are within Lhe therapeutic range fHalkin et al., 1975; Nation et al., 1977; Strong et al., 1973; Strong et al.; 1975).
3.3.4 Physiological Considerations
cated by gastrointestinal and central nervous symptoms, probably due to formation of toxic metabolites (Boyes et aI., 1971; Scott et al., I 970a). In animals with a portacaval shunt, which allows the absorbed drug to bypass the liver after absorption into the portal circulation, bioavailability is increased from 14.8 to 81.3 % (Gugler et aI., 1975). Similarly, patients with portacaval shunt or severe liver disease might have enhanced oral bioavailability due to reduced 'first pass' metabolism.
Lignocaine extraction ratios from blood of 100 % in the isolated perfused rat liver (Nyberg et al., 1977) and 70 % in man have been reported (Stenson et al., 1971). In a study of patients with class II and III heart disease, the hepatic extraction ratio did not systematically change with diminished' cardiac index or hepatic blood flow, as estimated by indocyanine green clearance (Stenson et al., 197 J). From these 3.4 Distribution and Protein Binding data it was proposed that lignocaine clearance in man is determined primarily by blood flow to the liver. 3.4.1 General Considerations Animal experiments showing interactions between Because of the common use of the intravenous lignocaine and drugs that alter hepatic blood flow route of administration of lignocaine and because of (Benowitt et al., 1974a; Branch et al., 1973), and iso- its rapid onset of action, distributional considerations lated perfused liver experiments in which flow is are vital in understanding the clinical pharmacology manipulated (Shand et al., 1975), support the perfu- of lignocaine. Presumably, the pharmacological and sion-limited clearance concept (see also Nies et al., toxic effects depend on the concentrations of the drug 1976). in the myocardium and brain. The concentrations in In the haemorrhaged monkey and probably also in these tissues in turn depend on the concentrations of patients with severe cardiac disease, clearance is ... lignocaine in'plasma; on- plasma protein binding,.and-_ decreased beyond that which can be accounted for by on tissue partition characteristics. The rate of diminished blood flow in the liver (Benowitz et al., transport of lignocaine to and the rate and extent of I 974b). Furthermore, antipyrine, which is ht:lieved to _,partition into and out of various tissues also influence be eliminated independently of hepatic blood flow, is the time course of the blood lignocaine concentration cleared more slowly in patients with myocardial in- and the observed pharmacokinetics. farction and cardiac failure (Prescott et al., 1976). Presumably, hepatocellular dysfunction and reduced 3.4.2 Protein and Tissue Binding metabolic activity (Tokola et al., 1975) complicate the At the usual therapeutic blood lignocaine conperfusion-limited metabolic model in situations of cir- centration, 70% is bound to plasma proteins (Tucker et al., 1970). At higher concentrations, less is bound; culatory insufficiency. e.g. about 60 % with concentrations of 6 to I OJlg/ ml plasma. The observed changes in binding would be 3.3.5 'First Pass' Hepatic Metabolism A consequence of avid hepatic extraction and expected to have negligible effects on volume of dismetabolism of lignocaine is extensive 'fIrst pass' tribution and clearance. Lignocaine is less well bound to erythrocytes than hepatic metabolism. Oral bioavaiiability of lignocaine is estimated to be 35 % (Boyes et al., 197 Conse- to plasma protein and the concentration in whole quently, oral administration of doses of lignocaine blood differs from that in plasma. The plasma:blood comparable with ;intravenous doses results in ratio has been determined to be 1.5 at a whole blood subtherapeutic blood lignocaine concentrations. At- concentration of 5Jlg/ ml (Tucker et al., 1970). The tempts to give higher doses orally have been compIi- ratio becomes smaller with increasing concentration
n.
