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Boards: Pharmacology > Local Anesthetics > Flashcards

Local Anesthetics Flashcards

1
Q

LA MOA

A

Reversibly block generation, propagation of electrical impulses in nerves via blockade of VG Na channels
o Impedes membrane depolarization, nerve conduction/excitation
o Also block voltage-dependent K, Ca channels with lower affinity than VG Na
o +/- intracellular sites involved in signal transduction of GPCRs

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2
Q

NaV Channel Structure

A

o Large alpha (~2000 amino acids) with four domains that creates pore
o Each domain = 6 helical segments S1-S6, voltage sensor at S4 of each domain
o beta2/4 subunit, beta1/3
 Influence activation, inactivation of states of channel
o Binding site at DIV-S6, intracellular access only

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3
Q

3 States of NaV

A

o Resting state = closed at RMP
o Open state = during depolarization, M gates open
o Inactivated state = closed, allows repolarization with H gates closed

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4
Q

Steps in NaV Activation

A

At RMP -70mV, m gate closed

S4 segment detects when MP reaches -55mV –> m/activation gate opens quickly
 Opening of activation gate allows Na to flow into cell, raising MP to +30mV

At -55mV, inactivation gate (H gate) starts closing but closes MUCH slower
* 0.5-2msec

Once H gate closed, not capable of reopening for another 2-5msec –> allows membrane to repolarize, return to resting state

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5
Q

NaV Channel Distributions - cardiac m

A

1.1, 1.3, 1.5

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6
Q

NaV Channel Distributions - skeletal m

A

1.4

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7
Q

NaV Channel Distributions - CNS/PNS

A

1.1,2,3,5,6

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8
Q

NaV Channel Distribution - Pain

A

6, 1.7, 1.8, 1.9

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9
Q

NaV 1.1, 1.3, 1.5?

A

Cardiac Cells

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10
Q

NaV 1.4?

A

Skeletal M

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11
Q

NaV 1.1, 2, 3, 5, 6?

A

CNS, PNS

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12
Q

NaV 1.7-1.9?

A

DRG

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13
Q

Modulated R Hypothesis

A

 LAs: high affinity for channel in open, inactivated states; low affinity in resting state
 Lipid-soluble (non-ionized, inactive) form enters via membrane
 Lipid-insoluble (ionized, active) form enters through channel hydrophilic pore
* Only open when gates of channel open –> cumulative binding of LAs to Na channel when channels active

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14
Q

Which form of LA is lipid soluble?

A

The non-ionized, inactive form

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15
Q

Which form of LA is non-lipid soluble?

A

The ionized, active form

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16
Q

Guarded R Hypothesis

A

 LAs bind to R inside channel w/ constant affinity, but channel must be open for access
 Increasing frequency of stimulation increases # of Na channels open, increasess binding of LAs

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17
Q

Use-Dependent Block

A

Increased Frequency if stimulation increases # of NaV open –> increases binding of LAs

Applies to both Modulated R hypothesis, Guarded R Hypothesis

Biggest difference then becomes affinity of LA for R

Depth of block also increases with repetitive membrane depolarization

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18
Q

Tonic Block

A

blockade obtained on unstimulated nerves, is constant

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19
Q

Differential Blockade

A

Classified by Glasser, Erlanger in 1929
Basic principle: vasodilation –> sensory (temperature, sharp pain, light touch) –> motor

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20
Q

What is differential blockade affected by?

A
  • Fiber length
  • Length exposed to drug
  • Myelination: can cause ax to pool adjacent to nerve
  • Frequency of stimulation
  • Drug concentration
  • Drug properties
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21
Q

What is the critical length that a nerve must be exposed to to completely block the fiber?

A

3 Nodes of Ranvier

Longer fibers with longer distance btw NoR/greater internodal distance less susceptible to LA

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22
Q

Decremental Conduction

A

Decreased ability of successive NoR to propagate impulse in presence of LA
* 74-85% Na conduction blockade: progressive decrease in amplitude of impulse, until decays below threshold
* >84% Na conductance blocked at three consecutive nodes –> complete blockade of propagation
* Propagation of impulse can be stopped even if node has been rendered completely inexcitable

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23
Q

Clinical Effect of Decremental Conduction?

