Overview Local Anesthetics/ Local Anesthesia · Local anesthetics are weak bases ! Proportion of base:salt depends on ! pH ! pK of amino group ! Both base and ionized form are required

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Local Anesthetics/Local Anesthesia

Ian P. Herring, DVM, MS, DACVO

Overview

�  Structure and Mechanisms

�  Functional Chemistry

�  Adverse Effects

�  Clinical Applications

LA History

�  Cocaine �  Albert Niemann isolated crystals from coca

shrub in 1860...dubbed “cocaine” �  employed by Carl Koller as an ophthalmic

anesthetic in humans in 1884, following animal studies

�  Amylocaine (1903), Novocaine (1905) �  first synthetic ester-type anesthetics

�  Lidocaine (1943) �  first synthetic amide-type anesthetic

LA Structure

•  All local anesthetics possess this general structure •  Classified as either esters or amides

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Structural Classification

of Local Anesthetics

Esters Amides

Cocaine Lidocaine

Proparacaine Bupivicaine

Tetracaine Mepivicaine

Benoxinate

Procaine

Chemistry

�  Local anesthetics are weak bases

�  Proportion of base:salt depends on �  pH

�  pK of amino group

�  Both base and ionized form are required for activity �  Enter nerve fiber as free base (uncharged) �  Cationic form blocks inner surface of Na+ channel

�  Agents with lower pK = more rapid onset due to more rapid diffusion across cell membrane

Functional Chemistry �  Both free base and ionized forms critical to activity

�  Enter nerve as free base ionized form blocks Na+ channel on cytoplasmic side

Structure

�  Aromatic ring �  Determines lipophilicity

influences diffusion across membranes �  Influences toxicity

�  Linkage determines stability �  Esters rapidly hydrolyzed

�  Amides undergo hepatic metabolism; more stable

�  Amino group also helps determine lipophilicity

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Local Anesthesia: MOA �  Reversible inhibition of action potential propagation

in sensory nerve fibers via Na+ channel blockade

Primary factors affecting LA efficacy/potency

�  Lipophilicity of agent

�  Vascular effects of agent

� Nerve fiber type

�  Local pH vs agent pK

�  others

Functional Chemistry

Activity determined by:

�  Lipid solubility

�  Influences potency, protein binding and duration of action

�  Varies with # of carbons on aromatic ring &/or amino group

�  Ionization constant (pK)

�  Determines proportion of ionized vs non-ionized

�  Physiologic factor and environment also play important roles!

Functional Chemistry

Activity determined by: �  Lipid solubility

�  Influences potency, protein binding and duration of action

�  Varies with # of carbons on aromatic ring or amino group

Agent Lipid Solubility

Relative Potency

Protein binding (%)

Duration (min)

Procaine 1 1 6 60-90

Lidocaine 4 2 65 90-120

Bupivicaine 80 8 80 180-600

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Functional Chemistry

Activity determined by: �  Ionization constant (pK)

�  Determines proportion of ionized vs non-ionized

�  Lower pK = more rapid onset

Agent pK %free base at pH 7.4

Anesthetic onset

Lidocaine 7.9 25 2-4 min

Bupivicaine 8.1 18 5-8 min

Functional Chemistry

�  Local anesthetic efficacy is reduced in face of inflammation

�  Potential mechanisms:

�  Inflammatory acidosis?

�  Vasodilation?

�  Peroxynitrite formation?

Local anesthetic effects

�  Nerves = decreased impulse conduction �  Susceptibility varies

�  Small diameter fibers and non-myelinated fibers are more susceptible than large, myelinated fibers

�  Vascular smooth muscle = relaxation/vasodilation

�  CNS = increased excitability or depression

�  Heart = decreased excitability

Nerve fiber sensitivity to local anesthetics

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Differential Nerve

Inhibition

�  Non-myelinated fibers are most sensitive

�  2-3 adjacent nodes of Ranvier must be blocked

to impair nerve conduction

�  Nodes closer together in small diameter fibers (e.g. type Aδ pain fibers) .˙. easier to achieve block

Vasodilatory Effects

�  Caused by blockade of Na+ channels in vascular smooth muscle

�  Consequences: �  Increase rate of anesthetic removal from site

diminished duration of action

�  Hypotension

�  Can ameliorate this via concurrent vasoconstrictor use prolongs anesthetic duration (also reduces risk of

systemic toxicity)

Adverse Effects �  Allergic reaction (uncommon to rare)

�  Most commonly associated with ester forms metabolized to PABA allergic reaction

�  Amides not metabolized to PABA �  Preservatives in amide compounds undergo metabolism

to PABA, however

�  Systemic toxicity (cardiovascular, CNS) �  Inadvertent intravascular injection �  Systemic distribution following regional injection

�  Evaluate systemic dose!