187
Clinical Pharmacokinetics of Lignocaine
due to relatively less plasma protein binding. Lignocaine concentrations are reported in terms of whole blood, plasma, and serum, and for comparison, appropriate corrections have to be made. Lignocaine partitions extensively into body tissues. Partition coefficients between tissue and plasma at steady state have been determined in the rhesus monkey (Benowitz et aI., 1974b). Assuming the partition is similar in man and monkey, lignocaine has a high affinity for spleen (tissue to plasma partition coefficient 3.5), lung (3. I), kidney (2.8), less for adipose tissue (2.0), brain (J .2), and heart (0.96), and least for musculoskeletal tissues (0.6). Lignocaine is a weak base with a pKa (7.85) near the physiological pH observed in tissues. In an acid environment, more lignocaine is ionised. The pH of ischaemic myocardial tissue is lower than that of normal myocardial tissue. Ionised lignocaine might then be trapped and accumulated in such regions. This
phenomenon could account for the differential effects of lignocaine in normal and diseased myocardium (Hondeghem, 1976; Kupersmith et aI., 1975). 3.4.3 Time Course of Distribution
The time course of distribution of lignocaine into tissues has important consequences with respect to the time course of drug effect. It is difficult to measure drug concentrations in tissues in man. Partition coefficients and blood flow characteristics obtained from animals have been used to develop computer perfusion models of drug distribution and pharmacokinetics (Benowitz et aI., 1974a). Our statements about the time course of distribution are based on such computer simulations, as shown in figure I. After intravenous injection, lignocaine passes through the right side of the heart and into the pulmonary circulation. Because of the high affmity of pulmonary tissue for lignocaine and because of the
100
80 Metabolism
Time (min)
Fig. 1. (Compartmental analysis). Perfusion model simulation of the distribution of lignocaine in various tissues and its elimination after intravenous infusion of l00mg over 1 minute in a 70kg man (from Benowitz et al., 1974a; reproduced with permission of publisher).
Clinical Pharmacokinetics of Lignocaine
188
high incoming blood concentration of drug, a large proportion of lignocaine is initially sequestered into the lung. Thus the lung dampen..8 the peak lignocaine concentrations seen after a bolus. In patients with an intracardiac right-to-Ieft shunt or a pulmonary arterio-venous fIstula, greater than ordinary concentrations of lignocaine might enter the systemic circulation and thereby increase the risk of toxicity after a standard dose. Shortly after injection of lignocaine, the drug distributes preferentially into tissues that have the highest affinity· for it. The rate of accumulation in any tissue depends on the blood flow to that tissue. Accumulation of lignocaine occurs rapidly in heart, brain, kidney, and other viscera and more slowly in muscle and adipose tissue. In a short time, most of the drug has left the central blood pool and is found in tissues. Because of the avidity with which tissues take up lignocaine, only about 6 % of the lignocaine in the body at steady state is found in the blood volume. Lignocaine then redistributes from well perfused tissue to muscle and adipose tissues. This accounts for the rapid disappearance of antiarrhythmic effects
noted after single injections. Muscle and adipose tissues, because of their large mass, accumulate drug and become the major storage reservoirs. In the late disposition phase when blood lignocaine concentrations are low, tissues release lignocaine slowly back into the central circulation and the drug is eliminated. This phase is characterised by the terminal half-life of the drug. 3.4.4 Haemodynamic lrifluencesPerfusion Model Because lignocaine is often used in patients with cardiac disease, the effects of cardiac failure on distribution of drug have been of concern (Benowitz and Meister, 1976). Both cardiac failure and haemorrhage are associated with tissue hypoperfusion, sympathetic nervous stimulation, and redistribution of blood flow. Data obtained from the monkey during haemorrhage were used in the perfusion model to predict what might occur during severe cardiac failure in man (Benowitz et aI., 1974b). Computer simulations, . shown in fIgure 2, predict higher concentrations of drug in blood due to decreased blood flow to and up-
70
Control-30% Haemorrhage_ - _ 40 30
20
2
4
8
16
32
64
128
256
Time (min) Fig. 2. (Perfusion model). Perfusion model simulation of the distribution of lignocaine in various tissues in man after a 1 minute injection of 100mg in a 70kg man, showing the effect of haemorrhage (from Benowitz et aI., 1974b; reproduced with permission of publisher).
