LOCAL ANESTHETICS

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LOCAL ANESTHETICS

• A.Ghaleb,MD

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LOCAL ANESTHETICS

• The electrical potential inside the cell is
  negative and close to the potential that would be
  determined by potassium alone.
• This is the resting potential (-70 mV). During
  the transmission of an action potential, sodium
  moves into the cell through open sodium channels,
  depolarizing the cell.
• Local anesthetics are compounds with the ability
  to interrupt the transmission of the action
  potential in excitable membranes. They bind to
  specific receptors on the Na channels and their
  action at clinically recommended doses is
  reversible.

3
Historical perspective

• The natives of Peru chewed coca leaves and knew
  about their cerebral-stimulating effects. The
  leaves of erythroxylon coca were taken to Europe
  where Niemann isolated cocaine in Germany in
  1860.
• Koller in 1884 is credited with the introduction
  of cocaine as a topical ophthalmic local
  anesthetic in Austria.
• Cardiovascular side effects as well as potential
  for dependency and abuse were soon recognized,
  which led to the search for a better local
  anesthetic.

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Historical perspective

• 1850s invention of the syringe and hypodermic
  hollow needle
• 1884 Halsted, blocks the brachial plexus with a
  solution of cocaine under direct vision (surgical
  exposure).
• 1897 Braun in Germany relates cocaine toxicity
  with systemic absorption and advocates the use of
  epinephrine.
• 1898 Bier performs the first planned spinal
  anesthesia.
• 1911 Hirschel performs the first percutaneous
  axillary block
• 1911 Kulenkampff performs the first percutaneous
  supraclavicular block
• Date of introduction in clinical practice of some
  local anesthetics

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Historical perspective

• 1905 procaine 1932 tetracaine 1947 lidocaine
  1955 chloroprocaine (last ester type local
  anesthetic introduced that is still in clinical
  use) 1957 mepivacaine 1963 bupivacaine 1997
  ropivacaine 1999 levobupivacaine.

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Chemical structure

• weak bases with a pka above 7.4 and poorly
  soluble in water.
• Commercially available as acidic solutions (pH
  4-7) of hydrochloride salts, which are
  hydrosoluble.
• A typical local anesthetic is composed of two
  portions linked together by a chemical chain. One
  portion consists of a benzene ring (lipid soluble
  hydrophobic) and the other is an amine group
  that is ionizable and water-soluble
  (hydrophilic).
• The chemical chain can be either ester type
  (-CO-) or amide type (-HNC-) defining two
  different groups of local anesthetics, esters and
  amides.

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• The injected local anesthetic volume spreads
  initially by mass movement.
• This first step determines how much local
  anesthetic effectively reaches the nerve.
• Moves across points of least resistance, which
  do not necessarily lead into the desired
  nerve(s), stressing the need to bring the needle
  in proximity to the target nerve(s).
• The local anesthetic solution diffuses through
  tissues each layer of them acting as a physical
  barrier and in the process part of the solution
  gets absorbed into the circulation.
• Finally a small percentage of the anesthetic
  reaches the target nerve membrane at which point
  the different physicochemical properties of the
  individual anesthetic will dictate the speed,
  duration and nature of the interaction with the
  receptors.

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Structure-activity relationship

• Lipid solubility
• Determines both the potency and the duration of
  action of the local anesthetics by binding the
  drug close to the site of action and thereby
  decreasing the rate of metabolism by plasma
  esterase and liver enzymes.
• In addition the local anesthetic receptor site
  on Na channels is thought to be hydrophobic, so
  its affinity for hydrophobic drugs is greater.
• Hydrophobicity also increases toxicity, so the
  therapeutic index actually is decreased for more
  hydrophobic drugs.

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Structure-activity relationship

• Protein binding
• Related to duration of action.
• In the body, local anesthetics are bound in large
  part to plasma and tissue proteins. The bound
  portion is not pharmacologically active. The most
  important binding proteins in plasma are albumin
  and alpha-1-acid glycoprotein (AAG)
• The fraction of drug bound to protein in plasma
  correlates with the duration of action of local
  anesthetics bupivacaine gt ropivacaine gt
  mepivacaine gt lidocaine gt procaine and
  2-chloroprocaine.
• This suggests that the bond between the local
  anesthetic molecule and the sodium channel
  receptor protein may be similar to that of local
  anesthetic binding to plasma protein (similar
  amino acid sequences).
• Drugs as lidocaine, tetracaine and bupivacaine
  have been incorporated into liposomes to prolong
  the duration of action and decrease toxicity.
  Liposomes are vesicles with two layers of
  phospholipids, which slow down the release of the
  drug effectively prolonging the duration of action