�  Concurrent vasoconstrictor will minimize

Improving Efficacy of Regional Anesthetics?

�  Concurrent vasoconstrictor

�  Epinephrine (1:100,000 - 1:200,000)

�  Slows clearance: duration of effect & systemic toxicity

�  Reduced surgical bleeding

�  Concurrent buffering agent

�  Bicarbonate (0.06 meq/ml; 1 ml of 1M solution/10 ml LA)

�  Increased pH = increased free base (non-ionized)

�  Addition of hyaluronidase (15 IU/ml of LA)

�  Evidence of efficacy inconclusive

�  May allow reduced volume of anesthetic in PB block

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Clinical Application

Relevant Clinical Options �  Local Anesthesia

�  Topical �  Subconjunctival �  Intracameral

�  Regional Anesthesia �  Peribulbar (extraconal) �  Parabulbar (episcleral/sub-Tenon’s) �  Retrobulbar (intraconal)

�  Others �  Splash block �  LA-infused sponge

Topical Anesthesia Indicated for brief diagnostic and therapeutic corneoconjunctival procedures

Benefits Limitations

Simple Limited duration

Rapid onset Incomplete analgesia

Inexpensive Limited to corneoconjunctival surface

No akinesia

Adverse effects

Topical Anesthetics

�  Commonly utilized agents in veterinary ophthalmic

practice

�  Proparacaine

�  Tetracaine

�  Oxybuprocaine

�  Several others have been investigated

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Topical Agents �  Agents vary in:

�  Duration of effect

�  Tolerance/reactions �  Effect on tear film

�  All act rapidly, rapid decay in effect

�  All affect corneal thickness �  Not likely clinically relevant

�  All have antimicrobial properties �  Evidence of relative effects variable

�  Effect of preservatives?

Proparacaine �  0.5% solution

�  Well-tolerated

�  No irritation reported

�  Refrigerated storage

�  Short term at room temp OK

�  Discard if discolored (yellow)

Proparacaine: Clinical Effects Dogs Cats Horses

Onset <1 min <1 min <1 min

Duration (total) 45-55 min 25 min 25-35 min

Duration (max) 15 min 5 min 20 min*

Other Multiple doses extend duration

Reports vary on completeness of anesthesia

Ref Herring, et al AJVR, 2005 Ventrui, et al. VO, 2017

Binder&Herring AJVR, 2006

Kalf, et al. AJVR, 2008 *Sharrow-Reabe, et al JAVMA, 2012 Pucket, et al. AJVR, 2013

Tetracaine �  0.5 – 1% aqueous and 0.5% viscous solution

�  Typically reported to cause more discomfort/irritation upon instillation than other topical agents

�  Room temperature storage

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Tetracaine: Clinical Effects

Dogs

0.5% viscous

Duration (total) 34 min

Duration (max) Up to 70 min

Other Longer effect than topical proparacaine or lidocaine

Refs Venturi, et al VO 2017

Tetracaine Horses Horses Horses

0.5% solution 1% solution 0.5% aqueous

0.5% viscous

Duration (total) 30 min 50 min

Duration (max) 5.5 min 15 min 20 min 30 min

Other Multiple doses extend duration Well-tolerated

Multiple doses extend duration Well-tolerated

Monclin, et al EVJ, 2011

Monclin, et al EVJ, 2011

Sharrow-Reabe & Townsend JAVMA, 2012

Oxybuprocaine

�  0.4% solution

�  Room temperature storage

�  Well-tolerated

Oxybuprocaine: Clinical Effects

Dogs Cats Horses

Onset <1 min <1 min <1 min

Duration of Effect

55 min 45 min >75 min

Maximal Effect 15 min 5 min ---

Other Well-tolerated

Ref Douet, et al. AJVR, 2013

Guidici, et al. VO, 2015

Little, et al. CVJR, 2016

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Topical Anesthetics: Horses

�  Topical proparacaine, lidocaine, bupivicaine, mepivicaine

�  Mepivicaine failed to produce complete anesthesia

�  Bupivicaine provided longest duration of action (60 minutes)

Lidocaine Ophthalmic Gel

�  3.5% gel

�  Room temperature storage

Topical Anesthetics: Adverse Effects

�  Acute, including single application �  Stinging, discomfort

�  Superficial punctate keratitis �  Altered lacrimation, blink rate

�  Allergic reaction (rare) �  Endothelial toxicity (open cornea)

�  Chronic use/abuse �  Necrotizing keratitis �  Stromal infiltrates, ring infiltrates

�  Persistent epithelial defects �  Uveitis

American Academy of Ophthalmology

Adverse Effects (cont) �  Decreased epithelial migration

Delayed corneal healing

�  Damage to epithelial microvilli, microplicae Diminished tear film adhesion

�  Preservative adverse effects?