A

Why blocks with small volume/high concentration have greater duration and extent than large volume/low concentration despite same total drug dose

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24
Q

Sub Blocking Concentrations of LAs

A

Large portion of sensory information transmitted by peripheral nerves carried via coding of electrical signals in after-potentials, after oscillations

Suppress intrinsic oscillatory after-effects of impulse discharge without significantly affecting AP conduction

Possible mechanism of blockade: disruption of coding of electrical information

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25
Q

Other Actions when LAs Admin Centrally:

A

o Na channel blockade
o K, Ca channels: dorsal horn of spinal cord, altered sensory processing
o Substance P binding (tachykinin), evoked increase iCa
o Glutaminergic transmission –> decreased NMDA, neurokinin-mediated transmission
o Targeting of large nerves, nerve trunk (BP, LST): somatosensory arrangement of nerve fibers also affects progression of block

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26
Q

Chemical Structure

A

 Lipophilic aromatic (benzene) ring
 Hydrophilic amine group (tertiary or quaternary amine)
 Intermediate chain linkage - ester or amide

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27
Q

Esters

A

O-C; hydrolyzed by plasma esterases (one i)
o Procaine
o Tetracaine
o Chloroprocaine

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28
Q

Amides

A

Metabolized by liver (two is)
o Lidocaine
o Ropivacaine
o Bupivacaine, levobupivacaine
o Mepivacaine

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29
Q

Chirality

A

mostly racemic mixture that 50:50 R-, S-

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30
Q

Which three LAs are achiral?

A
  1. Tetracaine
  2. Prilocaine
  3. Lidocaine
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31
Q

Which two LAs are pure S isomers?

A

Levobupivacaine, ropivacaine

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32
Q

Difference btw R, S enantiomer

A

o R-enantiomers assoc with greater in vitro potency, greater therapeutic efficacy but also increased CV, CNS toxicity

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33
Q

LA Activity - not important factors

A

Diffusion coefficient, MW not important factors in determining activity
 MW very similar btw LAs, 220-228Da

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34
Q

pKa of Locals

A

WEAK BASES
Formulated as acid solutions

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35
Q

Formulation of LAs

A

acidic HCl solutions (pH 4-7)
 Formulation in acidic solutions increases CHECK THIS ionized portion –> improves H2O solubility

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36
Q

Locals with Higher pKas

A

 Increased pKa –> increased BH+ at physiologic pH (7.4) (increased ionization) –> slow onset
 Higher pKa, more drug ionized at physiologic pH – ionized form = ACTIVE
* More ionized form, more drug to interact with receptor
* BUT moves more slowly across hydrophobic cell membrane, thus slower onset

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37
Q

LA with Lower pKas

A

(eg lidocaine): more uncharged base, faster onset
o Once intracellular, becomes ionized – interact with R

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38
Q

Role of Lipid Solubility

A

determines penetration of nerve cell membrane
Increased lipid solubility –> increased potency, decreased concentration needed for blockade
 More lipid soluble, better penetration through lipid membrane, faster onset in unmyelinated nerves

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39
Q

Effect of Myelination on Onset of LA

A

delayed onset DT trapping in myelin, other lipid compartments
* Net effect of ing lipid solubility = delayed onset of LAs
* Increased duration due depot for slow release of drug

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40
Q

Protein Binding

A

Only free drug active: increased protein binding –> increases duration of action

Don’t know why: Likely related to membrane or extracellular proteins in membrane

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41
Q

Onset

A

pKa, lipid solubility, concentration, volume, frequency of membrane stimulation, pH of site
 Addition of HCO3 to increase pH –> promotes more un-ionized base to be present to hasten onset B > BH+ (contradicting studies
 Ex: LAs will not work around infected abscess with acidic pH

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42
Q

Potency?

A

Correlates to lipid Solubility

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43
Q

Duration?

A

Protein binding
site of administration, vasomotor tone

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44
Q

Differential Blockade?

A

fiber size, length, myelin, frequency of stimulation, concentration, drug properties

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45
Q

Which LAs show greater differential blockade?

A

Amides
Increased pKa
Decreased lipid solubility

More potent blockade of C fibers than fast-conducting A fibers

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46
Q

Benefits of Differential Blockade?

A

 More differential blockade, more sparing of certain types of nerve fibers
 At higher concentrations, drug properties become less important for differential blockade
* High concentration of ANY LA, differential blockade goes away
B > C = Adelta > Agamma > Abeta >Aalpha
Drink Good Beer Always

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47
Q

Absorption Factors

A

 Site of injection, vascularity
 Intrinsic lipid solubility
 Vasoactivity of agent
 Dose admin
 Additives, other formulation factors that modify local drug residence, release
 Influence of nerve block in region (VD)
 Pathophysiologic state of patient

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48
Q

Why is systemic absorption important?

A

Lower systemic absorption, greater margin of safety

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49
Q

Increased vascularity…

A

Increased absorption
 Increased peak plasma concentration (Cmax)
 Decreased time to peak plasma concentration (Tmax)
Intercostal > epidural > brachial plexus > femoral/sciatic
* Study only done using those sites
* Related to differences in vascularity
* Intrathecal much lower systemic absorption than epidural

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50
Q

What is the order of block absorption?

A

Intercostal > epidural > brachial plexus > femoral/sciatic
* Study only done using those sites
* Related to differences in vascularity
* Intrathecal much lower systemic absorption than epidural

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51
Q

What features increase absorption?