Clinical Pharmacokinetics of Lignocaine
189
take by tissues. Preservation of blood flow to heart repeated doses or with prolonged infusion, tissues and brain, in the presence of higher concentrations of become more saturated. The u phase becomes less drug in the blood, leads to higher concentrations of prominent and a slower (M disappearance phase, with lignocaine in these organs soon after injection. Thus, average half-lives of 80 to 108 minutes, becomes the adverse effects of lignocaine involving the central dominant (Boyes et at., 1971; Nation et at., 1977; nervous system and heart are more likely to occur in Thomson et aI., 1973; Tucker and Boas, 1971). the presence of haemorrhage and presumably cardiac A two compartment body model may be adequate failure. These predictions are consistent with clinical to predict effects and accumulation of lignocaine with observations in man (Pfeifer et at., 1976). prolonged administration in persons without cardiac The rate of presentation of drug to tissue is slowed disease. As will be discussed, a two compartment in states of circulatory insufficiency. This results in a analysis does not predict the accumUlation time reduced rate of overall tissue uptake and a decreased course in patients with myocardial infarction. Tucker initial volume of distribution. Decreased steady state and Boas (J 97 I) showed that a three compartment volume of distribution of lignocaine has also been re- model fits their data most closely. However, their adported in man and observed in the haemorrhaged ditional compartment is a small central one. The termonkey (Benowitz et at., I 974a; Thomson et at., . minal phase is similar to that observed in other 1973). This is difficult to understand on the basis of studies with normal volunteers. Distribution and elimination of drugs begin imhaemodynamic change alone. Possible alternative explanations include altered tissue affinity related to car- mediately after intravenous injection. Estimates of diac failure or functional sequestration of drug in volume of distribution are dependent upon rates of administration and elimination and upon time (Niazi, some tissues owing to patterns of shunting. 1976). Figure 3 shows computed volume of distribuThe perfusion model does not consider such factors as time required for mixing in the venous pool, tjon changes with time after a single intravenous innonlinear or altered protein binding, nonhomogeneity jection in a typical normal subject and a typical caror shunting of blood flow within organs, time re- diac failure patient. The steady state volume of disquired for diffusion of drug from blood into tissues, tribution is the only one that is truly independent of nonlinear metabolism, or the effects of the drug itself on circulatory dynamics (Benowitz et at., 1974a; 120 Wiklund, 1977), all of which might be important Normal ,...effects. Nevertheless, the perfusion model does pro100 vide some insight into the effects of circulatory facIii Cardiac failure ~ 80 tors on lignocaine concentrations and effects. ------~~----~\--
4. Pharmacokinetics in Man 4.1 Healthy Volunteers
Vp • Vdss "" Vd~ •
'0.,
E :J
0
After rapid intravenous injection, lignocaine exhibits multicompartmental kinetics. The initial (u) exponential decay phase, with average half-lives of 5 to 10 minutes (Boyes et aI., 1971; Thomson et aI., 1973; Tucker and Boas, 1971), corresponds to the rapid disappearance of clinical effects after a single dose. With
>
0
20
40
60
80
100
120
j--J
1440
Minutes Fig. 3. Computed volume of distribution as a function of time after rapid intravenous injection of lignocaine. Computations are based on the method of Niazi (1976), using pharmaco kinetic data from Thomson et al. (1973).
Clinical Pharmacokinetics of Lignocaine
rates of administration and elimination and would be the best parameter for comparing different patient populations (Klotz, i 976). Unfortunately, different investigators report different terms of volume of distribution making comparison difficult. The volume of distribution of the central compartment is useful because it can be used to predict blood levels after rapid injection: estimates range from 23.6 to 62.4 litres (Boyes et ai., 1971; Nation et ai., 1977; Thomson et aI., 1973). Steady state volume of distribution describes the total amount of lignocaine in the body as a function of blood lignocaine concentration during constant infusion, and estimates for this volume range from 46.5 to 157 litres. As is the case for many highly tissue-soluble drugs, there is considerable variability in volumes of distribution making it problematic to apply an average figure to any particular patient. We have been unable to find data demonstrating a correlation between lignocaine volumes of distribution and body weight. Data from Rowland et al. (I 97 1) and Nation et al. (J 977) even show a trend toward an inverse relationship. In the Rowland et al. (J 97 J) study, the negative correlation between Vdss and body weights reached significance (r = - 0.66, p < 0.05). We cannot explain negative correlations. The lack of a positive correlation between initial volume of distribution and· body weight suggests that a fixed initial dose is appropriate. In common with volume of distribution, clearance varies markedly among normals (Rowland et aI., 1971) and does not positively correlate with body weight. Average estimates for plasma clearance range from 0.54 to 1.44 litres/minute (Boyes et aI., 1971; Nation et aI., 1977; Thomson et aI., 1973; Tucker and Boas, J97 J). This clearance represents a large fraction of hepatic plasma flow, which is consistent with a high hepatic extraction ratio. Table III summarises pharmacokinetic data obtained in both normal subjects and diseased patients. 4.2 Influence of Age The influence of age has been investigated by Nation et al. (J 977). 6 elderly male subjects (61 to 71
190
years of age) and 4 young control subjects (22 to 26 years of age) were given 50mg lignocaine intravenously. Clearanc.e did not differ in elderly and young patients. In the elderly, a longer terminal halflife (J 39.6 ± 64.1 compared with 80.6 ± 9.4 minutes) and an increased volume of distribution (e.g. steady state volume of distribution 1.128 ± 0.37 compared with 0.651 ± 0.17L/kg body weight in the younger subjects) were observed.
