Title: Local Anesthetics
1Local Anesthetics
Kevin Armstrong MD Department and Anesthesia and
Perioperative Medicine November 2007
2Important points
- History
- Some differences
- How they work
- Test dose
- Onset
- Adjunvants
- Lipid rescue
- Newer delivery systems
- Tumescence
3History of Local Anesthetics
- Cocaine isolated 1856
- 1884 cocaine used in occular surgery
- 1880s Regional anesthesia plexus
- 1898 cocaine used in spinal anesthesia
- 1905 1st synthetic LA (procaine) introduced
- 1943 lidocaine synthesized
- Mepivacaine (1957), Bupiv (63), Ropiv (96)
4Differences in structure of local anesthetics
- Esters versus Amides
- Affect metabolism
- Affect toxicity
- Allergic potential
5Types of Local Anesthetics
6Types of Local Anesthetics
Esters Procaine chloroprocaine tetracaine cocaine
7Types of Local Anesthetics
Amides Lidocaine prilocaine mepivacaine bupiva
caine ropivacaine
8sitemaker.med.umich.edu
9Mechanism of Action for Local Anesthetics
- Block propagation of action potential along
neuron - prevent depolarization through blockade of Na
Channel - voltage gated K channels also blocked by LA
- but the affinity of receptor much less
- Lido 4-10x less Bupiv 10-80x less
- NB K channel involved in repolarization
- Voltage gated Na and Ca channels in DRG are
similar
10Ty
11Mechanism of Action for Local Anesthetics
Domain 4 S4 subunit
12FIGURE 1. Model of the fourth homologous domain
(D4) of the human skeletal muscle sodium channel
(hNaV1.4) with the S4 segment depicted as a
rotating cylinder. Four S4 residues are shown
Arg1451 (R2), Leu1452, Ala1453, and Arg1454 (R3).
The positions of the residues around the S4
segment roughly correspond to those of an
helical model. A depolarizing rotation transfers
R2 and R3 from an intracellularly to an
extracellularly accessible crevice, whereas
Leu1452 and Ala1453 are translocated in the
opposite direction. Coupled Movements in
Voltage-gated Ion Channels Richard Horn Journal
of General Physiology, Volume 120, Number 4,
October 2002 449-453
13(No Transcript)
14Tetrododoxin
- Toxin from puffer fish
- Blocks the Na channel
- Used in research
- Blocks from the outer side of cell
15Local Anesthetics
- Activity of local anesthetics is a function of
their lipid solubility, diffusibility, affinity
for protein binding, percent ionization at
physiologic pH, and vasodilating properties.
16Local Anesthetics
- Lipid solubility is an important characteristic.
Potency is related to lipid solubility, because
90 of the nerve cell membrane is composed of
lipid. This improve transit into the cell membrane
17Local Anesthetics
- Diffusibility (how well the LA diffuses diffuses
through tissue to its site of action) will also
influences the speed of action onset.
18Local Anesthetics
- Protein binding is related to the duration of
action. The site of action (the Na channel) is
primarily protein in a lipid environment. Binding
affinity will thus affect duration of action. - Protein binding also plays a part in the
availability of the drug as LA binds to
lipoproteins in the blood stream. - And transfer to fetuses
19Summary
- Clinical Pharmacology
- The potency of Local Anesthetics, their onset and
duration of action are primary determined by
physicochemical properties of various agents and
their inherent vasodilator activity of same local
anesthetics. - Lipid solubility is the primary determinant of
anesthetic potency and it is expressed as lipid
water Partition Coefficient - Protein binding influences the duration of action
- pKa of Local anesthetics determines the onset of
action - The addition of vasoconstrictors, such as
epinephrine or phenylephrine can prolong duration
of action of local anesthetics, decrease their
absorption (and the peak plasma level) and
enhance the blockade.
20From NYSORA web site
Properties of Local Anesthetic Agents
21pKa
- Understanding LA as they relate to pKa
22- The pH of the tissue and pKa of the agentThe pH
and pKa are the most important factors. The pH of
the tissue determines the ratio of ionized to
non-ionized drug. This ratio, in turn, depends on
the pKa of the drug. Understanding the ionization
is necessary to understanding the drug's
pharmacological characteristics, such as onset,
duration and pharmacodynamics.
