Local Anesthetics

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					Local Anesthetics

   Brendan Astley MD
      October 2008
                Local Anesthetics
   Used at multiple sites throughout the body:
       Epidural
       Spinal
       Peripheral nerve blocks
       IV (Bier Block)
       Skin sites locally
              Amides and Esters
   Lidocaine (Xylocaine)       Chloroprocaine
   Bupivacaine (Marcaine)
                                Cocaine (crack)
   Etidocaine (Duranest)
                                Procaine
   Mepivacaine                 Tetracaine (Pontocaine)
   Prilocaine (Citanest)
   Ropivacaine
           Mechanism of Action
   Local anesthetics work in general by binding to
    sodium channel receptors inside the cell and thereby
    inhibiting action potentials in a given axon. They
    work the best when the axon is firing.
   The Cell membrane consists of ion pumps, most
    notably the Na/K pump that create a negative 70mV
    resting potential by pumping 2 K+ intracellular for
    every 3 Na+ it pumps extracellular.
    Mechanism of Action (cont’d)
   If the resting potential encounters the proper
    chemical, mechanical or electrical stimuli to reduce
    the membrane potential to less than -55 mV then an
    action potential is produced that allows the influx of
    sodium ions. LA act here to block the Na influx.
   The influx allows the membrane potential to further
    increase to +35mV temporarily.
   Sodium and potassium channels along with the
    sodium/potassium pump eventually returning a given
    axon back to it’s resting membrane potential after an
    action potential.
             Mechanism of Action
   Benzocaine….
       Does not exist in a charged form how does it
       Most likely by expanding the lipid membrane of
        the axon and therefore inhibiting the transport
        mechanisms of Na and K ions.
            General Structure
   A lipophilic group…usually a benzene ring
   A Hydrophilic group…usually a tertiary amine
   These are connected by an intermediate chain
    that includes an ester or amide linkage
   LAs are weak bases
                      Lipid solubility
   Most lipid soluble:
       Tetracaine
       Bupivicaine
       Ropivacaine
       Etidocaine
   Increased lipid solubility also equals greater potency and
    longer duration of action.
       Why?
       Because it has less of a chance of being cleared by blood flow
   Decreased lipid solubility means a faster onset of action.
   What else effects onset of action???
   Local anesthetics with a pKa closest to physiological
    pH will have a higher concentration of nonionized
    base that can pass through the nerve cell membrane,
    and generally a more rapid onset.
   The charged cation form more avidly binds to the
    Na+ channel receptors inside the cell membrane.
   pKa > 7.4 more cations, pKa < 7.4 more anions
         Not all Axons are equal
   Aa- Motor with fast conduction 70-120m/s, diameter
    12-20mm, myelinated and not very sensitive to local
   Aa- Type Ia and Ib- proprioception fast conduction
    again 70-120m/s, same diameter as above, a little
    more sensitive to LA, myelinated
   Ab- Touch pressure and proprioception, smaller
    diameter 5-12mm and slower conduction 30-70m/s,
    myelinated and as sensitive to LA as type Ia and Ib
         Not all Axons are equal
   Ag- motor (muscle spindle) smaller diameter
    3-6mm, slower conduction 15-30m/s same LA
    sensitivity as type Ia and Ib fibers
   Ad- Type III fibers, pain, cold temperature and
    touch, smaller diameter 2-5mm, 12-30m/s,
    more sensitive to LA than the above fibers and
           Not all Axons are equal
   B fibers- Preganglionic autonomic fibers, <3mm diameter, 3-
    14m/s conduction speed and very sensitive to LA. Some
   C fibers- Type IV fibers in the dorsal root, pain warm and cold
    temp. and touch, .4-1.2mm in diameter, slow conduction again
    at .5-2m/s, very sensitive to LA, not myelinated.
   C fibers- Postganglionic sympathetic fibers, smaller diameters
    at .3-1.3mm, slow conduction at .7-2.3m/s, very sensitive to
    LA and no myelination.
   In general this all means that the autonomic nerves are blocked
    before the sensory nerves which are blocked before the motor
   Bupivacaine, Etidocaine and Ropivacaine-
    very high potency and lipid solubility, very
    long duration and protein binding also.
