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Chapter 15: Local Anesthesics

Table of Contents

Overview: Chemical Properties Pharmacokinetics o Absorption and Distribution o Pulmonary Extraction o Placental Transfer o Clearance Vasoconstrictors with local anesthetics

Local Anesthetic Combinations Side-Effects/Toxicities Clinical Uses

Local Anesthetic Agents

Overview --Chemical Properties: o Structural Aspects Lipophilic component Connecting chain (ester or amide) Ionizable group o Racemates/Pure Isomers Pipecoloxylidide-agents (mepivacaine (Carbocaine), ropivacaine (Naropin)) Chiral agents (asymmetric carbon); left-(S), right-(R)-handed configurations Mepivacaine (Carbocaine) & bupivacaine (Marcaine) are used clinically as racemates (50:50 mixture) of enantiomers o S enantiomers of mepivacaine (Carbocaine) & bupivacaine (Marcaine): less toxic than racemates Ropivacaine (Naropin): pure S enantiomer o Pharmacological activity (2 factors--one that considers chemical aspects alone and the second that considers interaction with receptors) Balance between lipophilic & hydrophilic characteristics Potency of stereoisomers (e.g.,ropivacaine (Naropin) & mepivacaine (Carbocaine)) o Duration of action: Esters: shorter duration of action (compared to local anesthetics with amide linkages) o Properties: Local Anesthetics are weak bases:

Existing as either uncharged base or cation (postiively charged) Proportions depending on pKa & pH (as described by the HendersonHasselbalch equation) log ([cationic form] / [uncharged form]) = pKa - pH Most local anesthetics have pKa's ranging from 8.0-9.0, therefore at physiological pH, most local anesthetic molecules will be positively charged (cationic form) o Cationic form: probably physiologically active form at the receptor o Uncharged form: important for penetration across biological membranes to reach site of action o Local anesthetic receptor localization internal side of the cell membrane {requiring penetration by uncharged form} In infected tissue, extracellular pH is lower; more drug in ionized state; less likely to diffuse into the cell; reduced local anesthetic effect Esters: Cocaine Procaine (Novocain) Benzocaine (Cetacaine) Tetracaine, Chloroprocaine (Nesacaine)

Amides: Lidocaine (Xylocaine), Mepivacaine (Polocaine/Carbocaine),

Etidocaine (Duranest), Bupivacaine (Marcaine), Prilocaine

Local Anesthetics: Esters

Benzocaine (ester)

Procaine (ester)

Local Anesthetics: Amides

Mepivacaine (Polocaine/Carbocaine) Bupivacaine (Marcaine)


Local anesthetics: weak bases; pKa somewhat above physiologic pH o less than 50% of molecules are in the lipid-soluble, un-ionized form at pH 7.4 At pH 7.4: 5% of tetracaine (pontocaine) molecules are un-ionized o Local infection (acidosis) increases the ionized drug fraction (less drug available to penetrate across membranes and bind to intracellular local anesthetic receptor) o Local anesthetics with pKs closest to physiologic pH are associated with more rapid onset of action (better ratio of ionized to un-ionized drug) Vasodilator properties of the local anesthetic: o Affect both apparent potency and duration of action o Lidocaine (Xylocaine), for example causes greater vasodilation compared to mepivacaine (Carbocaine) and therefore is associated with: 1. Enhanced systemic absorption 2. Shorter duration of action Lipid solubility: o Bupivacaine (Marcaine) & etidocaine (Duranest) (similar vasodilation) o Following epidural: mepivacaine (Carbocaine) plasma concentration higher than that for etidocaine (Duranest)

Etidocaine (Duranest): greater lipid solubility leads to increased tissue sequestration (reduced drug available) Absorption & Distribution: o Factors: Injection site Vascularity: o Highly vascular area (e.g. tracheal mucosa): promotes rapid absorption resulting in higher blood levels o Poorly vascular area (tendon) is associated with relatively poor absorption Regional anesthesia (block of large nerves): o Maximum blood levels (highest to lowest) o Intercostal (highest) > caudal > epidural > brachial plexus > sciatic nerve {lowest} Dosage: Presence of vasoconstrictors (e.g. epinephrine) Reduced systemic absorption due to local vasoconstriction o Increased neuronal uptake (higher local concentration) o Blood levels: reduced as much as 1/3 The presensce of vasoconstrictors have a particularly significant effect for local anesthetics with intermediate/short duration of action (e.g.,procaine (Novocain), lidocaine (Xylocaine), mepivacaine (Carbocaine) [not prilocaine (Citanest)]) o Vasoconstrictor addition has a lesser effect for more lipid soluble (longer-acting) agents: bupivacaine (Marcaine), etidocaine (Duranest). The lipid solubility of these agents tend to keep them in the local tissue site intrinsically. o Cocaine: local anesthetic with intrinsic sympathomimetic, vasoconstrictive properties Spinal anesthesia:-- enhancement & prolongation of local anesthetic spinal anesthesia by: 1. Activating alpha2 adrenergic receptors (inhibit substance P release & reduce dorsal horn neural activity) Addition of clonidine (alpha2 receptor agonist, Catapres) to local anesthetic solutions enhance the local anesthetic effect through reduction in neuronal activity & inhibition to substance P release) 2. Reduced systemic absorption 3. Increased local neuronal uptake Chemical properties of the drug o Plasma concentration-- determined by:

