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PHARMACOLOGY OF REGIONAL OPHTHALMIC ANESTHESIA

PHARMACOLOGY OF REGIONAL OPHTHALMIC ANESTHESIA. Berrin Gunaydin, MD, PhD Gazi University Scool of Medicine Department of Anesthesiology Ankara, Turkey www.berringunaydin.com. OUTLINE.

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PHARMACOLOGY OF REGIONAL OPHTHALMIC ANESTHESIA

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  1. PHARMACOLOGY OF REGIONAL OPHTHALMIC ANESTHESIA Berrin Gunaydin, MD, PhD Gazi University Scool of Medicine Department of Anesthesiology Ankara, Turkey www.berringunaydin.com

  2. 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

  3. Chronology of Amide Local Anesthetic Development • 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) • Agent Initial investigator Date • CocaineC17H21NO4 Niemann 1860 • BenzocaineC9H11NO2 Salkowski1895 • ProcaineC13H20N2O2 Einhorn 1904 • DibucaineC20H29N3O2 Meischer 1925 • TetracaineC15H24N2O2 Eisler 1928 • Etidocaine C17H28 N202Adams,Kronberg, Takman1972 • LidocaineC14H22N2O Löfgren, Lundquist 1943 • ClorprocaineC13H19CIN2O2Marks, Rubin1952 • MepivacaineC15H22N2O Ekenstam 1957 • BupivacaineC18H28N2O Ekenstam 1963 • PrilocaineC13H20N2O Lofgren 1959 • ArticaineC13H20N2O3S Rusching 1969 • RopivacaineC17H26N2O Ekenstam&Sandberg 1996 • Levobupivacaine Ekenstam&others1999 (Butterworth J. Clinical Pharmacology of Local Anesthetics)

  4. Ester linkage-COO I.LOCAL ANESTHETICS (LA) Chemical structureAromatic ring-intermediate chain-amino group • Amid linkage-NHCO Veering B. Local Anesthetics

  5. Properties of local anesthetics • Ionization • Lipid solubility • Protein binding • Chirality • Mechanism of action • Metabolism and elimination • Toxicity

  6. Physicochemical properties of local anesthetics Lipid solubility Potency Protein binding Duration of action • pKa • Onset time

  7. Bupivacaine, Etidocaine, Mepivacaine, Prilocaine, Ropivacaine • Have asymmetric carbon molecule AYNA Levobupivacaine, Ropivacaine are chiral

  8. 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

  9. 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

  10. Mechanism of action

  11. 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

  12. Elimination • Ester local anesthetics are almost entirely eliminated in plasma by ester breakdown except cocaine • Amide local anesthetics except prilocaine are metabolized in liver (>90%) • 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)

  13. Elimination ESTERS AMIDES

  14. Metabolism ESTERS AMIDES

  15. Toxicity of ESTER TYPE LA 15 Veering B. Local Anesthetics

  16. Toxicity of AMIDE TYPE LA 16 Veering B. Local Anesthetics

  17. 17

  18. 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 18

  19. 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) 19

  20. II.ADJUVANTS Hyaluronidase Vasoconstrictors - Epinephrine Alkalinization (pH adjustment with sodium bicarbonate) Others 20

  21. 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 21

  22. Hyaluronidase II • Addition of hyaluronidase to mixture of lidocaine+bupivacaine 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

  23. Vasoconstrictors I Optimal concentration of epinephrine is 1:200000 (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

  24. 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

  25. 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)

  26. 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 Lidocaine, Prilocaine or Mepivacaine 9 mL + 1 mL 8.4% NaHCO3 Bupivacaine,Levobupivacaine or Ropivacaine 9.9 mL + 0.1 mL 8.4% NaHCO3

  27. 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-vecuronium Reah et al. Anaesthesia 1998

  28. PreservativesPreserves the stability of LA drugs in solution • PABA (such as methy/ethyl or propyl paraben) • Metabisulfite (sodium bisulfite) • Ethylendiaminetetraacetate (EDTA)

  29. 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

  30. 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.

