PHARMACOLOGY OF REGIONAL OPHTHALMIC ANESTHESIA

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PHARMACOLOGY OF REGIONAL OPHTHALMIC ANESTHESIA

• Berrin Gunaydin, MD, PhD
• Gazi University Scool of Medicine
• Department of Anesthesiology
• Ankara, Turkey
• www.berringunaydin.com

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OUTLINE

• Overview of pharmacology of commonly used
  local anesthetics and adjuvants
  for ophthalmic regional anesthesia
• Efficacy of these drugs with regard to improving
  akinesia, analgesia, speed of onset and reducing
  block failure

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Chronology of Amide Local Anesthetic Development

• Agent Initial investigator Date
• Cocaine C17H21NO4 Niemann 1860
• Benzocaine C9H11NO2 Salkowski 1895
• Procaine C13H20N2O2 Einhorn 1904
• Dibucaine C20H29N3O2 Meischer 1925
• Tetracaine C15H24N2O2 Eisler 1928
• Etidocaine C17H28 N202 Adams,Kronberg,
  Takman 1972
• Lidocaine C14H22N2O Löfgren, Lundquist 1943
• Clorprocaine C13H19CIN2O2 Marks, Rubin 1952
  
• Mepivacaine C15H22N2O Ekenstam 1957
• Bupivacaine C18H28N2O Ekenstam 1963
• Prilocaine C13H20N2O Lofgren 1959
• Articaine C13H20N2O3S  Rusching 1969
• Ropivacaine C17H26N2O
  EkenstamSandberg 1996
• Levobupivacaine   Ekenstamothers 1999
  (Butterworth J. Clinical Pharmacology of Local
  Anesthetics)

• Carl Koller, an ophthalmology trainee took
  cocaine orally and noticed numbness in his tongue
• Koller and Gartner reported topical cocaine
  anesthesia of the eye in animals and human (1884)

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I.LOCAL ANESTHETICS (LA) Chemical
structureAromatic ring-intermediate chain-amino
group

• Ester linkage-COO

• Amid linkage-NHCO

Veering B. Local Anesthetics
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Properties of local anesthetics

• Ionization
• Lipid solubility
• Protein binding
• Chirality
• Mechanism of action
• Metabolism and elimination
• Toxicity

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Physicochemical properties of local anesthetics
pKa (25?C) Onset time PB () Potency Duration
ESTERS Cocaine 8.7 Slow 98 High Long
Procaine 8.9 Slow 6 Low Short
Amethocaine 8.5 Slow 76 Medium Medium
AMIDES Lidocaine 7.7 Fast 64 Medium Medium
Prilocaine 7.8 Fast 55 Medium Medium
Mepivacaine 7.6 Fast 75 Medium Medium
Etidocaine 7.7 Fast 94 High Long
Bupivacaine 8.1 Medium 95 High Long
Ropivacaine 8.2 Medium 94 Medium Long
Levobupivacaine 8.1 Medium 96 High Long
Lipid solubility
Potency
Protein binding Duration of
action

• pKa
• Onset time

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• Bupivacaine, Etidocaine, Mepivacaine, Prilocaine,
  Ropivacaine
• Have asymmetric carbon molecule

AYNA
Levobupivacaine, Ropivacaine are chiral
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• Bupivacaine prilocaine contain chiral carbon
• Both have R and S configuration (racemic)
• Cocaine, naturally original LA, is a pure
  levarotatory enantiomer (?-cocaine)
• Dextrorotatory cocaine (?-cocaine or
  pseudococaine)
• Stereospecificty has not been investigated until
  bupivacaine cardiotoxicity

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R () bupivacaine has a much longer dwell time in
cardiac sodium channels than the S(-) form.Of
additional signficance more potent depressant
effect on brain-stem cardiorespiratory neurons of
R() bupivacaine compared with its S(-)
enantiomer
De Jong RH. Local Anesthetic Pharmacology
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Mechanism of action
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Metabolism