Rate of tissue distribution Rate of drug clearance Consider lidocaine (Xylocaine) distribution-- IV infusion: duration = 1minute Initial high uptake into lungs and redistribution to highly perfusion tissues (heart, kidney, brain) o Redistribution: limited solubility important. A highly soluble agent in a tissue will be more likely to remain in that initial site of concentration. o Following distribution to brain, kidney, heart-redistribution to other tissues (less perfused)-- e.g. muscle, fat o Other factors influencing local anesthetic distribution/plasma concentrations Patient age, liver function, cardiovascular status, protein binding o "Amide" local anesthetic agents more widely distributed compared to "ester" local anesthetics o Pulmonary Extraction Pulmonary extraction from the venous circulation limits the amount of local anesthetic (lidocaine (Xylocaine), bupivacaine (Marcaine), & prilocaine (Citanest)) that will reach the systemic circulation Bupivacaine (Marcaine): dose-dependent, first pass extraction (saturable, uptake) o Propranolol (Inderal) inhibits bupivacaine (Marcaine) extraction o Propranolol (Inderal) reduces lidocaine (Xylocaine) & bupivacaine (Marcaine) plasma clearance o Placental Transfer Dependency: o Plasma protein binding influences: Rate and extent of local anesthetic diffusion across the placenta Ester-local anesthetics are not associated with significant placental transfer (due to rapid hydrolysis) Fetal acidosis which may occur during prolonged labor, promotes, by ion trapping mechanism, accumulation of local anesthetic in the fetus o Clearance: Amides -- hepatic (minimal renal excretion of unchanged drug) Esters--rapid clearance; short elimination halftime due to rapid hydrolysis Miller, R.D., Local Anesthesia, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 425-433. Stoelting, R.K., "Local Anesthetics", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, pp 158-181.

0. 1. 2.

Vasocontrictors added to local anesthetic solutions

Purpose of adding epinephrine to a local anesthetic solution: Increased duration: addition of epinephrine (1:2000,000 or 5 ug/ml) to cause vasoconstriction o Reduced systemic absorption o Higher anesthetic concentration near nerve fibers o Prolongation of conduction blockade (about 50% longer) o Reduced systemic absorption (by about 33%) Factors influencing the effectiveness of epinephrine on local anesthesia: Dependencies -o Which anesthetic is used: Reduced effect of epinephrine on duration of conduction blockade and systemic absorption comparing mepivacaine (Carbocaine) and etidocaine (Duranest) [these are more lipophilic] with lidocaine (Xylocaine), which is less lipophilic More lipophilic local anesthetics will tend on their own to associate strongly with tissues o Level of sensory blockade needed for spinal or epidural anesthesia Duration of lower extremity sensory anesthesia extended by epinephrine or phenylephrine (Neo-Synephrine); this effect is not observed for abdominal region anesthesia Conditions: epinephrine (0.2 mg) or phenylephrine (NeoSynephrine) (2 mg) added to mepivacaine (Carbocaine) or lidocaine (Xylocaine) -- placed in subarachnoid spaces o Spinal anesthesia -- tetracaine (pontocaine): duration of action extended by vasoconstrictors Condition 1: epinephrine plus tetracaine (pontocaine) (6 mg, low-dose)result: increase in spinal anesthesia success rate Condition 2: epinephrine plus tetracaine (pontocaine) (10 mg, higher dose)- result: no increase in spinal anesthesia success rate Prolongation of local anesthetic action (no effect by epinephrine on time-to-onset): Mechanisms -o Decreased systemic absorption o Increased local anesthetic concentration in the vicinity of sensory nerves o Increased uptake of the local anesthetic Advantages of reduced local anesthetic systemic absorption: o Local anesthetic absorption rate more likely to match metabolic rate resulting in less local anesthetic systemic toxicity Toxicities associated with systemic epinephrine absorption: o Local anesthetic + epinephrine: increased cardiac irritability which may cause an increased risk of cardiac arrhythmias o Increased possibility of hypertensive response in susceptible patients Other agents which may be added to local anesthetics that affect duration of action o Dextran (low-molecular-weight) when added to local anesthetic solutions result in increased peripheral nerve block anesthesia duration (probably due to a reduction in local anesthetic systemic absorption)