A

–Decreased lipid solubility, decreased protein binding
Lidocaine, mepivacaine > bupivacaine, ropivacaine

Increased lipid sol, increased protein binding = less absorption – bind to neural, non-neural lipid-rich tissues so less systemic absorption

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52
Q

Vasoactivity of LAs

A

 Most LAs cause vasodilation, which decreases time to peak plasma concentrations (increases Tmax)
 Ropivacaine, levobupivacaine = vasoconstriction, Tmax

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53
Q

Toxicity

A

lower Tmax (less time to reach peak plasma concentration), higher Cmax (higher peak plasma concentrations)
 Greatest risk systemic toxicity: Tmax arterial blood, 5-45’ after inj depending on site of block, speed of inj, drug
 Risk of systemic toxicity coincides with Tmax, independent of dose
 Faster speed of injection, increased Cmax (peak plasma concentration

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54
Q

Distribution

A

Degree of tissue distribution, protein binding related to apparent volume of distribution at steady state (Vdss): free fraction governs tissue concentration

Usually paralleled by degree of protein binding

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55
Q

Distribution of Amino-Esters

A

rapid plasma hydrolysis by pseudocholinesterases, limited distribution

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56
Q

Distribution of Amino-Amides

A

Widely Distributed
-Can be affected by a1-acid glycoprotein (AAG) concentrations
-pulmonary first pass effect

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57
Q

a1 Acid glycoprotein (AAG)

A
  • Increased AAG –> increase TOTAL LA concentration, but NOT free (active) fraction (amides)
  • AAG = acute phase reaction protein produced by the liver in response to inflammation
  • Normally low in plasma, serum concentrations can increase 2-5x
  • Academic > clinical
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58
Q

Pulmonary First Pass (Depot Effect)

A

risk of toxicity with R–>L cardiac shunts

Normal: temporarily increases plasma concentration of drug, lungs able to attenuate toxic effects after accidental IA injection
* Mostly dependent on lipid solubility, pKa
o More lipid soluble agents –> more pulmonary uptake
o Lower pKas = greater unionized form, which accumulates in the lung

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59
Q

Consequences of R to L Shunt with Pulmonary First Pass/Depot Effect

A
  • Some of drug will bypass first pass due to shunt
  • Increased toxicity so increase dose CLINICALLY RELEVANT
  • Most pulmonary first pass: bupivacaine > etidocaine > lidocaine, levobupivacaine > ropivacaine
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60
Q

Rapid distribution goes where?

A

Milk, muscle

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61
Q

Drugs that diffuse most readily into milk

A

relatively lipophilic, unionized (Lower pKa), not strongly protein bound, low MWs

FARAD: recommends 24hr meat, milk withhold on lidocaine

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62
Q

Placental Transfer

A

Limited for esters due to rapid metabolism, enhanced for amides by “ion trapping”

Unionized form rapidly crosses placenta –> once in more acidic fetal circulation, ionized drug forms more readily –> gets “stuck” in fetal circulation

Back transfer from fetus to mother occurs with bupivacaine, NOT lidocaine

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63
Q

Degree of LA binding to both maternal, fetal plasma proteins also important determinant of placental transfer of LAs

A
  • Only unbound, free drug crosses placenta
  • Fetal AAG content, binding < maternal, F:M of highly protein-bound LAs lower than less-protein bound
    o Ex: bupivacaine F:M 0.36, lidocaine F:M 1.0
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64
Q

Fetal Metabolism of LAs

A

Fetus/neonate able to metabolize, eliminate lidocaine better than bupivacaine

  • If high plasma concentrations of local in maternal blood likely, potentially delay delivery if bupivacaine to allow bup to transfer back to maternal circulation
  • Do not have to delay delivery if lidocaine bc ion trapped, can eliminate just fine
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65
Q

Poor water solubility of LAs…

A

Limited renal excretion

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66
Q

Amino Esters metabolism and excretion

A

Hydrolyzed by plasma pseudocholinesterases, excreted in urine
* Additional contributions from esterases in RBCs, liver, synovial fluid
* Chloroprocaine = most rapid clearance, fast hydrolysis rate
* Procaine IV admin in horses: t1/2 = 50’, Vd 6.7L/kg
* Hydrolysis products of procaine, chloroprocraine, tetracaine = pharmacologically inactive

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67
Q

Cocaine

A
  • Illegal use in race horses, dogs
  • Ester hydrolysis in plasma; N-demethylation in liver to norcocaine, which undergoes further hydrolysis
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68
Q

Benzocaine, Procaine

A

para-aminobenzoic acid metabolite  allergic reaction
* Why esters more assoc with allergic reactions than amides

