NYSORA - The New York School of Regional Anesthesia: Local Anesthetics Local Anesthetics ================================================================================ Vijay Patel on 16/03/2009 22:50:00 Local anesthetics bind directly within the intracellular portion of voltage-gated sodium channels. The degree of block produced by local anesthetics is dependent upon how the nerve has been stimulated and on its resting membrane potential. Local anesthetics are only able to bind to sodium channels in their charged form and when the sodium channels are open MECHANISM OF ACTION Local anesthetics block the generation and conduction of nerve impulses at the level of the cell membrane by preventing the transient increase in permeability of excitable membranes. Local anesthetics bind directly within the intracellular portion of voltage-gated sodium channels. The degree of block produced by local anesthetics is dependent upon how the nerve has been stimulated and on its resting membrane potential. Local anesthetics are only able to bind to sodium channels in their charged form and when the sodium channels are open. In this situation, the local anesthetic is able to bind more tightly to and stabilize the sodium channel. Differences in pKa, lipid solubility, and molecular size influence the binding of local anesthetics to to the sodium channels. In general, small nerve fibers are more sensitive to local anesthetics than large nerve fibers. However, myelinated fibers are blocked before non-myelinated fibers of the same diameter. Autonomic fibers, small unmyelinated C fibers (mediating pain) and small myelinated A-delta fibers (mediating pain and temperature sensation) are blocked before larger myelinated A-gamma, A-beta, or A-alpha fibers (mediating touch, pressure, muscle and postural inputs). Small, sensory fibers are preferentially blocked since nerve conduction is more easily blocked over shorter distances and these fibers have longer action potentials allowing more of the local anesthetic to bind. Clinically, the loss of nerve function proceeds as loss of pain, temperature, touch, proprioception, and then skeletal muscle tone. PROPERTIES OF LOCAL ANESTHETIC AGENTS Properties Amino esters Amino amides Metabolism rapid by plasma cholinesterase slow, hepatic Systemic toxicity less likely more likely Allergic reaction possible - PABA derivatives form very rare Stability in solution breaks down in ampules (heat,sun) very stable chemically Onset of action slow as a general rule moderate to fast pKa's higher than PH = 7.4 (8.5-8.9) close to PH = 7.4 (7.6-8.1) CLINICAL PHARMACOLOGY The potency of Local Anesthetics, their onset and duration of action are primary determined by physicochemical properties of various agents and their inherent vasodilator activity of same local anesthetics. *Lipid solubility is the primary determinant of anesthetic potency and it is expressed as lipid: water Partition Coefficient *Protein binding influences the duration of action *pKa of Local anesthetics determinates the onset of action *The addition of vasoconstrictors, such as epinephrine or phenylephrine can prolong duration of action of local anesthetics, decrease their absorption (and the peak plasma level) and enhance the blockade Agent Pot. Onset pKa %PB P. coef Procaine 0.5-1% (Novocain) 1 Rap 8.9 5.8 0.02 Chloroprocaine 2-3% (Nesacain) 4 Rap 8.7 ? 0.14 Tetracaine 0.1-0.5% (Pontocain) Slow 8.5 75.6 4.1 Lidocaine 1-5% (Xylocaine) 1 Rap 7.9 64.3 2.9 Mepivacaine 1.5% (Carbocaine) 1 Mod 7.6 77.5 0.8 Bupivacaine 0.25-0.75% (Marcainesensorcaine) 4 Slow 8.1 95.6 27.5 Etidocaine 0.5-1.5% (Duranest) 4 Rap 7.7 94 141 Prilocaine 1 7.9 55 0.9 Ropivacaine 0.75% (Naropin) 4 Mod 8.1 94 2.9 Local Anesthetic Time Line (minutes) Infiltration plain sol'n With Epinephrine Spinal plain With Epinephrine Epidural plain sol'n With Epinephrine Chloroprocaine 30-45 45-60 Lidocaine 60-120 90-180 Hyperbaric 60 60-90 80-120 120-180 Mepivacaine 90-140 140-200 Tetracaine Hyperbaric 120-180 180-400 Ropivacaine 140-200 160-220 Bupivacaine 180-360 300-480 Hyperbaric 120-360 120-360 180-360 120-240 LIDOCAINE Lidocaine is the most widely used local anesthetic agent because of inherent potency, rapid