LOCAL ANESTHETICS. Alison Clode, DVM, DACVO. Port City Veterinary Referral Hospital Portsmouth, New Hampshire
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1 LOCAL ANESTHETICS Alison Clode, DVM, DACVO Port City Veterinary Referral Hospital Portsmouth, New Hampshire New England Equine Medical and Surgical Center Dover, New Hampshire
2 Overview Molecular Structure Mechanism Side effects Ophthalmic Uses
3 Structure Hydrophobic aromatic ring Intermediate linkage site Hydrophilic ionizable amine
4 Structure Hydrophobic aromatic ring Establishes lipophilicity Can be altered with substitutions Influences diffusion across nerve cell membrane and metabolism Determines potency and toxicity (binding)
5 Structure Intermediate linkage site Ester (unstable) Hydrolyzed by plasma esterases Rapid process Amide (stable) Metabolized in the liver Slower process
6 Structure Hydrophilic ionizable amine Weak base with pka 8 to 9 Un-ionized fraction (tertiary amine, lipid-soluble) greater in neutral or basic environment Ionized fraction (quaternary amide, H 2 O-soluble) increases in acidic environment Determines time to onset based on tissue ph Formulated as hydrochloride salt to increase solubility and stability
7 Mechanism 1. Diffusion across cell membrane (un-ionized form) Neuron Un-ionized LA Na+ channel Na+
8 Mechanism 1. Diffusion across cell membrane (un-ionized form) 2. Amine ionizes to ammonium cation Neuron Ionized LA Un-ionized LA Na+ channel Na+
9 Mechanism 1. Diffusion across cell membrane (un-ionized form) 2. Amine ionizes to ammonium cation 3. Ionized form preferentially binds receptor located on intracellular domain of Na+ channel Neuron Ionized LA Un-ionized LA Na+ channel Na+
10 Mechanism 1. Diffusion across cell membrane (un-ionized form) 2. Amine ionizes to ammonium cation 3. Ionized form preferentially binds receptor located on intracellular domain of Na+ channel 4. Inhibition of Na+ influx 5. Inhibition of depolarization à no action potential Un-ionized LA Neuron Ionized LA Na+ channel Na+
11 More details Binding affinity of aromatic ring to inner aspect of Na+ channel determined by protein binding Increased protein binding à greater binding affinity à increased potency Binding is increased with greater activity of receptors, which occurs when neurons are rapidly firing Increased binding à increased anesthetic effect Small diameter neurons are more sensitive than larger diameter neurons Duration of activity is determined by contact time
12 Contact time influenced by: Lipid solubility (aromatic ring) Determines diffusion into neuron Correlates with binding affinity to sodium channels Increased lipophilicity à increased binding affinity Local environment Alkaline environment increases un-ionized (lipophilic, tertiary) proportion Acidic environment (i.e., infection) increases ionized (hydrophilic, quaternary) proportion Increased hydrophilic proportion correlates with increased time to onset because of decreased diffusion into neuron Concentration LA with greater lipid solubility are formulated in lower concentrations Rate of removal by diffusion and circulation
13 Methods to increase contact time: Addition of vasoconstrictor Epinephrine 1:100,000 to 1:200,000 Decreases clearance from site of action Decreases systemic absorption/toxicity Provides hemostasis May induce local tissue necrosis Addition of buffer 1:10 bicarbonate to lidocaine 1:20 bicarbonate to bupivicaine Increases local ph to increase un-ionized (diffusable) form of drug
14 More details CHARACTERISTIC DETERMINES MECHANISM Lipid solubility (aromatic ring) Plasma protein binding (aromatic ring) Ester versus amide (intermediate linkage) Potency Duration of action Metabolism Greater lipid solubility à greater diffusion into neuron Greater plasma protein binding à greater affinity for receptor proteins à prolonged presence at site of action Esterases versus hepatic metabolism pka (terminal amine) Time to onset HIGHER ph à greater lipid portion à greater diffusion à faster onset Adapted from Becker DE and Reed KL, Anes Prog, 2006