  31. 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

  32. Levobupivakain • Bupivakain’den daha mı az toksik? • Bupivakain kadar potent mi? • Bupivakain’in yerini alabilir mi?

  33. 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 bloğun başlaması daha erken bitmesi daha geç

  34. 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 basıncına etki benzer • Hastaların yaşlı olması ve yüksek volüm kullanılması nedeniyle Levo ve Ropi daha uygun

  35. Side Effects Lokal anestezik ilaca bağlı • Toksisite • SSS • KVS • Nörotoksisite (Lidokain, klorprokain) • Allerji • Methemoglobinemi ( Prilokain) Eklenen vazokonstriktöre bağlı Yönteme bağlı

  36. Cardiovascular System • Hızlı Na+ kanallarının blokajı • İletimde yavaşlama • QRS kompleksinde genişleme ve PQ intervalinde uzama • AV blok ve aritmiler • Kardiyak mitokondriyal enerji metabolizmasında blokaj • SSS aracılı kardiyak disritmiler

  37. Cardiotoxic effect İki aşamalıdır • Önce sempatik aktivasyon ile taşikardi, HT • Sonra aritmi ve kardiyak depresyon • Bupivakain>Levobupivakain>Ropivakain

  38. Cardiotoxicity Bupivacaine • Na kanallarından yavaş ayrıldığından selektif kardiyak etkileri var • Kalpte elektriksel iletiyi baskılar • Ventriküler aritmilere zemin hazırlar • Elektromekanik disosiasyona yol açar

  39. İV Levobupivakain • Epidural anestezi sırasında yanlışlıkla 19 mL % 0.75 Levo iv enjeksiyonu • Konuşma bozukluğu, eksitasyon • Nöbet ve KVS bulguları yok • 10 dk sonra plazma düzeyi 2.7 µg/mL • Bupivakain için toksik doz 2 - 4 µg/mL Anesth Analg 1999

  40. Levobupivakain-SSS toksisitesi • Kortikal ve subkortikal düzeylerde nöronal desenkronizasyon • Santral inhibitör yolağın bloğu • KVS toksik belirtilerinden önce oluşur • Levobupivakain ilebupivakainden daha az nörotoksisite • Hayvan çalışmalarında konvülsiyona yol açan doz (mg/kg) bupivakain’den %40 daha fazla

  41. Levobupivakain-SSS toksisitesi • Gönüllülerde bir çalışma • 40 mg intravenöz bupivakain veya levobupivakain • Bupivakain %91 SSS semptomları • Levobupivakain %64 SSS semptomları Nimmo W, Sanderson B. ESA abstract 1988

  42. Levobupivakain-KVS toksisitesi • Tüm hayvan çalışmalarında bupivakainle karşılaştırıldığında üstün kardiyak güvenlik profili • Yüksek dozlarda aritmi insidansı • Bupivakain’den 4 misli daha az • 3.4 kez daha kısa süreli • Kendiliğinden düzelir

  43. Levobupivakain-KVS toksisitesi Levobupivakain ve bupivakain’in KVS etkileri – gönüllülerde İV verilim Barsley H, et al. Br J Clin Pharmacol 1998

  44. Levobupivakain-KVS toksisitesi • 63 y, prostatektomi, genel anestezi • Yanlışlıkla IV 125 mg Levobupivakain • 5 dk sonra hipotansiyon, hafif bradikardi (55/dk) • Adrenalin bolus, noradrenalin inf • Operasyon sorunsuz tamamlanmış!

  45. SSS-KVS etkileri karşılaştırması • 13 gönüllü • Intravenöz infüzyon • Levobupivakain • Ropivakain • 10 mg/dk • SSS semptomları görülene dek • ECG, CO, MAP and KAH Stewart J et al. Anesth Analg 2003

  46. Lokal Anestezikler Metabolize Edildiği Yer Metabolitleri • Kokain Plazma esterazları (???) 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) Karaciğer (??) 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

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