LECTURE 4: LOCAL ANESTHETICS INTRODUCTION

y y

Ester Links are more prone to Hydrolysis than Amide Links ESTERS have a SHORTER duration of action A Larger Fraction in the Body Fluids at Physiologic pH will be the Charged Cationic Form

I. LOCAL ANASTHETIC y Local Anesthetics reversibly Block Impulse Conduction along Nerve Axons & other excitable membranes that utilize Sodium Channels as the Primary Means of Action Potential Generation y Agent that Interrupts pain impulses in a Specific Region of the Body WITHOUT a loss of Patient Consciousness y Normally, the process is COMPLETELY REVERSIBLE the agent DOES NOT produce any residual effect on the Nerve Fibers y All Local Anesthetics are Weak Bases, classified as Tertiary Amines II. CHEMICAL STRUCTURE

III. CLASSIFICATION OF LOCAL ANESTHETICS A. Classification Based on Structure (Type of Linkage) o Amino-Ester o Amino Amides ESTERS Cocaine Procaine Tetracaine Chloroprocaine Propoxycaine Benzocaine Dyclonine AMIDES Lidocaine Mepivicaine Prilocaine Bupivacaine Etidocaine Articaine Ropivacaine Levobupivacaine

1. Esters  Include Cocaine, Procaine, Tetracaine, and Chloroprocaine  Metabolism = they are Hydrolyzed in Plasma by PseudoCholinesterase (Enzymes found in the Neuromuscular Junctions)  One of the By-Products of this metabolism is ParaAminobenzoic Acid (PABA) the common cause of Allergic Reactions seen with this agents  This is why Amino-Esters are more common in Allergies because of PABA y Most Local Anesthetic Agents consist of a Lipophilic Group (frequently an Aromatic Ring) connected by an Intermediate Chain (commonly including an Ester or Amide) to an Ionizable Group (usually a Tertiary Amine) **NOTE: Majority of Esters are Metabolized by Enzymes (only SOME in the Liver) y PABA = a Byproduct of Metabolism ALLERGY! 1|Page

y 2. Amides  These include Lidocaine, Mepivicaine, Prilocaine, Bupivacaine, and Etidocaine  Metabolized in the LIVER into Inactive Agents (unlike Majority of Esters = metabolized by Enzymes)  True Allergic Reactions are RARE with Amides (especially with Lidocaine) due to the absence of PABA **Most Common Anasthetics: y Lidocaine = Most Common y Bupivacaine = Next to Lidocaine B. Classification Based on Duration of Action (Katzung) 1. Short Acting  Procaine  Chloroprocaine 2. Intermediate  Lidocaine  Mepivacaine  Prilocaine 3. Long-Acting  Tetracaine  Bupivacaine  Levobupivacaine  Etidocaine  Ropivacaine THE LOCAL ANASTHETICS

Local Anesthetics work to Block Nerve Conduction by reducing the Influx of Sodium Ions into the Nerve Cytoplasm (they prevent Sodium from entering the Nerve Cytoplasm) Sodium Ions cannot flow into the Neuron, thus the Potassium Ions CANNOT Flow Out thereby, we INHIBIT the Depolarization of the Nerve If this process can be Inhibited for just a few Nodes of Ranvier along the way, then Nerve Impulses generated downstream from the Blocked Nodes CANNOT propagate to the Ganglion Local Anesthetics BIND Directly to Intracellular Voltage-Dependent Sodium Channels (not just the Extracellular Type it must be the Intracellular Voltage-Dependent Sodium Channels)

A. Block Primarily OPEN and INACTIVE Sodium Channels at specific sites within the Channel o Local Anesthetics occupy the Open and Inactive Sodium Channels o Primary Mechanism = Blockade of Voltage-Gated Sodium Channels o They hinder Na+ Depolarization by preventing Na+ influx to the Cell without local anesthetics, Sodium enters the Cell and initiates an Action Potential **IMPORTANT Notes:  Cationic Form = Most Active form at the Receptor Site  Uncharged Form = for Rapid Penetration of Biologic Membranes  This is why surgeons say that Local Anesthetics are LESS Effective when injected into Infected Tissues infected tissues have Low Extracellular pH, therefore, a very low fraction of Non-Ionized Local Anesthetic is available for Diffusion into the Cell B. Interaction of Local Anesthetics with Na+ Channels

I. GENERAL MECHANISM OF ACTION 2|Page

C. Effects of the Local Anesthetics:

** Fig. 34.6 Interaction of local anesthetics with Na+ channels. The blocking site within the channel can be reached via the open channel gate on the inner surface of the membrane by the charged species, BH+ (hydrophilic pathway), or directly from the membrane by the unchanged species, B (hydrophilic pathway).