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69
Q

Benzocaine - other SE

A

metHb in people, dogs, cats
* Proposed MOA: direct oxidation of heme

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70
Q

Amino Amides Metabolism

A

Metabolized by CYP-450 system, excreted urine/bile
* Phase I: hydroxylation, N-dealkylation, N-demethylation
* Phase II reactions: metabolites conjugated with amino acids or glucuronide into less active, inactive metabolites

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71
Q

Amino Amide Excretion

A

Small portion excreted unchanged in urine
* Humans: 4-7% lidocaine, 6% bupivacaine, 16% mepivacaine
* 1.7-29% lidocaine in horses

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72
Q

Clearance of Amino Amides

A

Prilocaine > etidocaine > lidocaine > mepivacaine > ropivacaine > bupivacaine
* In humans, prilocaine cleared most rapidly: blood clearance values exceed hepatic blood flow, indicating extrahepatic metabolism

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73
Q

Prilocaine Metabolism

A

O-toluidine (orthotoluidine) –> oxidizes Hgb to metHb

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74
Q

Lidocaine Metabolism

A

MEGX/GX –> toxicity after prolonged infusions (esp renal failure, diabetes)
* Hydroxylation, demethylation in liver
* MEGX = monoethylglycinexylidide
o Activity 70% of lidocaine, potentially contributes to toxicity after long infusions
* GX = glycinexylidide (also active)
* Metabolites NOT detected in cows

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75
Q

Metabolism of Other Amides

A

(mepi, ropi, bupi): N-dealkylation, hydroxylation
* Produce less toxic metabolite pipecoloxylidide (PPX)
* Bup dealkylated metabolite: N-desbutylbupivacaine = ½ cardiotoxic, less CNS toxic vs bup
 Some further conjugated to glucuronides before eliminated in urine, bile

76
Q

How does age affect PK of LA?

A

 Neonates: increased absorption, in decreased Vd, increased t1/2, decreased plasma esterase activity
 Geriatrics: decreased hepatic clearance, increased t1/2

77
Q

How does pregnancy affect the PK of LA?

A

 increased nerve sensitivity (faster onset of blockade)
* Unlikely to be direct effect of progesterone on cell membrane
 increased hepatic blood flow: faster lido clearance
 decreased hepatic enzyme activity: slower bupivacaine, ropivacaine clearance
 decreased plasma esterase activity

78
Q

How does liver dz affect PK of LA?

A

Decreased metabolism of amides, decreased plasma esterases, decreased clearance
 Do not need to adjust for single dose but should for CRIs, repeated dosing, dosing intervals

79
Q

How does ax affect PK of LA?

A

 hepatic blood flow (any condition that decreases CO) = slower clearance, esp lido bc dependent on HBF for clearance
 Mep, bup – metabolism more dependent on activity of hepatic enzymes, effect of decreased hepatic blood flow less pronounced

80
Q

How does renal failure affect PK of LA?

A

 Decreased plasma pseudocholineresterase activity
 decreased amide metabolite excretion/increased amide metabolite (MEGX/GX)

81
Q

How does diabetes affect PK of lidocaine?

A

Increased hepatic clearance of lidocaine, decreased excretion of MEGX

82
Q

How does equine fasting affect PK of LA?

A

Decreases lidocaine clearance

83
Q

How do drugs affect PK of LAs?

A

increased plasma concentration, decreased elimination
 Any that decreases plasma esterase activity (neostigmine, acetazolamide)
 CYP1A2, CYP3A4 inhibitors (erythromycin): decreased hepatic clearance of amides
 Adrenergic R blocking agents that decrease liver perfusion, inhibit activity of hepatic microsomal metabolizing enzymes responsible for metabolism of amides

84
Q

How does temperature affect PK of LA?

A

Cooling increases pKa so more active, ionized form

85
Q

Baricity

A

one of most important physical properties during IT/subarachnoid admin
 Affects distribution, spread of solution  impact characteristics of block calculated ratio of density of solution to density of CSF both measured at same temp (37*C)
 Density: weight in grams of 1mL of solution, inversely related to temp

86
Q

Isobaric LAs

A

(= 1) – most LAs at room temp
Density of CSF = Density of LA

87
Q

Hypobaric

A

(<1) goes to non-dependent site bc density lower than CSF
* LAs warmed to body temp or diluted with water
* Addition of opioids will also make hypobaric

88
Q

Hyperbaric

A

– >1
-goes to dependent site (greater density than CSF), preferential blockade on sx side
* Decreased temp or dilute with dextrose or hypertonic solution or add epi

89
Q

Which locals have the highest pKa?

A

Procaine, chlorprocaine

90
Q

Which locals have the lowest pKas?

A

Mepivicaine, lidocaine, etidocaine

91
Q

Which LAs are least protein bound?

A

Procaine, chloroprocaine (6-7%)

92
Q

Which LAs >94% protein bound?

A

Tetracaine, ropivaine, bupivacaine, levo, etidocaine

93
Q

Which are short acting LAs?