23Henderson Hasselbalch equation
- The basis for understanding this equation is
knowing the pKa of the agents, remembering that
pKa equals the pH where the ionized and
non-ionized forms are at equilibrium. In other
words, 50 of each form is present. Local
anaesthetics are weak bases. For bases, the pKa -
pH relationship is described by the Henderson
Hasselbalch equation, as follows - pKa - pH log_ionized
- non-ionized
24Effect of pH, and pKa
- The pKa of amides ranges from 7.6 to 8.1. At
physiologic pH (7.4), most of the local
anaesthetic is in the ionized state (a charged
base). For example, lidocaine has a pKa of 7.9.
The above formulat determines that at physiologic
pH, lidocaine exists in a ratio of 31 ionized to
non-ionized - 7.9 - 7.4log ionized/non-ionized
- 0.5 log ionized/non-ionized
- 100.5ionized/non-ionized
- 3ionized
- 1non-ionized
25Low pH
- The pH of the tissue becomes relevant in
conditions of infection or inflammation, in which
the natural pH may be more acidic. This acidity
results in a greater proportion of the ionized
(charged) form of the anaesthetic, thereby
delaying or preventing the onset of action. For
example, if lidocaine (pKa 7.9) is administered
into an area of infection (pH 4.9) emanating from
a dental abscess, then - 7.9 - 4.9 log ionized/non-ionized
- 103 ionized/non-ionizedThe
resulting ratio of 1,0001 ionized to non-ionized
indicates a poorer penetration into the nerve
tissue and therefore a less effective nerve block
26Onset
- Is there a difference in the onset of different
local anesthetics?
27Onset from NYSORA web site
28Onset
- Does onset influence you practice?
- Where?
- OB
- RA
- Chronic pain
29Onset of Action
30Onset
A comparison of warmed Bupivacaine and lidocaine
forepidural top up for C/S BJA 1994 72
221-3 Warming improved onset for lidocaine to pin
prick Test dose lidocaine and epinephrine time
0 Inadequate anesthesia bupiv x2, warmed B 1 and
warmed L x 2
plt0.05 to all other groups
31Onset
- Studies looking at bupiv vs lidocaine
- ClarkV, McGradyE, SugdenC, DicksonJ, McLeodG.
Speed of onset of sensory block for elective
extradural Caesarean section choice of agent and
temperature of injectate. British Journal of
Anasthesia 1994 72 221 3. - 2
- NortonAC, DavisAG, SpicerRj. Lignocaine 2 with
adrenaline for epidural Caesarean section a
comparison with 0.5 bupivacaine. Anasthesia
1988 43 844 9. - 3
- ReidJAThorburnJ. Extradural bupivacaine or
lignocaine for elective Caesarean section the
role of maternal posture. British Journal of
Anasthesia 1988 61 149 53. - 4
- PaechMj. Epidural anasthesia for Caesarean
section a comparison of 0.5 bupivacaine and 2
lignocaine both with adrenaline. Anasthesia and
Intensive Care 1988 16 187 96
32- Extending low-dose epidural analgesia for
emergency - Caesarean section A comparison of three solutions
- D. N. Lucas, Anaesthesia, 1999, 54, pages
11731177 - Summary
- We conducted a prospective double-blind
randomised trial to compare bupivacaine 0.5 a
50 50 mixture of bupivacaine 0.5/lignocaine 2
with 1 200 000 adrenaline (final
concentration) and lignocaine 2 with 1 200
000 adrenaline for converting a low-dose labour
epidural into a block adequate for emergency
Caesarean section. Ninety patients were studied,
30 in each group. There was no difference between
the groups in the time taken for bilateral loss
of cold sensation to reach T4. Onset time was
unaffected by the existing sensory level
pre-Caesarean section top-up
33Onset
- B BL
L - (n¼30) (n¼30)
(n¼30) - Duration of epidural h 12.6 (6.2)
1.4 (5.6) 11.8 (5.3) - No. of low-dose top-ups 7.4 (5)
7.2 (4.1) 7.9 (4.8) - dose of bupiv labourmg 92.0 (57)
92.3 (49) 95.2 (48) - Time since l top-up min 92.3 (45.1)
75.1 (33.2) 69.3 (40.9) - Sensory level pre top-up T10 T10 T10
- Time to T4 min 14 12 10
- (1119.3
625 (8.817 638)
(918.5 636) - Maximum height of block T3 T3 T3
34Whats Available from NYSORA web site
Ropivacaine is a long-acting, amide-type local
anesthetic. Its structure and pharmacokinetics
are similar to those of bupivacaine, however,
ropivacaine exhibits significantly better
cardiotoxicity profile compared to bupivacaine.