4.3 Cardiac Failure
We recently reviewed the effects of cardiac failure on pharmacokinetics (Benowitz and Meister, 1976). Cardiac failure is associated with tissue hypoperfusion and compensatory activation of the sympathetic nervous system. The rate of distribution of lignocaine from blood into peripheral tissues is slowed, which diminishes the central volume of distribution. Reduced hepatic blood flow secondary to reduced cardiac output may directly impair clearance. In states of severe circulatory disturbance with tissue hypoxia, hepatocellti1ar· aysfundiori may reduce the· rate-of-metabolism of lignocaine (see section 3.4.4). Thomson et al. (J 973) found significant differencesin lignocaine kinetics between healthy_control ... _ subjects and patients with cardiac failure and attempted to relate these findings to haemodynamic measurements. The pharmacokinetics of I 1 patients with cardiac failure were studied on the same day that cardiac catheterisation was performed.. After intravenous doses of 50 or 100mg lignocaine, patients had reduced central and steady state volumes of distribution and reduced clearance. The terminal half-life of the drug was unchanged because of equal relative changes in volume of distribution and clearance. Total clearance was lower on the average in patients with reduced cardiac output. However, the observed range of cardiac outputs was too narrow to meaningfully predict clearance on the basis of cardiac output. No relationship between intracardiac pressures and clearance could be established. One patient was restudied after aortic and mitral valve replace-
6 7
6
23
4
AMI
N
N CF RD lD
RD
AMI AMI+CF
DuringVH After VH
lD
N
Prescott and Nimmo (1971)
Tucker and Boas (1971)
Thomson et al. (1973)
Collinsworth et al. (1975)
Prescott et aU 1976)
Williams et al. (1976)
Forrest et al. (1977)1
a
CP YN EN
Nation et al. (1977)h
b
c
YN = young normals EN = elderly normals GC = gas chromatography PI = plasma QMF = quadruple mass fragmentography BI = blood kg = kg body weight
d e f g h
0.40 ± 0.28 0.54 ± 0.13 0.56 ± 0.15
0.881 ± 0.308 1.30 ± 0.287
0.703 0.443 0.959 0.419
5.9 ± 4.2 7.6 ± 1.6 8.1 ± 1.9
5.3 ± 2.1
13.0 ± 3.9 20.0 ± 3.9
10.0 6.3 13.7 6.0
14.4 ± 3.2
SEM Harmonic mean Oral route Assuming steady state Assuming steady state on average dose. Patient FJ omitted
152.6 ± 129.9 64.0 ± 21.1 109.6 ± 47.7
4.50 ± 2.37 1.34 ± 0.16 2.33 ± 1.07
GC,PI
46.5 ± 12.5 77.3 ± 28.5
199.4 ± 115.8 130.1 ± 36.2
1.48 ± 0.65L/kgC
23.6 ± 5.6 23.7 ± 10.6
62.9 ± 39.0 39.4 ± 16.6
92.8 62.0 84.0 162.0
0.421 (0.282-0.723)
134 ± 30 0.98 ± 0.18 1.93 ± 0.48L/kg C
122 (78-240)
3.22 ± 0.54
6.6 ± 1.1 d ( 1.8-19.01 1.4 ± 0.26 d
2.67 e 1.50e
37.0 21.3 38.3 43.0
157 ± 35
GC, PI
GC, PI
GC,BI
4.3 ± 0.8 d 10.2 ± 2.0d
GC, PI
1.80 1.92 1.29 4.93
1.55 ± 0.18
2.47 ± 0.18
0.14 0.12 0.16 0.15
0.16 ± 0.05
3.3 (2.5-4.41
Vd~ (V darea)
18.2 ± 7.4
62.4 ± 30.1
1.47 ± 0.20
0.09 ± 0.05
steady state 1.44 ± 0.47
initial
l/min
~
ml/min/kgC
Clearance
Volume of distribution (litres)
a
t 1/2 (hours)
PI,QMF
GC, PI GC,PI GC,PI GC,PI
GC,PI
GC,PI
GC, PI
Assayb
N = normal CF = cardiac failure RD = renal disease lD = liver disease AMI = acute myocardial infarction VH = viral hepatitis CP = cardiac patients
12 4 6
AMI with- 12 out CF
Lelorier et al. ( 1977)9
4
10 8 6 8
5
6
5
N
Boyes et al. (19711
No.