Local Anesthetic Combinations

Local anesthetic combinations: Purpose o Prolonged duration (bupivacaine (Marcaine))& decreased time to onset (chloroprocaine (Nesacaine)) Concerns: o Chloroprocaine (Nesacaine) in the epidural space may lead to possibly reduced subsequent epidural space bupivacaine (Marcaine) analgesia efficacy during labor Mechanism -- chloroprocaine (Nesacaine) reduces pH which decreases the amount of nonionized (active) bupivacaine (Marcaine) o Tachyphylaxis to the mixture (possibly secondary to local acidosis caused by low pH of the chloroprocaine (Nesacaine) solution) Suggestion: increased chloroprocaine (Nesacaine) solution pH just before use may enhance chloroprocaine (Nesacaine)-mepivacaine (Carbocaine) combination efficacy Local anesthetic combination: Toxicity is additive

Stoelting, R.K., "Local Anesthetics", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, pp 158-181.

Local Anesthetic Side-Effects /Toxicities & Neurotoxicity

Overview o Primary side effects Allergic reactions Systemic toxicity Secondary to high plasma/tissue local anesthetic concentrations Manifestation: o Seizures Frequency: 1-4/1000 cases Bupivacaine (Marcaine) -- local anesthetic most likely to cause seizures Allergic Reactions: o Rare occurrence -- < 1% of local anesthetic adverse reactions due to allergic mechanism Higher-risk: ester-type local anesthetics (those which are metabolized to p-aminobenzoic acid-related compounds) o Allergic reaction following local anesthetic administration may be caused by preservatives (methylparaben or related structures) included in the preparation {preservatives are structurally similar to p-aminobenzoic acid} Antibody production may have been previously induced by the preservative (not reaction to the local anesthetic) o Cross Sensitivity May be due to common metabolite profile {p-aminobenzoic acid}

No cross sensitivity between ester vs. amide local anesthetic classes Patient with allergy to an ester local anesthetic drug may receive an amide local anesthetic The anesthetic agent thought to not produce an allergic reaction should not have preservatives {it is possible that the preservative is the allergen} Basis/evidence for local anesthetic allergies 0. Clinical history, intradermal testing 1. Suggestive: Rash, urticaria, laryngeal edema, possible hypotension, bronchospasm Caution: hypotension with syncope/tachycardia following epinephrine-containing local anesthetic injection; accidental intravascular injection 2. Intradermal testing: must use preservative-free drug

Local Anesthetic Systemic Toxicity

Overview o Systemic Toxicity Cause: Excessively high plasma local anesthetic concentration o Plasma concentration -- determinants Rate of entry into systemic circulation balanced by redistribution to tissue sites & clearance o Most common cause of toxic plasma local anesthetic concentrations - Accidental direct intravascular injection during peripheral nerve block or epidural anesthesia o Other cause of toxic plasma levels: -- excessive absorption from injection site (no intravascular injection) o Extent of systemic absorption -- dependencies Initial dose of administered Injection site vascularity Whether or not epinephrine was used to provide local vasoconstriction Properties of the drug itself CNS Toxicity-local anesthetics o Symptom development: Tongue and circumoral numbness (low concentration) CNS changes with local anesthetic entering the brain Initial symptoms: tinnitus, vertigo, restlessness Subsequent symptoms: slurred speech & skeletal muscle fasciculation (muscle twitching: often immediately precedes seizures) Tonic-clonic seizures