Duration of action for ropivacaine ranges 2.5-5.9
hours for epidural block to 8-13 hours for
peripheral nerve block. Ropivacaine is also less
lipid soluble and cleared via the liver more
rapidly than bupivacaine. Some studies have shown
less motor blocking effects of ropivacaine than
that of bupivacaine. Due to its better safety
profile and significantly better sensory-motor
differentiation, Ropivacaine is currently the
long-acting anesthetic of choice in our practice.
35From NYSORA web site
Mepivacaine is a local anesthetic of the amide
type with an intermediate duration of action.
Mepivacaine is used for infiltration and
transtracheal anesthesia, and peripheral,
sympathetic, regional (Bier block), and epidural
nerve blocks. Compared with lidocaine,
mepivacaine produces less vasodilatation and has
a more rapid onset and longer duration of action.
In our practice, this is the 1
intermediate-acting local anesthetic to use for
peripheral nerve blocks.
36Duration of Local anesthetics
- Dependent on
- 1)agent
- 2)site
- 3)adjuvant
- 4)route
- 5)vascularity
37Duration of Local anesthetics
Examples Lidocaine bupivacaine local
infiltration 30-60 min 120-240 minor nerve
block 60-120 180-360 major nerve
block 120-240 360-720 Epidural 30-90 180-300 a
ddition of epi improved improved
38From NYSORA web site
Local Anesthetic Time Line (minutes)
39Intravenous Lidocaine in Chronic Pain
- Tetrodotoxin TTX
- Some Na channels resistant to TTX
- These may be important in Chronic pain
- With Chronic pain probably up/down regulation
receptor types - IV lidocaine may work at these recptors
40Intravenous lidocaine in Chronic pain
- Systemic administration of local anesthetic
agents to relieve neuropathic pain.AUTHORS'
CONCLUSIONS Lidocaine and oral analogs were safe
drugs in controlled clinical trials for
neuropathic pain, were better than placebo, and
were as effective as other analgesics. Future
trials should enroll specific diseases and test
novel lidocaine analogs with better toxicity
profiles. More emphasis is necessary on outcomes
measuring patient satisfaction to assess if
statistically significant pain relief is
clinically meaningful - Cochrane Database Syst Rev. 2005 Oct
19(4)Challapalli V,
41Intravenous Lidocaine
- Intra-Op Lidocaine and Ketamine Effect on
Postoperative Bowel Function - This study is currently recruiting
patients.Verified by University of Saskatchewan
September 2005 - Purpose
- Bowel function after bowel surgery is delayed
(postoperative ileus)by both opiates and the
surgery itself. We hypothesized that decreasing
opiate use by other analgesics will speed the
return of bowel function after surgery. Lidocaine
and Ketamine are drugs that appear to be
synergistic and do not slow peristalsis. This
study is a Randomised Controlled Trial of
Lidocaine Infusion Plus Ketamine Injection versus
Placebo to to determine whether they will
decrease opiate use and then whether decreased
opiate use will speed the return of bowel
function.
42Intravenous Lidocaine
- Forty patients undergoing radical retropubic
prostatectomy were studied with one half of the
patients receiving a lidocaine bolus (1.5 mg/kg)
and infusion (3 mg/min) the other half received
a saline infusion. Lidocaine-treated patients
first experienced flatulence in a significantly
shorter time (P lt 0.01) than control patients.
Lidocaine patients' hospital stay was also
significantly shorter (P lt 0.05). IV lidocaine
initiated before anesthesia and continued 1 h
postoperatively significantly sped up the return
of bowel function. Lidocaine patients were also
more comfortable postoperatively - Lidocaine blood levels were variable (1.3-3.7
micro g/mL), but none approached a toxic level
(gt5 micro g/mL). - Lidocaine-treated patients had shorter hospital
stays, less pain, and faster return of bowel
function. In this population, lidocaine infusion
can be a useful adjunct in anesthetic management. - (Anesth Analg 199886235-9) Groudine, Scott B.
