Clinical Pharmacokinetics 6: 25-60 (1981) 0312-5963/80/0100-0025/$09.00/0 © ADIS Press Australasia Pty Ltd. All rights reserved.

Clinical Pharmacokinetics of the Non-depolarising Muscle Relaxants

M .1. Ramzan, A A. Somogyi, J.S. Walker, CA. Shanks and E.J. Triggs

Department of Pharmacy, University of Sydney, Sydney; Medizinische-Universitatsklinik, Univ.er­ sity of Bonn, Bonn; Department of Anaesthetics, Royal Prince Alfred Hospital, Sydney; and Department of Pharmacy, University of Queensland, St. Lucia, Brisbane

Summary Muscle relaxants are oj great benefit to the anaesthetist as adjuncts to anaesthesia. These drugs are used to Jacilitate endotracheal intubation and to reduce muscle tone during surgery, and may also find application in assisting ventilator care in the intensive care situation. The pharmacological eJJect oj the relaxants may be readily assessed by the anaesthetist by means oj a variety oj techniques to quantify muscular activity in response to electrical stimula­ tion. A number ojJactors may modify the effects of the muscle relaxants including anaesthetic agents, hypothermia, patient age and disease status and a variety of drugs. The disposition kinetics of the muscle relaxants have been well c/laracterised although in­ Jormation on protein binding and placental transfer is somewhat scanty. A common charac­ teristic oj their pharmacokinetics is multicompartmental behaviour. Clearance oj the relaxants ranges Jrom total elimination by the kidneys (gallamine) to substantial hepatic clearance (fazadinium), and thus their clearance may be adversely affected by renal or hepatic disease. Dosage regimens have been designed using knowledge oj the disposition kinetics of the relaxants to provide Jor continuous adequate relaxation during prolonged surgical procedures. With the use of sophisticated pharmacokinetic and pharmacodynamic models good rela­ tionships have been demonstrated between plasma concentrations of the relaxants throughout the entire range of relaxant response.

Neuromuscular blocking agents (muscle relaxants) (competitive) agents or as depolarising (non-competi­ are a group of drugs which possess as their principal tive) agents. For the purposes of this review only the action the property of inhibiting the transmission of clinical pharmacokinetics of the competitive muscle nervous impulses by acetylcholine and blocking relaxants will be considered. transmission across the skeletal myoneural Curare is the prototype of the non-depolarising (neuromuscular) junction. On the basis of the prim­ group which also includes the drugs dimethyl-d­ ary mechanism by which these drugs produce their tubocurarine (metocurine), gallamine, alcuronium, effect, they are classified either as non-depolarising pancuronium and fazadinium (fig. 1). d-Tubocurarine Pharmacokinetics of Non-depolarising Muscle Relaxants 26

is a curare alkaloid obtained from the extracts of the Amazonian liane, Chondodendron tomentosum. It is complex in structure and at present is only obtainable Glossary of symbols from imported botanical material, the supply of CSF Cerebrospinal fluid which may be precarious. As a result, attempts have been made to prepare synthetic material with a view EMG Electromyography to obtaining simpler substances having true cura­ HPLC High pressure liquid chromatography riform properties. HVPE High voltage paper electrophoresis Gallamine triethiodide, one of the first synthetic Xc/Xo Fraction of dose in the central compartment curare drugs, was synthesised by Bovet et al. (J 947), and alcuronium (diallylnortoxiferine) was produced k" Infusion rate mmmercifliiy liS 1I rel'mit of an invesiigaiion into the Cp Plasma conc6ntiation relaxant properties of congeners of the alkaloid tox­ CPss Steady-state plasma concentration iferine I, first investigated by Foldes et aI. (J 96 I). Css Minimum steady-state concentration Later pancuronium, at present the most potent of the min relaxant drugs, was synthesised, and most recently Cssmax Maximum steady-state concentration fazadinium has been developed as a result of the Cs Serum concentration search for a short-acting relaxant of the non­ D Intravenous bolus dose depolarising type. Metocurine was initially syn­ Volume of central compartment thesised as an investigational drug, but has recently been proposed as an alternative to d-tubocurarine in Volume of distribution at steady-state clinical anaesthesia (Savarese et al., 1977). These 6 Volume of distribution compounds are the principal muscle relaxants used in Total systemic plasma clearance clinical anaesthetic practice today. Half-life of the IX phase

Half-life of the ~ phase I. Clinical Use ofMuscle Relaxants Half-life of the 'Y phase

Neuromuscular blocking agents find their prin­ cipal clinical application as adjuncts to anaesthesia. These drugs are used by the anaesthetist to prevent reflex laryngospasm during endotracheal intubation, to the anaesthetist. Early attempts to study the effects and to reduce muscle tone during surgery. They may of muscle relaxants in man were based on clinical ob­ also find application to facilitate ventilator care in the servations of signs of muscle weakness, such as in­ intensive care unit. Before the introduction of these ability to open the mouth or eyes, protrude the agents, muscle relaxation during surgical procedures tongue, swallow or maintain grip strength (Foldes et was produced mainly by deep anaesthesia using high aI., 1961). Measurement of respiratory variables such concentrations of general anaesthetic agents. This was as minute volume and vital capacity have also been often associated with undesirable physiological conse­ used. A more satisfactory method of monitoring quences; for example, depression of myocardial con­ neuromuscular function is stimulation of an access­ tractility. ible peripheral motor nerve and observation or Clinical Assessment of Neuromuscular Blockade: measurement of the response of the skeletal muscle Monitoring of neuromuscular transmission in a supplied by this nerve. Supramaximal electrical patient during surgery provides valuable information stimulation, usually of the ulnar nerve, is commonly Pharmacokinetics of Non-depolarising Muscle Relaxants 27

used and the resulting activation of the muscle fibres rates of stimulation at 50 or more Hz (tetanus), post­ (e.g. thumb adduction) can be measured either tetanic single repeated stimuli (post-tetanic potentia­ mechanically (twitch tension) or electrically (evoked tion), or train-of-four stimulation at low frequencies electromyography, EMG). The pattern of evoked (e.g. 2 Hz for 2 seconds). muscle responses to changes in the frequency of The single twitch has been found useful as an ap­ stimulation may be used to identify and quantify proach to the comparative study of the muscle relax­ neuromuscular block. The evoked response can be ants. A control response is obtained and the percen­ measured with single repeated supramaximal nerve tage change from control establishes the onset of ac­ stimuli at rates of 0.1 to 2 Hz (single twitch), tetanic tion and potency of the drug. Duration of action of

H,C\4 CH, ~OJ3 >--?-CH 2 '1_'\ OH '1_,\OCH,

Oo~ N+ CH,O OH ~CH, / \ H,C H Tubocurarine Gallamine

CII:CH,

Pancuronium

I~ 0'\ -N+ H,C ;?' N_N:N_N CH, s:~~ V I'" ~ Fazadinium (AH6 8165)

Fig. 1. Chemical structure of 5 competitive neuromuscular blocking agents of clinical interest. d-Tubocurarine possesses one quarternary and one tertiary nitrogen group. but the tertiary nitrogen is presumably protonated at body pH. as indicated in the for­ mula above. The structure of dimethyl-d-tubocurarine (metocurine) is not included; it is similar to that of d-tubocurarine except that both hydroxyl groups and the tertiary nitrogen group are methylated. Pharmacokinetics of Non-depolarising Muscle Relaxants 28

the relaxant is indicated by the time required for 2. Factors Affecting Neuromuscular Blockade recovery of the response to control level (fig. 2). The single twitch, although useful, can detect only A variety of factors, including other drugs used in relatively high degrees of curarisation and as such the practice of anaesthesia, may modify the normal suffers from disadvantages in a clinical situation. neuromuscular blocking effects of the muscle relax­ Gissen and Katz (J 969) have found that the failure ants (table I). Only those factors which are relevant to of sustained response to tetanic stimulation at various the clinical pharmacokinetics of the muscle relaxants frequencies is a more sensitive index of neuromuscu­ will be discussed here. lar blockade than the single twitch. Thus, measure­ ment of tetanic response provides a mechanism for 2.1 Neuromuscular Blockade Reversal Agents demonstrating when a patient has more than barely recovered from neuromuscuiar biock. in post-tetanic Termination or reversal of a non-depolarising potentiation, the twitch responses immediately neuromuscular blockade is accomplished by the an­ following tetanus are larger than those preceding aesthetist with the use of drugs which inhibit the it. Epstein and Epstein (J 973) consider that the exist­ enzyme acetylcholinesterase. Clinically useful agents ence of the potentiation establishes the diagno­ of this type, neostigmine and pyridostigmine, act sis of residual depression of neuromuscular trans­ principally by increasing the concentration of acetyl­ mission. choline at the postjunctional membrane, thus allow­ Recently the use of train-of-four stimulation has ing acetylcholine to compete more effectively with the been found to provide a more sensitive method for the muscle relaxants for the receptor. To prevent un­ quantitative measurement of neuromuscular blockade desirable muscarinic effects atropine is administered (Ali et aI., 1970; 197Ia,b). Using this procedure the concomitantly with the reversal agent. ratio of the amplitude of the fourth response in the An additional surprising and somewhat puzzling train to the amplitude of the first is used to assess the effect of the anticholinesterase agents has been degree of block. The train-of-four ratio correlates well reported (Cohen et aI., 1957). Following intravenous with simple clinical tests commonly employed for administration of edrophonium or neostigmine a assessment of recovery from neuromuscular decrease in plasma concentration of d-tubocurarine blockade. was noted. Kalow (J 959) has suggested that this

0------< 5min

. 'I f

t t 2 3 4•

Fig. 2. A typical twitch response in a normal surgical patient. At time 1, a stable 100% twitch height was recorded, after which (time 2) gallamine triethiodide 2mg/kg (140mg) was administered as a bolus dose. This produced incomplete but marked neuromuscular paralysis. Following the peak action, the twitch height increased gradually until reversal with neostigmine and atro­ pine (time 4) when almost complete recovery occurred. Note the change in chart speed at time 3. Pharmacokinetics of Non-depolarising Muscle Relaxants 29

Table I. Factors affecting non-depolarising neuromuscular blockade

Factor / Agent Effect Reference

Hypothermia Enhancement of block. Decreased clearance and renal Ham et al. (1978) and biliary elimination of d-tubocurarine. Age Sensitivity to relaxants reported to vary from Stead (1955); Bush and Stead decreased to similar to increased in the neonate. (1962); Lim et al. (1964); Churchill-Davidson and Wise (1964) Sensitivity to relaxants reported to vary from Durrans (1952); Dundee (1954); decreased to similar to increased in geriatrics. Chmielewski et al. (1978); Gray (1947) Plasma clearance of pancuronium reduced with McLeod et al. (1979) advancing age. Plasma clearance of pancuronium unaltered Somogyi (1979) with advancing age. Acid-base balance Respiratory acidosis enhances d-tubocurarine block, Baraka (1964); Bridenbaugh but decreases gallamine block. Respiratory alkalosis et al. (1966) decreases d-tubocurarine block. Electrolyte status Decreased K', Ca" enhances block. Miller (1975) Blood flow to muscle Reduced flow may delay onset of block and enhance Goat et al. (1976); Churchill­ block once established. Davidson (1959) Neuromuscular disease Increased sensitivity to muscle relaxants. Foldes (1957) (e.g. myasthenia gravis) Tetanus Possibility of prolonged half-life and block Duvaldestin et al. (1979) (?) with pancuronium. Renal disease May produce prolongation of block, dependent on the See section 5 relaxant employed. Hepatic disease May cause prolongation or 'resistance' to block See section 5 dependent on the relaxant employed. Cardiovascular disease Prolongation of block due to elevated relaxant Dal Santo (1964) (e.g. haemorrhagic shock) plasma concentrations. Obstetrics Increased clearance, reduced half-life and decreased Duvaldestin et al. (1978c) (e.g. Caesarean section) block (?) with pancuronium Anticholinesterase drugs Reversal of block. Decreased plasma concentration Cohen et al. (1957) of relaxant (?). Other non-depolarising Additive or synergistic (?) block. Ghoneim et al. (1972); relaxants Schuh (1977) Depolarising relaxants May enhance block. Katz (1971a,b); Walts and Dillon (1969) Antibiotics Enhance block (in particular aminoglycosides, Fogdall and Miller (1974); tetracyclines, polymyxins) and may cause Pittinger and Adamson (1972) difficulties in reversal of blockade. Diuretics Frusemide enhances d-tubocurarine block. Miller et al. (1976) Inhalational Enhancement of block dependent on type and Miller et al. (1972); anaesthetics concentration of anaesthetic agent and relaxant. Stanski et al. (1979) Immunosuppressive Azathioprine decreases block. Vetten (1973); Dretchen agents et al. (1976) Pharmacokinetics of Non-depolarising Muscle Relaxants 30

