Anesthesia Pharmacology Chapter 17:  Local Anesthetics  

Local Anesthetic Agents

• Overview --Chemical Properties:

  • Structural Aspects

    • Lipophilic component

    • Connecting chain (ester or amide)

    • Ionizable group

  • Racemates/Pure Isomers

    • Pipecoloxylidide-agents (mepivacaine (Carbocaine), ropivacaine (Naropin))

      •  Chiral agents (asymmetric carbon); left-(S), right-(R)-handed configurations

      •  Mepivacaine (Carbocaine) and bupivacaine (Marcaine) are used clinically as racemates (50:50 mixture) of enantiomers

        • S enantiomers of mepivacaine (Carbocaine) and bupivacaine (Marcaine): less toxic than racemates

      •  Ropivacaine (Naropin): pure S enantiomer

  •  Pharmacological activity (2 factors--one that considers chemical aspects alone and the second that considers interaction with receptors)

    •  Balance between lipophilic and hydrophilic characteristics

    •  Potency of stereoisomers (e.g.,ropivacaine (Naropin) and mepivacaine (Carbocaine))

  • Duration of action:

    •  Esters: shorter duration of action (compared to local anesthetics with amide linkages)

  • Properties: Local Anesthetics are weak bases:

    •  Existing as either uncharged base or cation (postiively charged)

    •  Proportions depending on pK_a and pH (as described by the Henderson-Hasselbalch equation)

      •  log ([cationic form] / [uncharged form]) = pK_a - 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)

        • Cationic form: probably physiologically active form at the receptor

        • Uncharged form: important for penetration across biological membranes to reach site of action

        • 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: weak bases;  pKa somewhat above physiologic pH

  •  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

  • Local infection (acidosis) increases the ionized drug fraction (less drug available to penetrate across membranes and bind to intracellular local anesthetic receptor)

  • 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:

  •  Affect both apparent  potency and duration of action

  •  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:

  •  Bupivacaine (Marcaine) and etidocaine (Duranest) (similar vasodilation)

  •  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 and Distribution:

  • Factors:

    •  Injection site

      • Vascularity:

        • Highly vascular area (e.g. tracheal mucosa): promotes rapid absorption resulting in higher blood levels

        • Poorly vascular area (tendon) is associated with relatively poor absorption

      • Regional anesthesia (block of large nerves):

        • Maximum blood levels (highest to lowest)

          • Intercostal (highest)  > caudal > epidural > brachial plexus > sciatic nerve (lowest)

    •  Dosage:

      •  Presence of vasoconstrictors (e.g. epinephrine)

        • Reduced systemic absorption due to local vasoconstriction

          •  Increased neuronal uptake (higher local concentration)

          •  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)])

          •  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.

          •  Cocaine: local anesthetic with intrinsic sympathomimetic, vasoconstrictive properties

        • Spinal anesthesia:-- enhancement and prolongation of local anesthetic spinal anesthesia by:

          1. Activating alpha₂ adrenergic receptors (inhibit substance P release and 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 and inhibition to substance P release)

          2. Reduced systemic absorption

          3. Increased local neuronal uptake

    •  Chemical properties of the drug

  • Plasma concentration-- determined by:

    1.  Rate of tissue distribution

    2.  Rate of drug clearance

    3.  Consider lidocaine (Xylocaine) distribution-- IV infusion: duration = 1-minute

       •  Initial high uptake into lungs and redistribution to highly perfusion tissues (heart, kidney, brain)

         • Redistribution: limited solubility important. A highly soluble agent in a tissue will be more likely to remain in that initial site of concentration.

         • Following distribution to brain, kidney, heart-- redistribution to other tissues (less perfused)-- e.g. muscle, fat

  • Other factors influencing local anesthetic distribution/plasma concentrations

    •  Patient age, liver function, cardiovascular status, protein binding

  • "Amide" local anesthetic agents more widely distributed compared to "ester" local anesthetics

  • Pulmonary Extraction

    • Pulmonary extraction from the venous circulation limits the amount of local anesthetic (lidocaine (Xylocaine), bupivacaine (Marcaine), and prilocaine (Citanest)) that will reach the systemic circulation

    • Bupivacaine (Marcaine): dose-dependent, first pass extraction (saturable, uptake)

      •  Propranolol (Inderal) inhibits bupivacaine (Marcaine) extraction

      •  Propranolol (Inderal) reduces lidocaine (Xylocaine) and bupivacaine (Marcaine) plasma clearance

  • Placental Transfer

    • Dependency:

      • 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

  • 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.