43IV Local Anesthetics
- Effect of ciprofloxin on the pharmacokinetics of
intravenous lidocaine. - BACKGROUND AND OBJECTIVE Recent studies have
suggested that cytochrome P-450 isoenzyme 1A2 has
an important role in lidocaine biotransformation.
We have studied the effect of a cytochrome P-450
1A2 inhibitor, ciprofloxacin, on the
pharmacokinetics of lidocaine - ). CONCLUSION The plasma decay of intravenously
administered lidocaine is modestly delayed by
concomitantly administered ciprofloxacin.
Ciprofloxacin may increase the systemic toxicity
of lidocaine - Eur J Anaesthesiol. 2005 Oct22(10)795-9.
Isohanni
44Safety Issues Related to Local Anesthetics
45Safety Issues Related to Local Anesthetics
- Related to
- Drug
- Dose
- Site of administration
- Condition of the patient
46CNS Toxicity
Tends to occur first (relative to CVS
toxicity) See excitatory signs and symptoms
first Followed by depressant signs Circumoral
and tongue numbness Lightheadedness and
tinnitus Visual disturbance Muscle
twitching Convulsions COMA Respiratory
arrest CVS depression
47CVS Toxicity
Alteration in the excitatory mechanism slower
depolarization decreased HR prolonged PR
interval widened QRS Arrythmias bradycardia ec
topic beats ventricular fibrillation Decreased
cardiac output on the basis of HR contractility
48Treatment of Toxicity
49Treatment of Toxicity
Identify the problem signs and
symptoms temporal relationship IV
injection 40-60 min post for peak plasma
levels CNS treatment with benzodiazepines
50Treatment of Toxicity
CVS signs and symptoms CNS effects CVS
effects arrythmia QRS change signs of
collapse fall in BP With CVS toxicity The agent
is an important consideration
51Treatment of Toxicity
When there is CVS collapse ACLS A B
Cs defibrillation Epinephrine Vasopressin Lidoca
ine? Bretylium? Amiodarone
52Lipid Rescue
53Nanoparticles
- Scavenging Nanoparticles An Emerging Treatment
for Local Anesthetic Toxicity - The authors of the lipid-based studies speculated
that four mechanisms may play a role in the
success of resuscitation. In their primary
hypothesis, the lipid infusion may create plasma
lipid droplets capable of segregating uncharged
bupivacaine molecules from plasma, which makes
them unavailable for interaction at their target
sites. The authors supported this theory by
showing that bupivacaine molecules preferentially
segregated from plasma to their lipid infusion in
a 112 ratio. 29 In two of the other proposed
mechanisms, the lipid acts within tissue. Here,
lipid or its component fatty acids either
interact in a clinically significant way with
tissue bupivacaine molecules or directly overcome
bupivacaines inhibitory effect on cellular
metabolism by supplying substrate for cellular
energy production.30,31 30, 31 Finally, the
lipid infusion may act on nitric oxide pathways
and reverse bupivacaines inhibitory effects. 29
Building on this work and assuming that
sequestration of bupivacaine is an important
aspect of resuscitation in the aforementioned
lipid-based studies, some investigators have
hypothesized even greater segregation of
bupivacaine into lipid may occur with large
reductions in particle size to the dimension of
the nanometer. - Regional Anesthesia andPMJuly - May, 2005 pp
380-384 Renehan,
54Regional Anesthesia andPMJuly - May, 2005 pp
380-384 Renehan,
55Regional Anesthesia andPMJuly - May, 2005 pp
380-384 Renehan,
56Toxicty
Email
57Special preparations
EMLA lidocaine 2.5 prilocaine 2.5 requires
45-60 application on intact skin TAC tetracaine
0.5 epi 1 in 2000 cocaine 10 application into
wound maximum dose for kids 0.05ml/Kg toxicity
due to cocaine Tumescent Anesthesia lidocaine
dilute epi liposuction dose 35-55mg/Kg Peak
levels 8-12h later
58Special preparations
www.aafp.org
59Topical Local anesthetics
- Tetracaine, Adrenaline (Epinephrine), and Cocaine
- Tetracaine, adrenaline, and cocaine (TAC), a
compound of 0.5 percent tetracaine (Pontocaine),
0.05 percent epinephrine, and 11.8 percent
cocaine, was the first topical anesthetic mixture
found to be effective for nonmucosal skin
lacerations to the face and scalp.2 From 2 to 5
mL of solution is applied directly to the wound
using a cotton-tipped applicator with firm
pressure that is maintained for 20 to 40
minutes.2,3 However, the use of TAC is no longer
supported by the literature because of general
concern about toxicity and expense, and federal
regulatory issues involving medications
containing cocaine. - Principles of Office Anesthesia Part II. Topical
Anesthesia - SURITI KUNDU, M.D.,
60EMLA
- Eutectic Mixture of Local Anesthetics
- Most pure anesthetic agents exist as solids.