Subjects a
Author
Table III. Pharmacokinetic data after intravenous administration of lignocaine
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Clinical Pharmacokinetics of Lignocaine
ment, and the iignocaine disposition kinetics had returned toward normal values. Aps et al. (1975) compared patients ,vith myocardial infarction but without cardiac failure with patients after cardiothoracic surgery who had evidence of circulatory disturbances and hepatic dysfunction. They observed that plasma concentrations of lignocaine at the end of the infusion period, which ranged from 6 to 72 hours (mean 25 hours), were 50 % greater in the postoperative group. Specific conclusions about clearance cannot be made, however, because the relation of each patient's drug infusion rate to blood concentrations of drug, and documentation of whether or not steady state was achieved were not available. They observed that the disappearance half-life of lignocaine in the 5 hours after stopping a prolonged infusion was slower in the postoperative group than the acute myocardial infarction group (mean of 5.0 versus 2.4 hours). This 5 hour period was probably too short to estimate confidently the terminal elimination half-life and the numbers may underestimate the true terminal half-life. In comparing these small groups of patients, given the same loading and infusion dose regimens, the trough' in . blood lignocaine concentration that occurred clearly about 30 minutes after initiation of infusion in the in. -rarction group was much less pronounced in the. postoperative group. Zito et al. (I 977) purported that the dip' in blood lignocaine concentration was less pronounced in 8 patients with acute myocardial infarction, some of whom were in cardiac failure, compared with normal subjects. However, after correction for the high initial blood lignocaine concentrations in the acute myocardial infarction group, the differences in dips disappear. Plasma lignocaine concentrations in patients with acute myocardial infarction and cardiac failure receiving constant infusions have also been measured by Prescott et al. (I 976). After a brief initial decay phase, the terminal half-life of lignocaine was 4.3 hours in patients without cardiac failure and 10.2 hours in patients with cardiac failure. At the same infusion rate, the blood levels of drug at termination of infusion were 46 % higher in patients with cardiac failure. Of
192
note was 1 patient in cardiogenic shock who had no decline in blood lignocaine concentration for 6 hours after the infusion was stopped, suggesting complete failure of hepatic clearance. Nation et al. (I977) investigated lignocaine pharmacokinetics in I 3 cardiac patients, 7 with overt cardiac failure. Omitting I extraordinary patient who virtually did not eliminate the drug at all (the terminal half-life was given as 24.5 hours), the average half-life was 5.5 ± 2.4 hours (mean ± SD) for 6 cardiac failure patients, compared with 3.1 ± 1.7 hours for 5 patients without cardiac failure. Unfortunately, plasma lignocaine concentrations were followed for only 5 hours after stopping the infusion so that these results may be biased. Accumulation of lignocaine metabolites has been reported in patients with cardiac failure. Halkin et al. (I975) measured blood concentrations of the active metabolite MGEX in 31 patients receiving prolonged infusion of lignocaine for treatment of arrhythmias. MEGX concentrations were significantly higher in the presence of cardiac failure. One patient exhibited symptoms of neurological toxicity with a therapeutic lighocaine-Ievet-but with an unusually -high-MEGX-level.