Presentation: generalized seizure (tonic general muscular contractions) with alternating contractions and relaxations. Duration: one- two minutes Consciousness: Loss of Consciousness o Factors influencing CNS toxicity Plasma concentration-- specific drug dependent Lidocaine (Xylocaine), mepivacaine (Carbocaine), prilocaine (Citanest): CNS effects (5-10 ug/ml): Bupivacaine (Marcaine): CNS effects [seizures] (4-5 ug/ml) Rate of injection -- (i.e. rate of rise of serum concentration): may be more important than total amount of drug injected Lidocaine (Xylocaine) -- must also consider active metabolites, e.g.monoethylglycinexylidide, which may contribute to additive toxicity with lidocaine (Xylocaine) following epidural administration Inverse relationship between PaCO2 and local anesthetic seizure thresholds (possibly related to variation in cerebral blood flow & drug delivery) Hyperkalemia-- promoting depolarization: increased local anesthetic toxicity Hypokalemia-promoting membrane hyperpolarization: decreased local anesthetic toxicity Increased (probably) lidocaine (Xylocaine) neurotoxicity in patients treated with mexiletine (Mexitil) during perioperative time frame. Treatment: Seizures Assure adequate ventilation with oxygen Rapid onset of arteriole hypoxemia & metabolic acidosis Add supplemental oxygen when local anesthetic toxicity first appears Seizure suppression IV midazolam (Versed) or diazepam (Valium) Neurotoxicity o Overview -- Neurotoxicity as a consequence of local anesthetic injection into subarachnoid or epidural spaces Effects: Groin numbness Long-lasting, isolated myotomal (muscle segment) weakness Cauda equina syndrome Subarachnoid-space injections: Transient radicular irritation Permanent neurological injury following regional anesthesia: rare Transient Radicular Irritation o Anatomical Location: lumbosacral nerves o Manifestation: moderate/severe lower back, buttocks, posterior thigh pain o time to onset: by 24 hours following spinal anesthesia complete recovery

Type of pain (delayed onset): neural inflammatory Pain treatment: if severe, opioids o Time to recovery: within one-week o Pharmacological issues: Transient radicular irritation -- may not be dependent on anesthetic concentration {frequency comparable following several lidocaine (Xylocaine) concentrations} Spinal anesthesia with tetracaine (pontocaine): reduced incidence of transient radicular irritation relative to lidocaine (Xylocaine) o Transient ischemia due to lengthened exposure to local anesthetic as a result of concurrent epinephrine or phenylephrine (Neo-Synephrine) use {in the anesthetic solution} may contribute to transient neurological symptoms Cauda equina Syndrome o Definition: injuries (diffuse) across lumbosacral plexus causing: Sensory anesthesia Bowel & bladder sphincter dysfunction Paraplegia o Circumstances of clinical occurrence: Microcatheters (28 gauge) delivering hyperbaric 5% lidocaine (Xylocaine) may cause nonhomogeneous local anesthetic distribution-- pooling of high anesthetic concentration on stretched nerves (lithotomy position). Following intrathecal lidocaine (Xylocaine) [100 mg 5% lidocaine (Xylocaine), 25-gauge needle] Intended epidural anesthesia Anterior Spinal Artery Syndrome o Manifestation: lower-extremity paresis (variable sensory deficit following neural blockade resolution) o Possible mechanisms Thrombosis Anterior artery spasm Hypotension/vasoconstrictor drugs o Possible Predisposing conditions: Advanced age Peripheral vascular disease o Differential diagnosis -- similar symptoms to that caused by: Epidural abscess-mediated or hematoma-mediated spinal cord compression Primary Reference: Stoelting, R.K., "Local Anesthetics", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, pp 158-181. Miller, R.D., Local Anesthesia, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 425-433. White, P. F. "Anesthesia Drug Manual", W.B. Saunders Company, 1996.

Local Anesthetics: Clinical Uses

Overview o Most frequent use: regional anesthesia o Less common use: Prevention & treatment of cardiac arrhythmias Prevention/management: increased intracranial pressure (ICP) Lidocaine (Xylocaine) (1.5 mg/kg IV): effective as thiopental (Pentothal) in preventing ICP increases associated with tracheal intubation Mechanism: (probable) -- lidocaine (Xylocaine)-mediated decrease in cerebral blood flow (CBF) by increasing cerebral vascular resistance Reduced CBF leads to reduced cerebral blood volume leads to reduced ICP Advantage of lidocaine (Xylocaine) vs. barbiturates: reduced risk of drug-induced hypotension Lidocaine (Xylocaine) also reduces blood pressure response to direct laryngoscopic tracheal intubation, an effect probably secondary to generalized cardiovascular depression Analgesia Treatment of grand mal seizure

Regional Anesthesia
Classification: Six Placement Sites Surface/topical Local Peripheral nerve anesthesia infiltration block Bier block (IV regional anesthesia) Epidural anesthesia Spinal anesthesia (subarachnoid)

Epidural anesthesia (image courtesy of the University of Kansas Medical Center, Department of Nurse Anesthesia)

Spinal anesthesia (subarachnoid) (image courtesy of the University of Kansas Medical Center, Department of Nurse Anesthesia)

Topical/Surface anesthesia o Location: application to mucous membranes Nose Mouth Esophagus Tracheobronchial tree Genitourinary tract o Commonly used drugs: Cocaine (4%-10%) > 50% of rhinolaryngologic cases (USA) Unique pharmacological property: produces localized vasoconstriction as well as anesthesia o Localized vasoconstriction: 1. less bleeding 2. improved surgical field visualization Cocaine substitution: o lidocaine (Xylocaine) -oxymetazoline (Afrin) combinations o tetracaine (pontocaine)-oxymetazoline (Afrin) combinations Tetracaine (pontocaine) (1%-2%) Lidocaine (Xylocaine) (2%-4%) o Ineffective agents: Procaine (Novocain) & chloroprocaine (Nesacaine): poor mucous membrane penetration

