Local Anesthetics

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.

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.

Local Anesthetic Time Line (minutes)

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 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 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 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 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 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 <3 months.

Benzocaine is a short-acting local anesthetic of the ester type. It is used for topical anesthesia in a wide variety of clinical situations including mucous membrane anesthesia prior to endoscopic examination or instrumentation, gag reflex suppression, and anorectal disorders and various pain syndromes. It is available in many dosage forms including gels, creams, ointments, lotions, aerosols, and lozenges. Many nonprescription products are available for the temporary relief of dental or oral pain. Benzocaine and tetracaine are more likely to cause contact sensitization than are other local anesthetics.

Benzocaine is minimally absorbed and therefore relatively free from systemic side effects or adverse drug interactions. Onset of action is rapid, with initial effects obtained in about 1 minute and action lasting about 15-20 minutes. It is metabolized hepatically. Metabolites are renally excreted.

Etidocaine is a long-acting local anesthetic of the amide type. It is used for epidural, local, and retrobulbar anesthesia in surgical and dental procedures. Like lidocaine, it has a rapid onset of sensory and motor blockade, but duration of analgesia is 1.5-2 times longer than lidocaine when given epidurally. This difference is greater following peripheral nerve block. Etidocaine produces profound motor blockade and muscle relaxation when used for epidural analgesia. Etidocaine is rapidly absorbed from parenteral injection sites, and epidural injections of 1% solutions result in anesthesia within 2-8 minutes, with complete sensory and motor blockade occurring in less than 20 minutes. Duration of action varies between 4.5-13 hours. Etidocaine passively diffuses across blood-brain and placental barriers, and fetal plasma levels are usually 20-30% of maternal plasma concentrations.

Procaine hydrochloride is a short-acting, slow onset, low potency local anesthetic of the ester type used for local, regional and short acting spinal anesthesia. It lacks topical anesthetic activity. Its toxicity is the standard against which others are compared.

Systemic absorption of procaine depends on the dose, concentration, route of administration, local tissue vascularity, and degree of vasodilation. A vasoconstrictor such as epinephrine may be necessary to counteract the vasodilation produced by procaine. Chemical Structure will slow the rate of absorption, prolong the duration of action, and maintain hemostasis. Anesthesia is obtained within 2-5 minutes and lasts approximately 1 hour.

Chloroprocaine is a short-acting local anesthetic of the ester type, similar in structure to procaine. Chloroprocaine is used for infiltration anesthesia, peripheral, sympathetic, epidural, caudal, and intravenous regional (Bier block) blocks. Chloroprocaine is not effective as a topical anesthetic, and it is not available for subarachnoid use.

Absorption depends on the dose, concentration, route of administration, tissue vascularity, and degree of vasodilation. However, due to its rapid hydrolysis in the blood, toxic levels are rare even with high doses. The addition of epinephrine slows the rate of absorption, prolong the duration of action. Anesthesia is obtained within 6-12 minutes and lasts approximately 30-60 minutes (60-90 minutes when epinephrine is added).

Tetracaine is an ester-type local anesthetic with an intermediate to long duration of action. Relative to other local anesthetics, tetracaine is significantly more toxic. Tetracaine is available in various injectable forms for spinal anesthesia, as well as preparations for topical use. These preparations are typically used prior to examination of the larynx, trachea, or esophagus, to abolish laryngeal and esophageal reflexes and provide local analgesia.

Systemic absorption of tetracaine depends on the dose, concentration, route of administration, tissue vascularity and degree of vasodilatation. Systemic absorption from topical preparations is minimal, but application to broken or bruised skin greatly increases absorption. When used for spinal anesthesia the onset of action can be delayed, with a duration of 1.5-3 hours. The addition of a vasoconstrictor can substantially prolong the duration of spinal anesthesia achieved with tetracaine. For topical and aerosol solutions, the onset of action is 3-10 minutes and the duration of action is 30-60 minutes. For ophthalmic preparations, the onset of action is about 15 seconds, with a duration of 15 minutes. Due to its potential for toxicity, tetracaine is infrequently used for neuronal blockade.

Cocaine is a naturally occurring alkaloid present in the leaves of Erythroxylon coca. Cocaine is commercially available in a variety of forms and it is applied to mucous membranes of the oral, laryngeal, and nasal cavities for use as a topical anesthetic. Cocaine causes significant euphoria, and abuse and it can lead to physical dependence. Despite being an excellent local anesthetic, the risk of abuse and the intense local vasoconstriction it produces prevent cocaine from being more widely used clinically.

Cocaine is well absorbed from all mucous membranes, especially from damaged or inflamed tissue. Although topical vasoconstriction can limit the absorption rate, significant systemic absorption can occur. When used for topical anesthesia, the onset of action occurs within 1 minute, and maximum effect is within 5 minutes. The duration of action is about 30 minutes.