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    Local Anesthetics

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    Important points

    y History

    y Some differences

    y How they work

    y Test dosey Onset

    yAdjunvants

    y Lipid rescue

    y Newer delivery systems

    y Tumescence

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    History of Local Anesthetics

    y Cocaine isolated 1856

    y 1884 cocaine used in occular surgery

    y 1880s Regional anesthesia plexus

    y 1898 cocaine used in spinal anesthesia

    y 1905 1st synthetic LA (procaine) introduced

    y 1943 lidocaine synthesized

    y Mepivacaine (1957), Bupiv (63), Ropiv (96)

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    Differences in structure of local anesthetics

    Esters versus Amides

    1) Affect metabolism

    2) Affect toxicity3) Allergic potential

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    Types of Local Anesthetics

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    Types of Local Anesthetics

    Esters

    Procaine

    chloroprocainetetracaine

    cocaine

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    Types of Local Anesthetics

    Amides

    Lidocaine

    prilocaine

    mepivacaine

    bupivacaine

    ropivacaine

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    sitemaker.med.umich.edu

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    Mechanism of Action for Local Anesthetics

    Block propagation of action potential along neuron

    prevent depolarization through blockade of Na Channel

    voltage gated K channels also blocked by LA

    but the affinity of receptor much less

    Lido 4-10x less Bupiv 10-80x less

    NB K channel involved in repolarizationVoltage gated Na and Ca channels in DRG are similar

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    Ty

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    Mechanism of Action for Local Anesthetics

    Domain 4

    S4 subunit

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    FIGURE 1. Model of the fourth homologous domain (D4) of the human skeletal muscle sodium

    channel (hNaV1.4) with the S4 segment depicted as a rotating cylinder. Four S4 residues are

    shown: Arg1451 (R2), Leu1452, Ala1453, and Arg1454 (R3). The positions of the residues around

    the S4 segment roughly correspond to those of an helical model. A depolarizing rotation transfers

    R2 and R3 from an intracellularly to an extracellularly accessible crevice, whereas Leu1452 and

    Ala1453 are translocated in the opposite direction.

    Coupled Movements in Voltage-gated Ion ChannelsRichard Horn Journal of General Physiology, Volume 120, Number 4, October 2002 449-453

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    Tetrododoxin

    y Toxin frompuffer fish

    y Blocks the Na channel Used in research

    Blocks from the outer side of cell

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    Local Anesthetics

    yy Activity of local anesthetics is a function of their lipidActivity of local anesthetics is a function of their lipidsolubility, diffusibility, affinity for protein binding,solubility, diffusibility, affinity for protein binding,percent ionization at physiologic pH, andpercent ionization at physiologic pH, and

    vasodilating properties.vasodilating properties.

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    Local Anesthetics

    y Lipid solubility is an important characteristic.Potency is related to lipid solubility, because 90% ofthe nerve cell membrane is composed of lipid. This

    improve transit into the cell membrane

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    Local Anesthetics

    y Diffusibility (how well the LA diffuses diffusesthrough tissue to its site of action) will alsoinfluences the speed of action onset.

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    Local Anesthetics

    yy Protein binding is related to the duration of action.Protein binding is related to the duration of action.The site of action (the Na channel) is primarilyThe site of action (the Na channel) is primarilyprotein in a lipid environment. Binding affinity willprotein in a lipid environment. Binding affinity willthus affect duration of action.thus affect duration of action.

    yy Protein binding also plays a part in the availability ofProtein binding also plays a part in the availability ofthe drug as LA binds to lipoproteins in the bloodthe drug as LA binds to lipoproteins in the bloodstream.stream.

    yy And transfer to fetusesAnd transfer to fetuses

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    Summary

    y Clinical Pharmacologyy The potency of Local Anesthetics, their onset and duration of action areprimary determined byphysicochemical properties of various agentsand their inherent vasodilator activity of same local anesthetics.

    y Lipid solubility is the primary determinant of anesthetic potency and it

    is expressed as lipid: water Partition Coefficienty Protein binding influences the duration of actiony pKa of Local anesthetics determines the onset of actiony The addition of vasoconstrictors, such as epinephrine or phenylephrine

    can prolong duration of action of local anesthetics, decrease theirabsorption (and the peakplasma level) and enhance the blockade.