effect may be a separate function of these anti­ renal elimination of the relaxants during hypothermia cholinesterase agents. However, experiments carried may occur. Later it was noted that the serum out in greyhound dogs in our laboratory failed to clearance and elimination (renal and biliary) of d­ show any change in the plasma concentrations of tubocurarine in the cat was decreased at 28°e as com­ gallamine when neostigmine and atropine were ad­ pared with that at 34°C and 39°e (Ham et aI., 1978). ministered at two dosage levels (unpublished observa­ These workers have stated that if their results can be tions). extrapolated to man 'then the extent of clinical hy­ Katz (1971) noted that the degree of neuromuscu­ pothermia will determine the resultant effect of lar blockade at the time when the reversal agent is ad­ neuromuscular blockade'. ministered determines the speed and extent of an­ Hypothermia does not alter the ability of neo­ tagonist action. The greater the degree of recovery stigmine (or pyridostigmine) to antagonise d­ from the block prior to injection of neostigmine, the tubocurarine block. However, if a patient is hypother .. shorter the recovery time to control twitch height. mic, increasing the body temperature may lessen the Thus, any factor acting to prolong the neuromuscular block making it easier to antagonise (Miller, 1975). block must be taken into account with respect to ade­ quate reversal. For example, if the rate of relaxant elimination is decreased, as with renal failure, the 2.3 Age relaxant concentration at the time of attempted rever­ sal may be high enough for paralysis to reappear after Few studies have been carried out on the disposi­ the effect of the reversal agent has dissipated (Miller tion kinetics of the muscle relaxants in patients of and Cullen, 1976), which suggests that renal excre­ varying age. Mcleod et al. (1979) have noted a sig­ tion is more important to .the termination of relaxant nificant relationship between ageing and pharma­ than reversal agent action (Miller and Roderick, cokinetics of pancuronium, as assessed by a 1977). progressive reduction in pancuronium clearance with The actual agent (relaxant) utilised to produce increasing patient age. Decreased elimination with neuromuscular block seems also to playa part in the age of pancuronium via the renal or hepatic routes reversal. The blockade from gallamine appears to re­ may be responsible for these changes. McLeod and quire more neostigmine and takes longer for antagon­ his colleagues suggested that as patients age the rate ism as compared with d-tubocurarine or pan­ of decline of muscle relaxant plasma concentration curonium blockade (Miller et al., 1972; Monk, 1972). will decrease, so that an increase in recovery time might be expected. A re-evaluation of data from this laboratory did show a poor correlation (r2 = 0.006) 2.2 Hypothermia between pancuronium clearance and age for 38 patients aged between 15 and 77 years (Somogyi, Recent studies by several investigators (Miller and 1980). Chmielewski et aI. (1978) failed to detect any Roderick, 1977; Miller et al; 1975) have demon­ difference in recovery time between groups of elderly strated that hypothermia prolongs a non-depolarising and young patients administered d-tubocurarine. block. These workers were able to show that less d­ tubocurarine or pancuronium was necessary when administered by continuous infusion to maintain 2.4 Inhalation Anaesthetics 90 % depression of twitch tension at 28°C compared with either 37° or 41°C in the cat. It was suggested Inhalation anaesthetic agents augment the that as well as influencing the release of acetylcholine neuromuscular blocking properties of the non­ at the neuromuscular junction, decreased biliary and depolarising muscle relaxants, the degree of potentia- Pharmacokinetics of Non-depolarising Muscle Relaxants 31

tion being dependent on the particular relaxant and One of the most significant analytical advances the type and concentration of anaesthetic agent used. was made by Cohen (I963a) who developed a The requirement for a relaxant is least during anaes­ fluorimetric method for the analysis of d­ thesia with halothane, followed by diethyl ether, tubocurarine. This method involved complexation enflurane and isoflurane. The mechanism of this an­ of the drug with a fluorescein dye (rose bengal), aesthetic potentiation of the effects of the muscle subsequent extraction of the complex into a relaxants is the subject of some controversy, but it is phenolchloroform phase and detection by spec­ believed that the anaesthetic seems to modify some trophotofluorimetry. This method proved element in the depolarisation process (Waud et al., satisfactory for the measurement of as little as 1973). 'Recently, using a model incorporating both 0.02J.1g/ml of d-tubocurarine in aqueous solutions. pharmacokinetic and pharmacodynamic concepts (see Cohen (1963b), however, found that extraction of d­ section 7), it has been shown that the increased tubocurarine had to be achieved as a preliminary step response to d-tubocurarine that occurs with if this general method was to be used for quantitation halothane anaesthesia is due to an increase in muscle of the drug in biological fluids and tissues. Further sensitivity (Stanski et al., 1979). progress was made by Kersten et al. (1973) who used the above rose bengal procedure to develop a method for the determination of pancuronium in plasma, bile 2.5 Diuretics and urine. Moreover, this method did not require prior extraction of the relaxant from the fluid sample. A recent publication has suggested that frusemide Recently several workers have suggested modifica­ may augment d-tubocurarine-induced neuromuscular tions or simplifications of this original procedure for blockade (Miller et al., 1976). The authors speculate pancuronium (Watson and McLeod, 1977; Wingard that the potentiation of block by the diuretic may be et aI., 1979). due to redistribution of d-tubocura~ine from inactive Based on this original method for pancuronium, a (tissue) to active sites and/or a depressant effect of method for the direct determination of d-tubocurarine the diuretic on the neuromuscular junction. This in plasma has now been developed in this laboratory phenomenon would be of particular significance in using the sulphonated fluorescent dye Xylene Red B patients undergoing renal transplantation surgery, as (Ramzan et al., I 980a). Duvaldestin et al. (I 977) have diuretics are often used to induce diuresis in the also adapted the rose bengal method of Kersten et al. newly transplanted kidney. Such patients are already (973) to determine gallamine concentrations in at risk of prolonged neuromuscular blockade because plasma, as have Agoston et al. (978). The latter of retarded relaxant elimination and/ or interaction workers made use of the dye eosin as the counter with antibiotics (see table I). anion for the determination of gallamine in serum, while the method for determination of the relaxant in bile and urine was identical to that described by 3. Analytical Techniques Kersten et al. (973). Most recently, Ramzan et al. o980b) have also used a modified rose bengal tech­ Lack of a sensitive chemical assay for the analysis nique to measure gallamine in urine and plasma, and of d-tubocurarine and other muscle relaxants in a similar procedure has been developed in this biological media has seriously hampered the study of laboratory for the determination of alcuronium in the phYSiological distribution and fate of these drugs. plasma (Walker et aI., 1980). However, during the last 2 decades several important The original rose bengal ion-complexing method articles have been published with respect to such of Cohen (I963a,b) has undergone further develop­ methods of analysis. ment by replacing the dye with P2s-labelled rose Pharmacokinetics of Non-depolarising Muscle Relaxants 32

bengal, such that the relaxant-dye complex can be patients surgery represents an invasion of the organ­ determined by scintillation counting (radiometry). ism, and haemodynamic and physiological changes This method has been successfully used to measure occur during surgery (Kehlet and Binder, 1973) fazadinium concentrations in plasma (D'Souza et al., which may alter both the renal (Miller et aI., 1979) 1979). and metabolic (Pessayre et aI., 1978) elimination of One point of contention is that all the assay pro­ drugs. Thus, pharmacokinetic parameters and their cedures described above, using dye-relaxant complex­ interindividual variability for the muscle relaxants ation methods, do not differentiate between the drugs should be considered in the light of the above-men­ and their possible metabolites, but measure both tioned factors. unless chromatographic separation is achieved prior to complex formation. Further, all studies conducted to date have measure,tj only totlli drug; i.e., boih ihe 4. i Absorplion active free drug and that bound to plasma proteins. A radioimmunoassay for the determination of d­ The muscle relaxants having 1 to 3 quaternary tubocurarine has now been available for several years ammonium groups (fig. 1) are ionised and positively (Horowitz and Spector, 1973). The advantage of this charged, irrespective of the pH. They have negligible assay over previous methods of analysis for d­ peroral absorption and must be administered intra­ tubocurarine appears to lie in its sensitivity and in the venously in clinical practice. fact that no extraction from biological material is re­ quired. Recently an initial report has appeared on a radioimmunoassay for metocurine (Matteo and 4.2 Entry into Red Blood Cells Khambatta, 1979), but as yet such radioim­ munoassays do not exist for the other relaxants. The red blood cell presents a barrier to the dis­ A most promising analytical breakthrough has tribution of the relaxants, as do other lipophilic been the use of high pressure liquid chromatography membranes. It appears from the early work of (HPLC) for the determination of muscle relaxants. A Mahfouz (I949), using bioassay techniques, that no preliminary report has appeared on the determination d-tubocurarine enters the red blood celL However, of d-tubocurarine (de Bros and Gissen, 1979). In the evidence has also been presented to suggest that both authors' opinion, as this technique is developed gallamine and alcuronium are associated with red further to incorporate all the muscle relaxants it will blood cells following equilibration with human whole provide the most valuable information on the disposi­ blood (Feldman et al., 1969; Waser and Luthi, 1966). tion of these drugs, since for the first time a tool exists However, from consideration of all of these results, it for the simultaneous determination of the intact is apparent that during the normal period of phar­ relaxant and its metabolites. macological action of these drugs entry into red blood cells is relatively insignificant.

4. Pharmacokinetics in 'Normal' Patients 4.3 Arterial-Venous Distribution Muscle relaxants are administered to patients un­ dergoing general anaesthesia and not usually to nor­ Cohen et al. (1957) examined distribution ratios mal volunteers. Most authors have, however, between arterial and venous plasma in humans classified patients undergoing general anaesthesia for following intravenous injection of d-tubocurarine. elective surgery and with apparently normal kidney Their results showed that at early time points follow­ and liver function as 'normal patients'. But in all ing injection the arterial concentrations were substan- Pharmacokinetics of Non-depolarising Muscle Relaxants 33

Table II. Extent of plasma protein binding of relaxant drugs (mean ± SE)

Concentration Protein Method Protein Reference range binding (%)'

d-Tubocurarine O.2-2.0Ilg/ml 51 Equilibrium dialysis Heparinised normal plasma Meijer et al. (1979)

4.0-6.0Ilg/ml 50.6 (3.4)b Equilibrium dialysis Normal plasma Clissold et al. (1975) 4S.4 (1.3)b Uraemic plasma

5.0Ilg/ml 23.S (0.7)b Equilibrium dialysis 4% albumin Ghoneim and Pandya 15.S (0.3)b 2 % y-globulin (1975)

5.0Ilg/ml 44.7 (7.7l" Equilibrium dialysis Normal plasma Ghoneim et al. (1973) 36.S (5.3l" Plasma-hepatic disease 41.2 (5.4)a Plasma-renal disease

50.0Ilg/ml 39.9 (3.1)a Normal plasma 37.1 (S.5)a Plasma-hepatic disease 42.4 (9.3)a Plasma-renal disease

50.0Ilg/ml 31.3-3S.S Gel filtration Normal plasma

20.0Ilg/ml 33 Equilibrium dialysis Normal plasma Cohen et al. (1967)

20.0flg/ml 60-75 Electrophoresis Albumin Aladjemoff et al. (195S)

Gallamine Not specified 40 Electrophoresis Albumin Skivington (1972) 70 ~-globulin 30 y-globulin

Alcuronium 0.1-2.0Ilg/ml 40 Equilibrium dialysis Normal plasma Raaflaub a nd Frey (1972)

Pancuronium 0.12Ilmol/L 722 Ultrafiltration Albumin Thompson (1976) SO.53 y-globulin

0.03-0.3Ilg/ml 20 Equilibrium dialysis Normal serum Waser (1973) IOllg/ml 6

Metocurine 0.05-0.5Ilg/ml 35 Equilibrium dialysis Heparinised normal plasma Meijer et al. (1979)

0.07-9.7 x 1O- 6M 31.1-42.1 Equilibrium dialysis Normal plasma Olsen et al. (1975)

Not specified 7.4 Electrophoresis Albumin Skivington (1972) 3.S a-globulin 37.9 ~-globulin 50.9 y-globulin Not specified 70 Ultrafiltration Normal plasma Dal Santo (1964)

(Continued overleaf) Pharmacokinetics of Non-depolarising Muscle Relaxants 34

Table II. (contd)

Concentration Protein Method Protein Reference range binding (%)'

Fazadinium Not specified 17 Equilibrium dialysis Normal plasma Tyers (1975)

Figures in parentheses indicate: a Standard deviation b Standard error of the mean. 2 At a pancuronium concentration of 1.07mg/L. 3 At a pancuronium concAntr"tion of 1,51mg/L.