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

  • Reduced systemic absorption

  • Higher anesthetic concentration near nerve fibers

  • Prolongation of conduction blockade (about 50% longer)

  • Reduced systemic absorption (by about 33%)

• Factors influencing the effectiveness of epinephrine on local anesthesia: Dependencies --

  • 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

  • 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 (Neo-Synephrine) (2 mg) added to mepivacaine (Carbocaine) or lidocaine (Xylocaine) -- placed in subarachnoid spaces

  • 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 --

  • Decreased systemic absorption

  • Increased local anesthetic concentration in the vicinity of sensory nerves

  • Increased uptake of the local anesthetic

• Advantages of reduced local anesthetic systemic absorption:

  • Local anesthetic absorption rate more likely to match metabolic rate resulting in less local anesthetic systemic toxicity

•  Toxicities associated with systemic epinephrine absorption:

  • Local anesthetic + epinephrine:­ increased cardiac irritability which may cause an increased risk of cardiac arrhythmias

  • Increased possibility of hypertensive response in susceptible patients

• Other agents which may be added to local anesthetics that affect duration of action

  • 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

  • Prolonged duration (bupivacaine (Marcaine))and decreased time to onset (chloroprocaine (Nesacaine))

•  Concerns:

  • 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)

  • 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 Anesthetics: Clinical Uses

• Overview

  • Most frequent use: regional anesthesia

  • Less common use:

    •  Prevention and 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

• Topical/Surface anesthesia

  • Location: application to mucous membranes

    •  Nose

    •  Mouth

    •  Esophagus

    •  Tracheobronchial tree

    •  Genitourinary tract

  • Commonly used drugs:

    • Cocaine (4%-10%)

      •  > 50% of rhinolaryngologic cases (USA)

      •  Unique pharmacological property: produces localized vasoconstriction as well as anesthesia

        •  Localized vasoconstriction:

          1. less bleeding

          2. improved surgical field visualization

      •  Cocaine substitution:

        •  lidocaine (Xylocaine) -oxymetazoline (Afrin) combinations

        •  tetracaine (pontocaine)-oxymetazoline (Afrin) combinations

    • Tetracaine (pontocaine) (1%-2%)

    • Lidocaine (Xylocaine) (2%-4%)

  • Ineffective agents:

    • Procaine (Novocain) and chloroprocaine (Nesacaine): poor mucous membrane penetration

  • Nebulized lidocaine (Xylocaine)-- surface anesthesia

    • Upper and 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

        • Reasons:

          • Large surface area

          • Significant vascularity of tracheobronchial region

  • Skin Surface Application

    • Barrier: keratinized skin layer

      • Higher local anesthetic concentrations required:

        •  5% lidocaine (Xylocaine)-prilocaine (Citanest) cream (2.5% lidocaine (Xylocaine) and 2.5% prilocaine (Citanest))

          • no local irritation

          • even absorption

          • no systemic toxicity

      • Combination of local anesthetic: Definition: eutectic mixture of local anesthetics (EMLA)

        • 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

      • 1-2 grams of EMLA cream/10 cm² of skin plus occlusive dressing

      • Duration of application to achieve adequate local anesthesia-- examples:

        • Skin-graft harvesting: two hours

        • 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:

        • Predisposes to false negatives [decreases flare response associated with weakly positive reactions]

    • Factors affecting EMLA analgesia time to onset, duration of action, and 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)

        • [if EMLA cream is used while other methemoglobin-inducing 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

        •  Skin or mucous membrane application: pain or leave due to

          1. dermatoses

          2. hemorrhoids

          3. minor burns

        •  Reduce pain associated with sigmoidoscopy

        •  Upper airway anesthesia prior to direct laryngoscopy

        •  Not recommended for:

          • nasal/tracheal mucosal application (irritation)

      •  Dyclonine (Dyclone, Seroquel 5%-1%), piperocaine, hexylcaine-- applications

        •  Mucous membrane anesthesia for direct laryngoscopy

        •  Dyclonine (Dyclone): upper airway anesthesia for patients allergic to bupivacaine (Marcaine) and procaine (Novocain)

          • 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. 

• Definition: Extravascular placement of the local anesthetic in the region to be anesthetized

  •  Example: subcutaneous local anesthetic injection in support of intravascular cannula placement

• Preferred local anesthetics for local infiltration

  •  Most common: lidocaine (Xylocaine)

  •  Other choices: 0.25% Ropivacaine (Naropin) or Bupivacaine (Marcaine) (effective for pain management at inguinal operative location)

• Duration of action:

  •  Duration extended by 2X using 1:200,000 epinephrine

  •   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.