Eutectic mixtures are liquids and melt at lower
temperatures than any of their components,
permitting higher concentrations of anesthetics.
Eutectic mixture of local anesthetics (EMLA)
represents the first major breakthrough for
dermal anesthesia on intact skin. It consists of
25 mg per mL of lidocaine, 25 mg per mL of
prilocaine, a thickener, an emulsifier, and
distilled water adjusted to a pH level of 9.4.3 - Etymology Greek eutEktos easily melted, from eu-
tEktos melted, from tEkein to melt -- more at
THAW1 of an alloy or solution having the
lowest melting point possible2 of or relating
to a eutectic alloy or solution or its melting or
freezing point - Principles of Office Anesthesia Part II. Topical
AnesthesiaSURITI KUNDU, M.D.,
61Iontophoresis
- Iontophoresis is a method of delivering a topical
anesthetic with a mild electric current.
Lidocaine-soaked sponges are applied to intact
skin, and electrodes are placed on top of the
anesthetic. A DC current is then applied to the
skin (Figure 2). The anesthetic effect occurs
within 10 minutes and lasts approximately 15
minutes. The depth of anesthesia can reach up to
1 to 2 cm.12 - Although the effectiveness of iontophoresis has
been compared favorably to that of EMLA, it
remains underused. Some patients find the mild
electrical sensation uncomfortable. The apparatus
is expensive and bulky, and cannot be used over
large surface areas of the body.8 Other
applications using iontophoresis are still being
developed. - Principles of Office Anesthesia Part II. Topical
AnesthesiaSURITI KUNDU, M.D., -
62Iontophoresis
63Iontophoresis
- Comparison of EMLA and lidocaine iontophoresis
for cannulation analgesia.CONCLUSIONS Although
lidocaine iontophoresis is effective more quickly
than the eutectic mixture of local anaesthetic
cream, the superior quality of analgesia produced
by the eutectic mixture in this study should be
borne in mind if these treatments are used
electively - Eur J Anaesthesiol. 2004 Mar21(3)210-3. Moppett
64Liposomes
- Liposomes are comprised of lipid layers
surrounded by aqueous layers. They are able to
penetrate the stratum corneum because they
resemble the lipid bilayers of the cell membrane.
A liposomal delivery system recently became
available as an over-the-counter product called
ELA-Max. It contains 4 percent lidocaine cream in
a liposomal matrix and is FDA-approved for the
temporary relief of pain resulting from minor
cuts and abrasions. ELA-Max is applied to intact
skin for 15 to 40 minutes without occlusion.15-17
In limited studies, ELA-Max has also proved
effective in providing dermal analgesia before
chemical peeling.18 The safety of its application
to mucous membranes has not been evaluated.5
Despite a paucity of data and lack of an FDA
indication, clinicians are be - ginning to use ELA-Max for topical anesthesia
before other dermatologic procedures.
65Liposome
www.bioteach.ubc.ca
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68Liposomal Bupivacaine
- A Novel Liposomal Bupivacaine Formulation to
Produce Ultralong-Acting Analgesia - Conclusions This novel liposomal formulation had
a favorable drug-to-phospholipid ratio and
prolonged the duration of bupivacaine analgesia
in a dose-dependent manner. If these results in
healthy volunteers can be duplicated in the
clinical setting, this formulation has the
potential to significantly impact the management
of pain. - Anesthesiology Volume 101(1) July 2004 pp
133-137 Grant,
69Liposomal Bupivacaine
- The median duration of analgesia with 0.5
standard bupivacaine was 1 h. The median
durations of analgesia after 0.5, 1.0, and 2.0
liposomal bupivacaine were 19, 38, and 48 h,
respectively. - Although the data presented with this novel LMVV
formulation are very encouraging because we found
that LMVV bupivacaine was well tolerated and that
it significantly prolonged the duration of
analgesia compared to standard bupivacaine, there
are a number of issues that must be resolved
before the formulation can be introduced for
clinical use. Stability of the formulation during
prolonged storage, batch-to-batch variability in
physicochemical characteristics, and adaptability
of the method for upscaling for large batch sizes
remain to be determined. The primary objective of
the current study was to establish proof of
concept regarding the efficacy of LMVV
bupivacaine in humans. The dose of LMVV
bupivacaine administered in this study was
lowonly 17.5 mg. Before the efficacy of LMVV
bupivacaine in various painful conditions can be
evaluated, a study to determine its maximum
tolerated dose in humans is necessary.