 

The Blocking Site within the Channel can be reached via the Open Channel Gate on the Inner Surface by the Charged Species (BH+ -Hydrophilic Pathway) Blocking Site can also be reached Directly from the Membrane by the Uncharged Species (B Hydrophobic Pathway) **NOTE: To be able to Penetrate the Membrane y CHARGED Species (BH+) = goes through the Open Channels y UNCHARGED Species (B) = Sodium Receptor on the Membrane

1. Slow Rate of Depolarization  Decrease in the Rate of Rise in the EPSP SLOWER rise of the Curve 2. Reduce Height of Action Potential  Action Potential curve is LOWER than that of a Normal Action Potential 3. Reduce Rate of Rise of Action Potential

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4. Slow Axonal Conduction  There is a Decrease in the Overshoot Slowing Down of Axonal Conduction 5. Ultimately prevent Propagation of Action Potential 6. DO NOT alter resting Membrane Potential 7. Increase Threshold Potential  There is a Rise in the Threshold Potential there must be a Stronger Stimulus to elicit a response D. General Characteristics of Local Anesthetics (LA) o LAs block Action Potential generation by Blocking Na+ Channels o They are Amphiphilic Molecules, with a Hydrophobic Aromatic Group, and a Basic Amine Group o LAs act in their Cationic Form but must reach their site of Action by Penetrating the Nerve Sheath and Axonal Membrane as Unionized Species (they therefore have to be Weak Bases) 1. Many LAs show Use-Dependence (Depth of Block Increases with Action Potential Frequency:  Because Anesthetic Molecules gain access to the Channel more readily when the Channel is Open  Because Anesthetic Molecules have Higher Affinity for Inactivated than for Resting Channels  NOTE: Use Dependence is mainly of Importance in relation to Antiarrhythmic and Anticonvulsant Effects of LAs 2. LAs Block Conduction in the Following Order:  Small Myelinated Axons  Non-Myelinated Axons  Large Myelinated Axons

**NOTE: Nociceptive & Sympathetic Transmission is Blocked FIRST II. FACTORS AFFECTING LOCAL ANESTHETIC ACTION y Remember, Local Anesthetics are WEAK Bases A. Effect of Ph o One of the more Important Factors o Charged (Cationic) form BINDS to the Receptor Site; Uncharged form Penetrates the Membrane o Efficacy of Drug can be changed by Altering Extracellular or Intracellular Ph B. Effect of Lipophilicity (Lipid Solubility) o It is the Primary Intrinsic Determinant of Potency Chemical Compounds which are Highly Lipophilic tend to penetrate the Nerve Membrane easily (Less Molecules are required for Conduction Blockade, therefore, it has Enhanced Potency) o The More Lipid Soluble a Local Anesthetic is the MORE Potent Local Anesthetic (not always) **EXCEPTION: Injecting a Lipid Soluble Local Anesthetic in an OBSESE Person:  The Local Anesthetic will be more attracted to the Lipids (Fat Depot) C. Effect of Protein Binding o Increased Binding INCREASES duration of Action o Ex) A Short Potent Drug which binds to protein Increases Duration **Actual Amount of Protein Binding:

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Bupivacaine = 95% (High Risk of Overdosage Most Cardiotoxic!) Etidocaine = 95% Lidocaine = 65% Prilocaine = 55% Procaine = 6%

 

LAs diffuse from Outer Surface (Mantle) to the Center (Nerve Core) along a Gradient Mixed Nerve = Nerve Fibers in the Mantle Blocked First

G. Fiber Size and Function o When we give a Local Anesthetic = DELTA Fibers take effect first (because they are very small and they sub-serve Pain)
FIBER DIAMETER FUNCTION MYELINATION SENSITIVITY TO BLOCK

D. Effect of Diffusibility o Increased Diffusibility = Decreased Time of Onset o Diffusibility = Ability of the Drug to pass or spread o The More Diffuse (diffuses faster) a Local Anesthetic is of Onset

Type A-Alpha

12-20 5-12 3-6 3-5 <3 0.4-1.2 0.3-1.3

LESS Time

E. Effect of Vasodilator Activity o Greater Vasodilating Activity = Decreased Potency and Decreased Duration of Action o Ex) Epinephrine (Vasocontrictor) + Local Anesthetic = INCREASED Duration of Action and Potency F. Nerve Fiber Classification is Based on: 1. Fiber Diameter  The Smaller the Fiber, the Faster the Blockade  But with Myelinated Fiber, it is even faster due to the Nodes of Ranvier  Fast Conductors are Blocked Faster  Greater concentrations of Las are needed for Large Diameter Fibers 2. Myelination  Myelinated Fibers are Blocked First  Preganglionic Type-B Fibers readily blocked! 3. Position in the Nerve Bundle

Type A-Beta Type A-Gamma Type A-Delta Type B Type C Dorsal Root Type C Postganglionic