• Procedure: local anesthetic injection into tissues around individual nerves or nerve plexuses (e.g. brachial plexus)

• Mechanism:

  •  Local anesthetic diffusion path: nerve outer surface (mantle) to the nerve core [driving force: concentration gradient]

  •  Anesthetized first: mantle fibers (innervating more proximal structures)

  •  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)

  • Sequence of onset and recovery (motor anesthesia first or sensory anesthesia first): dependent on anatomical locations within the nerve fiber

• Rapidity of onset: Dependencies

  • 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 and 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 and more likely to cause systemic toxicity; not recommended for peripheral nerve block or for local infiltration

• Duration of action-dependencies

  • Drug lipid solubility

  • Extent of drug protein binding

  • Dose

  • 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)

Intravenous Regional Anesthesia (Bier Block)

• Procedure:

  • Local anesthetic injection into an extremity isolated by tourniquet

  • Result: rapid anesthesia onset; skeletal muscle relaxation

• Duration of anesthetic action:

  • Dependent on how long the tourniquet is kept inflated

  • Following tourniquet deflation: rapid recovery as blood dilutes local anesthetic concentration

• Probable Mechanism:

  • Drug action on nerve endings and nerve trunks

• Choice of local anesthetics

  •  Ester or amide type IV local anesthetics may be used

  •  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

  •    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))

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.

• Definition

  • 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

  •  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:

  •  Lidocaine (Xylocaine): frequently used; diffuses well for tissues

  •  Bupivacaine (Marcaine) and Ropivacaine (Naropin) (0.5%-0.75%):

    • Prolonged sensory anesthesia

    • Motor anesthesia: less intense and 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 and 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) and 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:

        • Mepivacaine (Carbocaine): less readily metabolized by the fetus or neonate compared to adult: longer halftimes of elimination

        • Increased lipid solubility and protein binding of bupivacaine (Marcaine) may reduce its access to the fetus.

        • Lidocaine (Xylocaine): (even low doses) leads to  maternal systemic absorption and consequently fetal systemic presence

        • Bupivacaine (Marcaine): not detectable in neonatal plasma (one day following cesarean section using bupivacaine (Marcaine)-spinal anesthesia

• Systemic local anesthetic absorption -- specific examples

  • Lidocaine (Xylocaine) -- peak plasma levels: 3-4 ug/mL following 400 mg injected epidurally

  • 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.

• Definition

  • Anesthesia following local anesthetic injection into lumbar subarachnoid space.

• Site of action:

  •  Primary: preganglionic fibers leading the spinal cord in the anterior rami

  •  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

  • Level of sympathetic nervous system "denervation": extends about two spinal segments cephalad (above) the level sensory anesthesia

  • Level of motor anesthesia extends about two segments below sensory anesthesia

  • Reason: differential sensitivity to local anesthesia

• Factors affecting local anesthetic dosages:

  1. Patient height (determines subarachnoid spatial volume)

  2. Segmental level of anesthesia required

  3. Duration of anesthesia required

  4. Total local anesthetic dose: more important than concentration or volume effects

• Local anesthetics used for spinal anesthesia

  • 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%.

        • 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:

        • Reduced venous return to heart leads to decreased cardiac output and consequently decreased systemic blood-pressure

        •  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:

  • Excessive sympathetic stimulation

    • Norepinephrine and dopamine reuptake blockade

• Pharmacokinetics

  • Peak plasma concentrations:

    • 30-40 minutes following intranasal administration

    • 5 minutes following IV/smoke administration

  • Maximal physiological effects: intranasal cocaine (15-40 minutes)

  • Duration of effects: 60 minutes or longer following peak effect

  • Elimination halftime -- 60-90 minutes

  • Metabolism: plasma esterases

•   Adverse Effects: acute administration

  •  Coronary vasospasm/myocardial ischemia/infarction

  •  Cardiac arrhythmias (including ventricular fibrillation)

  •  Hypertension

  •  Myocardial ischemia may be long lasting, possibly secondary to delayed coronary artery vasospasm

  •  Dose-dependent reduction in uterine blood flow may lead to fetal hypoxemia

  •  Hyperpyrexia/seizures

  •  Topical cocaine + epinephrine or cocaine administration in the presence of myocardium-sensitizing volatile anesthetics, e.g. halothane:

    • 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:

  • Nitroglycerin

  • IV diazepam (Valium) for management of cocaine induced seizures

  • 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.