A

Procaine, chloroprocaine

94
Q

Which are the most potent LAs?

A

Tetracaine
Bup/levo bup
etidocaine

95
Q

Which are the least potent?

A

Procaine, Chloroprocaine < lidocaine, prilo, mepivacaine

96
Q

Which LA is intermediate potency?

A

Ropivcaine

97
Q

Which are intermediate (50-70%) protein bound?

A

Lidocaine
Mepivacaine
Prilocaine

98
Q

Which LAs are the most lipid soluble?

A

Bup/levobup < tetracaine < etidocaine

99
Q

Which local is the most CNS toxic?

A

Bupivacaine

100
Q

LA Duration of Action

A

procaine, Chloroprocaine < lido< mepivacaine, prilocane <ropi< tetracaine, bup, levobup, etidocaine

101
Q

Amino Esters

A
  1. Procaine
  2. Benzocaine
  3. Chloroprocaine
  4. Tetracaine
102
Q

Procaine

A

 Prototypical ester
 Fastest onset, 30-60’ duration
 CNS stimulant – illegal use in race horses
 Infiltration, NBs, +/- IT for short procedures
 Not very effective topically
 PABA –> allergic reaction

103
Q

Benzocaine

A

Ester
 Fast onset
 TOPICAL ONLY
 PABA –> allergic reactions
 MetHb
 Fish anesthesia (MS-222)

104
Q

Chloroprocaine (1-3%)

A

 Ester: Fast onset, 30-60’ duration
 Human OB ax, not used regularly in vetmed
 Highest pKa, fast onset due to highly concentrated form

105
Q

Tetracaine

A

 AKA amethocaine
 Slow onset, except when admin intrathecal
 High toxicity potential, not used in vet med
 Humans: fast onset (3-5’) via IT, 2-3hr duration
 Lido + tetracaine latch = better, faster dermal ax than EMLA cream
 Rapid absorption from MM (fatalities in human med), excellent topical anesthesia

106
Q

Lidocaine

A

 Prototypical amide, fast onset, 1hr duration
* Low pKa, not highly protein bound, can cause local VD
* Prolonged up to 3h with epi
 Infiltration, NBs, epidural, IT, IVRA
 Some topical: mucosal (lido spray for larynx), EMLA, lidocaine patches (+/- tetracaine)

Also administered systemically

107
Q

EMLA Cream

A

Lidocaine 2.5%, prilocaine 2.5%

108
Q

Systemic Administration of Lidocaine

A

 Systemic: analgesia, anti-inflammatory, anti-arrhythmic (class 1b), MAC sparing in dogs, cats, goats, horses, calves
* Analgesia MOA: thought to include action of Na, Ca, K channels, NMDA R
* +/- Improve intestinal motility in horses, prevent POI esp if reperfusion injury

109
Q

FARAD - Lidocaine

A

Cattle:
* Epidural: 1d meat, 24hr milk
* Infiltration (inverted L block): 4d meat, 72hr milk
* Lido + epi for epidural, infiltration: 1d meat, 24hr milk

Goats
* Infiltration, epidural – single or multiple
doses: 1d meat, 24hr milk

Sheep
* Infiltration, epidural – single or multiple doses: 1d meat, 24hr milk

110
Q

Does lidocaine trigger MH?

A

One paper in humans, not validated in vet med

111
Q

Max Dosing Lidocaine

A
  • Cats 3-5mg/kg
  • Dogs 6-10mg/kg
  • Sheep 6mg/kg
112
Q

Mepivacaine

A

 Fast onset, 1-2h duration due to less VD compared to lidocaine
 Infiltration, NB
 Poor topical efficacy
 Drug of choice for diagnostic NBs in horses DT decreased neurotoxicity
 Very slow metabolism in fetus, newborn

113
Q

Max Dosing Mepivacaine

A
  • Cats 2-3mg/kg
  • Dogs 5-6mg/kg
  • Sheep 5-6mg/kg
114
Q

Bupivacaine

A

Slow onset (20-30’), 3-10hr duration  high pKa, highly protein bound, highly lipophilic, minimal VD so sticks around at block site longer

Infiltration, NB, epidural, IT

Poor topical efficacy

Not recommended for IV DT cardiotoxicity, FATAL

115
Q

Levobupivacaine

A

S-enantiomer of bupivacaine, decreased CV toxicity

116
Q

Intrinsic Blockade Properties of Bupivacaine

A

Intrinsic differential blocking properties, esp at low concentrations – indicated when sensory accompanied by minimal motor blockade required

117
Q

Max Dosing Bupivacaine

A
  • Cats 1-1.5mg/kg
  • Dogs 2mg/kg
  • Sheep: 2mg/kg
118
Q

Ropivacaine

A

 S-enantiomer, decreased CV toxicity vs R-enantiomer
 Similar onset to bupivacaine
 Differential blockade: motor blockade less affected at equipotent doses of bup
 Infiltration, NB, epidural, IT
 Up to 6hr duration