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    From NYSORA web site

    Properties of Local Anesthetic Agents

    PROPERTIES AMINOESTERS AMINOAMIDES

    Metabolism rapid by plasma cholinesterase slow, hepatic

    Systemic toxicity less likely more likely

    Allergic reaction possible - PABA derivatives form very rare

    Stability in solution breaks down in ampules (heat,sun) very stable chemically

    Onset of action slow as a general rule moderate to fast

    pKa's higher than PH = 7.4 (8.5-8.9) close to PH = 7.4 (7.6-8.1)

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    pKa

    y Understanding LA as they relate to pKa

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    y The pH of the tissue and pKa of the agent

    The pH and pKa are the most important factors.

    The pH of the tissue determines the ratio ofionized to non-ionized drug. This ratio, in turn,depends on the pKa of the drug. Understanding theionization is necessary to understanding the drug's

    pharmacological characteristics, such as onset,duration and pharmacodynamics.

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    Henderson Hasselbalch equation

    y The basis for understanding this equation is knowing thepKa of the agents, remembering that pKa equals the pH

    where the ionized and non-ionized forms are atequilibrium. In other words, 50% of each form is present.

    Local anaesthetics are weak bases. For bases, the pKa - pHrelationship is described by the Henderson Hasselbalchequation, as follows:

    y pKa - pH= log_ionized

    non-ionized

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    Effect ofpH, and pKa

    y The pKa of amides ranges from 7.6 to 8.1. At physiologicpH (7.4), most of the local anaesthetic is in the ionized state(a charged base). For example, lidocaine has a pKa of 7.9.The above formulat determines that at physiologic pH,

    lidocaine exists in a ratio of 3:1 ionized to non-ionized:y 7.9 - 7.4=log [ionized/non-ionized]

    y 0.5 =log [ionized/non-ionized]

    y 3=ionized/non-ionized

    y

    3ionized~1non-ionized

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    LowpH

    y The pH of the tissue becomes relevant in conditions ofinfection or inflammation, in which the natural pH may bemore acidic. This acidity results in a greater proportion ofthe ionized (charged) form of the anaesthetic, therebydelaying or preventing the onset of action. For example, if

    lidocaine (pKa 7.9) is administered into an area of infection(pH 4.9) emanating from a dental abscess, then:

    y 7.9 - 4.9 = log [ionized/non-ionized]y 103 = ionized/non-ionized

    The resulting ratio of 1,000:1 ionized to non-ionizedindicates a poorer penetration into the nerve tissue andtherefore a less effective nerve block

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    Onset

    y Is there a difference in the onset of different localanesthetics?

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    Onset

    AGENT Pot. Onset pKa %PB P. coef

    Procaine 0.5-1% (Novocain) 1 Rap 8.9 5.8 0.02

    Chloroprocaine 2-3% (Nesacain) 4 Rap 8.7 ? 0.14

    Tetracaine 0.1-0.5% (Pontocain) 16 Slow 8.5 75.6 4.1

    Lidocaine 1-5% (Xylocaine) 1 Rap 7.9 64.3 2.9

    Mepivacaine 1.5% (Carbocaine) 1 Mod 7.6 77.5 0.8

    Bupivacaine 0.25-0.75% (Marcainesensorcaine) 4 Slow 8.1 95.6 27.5

    Etidocaine 0.5-1.5% (Duranest) 4 Rap 7.7 94 141

    Prilocaine 1 7.9 55 0.9

    Ropivacaine 0.75% (Naropin) 4 Mod 8.1 94 2.9

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    Onset

    y Does onset influence you practice?

    y Where? OB

    RA Chronic pain

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    Onset of ActionOnset of Action

    y Low pH as found in sites of infection will slow or prevent onset.

    y The pKa values of most amides are similar; therefore, onsets aresimilar.

    y Bupivacaine's higher pKa results in a slightly slower onset.

    y The time for diffusion to the nerve is a factor --infiltrations are rapid;

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    Onset

    A comparison of warmed Bupivacaine and lidocaine forepidural top up for C/S

    BJA 1994 72 221-3

    Warming improved onset for lidocaine to pin prick

    Test dose lidocaine and epinephrine time 0

    Inadequate anesthesia bupiv x2, warmed B 1 and warmed L x 2

    Bupiv0.5%

    (n=27) 20oC

    Lidocaine 2%n=28, 20oC

    Bupiv 0.5%38oC n=29

    Lido 38oCN=27

    Onset to T6 29.9 (7.1) 27.0 (6.9) 29.8