tially higher than the corresponding venous con­ 1975). Controversy still continues about the extent of centrations; equilibration was complete within 20 pancuronium protein binding. Waser (1973) has minutes. Little other work has been conducted in this reported a value of 20 % bound, while Thompson's area, other than a study with gallamine where no sig­ (1976) results suggest a much greater degree of bind­ nificant arteriovenous differences in plasma con­ ing of pancuronium to y-globulin and albumin oc­ centration were noted over the first 60 minutes after curs. Thus, Thompson postulated that at clinical drug administration, in 5 patients receiving gallamine plasma levels of 1 to 2~gl ml, less than 13 % of a dose 4mg/kg by bolus injection (Ramzan et al., 1980c). of pancuronium would be unbound and active. How­ ever, these plasma concentrations reported by 4.4 Binding to Plasma Proteins Thompson are very high, as clinical levels of pan­ curonium are usually below O.5Ilg/ml (Somogyi et It has been known for some time that substances al., 1976); hence, it is difficult to extrapolate with quarternary ammonium groups can be bound by Thompson's findings to the lower concentrations en­ plasma proteins. As expected, evidence of the binding countered in clinical apaesthetic practice. Protein of d-tubocurarine and other relaxants by such pro­ binding appears to be much less important in the case teins has been reported (table 11). The percentage of of fazadinium. Only 10% was bound by rat plasma relaxant which is plasma protein-bound varies with and 17 % by human plasma (Tyers, 1975). Protein the particular agent employed. The binding of d­ binding data for alcuronium is scarce but the percen­ tubocurarine has been studied most extensively, and tage bound to total protein has been reported to be 30 to 50 % of the drug over a concentration range of 40% (Raaflaub and Frey, 1972). 0.2 to 500~g/ml has been reported to be bound to The importance to the anaesthetist of protein bind­ proteins, mostly albumin and y-globulin (see ing is that if this should be abnormal it may account table 11). Similar values have been noted for gallamine for some of the variations in response encountered binding (30 to 70 %) [Skivington, 1972]. The greatest with muscle relaxants. Possible changes in plasma percentage binding appears to occur with metocurine proteins associated with various disease states may (70%) [Dal Santo, 1964]. However, lower (30 to influence the binding properties of these drugs, and 40 %) figures for metocurine have been noted by the significance of such changes will be presented in other workers (Meijer et al., 1979; Olsen et al., later sections of this review. Pharmacokinetics of Non-depolarising Muscle Relaxants 35

4.5 Placental Transfer of paralysis, and concluded that the placenta formed a barrier to transfer of the drug. However, subsequent Following the report of Whitacre and Fisher workers have shown that the human placenta is an (1945) that d-tubocurarine was a useful adjunct to an­ incomplete barrier to the relaxants. Placental transfer aesthesia for Caesarean section, muscle relaxants of d-tubocurarine, gallamine, pancuronium and have become generally accepted in obstetric practice. fazadinium has been demonstrated, and further Early workers had noted that the infants of mothers details are presented in table III. No clinical effect of given the relaxant during labour showed no evidence the relaxants on the fetus has been observed.

Table JII. Placental transfer of muscle relaxants

Oose No. of Maternal Fetal cord Injection Cord/mater- Reference patients plasma conc. plasma conc. to delivery nal ratio (% 1 (Ilg/mll' (Ilg/mll' time (min.l

d- Tubocurarine 4 1.1-3.2 NO-LO Elert and Cohen (19621

15-20mg 6 0.4-2.5 NO-0.7 6-17 Crawford and Gardiner (19561 18-42mg 124 14.1-23.3 NO 6-19 Cohen et al. (1953)

Gallamine 80mg Schwarz (19581 80mg 13 1.0-20.0 1.0-3.0 3-19 Crawford and Gardiner (1956)

Alcuronium 10-15mg 19 0.3- > 3.0 NO-O.4 3-25 Thomas et al. (1969)

Pancuronium 0.06-0.10mg/kg 33 0.19-0.55 0.04-0.14 3-36 19-43 Ouvaldestin et al. (1978) 4mg 10 0.2-0.46 0.04-0.10 3-20 10-40 Booth et al. (1977) 0.075-0.12mg/kg 19 0.2-1.5 ND-0.l0 3-40 Heaney (1974) 0.07-0.lOmg/kg 20 5-20 Speirs and Sim (1972)

Metocurine 0.OO5mg/kg 18 1.74-4.42' 0.14-0.24' 2-10 4-12 Kivalo and Saarikoski (1976)

Fazadinium 0.5-0.9mg/kg 10 ND-2.1 ND-0.53 10-21 Blogg et al. (1975)

NO = not detectable. 2 Significant increase in iodine concentration in fetal blood. 3 Neonate excreted 0 to 4 % of maternal dose. 4 Determined as nCi/ml ,.c. Pharmacokinetics of Non-depolarising Muscle Relaxants 36

4.6 Passage into Cerebrospinal Fluid (CSF) tubular secretion. However, the protein binding data of Thompson (J 976) implies that the renal clearance Recently Matteo et al. (J 977), using a radioim­ of free (unbound) pancuronium is far in excess of the munoassay for d-tubocurarine, found that the relax­ normal glomerular filtration rate, implying active ant could be detected in human CSF soon after intra­ tubular secretion for this relaxant. These conflicting venous injection. These workers concluded that the results suggest the need for a controlled study of rapid appearance of d-tubocurarine in lumbar spinal relaxant excretion, involving measurement of protein fluid is probably the result of diffusion of the relaxant binding as well as serial urinary excretion data. from blood vessels supplying the spinal cord into the For d-tubocurarine, the kidney represents the CSF, but noted that a very high blood-CSF gradient is main route of elimination from the body. In the intact necessary for the diffusion to occur. These results dog 75 % of the dose is excreted unchanged in the agree \vith those of Devasankaiaiah et at. (1973) and fiist 24 hours (Cohen et al., 1967). However. a secon­ Haranath et al. (J 973) who demonstrated the passage dary avenue of excretion exists from the body via the of d-tubocurarine and gallamine, respectively, into liver and the biliary system. In the dog 12 % of a dose the CSF of both dogs and humans. Concentrations of is excreted in the bile (Cohen et al., 1967). Evidence muscle relaxants in the CSF are, however, small and was also presented to suggest that about I % of this are unlikely to produce any adverse effect in man. amount was excreted as a N-dealkylated metabolite. However, Meijer and Weitering (J 970), studying the biliary excretion of d-tubocurarine in perfused rat 4.7 Elimination (Excretion and Metabolism) liver, failed to detect any such metabolites. Thus, whether or not this alternate mechanism for elimina­ The clinically useful muscle relaxants may be tion of d-tubocurarine is of major importance in divided into two broad groups from the point of view humans remains to be demonstrated. oftheir excretion and metabolic transformation in the Biliary excretion of alcuronium accounts for about body. The first of these groups includes gallamine and 10% of an injected dose in the cat (Waser and Luthi, alcuronium which, according to presently available 1966), and in man some 15 to 20 % is eliminated by evidence, do not undergo metabolic changes in the this route with the remainder excreted by the kidneys body and are excreted unchanged, primarily in the (Raaflaub and Frey, 1972). urine. Members of the second group (d-tubocurarine, Studies by Feldman et al. (1969) in the dog indi­ metocurine, pancuronium and fazadinium) undergo cate that minimal amounts of gallamine are excreted partial to substantial metabolic destruction in the in the bile even in the presence of bilateral renal ped­ body, albeit at a slow rate, with a variable portion of icle ligation. This has been confirmed in man by the injected dose being excreted in the urine (see Agoston et al. (I978) who detected negligible table IV). amounts (0.1 to 0.4 % of the dose) of gallamine in The mechanism of the renal excretion of muscle bile collected for 12 hours following administration relaxants appears to be predominantly due to filtra­ to 4 patients. tion by the renal glomerulus, since the permanently The excretion of d-tubocurarine and gallamine in charged drugs would not be expected to undergo reab­ humans is similar to that predicted from animals. In sorption across the renal tubular epithelium. Cohen the past, however, such knowledge for the most part (J 966) found that the renal clearance of H3-d­ has been obtained from clinical observation of cases tubocurarine in the dog was essentially the same as of prolonged neuromuscular blockade in renal that for urea, and concluded that the elimination of disease, and not from actual measurement of drug the relaxant by the kidney could be explained in terms levels (Churchill-Davidson et al., 1967). Recently, of glomerular filtration alone without evoking renal with the advent of sensitive analytical methods, these Pharmacokinetics of Non-depolarising Muscle Relaxants 37

earlier observations have been confirmed. Miller et ai. curonium. Of these metabolites, which total about (1977) found that in 3 patients with normal renal 30 % of the dose, 3-0H pancuronium is the most pre­ function the urinary excretion of d-tubocurarine dominant. These metabolites are pharmacologically varied between a mean of 16.8 % and 38.8 % of the active. Miller et al. (1978) have recently demonstrated injected dose for a 4- and 24-hour urine sample, in man that compared with the parent drug, the 3-0H respectively. These values correspond well with those metabolite was half as potent, while the other 2 meta­ reported by Matteo et al. (1975), and are also in broad bolites had 2 % of the potency of pancuronium. The agreement with those predicted using the phar­ authors were unable to demonstrate any significant macokinetic models of Gibaldi et al. (I 972a) and difference in the pharmacokinetics of pancuronium Wingard and Cook (1976). The excretory rate of and its 3 metabolites, although the elimination half­ gallamine in humans has also been recently reported. life tended to be longer and clearance less with pan­ Agoston et al. (1978) observed in 15 patients that 53 curonium. to 95 % of the dose was excreted in the urine as Duvaldestin et al. (1978a) reported that 24 hours unchanged drug in 24 to 30 hours. after dosing a total of 46 % of the dose of pan­ Pancuronium elimination incorporates renal, bili­ curonium is recovered in the urine as intact drug plus ary and metabolic clearance. Agoston et al. (I973) metabolites. Possibilities which may exist to account first reported that approximately 30 % of the dose for the fate of the remaining portion of the dose in­ was recovered in the urine as intact drug during the clude that of delayed excretion in the urine (implying 30 hours after drug administration. Somewhat higher a much longer terminal elimination half-life than that percentages of the dose excreted in the urine have found in plasma, due perhaps to extensive liver bind­ been noted by Buzello (1 975) who reported a figure of ing as suggested by Agoston et aI., 1977), or the ex­ 40 % in 12 hours, while Somogyi et ai. (I 977a) found cretion of unknown metabolites in urine or bile, or 41 % urinary excretion in 24 hours. Agoston et ai. finally elimination of the drug via intestinal secretion. (1973) also reported that considerable fluctuations in This latter route of elimination has been reported to the excretion rate occurred for pancuronium which occur for another quaternary ammonium compound were found not to correlate with urine flow rate. Vree (Hallen et al., 1979). et ai. (1978) have recently reported that when renal Virtually no data have been available on the clearance of pancuronium is plotted against urine elimination of metocurine in man until very recently. flow rate a poor correlation is obtained in patients In earlier studies in the dog (Dal Santo, 1964) and rat with normal kidney function, but that the strength of (Hughes et al., 1973; Meijer et al., 1976) no metabol­ the correlation is increased in patients with impaired ites of the drug were detected and urinary excretion renal function. As a result, they concluded that the seemed to be the major elimination pathway. In view renal excretion of pancuronium was not a simple of the current interest in the USA in metocurine, linear process. Nevertheless, the renal clearance Meijer et al. (1979) have recently compared its phar­ (time-averaged) of approximately 40ml/minute was macokinetics in man to that of d-tubocurarine, with consistent with glomerular filtration alone. special reference to possible biotransformation and The biliary elimination of pancuronium accounts hepatic elimination of these compounds. Recovery of for about 6 % of the dose as intact drug (Agoston et the curares from urine, 48 hours after injection, al., 1973; Buzello, 1975). Metabolism, presumably varied widely from 36 to 95% for d-tubocurarine hepatic, has also been shown to occur. 3 metabolites and 46 to 58 % for metocurine (table IV). Biliary ex­ have been recovered in the urine and bile of patients. cretion was also higher in the case of d-tubocurarine These metabolites are formed by hydrolysis of the compared with metocurine. No metabolites of d­ acetyl group at the 3 and 14 positions, to yield either tubocurarine or metocurine were detected in bile or mono-(3-0H or 17-0H) or dihydroxy O,17-0H) pan- urine. Combining their urinary and biliary excretion

