Skeletal muscle relaxants in anaesthesiology

Abstract

During the 16th century, European explorers found that the Indians along the Amazon and Orinoco Rivers were using an arrow poison, named curare, that produced death by skeletal paralysis. Curare is one of several different resinous substances obtained from extracts of South American trees including species of chondrodendron. The pharmacological active ingredient of curare used medically is the alkaloid d-tubocurarine. Muscle relaxation or paralysis results from an interruption in the pathways for nervous impulses between the nervous system and muscle. Most drugs may also exert a variable degree of prejunctional effect. Several drugs have as their major action the interruption of transmission of the nerve impulse at the skeletal neuromuscular junction (NMJ). The neuromuscular blocking drugs (NMB) are quaternary ammonium compounds. Positive charges at these sites in the molecules mimic the quaternary nitrogen atom of the transmitter ACh and are the principal reason for the attraction of these drugs to cholinergic receptors. All muscle relaxants contain two positive charges or at least two potential positive charges (except gallamine which has 3); these are separated by a bridging structure that is lipophilic, different for various series of muscle relaxants and is a major determinant of potency. The NMBs are classified either as nondepolarising (competitive blocking) agents, or as depolarising agents. Nondepolarising drugs are for the most part relatively bulky, rigid molecules (e.g., d-tubocurarine, the toxiferines, the benzylisoquinolines, the ammonium steroids such as pancuronium) and occupy one or both of the receptor sites and thus prevent depolarisation by denying ACh access to the receptors. These drugs can be antagonised by anticholinesterase agents such as neostigmine, which prevent breakdown of ACh so that more of it is present to compete with the relaxant drug. Depolarising NMBs (e.g., decamethonium, succinylcholine) generally have a more flexible structure that enables free bond rotation. Succinylcholine is the only one depolarising drug currently used; it acts by causing a prolonged depolarisation of the muscle end plate, making it unresponsive to ACh. Such a block is not antagonised by neostigmine. Anticholinesterase drugs, in fact, prolong a succinylcholine block. All muscle relaxants are ionised and positively charged irrespective of the pH and thus poorly lipid soluble. Because of this they do not readily cross the blood-brain barrier, cell membranes or placenta and are generally not actively metabolised by the liver, although some of the steroidal derivatives are an exception. The Pharmacokinetics of NMBs is described by 2- or 3-compartment models. The volume of distribution of these drugs is relatively small due to their poor lipid solubility. The pharmacokinetic behavior of this class of agents is little influenced by age or anaesthetic agents; however, hepatic or renal disease may profoundly alter their excretion pattern, resulting in prolonged duration of neuromuscular blockade. For most of these agents, biotransformation plays an important role in their total elimination. Adverse side effects that may accompany the administration of succinylcholine include cardiac dysrhythmias, hyperkalemia, myalgia, myoglobinuria, increased intragastric pressure, increased intraocular pressure, increased intracranial pressure, and sustained skeletal muscle contractions. Drugs administered in the perioperative period, such as (a) volatile anaesthetics, (b) aminoglycoside antibiotics, (c) local anaesthetics, (d) cardiac antidysrhythmic drugs, (e) diuretics, and (f) magnesium, lithium and gaglionic-blocking drugs, may enhance the effects of nondepolarising NMBs at the NMJ. Changes unrelated to concurrent drug therapy, such as (a) hypotension, (b) acid-base alterations, (c) changes in serum potassium concentrations, (d) adrenocortical dysfunction, (e) thermal (burn) injury and allergic reactions, may also influence the characteristics of neuromuscular blockade produced by nondepolarising NMBs. Combinations of nond polarising NMBs may produce a degree of neuromuscular blockade that is different from the degree that would be produced by either drug alone. In addition, gender may influence the duration of neuromuscular blockade produced by nondepolarising NMBs. Ageing may influence the duration of action of NMBs. In paediatric patients there are alterations in neuromuscular function across the age ranges: the neonatal NMJ is more sensitive than that of the adult, but pharmacokinetic factors often counterbalance this sensitivity and consequently, in many cases, the nondepolarising-blocking agents requirement in the neonate is similar to that of the adult. The onset of action is more rapid in infants than in children and that, in general, children require more NMB by weight than do infants or adult to obtain similar levels of paralysis. Children recover more rapidly than other age groups, although infants may recover more rapidly from drugs which are metabolised in the plasma. In elderly patients, the duration of action of nondepolarising NMBs is often prolonged, probably owing to decreased clearance of drugs by the liver and kidneys; as a result, the dose of NMBs should probably be reduced. Several diseases can diminish or augment the neuromuscular blockade produced by nondepolarising NMBs. The duration of effect and time to recovery are increased in patients with renal and hepatic failure, possibly due to reduced plasma cholinesterase concentrations. Myasthenia gravis markedly augments the neuromuscular blockade from these drugs. Pancuronium is the most commonly used long-acting nondepolarising neuromuscular blocking drug. Doxacurium and pipecuronium resemble puncuronium, but, unlike pancuronium, these drugs are devoid of cardiovascular side effects. d-tubocurarine, metocurine and gallamine are largely replaced in clinical practice with drugs possessing more efficient and predictable clearance mechanisms. The intermediate-acting nondepolarising neuromuscular drugs, atracurium, vecuronium, rocuronium and cisatracurium possess efficient clearance mechanisms that minimize the likelihood of significant cumulative effects with repeated injections or continuous infusions; these drugs are useful especially when tracheal intubation or skeletal muscle relaxation are needed for short operations, such as outpatient procedures. Mivacurium is the only clinically useful short-acting nondepolarising neuromuscular-blocking drug; ORG 9487 is more rapid in onset than mivacirium, but has a similar duration of action.