Proprioception, Motor Touch, Pressure Muscle Spindles Pain, Temperature Preganglionic Autonomic Pain Postganglionic

Heavy Heavy Heavy Heavy Light None None

+ ++ ++ +++ ++++ ++++ ++++

1. A-Fibers
AFIBER DIAMETER CONDUCTION VELOCITY FUNCTION REMARKS

AAlpha

12-20 um

70-120 m/s

Motor Function Proprioception Reflex Activity Motor Proprioception Touch Pressure

Largest Afferent & Efferent from Muscle&Joint

A-Beta

5-12 um

30-70 m/s

Large as AAlpha Afferent & Efferent from

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Touch & Pressure AGamma ADelta 3-6 um 15-30 m/s Muscle Spindle Tone Pain and Temperature Signal Tissue Damage

Muscle&Joint

y y

2-5um

12-30 m/s

Thinnest

In General, Small Nerve Fibers are MORE Susceptible than Large Fibers However, these factors are also Important in determining Susceptibility: o The Type of Fiber o Degree of Myelination o Fiber Length o Frequency-Dependence

2. B-Fibers  Diameter = 2-5 um  Myelinated Preganglionic Autonomic  Innervated Vascular Smooth Muscles  Though Myelinated, they are more readily BLOCKED by Local Anesthetics than C-Fibers **IMPORTANT Notes: y Both A-Delta Fibers and C-Fibers transmit PAIN and are Blocked by the SAME Concentration of Local Anesthetics 3. C-Fibers  Diameter = 0.4-1.2um  Non-Myelinated Postganglionic Autonomic  Very Small Nerves  Smallest Nerve Fibers Slow Transmission  Transmit Dull Pain and Temperature III. SUSCEPTIBILITY TO BLOCK BY LOCAL ANESTHETICS OF TYPES OF NERVE FIBERS

IV. ORDER OF SENSORY FUNCTION BLOCK y Pain (Small Fibers) y Cold y Warmth y Touch y Deep Pressure y Motor **IMPORTANT Notes: o The appendix may be removed already, even if the Legs are still Movement o Pain is the FIRST to be Blocked (because they are supplied by Small Fibers) o Depending on the Concentration that we give, the Motor Function can disappear **NOTE: Recovery is in the REVERSE Order o Motor = First to Recover! o Pain = Last to Recover! **Epidural Anesthesia in Pregnancy: o Indwelling Catheter inside the Epidural Space (Potential Space) o We introduce Local Anesthetics at certain concentrations (Most Common for Epidural = Bupivacaine)

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o We should use the Smallest Concentration that will give Local Anesthesia to AVOID losing the Motor Function (Epidural only blocks Sensory Function) o If Motor Function is abolished = Caesarian Section! V. TOXICITIES OF LOCAL ANESTHETICS y Local Anesthetics have LOW Toxicity Indices y Essentially ALL Systemic Toxic Reactions associated with Local Anesthetics are the result of Over-Dosage leading to High Blood Levels of the Agent given y To Avoid Systemic Toxic Reactions to a Local Anesthetic the SMALLEST Amount of the Most Dilute Solution that effectively blocks Pain should be administered A. Hypersensitivity o Toxic Reaction (RARE) Some patients are Hypersensitive (Allergic) to some Local Anesthetics o Usually occurs in patients given with Amino-Ester Types of Local Anesthetics (because of PABA) o A Careful Patient History should be taken to identify (+) Allergy **NOTE: There are Two Types of Local Anesthetics = Amide Type and Ester Type  A Patient who is allergic to one type may or may not be allergic to the other type  Ie) A Patient allergic to an Amide may not be Allergic to an Ester (vice versa) B. Central Nervous System Toxicities o Absorbed Systematically in Excessive Amounts = Cause Central Nervous System (CNS) Excitement o Absorbed in even Higher Amounts = Cause CNS Depression

o Chloroprocaine and Lidocaine appear to be more Neurotoxic than other Local Anesthetics when used for Spinal Anesthesia, producing Transient Radicular Irritation 1. Excitement  Tremors, Shivering, and Convulsion characterize the CNS Excitement 2. Depression  CNS Depression is characterized by Respiratory Depression and, if enough of the Drug is absorbed, Respiratory Arrest (usually the cause of DEATH) C. Cardiovascular Toxicities o If too much of the Drug is absorbed Systematically = Cardiovascular Depression o Bupivacaine = Most Notorious because it takes longer for it to dissociate from the Receptors o Peripheral Vascular Action = Arteriolar Dilation (EXCEPT Cocaine which is Vasoconstrictive) o Hypotension and a certain type of Abnormal Heartbeat (Atrioventricular Block) characterize such Depression these may ultimately result in BOTH Cardiac and Respiratory Arrest **NOTE: Ropivacaine  It has similar effects with Bupivacaine  However, it has a LOWER Potential for CVS Toxicity D. Signs of Toxicity occur on a Continuum (From EARLY to LATE Stages of Toxicities) o Circum-Oral and Tongue Numbness (First Sign of Toxicity) o Lightheadedness o Tinnitus 7|Page

