Neuro: 2:00 - 3:00 Scribe: Taylor Nelson

Neuro: 2:00 - 3:00 Scribe: Taylor Nelson

Monday, January 26, 2009 Proof: Chaz Capra

Dr. McKeown Local Anesthetics Page 1 of 5

Abbreviations: LA=Local Anesthetic

I.  Local Anesthetics [S2,3]

a.  Beginning of 19th century European colonists begin bringing back some substances from Peru

i.  Particularly the plant Erythroxylon coca, they extracted alkaloids from this plant

ii.  The powdered extract would numb the lips and tongue

iii.  Became of great interest in the 1880’s

b.  Carl “Coca-Koller” is an aspiring ophthalmologist at the University of Vienna and wants a new local anesthetic to perfect eye surgery

i.  Ether has been in use up to this point but is a poor choice for eye surgery as it is emetogenic (induces vomiting)

ii.  Increased intraocular pressure due to vomiting is devastating following eye surgery

iii.  Wanted something to apply to the eye topically

1.  Freud is using cocaine at the time to help a friend break a morphine addiction and tells Koller it may be of use in eye surgery as an anesthetic

2.  Koller decides to run with the idea, and is able to take a distilled solution of cocaine and anesthetize the eye of a frog

a.  From this point on cocaine is used all over the world

b.  It is the first topical anesthetic/demonstration of a local anesthetic

c.  Used for everything from topical applications, to peripheral nerve blocks, to dentistry, to spinal anesthesia in dogs in 1885 [S4]

II.  Local Anesthetics [S5]

a.  Will be discussing the chemical structure of local anesthetics, how these drugs work, external factors that will affect a nerve block, important considerations of toxicity with these drugs, and some clinical correlates at the end of the lecture

III.  Local Anesthetic Structure [S6]

a.  This is just a generic diagram of any local anesthetic

b.  You will find three chemicals essentially:

i.  On the left, the (1) aromatic portion which gives a LA its lipophilic properties, these drugs are both ionized and lipophilic at the same time because of the structures attached – the benzene ring and it’s side chains affects the lipophilicity of these compounds

ii.  The (2) hydrophilic group is the ionized structure on the opposite end, this amine portion will be where you carry a proton or don’t carry a proton making it hydrophilic or not hydrophilic respectively

iii.  The (3) intermediate chain determines a great deal as far as distinguishing theses drugs from one another, breaks them into two families: esters (top) and amides (bottom)

c.  [S7] Procaine (ester) on the top was the first local to come about after cocaine and lidocaine (amide) came about much later

IV.  Local Anesthetics – Esters [S8]

a.  Members of the ester family, some still widely used in the clinical setting

b.  Benzocaine used topically in dental practice before giving a nerve block

c.  Tetracaine drops used as topical anesthesia for things like cataracts

V.  Local Anesthetics – Amides [S9]

a.  Some of the amide family

b.  Lidocaine is very common (he uses it almost every day), a middle of the road kind of local anesthetic

c.  Bupivicaine is a longer acting drug

VI.  Metabolism [S10]

a.  Breaking these compounds into the ester and amide groups, one of the important distinctions between these families is the way they are metabolized

i.  Amide-type local anesthetics are primarily metabolized in the liver by the cytochrome P450 system, and excreted by the kidney unchanged with their metabolites

ii.  [S11] Ester-type local anesthetics are hydrolyzed in the plasma by pseudocholineterases, as soon as esters hit the blood stream metabolism begins immediately – metabolites formed by this breakdown are clinically important especially p-aminobenzoic acid (PABA)

1.  Allergic reactions are rare but if you do have an allergic reaction it will most likely be due to these metabolites

2.  A patient with liver failure who doesn’t produce pseudocholinesterases or who produce atypical pseudocholinesterases would also be clinically important as these people will be more susceptible to the toxicity of the systemic anesthetic

