Kip A. Lemke
Local and regional anesthetic techniques are gaining widespread acceptance in the management of pain in small and large animals (Lemke & Dawson, 2000; Anderson & Muir, 2005; Valverde &
Gunkel, 2005). In recent years, a clearer understanding of the pathophysiology of pain has provided the conceptual framework for a more rational use of these techniques (Muir & Woolf, 2001;
Lemke, 2004; Lamont, 2008; Lemke & Creighton, 2010). Tissue trauma and inflammation produce sensitization of the peripheral nervous system, and the subsequent barrage of nociceptive input produces sensitization of neurons in the dorsal horn of the spinal cord. Because local and regional anesthetic techniques are the only analgesic techniques that produce complete blockade of periph-eral nociceptive input, they are the most effective way to prevent sensitization of the central nervous system (CNS) and the devel-opment of pathological or maladaptive pain. Lidocaine can also be administered systemically to reduce anesthetic requirements and to manage certain types of pain in veterinary species (Valverde et al., 2004; Robertson et al., 2005). The precise mechanism underlying the antinociceptive effects of systemically administered lidocaine is unclear, but peripheral and central neural mechanisms have been proposed (Cook & Blikslager, 2008).
STRUCTURE AND PHYSICAL PROPERTIES
Local anesthetics penetrate peripheral nerves and induce reversible blockade of impulse conduction in myelinated and unmyelinated nerve fibers by inhibiting voltage-gated sodium channels. These drugs are weak bases, and are classified as aminoesters (e.g., pro-caine) or amino amides (e.g., lidocaine or lignopro-caine) (Figure 6.1).
All local anesthetics have an aromatic group that is connected to a tertiary amine group by either an ester (RCOOR’) or an amide (RNHCOR’) linkage. As a general rule, the structure of the aro-matic group determines the lipid solubility of the drug, and the structure of the tertiary amine determines the water solubility of the drug.
At physiological pH (7.4), the tertiary amine group readily accepts protons and the local anesthetic molecule exists in equi-librium as a neutral, lipid-soluble base and as a positively charged, water-soluble acid. The dissociation constant, or pKa, is the pH at which concentrations of neutral base and positively charged acid are equal. Most local anesthetics have pKa values in the range
7.5–8.5. As the pKa value decreases, a greater fraction of the drug exists as neutral base and more molecules penetrate the lipid mem-branes, and the onset of action tends to be more rapid. Conversely, as the pKa value increases, a greater fraction of the drug exists as positively charged acid and fewer molecules penetrate the lipid membranes, and the onset of action tends to be slower.
The structure of the aromatic group determines the lipid solubility of local anesthetics as well as potency, duration of action, and binding to tissue and plasma proteins (Table 6.1). Drugs with low lipid solubility (procaine) tend to have low potency, a short duration of action, and limited protein binding. Drugs with intermediate lipid solubility (lidocaine) tend to have intermediate potency, an intermediate duration of action, and intermediate protein binding.
Drugs with high lipid solubility (bupivacaine) tend to have high potency, a long duration of action, and high protein binding.
Some local anesthetics (mepivacaine, bupivacaine, ropivacaine) have an asymmetrical carbon atom, and exist in solution as paired stereoisomers or enantiomers. These enantiomers are mirror images of each other, and cannot be superimposed without breaking the chemical bonds. The physical properties of enantiomers are identi-cal, but their biological activity can differ significantly. Enantiomers are classified based on their ability to rotate a plane of polarized light when dissolved in a specified solvent. Enantiomers that rotate polarized light to the right are designated dextrorotatory (d or+) isomers, and those that rotate polarized light to the left are des-ignated levorotatory (l or −) isomers. Racemic mixtures contain equal amounts of both enantiomers. Mepivacaine and bupivacaine are supplied as racemic mixtures, and levobupivacaine and ropiva-caine are supplied as the pure levorotatory enantiomer.
Another method of classification is based on unequivocal des-ignation of molecular structure by assigning sequence priority to groups attached to a tetrahedral chiral center. A clockwise group sequence is designated as the R isomer, and a counterclockwise group sequence is designated as the S isomer. It should be noted that no fixed relationship between the d/l and R/S designations exists.