   Lidocaine, Prilocaine and Mepivacaine- have
    intermediate potency and lipid solubility and
    intermediate duration of action and protein
   Chloroprocaine and Procaine- have low
    potency and lipid solubility and also low
    duration and protein binding.
   Cocaine- has intermediate potency and
    solubility and intermediate duration and
    protein binding
   Tetracaine- has high potency and lipid
    solubility along with a long duration of action
    and high protein binding
           Plasma protein binding
   What protein are LAs bound???
       Mostly a1-acid glycoprotein
       To a lesser degree albumin
   Mucous membranes easily absorb LA
   Skin is a different story…
   It requires a high water conc. for penetration and a
    high lipid concentration for analgesia
   Which LAs can we use for this?
       EMLA cream- 5% lidocaine and 5% prilocaine in an oil-
        water emulsion
       An occlusive dressing placed for 1 hour will penetrate 3-
        5mm and last about 1-2 hours.
       Typically 1-2 grams of drug per 10cm2 of skin
      Rate of systemic absorption
   Intravenous > tracheal > intercostal > caudal >
    paracervical > epidural> brachial plexus >
    sciatic > subcutaneous
   Any vasoconstrictor present??
   High tissue binding also decreases the rate of
   Amides…
       N-dealkylation and hydroxylation
       P-450 enzymes, liver, slower process than esterase activity
       Prilocaine>lidocaine>mepivacaine>ropivacaine>bupivacai
       Prilocaine has a metabolite….
            o-toluidine
       This causes methemoglobin to form (Benzocaine can also
        cause methemoglobin to form)
       Treated with methylene blue 1-2mg/kg over 5 minutes
            Reduces methemoglobin Fe3+ to hemoglobin Fe2+
   Esters…
       Pseudocholinesterase
   Procaine and benzocaine are metabolized to…
       PABA (p-aminobenzoic acid) allergy risk
   Tetracaine intrathecal has it’s action
    terminated by…
       No esterase activity intrathecally therefore
        absorption into bloodstream terminates it’s action
                   Clinical Uses
   Esters
       Benzocaine- Topical, duration of 30 minutes to 1
       Chloroprocaine- Epidural, infiltration and
        peripheral nerve block, max dose 12mg/kg,
        duration 30minutes to 1 hour
       Cocaine- Topical, 3mg/kg max., 30 minutes to one
       Tetracaine- Spinal, topical, 3mg/kg max., 1.5-6
        hours duration
                   Clinical Uses
   Bupivacaine- Epidural, spinal, infiltration, peripheral
    nerve block, 3mg/kg max., 1.5-8 hours duration
   Lidocaine- Epidural, spinal, infiltration, peripheral
    nerve block, intravenous regional, topical, 4.5mg/kg
    or 7mg/kg with epi, 0.75-2 hours duration
   Mepivacaine- Epidural, infiltration, peripheral nerve
    block, 4.5mg/kg or 7mg/kg with epi, 1-2 hours
   Prilocaine- Peripheral nerve block (dental), 8mg/kg,
    30 minutes to 1 hour duration
   Ropivacaine- Epidural, spinal, infiltration, peripheral
    nerve block, 3mg/kg, 1.5-8 hours duration
                Systemic Toxicity
   Blockage of voltaged-gated Na channel affects
    action potential propagation throughout the
    body…therefore the potential is present for
    systemic toxicity.
   Mixtures of LA have additive affects
       i.e. a 50% toxic dose of lidocaine and a 50% toxic
        dose of bupivicaine have 100% the toxic affect of
        either drug
                Systemic Toxicity
   Neurological
       Symptoms include cicumoral numbness, tongue
        paresthesia, dizziness, tinnitus, blurred vision,
        restlessness, agitation, nervousness, paranoia,
        slurred speech, drowsiness, unconsciousness.
       Muscle twitching heralds the onset of tonic-clonic
        seizures with respiratory arrest to follow.
          Local anesthetic toxicity
   Seizure treatment:
       Thiopental 1-2mg/kg abruptly terminates seizure
       Benzos and hyperventilation…decrease CBF and
        therefore drug exposure. These raise the threshold
        of local anesthetic-induced seizures
   Chloroprocaine injected intrathecally can
    cause prolonged neurotoxicity. This is likely
    due to a preservative no longer used with this
    agent. (Sodium bisulfate)
         Local anesthetic toxicity
   Repeated doses of 5% lidocaine and .5% tetracaine
    may be responsible for cauda equina syndrome
    following infusion through small bore catheters in
    spinal anesthetics.