• Ester type local anesthetics are split in plasma
  by pseudocholinesterase
• Primary metabolic product is p-aminobenzoic acid
  (PABA) which is highly allergenic
• Plasma half-life significantly prolongs in case
  of deficiency or presence of atypical
  pseudocholinesterase
• Since amide type local anesthetics are
  metabolized in the liver, only 1-3 can be seen
  in the urine

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Elimination

• Ester local anesthetics are almost entirely
  eliminated in plasma by ester breakdown except
  cocaine
• Amide local anesthetics except prilocaine are
  metabolized in liver (gt90)
• Lidocaine and etidocaine have high extraction
  rate (elimination depends primarily on liver
  perfusion)
• Bupivacaine and mepivacaine have limited hepatic
  extraction rate
• Prilocaine has a high elimination rate
  (considerably eliminated outside the liver)

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Elimination
Local anesthetics Elimination
Cocaine
Procaine
Amethocaine
Lidocaine
Prilocaine
Mepivacaine
Bupivacaine
Ropivacaine
Levobupivacaine
ESTERS
AMIDES
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Metabolism
Local anesthetics Metabolism-breakdown products Metabolism-breakdown products
Cocaine in plasma by pseudocholinesterase Benzil-ekgonin, Ekgonin metil ester, Ekgonin
Procaine in plasma by pseudocholinesterase PABA, Dietil amino etanol
Amethocaine in plasma by pseudocholinesterase p-butil amino benzoik asit
Lidocaine in liver by CP450 (CYP1A2 CYP3A4 at low and high , respectively) Mono ethy glysi xsilid (MEGX) Glysin xyilid (GX)
Prilocaine O-tolidin, Nitrozotolidin
Mepivacaine Oksopipekolo-ksilid, CH3oksopipekolo-ksilid
Bupivacaine Desbutil-bupivakain Hidroksi-bupivakain
Ropivacaine OH-pipekoloksilid (PPX) 3 ,4 OH-ropivakain
Levobupivacaine Desbutil-bupivakain Hidroksi-bupivakain
ESTERS
AMIDES
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Toxicity of ESTER TYPE LA
Cocaine ester of benzoic acid, excellent topical anesthetic (4-10), only LA producing vasoconstriction at clinical concentrations, high potential for systemic toxicity
Procaine Derivative of PABA, weak LA, slow onset, short duration of action, low potency and rapid plasma hydrolysis lead to low systemic toxicity but hydrolization to PABA may cause allergic reactions after repeated use
Amethocaine Butyl aminobenzoic acid derivative of procaine, potent ,long acting, hydrolysis by plasma cholinesterase (slower than procaine), potential for systemic toxicity is HIGH
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Veering B. Local Anesthetics
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Toxicity of AMIDE TYPE LA
Lidocaine Most versatile, commonly used,rapid onset of action,moderate duration of action prolongs with epinephrine, safely used for all types of local anesthesia, potential for systemic toxicity is INTERMEDIATE
Prilocaine toluidine derivative tertiary amine,clinical profile similar to lidocaine, LEAST TOXIC amino-amide LA, significant methemoglobinemia can occur gt10 mg/kg
Mepivacaine Structurally related to lidocaine, rapid onset of action, duration of action is somewhat longer than lidocaine, epinephrine prolongs duration of action by 75, potential for systemic toxicity is SIMILAR TO LIDOCAINE
Etidocaine Structurally similar to lidocaine, faster onset of action and similar duration of action when compared to bupivacaine, LESS TOXIC than other long acting LA due to its greater distribution and clearance, not in current practice
Bupivacaine Homologue of mepivacaine, greater anesthetic potency, prolonged duration of action, onset of analgesia is slow, MORE CARDIOTOXIC than equipotent doses of lidocaine
Ropivacaine S-enantiomer of bupivacaine, long acting LA, LESS ARRHYTHMOGENIC than bupivacaine
Levobupivacaine
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Veering B. Local Anesthetics
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Local Toxicity