MECHANISM OF ACTION
Local anesthetics block the conduction of nerve impulses by inhibit-ing voltage-gated sodium channels in neuronal membranes. The
Pain Management in Veterinary Practice, First Edition. Edited by Christine M. Egger, Lydia Love and Tom Doherty.
C2014 John Wiley & Sons, Inc. Published 2014 by John Wiley & Sons, Inc.
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86 Section 2 / Pharmacology of Analgesic Drugs
H2N
Procaine
Lidocaine CH3
CH3
—COO— CH2CH2N (CH2CH3)2
—NHCO — CH2N (CH2CH3)2 Aromatic
ring
Ester linkage
Tertiary amine (–NR2H+)
Aromatic ring
Amide linkage
Tertiary amine (–NR2H+)
Figure 6.1. Chemical structure of aminoester (procaine) and aminoamide (lidocaine) local anesthetics. Procaine and lidocaine are the prototypical aminoester and aminoamide local anesthetics, respectively. All local anesthetics have an aromatic ring connected to a tertiary amine with either an ester or an amide linkage. The aromatic ring determines the lipid solubility and the tertiary amine determines the water solubility of the drug. Ester-linked local anesthetics are metabolized rapidly by plasma esterases, and amide-linked local anesthetics are metabolized more slowly by the liver.
binding site for local anesthetics is located on the cytoplasmic or intracellular surface of the sodium channel (Figure 6.2). The neu-tral base must diffuse across the lipid membrane and dissociate from the membrane to gain access to this site. Once inside the cell, the tertiary amine group is protonated and the charged acid binds to the sodium channel. Local anesthetics stabilize inactive conformational states of the sodium channel and delay reactiva-tion of the channel rather than physically blocking the pore. Only
LA + H+ <– LAH+
LA + H+ –> LAH+
Na+ Extracellular pH 7.4
Intracellular pH 6.9
Figure 6.2. Diffusion and binding of local anesthetics to voltage-gated sodium channels. The binding site for local anesthetics is on the cytoplasmic or intracellular surface of the sodium channel. Neutral local anesthetic base diffuses across the lipid membrane. Once inside the cell, the tertiary amine group is protonated and local anesthetic binds to the sodium channel and stabilizes inactive conformational states. LA,neutral local anesthetic; LAH+, protonated local anesthetic
moderately lipid-soluble local anesthetics with pKa values close to physiological pH can penetrate the connective tissue sheaths and neuronal membranes, gain access to the cytoplasmic binding site, and inactivate sodium channels.
ANATOMY OF PERIPHERAL NERVES
Peripheral nerves are composed of different types of sensory, motor, and autonomic nerve fibers surrounded by connective tis-sue sheaths. Local anesthetics injected near peripheral nerves must penetrate these connective tissue sheaths before reaching the neu-ronal membrane. Diffusion of the local anesthetics away from the injection site is a function of tissue binding and uptake into the systemic circulation.
Sensory nerve fibers are classified by axon diameter, the presence or absence of myelination, and their response to mechanical, ther-mal, and chemical stimuli (Table 6.2). A-beta (A) sensory fibers have large myelinated axons that conduct impulses at a velocity of
Table 6.1. Physical properties of local anesthetics
Drug pKa
Onset of action (min)
Relative lipid solubilitya
Relative potencya
Duration of action (min)
Plasma protein binding (%) Low potency and short duration of action
Procaine 8.9 10–20 1 1 30–60 6
Intermediate potency and duration of action
Lidocaine 7.9 5–10 1.4 2 60–120 65
Mepivacaine 7.7 5–10 12.4 2 90–180 78
High potency and long duration of action
Bupivacaine 8.1 10–20 204 4 180–360 95
Levobupivacaine 8.1 10–20 204 4 180–360 95
Ropivacaine 8.1 10–20 68 3 120–240 94
aLipid solubility and potency are relative to procaine.