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Structure-activity relationship

• Protein binding
• This suggests that the bond between the local
  anesthetic molecule and the sodium channel
  receptor protein may be similar to that of local
  anesthetic binding to plasma protein (similar
  amino acid sequences).
• Drugs as lidocaine, tetracaine and bupivacaine
  have been incorporated into liposomes to prolong
  the duration of action and decrease toxicity.
  Liposomes are vesicles with two layers of
  phospholipids, which slow down the release of the
  drug effectively prolonging the duration of
  action

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Structure-activity relationship

• The pka of the local anesthetic determines the
  ratio of the ionized (cationic) and the uncharged
  (base) form of the drug.
• The pka for local anesthetics ranges from 7.6 to
  9.2.
• By definition the pka is the pH at which 50 of
  the drug is ionized and 50 is present as a base.
• The pka generally correlates with the speed of
  onset of most local anesthetics. The closer the
  pka to the physiologic pH the faster the onset
  (e.g., lidocaine with a pka of 7.7 is 25
  non-ionized at ph 7.4 and has a more rapid onset
  of action than bupivacaine with a pka of 8.1
  which is only 15 non-ionized).
• One important exception is 2-chloroprocaine with
  a pka of 9.0 and very short onset of action. This
  fast onset could be related to its low toxicity,
  which allows for high concentrations to be used
  clinically. It is also claimed to have also
  better tissue penetrability.

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Mechanism of action and sodium channels

• The non-charged hydrophobic fraction (B) crosses
  the lipidic nerve membrane and initiates the
  events that lead to blocking of sodium channels.
• Once inside a new equilibrium, dictated by the
  compound pka and the intracellular pH, is reached
  between the non-charged and charged (BH)
  fractions.
• Because of the relative more acidic intracellular
  environment, the relative proportion of charged
  fraction increases. This fraction interacts with
  the Na channel.
• Local anesthetics do not ordinarily affect the
  membrane resting potential.

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Mechanism of action and sodium channels

• The Na channel is a protein structure that
  communicates the extracellular of the nerve with
  its axoplasm and consists of four repeating alpha
  subunits, a beta-1 and beta-2 subunits. The alpha
  subunits are involved in ion movement and local
  anesthetic activity.
• It is generally accepted that local anesthetics
  main action involves interaction with specific
  binding sites within the Na channel.
• The voltagedependence of channel opening is
  hypothesized to reflect conformational changes in
  response to changes in transmembrane potential.
  The voltage sensors or gates are located in the
  S4 helix the S4 helices are both hydrophobic and
  positively charged.

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Mechanism of action and sodium channels

• The Na channels seem to exist in three different
  states, closed, open and inactive.
• With depolarization the protein molecules of the
  channel undergo conformational changes from the
  closed (resting) state to the ion-permeable state
  or open state.
• The channel goes then through a transitional
  inactive state where the proteins leave the
  channel still closed and ion-impermeable.
• With repolarization the proteins revert to their
  resting configuration. Local anesthetics may also
  block in some degree calcium and potassium
  channels as well as N-methyl-D-aspartate (NMDA)
  receptors.
• Other drugs like tricyclic antidepressants
  (amitriptyline), meperidine, volatile anesthetics
  and ketamine also have sodium channel-blocking
  properties

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Frequency and voltage dependence of local
anesthetic action

• A resting nerve is much less sensitive to local
  anesthetic than one that is being stimulated.
• The degree of block also depends on the nerve
  resting membrane potential, a more positive
  membrane potential causes a greater degree of
  block.
• These frequency and voltage dependent effects
  occur because the local anesthetic in its charged
  form gain access to its biding site within the
  channel only when the Na channel is in an open
  state

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Pregnancy and local anesthetics

• Increased sensitivity (more rapid onset, more
  profound block) may be present during pregnancy.
• Also alterations in protein binding of
  bupivacaine may result in increased
  concentrations of active unbound drug in the
  pregnant patient.
• During pregnancy, placental transfer is more
  active for lipid soluble local anesthetics,
  whereas higher protein binding becomes an
  obstacle to such transfer. In any case, agents
  with a pka closer to physiologic pH have a higher
  placental transfer. For example the umbilical
  vein/maternal vein ratio for mepivacaine is 0.8
  (pka 7.6) while for bupivacaine is 0.3 (pka 8.1).