• Neurototxicity (direct injection to nerve)
• rarely occurs when local anesthetics used alone
  for ophthalmic anesthesia, however it can happen
  with vasoconstrictors and high orbital pressures
• Myotoxicity (direct injection to muscle)
• to m.inferior oblique and rectus during
  inferotemporal injection and to m.rectus medial
  during medial cantus injection

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Systemic Toxicity

• Cardiovascular collapse
• Coma
• Convulsions
• Myoclonic jerks
• Tremors
• Garrulousness
• Circumoral numbness
• Omnius feelings
• Tinnitus, Vertigo
• Metalic .

• Central Nerve System (CNS)
• With increased local anesthetic doses seizures
  may arise in the amygdala
• Further local anesthetic dosing leads to CNS
  excitation progressing to CNS depression and
  eventual respiratory arrest
• Cardiovascular System (CVS)

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II.ADJUVANTS

• Hyaluronidase
• Vasoconstrictors - Epinephrine
• Alkalinization
• (pH adjustment with sodium bicarbonate)
• Others

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Hyaluronidase I

• Enzyme that reversibly liquefies the interstitial
  barrier by depolimerization of the hyaluronic
  acid to tetrasaccharide
• 5-150 IU/mL (15 IU/mL in UK)
• Available as a powder in LA solution
• Orbital swelling due to rare allergic reactions
  or excessive doses and orbital pseudotumour

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Hyaluronidase II

• Addition of hyaluronidase to mixture of
  lidocainebupivacaine decrease onset time during
  retrobulbar anesthesia
• Addition of both epinephrine and hyaluronidase to
  pH-adjusted bupivacaine prolongs the duration of
  action during peribulbar block

Nicoll et al. Anesth Analg1986 Zahl et al.
Anesthesiology 1990
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Vasoconstrictors I

• Optimal concentration of epinephrine is 1200000
  (5 µg/mL)
• Recommended dose 3-5 µg/kg
• Absorption of the local anesthetic is reduced
• Thus, avoids high concentrations of LA in the
  plasma
• Allows higher dose administration

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Vasoconstrictors II

• Increase duration of block particularly short
  acting LA
• Minimize bleeding from small vessels
• May cause vasoconstriction of the ophthalmic
  artery compromising retinal circulation
• Epinephrine containing solutions should be
  avoided in elderly suffering from cerebrovascular
  and cardiovascular diseases

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Epinephrine

• Addition of epinephrine to lidocaine and
  mepivacaine markedly prolongs the duration of
  action (in addition to the vasocontriction and
  physochemical properties like local binding or
  intrinsic vasoactivity may contribute)
• However, addition of epinephrine to prilocaine,
  etidocaine (hardly prolongs the duration of
  action), and bupivacaine (is relatively small)

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Alkalinization

• Local anesthetics penetrate nerve cell membranes
  in non-ionized form and intracellularly in their
  ionized form
• Addition of sodium bicarbonate to LA (which are
  weak bases) increases their pH thus decreasing
  the ionized/nonionized ratio
• 30-50 reduction in onset time
• Extent and quality of block improved

Recommended doses for avoiding precipitation Lidoc
aine, Prilocaine or Mepivacaine 9 mL 1 mL 8.4
NaHCO3 Bupivacaine,Levobupivacaine or Ropivacaine
9.9 mL 0.1 mL 8.4 NaHCO3
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Short acting LA
Lidocaine
Prilocaine
Mepivacaine
Bupivacaine
Ropivacaine
Levobupivacaine

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Others

• Clonidine
• Mhajed et al, Reg Anesth 1996
• Connely et al. Reg Anesth Pain Med 1999
• Temperature
• Onset time decreases for all LA at body
  temperature
• Mixture
• Lidocaine-bupivacaine-hyaluronidase-epinephrine-ve
  curonium
• Reah et al. Anaesthesia 1998

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PreservativesPreserves the stability of LA drugs
in solution