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6 / Local Anesthetics 87
Table 6.2. Types of neurons blocked with local anesthetics
Neuron type Function Myelination
Order of
blockade Signs of blockade A alpha Motor skeletal muscle Myelinated Fifth Loss of motor function A beta Sensory touch, pressure Myelinated Fourth Loss of sensation to
touch and pressure A gamma Motor muscle spindles,
proprioception
Myelinated Third Loss of proprioception A delta Fast pain, temperature Myelinated Second Pain relief, loss of
temperature sensation
B Autonomic, preganglionic
sympathetic
Myelinated First Increased skin
temperature
C Slow pain, autonomic,
postganglionic
sympathetic, polymodal nociceptors
Unmyelinated Second Pain relief, loss of temperature sensation
greater than 30 m/s. The free nerve endings of these fibers respond to non-noxious mechanical stimuli (touch), but do not respond to noxious stimuli directly. A-delta (A␦) nociceptive fibers have small myelinated axons that conduct impulses at a velocity of 10–30 m/s and carry the nociceptive input responsible for the fast sharp pain that occurs immediately after injury. The free nerve endings of these fibers contain membrane-bound receptors that respond primarily to intense mechanical and thermal stimuli and are called mechanoth-ermal nociceptors. C-nociceptive fibers have small unmyelinated axons that conduct nerve impulses at a velocity of less than 3 m/s.
The free nerve endings of these fibers contain membrane-bound receptors that respond to chemical as well as thermal and mechani-cal stimuli, and are mechani-called polymodal nociceptors. The nociceptive input responsible for the prolonged dull pain that occurs several seconds after a painful stimulus is carried by C fibers. Some local anesthetics (bupivacaine) preferentially block nociceptive A␦and C fibers.
Motor and autonomic fibers are also blocked by local anesthetics.
These fibers are also classified by axon diameter and the presence or absence of myelination. A-alpha (A␣) motor fibers directly inner-vate skeletal muscles and have large myelinated axons that conduct impulses at a velocity of greater than 70 m/s. A-gamma (A␥) fibers control muscle spindle tone and have small myelinated axons that conduct impulses at a velocity of 10–30 m/s. The postganglionic autonomic fibers that regulate vascular smooth muscle tone are small unmyelinated C fibers. Blockade of these fibers is respon-sible for the decrease in blood pressure observed after epidural administration of local anesthetics.
The location of nerve bundles within large peripheral nerves, the presence or absence of myelination, and the discharge rate influence the onset and duration of neural blockade. Generally, nerve bundles innervating proximal regions are located more superficially in large peripheral nerves than those innervating distal regions. Local anes-thetics penetrate superficial nerve bundles first and proximal areas are blocked sooner than more distal areas. The presence or absence of myelination also influences the uptake of local anesthetics by nerve fibers. As a general rule, small myelinated and unmyelinated nerve fibers are blocked before large myelinated fibers, and the
con-ventional understanding has been that small sensory fibers, specifi-cally myelinated (A␦) and unmyelinated (C) nociceptive fibers are blocked before larger sensory (A) and motor (A␣) fibers. How-ever, small unmyelinated (C) fibers are more resistant to blockade with local anesthetics than previously thought (Wildsmith et al., 1987). In certain circumstances, transmission mediated by unmyeli-nated C fibers can persist even after complete motor blockade has been established (Gokin et al., 2001). The discharge rate of the nerve fiber also influences the development of neural blockade. Local anesthetics have a higher binding affinity for open and inactivated sodium channels than they do for resting channels. Increased bind-ing of local anesthetics to sodium channels at high discharge rates stabilizes inactive conformational states and enhances the develop-ment of neural blockade. This enhancedevelop-ment of neural blockade at high discharge rates is termed phasic or use-dependent blockade. A damaged nerve fiber may develop ectopic high-frequency impulse generation, and use-dependent blockade may allow for more effec-tive analgesia at lower concentrations of local anesthetics (Brau et al., 2001; Hoffmann et al., 2008).
