Research Article: New Formulations of Local Anaesthetics—Part I

Date Published: December 5, 2012

Publisher: Hindawi Publishing Corporation

Author(s): Edward A. Shipton.


Part 1 comments on the types of local anaesthetics (LAs); it provides a better understanding of the mechanisms of action of LAs, and their pharmacokinetics and toxicity. It reviews the newer LAs such as levobupivacaine, ropivacaine, and articaine, and examines the newer structurally different LAs. The addition of adjuvants such as adrenaline, bicarbonate, clonidine, and corticosteroids is explored. Comment is made on the delivery of topical LAs via bioadhesive plasters and gels and controlled-release local anaesthetic matrices. Encapulation matrices such as liposomes, microemulsions, microspheres and nanospheres, hydrogels and liquid polymers are discussed as well. New innovations pertaining to LA formulations have indeed led to prolonged action and to novel delivery approaches.

Partial Text

Local anaesthetics (LAs) are used clinically for anaesthesia and analgesia either following surgery or for management of other acute and chronic pain conditions; they only last a few hours. Part 1 of this paper deals with the newer LAs, more recent LA formulations, a better understanding of the mechanisms of action of LAs, and their pharmacokinetics and toxicity.

Lignocaine is perhaps most commonly used or known local anaesthetic agent; it is used either in local or regional anaesthesia, or in epidural or spinal blockade; it has a number of uses in anaesthesia and pain medicine. However, it is also given parenterally in the management of neuropathic pain states. EMLA, a eutectic mixture of lignocaine and prilocaine, is an effective topical anaesthetic in preventing pain associated with needle procedures [6].