4.4 Myocardial Infarction There is evidence that lignocaine pharmacokinetics may differ in patients with myocardial infarction, even without overt circulatory disturbance, from that observed in normal persons. Aps et al. (1975) studied dosing regimens in patients with myocardial infarction but without cardiac failure. They noted that in all patients who received an infusion for more than 8 hours, lignocaine concentrations continued to increase an average of 25 % between 8 and 25 hours; a postinfusion half-life in normal subjects. was observed. As mentioned previously, Prescott et al. (1976) studied patients receiving infusions oflignocaine during treatment for acute myocardial infarction. They showed that blood lignocaine concentrations increased over the entire infusion period of 48
193
Clinical Pharmacokinetics of Lignocaine
hours. Similar fIndings were reported by LeLorier et al. (I977). They found in 12 patients receiving a Img/kg.body weight bolus plus a maintenance infusion of 20pg/kg body weight/minute during uncomplicated acute myocardial infarction, an increase in plasma lignocaine concentration from 1.85 ± 0.47 (mean ± SD) after 6 to 12 hours to 4.32 ± 1.64pg/ml at the end of infusion (after 27 to 60 hours). The half-life after discontinuation of infusion was 3.22 ± 0.54 hours. The observed terminal half-lives do not explain the progressive increase in blood lignocaine concentrations during prolonged infusion of lignocaine observed by Aps et al. (J 975), Prescott et al. (I 976) and LeLorier et al. (I 977). The discrepancy suggests that either an additional tissue compartment or nonlinear clearance of lignocaine must be considered in predicting accumulation of lignocaine in patients with myocardial infarction. Nonlinear clearance might conceivably result from saturation of metabolising enzymes or the effect of accumulating lignocaine or its metabolites on hepatic blood flow or metabolic capacity. Lalka et al. (I976) reported that lignocaine clearance is nonlinear, with reduced clearance· during greater infusion rates, even in normal persons. This was not observed in an earlier study by Rowland et al. (I 97 I) in which 50 or 100mg of lignocaine was injected intravenously. However, studies usi~g a single intravenous injection might not be as sensitive to changing clearance rates as those using a constant infusion.
4.5 Hepatic Disease In 8 patients with alcoholic cirrhosis, Thomson et al. (I 973) found that clearance was reduced (6.0 versus 10.Oml/minute/kg body weight in normal subjects), that steady state volume of distribution was increased (2.31 versus 1.32L1kg body weight), and that the terminal half-life was prolonged (296 versus 108 minutes). Similar results were observed by Williams et al. (I 976) in patients with viral hepatitis, studied during the active phase and again after recovery. They
reported reduced clearance (I3 versus 20ml/ minute/kg body weight), increased steady state volume of distribution 0.1 versus 2.0L/kg body weight), and a prolonged terminal half-life (t 60 versus 90 minutes). Adjepon-Yamoah et al. (1974) reported 1 patient with fulminant hepatitis who had a terminal half-life of 19.1 hours. Forrest et al. (I 977) determined the half-lives of antipyrine, paracetamol, and lignocaine in 23 patients with chronic liver disease of various causes and severity. The mean lignocaine disappearance half-life was 6.6 hours, compared with a control value of 1.4 hours in healthy subjects. Compared with the other drugs, prolongation of lignocaine half-life was the most sensitive index of liver disease, both in terms of extent of prolongation 071 % versus I 53 % for antipyrine and 45 % for paracetamoJ) and proportion of the patient population exhibiting abnormal half-lives (90 % versus 53 % for both antipyrine and paracetamoJ).
4.6 Renal Disease Thomson et al. (I 973) administered short infusions of lignocaine to 6 patients with terminal renal failure, 5 of whom were on chronic haemodialysis. They found no signifIcant changes in any of the pharmacokinetic parameters. Collingsworth et al. (1975) studied the pharmacokinetics of lignocaine during a 12 hour infusion in 4 patients on chronic haemodialysis. Their data were fItted to either a two or three compartment body model. Mean clearance and steady state volume of distribution were similar to those reported for normal subjects by other investigators. Mean terminal half-life averaged 148 minutes, which is longer than the half-life reported in most studies of normal SUbjects. Central volumes of distribution ranged from 1.6 to 6.5 litres, which are much smaller than that observed in other studies. An important methodological consideration in their study was the 12 hour infusion, in contrast to the rapid injections or short infusions used by other investigators. After prolonged infusion, the ex phase is minimised and the
Clinical Pharmacokinetics of Lignocaine
central compartment is difficult to compute with confidence. Conceivably, a slowly equilibrating tissue compartment might also be unmasked after prolonged infusion, which would not be observed after rapid injection. Thus, the reported differences in central volume of distribution might be due to differences in the methods used. Collinsworth et al. (1975) studied accumulation of metabolites during lignocaine infusion in uraemic patients. MEGX did not accumulate, and the MEGX terminal half-life paralleled the lignocaine terminal half-life. Presumably, MEGX is rapidly metabolised and the formation of MEGX from lignocaine is rate limiting in the MEGX terminal half-life. In contrast, GX, half of which is normally excreted by the kidney, accumulated progressively over 12 hours and persisted for 12 hours after discontinuing the infusion in 2 patients.