Nebulized lidocaine (Xylocaine)-- surface anesthesia Upper & lower respiratory tract prior to bronchoscopy or fiber-optic laryngoscopy Treatment for intractable cough Normal subjects: No effect on airflow resistance (they produce some bronchodilation) Patients with asthma: nebulized lidocaine (Xylocaine) may increase airflow resistance (bronchoconstriction)-- concern if bronchoscopy is intended for this patient group Systemic concentration following nebulized lidocaine (Xylocaine) Following mucosal absorption: systemic concentration may be similar to IV injection o Reasons: Large surface area Significant vascularity of tracheobronchial region Skin Surface Application Barrier: keratinized skin layer Higher local anesthetic concentrations required: o 5% lidocaine (Xylocaine)-prilocaine (Citanest) cream {2.5% lidocaine (Xylocaine) & 2.5% prilocaine (Citanest)} no local irritation even absorption no systemic toxicity Combination of local anesthetic: Definition: eutectic mixture of local anesthetics (EMLA) o Melting point of combined drug is lower then either lidocaine (Xylocaine) or prilocaine (Citanest) alone. General definition: eutectic--said of a mixture which has the lowest melting point which it is possible to obtain by the combination of the given components. Application Characteristics 2 1-2 grams of EMLA cream/10 cm of skin plus occlusive dressing Duration of application to achieve adequate local anesthesia-examples: o Skin-graft harvesting: two hours o Cautery of genital warts: 10 minutes Clinical uses of EMLA applications-- pain relief for: Venipuncture Lumbar puncture Myringotomy in adults and children Arterial cannulation Special uses in combination with nitroglycerin ointment -- makes venous cannulation easier by causing vasodilation EMLA use in blood sampling: no effect on blood analysis

EMLA use in preventing pain associated with intradermal skin tests: o Predisposes to false negatives [decreases flare response associated with weakly positive reactions] Factors affecting EMLA analgesia time to onset, duration of action, & efficacy Skin blood flow Epidermal/girl thickness Application duration Presence of pathology Blacks: possibly less responsive than whites Contraindications/Concerns Methemoglobin levels secondary to prilocaine (Citanest) metabolism may be of concern in young children (< three months) o [if EMLA cream is used while other methemoglobininducing drugs are used [e.g. sulfonamides, acetaminophen, phenytoin (Dilantin), nitroglycerin, nitroprusside sodium (Nipride)] EMLA cream not recommended for mucosal application due to faster lidocaine (Xylocaine)/prilocaine (Citanest) absorption EMLA cream not recommended for application to skin wounds (wound infection risk, increased) EMLA cream not recommended for patients taking mexiletine (Mexitil, amine lidocaine analog) (in antiarrhythmic drug) since additive/synergistic effects may occur EMLA cream: contraindicated in patients are allergic to amide local anesthetics Other topical local anesthetic formulations Pramoxine (Tronothane, Prax) -- applications o Skin or mucous membrane application: pain or leave due to 0. dermatoses 1. hemorrhoids 2. minor burns o Reduce pain associated with sigmoidoscopy o Upper airway anesthesia prior to direct laryngoscopy o Not recommended for: o nasal/tracheal mucosal application (irritation) Dyclonine (Dyclone, Seroquel 5%-1%), piperocaine, hexylcaine-applications o Mucous membrane anesthesia for direct laryngoscopy o Dyclonine (Dyclone): upper airway anesthesia for patients allergic to bupivacaine (Marcaine) and procaine (Novocain) o Rationale: ketone structure dyclonine (Dyclone) makes cross sensitivity with amide or ester local anesthetics less likely

Primary Reference: Stoelting, R.K., "Local Anesthetics", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, pp 158-181; Miller, R.D., Local Anesthesia, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 425-433.

Local Infiltration

Definition: Extravascular placement of the local anesthetic in the region to be anesthetized o Example: subcutaneous local anesthetic injection in support of intravascular cannula placement Preferred local anesthetics for local infiltration o Most common: lidocaine (Xylocaine) o Other choices: 0.25% Ropivacaine (Naropin) or Bupivacaine (Marcaine) (effective for pain management at inguinal operative location) Duration of action: o Duration extended by 2X using 1:200,000 epinephrine o Caution: Epinephrine-containing local anesthetic solution should not be injected intracutaneously (intradermal) or into tissues supplied by "end-arteries" such as ears, nose, fingers because vasoconstriction may be sufficiently severe to produce tissue ischemia and gangrene.