~ Pancuronium (contd) Ol 3 7 6 Cholecystectomy 37.3 (8.9)2,3 Agoston et al. (1973) Ol 8 6 6 Pelvic operations 43.5 (4.3)2,3 Agoston et al. (1973) Co ::J ~ 10 Normals 3 Lubke and Bihler(1971) n' (J) So Metocurine z o 5 0.05 Cholecystectomy 52.2 (2.2)2 2.1 (0.4)2 Meijer et al. (1979) ::J a. CD Fazadinium "8 0; 10 1.5 Normals 50 (3)2,3 <3 Duvaldestin et al. (1978b) ::J. !Il. ::J 7 0.5-0.75 Normals 70-803 3 Blogg et al. (1973) co s: c: 1Il ~ ::0 m- Ol x '"::J Iii

a = mg 1 Metabolites in bile were not detected in any studies. 2 Figure in parentheses is standard error of measurement. 3 Assay done was for total metabolites plus unchanged drug. w CD Pharmacokinetics of Non-depolarising Muscle Relaxants 40

data still left some 30 to 40 % of the dose of these varied quite widely, and if there is any regularity in relaxants unaccounted for. These workers, therefore, the concentration-time curves it is not apparent in concluded that apart from urinary and biliary excre­ their levels but in their shapes. All curves show an in­ tion, alternate excretory routes such as salivary itial rapid drop in plasmal serum levels which is then and/ or intestinal excretion must be involved in d­ followed by a gradual decline. The haIf-life of the in­ tubocurarine and metocurine elimination. itial rapid phase varies between 2 and 13 minutes Animal studies conducted both in vivo and in with a mean of about 6 minutes (e.g. KaIow, 1959). vitro using 3H- or 14C-fazadinium have shown that The slower phase has been assumed to proceed with a fazadinium is extensively metabolised to inactive mean half-life of 45 minutes (Cohen et ai., 1965; metabolites (Blogg et aI., 1973; Bolger et ai., 1972). KaIow, 1959). KaIow (J 953) reported similar results In the rat, fazadinium was extensively metabolised, in studies of the urinary excretion of d-tubocurarine less than 5 96 being excreted as unchanged drug in the in man. In addition. ht: abu pusiuiait:d ihe existence urine. The principal route for excretion of radioac­ of a third elimination phase consisting of destruction tivity was bile. High voltage paper electrophoresis of the drug and having a half-life of 3.5 hours. (HVPE) showed that the biliary metabolite was Horowitz and Spector (1973), using a radioim­ neutral, while polarography of bile revealed that the munoassay procedure for d-tubocurarine, were able -N-N = N-N- linkage of fazadinium was absent. In to sample for 24 hours postadministration and found the rabbit less than 5 % of a dose was excreted a biphasic decay in the plasma concentration-time unchanged in the urine, together with an unidentified curve. Their work, however, indicates that the rapid metabolite. In the dog some 60 % of the radioactivity fall-off is only seen in the first 15 minutes post­ as the parent drug was excreted in bile and urine dur­ administration, and that the slower decline proceeds ing 0 to 6 hours. with a half-life of from I to 2 hours. Studies with fazadinium in man (Blogg et aI., The disposition kinetics of d-tubocurarine have 1973) have shown that 70 to 80% of radioactivity is been described by mathematical models. Combining excreted in 0.4 hours in the urine. HVPE showed that plasma concentrations of the drug obtained from 4 only fazadinium was present in O.4-hour urine; how­ patients (Cohen et aI., 1965), and urinary excretion ever, in later samples a neutrai metaboiite was data from a further 4 unanaesthetised human volun­ detected. teers (Kalow, 1953), Gibaldi et aI. (I 972a) proposed a Details of the elimination characteristics of all the 3-compartment model to describe the pharmaco­ muscle relaxants are summarised in table IV. kinetics of d-tubocurarine in man. Use of this model results in a triexponential equation (1) which may be used to predict the fraction of the dose in the central 4.8 Disposition Kinetics of Muscle Relaxants compartment (Xc/Xa) at any time (t) following a rapid intravenous injection: 4.8.1 d-Tubocurarine Xc/Xo = 0.62e-0.1t + 0.28e-o.01St + Plasma levels of d-tubocurarine in man following 0.1 Oe - O.003t (Eq. I) intravenous injection have been determined in numerous studies and have been reviewed by, for ex­ Assuming that the site of action of d-tubocurarine ample, Foldes (J 957), Kalow (J 959) and Wingard was located in the central compartment, Gibaldi et aI. and Cook (1977). Apart from the studies of Cohen et (1972a) obtained an excellent correlation between pre­ al. (1965), Horowitz and Spector (1973), Miller et aI. dicted durations of neuromuscular blockade in man (J 977) and Ramzan et al. (J 978), the plasma sam­ and those found experimentally by Waits and Dillon pling time has been limited to just 60 minutes post­ (J 968). Recently, Wingard and Cook (I976) have drug administration. The results of each study have averaged the serum concentrations of d-tubocurarine Pharmacokinetics of Non-depolarising Muscle Relaxants 41

found by Horowitz and Spector (1973) and found that ment [CP(t)] could be predicted at any time (t) by use the concentration-time relationship could best be of the following equation: described by equation 2: Cp(t) = 2.92e - 0.0838t + 0.642e - 0.0059t (Eq. 3) Cit) '"' 7.17e-0.74t + 1.66e-0.0704t + The chosen 2-compartment open model was also 0.808e - 0.00456t (Eq. 2) able to characterise adequately the plasma concentra­ These workers also examined the relationship be­ tion-time data obtained from patients receiving mult­ tween the serum relaxant concentration and intensity iple doses of d-tubocurarine, with the phar­ of effect, in this case from the data of Matteo et al. macokinetic parameters from both groups being in (1974), and obtained good agreement between the good agreement. simulated and experimental time course of recovery Subsequent studies carried out in our laboratory from neuromuscular blockade with 5 different thera­ using 2 different dosage regimens for d-tubocurarine peutic doses. Miller et al. (1977) compared the phar­ (bolus plus infusion and constant-rate infusion) have macokinetics of d-tubocurarine in patients with and also indicated that a biexponential equation is suffi­ without renal failure, and also used a triexponential cient to characterise the observed plasma concentra­ equation to describe the disposition of the drug. They tion-time data (Ramzan et aI., 1980a; Shanks et al., noted that comparisons of the measured and predicted I 979a). Furthermore, in 2 recent studies with d­ relaxant levels indicated that the model of Gibaldi et tubocurarine using a dual infusion technique, a biex­ al. (1972a) predicted their results more closely than ponential equation was significantly preferred over did that of Wingard and Cook (1976). However, they the more complicated triexponential equation found it necessary to assume a central compartment (Sheiner et al., 1979; Stanski et al., 1979). volume of distribution (V dJ for d-tubocurarine of 97.7ml/kg as opposed to the value of 72ml/kg 4.8.2 Gallamine calculated by Gibaldi et al. (1972a). The difference be­ Until relatively recently the only information tween the 2 models in predicting measured d­ available on the disposition of gallamine has been tubocurarine concentrations in Miller et al.'s (1977) from animal studies using radioactively labelled study is a reflection of the difference in the terminal material (Dal Santo, 1972; Feldman et al., 1959). half-lives of the drug calculated from the exponential Like d-tubocurarine, recent studies have indicated terms in the respective equations. The model of that the pharmacokinetics of gallamine in man show Gibaldi et al. (1972a) and Wingard and Cook (1976) pronounced multicompartment behaviour (Agoston give predicted terminal half-lives of 231 and 150 et al., 1978; Buzello and Agoston, I 978a,b; minutes respectively for d-tubocurarine (see table V). Duvaldestin et al., 1977; Ramzan et al., I 980b,c). In contrast to these results, in a study carried out Duvaldestin et al. (1977) were able to characterise the in the authors' laboratory with normal surgical plasma concentration-time data adequately with a 2- patients administered d-tubocurarine at a dose level of compartment model, whereas Agoston et al. (1978) 20mg/m2 body surface area (0.45 to 0.67mg/kg), noted that 3 phases (i.e. 3-compartment model and sampling for 4 to 5 hours postdrug administra­ behaviour) were apparent in the decline of serum con­ tion, a biexponential equation interpreted as a 2-com­ centrations of gallamine in their study. These latter partment open mamillary model was found to be workers, however, presented no statistical evidence as most appropriate in explaining the observed data to why the 3-compartment model was preferred over (Ramzan et al., 1978). This choice was made on the the simpler 2-compartment system. It is quite pos­ basis of rigorous statistical methods suggested by sible that the resolution of the appropriate number of Boxenbaum et al. (1974). It was found that the exponential terms in the serum/plasma data for plasma concentrations in the central plasma compart- gallamine may be dependent upon the sampling Table V. Pharmacokinetic values for muscle relaxants in normal subjects undergoing elective surgery (mean ± SD)

""tl ::T No. of Age Dose Volumes of distribution (ml/kg) Half-lives (min) Total systl3rnic plasma clearance Reference III patients range III3 n (y) Vd Vd~ ml/min ml/min/kg ml/min/m2 Vc ss t /2" t'/2~ t /2y 0 ' ' 2r. d-Tubocurarine "!P. c'i" 5 40-70 0.5mg/kg 47(2)' 387 1.7 (0.4)' 24 (7)' 347 (17)' 56 (13)' Meijer et al. '" (1979) sa. 84-119 2.25-2.60 Z 28 21-49 6.8mg then 80-100 290-300 4.8-6.4 Stanski et al. 0 1.2~g/kg/min(40) (100) (4.0) (69) (0.95) (1979) (1979) "a.I 10 9.3~g/kg/min200 (80) 520 (180) 670 (100) 18.3 (12.2) 275 (89) 1.81 (0.49) Shanks et al. "tl (1979) Q. III 12 17-72 0.540mg/kg 158 (16)' 602 (70)' 11.6 (1.9) 172 (23), 2.69 (0.29) Ramzan et al. ~: (198Oa) <0" 10 30-45 + mg 8.3-10.6 117-144 Ramzan et al. :s: (1978) !!l" 62 462 52 Buzello and 3 3.8l 20.6l 4.0 CD Agoston ::Jl (1978a) iii" )( 5 0.5mg/kg 98 6.9 46 231 Miller et al. III (1977) .... '"" 5 0.3mg/kg 2.8-3.2l 0.9 10 152 Wingard and Cook (1976) 70 6.9 46 231 Gibaldi et al. (1972a)

Gallamine 7 12-51 4mg 150 (30) 290 (50) 340 (90) 16.1 (11.8) 150 (27) 1.59 (0.30) Ramzan et al. (198Oc) 14-67 6mg 120 (50) 260 (40) 310 (70) 15.8 (11.4) 151 (32) 1.44 (0.40) Ramzan et al. (198Oc) 17 11-72 2 + (0.5-2)mg/kg 100 (20) 210 (50) 220 (50) 6.7-10.4 135 (33) 1.20 (0.32) Ramzan et al. (198Ob) 15 17-73 2.5mg/kg < 5.0 30-39 138-144 Agoston et al. (1978) 7 3.5 (1.7)l 21.9 (5.0)l 2.0 (1.0) 32 (9) 140 (30) 117 (37) Buzello and Agoston (1978a) 6 22-51 1.4-4mg/kg 120 (40) 17.0 (6.0) 128 (24) 51 (16) Duvaldestin et al. (1977)

~ ~ Alcuronium Q) 19 0.25 0.125mg/kg 125 (25) 313 (95) 364 (104) 13.8 (7.6) 199 (78) 90 (26) 1.34 (0.35) Walker et al. 19-80 + 3Q) (1980) 0" 207 (31) 94 (11) C. 6 20mg 3.3 (0.7)L 28.0 (5.0)L 2.0 (1.0) 19 (5) Buzello and :::l Agoston ~ 1r (1978a) en 6 20mg 12.6L 25.0L 200 99 Raaflaub and So Frey (1972) Z 0 =?a. Pancuronium CD 18 45 (12) 0.1-0.16mg/kg 345 (110)' 10.6 (5.5)' 114 (27)' 78 (23)' Ouvaldestin "8 iii" et al. (1978a) :::l. !!l. 18 30 (7) 0.06-0.01 mg/kg 380 (119)' 13.2 (5.9)' 146 (38)' 62 (9)' Ouvaldestin :::l co et al. (1978a) s: 15 22-76 4-14.6mg 300 (80) 2.11 (0.81) Somogyi c en et al. (1978) "1E" 12 0.1-0. 18mg /kg 120 (10)' 240 280 (20)' 10.7 (1.3)' 114 (10)' 1.86 (0.12)' Ouvaldestin ::0 ~ et al. (1978a) Q) x 5 27-65 4mg 19.5 (3.3)L 43.9L 343 (110) Hull et al. Q) ;a (1978) en 21 48 (5) O.04mg/kg 70 (10) 240 (30) 1.76 (0.30) Miller at al. (1978) 6 6mg 2.3 (0.7)L 21.0 (3.4)L 1.0 (0.5) 14 (5) 250 (156) 79 (18) Buzello and Agoston (1978a) 7 26-73 6mg 100 (30) 260 (40) 340 (70) 12.5 (4.2) 133 (25) 123 (41) Somogyi et al. (1976) 6 20-46 4mg 80 (10)' 150 (10)' 74 (8)' McLeod et al. (1976)

Metocurine 5 40-70 0.05mg/kg 66 (12)' 422 1.9 (0.2)' 29 (7)' 217 (41)' 97 (10)' Meijer et al. (1979)

Fazadinium 5 52-74 70mg 41 (15)' 184 226/76)' 1.6 <0.3)' 50 (6)' 185 (49)' O·Souza et al. (1979) 10 20-52 1.5mg/kg 100 (10)' 230 (20)' 12.3 (1.9)' 76 (5)' 132 (11)' Ouvaldestin et al. (1978b)