   Pooling of drug around the cauda equina resulted in
    permanent neurological damage
   Animal studies suggest that neuro damage is:
    Lido=tetracaine>bupivacaine>ropivacaine. Also
    perservative free chloroprocaine may be neurotoxic
           Local anesthetic toxicity
   Transient Neurological Symptoms
   This is associated with dysethesia, burning pain and
    aching in lower ext, buttocks.
   Follows spinal anesthesia with variety of agents
    (lido), attributed to radicular irritation and resolves in
    1 week usually
   Risk factors include
       Lidocaine intrathecally
       Lithotomy position
       Obesity
       Outpatient status
        Local anesthestic toxicity
   Respiratory center may be depressed
    (medullary)…postretrobulbar apnea syndrome
   Lidocaine depresses hypoxic respiratory drive
   Direct paralysis of phrenic or intercostal
             LA cardio toxicity
   All LA’s depress spontaneous Phase IV
    depolarization and reduce the duration of the
    refractory period
   Myocardial contractility and conduction
    velocity are depressed at higher concentrations
   All LA’s except cocaine cause smooth muscle
    relaxation and therefore vasodilation (art)
    whick can lead to brady, heart block and
    hypotension…cardiac arrest.
            LA cardio toxicity
   Major cardiovascular toxicity usually results
    from 3 times the blood concentration of LA
    that causes seizures.
   Therefore cardiac collapse is usually the
    presenting sign under GA.
   R isomer of bupivacaine avidly blocks cardiac
    sodium channels and dissociates very slowly.
    Making resuscitation prolonged and difficult.
             LA cardio toxicity
   Levo-bupivacaine (S isomer) is no longer
    avaliable in the US but had a cardiovascular
    profile similar to ropivacaine.
   Ropivacaine has a larger therapeutic index and
    it is 70% less likely to cause severe cardiac
    dsyrhythmias than bupivacaine
   Also ropviacaine has greater CNS tolerance
   The improved safety profile is due to a lower
    lipid solubility
           LA toxicity treatment
   Supportive care: intubation, vasopressors, appropriate
    defibrillation, fluids, stop injection of LA, anything
   Intralipid…Bolus 1cc/kg of 20% intralipid,
    0.25cc/kg/min of 20% intralipid for 10 minutes
   Bolus can be repeated every 5 minutes up to a
    maximum of 8cc/kg of 20% intralipid
   Cardiac support should be continued as ACLS
   Epi and vasopresin should likely both be used in the
    resusitation efforts (animal model data from A & A)
    True Allergic Reactions to LA’s
   Very uncommon
   Esters more likely because of p-aminobenzoic
    acid (allergen)
   Methylparaben preservative present in amides
    is also a known allergen
Local Anesthetic Musculoskeletal
   Cause myonecrosis when injected directly into
    the muscle
   When steroid or epi added the myonecrosis is
   Regeneration usually takes 3-4 weeks
   Ropivacaine produces less sereve muscle
    injury than bupivacaine
                Drug Interactions
   Chloroprocaine epidurally may interfere with the analgesic
    effects of intrathecal morphine
   Opioids and a2 agonists potentiate LA’s
   Propranolol and cimetidine decrease hepatic blood flow and
    decrease lidocaine clearance
   Pseudocholinesterase inhibitors decrease Ester LA metabolism
   Dibucaine (amide LA) inhibits pseudocholinesterase used to
    detect abn enzyme
   Sux and ester LA need pseudochol. for metabolism therefore
    adminstering both may potentiate their activity
   LA potentiate nondepolarizing muscle relaxant blockade
Other agents with LA properties
   Meperidine
   TCAs (amitriptyline)
   Volatile anesthetics
   Ketamine
   Tetrodotoxin (blocks Na channels from the
    outside of the cell membrane) Animal studies
    suggest that when used in low doses with
    vasoconstrictors it will significantly prolong
    duration of action of LA.
   Clinical Anesthesiology, Morgan and Mikhail

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