onset, tissue penetration and effectiveness. This agent is available as an ointment, jelly, patch, or aerosol for topical use, as an oral solution, and as an injection for local infiltration, peripheral nerve block, epidural block and Bier's block. The absorption of lidocaine after subcutaneous injection is relatively small, however repeated dosing may result in detectable lidocaine blood levels due to gradual accumulation of the drug or its metabolites. The duration of action of subcutaneously administered lidocaine is 1-3 hours. The addition of epinephrine 1:200,000 to 1:100,000 to lidocaine slows the vascular absorption of lidocaine and prolongs its effects. BUPIVACAINE Bupivacaine is a long-acting local anesthetic of the amide type recommended for infiltration, peripheral nerve block, epidural and spinal anesthesia. Its onset of action is rapid (1-5 minutes) if used for spinal anesthesia but slower when used for peripheral nerve block. Its duration is significantly longer than that of other commonly used local anesthetics. Useful concentration of the drug range from 0.125% to 0.75%. Lower concentration may provide differential sensory motor block. Bupivacaine is available in multiple forms including sterile isotonic solutions with or without the preservative methyl paraben, and hyperbaric solutions consisting of bupivacaine hydrochloride in dextran. All forms are available with epinephrine. The main disadvantage of bupivacaine is the severe cardiotoxicity which may occur with high plasma levels. ROPIVACAINE Ropivacaine is a long-acting, amide-type local anesthetic. Its structure and pharmacokinetics are similar to those of bupivacaine, however, ropivacaine exhibits significantly better cardiotoxicity profile compared to bupivacaine. Duration of action for ropivacaine ranges 2.5-5.9 hours for epidural block to 8-13 hours for peripheral nerve block. Ropivacaine is also less lipid soluble and cleared via the liver more rapidly than bupivacaine. Some studies have shown less motor blocking effects of ropivacaine than that of bupivacaine. Due to its better safety profile and significantly better sensory-motor differentiation, Ropivacaine is currently the long-acting anesthetic of choice in our practice. LEVOBUPIVACAINE Levobupivacaine is an amino amide type of local anesthetic. Levobupivacaine is the S (-)-enantiomer of bupivacaine. Levobupivacaine produces sensory and motor blockade that is similar to bupivacaine. Its onset time, maximum spread of sensory block, or intensity of motor block in patients receiving lumbar epidural anesthesia with levobupivacaine is comparable to that of bupivacaine. Levobupivacaine exhibits less cardiotoxicity than bupivacaine. The threshold for CNS effects of levobupivacaine is also higher than that of bupivacaine. Its primary use is in epidural anesthesia. The data on its efficacy in peripheral nerve blockade is sparse; however it should be quite similar if not identical to that of bupivacaine. MEPIVACAINE Mepivacaine is a local anesthetic of the amide type with an intermediate duration of action. Mepivacaine is used for infiltration and transtracheal anesthesia, and peripheral, sympathetic, regional (Bier block), and epidural nerve blocks. Compared with lidocaine, mepivacaine produces less vasodilatation and has a more rapid onset and longer duration of action. In our practice, this is the #1 intermediate-acting local anesthetic to use for peripheral nerve blocks. PRILOCAINE Prilocaine is a local anesthetic of the amide class used primarily for dental anesthesia. It has an intermediate duration of action and is longer acting than lidocaine. Lidocaine and prilocaine are combined in a topical formulation for use on intact skin for local analgesia. An example is EMLA cream, which provides dermal analgesia by the release of lidocaine and prilocaine into the epidermal and dermal layers of the skin and accumulation of drug near dermal pain receptors. However, there have been reports of significant methemoglobinemia (20-30%) in infants and children following excessive applications of EMLA cream. These cases involved the use of large dosages, larger than recommended areas of application, or occurred in infants