Standard error of the mean. w~ Pharmacokinetics of Non-depolarising Muscle Relaxants 44

schedule employed, especially at early time points. 3-compartment open model. Raaflaub and Frey This view is further supported by the fact that the (I 972) did not discuss the criteria used in the choice half-life of the first phase noted by Agoston et al. of their model, but only stated that a 2-compartment (I 978) was less than 5 minutes, as compared with 17 open model was adopted to characterise the plasma minutes reported by Duvaldestin et al. (I 977). concentration-time data following administration of More recently, Ramzan et al. (I 980b) determined lH-aicuronium to patients. Buzello and Agoston plasma concentrations of gallamine in patients un­ (J978a) re-evaluated the data of Raaflaub and Frey dergoing anaesthesia for elective surgery, with sam­ (I 972), and claimed that the plasma level-time curve pling for periods up to 5 to 10 hours postdrug ad­ of alcuronium in man was triphasic in nature. ministration. Using the methods suggested by Boxen­ Buzello and Agoston (I 978a), however, also pre­ baum et al. (I974), the 2-compartment open model sented no statistical evidence as to why a triexponen­ (biexponential equation) was chOSen as the simplest Hal function was prefened over the simpier biexpo­ model consistent with the observed data. The biexpo­ nential one. nential equation describing the plasma concentration In a very recent study originating from the (Cp) with time (t) in these patients was: authors' laboratory (Walker et aI., 1980), plasma levels of alcuronium were determined in normal Cp = 12.0Ie-O.1227t + 9.32e-O.0052t (Eq.4) surgical patients for periods up to 8 hours following In a further II patients who had received the same single intravenous bolus doses (0.25mg/kg). Apply­ initial dose (2mg/kg), and required additional doses ing the statistical criteria of Boxenbaum et al. (1974), (0.5 to 2mg/kg), the same model was found to as used for digoxin by Kramer et al. (J 974), a signifi­ satisfactorily characterise the disposition of gall­ cant preference was demonstrated for the biexponen­ amine. No major differences were noted when the tial model in all but I patient. The biexponential equa­ pharmacokinetic parameters between the single and tion describing the plasma concentration (Cp) of multiple dose patients were compared. In another alcuronium with time (t) in this group of patients was study in which 2 higher (4 and 6mg/kg) dosage levels found to be: were used, the biexponential equation was again found to be sufficient (Ramzan et ai., I 980c). Cp = i .43e - o.om + 0.64e - 0.0036t (Eq.5) Furthermore, no significant differences in the various pharmacokinetic parameters were noted between the Further, this chosen model was found to ade­ patients receiving the 4 and 6mg/kg doses. However, quately describe the disposition kinetics of alcu­ the distribution and clearance terms obtained from ronium in a group of normal patients· who were ad­ the 4 and 6mg/kg data were found to be significantly ministered multiple doses of relaxant; there being no higher than those obtained with the lower (2mg/kg) significant statistical differences between the model­ single and multiple dose patients (see table V). independent pharmacokinetic parameters from both groups. It is interesting to note (table V) that the 4.8.3 Alcuronium pharmacokinetic parameters of alcuronium obtained Like the non-depolarising muscle relaxants dis­ from our study are comparable with those reported cussed so far, alcuronium plasma concentration-time earlier by Raaflaub and Frey (J972), with any slight decay curves following bolus IV administration also discrepancies being explicable by differences in model show multicompartmentai characteristics (Buzello interpretation. and Agoston, 1978a; Raaflaub and Frey, 1972; Walker et al., 1980). There has been some contro­ 4.8.4 Pancuronium versy, however, over whether the pharmacokinetic Pharmacokinetic studies with pancuronium in behaviour of alcuronium is better described by a 2- or surgical patients have also indicated that this agent Pharmacokinetics of Non-depolarising Muscle Relaxants 45

shows pronounced muIticompartment behaviour whose mean values range between 1.61 and (Agoston et al., 1973; Buzello, 1975; Gibaldi et al., 1.86ml/minute/kg. 1971; Mcleod et ai., 1976; Somogyi et al., 1976). Agoston and associates (1973) noted the presence of a 4.8.5 Metocurine terminal elimination phase (t1/2 = 108 to 147 To date only one study on the pharmacokinetics of minutes), together with 2 residual phases, when metocurine in man has been reported (Meijer et al., plasma concentration data for pancuronium was plot­ 1979). After intravenous administration of I4C_ ted against time. The 2 early phases were suggested as metocurine (0.05mg/kg) to 5 patients anaesthetised representing an initial distribution phase for the drug, with thiopentone and nitrous oxide, these workers followed by a redistribution to acceptor tissue depots found that the plasma disappearance of the relaxant and drug excretion. However, no attempt was made was triexponential in nature with a mean terminal by the authors to rigorously define the appropriate half-life of 217 minutes. The average equation pharmacokinetic model, other than to assess the half­ describing the pharmacokinetics of metocurine as the lives of these 3 phases. Buzello (1975) also noted that fraction of the dose in the central compartment the plasma concentration curves for the relaxant were (Xci Xo) with time (t) was: muItiexponential in character. A more rigorous definition of the disposition kinetics of pancuronium Xc/Xo = 0.703e-0.358t + 0.221e-0.024t + was presented by Mcleod et al. (J 976), who reported O.076e - 0.0032t (Eq. 6) on the pharmacokinetics of pancuronium in normal and renal failure patients. They used a 2-compart­ ment model to describe their data; however, their Thus, a 3-compartment open model was used by the method of obtaining parameter estimates was by authors to describe the plasma disappearance pattern means of an analogue computer. When compared and to calculate the various pharmacokinetic with the use of modern digital computers, the former parameters for metocurine (see table V). The volume have several drawbacks including a complete lack of of the central compartment (V dc) was about 10 % statistical output (parameter variability, weighted higher for metocurine than found by the same sums of squared deviations, etc.) and a much reduced authors for d-tubocurarine. The terminal half-life was degree of precision (Atkins, 1969). shorter, while the total body (plasma) clearance was Recently Somogyi et al. (J 976) showed that in some 70 % higher for metocurine as compared with their patients, the use of a 2-compartment model ade­ d-tubocurarine, in spite of the greater biliary quately described their plasma concentration-time clearance of the latter. data, whereas a 3-compartment model offered no significant improvement. The pharmacokinetic 4.8.6 Fazadinium parameters reported initially by these workers have Fazadinium also displays multicompartmental subsequently been verified by more recent studies car­ pharmacokinetics (D'Souza et al., 1979; Duvaldestin ried out in the authors' laboratory (Somogyi et al., et al., 1978b). Duvaldestin et ai. (I 978b), whose 1978), as well as by others. However, the data of study involved normal surgical patients receiving a Mcleod et al. (1976) [see table V], who used a dose of single dose of 1.5mg/kg of fazadinium, were able to 4mg of pancuronium, would appear to be inconsis­ characterise plasma concentrations of the relaxant up tent with those reported by other workers. In particu­ to 5 hours. The plasma level decay curve was found lar their values ofthe apparent volume of distribution to be biphasic in nature, and was interpreted accord­ (Vd~ and plasma clearance (CI~ are considerably ing to a 2-compartment open model on the basis that smaller; for example, their Clp of 7 4mll minute the curve was linear between 90 and 300 minutes and (1.1 mll minute/ kg) is far less than that of the others, that other workers proposing models for other non- Pharmacokinetics of Non-depolarising Muscle Relaxants 46

depolarising muscle relaxants had also used a similar 5. Pharmacokinetics in Disease States model (for example, Somogyi et al., 1976, for pan­ curonium). A non-linear iterative procedure was used 5.1 Renal Failure for fitting of the Cp-time data, thus giving accurate estimates of the coefficients and exponents of the Patients with renal failure respond differently to chosen equation. many drugs compared with patients with healthy Recently D'Souza et al. (1979) studied the kinetics kidneys. Several possible explanations for such of disposition of fazadinium in 5 patients each receiv­ phenomena have been postulated, including changes ing a single bolus dose of 70mg. Blood sampling was in the sensitivity to the drug, alteration in the dis­ carried out for periods up to 3 hours postinjection, tribution characteristics and accumulation of a drug with fazadinium plasma concentrations being given according to the usual therapeutic regimen, mea<;ured using the radiometric melhou uescribed because of decreased elimination secondary either to a earlier (see section 3). The plasma concentration-time slower rate of metabolism or to diminished renal ex­ data was analysed assuming 2-compartment open cretion. model behaviour and using non-linear regression When kidney disease produces an elevation of the techniques. When attempts were made to fit the data K+ and H+ concentrations in plasma and the ex­ to a 3-compartment open model, in 3 cases there was tracellular compartment, the theoretical possibility a slight improvement in fit, in another case the 2- exists that response to the relaxants will be altered compartment model gave a better fit, while in the (see table I). At present, however, detailed experimen­ fifth case the data could not be fitted satisfactorily to a tal data are lacking, although Miller et al. (1977) 3-compartment open model. The authors concluded found that the total d-tubocurarine plasma concentra­ that the simplest model consistent with their data was tion required to depress twitch tension was similar in a 2-compartment open model. From the coefficients patients both with and without renal failure. and exponents of the fitted equation obtained by The volumes of the various body compartments D'Souza et al. (1979), the following biexponential may be altered in renal failure due to disease per se, or equation may be used to predict plasma concentra­ to many influences secondary to the disease state. The tions (Cp) of fazadinium at any time (t) following presence of oedema or ascites may tend to increase the bolus injection of a dose of 70mg: volume of extracellular fluid. In pharmacokinetic terms the volume of distribution of a relaxant may be Cp = 92.02e-O.509t + 5.30e-O.OI5t (Eq.7) increased because of a reduction in plasma protein or a change in binding characteristics as a result of The model-independent pharmacokinetic para­ uraemia. The net effect of such protein binding meters obtained in this and a previous (Duvaldestin et changes usually results in an increase in unbound al., 1978b) study are presented in table V. Of interest drug, so that pharmacological or toxic effects may be are the high values for the total plasma clearance of encountered. Changing the drug dosage may fazadinium obtained in both studies, as compared therefore be necessary. The studies of Ghoneim et al. with the other muscle relaxants. This finding would (1973) and Clissold et al. (1975) have, however, failed apparently result from the short elimination half-life to show any significant difference in the proportions (tl/2~ for the relaxant, since the apparent volume of of d-tubocurarine binding to plasma proteins of distribution terms (VdiY are not dissimilar. The short healthy patients as compared with patients with renal t I /2~ does not appear to be a result of extensive meta­ disease. bolism in man (table IV), but may be a result of a Renal failure, accompanied by decreased urinary higher biliary excretion of fazadinium a.<; compared excretion, may also influence the action of non­ with the other muscle relaxants. depolarising relaxants via accumulation of those Pharmacokinetics of Non-depolarising Muscle Relaxants 47

relaxants which are excreted primarily (e.g. gall­ relaxation resulting from the drug in such patients amine) or partly (e.g. d-tubocurarine) unchanged in (Cozanitis and Haapanen, 1979; Havill et al., 1978). the urine. The neuromuscular effects of these agents The pharmacokinetic profile of several muscle are thought to be terminated following single moder­ relaxants in renal failure patients has now been eluci­ ate doses, by redistribution into tissues. After repe­ dated in man (table VO. Gibaldi et al. (J 972b), using ated doses these depots, however, may become satur­ computer simulations, predicted that the absence of ated and urinary excretion becomes the determining renal function would have little effect on the duration factor in the time course of the neuromuscular block. of relatively small single doses of d-tubocurarine, but The effect of renal failure on the action of non­ that the duration of action of large single doses and depolarising blocking agents, however, has been multiple doses would be prolonged significantly. somewhat contradictory, as assessed by clinical Miller et al. (1977) found that although there was a reports. Prolonged paralysis has been well docu­ longer duration of action of d-tubocurarine in patients mented following the use of gallamine in patients with renal failure which could be attributed entirely with renal failure (e.g. Feldman and Levi, 1963; to the absence of renal function, the suggestion was Lowenstein et al., 1970). Despite these reports, made that this relaxant may still be preferred to pan­ White et al. (1971) reported use of this drug, without curonium in such patients as it is less dependent on complications, in patients undergoing bilateral neph­ urinary excretion for its elimination than pan­ rectomies. They do point out that their failure to en­ curonium (see section 4.7). counter vrolonged paralysis or 'recurarisation' may McLeod et al. (I976) noted that nearly all the be the reSUlt of using a conservative dose in their model-associated pharmacokinetic parameters for study. pancuronium were altered in patients with renal d-Tubocurarine has been declared 'safe' in patients failure, as compared with normal individuals. Unfor­ with renal impairment in a number of series tunately, no assessment of the degree or duration of (Churchill-Davidson et al., 1967; Monks and neuromuscular blockade was made. Recently, in a Lumley, 1972; Samuel and Powell, 1970), and has similar study, Somogyi et al. (I 977b) found that the consequently been the relaxant of choice in anephric plasma clearance and terminal (M phase half-life of patients, as biliary excretion of the drug has been pancuronium were reduced significantly in renal shown to be markedly increased sufficient to compen­ failure. No changes in the volume of distribution sate for the reduced renal function (Cohen et al., terms were found. They noted that this prolongation 1967). However, prolonged curarisation or inade­ in half-life was often associated with an extended quate reversal has also been reported with the use of duration of blockade, and that the rate of recovery this agent in renal failure patients (Katz et al., 1967; from paralysis might also be decreased. Whereas in Logan et al., 1974; Miller and Cullen, 1976; Riordan normal patients given 6mg the recovery time to 10% and Gilbertson, 1971; Rouse et al., 1977). of control twitch height was about 79 minutes, the Pancuronium has also been administered to ter­ renal failure patients could be divided into 2 distinct minal renal failure patients with subsequent satisfac­ groups as regards recovery times: in the major group tory reversal of blockade (Kamvyssi-Dea et al., 1972; (n = 6), a prolonged duration of action (70 to 254 Slawson, 1972). There are now, however, several minutes, mean 143) was observed, an increase of reports of difficulty in reversal following its use in some 81 %; in the other 4 patients, the duration of ac­ such patients (Abrams and Hornbein, 1975; Havill et tion was markedly reduced and ranged from to to 54 al., 1978; Miller and Cullen, 1976; Popescu, 1972; (mean 26) minutes, such that these latter patients re­ Rouse et al., 1977; Somogyi et al., 1977b). quired up to double (J 2mg) the normal dose to A1curonium seems to be less frequently used in achieve adequate neuromuscular blockade. The renal failure; there have been 2 reports of persistent plasma concentrations at the time of recovery in these Table VI. Pharmacokinetic values for muscle relaxants in various diseases (mean ± SD) -0:r Disease / muscle No. of Age Dose Volumes of distribution (ml/kg) Half-lives (min) Total systemic Reference (mg) plasma clearance § relaxant patients range Q) (y) n Vc Vdss VdB t1/2n t'/2S t'/2y 0 Co ml/min ml/min/kg :::l ~ cr rn Renal failure So d- Tubocurarine 5 31-52 0.5mg/kg 97.7 330 Miller et al. Z (1977) 0 :::l Alcuronium 20 6.5 25L 24 99C 27 Buzello and a. Agoston (1978) "C Q. 20 960 Raaflaub and Q) :::!. Frey (1972) l!!. :::l Pancuronium 6 6 1.8 (0.7)L 15L 0.5 (0.1) 5(1) 1050 (390) Buzello and or 4 140 (51' 240 (30)' 20(2)' McLeod et x Q) al. (1976) :::l .... rn Liver disease (Total biliary destruction) Pancuronium 9 52-80 6-10 87.8 306.5 378.4 (171.7) 8.9 270 (101) 59.2 (127.9) (20.7) 1.06 Somogyi et al. (1977)