Injectable local anaesthetics are subject to absorption; a large fraction of the injected drug is removed by the systemic circulation and distributed to distant organs according to their vascular density [9]. Highly vascular organs (brain, heart, lung, liver, and kidneys) are exposed to unmetabolised local anaesthetic at peak concentration. The local anaesthetic is taken up within each organ according to its tissue-plasma partition coefficient. Most absorbed local anaesthetic is cleared from the liver. Hepatic clearance is a function of the hepatic extraction ratio and hepatic blood flow. The hepatic extraction ratio, in turn, is dependent on the ratio of free to protein-bound drug. Local anaesthetics bind tightly to plasma proteins greatly limiting the free fraction of available drug. Only the free or unbound fraction that is bioactive. Like most weak bases, local anaesthetics bind mainly to alpha-1-acid glycoprotein. Lignocaine, being moderately protein-bound, has a high hepatic extraction ratio (70–75% per pass) [9]. Clearance is therefore flow-limited and is reduced by factors that limit hepatic blood flow. Conversely, bupivacaine and ropivacaine, being highly protein-bound, are cleared <50% per pass; hence, their clearance depends on free drug concentration [9]. Low cardiac output states may not greatly affect the plasma concentration of the highly protein-bound agents, as their clearance is not flow limited. Intrinsic hepatic disease may alter clearance by altering plasma protein content and degree of protein binding, by decreasing the enzyme activity of the liver, and by reducing hepatic blood flow. Patients with liver disease may have single-shot blocks with normal doses. Doses for continuous infusion and repeat blocks need to be significantly reduced (10–50% relative to the degree of dysfunction) due to the risk of accumulation of the primary compound and its metabolites [10]. Patients with mild or controlled cardiac failure may not need a dose reduction for single-shot blocks. Doses of ropivacaine and bupivacaine for continuous infusion and repeat blocks need to be reduced, as their metabolites will be eliminated slowly. In patients with renal dysfunction, reduced clearance and faster absorption of local anaesthetic lead to an elevation in plasma concentration [10]. Clearance of both bupivacaine and ropivacaine has been shown to be reduced in uraemic patients [9, 10]. The clearance of one of the main metabolites of ropivacaine, 2,6-pipecoloxylidide (PPX), is also decreased in uraemic patients [9]. Local anaesthetics directly block transmission of pain from nociceptive afferents. Local anaesthetic agents are applied directly, and their efficacy results from action on the nerve where the inward Na+ current is blocked at the sodium ionophore during depolarisation. LAs not only block Na+ channels but Ca2+ and K+ channels [16–18], transient receptor potential vanniloid-1 receptors [19], and other ligand-gated receptors as well. Local anaesthetics also disrupt the coupling between certain G proteins and their associated receptors [20]. Through this action, LAs exert potent anti-inflammatory effects, particularly on neutrophil priming reactions [21]. Local anaesthetics inhibit local inflammatory response to injury that can sensitise nociceptive receptors and contribute to pain and hyperalgesia. Studies have observed that local anaesthetics reduce the release of inflammatory mediators from neutrophils, reduce neutrophil adhesion to the endothelium, reduce formation of free oxygen radicals, and decrease oedema formation [22]. There are, in addition, a variety of other antithrombotic and neuroprotective actions of intravenous LAs [20] that are independent of Na+ channel blockade but may account for many of the improvements in pain after surgery [16, 22]. Local anaesthetics can alleviate some types of neuropathic pain, and part of this effect may be related to sensitisation of the antinociceptive pain pathways that occur in the neuropathic pain state; spinal glial cells have been shown to play some part in this as well [23]. Toxicity primarily involves the central nervous system followed by the cardiovascular system. More potent agents (bupivacaine, levobupivacaine, ropivacaine) produce cardiotoxic effects at lower blood concentrations and doses than less potent LA agents (lignocaine) [29]. The (+)-(R)-enantiomers bind with greater affinity to cardiac Na+ channels than the (−)-(S)-enantiomers do. LA agents cause marked but reversible lesions to skeletal muscle tissue [3]. Myotoxicity seems to be explained by mitochondrial bioenergetics alteration. In the animal model, this toxic effect was significantly more severe in young rats [30]. The nitric oxide pathway is involved in the development of tachyphylaxis [31]. In addition, there is a growing amount of evidence that intra-articular administration of bupivacaine is chondrotoxic especially at a higher concentration and with prolonged exposure [24]. Adrenaline induces vasoconstriction, reducing local anaesthetic clearance from the site of action, thus prolonging the duration of action. Solutions such as 1 : 200000 or 1 : 400000 are commonly used [37]. Topical delivery systems for LA are characteristically composed by a diversity of formulations (viscosity inducing agents, preservatives, permeation enhancers, emollients,) and presentations such as semisolid (gel, creams, ointments), liquid (emulsions, dispersions), and solid (patches) pharmaceutical forms [41]. The proposed formulations aim to reduce the LA concentration used, increase its permeability and absorption, keep the LA at the target site for longer and decrease the clearance, and limit local and systemic toxicity [41]. A rapidly growing research topic is the use of vesicular carriers such as liposomes, niosomes, ethosomes (soft lipid vesicles), and elastic and deformable vesicles to provide an efficient dermal delivery system [46]. Encapsulation of local anaesthetic agents allows large doses to be released slowly and provides analgesia over a prolonged period without toxicity [47]. Encapsulating agents include liposomes [48], lipospheres [49], cyclodextrins [50], and microparticles [51]. Following injection of a depot of the formulation, much of the LA agent is bound or carried inside another agent and is not immediately available. The duration of the analgesia depends on the release rate of the LA agent from the carrier agent. Several properties such as hydrophobicity and internal membrane pH affect encapsulated drug release rates [3]. Some synergistic agents such as dexamethasone and clonidine encapsulated with the main effective agent have been formulated; these increased the anaesthesia time for several days [3, 52]. Local anaesthetics are widely used to manage acute, chronic, and cancer pain, for anaesthesia, and for diagnostic purposes. Local anaesthetics may have similar chemical structures, but differing pharmacokinetic properties and spectra of pharmacodynamic effects. This influences the selection of agents for use in various clinical situations [82]. New innovations pertaining to LA formulations lead to prolonged action or to novel delivery approaches. Decades after the introduction of local anaesthetics for analgesia/anaesthesia, new properties may still be discovered. New applications of this class of drugs may still be anticipated. The use of regional anaesthesia may affect cancer recurrence rates following surgical resection of tumours via immunomodulation [79]. The preservation of the body's immune processes by local anaesthetics needs to be further studied.The development of new effective delivery systems should suitably modulate the release rate of these drugs, extend their anaesthetic effect, and enhance their localisation; this should reduce problems of systemic toxicity. Part 2 of this paper will deal with new techniques for the delivery of topical and injectable local anaesthetics.   Source:


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