o Visual Disturbances o Muscular Twitching o Convulsions o Unconsciousness o Coma o Respiratory Arrest o Cardiovascular Collapse o Death VI. PHARMACOKINETICS OF LOCAL ANESTHETICS A. Absorption o Systemic Absorption of Injected Local Anesthetic from Site of Administration is modified by several Factors o This includes: Dosage, Site of Injection, Drug-Tissue Binging, Presence of Vasoconstricting Substance (such as Epinephrine) **IMPORTANT Note:  Application of Local Anesthetic to Highly Vascularized Area (such as the Tracheal Mucosa) results in a more rapid Absorption and higher blood levels **For Regional Anesthesia involving Block of Large Nerves: Intercostal (Highest Blood Level) > Caudal > Epidural > Brachial Plexus > Sciatic Nerve (Lowest) B. Distribution o Amide Local Anesthetics = widely distributed after IV-Bolus Administration o Ester Local Anesthetics = tissue distribution NOT extensively studied (due to Short Half Lives) C. Metabolism & Excretion

o Converted in the Liver or in Plasma to more Water-Soluble Metabolites, then Excreted in the Urine o Ester Type = Hydrolyzed very rapidly in the Blood by Butyrylcholinesterase (Pseudocholinesterase) o Amide Type = Hydrolyzed by the Liver Microsomal Cytochrome P450 Prolocaine (Fastest) > Etidocaine > Lidocaine > Mepivacaine > Ropivacaine > Bupivacaine & Levobupivacaine

TYPES OF LOCAL ANESTHESIA I. LOCAL INFILTRATION (LOCAL ANESTHESIA) y Occurs when the Nerve Endings in the Skin and Subcutaneous Tissues are Blocked by Direct Contact with a Local Anesthetic (Injected into the Tissue) A. Administration o Nerve itself has Direct Contact on the Nerve Endings Injected into the Tissue o It exerts its Action B. Purpose o Surgical Procedures involving a Small Area of Procedures o Ex) Skin Suturing II. TOPICAL BLOCK A. Administration o Applying the Anesthetic Agent to Mucous Membrane Surfaces o In this way = Blocking the Nerve Terminals in the Mucosa B. Purpose 8|Page

o This Technique is often used during Examination Procedures involving the Respiratory Tract C. Pharmacokinetics o Anesthetic Agent is Rapidly Absorbed into the bloodstream o For Topical Application (on the Skin), the Local Anesthetic is always used WITHOUT Epinephrine o Ex) The Topical Block easily Anesthetizes the Surface of the Cornea and the Oral Mucosa III. SURFACE ANESTHESIA A. Administration o Application of a Local Anesthetic to Skin or Mucous Membranes B. Purpose o Surface Anesthesia is used to relieve Itching, Burning, and Surface Pain o Ex) As seen in Minor Sunburns IV. NERVE BLOCK A. Administration o Local Anesthetic is Injected around a Nerve that leads to the Operative Site o Usually more Concentrated Forms of Local Anesthetic Solutions are used for this Type of Anesthesia B. Examples: o Axillary Block o Biers Block o Circumcision o Amputation of Fingers (Block the Median or Ulnar Nerve) **Biers Block (Intravenous Regional Anesthesia)

 

Into the Exsanguinated Veins of a Limb Distal to an Arterial Tourniquet placed proximally & distally From the Vein Injected, the LA diffuses out of the Vein to bathe the Nerve

V. PERIDURAL ANESTHESIA y Accomplished by Injecting a Local Anesthetic into the Peridural Space y Peridural Space = one of the coverings of the Spinal Cord VI. SPINAL ANESTHESIA y In Spinal Anesthesia, the Local Anesthetic is Injected into the Subarachnoid Space of the Spinal Cord y Subarachnoid Space = it is an ACTUAL Space!!!! VASOCONSTRICTORS y Vasoconstrictors Decrease the Rate of Vascular Absorption which allows more Anesthetic to reach the Nerve Membrane and Improves the Depth of Anesthesia y There is Variable Response between Local Anesthetic and the Location of Injection as to whether Vasoconstrictors Increase Duration of Action y 1:200,000 Epinephrine Appears to be the BEST Vasoconstrictor **IMPORTANT Notes: o Vasoconstrictors + Local Anesthetic = Allows more Anesthetic to Reach in the Nerve Membrane! o It also Increases Duration, Efficacy, Depth of the Anesthesia o The More Vascular the Area WITHOUT Vasoconstrictor = Poor Effect

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