(Cirrhosis)

Pancuronium 14 36-68 l00-250~g/kg173 (17)' 354 (57)' 416 (58)' 23.7 (4.6)' 208.2 (24.8)' 100.3 1.45 (0.11)' Duvaldestin et al. (1978a)

Caesarean section Pancuronium 21 0.06-0.1mg/kg 380 (120)' 13.2 (5.9)' 146 (38)' 61.8ml/ Duvaldestin min/m 2 et al. (1978cl (8.9)'

Standard error of the mean. 5; Pharmacokinetics of Non-depolarising Muscle Relaxants 49

patients were elevated but were declining rapidly (a globulin fraction increases, especially in chronic phase). These 'resistant' patients were similar in obstruction. The binding capacity of the serum pro­ patient characteristics to the other renal failure teins for various drugs has been found to be reduced patients, and were also eliminating pancuronium in patients with hepatic disease (Reidenberg, 1973, more slowly. Their resistance cannot be readily ex­ 1974), probably due to the low albumin levels. plained. Data about the protein binding of relaxants in liver The pharmacokinetic disposition of the other disease is relatively scanty. There is wide individual relaxants in renal failure is less detailed. Raaflaub and variation in the responses to these drugs, which has Frey (1972), based on the observation that been attributed by some investigators to differences in alcuronium is to a large extent (80 to 85 %) elimi­ the extents of protein binding (Aladjemoff et aI., nated by the kidneys, found that in a case of complete 1958). Dundee and Gray (J 953) and Haselhuhn anuria the elimination half-life of the drug from (J 957) reported an increased resistance to d­ plasma was prolonged to approximately 16 hours. tubocurarine in patients with liver dysfunction. This The disposition of gallamine in renal failure patients resistance was confirmed by El-Hakim and Baraka has not been studied, but recent unpublished studies (J 963) in patients with bilharzial cirrhosis. These from the authors' laboratory indicates that the workers suggested that the refractoriness to the relax­ elimination half-life is substantially prolonged with a ant was due to excessive binding of the drug to gam­ marked decrease in the plasma clearance of the drug. ma globulin. Payne and Webb (J 962) also found a Data on the effect of renal insufficiency on meto­ decreased effect of this relaxant in the presence of curine kinetics is also lacking, although Meijer et al. serum from jaundiced patients, which they suggested U 979) have stated that metocurine appears to be might be due to increased protein binding of the drug. more dependent on renal excretion for its elimination In contrast to these findings, EI-Hakim and than d-tubocurarine; therefore, use of the latter relax­ Baraka (J 963) noted that patients with obstructive ant is probably preferred to metocurine in patients jaundice showed a normal or even an increased sen­ with renal failure. sitivity to d-tubocurarine. Stout (J 963), Baraka and Gabali (J 968) and Stovner et al. (J 97 J) independently reported that d-tubocurarine requirements in patients 5.2 Liver Disease dUring surgery correlated directly with the plasma globulin level; the higher the latter, the larger the dose Human liver disease consists of an assortment of of the relaxant needed. These findings appear to con­ disturbances, which in addition to damage to the firm the previously mentioned studies where hepatic parenchyma and biliary tree may lead to an decreased sensitivity to the drug occurred in patients alteration of plasma protein synthesis. The damage to with hepatic disease, in which inversion of the the organ and the degree of its functional abnormality albumin/ globulin ratio is common in the chronic ac­ varies widely within any diagnosed disease process, tive states of the disease. Ghoneim et al. (J 973), how­ but it appears that patients with obstructive jaundice ever, found that there was no significant difference in and acute viral hepatitis have a much lesser degree of the proportions of d-tubocurarine to plasma proteins impairment than those with cirrhosis and chronic ac­ of healthy patients as compared with patients with tive viral hepatitis (Wilkinson and Schenker, 1975). cirrhotic liver disease. More recently Stovner (J 975) Obstruction of the biliary tract commonly leads to questioned his own previous findings and suggested changes in various functions of the liver. In early bili­ that the primary factor responsible for resistance in ary obstruction serum proteins are within normal liver disease was a tendency to a fall in blood pressure limits, but with time the serum albumin levels in response to anaesthesia and surgery, with the decline. With the increase in serum lipid, the ~- reduced tissue perfusion diminishing the action of d- Pharmacokinetics of Non-depolarising Muscle Relaxants 50

tubocurarine. This may also explain why gallamine, tions of bile acids decreases the initial hepatic uptake which is not as potent a histamine liberator as d­ process, thus prolonging the duration of effect. How­ tubocurarine, was preferred by EI-Hakim and Baraka ever, although no formal pharmacokinetic study was (t 963) for use as a relaxant in liver disease (cirrhosis performed by these authors their plasma concentra­ and obstructive jaundice). tion data suggest a volume of distribution change. As the liver is the major site for drug metabolism, Nevertheless, in patients with obstructive jaundice the patients with liver disease might be expected to show reduced total plasma clearance of pancuronium is a decrease in the elimination of those relaxants which associated with a more prolonged duration of effect. are predominantly metabolised in the liver. For those Duvaldestin et al. (197 8a), in their study of surgi­ drugs which are eliminated by other organs, par­ cal patients with liver cirrhosis, also noted profound ticularly the kidney, any effect due to hepatic dysfunc- changes in the disposition of pancuronium. Both dis- tion vlould be ex~wCted to be less significant. Hc\v- tribution and elimination phase half-lives fOi the drug ever, this presumption neglects the possibility of were prolonged significantly, to approximately twice altered renal function which may occur in advanced that observed in control patients. The increase in the cirrhosis (Lancestremere et ai., 1962; Onen, 1960). elimination half-life resulted in a decreased plasma Studies on the kinetics of muscle relaxants in clearance in spite of an increase in the distribution patients with hepatic disease have been lacking until volume. The patients with cirrhosis also tended to ex­ very recently (see table VI). Somogyi et al. (1977) and crete more drug plus metabolites (mean 67 %) than Duvaldestin et al. (1978a) have published investiga­ normal patients (mean 46 % ) in urine collected for 24 tions with pancuronium in patients with total biliary hours after dosing. Unfortunately, no measurement obstruction and cirrhosis, respectively. A major find­ of neuromuscular response was made, leaving the ing of the former study was that patients with biliary authors to speculate that the enhanced volume of dis­ obstruction had a significantly reduced plasma tribution noted in cirrhotic patients would necessitate clearance of the relaxant; a value less than one-half the use of higher doses of pancuronium to achieve that found for normal patients. This was not because adequate relaxation, but the reduced clearance would of a change in the volume of distribution, but was due slow the rate of recovery. As a result, it is also pos­ to prolongation of the terminal phase half-life of pan­ sible to specUlate that the anaesthetist administering curonium. These kinetic alterations were mirrored by small doses of pancuronium might then observe an increase in the duration of action of the relaxant, to 'resistance' to the relaxant until an adequate dose had 114 minutes compared with 79 minutes in normals, been reached. Thereafter, the effects of the reduced but the mean concomitant plasma concentration was plasma clearance in these patients would predomi­ the same as that in normal patients (0.25pg/mO. nate, and the patients would then demonstrate 'sen­ These workers also noted that with the exception of I sitivity' to the drug. patient, no resistance to the effect of the relaxant was encountered. At 24 hours after administration a mean of 41 % of the dose was eliminated as parent 5.3 Tetanus drug in the urine and II % as known metabolites. These authors concluded that the biliary elimination Duvaldestin et al. (1979) reported on the disposi­ pathway for pancuronium in man may be more im­ tion of pancuronium in patients with generalised portant than originally suggested. A more recent tetanus requiring muscle relaxation by infusion for a study in cats, conducted by Vonk et al. (1979), using period of between 8 and 24 days. The steady-state a steroidal muscle relaxant similar in structure to plasma concentration varied from 0.27 to pancuronium, has implied that rather than disturbing 0.48pg/ml, and renal clearance ranged from 18 to the biliary processes, the presence of high concentra- 90ml/ minute, and significantly correlated with Pharmacokinetics of Non-depolarising Muscle Relaxants 51

creatinine clearance (r2 == 0.86; p < 0.000. None of rate respectively may be calculated accordingly to the the patients developed severe renal insufficiency, fol1owing equations: although transient changes in renal function were Bolus dose = V d~ x CPss (Eq.8) noted, which may explain the long elimination half­ lives of 260 and 370 minutes in 2 patients compared Infusion rate = Cl x CPss (Eq.9) with 130 minutes in another 2 patients upon cessa­ p tion of the infusion. The authors concluded that there where V d~ is the apparent volume of distribution, Q p was no accumulation of pancuronium in their the plasma clearance and CPss the desired plasma con­ patients, and thus cardiovascular manifestations often centration. present in such patients are unlikely to be due to pan­ Somogyi et al. (1978) determined the clinical ap­ curonium. propriateness of a combined intravenous bolus and concomitant infusion of pancuronium administered to 16 patients undergoing surgery and requiring 5.4 Caesarean Section prolonged anaesthesia. Based on pharmacokinetic analyses and pharmacodynamic measurements, they In 2 1 patients undergoing Caesarean section recommended a loading dose of 62.5pg/kg (bolus) operation, Duvaldestin et al. (1978c) showed a sig­ and a constant-rate infusion ofO.35pg/kg/minute of nificant shortening of the elimination half-life of pan­ pancuronium. This they hoped would produce a curonium (by 22 %), and a corresponding increase in steady-state pancuronium plasma concentration of total plasma clearance. However, since these changes 0.2pg/ml, consistent with adequate relaxation as are modest, they are not expected to produce resis­ assessed by clinical impression and single twitch tance to the action of pancuronium. measurements. Indeed, at steady-state a mean con­ centration of 0.214pg/ml (SEM 0.012) was obtained with a single twitch height of 18 % of control. The 6. Relaxant Dose and Dosage Design duration of infusion varied from 43 to 296 minutes, resulting in a total administered dose of between 4.5 There appears to be great variability in the choice and 1.46mg. They observed that upon cessation of of an appropriate level of initial dosage of non­ the infusion the twitch height increased at it rate of depolarising neuromuscular blocking drugs reported I % per minute, thus giving the anaesthetist a dosing for relaxation during general anaesthesia. In our schedule which would both reduce the risk of over­ studies we have used d-tubocurarine at an initial dose dosage as wel1 as produce control1ed relaxation with level of 0.5mg/kg bodyweight (or 20mg/m2 body less perturbations in plasma concentrations than the surface area); pancuronium as a single 6mg or 8mg conventional multiple bolus dosing technique. bolus dose; gallamine as 2, 4 or 6mg/kg single doses; A similar dosage regimen has also been recently and alcuronium as a single dose of 0.25mg/kg. designed for d-tubocurarine in our laboratory Despite the successful use of these relaxants at the (Ramzan et al., I 980a). Using a loading bolus dose of dosages stated, we have noted (as have other workers) 540pg/kg and a constant-rate infusion of 2.9pg/ a variable response to them in a number of cases. In kg/ minute we were able to produce a steady-sta'te an aitempt to diminish the variation in response we plasma concentration of the relaxant after about an have designed new dosage regimens for some of the hour in 9 out of the 12 patients studied. In these 9 relaxants based on pharmacokinetic/ pharmaco­ patients the mean plateau concentration of d­ dynamic considerations. The new dosage regimens tubocurarine was found to be 1.09pg/ml, and this utilise a bolus dose plus a concomitant constant-rate concentration was associated with a mean of 95 % infusion, where the size of the bolus and the infusion neuromuscular paralysis. Dosage regimens designed Pharmacokinetics of Non-depolarising Muscle Relaxants 52

