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PHARMACOLOGY OF REGIONAL OPHTHALMIC ANESTHESIA Berrin Gunaydin, MD, PhD Gazi University Scool of Medicine Department of Anesthesiology Ankara, Turkey

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

2 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  AgentInitial investigatorDate  CocaineC 17 H 21 NO 4 Niemann1860  BenzocaineC 9 H 11 NO 2 Salkowski1895  Procaine C 13 H 20 N 2 O 2 Einhorn1904  DibucaineC 20 H 29 N 3 O 2 Meischer 1925  TetracaineC 15 H 24 N 2 O 2 Eisler1928  EtidocaineC 17 H 28 N Adams,Kronberg, Takman1972  Lidocaine C 14 H 22 N 2 OLöfgren, Lundquist1943  ClorprocaineC 13 H 19 CIN 2 O 2 Marks, Rubin1952  MepivacaineC 15 H 22 N 2 OEkenstam1957  Bupivacaine C 18 H 28 N 2 OEkenstam 1963  PrilocaineC 13 H 20 N 2 OLofgren1959  ArticaineC 13 H 20 N 2 O 3 S Rusching1969C H N O S  Ropivacaine C 17 H 26 N 2 O Ekenstam&Sandberg1996  Levobupivacaine Ekenstam&others 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)

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

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

6 6 pKa (25  C) Onset time PB (%)PotencyDuration ESTERS Cocaine8.7Slow98HighLong Procaine8.9Slow6LowShort Amethocaine8.5Slow76Medium AMIDES Lidocaine 7.7Fast64Medium Prilocaine7.8Fast55Medium Mepivacaine7.6Fast75Medium Etidocaine7.7Fast94HighLong Bupivacaine8.1Medium95HighLong Ropivacaine8.2Medium94MediumLong Levobupivacaine8.1Medium96HighLong Physicochemical properties of local anesthetics Lipid solubility Potency Protein binding Duration of action pKa Onset time

7 7 AYNA Bupivacaine, Etidocaine, Mepivacaine, Prilocaine, Ropivacaine Have asymmetric carbon molecule 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 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 10 Mechanism of action

11 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 11 Metabolism

12 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 Local anestheticsElimination Cocaine Procaine Amethocaine Lidocaine Prilocaine Mepivacaine Bupivacaine Ropivacaine Levobupivacaine ESTERS AMIDES

14 Metabolism Local anestheticsMetabolism-breakdown products Cocaine in plasma by pseudocholinesterase Benzil-ekgonin, Ekgonin metil ester, Ekgonin Procaine PABA, Dietil amino etanol Amethocaine 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, CH 3 oksopipekolo-ksilid Bupivacaine Desbutil-bupivakain Hidroksi-bupivakain Ropivacaine OH-pipekoloksilid (PPX) 3,4 OH-ropivakain Levobupivacaine Desbutil-bupivakain Hidroksi-bupivakain ESTERS AMIDES

15 15 Cocaineester of benzoic acid, excellent topical anesthetic (4-10%), only LA producing vasoconstriction at clinical concentrations, high potential for systemic toxicity ProcaineDerivative 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 AmethocaineButyl aminobenzoic acid derivative of procaine, potent,long acting, hydrolysis by plasma cholinesterase (slower than procaine), potential for systemic toxicity is HIGH Toxicity of ESTER TYPE LA Veering B. Local Anesthetics

16 16 LidocaineMost 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 Prilocainetoluidine derivative tertiary amine,clinical profile similar to lidocaine, LEAST TOXIC amino-amide LA, significant methemoglobinemia can occur >10 mg/kg MepivacaineStructurally 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 EtidocaineStructurally 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 BupivacaineHomologue of mepivacaine, greater anesthetic potency, prolonged duration of action, onset of analgesia is slow, MORE CARDIOTOXIC than equipotent doses of lidocaine RopivacaineS-enantiomer of bupivacaine, long acting LA, LESS ARRHYTHMOGENIC than bupivacaine Levobupivacaine Toxicity of AMIDE TYPE LA Veering B. Local Anesthetics

17 17

18 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

19 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)

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

21 21 Hyaluronidase I Enzyme that reversibly liquefies the interstitial barrier by depolimerization of the hyaluronic acid to tetrasaccharide 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

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: (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% NaHCO 3 Bupivacaine,Levobupivacaine or Ropivacaine 9.9 mL mL 8.4% NaHCO 3

27 Short acting LA Lidocaine Prilocaine Mepivacaine Bupivacaine Ropivacaine Levobupivacaine

28 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

29 Preservatives Preserves the stability of LA drugs in solution PABA (such as methy/ethyl or propyl paraben) Metabisulfite (sodium bisulfite) Ethylendiaminetetraacetate (EDTA)

30 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

31 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 SO 2 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.

32 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


34 34 Levobupivakain Bupivakain’den daha mı az toksik? Bupivakain kadar potent mi? Bupivakain’in yerini alabilir mi?

35 35 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 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

36 36 Peribulber anestezi Magalhaes et al.Racemic bupivacaine, levobupivacaine and ropivacaine in regional anesthesia for ophthalmology- a comparative study. Rev Assoc Med Bras 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

37 37

38 38 Side Effects Lokal anestezik ilaca bağlı Toksisite –SSS –KVS –Nörotoksisite (Lidokain, klorprokain) Allerji Methemoglobinemi ( Prilokain) Eklenen vazokonstriktöre bağlı Yönteme bağlı

39 39 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

40 40 Cardiotoxic effect İki aşamalıdır Önce sempatik aktivasyon ile taşikardi, HT Sonra aritmi ve kardiyak depresyon Bupivakain>Levobupivakain>Ropivakain

41 41 Cardiotoxicity Bupivacaine Na kanallarından yavaş ayrıldığından selektif kardiyak etkileri var Kalpte elektriksel iletiyi baskılar Ventriküler aritmilere zemin hazırlar Elektromekanik disosiasyona yol açar

42 Sodyum mmol/L OsmolalitypHH+ mmol/L Bupivakain % Bupivakain % Bupivakain % Ropivakain % Ropivakain % Levobupivakain % Levobupivakain % Levobupivakain %

43 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 µg/mL Anesth Analg 1999

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

45 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

46 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

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

48 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!

49 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

50 KokainPlazma esterazları (???)Benzil-ekgonin, Ekgonin metil ester, Ekgonin EsterProkainPara amino benzoik asit(PABA), Dietil amino etanol Kloro-prokainKloro amino benzoik asit Tetrakainp-butil amino benzoik asit LidokainMono etil glisin ksilid Glisin ksilid AmidArtikain(Kartikain)Karaciğer (??)Artikainik asit MepivakainOksopipekolo-ksilid, Metil oksopipekolo-ksilid PrilokainO-tolidin, Nitrozotolidin BupivakainDesbutil-bupivakain Hidroksi-bupivakain RopivakainOH-pipekoloksilid 3,4 OH-ropivakain LevobupivakainDesbutil-bupivakain Hidroksi-bupivakain Lokal Anestezikler Metabolize Edildiği Yer Metabolitleri

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