119
Q

Ropivacaine Biphasic Effect on Vasculature

A

> 1% vasodilation, <0.5% vasoconstriction

120
Q

Ropivacaine Max Dosing

A
  • Cats 1.5mg/kg (2)
  • Dogs 3mg/kg (4.4)
121
Q

Mixing of LAs

A

o Expectation: best of both worlds –> fast onset from lido, long duration from bupiv
o Reality: conflicting studies
 Similar onset to bupivacaine alone
 Shorter duration that bupivacaine alone
 Decreased depth of block? Increased post-op analgesia requirements

122
Q

Liposomal Bupivacaine

A

Nocita ® by Elanco
o Other formations: polylactide microspheres, cyclodextrin inclusion complexes
o Long-acting LA, up to 72hr

123
Q

Uses of Nocita

A

o Labeled for:
 Incisional infiltration after CCL sx 5.3mg/kg
 Nerve block for feline onychectomy 5.3mg/kg/forelimb
o Used extra-label for many px in dogs, cats

124
Q

Nocita Storage Instructions

A

discard after 4h, Carlson et al Vet Surg: up to 4d

125
Q

Epinephrine Additives

A

 Decreased absorption, decreased Cmax (decreases potential for systemic tox), increases duration in short-acting LAs – lido, mepiv
 Local VC delays absorption of LA
* decreases in peripheral nerve or spinal cord blood flow –> nerve, SC ischemia
* IT: regional dural VC, no decrease in SC or CBF
 decreases dose required, prolongs duration

126
Q

1:200,000 epi…?

A

1gm (1000mg)/200,000mL epi = 0.005mg/mL

127
Q

Epinephrine a2 Effects

A

may enhance analgesia: inhibition of presynaptic NT release from C, Adelta fibers in substania gelatinosa in DH of SC
* Also modify certain K channels in axons of peripheral nerves

128
Q

SE of Epi additives

A

systemic absorption: flushed area, increased HR, increased SV, increased CO, decreased SVR, (tachy)arrhythmias

 Avoid VCs for blockade of areas with erratic blood supply, without good collateral perfusion –> VC-induced tissue ischemia, necrosis (eg ring blocks)

129
Q

Prepared solutions of epinephrine

A

lower pH vs plain or freshly prepared solutions –> lower amt of unionized, slower onset of action

130
Q

Phenylephrine as an additive to LAs

A

significant decreases in sciatic N, skeletal m blood flow when admin w/ lidocaine

131
Q

Phentolamine

A

non-selective aR antag, approved for reversal of soft tissue ax, associated functional deficits resulting from local dental ax in humans

Can reverse effects of LAs potentiated with epi

132
Q

Hyaluronidase

A

 Depolymerization interstitial HA (main cement of interstitum), improves tissue penetration
Increased pH, increased B (increasedd amount of unionized drug), shorter onset/increased spread of block
 May increase Cmax (increase toxicity)

Possibly better quality of peribulbar, retrobulbar blocks in humans

133
Q

Opioids

A

 Opioid R on sensory neurons
 Increase depth, duration of blockade
 Ex: Synder 2016: bupivacaine, buprenorphine for infraorbital NB in dogs prolonged blockade duration 48-96hr
* Buprenorphine can block VG Na channels, prolong LA

134
Q

NaHCO3

A

 Increased pH, increased un-ionized fraction of drug –> in theory causes faster diffusion across lipid bilayer and then becomes ionized inside cell, shorter onset
 Ion trapping: Increases density, duration
 Decreased pain on injection, insertion of EC

135
Q

NaHCO3 Effect

A

 Most studies fail to show efficacy with intradermal admin, NB
* No effect of onset, extent, duration of skin ax in humans

 Greater effect when LA admin into acidic environment
* Ex: intravesicular instillation provided LA of bladder submucosa in human patients with interstitial cystitis
 Buffered LAs: greater effect when topically applied to cornea

136
Q

Amt of NaHCO3 that can be added?