• PABA (such as methy/ethyl or propyl paraben)
• Metabisulfite (sodium bisulfite)
• Ethylendiaminetetraacetate (EDTA)

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PABA

• Parabens are aliphatic esters of PABA
• Sodium benzoat and benzoic acid are not
  chemically parabens but close relation to
  structure might cause cross-reactivity with
  parabens
• Inhibit growth of fungi and yeast (less
  antibacterial) in multidose vials
• However, all parabens have been removed from the
  contemporary formulations, currently packaged as
  single-dose vials
• Of importance, ester based LA drugs like
  procaine, 2-chloroprocaine or tetracaine
  structurally related to PABA can be metabolized
  to PABA derivatives (30 skin reaction)

DiFazio and Rowlingson. Additives to local
anesthetic soutions. MacPherson Pharmaceutics for
the anaesthetist. Anaesthesia 2001
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• Metabusulfite (sodium bisulfite)
• An antioxidant to prevent breakdown of
  epinephrine in LA solution containing epinephrine
• Provides greater stability and shell life
  (usually pH?4.5)
• In case of low pH, this preservative leads to
  formation of SO2 and sulfurous acid (neurotoxic)

• EDTA
• added 2-chloroprocaine instead of metabisulfit is
  also potentially neurotoxic secondary to
  chelation of calcium ions in paraspinal muscles
  leading to severe muscle spasms

DiFazio and Rowlingson. Additives to local
anesthetic soutions.
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Adverse effects due to additives

• Patients at risk
• Children, especially neonates
• Patienst receiving TPN
• Patients receiving long term parenteral therapy
• Patients in ICU
• Patients suffering from chronic pain with
  indwelling pump systems

MacPherson Pharmaceutics for the anaesthetist.
Anaesthesia 2001
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Levobupivakain

• Bupivakainden daha mi az toksik?
• Bupivakain kadar potent mi?
• Bupivakainin yerini alabilir mi?

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Peribulber anestezi

• Di Donato et al. Efficacy and comparison of 0.5
  levobupivacaine with 0.75 ropivacaine for
  peribulbar anaesthesia in cataract surgery. Eur J
  Anaesthesiol 2006
• 208 hasta,katarakt operasyonu
• 0.5 Levo-6 mL
• 0.75 Ropivakain-6 mL
• Levobupivakain ile duyu ve motor blogun baslamasi
  daha erken bitmesi daha geç

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Peribulber anestezi

• Magalhaes et al.Racemic bupivacaine,
  levobupivacaine and ropivacaine in regional
  anesthesia for ophthalmology- a comparative
  study. Rev Assoc Med Bras 2004
• 97 hasta, katarakt cerrahisi
• 7 mL, 0.75 Bupi, Levo, Ropi
• Benzer anestezik etkinlik
• Göziçi basincina etki benzer
• Hastalarin yasli olmasi ve yüksek volüm
  kullanilmasi nedeniyle Levo ve Ropi daha uygun

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Side Effects

• Lokal anestezik ilaca bagli
• Toksisite
• SSS
• KVS
• Nörotoksisite (Lidokain, klorprokain)
• Allerji
• Methemoglobinemi ( Prilokain)
• Eklenen vazokonstriktöre bagli
• Yönteme bagli

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Cardiovascular System

• Hizli Na kanallarinin blokaji
• Iletimde yavaslama
• QRS kompleksinde genisleme ve PQ intervalinde
  uzama
• AV blok ve aritmiler
• Kardiyak mitokondriyal enerji metabolizmasinda
  blokaj
• SSS aracili kardiyak disritmiler

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Cardiotoxic effect

• Iki asamalidir
• Önce sempatik aktivasyon ile tasikardi, HT
• Sonra aritmi ve kardiyak depresyon
• BupivakaingtLevobupivakaingtRopivakain

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Cardiotoxicity

• Bupivacaine
• Na kanallarindan yavas ayrildigindan selektif
  kardiyak etkileri var
• Kalpte elektriksel iletiyi baskilar
• Ventriküler aritmilere zemin hazirlar
• Elektromekanik disosiasyona yol açar