SYSTEMIC ABSORPTION AND METABOLISM
Systemic absorption of local anesthetics is determined by dose, volume, and route of administration. Absorption from mucosal, pleural, and peritoneal surfaces is rapid, and peak plasma con-centrations are reached within 10 minutes. Plasma concon-centrations achieved after interpleural or intercostal administration are com-parable to those achieved after intravenous administration. Local anesthetics are also absorbed quickly from epidural injection sites, and peak plasma concentrations are reached in approximately 30 minutes. Absorption from subcutaneous sites is slower, and peak plasma concentrations are approximately half of those achieved after interpleural or intercostal administration.
Binding of local anesthetics to tissue proteins and the vas-cularity of the injection site also influence systemic absorption of local anesthetic drugs. Moderately lipid-soluble drugs (e.g., lidocaine/lignocaine) do not bind extensively to tissue proteins and are absorbed rapidly, and highly lipid-soluble drugs (e.g.,
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88 Section 2 / Pharmacology of Analgesic Drugs bupivacaine) bind extensively to tissue proteins and are absorbed
more slowly. All commonly used local anesthetics cause vasodi-lation that accelerates systemic absorption of the drug. Vasocon-strictors (e.g., epinephrine) can be added to local anesthetic solu-tions to delay absorption and reduce systemic toxicity, but they can also cause localized ischemia. Epinephrine decomposes rapidly on exposure to air or light, thus antioxidants (metabisulfite) are added, and the pH of local anesthetic solutions containing epinephrine is decreased to prolong the shelf life. The pH of solutions con-taining epinephrine ranges from 3.0 to 4.5, while the pH of solu-tions without epinephrine ranges from 4.5 to 6.5. Although the addition of epinephrine delays systemic absorption, the decrease in pH also delays the onset of action. Epidural administration of acidic local anesthetic solutions containing antioxidants has also been associated with neurotoxicity (Ravindran et al., 1982). His-torically, vasoconstrictors have been added to short-acting and intermediate-acting drugs (procaine, lidocaine); however, they have a limited effect on the duration of action and systemic absorption of long-acting drugs (bupivacaine). Given the potential for localized ischemia as well as the availability of long-acting local anesthetics with inherently slow systemic absorption, the addition of vaso-constrictors to local anesthetic solutions may have limited clinical utility.
Once absorbed into the systemic circulation, local anesthetics bind reversibly to plasma proteins (e.g.,␣-1 acid glycoprotein, albu-min) and red blood cells. The degree of tissue and protein binding influences the onset and duration of action, as well as the toxicity of local anesthetic drugs. Consequently, doses of local anesthetics should be calculated carefully for patients with significant anemia and hypoproteinemia. Aminoesters tend to be less lipid-soluble and protein-bound, and therefore have a faster onset and shorter duration of action. Conversely, aminoamides tend to be more lipid-soluble and protein-bound, and as a result have a slower onset and longer duration of action.
Aminoesters and aminoamides are metabolized by distinctly dif-ferent pathways and at very difdif-ferent rates. Aminoesters are rapidly hydrolyzed by the tissue and plasma esterases, and the metabolites are excreted by the kidneys. Aminoamides are metabolized primar-ily in the liver by cytochrome P450 enzymes at a relatively slow rate. Clearance of aminoamides is dependent on cardiac output and hepatic blood flow. In anesthetized animals, clearance of lidocaine decreases by approximately 50% and plasma concentrations double (Mather et al., 1986; Feary et al., 2005). The major routes of hep-atic metabolism are hydroxylation, N-dealkylation, and hydrolysis, with subsequent elimination of metabolites by the kidneys. The lungs also temporarily sequester a significant amount of drug after systemic absorption of local anesthetics. Doses of aminoamides should be calculated carefully for patients with hypoproteine-mia and delayed drug metabolism caused by advanced liver disease.