A

 0.1mEq/1mL LA – more than that will cause precipitation

137
Q

Carbonation

A

 Decreased onset, improve quality of block possibly DT decreased intracellular pH/ion trapping

138
Q

a2 agonists

A

Effect isn’t particularly DT a2 effect - no change in presence of alpha 2 reversal agents
 Clonidine extensively used in people to prolong duration of IT, epidural, PNBs

139
Q

MOA a2 agonists in LA

A

Hyperpolarization of C fibers
* Blockade of so-called hyperpolarization activated cation currents in C fibers
 Shorter onset, increase duration, increase quality

140
Q

Dose/Which a2s used

A

 0.5-2mcg/mL LA
 Xylazine, detomidine: epidurals in LA
 Dexmed, medetomidine: regional NB in SA

141
Q

Tachyphylaxis

A

o Decrease in duration, segmental spread, intensity of regional block despite repeated constant dosages
 Not related to: structural/pharmacological properties, technique, mode of admin
o Promoted by longer interanalgesic intervals btw injections
 Did not occur if inj repeated at intervals short enough to prevent return of pain, or at intervals with pain <10’

142
Q

PK Mechanisms of Tachyphylaxis

A

local edema
Increased epidural protein concentration
Changes in LA distribution in epidural space
Decrease in perineural pH (limits diffusion of LA from epidural space to binding sites in Na channels)
Increased epidural blood flow
Increase in local metabolism (favors clearance of LA from epidural space)

143
Q

PD Mechanisms of Tachyphylaxis

A

antagonistic effects of nucleotides, increased [Na], increased afferent input from nociceptors, receptor downregulation of Na channels

144
Q

Tachyphylaxis: spinal site of action, related to hyperalgesia

A

 Drugs that prevent hyperalgesia at spinal sites (NMDA R antag, NO-synthase inhibitors) prevent development of tachyphylaxis

145
Q

AEs

A

Increased lipid solubility, increased potency –> increased potential for toxicity (bup&raquo_space; lido, mep)

o Most common cause: inadvertent IV (IA) inj during PNB
 Incidence unknown in vet med
 Humans: 1 in 10,000 with PNBs highest incidence 7.5 in 10,000

146
Q

Do the S or R enantiomers have decreased potential for toxicity?

A

S enantiomers

147
Q

Toxic Dose Varies by:

A

 Route of administration
 Speed of administration
 Species
 Acid-base balance
 Concurrent drugs/anesthesia

148
Q

CNS Effects of LAs

A

 Low doses: effective anticonvulsants, sedative effects
 Humans: tongue numbness, light-headedness, dizziness, drowsiness, acute anxiety
 Horses: changes in visual function, rapid eye blinking, mild sedation, ataxia
 Inhibition of inhibitory IN

149
Q

CNS Effects: Inhibition of Inhibitory IN

A
  • Inhibit inhibitory cortical neurons in temporal lobe or amygdala –> faciliatory IN function in unopposed fashion –> increased excitatory activity –> m twitching –> grand mal sz
  • As plasma concentrations , LAs can inhibit both inhibitory, facilitatory pathways –> CNS depression, unconsciousness, coma
150
Q

What might be the first sign of toxicity with highly lipophilic, protein-bound LAs (bupivacaine)?

A

CNS depression (cyanosis, bradycardia, unconsciousness)

151
Q

Humans and CNS Effects

A

significant difference btw rate of sz development
* Caudal > brachial plexus > epidural

152
Q

CV:CNS Ratio

A

Conscious sheep: dose, plasma concentrations assoc with CV collapse (disappearance of pulsatile BP) calculated as CV:CNS ratio
* Supports notion that CNS tox precedes CV tox

153
Q

Effects of hypercapnia on CNS Effects of LAs

A

DECREASES seizure threshold
* Hypercapnia: increases CBF –> increases drug delivery to brain +/- decreases in plasma protein binding of LAs (increase in free drug)

154
Q

Effects of hypoxemia on CNS Effects of LAs?

A

Decreased sz threshold, increased CNS/CV Tox

155
Q

Seizure Doses LA - Dogs

A

Lido 21-22mg/kg
Bup 4-5
Rop 5

156
Q

Seizure Doses LA - Cats

A

Lido 12
Bup 5

157
Q

Seizure Doses LA - SHeep

A

Lido 6.8
Bup 1.6
Ropiv 3.5

158
Q

CV Effects

A

 Toxic effects complex, non-linear
 Cardiac Na channel blockade: decreased max rate of phase 0 depolarization
* Pronounced, evolving inhibition of cardiac conduction
 Prolongation of PR, QRS intervals and refractory period

159
Q

CV Effects of Subconvulsant Doses

A

myocardial depression, increase HR slightly, widen QRS complexes, no effect on BP, CO
* Long-acting LAs, R-enantiomers more arrhythmogenic than short-acting, pure S-enantiomers

160
Q

CV Effects of Convulsant Doses

A

profound sympathetic response, reverses induced myocardial depression –> increase HR, BP, CO –> arrhythmias, vtach/vfib
* Short acting LAs less arrhythmogenic than long acting
* Slower unbinding rates even though binding rates similar
* R > S (R-enantiomers = more arrhythmogenic)

161
Q

CV Effects of LA at Supraconvulsant Doses

A

bradycardia, hypotension, decreased contractility, asystole
 CNS toxic effects possibly involved: onset of resp failure accompanied by hypoxia, bradycardia, hypercapnia, acidosis

162
Q

How does potassium concentration affect toxicity?