VII.  Physiology of Nerve Transmission [S12]

a.  Cartoon of neuron and graph of action potential

b.  Nerve transmission begins as you have a peripheral stimulation of a nerve, you have a stimulus that will open voltage gated channels in this nerve membrane

c.  When the nerve cell is excited and the ion pores open you have a sudden influx of sodium across the cell membrane into the interior of the cell, the cell has a resting membrane potential relative to the exterior of about -70mV

d.  When you open the ion pores and have a sudden influx of sodium ions you suddenly reverse the resting membrane potential and you’ll find that the voltage as it changes depolarizes and you see the upward spike, referred to as phase 0

e.  At maximum depolarization (top of the spike) because of sodium/potassium ATPase pumps within these cells you begin a slower pumping out of potassium from the interior to the exterior of the cell to reestablish the resting membrane potential (denoted by the C on the graph)

VIII. LA mechanism of action [S13]

a.  Because LAs bind to Na+ channels in inactivated state, it prevents Na+ influx

b.  Without the Na+ influx you will not have depolarization of the nerve cell membrane

c.  If the nerve cell membrane does not reach the threshold you will not have an action potential propagated down the axon, so you silence all transmission down that nerve

d.  It is important to note that LAs DO NOT alter Resting membrane potential or Threshold level, but slow the rate of depolarization

e.  If the threshold is not met than an action potential is not generated, Las prevent the threshold from being met by blocking Na+ channels, and without a sufficient influx of Na+ the threshold is never reached so no action potential is propagated

f.  [S14] Some old theories state that because of the lipophilic nature of these drugs the drugs will cross a cell membrane and somewhat perturb or alter the dimensions of the ion channels by swelling the cell membrane and altering the dimensions of the pores so that sodium doesn’t come across – we know now that the perturbed membrane has very little if anything to do with the action of LAs

IX.  Mechanism of Action [S15]

a.  Diagram

i.  At the top of the diagram you have the LA (or at least the amide or lipophilic charged portion of the LA)

ii.  The lipophilic form will predominate

iii.  The non-ionized form will cross the lipid cell membrane, you lose the proton you cross the membrane

iv.  On the interior of the cell the molecule regains its proton (the non-ionized form crosses the membrane but you must have the charged form of the molecule occupy the space on the Na+ channel

v.  Then the molecule binds the sodium channel inactivating it and blocking the passage of sodium through the channel

X.  Myelination Figure [S16]

a.  The Schwann cells insulate the nerve, you have non-electrically active cells that insulate the axons

b.  If the grayed stippled area represents the LA, you see two axons: one thick that is very heavily myelinated and one thing that has thinner myelin

c.  The nodes are where the nerve will be susceptible for penetration by LA, rather than the LA traversing all the myelin and Schwann cells to get to the axon, penetration will be much more readily achieved at the nodes where there is less insulation

d.  Conventional thought is that if you block three nodes you will effectively block the nerve transmission

i.  The thinner fiber will be sufficiently blocked in this diagram whereas the thicker fiber probably will not

XI.  Degree of Blockade [S17]

a.  The degree of blockade is determined by the type of the fiber, the diameter of the fiber, the geographical arrangement, degree of myelination, and some other factors

XII.  Geographical Arrangement [S18]

a.  Cartoon of nerve fiber

i.  Axons have endoneurium bound around them

ii.  Connective tissue binds them into nerve fascicles

iii.  Around a fascicle you find perineurium

iv.  Fascicles are bound into a mixed nerve bundle or a nerve trunk

v. 

b.  To get blockade of this nerve trunk the LA must diffuse through all of these different levels to reach the axons and successfully block the nerve fibers

c.  The LA that is exposed to this nerve but does not penetrate through there will diffuse away from this nerve through the blood stream and become active for systemic toxicity and eventually excretion

d.  [S19] If this is a mixed nerve bundle you have the proximal fibers going to the shoulder arranged on the outside of the bundle and the smaller sensory fibers that have to travel farther distally to the fingertips are arranged on the inside of the bundle

i.  So as the LA begins penetrating the connective tissue the more proximal fibers will be anesthetized first so you could have a motor block of the muscles of the shoulder but still not have the sensory fibers of the distal appendages blocked

ii.  The block of the distal structures is delayed

XIII. For individual nerve fibers: [S20]

a.  To talk about individual nerve fibers and their different sensitivities that account for the loss of sensation, motor, etc.