15 Comparison Agent Concentration Duration to onset (min) Duration of action (hr) Lidocaine 1% 1 ½ - 1 Lidocaine 2% 1 ½ - 1 Lidocaine + epinephrine 1% Mepivacaine 2% Bupivacaine 0.25% Bupivacaine + epinephrine 0.25% 5 3 7
16 Topical LA Efficacy = ability to suppress corneal sensitivity Maximum effective concentration = concentration above which no increase in efficacy occurs Optimum effective concentration = concentration associated with least adverse effects ** Effects NOT additive **
17 Topical LA Side effects Corneal toxicity: 1. Localized or diffuse desquamation à superficial punctate keratitis 2. Diffuse necrotizing epithelial keratitis 3. Severe infiltrative keratitis, often in a ring formation 4. Persistent epithelial defects 5. Descemet s membrane folding Yagci A, et al., Cornea 2011
18 Topical LA Side effects Mechanisms of toxicity: Disrupt microvilli à altered tear film adherence Impede epithelial migration Direct effect on keratocytes and endothelial cells Ag-Ab deposition from epithelial cell breakdown Oxidative stress Decreased blink Decreased reflex tearing
19 Topical LA Side effects Ocular irritation: Conjunctival hyperemia, chemosis, lacrimation, blepharedema, pruritus Rapid onset Treat with compresses, topical anti-inflammatories Can generally use a different agent without problems
20 Topical LA Side effects IOP alterations? Topical anesthetics suspected to alter endothelial Na+/K+ pump à increased stromal hydration à increased central corneal thickness (CCT) Altered CCT may complicate diagnosis of glaucoma Thin corneas à underestimation of actual IOP Thick corneas à overestimation of actual IOP
21 Topical LA Side effects Systemic toxicity: No serious systemic reactions reported with appropriate use of topical anesthetics Systemic absorption problematic with: Large doses (inappropriate administration) Rapid absorption (i.e., conjunctival hyperemia) Unusually slow drug detoxification Unusually slow drug elimination
22 Topical LA Side effects Systemic hypersensitivity: LA are too small to be immunogenic on their own Hapten + carrier may à pseudoallergic reaction Suggestive of hypersensitivity but without known immune basis Anaphylactoid reaction = pseudoallergic reaction mimicking severity of IgE-mediated reaction Vasodilator release occurs, but via non-ige-mediated mechanism Angioneurotic edema, hives, bronchospasm, hypotension Rare
23 Topical LA Side effects CNS = stimulation followed by depression Cardiovascular = hypertension and tachycardia followed by hypotension and weak to absent pulse Respiratory = failure Becker DE and Reed KL, Anes Prog, 2006
24 Suggested maximum topical dosages Anesthetic agent Cocaine 4% Tetracaine 0.5% Proparacaine 0.5% Dosage for humans 20 mg (approximately 5 drops in each eye) 5 mg (approximately 7 drops in each eye) 10 mg (approximately 14 drops in each eye) Than TP and Bartlett JD. In Clinical Ocular Pharmacology, 2008.
25 Extrapolated*** maximum topical dosages Anesthetic agent Dosage for humans Dosage for dogs*** Tetracaine 0.5% 5 mg (approximately 7 drops in each eye) 1.5 mg (approximately 2 drops in each eye) Proparacaine 0.5% 10 mg (approximately 14 drops in each eye) 3.3 mg (approximately 5 drops in each eye) *** Extrapolations based on supposing 90 kg person and 30 kg dog *** Extrapolations are my own and should not be quoted as fact, just used for the sake of argument
26 Topical LA Contraindications Previous anaphylactoid reaction Anticholinesterase medication (neostigmine, pyridostigmine) Perforating ocular injury Endothelial damage Preservatives Culture collection
27 Specific topical LA
28 Cocaine Not commercially available as an ophthalmic solution Local anesthetic effects: 1% to 4% 1 drop of 2% Complete corneal anesthesia within 5 to 10 minutes Duration 20 minutes Incomplete anesthesia 1 to 2 hours Adrenergic effects: Diagnosis of Horner s (10%) Vasoconstriction
29 Cocaine Side effects Corneal epithelial toxicity Systemic toxicity 20 mg = 10 drops of 4% solution (humans) Excitement, restlessness, headache, rapid irregular pulse, nausea, vomiting, mydriasis Addiction