LOCAL TISSUE AND SYSTEMIC TOXICITY
Local anesthetics are safe drugs if they are used with reason-able care. Administration of an incorrect dose and inadvertent intravenous administration are probably the most common causes of systemic toxicity. Interpleural or intercostal administration of large doses is also a potential cause of systemic toxicity, espe-cially in small animals. Toxicity of local anesthetics is additive,
and care should be taken when multiple routes of exposure (e.g., topical and regional), mixtures of local anesthetics, or repeated dosing are employed. Some aminoesters (procaine) are deriva-tives of para-aminobenzoic acid and have the potential to cause allergic reactions, but they are used infrequently in veterinary medicine. Conversely, allergic reactions to aminoamide local anes-thetics are extremely rare, although some preservatives (methyl-paraben) can cause allergic reactions. Several veterinary species can develop methemoglobinemia after topical exposure to benzo-caine, though cats are most susceptible and benzocaine-containing products including Cetacaine (a combination of benzocaine, butam-ben, and tetracaine) should be avoided in this species (Davis et al., 1993).
Most commonly used local anesthetic solutions cause some degree of local tissue irritation, and inappropriate administration of concentrated solutions causes local tissue toxicity and nerve damage. Application of 5% lidocaine to peripheral nerves causes irreversible conduction block within minutes. Even standard con-centrations of commonly used local anesthetics (e.g., 2% lidocaine) produce localized tissue irritation and histological changes. Short-term in vitro exposure of articular chondrocytes to 2% lidocaine, 0.5% ropivacaine, or 0.5% bupivacaine also produces significant cytotoxicity, although the clinical significance of this is not known (Piper et al. 2011). Dilution of local anesthetics plays an important role in reducing local tissue toxicity. Preservatives are added to multi-dose local anesthetic solutions, and some of these preser-vatives are potentially allergenic (e.g., methylparaben) or neu-rotoxic (e.g., metabisulfite). To prevent neuneu-rotoxicity, only low concentrations (2% lidocaine, 0.5% bupivacaine) of single-dose preservative-free local anesthetic solutions should be administered by the intrathecal or epidural route. The relative potency and sys-temic toxicity of bupivacaine is approximately four times that of lidocaine. As a result, a 0.5% (5 mg/mL) solution of bupivacaine is equivalent to a 2% (20 mg/mL) solution of lidocaine in terms of potency and toxicity.
Systemic reactions to local anesthetics involve primarily the CNS, but the cardiovascular system can be affected if very large doses are given. Initial signs of CNS toxicity include sedation, disorientation, and ataxia. Muscle tremors, convulsions, and respi-ratory depression can occur after administration of large doses.
Threshold plasma concentrations for CNS toxicity are approx-imately 5–10 mcg/mL for lidocaine and mepivacaine, and 2–4 mcg/mL for bupivacaine, levobupivacaine, and ropivacaine.
Cats and horses are more likely than other domestic species to develop signs of CNS toxicity after administration of local anesthet-ics. In horses, muscle tremors developed after intravenous adminis-tration of lidocaine at a dose of 4.9 mg/kg (1.5 mg/kg bolus followed by a 0.3 mg/kg/min infusion) (Meyer et al., 2001). The intravenous dose of lidocaine that produces convulsions in cats (12 mg/kg) is approximately 50% lower than that in dogs (22 mg/kg), and the intravenous dose of bupivacaine that produces convulsions in cats (3.8 mg/kg) is only 25% lower than that in dogs (5 mg/kg) (Liu et al., 1983; Chadwick, 1985). Initial signs of CNS toxicity (seda-tion, ataxia) become apparent after administration of approximately half of the convulsive dose. Furthermore, moderate respiratory aci-dosis (PaCO2=60–80 mmHg) increases cerebral blood flow and the proportion of unbound free drug available for diffusion across neuronal membranes, decreasing the convulsive dose of lidocaine and bupivacaine by approximately 50% (Englesson, 1974). As a
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6 / Local Anesthetics 89 result, adequate ventilatory support, in addition to anticonvulsant
therapy (e.g., diazepam), is critically important in the management of systemic toxicity.