i.  A fibers are the thickest most heavily myelinated

1.  Transmit things like touch and motor stimulation efferently

ii.  Pain and temperature are mediated by much smaller diameter nerves

1.  A delta and C fibers which are very thinly or not at all myelinated

XIV.  Physical and Chemical Properties [S21]

a.  Lipid Solubility [S22]

i.  Determine potency, how dense of a block you get

ii.  The greater the lipid solubility of a drug the more potent the block will be

iii.  More groups substituted onto the benzene ring increases the lipophilicity of the substance and gives you a more potent nerve block

iv.  Procaine is pretty weak as far as potency goes (not used anymore clinically), Lidocaine is more substituted so it is more effective for successful nerve blocks

b.  Protein Binding [S23]

i.  Determines the duration of the block

ii.  A more potent drug like Lidocaine is also more protein bound exerting a longer duration of action

iii.  Major proteins that will bind up LAs systemically are Albumin and Alpha-1 acid globulin

iv.  Protein binding is greatly dependent on a neutral pH – in an acidonic patient you may not have effective protein binding which will lead to an inadequate block

v.  [S24] Graphic representation of protein binding

1.  A drug that is not very well protein bound will have a shorter duration of action

2.  The shorter duration is less protein bound and Ropivacaine and Bupivacaine give you a longer duration of action and are most commonly used clinically

c.  Ionization [S25]

i.  Going down to the opposite end, the substituted amide end

ii.  Subtituents influence the ionization of the drugs

iii.  The ionized compounds exist in equilibrium of their non-protonated to protonated forms

iv.  At physiologic pH (7.4) neither Procaine nor Lidocaine is at their neutral point (equilibrium)

v.  The farther away from its pKa a drug is when in the body the lipophilic uncharged form of the drug DOES NOT predominate meaning a less than desirable block will be achieved as it will set up slowly, wear off faster and give a less dense block

vi.  [S26] Ionization speed of onset graphic depiction

1.  Ropivacaine and bupivacaine are going to be protein bound and also less ionized so they will set up a little more slowly

vii. Ionization factors in when you talk about how fast you want the block to set up

viii.  [S27] When you’re factoring that in you take one of these compounds when they are at their pKa, which is from 7.5-9 depending on the compound

1.  At the physiologic pH of 7.4 only 5-20% of the LA is going to be active across the membrane

2.  Make this work better using sodiumbicarb (NaHCO3) to bring the LA closer to a pH of 7.4 making them more active and more likely to cross the cell membrane and get to and block the Na+ channels

d.  Stereochemistry [S28]

i.  [29] Mepivacaine, bupivacaine and ropivacaine have chiral centers, an assymetric carbon atom

ii.  You have two isomers in a racemic mixture the R isomer and the S isomer

1.  Dextro-isomer (R) = higher cardiac Na+ channel affinityàmore toxic, shorter duration

2.  Levo-isomer (S) = less toxic, longer duration

3.  Ropivicaine is a pure S enantiomer, less cardio-toxic than bupivacaine

XV. External Factors [S30]

a.  Vasoconstrictor

i.  Most of the time when people think they have had an allergic reaction to lidocaine because they have had a heart palpitation it is the vasoconstrictor epinephrine that is given in with the lidocaine in the injection

ii.  A vasoconstrictor added to a LA will cause vasoconstriction in the area of the injection which leads to a higher concentration of anesthetic at the site due to reduced blood flow to that area and less anesthetic redistributed systemically

iii.  Palpitation is probably due to getting a little LA with epinephrine in a small blood vessel and the epinephrine reaching the heart and doing what epinephrine does

XVI.  Toxicity Graph [S31]

a.  From top to bottom toxicity increases

i.  Cocaine has the most toxic affect of any of the LA

1.  Cocaine also has an inherent vasoconstriction effect

ii.  Clinically used LAs fall somewhere in the middle of the scale

b.  [S32] Clinical scenario of full blown toxicity

i.  CNS and cardiovascular toxicity are linked

ii.  As serum plasma LA concentration goes up you see clinical manifestations move form CNS affects to cardiovascular affects

iii.  If you direct directly into the vessel you will see a rapid onset and progression of symptoms

iv.  Due to the mechanism of action of blockage of Na+ channels it is very difficult to resuscitate a patient that experiences cardiovascular collapse due to LA

1.  [S33] Intralipid is fat that will bind up the lipophilic LA so that it is no longer active to do it’s “dirty work”, will also displace to an extent the LA that is being disruptive in the heart and brain tissues