30 Cocaine Contraindications Systemic hypertension Medication with adrenergic agonists Medication with anticholinesterases Angle-closure glaucoma
31 Tetracaine 0.5% - 1% solution Poor efficacy for scleral anesthesia Greater inhibition of bacterial growth than proparacaine High topical toxicity High systemic toxicity
32 Tetracaine in horses efficacy Maximal effect in 5 min 0.5% 1 drop 55% of horses 0.5% 2 drops 90% of horses 1% 1 drop 80% of horses EQUINE VETERINARY JOURNAL 69 Equine vet. J. (2011) 43 (1) doi: /j x Duration of corneal anaesthesia following multiple doses and two concentrations of tetracaine hydrochloride eyedrops on the normal equine cornea S. J. MONCLIN*, F. FARNIR and M. GRAUWELS Departments of Clinical Sciences, Ophthalmology and Animal Production, Faculty of Veterinary Medicine, Liège University, Belgium. Duration of maximal effect 5 min 16 min 15 min Total duration of effect 30 min 60 min 50 min
33 Tetracaine in horses efficacy Time of MAE Degree of MAE Duration of MAE 0.5% proparacaine 0.5% tetracaine 0.5% tetracaine (viscous) 10 min 0.5 cm 20 min 10 min 0.25 cm 20 min 10 min 0 cm 30 min
34 Tetracaine in horses side effects Normal horses 74 EQUINE VETERINARY JOURNAL Equine vet. J. (2011) 43 (1) doi: /j x 0.5% or 1% once Clinical exam Time 0, 2.5, 5 min TBUT Time 0, 2.5, 5 min Determination of tear break-up time reference values and ocular tolerance of tetracaine hydrochloride eyedops in healthy horses S. J. MONCLIN*, F. FARNIR and M. GRAUWELS Departments of Clinical Sciences, Ophthalmology and Animal Production, Faculty of Veterinary Medicine, Liège University, Belgium. 0.5% à significantly faster TBUT at 5 min 1% à significantly faster TBUT at 2.5 and 5 min
35 Proparacaine 0.5% solution Comparison with tetracaine: Less corneal/conjunctival penetration Less pain on administration Less inhibition of bacterial growth Refrigerate after opening Discard if discolored
36 Proparacaine in dogs efficacy Single drop Two drops 1 min apart Onset < 1 min < 1 min Duration of MAE Total duration 15 min 25 min 45 min 55 min
37 Proparacaine in cats efficacy Onset Duration of maximal effect Total duration of effect Single drop < 1 min 5 min 25 min
38 Proparacaine in horses efficacy Onset Time point of maximal effect Total duration of effect 0.2 ml once < 1 min 5 min 25 min
39 Benoxinate (oxybuprocaine) 0.25% + sodium fluorescein 0.35% + disodium fluorexon HMW hydrogel that does not stain contact lenses Bactericidal Primary use = applanation tonometry Significant increase in corneal thickness Low risk of local hypersensitivity reaction
40 Benoxinate (oxybuprocaine) in dogs efficacy Single drop 0.4% Onset < 1 min < 1 min Duration of MAE Total duration 30 min 30 min 55 min 55 min Single drop 1% tetracaine
41 Benoxinate (oxybuprocaine) in cats efficacy Onset Duration of MAE Total duration Single drop 0.4% 1 min 5 min 45 min
42 Injectable Local Anesthetics
43 Intracameral local anesthetics Preservative-free Lidocaine (1% or 2%) Ropivacaine (1%) Levobupivacaine (0.75%) Indicated for intraocular surgery Analgesia Mydriasis
44 Intracameral LA analgesia Reduces intraoperative pain Increases intraoperative patient compliance No alteration in short-term (1 month) or long-term (6 year): BCVA EC loss Corneal thickness PCO prevalence or severity
45 Intracameral LA mydriasis Relaxation of iris sphincter à mydriasis Comparison between topical mydriatics and intracameral lidocaine Greater dilation with lidocaine No need for intraoperative mydriatic
46 Intracameral LA toxicity In vitro lidocaine Transient decrease in cell viability, inhibition of cell proliferation, and DNA degradation In vivo in rabbits Potential EC microstructural alterations Caution should be exercised, particularly in cases with corneal pathology
47 Intracameral LA analgesia in dogs Lidocaine à Significantly reduced isoflurane requirements Significantly longer time to post-operative treatment failure (rescue analgesia) 5 hours versus 1.5 hours