�  Antimicrobial effects �  Preservative–free have less antimicrobial effect

Agent Preservative

Proparacaine Benzalkonium chloride

Tetracaine Chlorobutanol

Oxybruprocaine Chlorobutanol

Lidocaine gel Methylparaben, polyparaben

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Subconjunctival Anesthesia

� Utilized to provide corneal analgesia/anesthesia

� Mechanisms? �  Local corneoscleral diffusion to block nerves

entering cornea

�  Leakage from conjunctival bleb onto surface

�  Painful application!

Subconjunctival Anesthesia: Horses

�  0.2 ml subconjunctival administration �  Licodaine 2%

�  Bupivicaine 0.5%

�  Mepivicaine 2%

�  Incomplete corneal anesthesia of ≈1.5 - 2 hrs duration �  Mepivicaine had most rapid onset and longest duration

�  Subconjunctival hemorrhage common

�  Painful!

Intracameral Anesthesia �  Often combined with topical anesthesia for

intraocular procedures in humans

�  Preservative-free agents must be used �  Lidocaine (1%, 2% �  Ropivacaine (1%)

�  Levobupivicaine (0.75%)

Benefits Limitations

Analgesia No akinesia

Mydriasis Analgesic efficacy?

Toxicity??

Endothelium Retina

Intracameral Anesthesia: Dogs

�  Normal dogs

�  0.1 ml preservative-free 1% and 2% lidocaine

�  No significant adverse effects noted �  Clinical examination �  Pachymetry

�  Specular microscopy

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�  Normal dogs

�  Intracameral 0.1-0.3 ml, 1% or 2% lidocaine achieves mydriasis

�  Duration of action 1-2 hours �  affected by LA concentration and volume

Intracameral Anesthesia: Dogs

�  Normal dogs

�  0.3 ml 2% (preservative free) lidocaine provides analgesia �  Reduced intraoperative isoflurane requirement �  Significantly longer period until post-op analgesia

required

Intracameral Anesthesia: Dogs

Regional Anesthesia:

� Retrobulbar block

� Peribulbar block

� Sub-Tenon’s block

The Perfect Eye Block

Major Complications of Regional Block Procedures �  Globe perforation

�  Highest risk factor in humans is high myopia, especially due to associated staphyloma

�  EOM injury �  Direct trauma �  Pressure necrosis �  LA myotoxiticy

�  Hemorrhage �  Retrobulbar �  Subconjunctival

�  Optic nerve trauma

�  Brainstem anesthesia

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Retrobulbar Block

�  Intraconal administration of LA

Benefits Limitations

Rapid onset Placement accuracy?

Akinesia Risks:

Analgesia Brainstem anesthesia

Mydriasis Globe perforation

May avoid NM blockade Optic nerve damage

Low LA volume Myotoxicity

Retrobulbar hemorrhage

Peribulbar Block �  LA injected into extraconal space

�  LA spreads regionally, including intraconal

�  Requires larger LA volume than others; adjunctive hyaluronidase helps mitigate

Benefits Limitations

Decreased risk to intraconal structures compared to RB

Less akinesia (vs RB, ST)

Chemosis common

IOP rise

Reproducibility?

Risks:

Globe perforation

Hemorrhage

Myotoxicity

Sub-Tenon’s (parabulbar)

Block �  LA injected under Tenon’s (episcleral)

�  Needle versus blunt cannula

Benefits Limitations

Avoids globe and ON injury compared to RB; esp with blunt cannula

Akinesia may require higher LA volume than RB

Less LA volume than peribulbar

Chemosis, subconjunctival hemorrhage common

Excellent globe analgesia IOP rise

Serious complications rare

Regional Blocks: Veterinary Ophthalmic

Literature

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Retrobulbar Block: Dogs Technique

�  Evaluated 3 approaches

�  Inferior-temporal palpebral ideal �  Effective

�  Easiest to perform �  Good intraconal LA distribution

�  No adverse outcomes detected

Retrobulbar Block: Dogs Analgesic Efficacy

Reference Design Findings

Myrna, et al JAVMA 2010

22 dogs undergoing enucleation RB bupivicaine vs saline

9/11 control versus 2/11 bupivicaine dogs required rescue analgesia

Ploog, et al. JAVMA 2014

19 dogs undergoing enucleation Lidocaine-bupivicaine RB block versus infused sponges