to produce sustained muscular relaxation with other and demonstrated that in this circumstance one could relaxants are in the process of being developed in the expect the intensity of drug effect to be linearly related authors' laboratory. to log dose when effect was in the linear (20 to 80 %) effect range. He therefore predicted that, after bolus drug administration, the pharmacological activity 7. Plasma Concentration-Response should decline linearly (rather than exponentially) Relationship with time. Levy (I964b) was able to support the validity of this approach by using the clinical and ex­ The study of the effects of relaxant drugs on perimental data of Belville et al. (I 964). The results neuromuscular transmission is fundamental to basic showed that the plasma concentration of d­ in vitro pharmacology, but extrapolation of the results tubocurarine decreased exponentially with time after to the in vivo situation is rather more complicatecL an intramuscular injection of the drug in a human Whereas in in vitro organ bath experiments the con­ subject, while the degree of muscle relaxation (deter­ centration of drug (or dose) perfusing the muscle pre­ mined on the basis of decrease in grip strength) paration is known, in man one is able to measure the decreased linearly. Levy (1966) subsequently verified drug concentration only at a site (blood) distant to the this behaviour for d-tubocurarine on hand, head and site of action; hence there is a 'dysequilibrium' be­ diaphragmatic muscle using the data of Johansen et tween concentration and effect. Further, the plasma al. (1964). Gibaldi et al. (1971) were able to extend concentration of the relaxant is not constant unless a Levy's (1964a,b; 1966) initial ideas to the multicom­ specific dosing regimen (for example, constant-rate partment (triexponential) description of plasma con­ infusion) is employed to produce a constant plasma centrations of d-tubocurarine, and were able to level. Thus, the assessment of the potencies of the demonstrate a direct correlation between relaxant relaxant drugs in man cannot be readily established effect and concentration (or amount) of drug in the with conventional bolus dose techniques. The ideal central compartment of their 3-compartment model. situation is to compare actual steady-state free relax­ Deviations of predictions using their equations from ant concentration with the steady-state pharmacologi­ the observed effects were, however, noted with small cal response, thus establishing a plasma concentra­ doses of d-tubocurarine and with measurements of tion-response curve. effect (paralysis) made soon after drug administra­ Since the beginning ofthis decade several attempts tion. have been made to relate the concentration of the Matteo et al. (I 974), on the assumption that the relaxant drugs to their effect. It was believed as early effect of d-tubocurarine was related to the drug con­ as 1953 that the action of d-tubocurarine was related centration at the myoneural junction and furthermore to the drug content of the blood, and not to the that this concentration was related to that in serum, amount of drug in tissues; this view being supported attempted to correlate the serum concentration of the by the fact that the tissue content of the drug reached drug with its pharmacological response. The response its maximum after several hours, whereas the to d-tubocurarine was measured by twitch tension of paralytic action of the drug started rapidly and lasted the adductor muscle of the thumb in response to only several minutes with ordinary clinical doses. supramaximal stimulation of the ulnar nerve, and However, early attempts (Cohen et al., 1957) to relate serum concentrations were monitored by radioim­ plasma d-tubocurarine concentration to neuromuscu­ munoassay. By plotting serum relaxant concentration lar blockade in man demonstrated a poor degree of against percentage recovery of twitch (347 data points correlation. from 48 patients) a significant linear correlation was Levy (1964a) used a single compartment model to demonstrated (r = 0.7109). The mean serum con­ describe the disposition kinetics of a drug in plasma, centration of d-tubocurarine at 50 % recovery was Pharmacokinetics of Non-depolarising Muscle Relaxants 53

0.45 ± 0.13J.lg/ ml, and complete recovery occurred at The classical results obtained by Matteo et aI. a concentration of 0.20 ± 0.13J.lg/ mI. The correlation (1974) with d-tubocurarine have now been confirmed was not affected by the dose of relaxant or by the an­ with pancuronium (Agoston et al., 1977b) and aesthetics employed. metocurine (Matteo and Khambatta, 1979); we have That Cohen et al. (1957) were not able to also demonstrated a relationship between the plasma demonstrate a relationship between d-tubocurarine concentration of relaxant and degree of neuromuscu­ plasma concentration and neuromuscular blockade lar paralysis with both d-tubocurarine and pan­ probably resulted from 2 factors. First, the methods curonium (Shanks et aI., I 979a,b). used for determining neuromuscular blockade were More recent works have attempted to explain based upon muscular activity of the intercostal plasma concentration effect relationships for the muscles and strength of the biceps, which are not as relaxants throughout the entire course of drug action sensitive to the action of the relaxant as the evoked by use of pharmacodynamic models. Hull et al. twitch response. Secondly, the spectrophotometric (I978) found that the classical 2-compartment open method of analysis employed by Cohen et aI. (I957) mammillary model did not fit their bolus dose data was sensitive only to about 0.5 J.lg / ml of the relaxant. for pancuronium, as there was a significant hysteresis Matteo and co-workers (I 974) found that significant in each compartment when early plasma levels were neuromuscular blockade stilI existed at this drug con­ examined. Thus, a small effect compartment was centration. added to the model and connected to the central com­ The conclusion of Matteo et aI. (I 974) that the partment by a first-order transfer rate constant, such effect of d-tubocurarine was related to its serum con­ that the concentration of drug in the compartment at centration was questioned by Kopman (1975) and onset of effect was identical to that at offset of Feldman (1975). The issue arose from observations paralYSis. The authors assumed a constant (80 %) by Feldman and Tyrell (J 970) on the effects of d­ degree of protein binding for pancuronium and that tubocurarine given intravenously into an arm which instantaneous mixing of the drug occurred in the was isolated from the general circulation by a tourni­ blood. Their model explained somewhat the pheno­ quet. Feldman (J 975) suggested that what earlier menon of resistance to the relaxant in renal failure workers had demonstrated was that following injec­ patients, and was able to predict that in normal tion ofrelaxant the serum levels of drug in similar in­ patients an effect compartment level of 4.33mmol/L dividuals fall at approximately the same rate, and that of pancuronium was associated with 50 % recovery. the coincident recovery of neuromuscular blockade Whether this latter concentration could be used as a also occurs at similar rates in different individuals. guide for dosing of the relaxant was not stated. Matteo (I 975), in defending the apparent correlation A more realistic model has recently been presented between serum d-tubocurarine concentration and (Sheiner et al., 1979), which can examine relaxant blockade intensity, pointed out that there would be a pharmacodynamics and pharmacokinetics simul­ period when dynamic equilibrium exists between the taneously. If plasma concentration and pharmacologi­ relaxant concentrations in the serum, in the ex­ cal effect data are gathered when a steady-state is not tracellular fluid and at the endplate. He suggested that present, there occurs a 'dysequilibrium' between the the recovery phase following this equilibrium was concentration of drug in plasma and the site of action, when the correlation existed. However, using resulting in a plasma concentration-pharmacological physiological considerations Waud (1975) concluded effect dysequilibrium. The model developed by that the 2 groups of observations were not in dis­ Sheiner et al. (1979) adjusts for this temporal plasma agreement with each other or with the conventional concentration-pharmacological effect 'dysequilib­ views of neuromuscular physiology and phar­ rium' and allows the calculation of the expected macology. relationships at steady-state without steady-state Pharmacokinetics of Non-depolarising Muscle Relaxants 54

needing to be actually achieved. In this model (shown (1979) have also used the above model to study the in fig. 3), a first-order rate constant (keo) is used to comparative disposition of d-tubocurarine in man characterise the rate at which the effect site equilibr­ during nitrous oxide-narcotic and halothane anaes­ ates with the plasma concentration. Mathematically, thesia. the pharmacodynamic model is accomplished by Recent studies from this laboratory (Shanks et al., postulating a 'hypothetical' effect compartment, the 1979a,b) have highlighted the clinical implications of dynamics of which are adjusted by the rate constant effect kinetics for the relaxants. Using a slow infusion keo' The amount of drug in the effxt compartment technique it was found that the plasma concentration Ae is related to the observed effect by use of the well­ of both pancuronium and d-tubocurarine during known Hill equation (as proposed by Wagner, 1968), onset of action were substantially higher than those at a non-linear equation that characterises the sigmoid offset of effect, again demonstrating the latency to concentration- (or dose)-response relationship. peak effect of dyseqlliiihrium. i Ising the Hili equation Sheiner et al. (1979) demonstrated the utility of their we also characterised the entire range of response model using 2 different sets of plasma concentration both using onset and offset of action. Between 80 and and effect data for d-tubocurarine. Stanski et al. 20 % paralysis a very strong relationship (r = 0.929,

I I I k1e N I I 1.0

Y ~E Ae

o~------

Fig. 3. Diagrammatic representation of the pharmacokinetic and dynamic model proposed, when viewed as an N-compart­ ment mammillary model. A. represents the amount of drug in the hypothetical effect compartment and E is the fraction of max­ imal response (after Sheiner et aI., 1979). Pharmacokinetics of Non-depolarising Muscle Relaxants 55

p <0.00 1) was noted with pancuronium between the References rate of recovery and the rate of decline of (log) plasma Abrams, R.E. and Hornbeim, T.F.: Inability to reverse pan­ concentration. This relationship was obtained by curonium blockade in a patient with renal failure and hepatic examining data from 27 patients with various disease. Anesthesiology 42: 362-364 (1975). pathology (normal, renal failure and biliary obstruc­ Agoston. S.; Vermeer, G.A.; Kersten, U.W. and Meijer, D.K.F.: tion), and thus it was finally demonstrated that using The fate of pancuronium bromide in man. Acta Anaes­ thesiologica Scandinavica 17: 267-275 (1973). conventional pancuronium dosing techniques in man, Agoston, S.; Crul, E.J.; Kersten, U.W.; Houwertjes, M.C. and a slower rate of plasma concentration decline pro­ scar, A.H.J.: The relationship between disposition and dura­ duced a slower recovery rate, confirming previous tion of action of a congeneric series of steroidal neuromuscular clinical observations (D'Hollander et al., 1978). blocking agents. Acta Anaesthesiologica Scandinavica 27: Despite our results to the contrary (as presented 24- 30 (J 977 a). Agoston, S.; Crul, J.F.; Kersten, U.W. and Scaf, A.H.J.: Relation­ above), several workers have suggested that the rate ship of the serum concentration of pancuronium to its of disruption of the relaxant-receptor complex, rather neuromuscular activity in man. Anesthesiology 47: 509-572 than the plasma concentration of the relaxant, may be (J 977b). the predominant factor in the termination of action of Agoston, S.; Vermeer, G.A.; Kersten, U.W. and scar, A.H.J.: A relaxant drugs. Feldman and Tyrell (I970), on the preliminary investigation of the renal and hepatic excretion of gallamine triethiodide in man. British Journal of Anaesthesia basis of isolated arm experiments in man, have 50: 345-349 (J 978). postulated such a mechanism. This view has been Agoston, S.; Feldman, S.A. and Miller, R.D.: Plasma concentra­ supported by Goat et al. (I 976) and Heneghan et al. tions of pancuronium and neuromuscular blockade after injec­ (1978), since they show that recovery time is unrel­ tion into the isolated arm, bolus injection, and continuous in­ ated to muscle blood flow. However, recovery from fusion. Anesthesiology 51: 119-122 (1979). Aladjemoff. L.; Dikstein, S. and Shafrir, E.: Binding of d­ paralysis following bolus relaxant administration oc­ tubocurarine chloride to plasma proteins. Journal of Phar­ curs during the terminal elimination phase, when the macology and Experimental Therapeutics 123: 43-47 (J 958). pseudoequilibrium between plasma and muscle Ali, H.H.; Utting, J.E. and Gray, T.C.: Stimulus frequency in the results in a small drug concentration gradient which detection of neuromuscular block in humans. British Journal is unlikely to be affected by changes in muscle blood of Anaesthesia 42: 967-978 (J 970). Ali, H.H.; Utting, J.E. and Gray, T.C.: Quantitative assessment of flow (perfusion). Agoston et al. (1979) also speculate residual antidepolarising block. I.' British Journal of Anaes­ that the dissociation rate constant of the relaxant­ thesia 43: 473-477 (J97Ia). receptor complex is the rate limiting step in isolated Ali, H.H.; Utting, J.E. and Gray, T.e.: Quantitative assessment of arm (limb) experiments. However, as noted by residual antidepolarising block. II. British Journal of Anaes­ Stanski and Sheiner (I 979), this is not necessarily so, thesia 43: 478-485 (J 971 b). Atkins, G.L.: Comparison of analogue and digital computors, in since despite flow being established in the isolated Multicompartment Models in Biological Systems, pp.95-96 arm the delay in recovery can be explained by the (Methuen, London 1969). temporal dysequilibrium (Sheiner et al., 1979) that is Baraka, A.: The influence of carbon dioxide on the neuromuscular present during the distributive phase of relaxant dis­ block caused by tubocurarine chloride in the human subject. position. Thus, it would appear that the data of Feld­ British Journal of Anaesthesia 36: 272-277 (J 964). Baraka, A. and Gabali, F.: Correlation between tubocurarine re­ man and Tyrell (1970), and other workers (e.g. Mat­ quirements and plasma protein pattern. British Journal of An­ teo et al., 1974), are compatible with the kinetic prin­ aesthesia 40: 89-93 (J 968). ciples developed by Sheiner et al. (1979) with d­ Bellville, J.W.; Cohen, E.N. and Hamilton, J.: The interaction of tubocurarine. These principles assume a competitive morphine and d-tubocurarine on respiration and grip strength interaction between the relaxant and its receptor, with in man. Clinical Pharmacology and Therapeutics 5: 35-43 (J 964). the rate of decrease of the plasma concentration deter­ Blogg, e.E.; Simpson, B.R.; Martin, L.E. and Bell, J.A.: Proceed­ mining the rate of recovery from paralysis, as noted ings: Metabolism of 'H-AH8165 in man. British Journal of by Shanks et al. (I 979b) with pancuronium. Anaesthesia 45: 1233-1234 (1973). Pharmacokinetics of Non-depolarising Muscle Relaxants 56