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Sodyum mmol/L Osmolality pH H mmol/L
Bupivakain 0.25 133 272 6.96 109
Bupivakain 0.5 134 287 6.74 182
Bupivakain 0.75 125 281 6.57 269
Ropivakain 0.2 143 292 6.82 152
Ropivakain 0.5 126 287 6.65 222
Levobupivakain 0.25 149 308 6.42 379
Levobupivakain 0.5 151 322 6.04 914
Levobupivakain 0.75 151 334 5.85 1413
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IV Levobupivakain

• Epidural anestezi sirasinda yanlislikla 19 mL
  0.75 Levo iv enjeksiyonu
• Konusma bozuklugu, eksitasyon
• Nöbet ve KVS bulgulari yok
• 10 dk sonra plazma düzeyi 2.7 µg/mL
• Bupivakain için toksik doz 2 - 4 µg/mL

Anesth Analg 1999
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Levobupivakain-SSS toksisitesi

• Kortikal ve subkortikal düzeylerde nöronal
  desenkronizasyon
• Santral inhibitör yolagin blogu
• KVS toksik belirtilerinden önce olusur
• Levobupivakain ile bupivakainden daha az
  nörotoksisite
• Hayvan çalismalarinda konvülsiyona yol açan doz
  (mg/kg) bupivakainden 40 daha fazla

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Levobupivakain-SSS toksisitesi

• Gönüllülerde bir çalisma
• 40 mg intravenöz bupivakain veya levobupivakain
• Bupivakain 91 SSS semptomlari
• Levobupivakain 64 SSS semptomlari

Nimmo W, Sanderson B. ESA abstract 1988
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Levobupivakain-KVS toksisitesi

• Tüm hayvan çalismalarinda bupivakainle
  karsilastirildiginda üstün kardiyak güvenlik
  profili
• Yüksek dozlarda aritmi insidansi
• Bupivakainden 4 misli daha az
• 3.4 kez daha kisa süreli
• Kendiliginden düzelir

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Levobupivakain-KVS toksisitesi

• Levobupivakain ve bupivakainin KVS etkileri
  gönüllülerde IV verilim

Barsley H, et al. Br J Clin Pharmacol 1998
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Levobupivakain-KVS toksisitesi

• 63 y, prostatektomi, genel anestezi
• Yanlislikla IV 125 mg Levobupivakain
• 5 dk sonra hipotansiyon, hafif bradikardi (55/dk)
• Adrenalin bolus, noradrenalin inf
• Operasyon sorunsuz tamamlanmis!

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SSS-KVS etkileri karsilastirmasi

• 13 gönüllü
• Intravenöz infüzyon
• Levobupivakain
• Ropivakain
• 10 mg/dk
• SSS semptomlari görülene dek
• ECG, CO, MAP and KAH

Stewart J et al. Anesth Analg 2003
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Lokal Anestezikler
Metabolize Edildigi Yer Metabolitleri

• Kokain Plazma esterazlari (???) Benzil-ekgonin,
  Ekgonin metil ester, Ekgonin
• Ester Prokain Para amino benzoik asit(PABA),
  Dietil amino etanol
• Kloro-prokain Kloro amino benzoik asit
• Tetrakain p-butil amino benzoik asit
• Lidokain Mono etil glisin ksilid
• Glisin ksilid
• Amid Artikain(Kartikain) Karaciger
  (??) Artikainik asit
• Mepivakain Oksopipekolo-ksilid, Metil
  oksopipekolo-ksilid
• Prilokain O-tolidin,
• Nitrozotolidin
• Bupivakain Desbutil-bupivakain
• Hidroksi-bupivakain
• Ropivakain OH-pipekoloksilid
• 3 ,4 OH-ropivakain
• Levobupivakain Desbutil-bupivakain
• Hidroksi-bupivakain