PHARMACOLOGY OF
REGIONAL OPHTHALMIC
ANESTHESIA
Berrin Gunaydin, MD, PhD
Gazi University Scool of Medicine
Department of Anesthesiology
Ankara, Turkey
www.berringunaydin.com
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
2
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Chronology of Amide Local Anesthetic Development
Agent
Initial investigator
Date
•
Cocaine
C17H21NO
4
Carl Koller, an ophthalmology
trainee
tookNiemann
cocaine orally and noticed 1860

•

numbness
Benzocaine in his tongueC9H11NO2
Salkowski
1895
Koller and Gartner reported topical cocaine anesthesia of the eye in
Procaine
C13H20N2O2
Einhorn
1904
animals and human (1884)

Dibucaine
C20H29N3O2
Meischer
1925

Tetracaine
C15H24N2O2
Eisler
1928

Etidocaine
C17H28 N202

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
Levobupivacaine
Adams,Kronberg, Takman
C17H26N2O
(Butterworth J. Clinical Pharmacology of Local Anesthetics)
Ekenstam&Sandberg
Ekenstam&others
1972
1996
1999
I.LOCAL ANESTHETICS (LA)
Chemical structure
Aromatic ring-intermediate chain-amino group
• Ester linkage-COO
• Amid linkage-NHCO
Veering B. Local Anesthetics
4
Properties of local anesthetics
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Ionization
Lipid solubility
Protein binding
Chirality
Mechanism of action
Metabolism and elimination
Toxicity
5
Physicochemical properties of local anesthetics
pKa
PB (%)
(25C)
Onset
time
Potency
Duration
ESTERS
Cocaine
8.7
Slow
98
High
Long
Procaine
8.9
Slow
6
Low
Short
Lipid solubility
Potency
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
Protein binding
Duration of action
pKa
Onset time
6
Bupivacaine, Etidocaine, Mepivacaine,
Prilocaine, Ropivacaine
Have asymmetric carbon molecule
AYNA
Levobupivacaine, Ropivacaine
are chiral
7
• 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
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
9
Mechanism of action
10
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
11
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)
12
Elimination
ESTERS
Local anesthetics
Cocaine
Procaine
Amethocaine
AMIDES
Lidocaine
Prilocaine
Mepivacaine
Bupivacaine
Ropivacaine
Levobupivacaine
Elimination
Metabolism
ESTERS
Local anesthetics
Metabolism-breakdown products
Benzil-ekgonin, Ekgonin metil
ester, Ekgonin
Cocaine
Procaine
PABA,
in plasma by pseudocholinesterase
Dietil amino etanol
p-butil amino benzoik asit
Amethocaine
AMIDES
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
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
Veering B. Local Anesthetics
15
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 >10 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
16
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
18
Systemic Toxicity
– 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)
Cardiovascular collapse
Coma
Convulsions
Myoclonic jerks
Tremors
Garrulousness
Circumoral numbness
Omnius feelings
Tinnitus, Vertigo
Metalic ….
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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
21
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
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
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
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)
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
Short acting LA
Lidocaine
Prilocaine
Mepivacaine
Bupivacaine
Ropivacaine
Levobupivacaine
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-epinephrinevecuronium
Reah et al. Anaesthesia 1998
Preservatives
Preserves the stability of LA drugs in solution
• PABA (such as methy/ethyl or propyl paraben)
• Metabisulfite (sodium bisulfite)
• Ethylendiaminetetraacetate (EDTA)
PABA
– Parabens are aliphatic esters of PABA
– Sodium benzoat and benzoic acid are not chemically
parabens but close relation to structure might cause crossreactivity 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 singledose vials
– Of importance, ester based LA drugs like procaine, 2chloroprocaine 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
• Metabusulfite (sodium • EDTA
bisulfite)
• added 2• An antioxidant to prevent
chloroprocaine
breakdown of epinephrine
instead of metabisulfit
in LA solution containing
is also potentially
epinephrine
neurotoxic secondary
• Provides greater stability
to chelation of
and shell life (usually pH4.5)
calcium ions in
• In case of low pH, this
paraspinal muscles
preservative leads to
leading to severe
formation of SO2 and
sulfurous acid (neurotoxic)
muscle spasms
DiFazio and Rowlingson. Additives to local anesthetic soutions.
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
Levobupivakain
• Bupivakain’den
daha mı az toksik?
• Bupivakain kadar
potent mi?
• Bupivakain’in yerini
alabilir mi?
34
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
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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
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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
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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
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37
Side Effects
Lokal anestezik ilaca bağlı
• Toksisite
– SSS
– KVS
– Nörotoksisite (Lidokain, klorprokain)
• Allerji
• Methemoglobinemi ( Prilokain)
Eklenen vazokonstriktöre bağlı
Yönteme bağlı
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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
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Cardiotoxic effect
İki aşamalıdır
• Önce sempatik aktivasyon ile taşikardi, HT
• Sonra aritmi ve kardiyak depresyon
• Bupivakain>Levobupivakain>Ropivakain
40
Cardiotoxicity
Bupivacaine
• Na kanallarından yavaş ayrıldığından
selektif kardiyak etkileri var
• Kalpte elektriksel iletiyi baskılar
• Ventriküler aritmilere zemin hazırlar
• Elektromekanik disosiasyona yol açar
41
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
İV Levobupivakain
Anesth Analg 1999
• 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
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
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
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
Levobupivakain-KVS toksisitesi
Levobupivakain ve bupivakain’in KVS etkileri – gönüllülerde
İV verilim
Barsley H, et al. Br J Clin Pharmacol 1998
Levobupivakain-KVS toksisitesi
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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!
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
Lokal Anestezikler
Metabolize Edildiği Yer
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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
Glisin ksilid
Amid Artikain(Kartikain)
Mepivakain
Prilokain
Nitrozotolidin
Bupivakain
Hidroksi-bupivakain
Ropivakain
3 ,4 OH-ropivakain
Levobupivakain
Hidroksi-bupivakain
Mono etil glisin ksilid
Karaciğer (??)
Artikainik asit
Oksopipekolo-ksilid, Metil oksopipekolo-ksilid
O-tolidin,
Desbutil-bupivakain
OH-pipekoloksilid
Desbutil-bupivakain