Peripheral Nerve Block

Procedure: local anesthetic injection into tissues around individual nerves or nerve plexuses (e.g. brachial plexus) Mechanism: o Local anesthetic diffusion path: nerve outer surface (mantle) to the nerve core [driving force: concentration gradient] o Anesthetized first: mantle fibers (innervating more proximal structures) o Anesthetized last: core fibers (innervating more distal anatomy) Explanation of why anesthesia develops proximately first Recovery in the opposite direction (sensation returns proximally first; lastly the distal anatomy) Mixed peripheral nerves: (motor/sensory) o Sequence of onset & recovery (motor anesthesia first or sensory anesthesia first): dependent on anatomical locations within the nerve fiber Rapidity of onset: Dependencies o Drug pK dependency: pK (at a given tissue pH) determines the fraction all of local anesthetic in the nonionized formed.

Un-ionized form = lipid soluble, active form, capable of penetrating membranes combining with local anesthetic receptors located on the internal membrane surface. Examples: Lidocaine (Xylocaine) time to onset = 3minutes Bupivacaine (Marcaine) time to onset = 15 minutes Rationale: greater lidocaine (Xylocaine) fraction present in the un-ionized (uncharged) active form Specific examples: 0.5% bupivacaine (Marcaine) or ropivacaine (Naropin): similar onset & duration of brachial plexus block Ropivacaine (Naropin) (subclavian perivascular block): time to onset -- 4 minutes; sensory block duration -- > 13 hours Ropivacaine (Naropin): onset and duration of action similar to bupivacaine (Marcaine) Not recommended: Tetracaine (pontocaine): slow onset & more likely to cause systemic toxicity; not recommended for peripheral nerve block or for local infiltration Duration of action-dependencies o Drug lipid solubility o Extent of drug protein binding o Dose o Prolongation of drug effect: safer with added vasoconstrictor (e.g. epinephrine) than by increasing local anesthetic dose Example: bupivacaine (Marcaine) + epinephrine: peripheral nerve block may last 14 hours (in some reports)

Axillary Block: Drawing by Lindsey Parker, (c) University of Kansas Medical Center

Intravenous Regional Anesthesia (Bier Block)

Procedure: o Local anesthetic injection into an extremity isolated by tourniquet o Result: rapid anesthesia onset; skeletal muscle relaxation Duration of anesthetic action: o Dependent on how long the tourniquet is kept inflated o Following tourniquet deflation: rapid recovery as blood dilutes local anesthetic concentration Probable Mechanism: o Drug action on nerve endings & nerve trunks Choice of local anesthetics o Ester or amide type IV local anesthetics may be used o Most frequently used amide agents: Lidocaine (Xylocaine) Prilocaine (Citanest) At deflation, no clinically significant methemoglobinemia (3% of hemoglobin as methemoglobin)-- 10% required for cyanosis. Comparing comparable IV regional anesthesia with 50 ml (0.5%) lidocaine (Xylocaine) or prilocaine (Citanest): lower plasma prilocaine (Citanest) concentrations following tourniquet deflation, compared to lidocaine (Xylocaine) Prilocaine (Citanest) may be safer in terms of reduced systemic toxicity risk o Agents not recommended: Chloroprocaine (Nesacaine) -- High incidence of thrombophlebitis Bupivacaine (Marcaine) -- More likely than other local anesthetic to cause cardiotoxicity upon tourniquet deflation Ropivacaine (Naropin)-Might also cause cardiotoxicity upon tourniquet deflation (less likely than with bupivacaine (Marcaine))

Bier Block: Drawing by Lindsey Parker, (c) University of Kansas Medical Center Primary Reference: Stoelting, R.K., "Local Anesthetics", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, pp 158-181.; Miller, R.D., Local Anesthesia, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 425-433.

Epidural Anesthesia

Definition o Anesthesia caused by local anesthetic solutions injected into epidural or sacral caudal space Mechanisms:

Direct action on nerve roots and spinal cord following local anesthetic diffusion across the dura o Diffusion of local anesthetic into paravertebral region through the intervertebral foramina causing paravertebral nerve blocks Onset of action:15-30 minute delay Choice of local anesthetics: o Lidocaine (Xylocaine): frequently used; diffuses well for tissues o Bupivacaine (Marcaine) & Ropivacaine (Naropin) (0.5%-0.75%): Prolonged sensory anesthesia Motor anesthesia: less intense & shorter duration with ropivacaine (Naropin); greater tendency for Alpha- delta and C fiber blockade Reduced ropivacaine (Naropin) motor effects may be beneficial for obstetrical patients in labor & for patients experiencing acute/chronic pain Ropivacaine (Naropin)-Reduced systemic toxicity compared to bupivacaine (Marcaine) allows ropivacaine (Naropin) concentrations of up to 1% to be used surgically. Analgesia/anesthesia for labor/cesarean section similar with 0.5% bupivacaine (Marcaine) or ropivacaine (Naropin) [motor blocked duration shorter in parturients receiving ropivacaine (Naropin)] 0.25% ropivacaine (Naropin) & syrup.25% bupivacaine (Marcaine) (intermittent dosing into epidural space): equally effective in managing labor pain Postoperative analgesic: 0.2% ropivacaine (Naropin) (6-10 ml/hr) Local anesthetic plasma concentrations following epidural anesthesia in parturients: Local anesthetics: traverse the placenta and may affect the fetus for 24-48 hours (not necessarily adversely) Special considerations: o Mepivacaine (Carbocaine): less readily metabolized by the fetus or neonate compared to adult: longer halftimes of elimination o Increased lipid solubility and protein binding of bupivacaine (Marcaine) may reduce its access to the fetus. o Lidocaine (Xylocaine): (even low doses) leads to maternal systemic absorption and consequently fetal systemic presence o Bupivacaine (Marcaine): not detectable in neonatal plasma (one day following cesarean section using bupivacaine (Marcaine)-spinal anesthesia

Drawing by Lindsey Parker, (c) University of Kansas Medical Center

Comparison of Epidural vs. Spinal anesthesia Epidural----------------------------------Spinal

Often no zone of differential sympathetic nervous system blockade

Typically a zone of differential sympathetic nervous system blockade (differential effects due to concentration differences, different nerve fiber types and differences in nerve fiber sensitivity) Zone of differential motor blockade: average two segments below the sensory level

Zone of differential motor blockade may average up to four segments below the sensory level Larger local anesthetic dose required compared to spinal--

Smaller local anesthetic dose required compared to epidural--

greater systemic absorption

less systemic absorption

Systemic local anesthetic absorption -- specific examples o Lidocaine (Xylocaine) -- peak plasma levels: 3-4 ug/mL following 400 mg injected epidurally o Bupivacaine (Marcaine) --peak average plasma level 0.3 ug/mL --(after 30 minutes; 70-100 mg of 0.5% solution with 1:200,000 epinephrine) Peak plasma level 1 ug/mL-- if epinephrine is not included in the local anesthetic solution Epinephrine inclusion: general reduction of systemic local anesthetic absorption by 1/3 Consequences of systemic epinephrine absorption (low concentration, beta2 adrenergic receptor mediated effects notable): Peripheral vasodilation Reduced systemic blood-pressure Increased heart rate; increased myocardial contractility.

Spinal Anesthesia

Definition o Anesthesia following local anesthetic injection into lumbar subarachnoid space. Site of action: o Primary: preganglionic fibers leading the spinal cord in the anterior rami o Secondary: superficial spinal cord layers Zones of differential anesthesia-- causes 1. Local anesthetic concentration gradient effects 2. Different nerve fiber types have different sensitivities to local anesthetics Anesthesia levels o Level of sympathetic nervous system "denervation": extends about two spinal segments cephalad (above) the level sensory anesthesia o Level of motor anesthesia extends about two segments below sensory anesthesia o Reason: differential sensitivity to local anesthesia Factors affecting local anesthetic dosages: 0. Patient height (determines subarachnoid spatial volume) 1. Segmental level of anesthesia required 2. Duration of anesthesia required 3. Total local anesthetic dose: more important than concentration or volume effects

Local anesthetics used for spinal anesthesia

o o

Most commonly used agents: tetracaine (pontocaine), lidocaine (Xylocaine), bupivacaine (Marcaine) Characteristics of some drugs:

Lidocaine (Xylocaine): may be associated with a higher risk of transient neurological adverse effects compared to bupivacaine (Marcaine) If lidocaine (Xylocaine) used: limit dose to 60 mg Bupivacaine (Marcaine): More effective than tetracaine (pontocaine) in preventing lower-extremity tourniquet pain (orthopedic surgery cases) In parturients: intrathecal mepivacaine (Carbocaine, 2.5 mg) + 10 ug sufentanil (Sufenta): effective labor analgesia while allowing patients to continue to walk. Ropivacaine (Naropin) (3 ml of 0.5% or 0.75%): Sensory anesthesia present; however, motor blockade present in only 50% of patients if 0.5% dosage used. Chloroprocaine (Nesacaine) -- Not placed in subarachnoid space due to neurotoxicity risk Factors determining spread of drug following lumbar injection: Specific gravity of the local anesthetic solution Glucose addition: increased specific gravity above that of CSF (hyperbaric) Distilled water addition: decreased specific gravity below that of CSF (hypobaric) Duration of action: amides vs. esters CSF does not contain significant cholinesterase activity -- no enzymatic influence on ester local anesthetic duration: Duration of action of amides and ester-local anesthetics placed in subarachnoid spaces --influenced by the vascular drug absorption rates Intrathecal tetracaine (pontocaine): significant increase in spinal cord blood flow (preventable/reversible by epinephrine addition, which increases tetracaine (pontocaine)-induced spinal anesthesia, up to 2X);{less vasodilation with lidocaine (Xylocaine)} Bupivacaine (Marcaine): vasoconstriction

Drawing by Lindsey Parker, (c) University of Kansas Medical Center

Physiological Effects-- Spinal anesthesia


Consequences of sympathetic blockade: Arteriolar dilation No significant effect on systemic BP due to compensatory upper extremity vasoconstriction. No cerebrovascular vasoconstriction Total sympathetic blockade due to spinal anesthesia: associated with a reduction in systemic vascular resistance of < 15%. o Rationale: arteriolar smooth muscle does not dilate maximally because of intrinsic tone Many major cardiovascular response secondary to spinal anesthesia due to: Effects on venous circulation Venules: minimal intrinsic tone retention; maximal dilation during spinal anesthesia Consequences of venous-side dilation: o Reduced venous return to heart leads to decreased cardiac output and consequently decreased systemic blood-pressure o Severe systemic hypotension in hypovolemic patients Treatment: Alpha-adrenergic receptor agonist administration Slightly-head down patient repositioning Effects on heart rate:

Cardiac slowing (bradycardia) secondary to blockade of preganglionic cardiac accelerator nerves (T1 to T4) This bradycardia response may be worsened in the presence of reduced preload and as a result, reduce stimulation of atrial stretch receptors (which, when activated, cause cardioacceleration) Management of bradycardia secondary to T1 to T4 blockade may include administration of low-dose epinephrine {Clark Albert, MD, personal communication} High-spinal anesthesia: Effects on ventilation Apnea may occur due to abnormal medullary ventilatory center function {secondary to ischemia due to reduced cerebral blood flow} Apnea-- unlikely due to phrenic nerve paralysis

Primary Reference: Stoelting, R.K., "Local Anesthetics", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, pp 158-181.;Miller, R.D., Local Anesthesia, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 425-433.

Cocaine Toxicity

Mechanism: o Excessive sympathetic stimulation o Norepinephrine & dopamine reuptake blockade Pharmacokinetics o Peak plasma concentrations: o 30-40 minutes following intranasal administration o 5 minutes following IV/smoke administration o Maximal physiological effects: intranasal cocaine (15-40 minutes) o Duration of effects: 60 minutes or longer following peak effect o Elimination halftime -- 60-90 minutes o Metabolism: plasma esterases Adverse Effects: acute administration o Coronary vasospasm/myocardial ischemia/infarction o Cardiac arrhythmias (including ventricular fibrillation) o Hypertension o Myocardial ischemia may be long lasting, possibly secondary to delayed coronary artery vasospasm o Dose-dependent reduction in uterine blood flow may lead to fetal hypoxemia o Hyperpyrexia/seizures o Topical cocaine + epinephrine or cocaine administration in the presence of myocardium-sensitizing volatile anesthetics, e.g. halothane: o Enhanced cocaine-mediated cardiac stimulation

Cocaine may be contraindicated in patients with hypertension or coronary vascular disease and in patients receiving agents that enhance catecholamine effects (e.g., MAO inhibitors) Treatment of cocaine toxicity: o Nitroglycerin o IV diazepam (Valium) for management of cocaine induced seizures o Caution: esmolol (Brevibloc) management of cocaine-induced tachycardia may predispose to coronary vasospasm

Primary Reference: Stoelting, R.K., "Local Anesthetics", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, pp 158-181.; Miller, R.D., Local Anesthesia, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 425-433.

Local Anesthetics Listing

Benzocaine (generic) Bupivacaine (Marcaine) Butamben picrate (Butensin Picrate) Chloroprocaine (Nesacaine) Pramoxine (Tronothane, Prax)

Cocaine Dibucaine (Nupercainal, generic) Dyclonine (Dyclone) Etidocaine (Duranest) Lidocaine (Xylocaine)

Mepivacaine (Carbocaine) Ropivacaine (Naropin) Prilocaine (Citanest) Procaine (Novocain) Tetracaine (pontocaine)