4.7 Pharmacokinetic Drug Interactions Few reports of drug interactions in man involving lignocaine are available. From our previous discussion of lignocaine metabolism and distribution, 2 types of interaction can be expected. __ Fjr:stly, drugs that influence metabolic capacity might alter hepatic extraction of lignocaine. Inhibition of metabolic capacity has been observed in cats receiving SKF-525 (Lautt and Skelton, 1977) and in dogs receiving halothane (Burney and DiFazio, 1976). Metabolic induction was purported in I study of epileptic patients which showed that the disappearance rate of lignocaine was more rapid in 7 epileptics receiving various anticonvulsant drugs than in 6 control epileptics not receiving such therapy (Heinonen et aI., 1970). No further change was noted after additional treatment with phenobarbitone. Because hepatic extraction of lignocaine is usually extensive in man, it is unlikely that major changes in extraction would be produced by enzyme inducing drugs, but changes in hepatic blood flow, which have been reported with such drugs, could shorten the disappearance half-life of lignocaine.
194
Secondly, haemodynamic drug interactions might occur with drugs that alter hepatic blood now and/ or redistribute peripheral blood flow (Nies et al., 1976). D,l-propranolol, for example, decreases iignocaine clearance in anaesthetised dogs without altering hepatic extraction by reducing hepatic blood flow (Branch et aI., 1973). Noradrenaline (norepinephrine) infusion decreases and isoprenaline (isoproterenol) infusion increases hepatic blood flow and lignocaine clearance during constant infusion in the conscious rhesus monkey (Ben()witz et al., 1974b). Computer simulations utilising perfusion models predict that noradrenaline will also reduce and isoprenaline increase the central volume of distribution due to effects on the peripheral circulation (Benowitz et aI., I 974b). However, this prediction has not yet been examined experimentally. Administration of sodium nitroprusside, a potent vasodilator, in hypotensive doses to anaesthetised dogs did not alter lignocaine clearance or extraction (Shiroff et al., 1977). This suggests that systemic vasodilation in combination with normal cardiac output does not affect hepatic blood flow. The importance of drug interactions with lignocaine in the treatment of acutely illp~tient§ is ~~t known. Patients with circulatory insufficiency do ' receive vasoactive drugs, and the potential for drug interactions should be recognised. The circulatory disturbances associated with severe cardiac disease make evaluation of such interactions difficult.
5. Clinical Recommendations 5.1 Dosing Regimen With respect to dosing recommendations, the results of human pharmacokinetic studies can be summarised as follows: I) There is wide variability in drug disposition kinetics between patients, even whcn cardiac and hepatic status are considered, making specific dosing recommendations a problem. 2) After intravenous injection of lignocaine, multicompartment kinetics are observed. There is an
Clinical Pharmacokinetics of Lignocaine
Repeated short infusions of ~ in 5-min i nterva 1s (up to total of 150 mg)
®
195
®
Repeated short infusions of ~ in 5-min intervals (up to total of 300 mg)
Yes
Yes
I
®
CD
I
Trial with other antiarrhythmi c agents
Tri al with other antiarrhythmi c agents
10-30 min after last short infusion: jf arrhythmia recurs ®, give short infusion with 50% of last short infu?iQn_dQs~ __________ _ After 12-24 hours: consider reduc!ign_iQ infu?iQn_r~t~ gy_3Q-§O~ __ After 48 hours: consider discontinuation G
Fig. 4. Lignocaine dosing algorithm for the treatment or prophylaxis of cardiac arrhythmias. A) Administer dose over 1 minute. B) If lignocaine is given prophylactically in the absence of ventricular arrhythmias. assume 'No: C) In patients with severe cardiac failure or shock, there may be no elimination (see text). In this case, repeated short infusion of 25mg for recurrence of arrhythmias might be preferable to a maintenance infusion. D) Delivery by infusion pump is recommended. E) Such as procainamide, 100mg by slow infusion every 5 minutes to a maximum of l000mg. F) Probably due to trough (see text). If arrhythmia recurs later, a short infusion (20 to 50mg) followed by an increased infusion rate (increase of 0.5 to lmg/minute) can be tried. G) After discontinuation of infusion, BLe falls with a half-life of several hours (see text).
