Tim Sauvage, MS, CRNA, ARNP Local Anesthetics Tim Sauvage, MS, CRNA, ARNP

Mechanism of Action

Peripheral nerve Mixed nerves contain afferent and efferent fibers that may be myelinated or unmyelinated The axon in the nerve fiber is surrounded by endometrium, made up of glial cells Individual nerve fibers are gathered into fascicles and surrounded by perineurium made up of connective tissue The entire peripheral nerve wrapped in epineurium made up of dense connective tissue The protective layers are presented and not only protect the axon, but are barriers to our local anesthetics

Bilipid Layer Membrane Peripheral Nerves At rest, Na+ channels are closed, open Nar channels at depolarization Na channel is the target of local anesthetics to block neural action potential formation and propagation

Point: The N (unionized) will cause closure of the sodium channel, the NH+ (ionized) will directly inhibit the sodium channel binding with the local anesthetic receptor. Remember, ions do no cross membranes

Local Anesthetic Molecular Mechanism of Action Local anesthetics get on the sodium channel either by modification of lipid membrane surrounding it, or by direct interaction with the protein channel.

Allergic Reactions to Local Anesthetics True allergic reactions to local anesthetics are rare and usually involve type I (IgE) or type II (cellular immunity) reactions Type I reactions are a problem, as anaphalaxis may occur. More common with ester than amide local anesthetics True type I allergy to aminicamide agents is extrememly rare Esters allergy potential may be the result of metabolism to para-aminobenzoic acid, which is an allergen. Also to methylparaben and metabisulfite

Structure-Activity Relationships Determinant of Speed of Onset: Amount of Local Anesthetic in Un-ionized Form Relationship between pKa and time-to-onset of action of local anesthetics. Agents with lower pKas are more un-ionized at pH = 7,4. The un-ionized form of the drug penetrates the lipid bilayer of the nerve axon membrane. Thus, the more the local anesthetic is in the un-ionized form, the faster the molecules will pen­etrate the lipid bilayer of the nerve axon and the more quickly the conduction block will be established.

Agent pKa % Unionized at Ph=7.4 Relative Onset Time Procaine 8.9 3 Slow Tetracaine 8.6 14 Bupivacaine 8.1 17 Moderate Ropivacaine - Chloroprocaine 9.1 2 Fast* Lidocaine 7.7 24 Fast Etidocaine 33 Mepivacaine 7.6 39 Point of the Table: In general, the lower the pka of the local anesthetic, the greater the proportion of local anesthetic in unionized form at pH = 7.4, and the faster the onset of the conduction block

Determinant of Potency: Lipid Solubility There is a good (not perfect) relationship between lipid solubility and potency. The oil:water partition coefficient is a measure of lipid solubility. The greater the oil:water partition coefficient, the greater the lipid solubility of the agent. The oil that is used for the oil:water partition coefficient measurement is olive oil. Olive oil is similar in nature to lipids. Hence, the oil:water partition coefficient provides an indication of the lipid solubility of a local anesthetic. The greater the oil:water partition coefficient, the greater the lipid sol­ubility.

Point of the Table: In general, the more lipid soluble the local anesthetic, the greater its potency

Determinants of Duration of Action: Protein Binding and Lipid Solubility The duration of action of a local anesthetic is determined primarily by two properties of the local anesthetic. First: The degree of protein binding is the most important factor determining the duration of local anesthetic. The greater the protein binding, the longer the duration of action. Immediately after the injection of a local anesthetic, much of the agent binds to proteins in the vicinity of the injection site. As unbound anesthetic diffuses from the injection site, some of the protein-bound anesthetic is released and becomes available to diffuse to nerve axons. Thus, proteins serve as storage depots for the local anesthetics; there is a reservoir of local anesthetic bound to proteins, and the slow release of anes­thetic from the proteins maintains the supply of anesthetic to nerve axons.

Second: Lipid solubility is the second factor determining the duration of action of local anesthetics. Agents with greater lipid solubilities tend to have longer durations of action. After the local anesthetic is injected, some of it will dissolve in lipids in and around the site of injection. Agents with higher lipid solubilities will dissolve to a greater extent in surrounding lipids. Thus, the lipids act as a reservoir for lipid soluble agents, just as proteins act as a reservoir for agents that bind to proteins. As local anesthetic diffuses away from the site of injection, local anesthetic will diffuse out of the lipid compartment down a con­centration gradient and will act on the nerve to maintain the nerve block.

Question: What single change in a property of a local anesthetic will result in a more potent and. longer acting agent?

Answer: An increase in lipid solubility Answer: An increase in lipid solubility. An increase in lipid solubility will increase the duration of action and the potency.

Lipid solubility, protein binding, and duration of action of local anesthetics. The data in the table show that agents that are most lipid solubility and have the greatest protein binding are longest acting.

Point of the Table: The duration of action is greatest for local anesthetics that exhibit the greatest protein binding and the highest lipid solubilities. Protein binding, however, is more important than lipid solubility when it comes to duration of action.

Determinants of Blood Concentration of Local Anesthetic Blood concentration is determined by the presence or absence of a vasoconstrictor, tissue blood flow, con­centration injected, and number and frequency of injections. Loss of local anesthetic from the injection site is primarily by vascular absorption. The rate of absorption of a local anesthetic from an injection site is influenced by: Presence of a vasoconstrictor (e.g., epinephrine) in the solution containing the local anesthetic; epinephrine constricts arterioles (an alpha-adrenergic receptor action), and this decreases the rate of absorption from the injection site and prolongs the duration of action of the local anesthetic. Epineph­rine may increase the duration of spinal anesthesia by 75-100%.