Similarly effective in achieving post-op analgesia

Chow, et al. Vet Ophth 2015

31 dogs undergoing enucleation RB bupivicaine versus bupivicaine splash block

Similarly effective in achieving post-op analgesia

Retrobulbar Block: Dogs Globe Positioning

Reference Design Findings

Hazra, et al Vet Ophth 2008

10 dogs undergoing PE

RB block with 2% lignocaine

Adequate central positioning and akinesia

No effect on IOP

Ahn, et al. Vet Ophth 2013

10 dogs 3 treatments with 7+d washout:

Atracurium bolus

RB lidocaine

Sub-tenon’s lidocaine

Onset of akinesia more rapid for ST vs RB block

Duration of akinesia longer for ST block versus atracurium bolus

ST more effective for achieving mydriasis than RB

Lower volume of LA required for ST vs RB block

Retrobulbar vs Sub-Tenon’s: Dogs

�  10 normal dogs; 3 treatments with 7+ day washout:

�  Atracurium bolus

�  RB lidocaine

�  ST lidocaine

�  Primary Findings

�  Onset of akinesia more rapid for ST vs RB block

�  Duration of akinesia longer for ST block versus atracurium

�  ST more effective for achieving mydriasis than RB

�  Lower volume of LA required for ST vs RB block

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Sub-Tenon’s Block: Dogs

�  12 dogs undergoing phaco for cataract

�  One eye ST anesthesia (bupivicaine)

�  One eye NM blockade (pancuronium)

�  Good globe centration in all cases

�  ST caused anterior globe displacement �  Beneficial in 50%, inconsequential in 42%

�  1/12 in ST group vitreal expansion

�  3 techniques compared, 16 orbits for each, volume injected body weight dependent

�  RB: 1-2 ml injectate

�  PB-1: Entire volume via medial canthus

�  PB-2: Volume divided between dorsomedial and ventrolateral locations

�  Likelihood of injectate volume to produce regional anesthesia

Technique Within EOM cone

At EOM cone base

RB 40% 60%

PB-1 19% 63%

PB-2 31% 50%

Retrobulbar vs Peribulbar Block: Dogs

Retrobulbar vs Peribulbar Block: Dogs

�  6 normal dogs in randomized, masked cross-over trial

�  0.5% bupivicaine:iopamidol injected �  RB: 2 ml administered ventrolateral

�  PB: 5 ml divided between dorsomedial and ventrolateral sites

�  CT Evaluation of distribution and Clinical Evaluation of effect

�  Intraconal distribution of injectate �  2/6 in RB group; 4/6 in PB group

�  PB block more reliably induced corneal and periocular anesthesia and mydriasis

�  Complications of chemosis/exophthalmos more common with PB

Retrobulbar vs Peribulbar: Cats

�  Studied distribution of injectate for 3 protocols: �  RB: 1 ml RB injectate dorsomedially

�  PB-1: 4 ml PB injectate dorsomedially

�  PB-2: 2ml PB injectate dorsomedial and 2ml ventrolateral

�  Predicted anesthetic efficacy based upon distribution

�  RB: 71%

�  PB-1: 86%

�  PB-2: 67%

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Retrobulbar vs Peribulbar: Cats

�  6 normal cats in randomized cross-over trial

�  Mixture of 0.5% bupivicaine:contrast (+saline for PB) injected �  RB: 1 ml administered ‘intraconally’ through dorsomedial

approach

�  PB: 3.0 ml administered via dorsomedial approach (outside of EOM cone)

�  CT Evaluation of distribution and Clinical Evaluation of effect

�  Intraconal distribution of injectate �  3/6 in RB group; 6/6 in PB group

�  PB block more reliably induced corneal and periocular anesthesia; chemosis similarly evident for both block types

Retrobulbar Block: Horses

�  US guided injection of CT contrast medium

�  3 injection volumes evaluated �  4, 8, & 12 ml

�  Successful intraconal placement = agent reaching orbital fissure

�  Agent reached orbital fissure in 6/12 extraconal placements Volume Effect

Retrobulbar Block: Horses

�  Enucleation under GA for chronic ocular disease �  6 horses with RB block and 10 without

�  10-12 ml mepivicaine used

�  Severe bradyarrhythmia in 2/10 without RB block

�  Mild bradyarrhythmia in 1/6 with RB block

Subtenon’s Block: Horses

�  7 or 10 ml injected ST using 25 mm blunt cannula

�  Good distribution in posterior sub-Tenon’s space and around EOMs for both volumes

�  Intraconal distribution in only 3/20 injections

�  Distribution similar for both 7 and 10 ml �  chemosis worse for 10 ml

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Summary

�  A variety of local anesthetic approaches are available, depending on clinical needs

�  Many factors influence regional anesthetic efficacy

�  Be aware of them

�  Much remains to be investigated in realm of regional blocks in companion animals

Questions?