70Liposomes
- Liposomal Drug Delivery for Postoperative Pain
Management Translational vignette - Although the plasma concentration versus time
curve is flatter for the extended-release
formulation, overall bioavailability is similar.
Although the exact mechanism of in vivo drug
release from MVL particles is not known, it is
believed to be the result of a gradual erosion or
reorganization of the lipid membranes - Summary and Conclusions
- Liposomes are effective drug delivery systems to
improve the therapeutic efficacy of drugs by
increasing drug circulation times, facilitating
targeting of drugs, and enhancing stability
without compromising safety or tolerability.
Extended-release MVL preparation has proved to be
an effective drug delivery vehicle for morphine
sulfate extended-release MVL morphine sulfate
exhibits an extended duration of pain relief for
up to 48 hours postoperatively without
compromising safety or tolerability, according to
initial clinical studies. - Regional Anesthesia and PM Sept - May, 2005 pp
491-496 Eugene
71Encapsulation of mepivacaine
- Encapsulation of mepivacaine prolongs the
analgesia provided by sciatic nerve blockade in
mice.PURPOSE Liposomal formulations of local
anesthetics (LA) are able to control
drug-delivery in biological systems, prolonging
their anesthetic effect. This study aimed to
prepare, characterize and evaluate in vivo
drug-delivery systems, composed of large
unilamellar liposomes (LUV), for bupivacaine
(BVC) and mepivacaine (MVC). - CONCLUSION MVC(LUV) provided a LA effect
comparable to that of BVC. We propose MVC(LUV)
drug delivery as a potentially new therapeutic
option for the treatment of acute pain since the
formulation enhances the duration of sensory
blockade at lower concentrations than those of
plain MVC. - Can J Anaesth. 2004 Jun-Jul51(6)566-72. de
Araujo
72Uses of Local Anesthetics
- Topical
- Local infiltration
- Minor peripheral nerve blockade
- Major peripheral nerve blockade
- Neuraxial blockade
- Tumescent anesthesia
- Chronic pain
73IV Local anesthetics
- Perioperative Intravenous Lidocaine Has
Preventive Effects on Postoperative Pain and
Morphine Consumption After Major Abdominal
Surgery - IMPLICATIONS The perioperative administration of
systemic small-dose lidocaine reduces pain during
surgery associated with the development of
pronounced central hyperalgesia, presumably by
affecting mechanoinsensitive nociceptors, because
these have been linked to the induction of
central sensitization and were shown to be
particularly sensitive to small-dose lidocaine - lidocaine 2 (bolus injection of 1.5 mg/kg in 10
min followed by an IV infusion of 1.5 mg kg-1
h-1), - Anesth Analg 2004981050-1055 Koppert
74Tumescent Anesthesia
- Plasma lidocaine levels and risks after
liposuction with tumescent anaesthesia.Backgroun
d It is common today to use tumescent
anaesthesia with large doses of lidocaine for
liposuction. The purpose of the present study was
to evaluate lidocaine plasma levels and objective
and subjective symptoms during 20 h after
tumescent anaesthesia with approximately 35 mg
per kg bodyweight of lidocaine for abdominal
liposuction. Methods Three litres of buffered
solution of 0.08 lidocaine with epinephrine.
Results Lidocaine 33.2 /- 1.8 mg/kg was given
at a rate of 116 /- 11 ml/min. Peak plasma
levels (2.3 /- 0.63 microg/ml) of lidocaine
occurred after 5-17 h - Conclusion Doses of lidocaine up to 35 mg/kg
were sufficient for abdominal liposuction using
the tumescent technique and gave no fluid
overload or toxic symptoms in eight patients, but
with this dose there is still a risk of
subjective symptoms in association with the peak
level of lidocaine that may appear after
discharge. - Acta Anaesthesiol Scand. 2005 Nov49(10)1487-90.