Clinical signs of cardiovascular toxicity occur at doses that are approximately four times higher than those required to produce CNS toxicity. Local anesthetics produce direct effects on the heart and blood vessels, as well as indirect effects mediated by blockade of the autonomic nervous system. Toxic doses of local anesthetics depress myocardial contractility and cause peripheral vasodilation and profound hypotension. Conduction abnormalities and arrhyth-mias are rarely observed after administration of large doses of short-acting local anesthetics (e.g., lidocaine, mepivacaine). However, intravenous administration of large doses of long-acting local anes-thetics (e.g., bupivacaine) can produce ventricular arrhythmias and cardiovascular collapse in animals (Feldman et al., 1989). Newer long-acting local anesthetics (e.g., ropivacaine, levobupivacaine) appear to be less cardiotoxic than bupivacaine at equipotent doses (McClure, 1996; Foster & Markham, 2000).
Intravenous administration of a lipid emulsion (i.e., 20%
Intralipid) has been used to successfully treat bupivacaine toxic-ity in dogs (Weinberg et al., 2003). The emulsion may draw lipid-soluble local anesthetics from tissues and sequester them in the vascular compartment. Lipid-soluble local anesthetics also inhibit mitochondrial oxidation of free fatty acids that supply 70% of myocardial energy requirements. Lipid therapy may also restore normal mitochondrial function and myocardial energy production.
CLINICAL PHARMACOLOGY OF LOCAL ANESTHETICS
Articaine
The structure of articaine is unique among amide local anesthet-ics in that it contains an additional ester group, allowing for rapid metabolism by plasma esterases and a resultant short anesthetic time. In addition, the aromatic group is a thiophene ring instead of a benzene ring, thereby conferring increased lipid solubility and improving diffusion through tissues and possibly increasing efficacy (Katyal, 2010). The addition of epinephrine prolongs the duration of action of articaine, and this formulation (SeptocaineR) has gained widespread popularity in human dental procedures.
Although anecdotal reports of the use of Septocaine exist in vet-erinary dental procedures, no published data are available. The manufacturer recommends a maximum dose of 7 mg/kg for adults and children over 4 years of age.
Bupivacaine
In small animals, and to a more limited extent in large animals, perioperative use of bupivacaine has gained acceptance in recent years. The drug is a structural analog of mepivacaine and has a relatively long onset time (10–20 minutes) and duration of action (3–6 hours). The potency of bupivacaine is four times that of lido-caine and mepivalido-caine. The drug has a pKa of 8.1, and is highly lipid-soluble and protein-bound. Bupivacaine can be used for local infiltration as well as for peripheral and central (epidural) nerve blocks. It is also used to block digital nerves and manage pain in horses with acute laminitis. Bupivacaine is not approved for use in animals in North America. Several formulations are avail-able including 0.5% (5 mg/mL) racemic solutions with and without
preservative. Administration of less concentrated solutions (0.25%) may provide adequate sensory analgesia with limited motor block-ade. The total dose of bupivacaine should not exceed 1.5–2 mg/kg in healthy dogs and cats. For example, a healthy 3 kg cat should not be given more than 1 mL of the 0.5% solution.
Levobupivacaine
Levobupivacaine is the “levo” enantiomer of bupivacaine, and is used to a limited extent in animals. Like bupivacaine, the drug has a relatively long onset time (10–20 minutes) and duration of action (3–6 hours). The pKa, potency, lipid-solubility, and degree of protein binding of levobupivacaine are identical to those of bupi-vacaine; however, the drug is less likely to produce cardiovascular toxicity than bupivacaine. Levobupivacaine can be used for local infiltration as well as for peripheral and central (epidural) nerve blocks. The drug is not approved for use in animals in North Amer-ica. Several formulations are available including a 0.5% (5 mg/mL) solution.
Lidocaine/Lignocaine
Lidocaine is the most versatile and commonly used local anesthetic in veterinary medicine. The drug is an aminoamide with a relatively short onset time (5–10 minutes) and duration of action (1–2 hours).
Lidocaine has a pKa of 7.9 and is moderately lipid-soluble and protein-bound. The drug is effective topically at high concentra-tions, and can be used for local infiltration as well as for peripheral and central (i.e., epidural) nerve blocks. Lidocaine is approved for use in small and large animals in North America. Several formu-lations are available including a 10% (100 mg/mL) topical spray and a 2% (20 mg/mL) solution. Topical gels, creams, and patches are also available, but the time required to desensitize intact skin is approximately 1 hour. The total dose of lidocaine should not exceed 6–8 mg/kg in healthy dogs and cats. For example, a healthy 3 kg cat should not be given more than 1 mL of the 2% solution, or 0.2 mL of the 10% spray. See Chapter 9 for further discussion of novel formulations of lidocaine.