Blogg, C.E.; Simpson, B.R.; Tyers, M.B.; Martin, L.E. and Bell, elimination of d-tubocurarine-'H. Anesthesiology 28: J.A.: Human placental transfer of AH8165. Anaesthesia 30: 309-317 (1967). 23-29 (1975). Cohen, E.N.; Corbascio, A. and FJeischli, G.: The distribution and Boiger, L.; Brittain, R.T. and Jack, D.: Short-lasting competitive fate of d-tubocurarine. Journal of Pharmacology and Experi­ neuromuscular blocking activity in a series of azobis­ mental Therapeutics 147: 120-129 (1965). arylimidazo (I,2-a) pyridinium dihalides. Nature 238: Cohen, E.N.; Paulson, W.J.; Wall, 1. and Elert, B.: Thiopental, 354-355 (1972). curare and nitrous oxide anaesthesia for caesarean section with Booth, P.N.; Watson, MJ. and Macleod, K.: Pancuronium and studies on placental transmission. Surgery, Gynecology and the placental barrier. Anaesthesia 32: 320-323 (1977). Obstetrics 97: 456-462 (1953). Bovet, D.; Depierre, F. and Lestrange, Y.: Proprietecurarisantes Cohen, E.N.; Paulson, WJ. and Elert, B.: Studies of d­ des ethers phenolique a fonctiones ammonium quaternaires. tubocurarine with measurement of concentration in human Proceedings Academic des Sciences (Paris) 225: 74-76 (1947). blood. Anesthesiology 18: 300-309 (1957). Boxenbaum, H.G.; Riegelman, S. and Elashoff, R.M.: Statistical Cozanitis, D. and Haapanen, E.: Studies on muscle relaxants dur- estiniations of phaimacoki...'1ctics. Journal of Pharrra.acokinetics ing haemodialysis. A.eta ~A.. naest"'lesio!ogica ScandL'lavica 23: and Biopharmaceutics 2: 123-148 (1974). 225-234 (1979). Bridenbough, P.O.; Churchill-Davidson, H.C. and Churcher, Crawford, J.S. and Gardiner, J.E.: Some aspects of obstetric an­ M.D.: Effects of carbon-dioxide on actions of d-tubocurarine aesthesia. Part II. The use of relaxant drugs. British Journal of and gallamine. Anaesthesia and Analgesia 45: 804-810 (1966). Anaesthesia 28: 154-158 (1956). Bush, G.H. and Stead, A.L.: The use of d-tubocurarine in neonatal Dal Santo, G.: Kinetics of distribution of radioactive labeled anaesthesia. British Journal of Anaesthesia 34: 721-728 muscle relaxants. Investigations with CI4-dimethyl-d­ (1962). tubocurarine. Anesthesiology 25: 788-800 (1964). Buzello, W.: Der stoffwechsel von pancuronium beim menschen. Dal Santo, G.: Kinetics of distribution of radioactive labelled Anaesthesist 24: 13-18 (1975). muscle relaxants IV: Urinary elimination of a single dose of Buzello, W. and Agoston, S.: Comparative clinical phar­ I4C-gallamine. British Journal of Anaesthesia 44: 321-328 macokinetics of d-tubocurarine, gallamine, a1curonium and (1972). pancuronium. Anaesthesist 27: 313-318 (I 978a). de Bros, F. and Gissen, A.J.: Determination of d-tubocurarine by Buzello, W. and Agoston, S.: Kinetics of intercompartmental dis­ liquid chromatography. Abstracts of scientific papers, position and excretion of tubocurarine, gallamine, a1curonium Anesthesiology 51: (SuppJ.) S 265 (1979). and pancuronium in patients with normal and impaired renal Devasankaraiah, G.; Haranath, P.S.R.K. and Krishnamurty, A.: function. Anaesthesist 27: 319-321 (I 978b). Passage of intravenously administered tubocurarine into the li­ Chmielewski, A.T.; Loach, A.B. and Goat, V.A.: Recovery from quor space in man and dog. British Journal of Pharmacology neuromuscular biockade. A comparison belween old and 47: 787-798 (1973). young patients. Anaesthesia 33: 539-542 (1978). D'Hollander, A.A.; Camu, F. and Sanders, M.: Comparative Churchill-Davidson, H.C.: The causes and treatment of prolonged evaluations of neuromuscular blockade after pancuronium ad­ apnea. Anesthesiology 20: 535-541 (1959). ministration in patients with and without reqal failure. Acta Churchill-Davidson, H.C. and Wise, R.P.: The response of the Anaesthesiologica Scandinavica 22: 26-27 (1978). newborn infant to muscle relaxants. Canadian Anaesthetists' Dretchen, K.L.; Morgenroth lll, V.H.; Standaert, F.G. and Walts, Society Journal II: 1-6 (1964). L.F.: Azathioprine: Effects on neuromuscular transmission. Churchill-Davidson, H.e.; Way, W.L. and de Jong, R.H.: The Anesthesiology 45: 604-609 (1976). muscle relaxants and renal excretion. Anesthesiology 28: D'Souza, J.; Caldwell, J.; Dring, L.G.; Rouse, J.; Bevan, D.R. and 540-546 (1967). Smith, R.L.: 1lSi-Labelled Rose Bengal in the quantitative Clissold, S.E.; Luscombe, D.K. and Mustapha, M.S.: Proceedings: estimation of fazadinium and other quaternary ammonium Some pharmacological studies on uraemia. Journal of Phar­ compounds in biological fluids. Journal of Pharmacy and macy and Pharmacology 27: (Suppl.)-2, 37P (1975). Pharmacology 31: 416-418 (1979). Cohen, E.N.: Fluorescent analysis of d-tubocurarine hydro­ Dundee, J.W.: Relationship of dosage of d-tubocurarine and Iand­ chloride. Journal of Laboratory and Clinical Medicine 61: olissin to body weight sex and age. British Journal of Anaes­ 338-345 (l963a). thesia 26: 174-181 (1954). Cohen, E.N.: Quantitative determination of d-tubocurarine in Dundee, J.W. and Gray, T.e.: Resistance to d-tubocurarine body tissues and fluids. Journal of Laboratory and Clinical chloride in the presence of liver damage. Lancet 2: 16-17 Medicine 62: 979-984 (I 963b). (1953). Cohen, E.N.: Renal clearance of d-tubocurarine. Investigative Durrans, S.F.: Prolonged apnoea. Lancet 2: 539 (1952). Urology 4: 69-72 (1966). Duvaldestin, P.; Henzel, D.; Gilles, M.R.; Roze, C. and Desmon­ Cohen, E.N.; Brewer, H.N. and Smith, D.: The metabolism and to, J.M.: Etude de la pharmacocinetique de Ia gallamine chez Pharmacokinetics of Non-depolarising Muscle Relaxants 57

(,homme. Anesthesia 34: 235-239 (\ 977). Gibaldi, M.; Levy, G. and Hayton, W.: Kinetics of the elimination Duvaldestin, P.; Agoston, S.; Henzel, D.; Kersten, U.W. and Des­ and neuromuscular blocking effect of d-tubocurarine in man. monts, J.M.: Pancuronium pharmacokinetics in patients with Anesthesiology 36: 213-218 (\ 972a). liver cirrhosis. British Journal of Anaesthesia 50: 1131-1136 Gibaldi, M.; Levy, G. and Hayton, W.L.: Tubocurarine and renal (\ 978a). failure. British Journal of Anaesthesia 44: 163-165 (\ 972b). Duvaldestin, P.; Henzel, D.; Demetriou, M. and Desmonts, J.M.: Gibaldi, M.; Levy, G. and Weintraub, H.: Drug distribution and Pharmacokinetics of fazadinium in man. British Journal of pharmacologic effects. Clinical Pharmacology and Thera­ Anaesthesia 50: 773-777 (1978b). peutics 12: 734-742 (197!). Duvaldestin, P.; Demetriou, M.; Henzel, D. and Desmonts, J.M.: Gissen, A.J. and Katz, R.L.: Twitch, tetanus and post tetanic po­ The placental transfer of pancuronium and its phar­ tentiation as indices of nerve muscle block in man. macokinetics during caesarian section. Acta Anaesthesiologica Anesthesiology 30: 481-487 (1969). Scandinavica 22: 327-333 (1978c). Goat, V.A.; Yeung, M.L.; Blakeney, C. and Feldman, S.A.: The Duvaldestin, P.; Gilbert, c.; Henzel, D.; Guy, P. and Desmonts, effect of blood flow upon the activity of gallamine triethiodide. J.M.: Pancuronium blood level monitoring in patients with British Journal of Anaesthesia 48: 69-73 (\976). tetanus. Intensive Care Medicine 5: 111-114 (\ 979). Gray, T.C.: Use of d-tubocurarine chloride in anaesthesia. Annals Elert, B. and Cohen, E.N.: A microspectrophotometric method for of the Royal College of Surgeons of England I: 191-203 the analysis of minute concentrations of d-tubocurarine (1947). chloride in plasma. American Journal of Medical Technology Hallen, B.; Sundwall, A.; Elwin, C.E. and Vessman, J.: Renal, 28: 125-134 (1962). biliary and intestinal clearance of a quaternary ammonium EI-Hakim, M. and Baraka, A.: d-Tubocurarine in liver disease. compound, emepronium in the dog. Acta Pharmacologica et Kasr-EI-Aini Journal of Surgery 4: 99-104 (1963). Toxicologica 44: 43-59 (\ 979). Epstein, R.A. and Epstein, R.M.: The electromyogram and the Ham, J.; Miller, R.D.; Benet, L.Z.; Matteo, R.S. and Roderick, mechanical response of indirectly stimulated muscle in L.L.: Pharmacokinetics and pharmacodynamics of d­ anesthetized man following curarization. Anesthesiology 38: tubocurarine during hypothermia in the cat. Anesthesiology 212-223 (\ 973). 49: 324-329 (1978). Feldman, S.A.: Serum dTc and neuromuscular blockade in man Haranath, P.S.; Krishnamurty, A.; Rao, L.N. and Seshagirirao, (corresp). Anesthesiology 42: 644-645 (\ 975). K.: Passage of gallamine from blood into the liquor space in Feldman, S.A. and Levi, J.A.: Prolonged paresis following man and in dog. British Journal of Pharmacology 48: 640-645 gallamine. British Journal of Anaesthesia 35: 804-806 (\ 963). (1973). Feldman, S.A. and Tyrrell, M.F.: A new theory on the termina­ Haselhuhn, D.H.: The use of pentothal in the presence of severe tion of action of the muscle relaxants. Proceedings of the hepatic disease. Anaesthesia and Analgesia 36: 73-75 (1957). Royal Society of Medicine 63: 692-695 (\ 970). Havill, J.H.; Mee, A.D.; Wallace, M.R.; Chin, L.S. and Rothwell, Feldman, S.A.; Cohen, E.N. and Golling, R.C.: The excretion of R.P.: Prolonged curarisation in the presence of renal impair­ gallamine in the dog. Anesthesiology 30: 593-598 (1969). ment. Anaesthesia and Intensive Care 6: 234-238 (1978). Fogdall, R.P. and Miller, R.D.: Prolongation of a pancuronium­ Heaney, G.A.H.: Pancuronium in maternal and foetal serum. 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