Nordstrom
75Tumescent Anesthesia
- Deaths Related to Liposuction
- Conclusions Tumescent liposuction can be fatal,
perhaps in part because of lidocaine toxicity or
lidocaine-related drug interactions. - In tumescent liposuction, reported doses of
lidocaine range from 10 to 88 mg per kilogram,8
several times higher than the maximal recommended
dose of 4.5 mg per kilogram (or up to 7 mg per
kilogram with epinephrine) typically used for
subcutaneous infiltration.21,22 The 1991
guidelines of the American Academy of
Dermatologists for tumescent liposuction
suggested a maximal dose of 35 mg of lidocaine
per kilogram,23 which was increased to at least
55 mg per kilogram in 1997 - NEJM V3401471-1475 Rama
76Myotoxicity
The long term myotoxic effects of bupivacaine
and ropivacaine after continuous peripheral nerve
blocks.IMPLICATIONS In a period of 4 wk after
peripheral nerve block, both long-acting local
anesthetics, bupivacaine and ropivacaine,
produced calcific myonecrosis suggestive of
irreversible skeletal muscle damage. In
comparison with ropivacaine, however, the extent
of bupivacaine-induced muscle lesions was
significantly larger. Anesth Analg. 2005
Aug101(2)548-54, Zink W,
77CVS Toxicity
Cardiovascular collapse on the basis of
malignant rhythm decreased contractility vascu
lar dilation
78Newer Local anesthetics
- Direct cardiac effects of intracoronary
bupivacaine, levobupivacaine and ropivacaine in
the sheep.In previous preclinical studies we
found that central nervous system (CNS)
excito-toxicity reversed the cardiac depressant
effects - All three drugs produced tachycardia, decreased
myocardial contractility and stroke volume and
widening of electrocardiographic QRS complexes.
Thirteen of 19 animals died of ventricular
fibrillation No significant differences in
survival or in fatal doses between these drugs
were found. - The findings suggest that ropivacaine,
levobupivacaine and bupivacaine have similar
intrinsic ability to cause direct fatal cardiac
toxicity when administered by left intracoronary
arterial infusion in conscious sheep and do not
explain the differences between the drugs found
with intravenous dosage - Br J Pharmacol. 2001 Feb132(3)649-58. Chang
DH,
79Limitations of Local Anesthetics
Amount and complexity of the work to be
done Patient Area to be anesthetized Duration of
procedure Immobility
80New and not-so new Developments in Local
Anesthetics
Toxicity Duration Ropivacaine Levobupivacaine
liposomal encapsulated local anesthetics surfa
ce, charge, size lamella structure
81Ropivacainedepts.washington.edu/anesth/
regional/ropivacainetext.html
- Pharmacokinetic parametersRopivacaine is 2-3
times less lipid soluble and has a smaller volume
of distribution, greater clearance, and shorter
elimination half-life than bupivacaine in
humans.3 The two drugs have a similar pKa and
plasma protein binding
82Ropivacainedepts.washington.edu/anesth/
regional/ropivacainetext.html
- Ropivacaine is slightly less potent than
bupivacaine.When used for spinal anesthesia,
0.75 ropivacaine produces less intense sensory
and motor block than 0.5 bupivacaine.5 However,
multiple clinical trials comparing the two local
anesthetics in epidural and axillary block
demonstrate similar potency of bupivacaine and
ropivacaine with respect to the intensity of
sensory anesthesia.
83Ropivacainedepts.washington.edu/anesth/
regional/ropivacainetext.html
- Epinephrine does not prolong the duration of
ropivacaine block.The addition of epinephrine
does not prolong the duration of ropivacaine in
subclavian brachial plexus17,18 or epidural19
block. Low concentrations of ropivaciane may
produce clinically significant vasoconstriction,
which is not increased further by the addition of
epinephrine.