Intravenous Lidocaine
Systemic administration of lidocaine can be used to reduce the minimum alveolar concentration (MAC) of inhalational anesthet-ics, provide analgesia, control ventricular arrhythmias, and prevent postoperative ileus (Muir et al., 2003). An intravenous loading dose of 1–2 mg/kg is appropriate for dogs. Intraoperatively, intravenous infusion rates for dogs are 50–100 mcg/kg/min. Postoperatively, lower intravenous infusion rates of 12–25 mcg/kg/min are used to provide analgesia and to improve gastrointestinal motility.
Objective clinical data on the use of intraoperative and postoper-ative lidocaine infusions in cats are limited. Intravenous lidocaine at the doses required to reduce the MAC of inhalational anesthetics in cats leads to greater cardiovascular depression than an equipo-tent dose of isoflurane alone (Pypendop & Ilkiw, 2005a; Pypendop
& Ilkiw, 2005b). In addition, lidocaine infusions do not affect the thermal threshold in conscious cats (Pypendop et al., 2006). How-ever, it should be noted that lidocaine may be more effective as an antihyperalgesic agent in conditions of central sensitization, rather than a primary antinociceptive agent. In addition, it is established that postoperative intestinal function is improved by perioperative lidocaine infusions in humans (McCarthy et al., 2010). Because this benefit may extend to veterinary species, including cats, selected
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90 Section 2 / Pharmacology of Analgesic Drugs feline patients undergoing abdominal surgeries may be considered
for low-dose (∼12 mcg/kg/min) perioperative intravenous lido-caine.
Systemic administration of lidocaine can be used intra- and post-operatively in horses to provide analgesia and to improve gastroin-testinal motility (Malone et al., 2006) (Chapter 30). Rapid intra-venous administration of lidocaine can cause muscle tremors and collapse in horses, and loading doses should be given slowly. An intravenous loading dose of 1–2 mg/kg, administered over 5–10 minutes, is appropriate for most healthy, awake patients. Lidocaine is administered intravenously at a rate of 2–3 mg/kg/h. Objective clinical data on the perioperative use of lidocaine infusions in rumi-nants and swine are limited.
Mepivacaine
Mepivacaine is another local anesthetic that is used commonly in small and large animals. It is an aminoamide with potency, toxicity, and onset of action comparable to lidocaine, but with a slightly longer duration of action. Mepivacaine has a pKa of 7.7, and is moderately lipid-soluble and protein-bound. The drug can be used for local infiltration and for peripheral and central (epidural) nerve blocks. Mepivacaine is approved for use in dogs and horses in North America. The drug produces limited local tissue inflammation, and is used frequently for diagnostic nerve blocks and intra-articular injections in horses. Mepivacaine is available as a 2% (20 mg/mL) racemic solution.
Proparacaine
Proparacaine is one of the few local ester anesthetics currently employed in clinical veterinary practice. It is a topical ophthalmic anesthetic agent widely used to desensitize the cornea for intraoc-ular pressure measurements, collection of conjunctival samples, or minor corneal surgery. In cats and horses, maximal effect occurs within 5 minutes of administration and wanes by 25 minutes (Binder
& Herring, 2006; Kalf et al., 2008). In dogs, the anesthetic effects appear to last much longer (∼45 minutes) and can be extended by multiple applications (Herring et al., 2005 ).
Ropivacaine
Ropivacaine is a structural analog of bupivacaine. The drug is mar-keted as the pure “S” enantiomer, and is used to a limited extent in animals. Ropivacaine has a relatively long onset time (10–20 min-utes) and duration of action (2–4 hours), and the drug is slightly less potent than bupivacaine. The pKa and protein binding of ropi-vacaine are similar to that of bupiropi-vacaine. The lipid solubility of ropivacaine is approximately half that of bupivacaine, and the drug is less likely to produce cardiovascular toxicity. Ropivacaine can be used for local infiltration and for peripheral and central nerve blocks. It is not approved for use in animals in North America.