A

INCREASES toxicity
* Potassium gradient most important in establishing membrane potential in cardiac myocytes
* Cardiotoxic doses of lido, bupivacaine halved when K >5.4mEq/L in dogs

163
Q

Neurotoxicity

A

 Concentration dependent
 Proposed MOA: injury to Schwann cells, inhibition of fast axonal transport, disruption of blood-nerve barrier, decreased neural blood flow with assoc ischemia, disruption of cell membrane integrity DT detergent property of LAs

Spinal cord, nerve roots more prone to injury
Most LAs increase spinal BF

164
Q

Order of LA Neurotoxicity

A

 Procaine </= mepivacaine < lidocaine < Chloroprocaine < ropivacaine < bupivacaine

165
Q

Myotoxicity

A

 Concentration-dependent, generally regenerative, clinically imperceptible
 Bupivacaine most myotoxic
* Dysregulation of intracellular [Ca] +/- changes in mitochondrial bioenergetics
 Pigs: bupivacaine, ropi = irreversible skeletal m damage
* Calcific myonecrosis 4wks after PNB

166
Q

Chrondotoxicity

A

 Time, concentration-dependent
* Greater risk for chrondolysis with longer exposure to higher [LA]
* Mepivacaine = best
 Intact articular surface not protective

167
Q

Chrondotoxic LAs?

A

Mepivacaine < ropivacaine < bupivacaine = lidocaine (chondrocyte necrosis)

168
Q

Methemoglobinemia

A

Oxidative damage to hemoglobin molecule: iron (Fe2+) oxidized to ferric form, Fe3+

Cannot bind oxygen, decreases carrying capacity

Oxidative denaturation –> Heinz body formation –> irreversible, decreases lifespan of RBCs
* Only sign if chronic
* Chocolate-brown blood, not responsive to O2 therapy

169
Q

Which LAs cause methemoglobinemia?

A

Benzocaine, prilocaine
* Benzocaine: nasopharyngeal MM, IN, dermal admin
* Prilocaine: MHb in mother, fetus following epidural

170
Q

MetHgb: 0-2%

A

Physiologic

171
Q

MetHgb 10-20%

A

Well tolerated

172
Q

MetHgb >30%

A

Clinical Signs of Hypoxia

173
Q

MetHgb >55%

A

lethargy, stupor, shock

174
Q

MetHgb >70%

A

death

175
Q

Tx MetHgb

A

1% methylene blue, dextrose
* Dogs: 4mg/kg
* Cats: 1-2mg/kg, avoid repeated doses DT markedly aggravated subsequent hemolysis
* Requires NADPH to be effective, dextrose = major source of NADH

176
Q

Allergic Reactions

A

Amino-esters metabolized to PABA –> allergic reactions

Can also have preservatives in amide preparations = PABA
* Methylparaben
* Sodium metabisulfite

Anaphylaxis: bronchospasm, upper airway edema, vasodilation, increased capillary permeability, cutaneous wheal/flare

177
Q

Oral Ingestion

A

 Lidocaine, tetracaine, benzocaine – ingestion of topical preparations, laryngeal spray prior to intubation
 Prolonged sedation, VD/hypotension, arrhythmias, resp depression, sz, death

178
Q

Preservatives

A

concerns for neurotoxicity
 Sodium metabisulfite
 Chlorobutanol
 Methyparaben
 Disodium EDTA
 Benzathonium chloride

MUST USE PF FREE ON BOARDS FOR EPIDURAL ADMIN

179
Q

Tx LAST

A

o Discontinue local use
o Intubation, oxygen therapy, benzodiazepine for CNS toxicity
o CPR, epi, defibrillation if warranted for CPA
o Amiodarone for ventricular arrhythmias – class III, K+ channel blocker
o 20% lipid emulsion
o Insulin, dextrose

180
Q

Epinephrine in LAST

A

 Low dose epi <1mcg/kg
 High dose epi + lipid therapy = higher incidence ventricular arrhythmias, hyperlactatemia, hypoxia, acidosis, pulmonary edema

181
Q

Which anti arrhythmic should be used in LAST?

A

Amiodarone for ventricular arrhythmias – class III, K+ channel blocker

182
Q

Is propofol an acceptable substitute for lipid emulsion therapy?

A

No, bc only 10% lipid

183
Q

Why give insulin, dextrose with LAST?

A

Decrease outward potassium current

184
Q

What do we avoid in LAST?

A

lidocaine/procainamide, vasopressin, Ca channel blockers (IV, diltiazem), beta blockers

185
Q

Why do we avoid vasopressin with LAST?

A

increases risk of pulmonary hemorrhage, worse outcome in rats when admin alone or with epi

186
Q

Why do we avoid Ca channel blockers with LAST?

A

exaggerated cardiodepressant effects

Boards: Pharmacology (9 decks)

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