Clinical Pharmacokinetics of the Non-Depolarising Muscle Relaxants
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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