48 Intracameral LA mydriasis in dogs In vivo 1% lidocaine, 2% lidocaine, BSS 0.1 ml, 0.2 ml, 0.3 ml All à pupil diameter > 10 mm Most rapid onset with 0.3 ml 2% Most delayed onset with 0.1 ml 1% Longest duration with 0.3 ml 2% Shortest duration with 0.1 ml 1%
49 Intracameral LA toxicity in dogs In vivo evaluation 1% lidocaine versus 2% lidocaine versus BSS No changes: EC density EC morphology Corneal edema Corneal thickness IOP
50 Retrobulbar LA Block CN II, CN III, CN IV, CN VI, ophthalmic and maxillary of CN V Indications: Analgesia Akinesia Mydriasis Parness G, et al., CEACCP 2005
51 Retrobulbar LA Retrobulbar (intraconal) More risky More rapid onset Smaller volumes Peribulbar (extraconal) Less risky Slower onset Larger volumes Possible complications Retrobulbar hemorrhage Ptosis Globe perforation Chemosis Parness G, et al., CEACCP 2005
52 Retrobulbar LA Review of clinical trials in human ophthalmology comparing RB and PB No significant difference in pain control No significant difference in akinesia rates Greater (but not significant) need for repeat injections with PB technique No significant difference in effect with or without sedation Greater occurrence of chemosis with PB Retrobulbar hemorrhage in 1 patient in RB group Persistent ptosis in ~1% in each group * Alhassan MB, et al., The Cochrane Collaboration, 2011
53 Retrobulbar LA in horses U/S-guidance with CT evaluation of contrast spread: Better caudal spread of contrast with intraconal placement Extraconal may result in caudal contrast spread GA with or without RB block: Without RB block à significant decrease in HR Globe traction Pressure on orbital fat pad Increased incidence of bradyarrhythmias
54 Retrobulbar LA in cattle Comparison of modified RB and Peterson blocks Retrobulbar: D, V, M, L quadrants 10 ml volume each spot Peterson: Notch formed by supraorbital process + zygomatic arch + coronoid process 12 ml total volume Broader spread with RB Consistent infiltration of oculomotor bundle with RB
55 Retrobulbar LA in dogs ITP technique Mild exophthalmos Increase in PD No alteration in IOP Central positioning of globe No adverse effects post-anesthesia STT Corneal sensitivity Ocular motility Less consistent mydriasis than subtenon s injection, but effective pain control
56 Retrobulbar LA in dogs analgesia Decreased need for rescue analgesia following enucleation Possible improvement in pain control with injection versus LA-soaked hemostatic sponge Myrna K et al., JAVMA 2010 Ploog et al., JAVMA 2014 Chow D et al., VO 2015 Possible improvement in pain control with preoperative injection versus intra-operative splash block
57 Retrobulbar LA in cats Distribution study RB (1 ml dorsomedial) PB1 (4 ml dorsomedial) PB2 (2 ml dorsomedial + 2 ml ventrolateral) RB à intraconal (5/7), extraconal (4/7) PB1 à intraconal (7/7), extraconal (7/7) PB2 à intraconal (6/6), extraconal (6/6) Estimated clinical success: RB 71% PB1 86% PB2 67%
58 Systemic infusion of local anesthetics Pre-emptive therapy for painful procedures Limited evaluation specific to ocular surgeries In dogs prior to cataract surgery Bolus + CRI of lidocaine versus morphine versus saline control Routine phacoemulsification (research dogs) Saline: 100% treatment failure within 15 min post-op Morphine: 50% treatment failure within 1 hour post-op Lidocaine: 50% treatment failure within 1.75 hours post-op
59 Summary local anesthetics Structure hydrophobic aromatic ring, ester or amide linkage, hydrophilic ionizable amine Mechanism of action penetrate neuron, bind and block Na+ channel, inhibit depolarization Local and systemic toxicities Local anesthetics are necessary, but must be used judiciously, particularly when considering the size and absorptive capacity of some of our veterinary patients*** Topical application relative efficacy versus topical side effects versus systemic absorption Intracameral injection relative efficacy versus intraocular toxicity Retrobulbar injection relative efficacy versus injection risks Systemic infusion relative efficacy versus alternatives
60 Questions?
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