2. Tracheal 7. BrachialPlexus High blood flow to tissue where anesthetic is injected; the greater the blood flow, the faster the agent is absorbed into the circulation and washed away from the injection site. Thus, in tissues with higher blood flows, the duration of action is reduced. Tissues ranked from highest to lowest blood flows are shown immediately below. Note that blood concentration after epidural anesthe­sia will generally be higher than after subarachnoid block. Note also that the likelihood of toxicity is increased when a local anesthetic is injected at sites with higher tissue blood flows; the greater the tis­sue blood flow, the greater the rate of absorption of local anesthetic from the site of injection. 1. Intravenous 6. Epidural 2. Tracheal 7. BrachialPlexus 3. Intercostal 8. Subarachnoid, Sciatic, Femoral 4. Caudal 9. Subcutaneous 5. Paracervical (From Morgan, Mikhail and Murray, Clinical Anesthesiohgy, 2006, p269; Barash, Clinical Anesthesia. 2006, p460).

Factors Unrelated to Physicochemical Properties that Prolong Conduction Block Presence of vasoconstrictor (epinephrine or phenylephrine): vasoconstriction at the site of injection decreases blood flow and slows the removal of the local anesthetic from the site of injection. Concentration of local anesthetic injected: the greater the concentration of the injected local anesthetic, the longer the conduction block. Blood flow: the lower the blood flow to the tissue at the injection site, the slower the removal of agent and the longer the duration of the conduction block; removal of local anesthetic by blood is slower after subarachnoid injection compared with epidural injection.

Mechanism of Action of Local Anesthetics Interaction of Local Anesthetics with Nerve Axon Local anesthetics block sodium channels. A number of mechanisms have been put forth to explain how local anesthetics produce their nerve-blocking effects. The most popular theory, illustrated , postulates that the un-ionized form of the local anesthetic diffuses into the nerve axon and the ionized form binds to receptors on the sodium channel when the channel is in the inactivated state. So long as the sodium channel is inactivated, action potentials cannot be generated. LA = local anesthetic.

Height of Sensory Versus Motor Block After Subamchnoid (Spinal) Injection of local Anesthetic Sympathetic block is 2 to 6 dermatomes higher than sensory block. Motor block is 2 dermatomes lower than sensory block. Metabolism Ester local anesthetics are metabolized by plasma pseudocholinesterase. Amides are metabolized by the liver. Toxicity Systemic toxicity is determined by the concentration of local anesthetic achieved in the blood. A number of factors determine the concentration of local anesthetic achieved in the blood (described

Manifestations of Toxicity The toxic manifestations of lidocaine (2-4 ug/ml is therapeutic plasma concentration) are (from Barash, Clinical Anesthesia, 2006, p464and Millet, Anesthesia, 2005, pp592-596): Point of the Table: Manifestations are proportional to the amount of over dose.

Pharmacokinetics Absorption If the area around the injected local anesthetic provides a weak barrier to their penetration, this will account for a rapid onset of action. Systematic absorption (blood) is proportional to the vascularity of the area injected. As absorption increases so must vascularity increase. (as noted earlier) Presence f a vasoconstrictor will decrease absorption of the local anesthetic and therefore, there is more anesthetic and there is more anesthetic for neuronal uptake, enhances the quality of analgesia, prolongs duration of action, and limits toxic side effects Tissue binding of the local anesthetic will slow the absorption of the drug. The greater the amount of the tissue bound drug, the less will be available for absorption.

Distribution Tissue perfusion of the highly perfused organs (brain, liver, lungs, kidneys, and heart) are responsible for the initial rapid uptake of the drug This is followed by a slower redistribution to moderately perfused tissue (muscle and gut).

Metabolism and Excretion Esters Metabolized by pseudocholinesterase (plasma cholesterase or butyryl-cholinesterase) Usually rapid and excreted in urine Amides Meabolized (N-dealkylation and hydroxylation) by microsomal P-450 enzymes in the liver Rate of metabolism of drug depends on the drug itself, function of the liver, and liver blood flow to other organs

Local Anesthetic Effects on Organ Systems Neurological The CNS is vulnerable to the local anesthetic toxicity and is the site of overdose in awake patients Some specific local anesthetics have their own application like lidocaine IV, cocaine, and chloroprocaine

Respiratory Lidocaine depresses hypoxic drive, i.e., the ventilatory response to low PaO2 Apnea may result from phrenic and intercostal nerve paralysis Relax bronchial smooth muscle

Cardiovascular (many) Depress myocardial automatically and reduce the duration of the refractory period Myocardial contractibility and conduction velocity are depressed (at higher concentration) Smooth muscle relaxation (arteriole dilation) The combination of bradycardia, heart block, and hypotenstion may culminate in cardiac arrest May be cardiotoxic (bupivicaine)

Musculoskeletal When local anesthetics are injected into skeletal muscle, they are myotoxic. Takes 3-4 weeks to heal Steroid injection or epinephrine injection worsens the muscle necrosis

Hematological Lidocaine decreases coagulation and enhances fibrinolysis in whole blood Lidocaine prevents thrombosis and decreases platelet aggregation

Conclusion Local and regional anesthesia techniques depend on local anesthetics to produce loss of sensory, motor, and autonomic function when the drugs are applied topically or injected Each local anesthetic is unique when it relates to sensitivity, potency, duration, onset, and absorption. Each having its own characteristic that makes it unique

Questions?