84Ropivacainedepts.washington.edu/anesth/
regional/ropivacainetext.html
- Ropivacaine is indistinguishable from bupivacaine
when used in obstetric anesthesia.When
continuous infusions of 0.25 ropivacaine were
compared with 0.25 bupivacaine in lumbar
epidural labor analgesia in two randomized
double-blind clinical trials, no difference was
detected in between the two drugs in intensity,
duration or incidence of motor block, onset and
quality of sensory analgesia, number of
instrumented deliveries, number of C-sections, or
neonatal neurobehavioral scores at 24 hours.11,12
Neonates in the ropivacaine group had higher
neurobehavioral scores before 24 hours
85- Conclusions Ropivacaine is slightly less potent
than bupivacaine, but multiple studies show that
it can provide adequate surgical anesthesia when
used in similar concentrations. Ropivacaine is
half as potent as bupivacaine in its direct
negative inotropic effect and slowing of
ventricular conduction. A potential for sudden
ventricular arrhythmias still exists with
systemic ropivacaine toxicity. Any slight
advantage ropivacaine has over bupivacaine may be
eliminated if higher concentrations of
ropivacaine are used.
86Ropivacaine
87Ropivacaine
Arterial and Venous Pharmacokinetics of
Ropivacaine with and without Epinephrine after
Thoracic Paravertebral Block.BACKGROUND
Animal and volunteer studies indicate that
ropivacaine is associated with less neurologic
and cardiac toxicity than bupivacaine.
Ropivacaine may offer advantages when used for
thoracic paravertebral block. This study was
designed to describe the pharmacokinetics of
ropivacaine after thoracic paravertebral block.
METHODS Twenty female patients undergoing
elective unilateral breast surgery were randomly
assigned to receive a single bolus thoracic
paravertebral injection of 2 mg/kg ropivacaine,
with or without 5 mug/ml epinephrine.
Simultaneous arterial and venous blood samples
were obtained for plasma ropivacaine assay. Data
were analyzed with NONMEM, using two possible
absorption models conventional first-order
absorption and absorption following the inverse
gaussian density function. RESULTS Epinephrine
reduced the peak plasma concentrations and
delayed the time of peak concentration of
ropivacaine in both the arterial and venous
blood. The time course of drug input into the
systemic circulation was best described by two
inverse gaussian density functions. The median
bioavailability of the rapid component was
approximately 20 higher when epinephrine was not
used. The mean absorption times were 7.8 min for
the rapid absorption phase and 697 min for the
slow absorption phase, with wide dispersion of
the absorption function for the acute phase. The
half-time of arterial-venous equilibration was
1.5 min. CONCLUSION The absorption of
ropivacaine after thoracic paravertebral block is
described by rapid and slow absorption phases.
The rapid phase approximates the speed of
intravenous administration and accounts for
nearly half of ropivacaine absorption. The
addition of 5 mug/ml epinephrine to ropivacaine
significantly delays its systemic absorption and
reduces the peak plasma concentration. Anesthesi
ology. 2005 Oct103(4)704-711. Karmakar .
88Ropivacaine
- Bupivacaine, levobupivacaine and ropivacaine
are they clinically different?Evaluating
randomised, controlled trials that have compared
these three local anaesthetics, this chapter
supports the evidence that both levobupivacaine
and ropivacaine have a clinical profile similar
to that of racemic bupivacaine, and that the
minimal differences observed between the three
agents are mainly related to the slightly
different anaesthetic potency, with racemic
bupivacainegtlevobupivacainegtropivacaine. However,
the reduced toxic potential of the two pure
left-isomers supports their use in those clinical
situations in which the risk of systemic toxicity
related to either overdosing or unwanted
intravascular injection is high, such as during
epidural or peripheral nerve blocks - Best Pract Res Clin Anaesthesiol. 2005
Jun19(2)247-68. Casati.
89Levobupivacaine
- The central nervous system and cardiovascular
effects of levobupivacaine and ropivacaine in
healthy volunteers.We compared the central
nervous system (CNS) and cardiovascular effects
of levobupivacaine and ropivacaine when given IV
to healthy male volunteers (n 14) in a
double-blinded, randomized, crossover trial.
Subjects received levobupivacaine 0.5 or
ropivacaine 0.5 after a test infusion with
lidocaine to become familiar with the early signs
of CNS effects. IMPLICATIONS This study compared
directly, for the first time, the toxicity of
levobupivacaine and ropivacaine in healthy
volunteers. Levobupivacaine and ropivacaine
produced similar central nervous system and
cardiovascular effects when infused IV at equal
concentrations, milligram doses, and infusion
rates. - Anesth Analg. 2003 Aug97(2)412-6, Stewart
90Chirality