Clinical Pharmacokinetics of Lignocaine.
196
iIlitial rapid decline in blood and presumably in mended to achieve persistent therapeutic blood levels cardiac tissue concentrations due to tissue distri- (Scott et aI., I 970b; Shen and Gibaldi, 1974); bution. however, in patients with circulatory insufficiency, 3) With continuous infusion, blood lignocaine blood flow to and absorption from muscles may be concentrations approach a plateau in normals after 3 erratic. to 4 hours. In patients with myocardial infarction but Based on the doses used by Lie et ai. (t 974) and without circulatory insufficiency, this plateau usually considering the pharmacokinetic data as discussed in becomes apparent within 8 to 10 hours. In patients sections 4.1 to 4.6, we developed the dosing algowith circulatory failure, blood lignocaine concentra- rithm shown in figure 4. This algorithm requires the tions may continue to rise for more than 24 to 48 following comments: (t) the regimens have not been hours. tested explicitly; (2) there is no pharmacokinetic 4) In patients with cardiac failure, a decreased model describing the accumulation of lignocaine with volume of distribution and a decreased clearance lead long-term infusion in patients with acute myocardial to higher blood lignocaine concentrations after a par- infarction, especially in the presence of cardiac failure; (3) the regimen is designed more toward ticular dose. 5) Lignocaine clearance is reduced in (and is a minimising toxicity than toward guaranteeing relatively sensitive index 00 liver disease. efficacy; and (4) any fixed dosing recommendation 6) When lignocaine is administered by bolus in- does not consider variation in severity of disease jection followed by constant infusion, blood ligno- . states, differences in potential benefit and risk among caine concentration may fall to subtherapeutic levels; patients, or the role of alternative or combined drug this trough occurs during the redistribution phase of treatment approaches. the initial injection and before substantial blood lignocaine concentrations are achieved as a result of the infusion. Several approaches have been described for rapidly 5.2 Indications for Blood Lignocaine attaining and maintaining a constant tissue-blood Concentration Measurement level of lignocaine. I) An initial bolus followed by constant infusion, Although measurements of blood lignocaine -cori~· supplemented by smaller repeated injections as re- centration are not difficult, they are not widely availquired to treat recurrent premature ventricular con- able. The role of blood lignocaine concentration tractions, is a common practice. A potential hazard of measurement in clinical practice will depend on the this method is toxicity to the central nervous system determination of the risk of unheralded major toxrelated to transient high concentrations of lignocaine icity, which still awaits clarification. Measurements in blood and brain. With slow bolus injections over at of blood lignocaine concentration appear useful in the least I minute, this risk is minimised. • following situations: (I) in patients in shock, who 2) Rapid high dose infusion over 20 to 60 may have markedly reduced clearance; (2) during minutes followed by a maintenance infusion has been prolonged infusion (greater than 24 hours), especially recommended to achieve therapeutic concentrations in patients with cardiac or hepatic failure, because of rapidly and smoothly (Greenblatt et aI., 1976; Levy et the risk and unpredictability of accumulation; (3) in aI., 1977; Wagner, [974). This has the disadvantage patients who are refractory to the usual doses, to of requiring close supervision of infusion and carries clarify whether ineffectiveness is due to pharmacothe hazard of serious overdosage if an error is made. kinetic or to target organ factors; an~ (4) in assisting 3) The combination of an intravenous injection in the clinical" diagnosis of lignocaine toxicity in the with an intramuscular injection has been recom- presence of ambiguous signs and symptoms.
197
Clinical Pharmacokinetics of Lignocaine
A cknow ledgements The research studies included in this review were supported in part by the National Institutes of Health grant GM-16496. Dr Meister is supported by training grant GM-O 1791. We are grateful to Drs Leslie Benet and Richard D. Mamelok for critical review of the manuscript.
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Clinical Pharmacokinetics of lignocaine
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Author's address: Dr Neal L. Benowitz. 5 H 4, Clinical Pharmacology Unit, San Francisco General Hospital Medical Center, 1001 Potrero Avenue, San Francisco, California 94110 (USA).
