Local Anesthetics

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Local Anesthetics
Kevin Armstrong MD Department and Anesthesia and
Perioperative Medicine November 2007
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Important points

• History
• Some differences
• How they work
• Test dose
• Onset
• Adjunvants
• Lipid rescue
• Newer delivery systems
• Tumescence

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History 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)

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Differences in structure of local anesthetics

• Esters versus Amides
• Affect metabolism
• Affect toxicity
• Allergic potential

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Types of Local Anesthetics
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Types of Local Anesthetics
Esters Procaine chloroprocaine tetracaine cocaine
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Types of Local Anesthetics
Amides Lidocaine prilocaine mepivacaine bupiva
caine ropivacaine
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sitemaker.med.umich.edu
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Mechanism 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

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Ty
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Mechanism of Action for Local Anesthetics
Domain 4 S4 subunit
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FIGURE 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
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Tetrododoxin

• Toxin from puffer fish
• Blocks the Na channel
• Used in research
• Blocks from the outer side of cell

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Local 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.

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Local 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

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Local Anesthetics

• Diffusibility (how well the LA diffuses diffuses
  through tissue to its site of action) will also
  influences the speed of action onset.

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Local 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

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Summary

• 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.

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From NYSORA web site
Properties of Local Anesthetic Agents
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pKa

• Understanding LA as they relate to pKa

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• 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.

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Henderson 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

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Effect 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

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Low 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

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Onset

• Is there a difference in the onset of different
  local anesthetics?

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Onset from NYSORA web site

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Onset

• Does onset influence you practice?
• Where?
• OB
• RA
• Chronic pain

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Onset of Action
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Onset
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
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Onset

• 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

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• 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

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Onset

• 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

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Whats 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.
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From 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.
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Duration of Local anesthetics

• Dependent on
• 1)agent
• 2)site
• 3)adjuvant
• 4)route
• 5)vascularity

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Duration 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
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From NYSORA web site
Local Anesthetic Time Line (minutes)
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Intravenous 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

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Intravenous 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,

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Intravenous 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.

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Intravenous 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.

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IV 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

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Safety Issues Related to Local Anesthetics
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Safety Issues Related to Local Anesthetics

• Related to
• Drug
• Dose
• Site of administration
• Condition of the patient

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CNS 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
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CVS 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
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Treatment of Toxicity
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Treatment of Toxicity
Identify the problem signs and
symptoms temporal relationship IV
injection 40-60 min post for peak plasma
levels CNS treatment with benzodiazepines
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Treatment 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
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Treatment of Toxicity
When there is CVS collapse ACLS A B
Cs defibrillation Epinephrine Vasopressin Lidoca
ine? Bretylium? Amiodarone
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Lipid Rescue

• Relatively new concept

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Nanoparticles

• 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,

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Regional Anesthesia andPMJuly - May, 2005 pp
380-384 Renehan,
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Regional Anesthesia andPMJuly - May, 2005 pp
380-384 Renehan,
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Toxicty

Email
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Special 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
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Special preparations
www.aafp.org
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Topical 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.,

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EMLA

• 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.,

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Iontophoresis

• 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.,

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Iontophoresis
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Iontophoresis

• 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

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Liposomes

• 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.

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Liposome
www.bioteach.ubc.ca
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Liposomal 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,

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Liposomal 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.

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Liposomes

• 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

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Encapsulation 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

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Uses of Local Anesthetics

• Topical
• Local infiltration
• Minor peripheral nerve blockade
• Major peripheral nerve blockade
• Neuraxial blockade
• Tumescent anesthesia
• Chronic pain

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IV 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

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Tumescent 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

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Tumescent 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

76
Myotoxicity
 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,
77
CVS Toxicity
Cardiovascular collapse on the basis of
malignant rhythm decreased contractility vascu
lar dilation
78
Newer 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,

79
Limitations of Local Anesthetics
Amount and complexity of the work to be
done Patient Area to be anesthetized Duration of
procedure Immobility
80
New and not-so new Developments in Local
Anesthetics
Toxicity Duration Ropivacaine Levobupivacaine
liposomal encapsulated local anesthetics surfa
ce, charge, size lamella structure
81
Ropivacainedepts.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

82
Ropivacainedepts.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.

83
Ropivacainedepts.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.

84
Ropivacainedepts.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.

86
Ropivacaine
87
Ropivacaine
 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 .
88
Ropivacaine

• 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.

89
Levobupivacaine

• 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

90
Chirality