Several formulations are available, including a 0.75% (7.5 mg/mL) solution. Administration of less concentrated solutions (0.5%) may provide adequate sensory analgesia with limited motor blockade.
Mixtures of Local Anesthetics
Mixtures of a short-acting local anesthetic (e.g., lidocaine or mepi-vacaine) with a long-acting one (e.g., bupimepi-vacaine) have the poten-tial advantage of producing a rapid onset with a prolonged duration of action. However, data from clinical studies in humans indicate that there is little change in onset time and there is a significant
reduction in duration of action when the mixture is compared to the long-acting local anesthetic alone (Galindo & Witcher, 1980; Cuvil-lon et al., 2009). Because toxicity of local anesthetics is additive, administering mixtures of local anesthetics offers no advantage.
Methods for Potentiating Local Anesthesia
Bicarbonate can be added to local anesthetics to increase the pH and to reduce pain associated with injection (Hanna et al., 2009; Cepeda et al., 2010), although clinical results are inconsistent (Burns et al., 2006). Theoretically, alkalinization increases the amount of non-ionized drug, resulting in a shorter onset time (Lee et al., 2012).
However, data from clinical research with human subjects indi-cate that alkalinization of a local anesthetic solution produces an inconsistent effect on the time of onset (Candido et al., 1995). The ratio of bicarbonate to lidocaine or bupivacaine should be kept at 1:9 because higher ratios may cause precipitation. Bupivacaine in particular precipitates easily as the pH is adjusted upward.
Many commercially available formulations of local anesthetics contain epinephrine to counteract vasodilation and decrease the rate of vascular absorption. Alternatively, epinephrine can be added to make a 1:200,000 solution (0.1 mL epinephrine [1 mg/mL] added to 20 mL local anesthetic). Addition of epinephrine extends the dura-tion of acdura-tion of peripheral and central neural blockade with short-acting local anesthetics (e.g., lidocaine or mepivacaine), but it has a limited effect on the duration of action of long-acting local anes-thetics (e.g., bupivacaine). Local anesthetic solutions that contain epinephrine can be applied to the surgical field to provide hemosta-sis, but these solutions can also produce localized ischemia. Local anesthetic solutions that contain epinephrine should not be injected in extremities (e.g., distal limbs and pinnae) as vasoconstriction can cause ischemic damage and subsequent tissue necrosis. Addi-tionally, systemic absorption of epinephrine can precipitate cardiac arrhythmias and hypertension.
The␣-2 agonist clonidine is used as an adjunct with local anes-thetics to prolong the duration of neural blockade in human patients.
Recently, dexmedetomidine, a more selective␣-2 agonist, was used as an adjunct with levobupivacaine to prolong the duration of neu-ral blockade of the brachial plexus in human patients (Esmaoglu et al., 2010). In dogs, either perineural or systemic administration of medetomidine (10 mcg/kg) with mepivacaine prolongs the dura-tion of sensory and motor blockade of the radial nerve (Lamont &
Lemke, 2008). Systemic adverse effects of␣-2 agonists may occur even when administered perineurally at low doses; patients should be volume-replete and have normal cardiovascular function.
Opioids are often mixed with local anesthetics for epidural administration. Additionally, some opioids have been used to extend the duration of peripheral nerve blocks. In particular, the mixed agonist–antagonist opioid buprenorphine has been used in regional blocks for oral surgery (Modi et al., 2009). Many full agonists, including morphine and fentanyl, have also been used to extend the duration of a variety of central and peripheral nerve blocks; however, the results of studies designed to determine the efficacy of this adjunctive technique are mixed (Axelsson & Gupta, 2009).
Dexamethasone has been combined with a variety of local anes-thetics to prolong the duration of peripheral nerve blockade (Yoshit-omi et al. 2008; Parrington et al., 2010). Corticosteroids should be administered cautiously and avoided entirely if patients are receiv-ing NSAIDs.
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