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Pregnancy and local anesthetics

• In the presence of fetal acidosis, local
  anesthetics cross the placenta and become ionized
  in higher proportion than at normal pH. As
  ionized substances they cannot cross back to the
  maternal circulation (ion trapping).
  2-chloroprocaine with its very short maternal and
  fetal half-lives is theoretically an ideal local
  anesthetic in the presence of fetal acidosis.

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Fiber size and pattern of blockade

• As a general rule small nerve fibers are more
  susceptible to local anesthetics
• However other factors like myelinazation and
  relative position of the fibers (mantle and core)
  within a nerve also play a role.
• The smallest nerve fibers are nonmyelinated and
  are blocked more readily than larger myelinated
  fibers.
• However myelinated fibers are blocked before
  nonmyelinated fibers of the same diameter.
• In general autonomic fibers, small nonmyelinated
  C fibers (mediating pain), and small myelinated A
  delta fibers (mediating pain and temperature) are
  blocked before A gamma, A beta and A alpha fibers
  (carrying postural, touch, pressure and motor
  information).

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Fiber size and pattern of blockade

• In large nerve trunks motor fibers are usually
  located in the outer portion of the bundle and
  are more accessible to local anesthetic. Thus
  motor fibers may be blocked before sensory fibers
  in large mixed nerves.
• In addition the frequency-dependence of local
  anesthetic action favors block of small sensory
  fibers. They generate long action potential (5
  ms) at high frequency, whereas motor fibers
  generate short action potentials (0.5 ms) at
  lower frequency. These characteristics of sensory
  fibers in general, and of pain fibers in
  particular, favor frequency-dependent block.

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Modulating local anesthetic actionpH adjustment

• Local anesthetics pass through the nerve membrane
  in a non-ionized hydrophobic (lipid soluble) base
  form.
• In the axoplasm they equilibrate into an ionic
  form that is active within the sodium channel.
  The rate-limiting step in this cascade is
  penetration of the local anesthetic through the
  nerve membrane.
• All available local anesthetics contain very
  little drug in the non-ionized state. This
  fraction depends on the pka of the drug and the
  ph of the solution.
• Changes in ph can produce a shortening of the
  onset time, being the limiting factor for ph
  adjustment the solubility of the base form of the
  drug (precipitation).
• DiFazio et al (Anesth Analg 198665 760-64)
  demonstrated more than 50 decrease in onset of
  epidural anesthesia when the pH of commercially
  available lidocaine with epinephrine was raised
  from 4.5 to 7.2 by the addition of bicarbonate.

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Modulating local anesthetic actionpH adjustment

• Hilgier (Reg Anesth 198510 59-61) reported a
  marked improvement in the onset time for brachial
  plexus anesthesia when bupivacaine with
  epinephrine (pH 3.9) was alkalinized to pH 6.4
  before injection.
• However, when only small changes in pH can be
  achieved because of the limited solubility of the
  base, only small decreases in onset time will
  occur, as when plain bupivacaine is alkalinized.
  For each local anesthetic there is a ph at which
  the amount of base in solution is maximal (a
  saturated solution).
• Chloroprocaine plus 1 mL of sodium bicarbonate
  for 30 mL of solution raises the pH to 6.8.
  Adding 1 mL of sodium bicarbonate per 10 mL of
  lidocaine or mepivacaine raises the pH of the
  solution to 7.2 and adding 0.1 mL of bicarbonate
  per 10 mL of bupivacaine raises the pH of the
  solution to 6.4

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Modulating local anesthetic actionpH adjustment

• Carbonation
• Another approach to shortening onset time has
  been the use of carbonated local anesthetic
  solutions. The solution contains large amounts of
  carbon dioxide, which readily diffuses into the
  axoplasm of the nerve lowering the ph and
  favoring the formation of the cationic active
  form of the local anesthetic. Carbonated
  solutions are not available in the United States

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LOCAL ANESTHETICS ADDITIVES

• Vasoconstrictors to prolong the anesthetic effect
  and to decrease absorption.
• Epinephrine is also used to detect intravascular
  injection (test dose).
• Vasoconstrictors may also improve the quality and
  density of the block especially with spinal and
  epidural anesthesia. This has been demonstrated
  with tetracaine, lidocaine and bupivacaine. The
  mechanism is unclear.
• Epinephrine may simply increase the amount of
  local anesthetic available by reducing
  absorption. It could have also some anesthetic
  effect by means of its alpha 2-agonist actions.
• Subarachnoid epinephrine potentially delays the
  time for urination, which may delay discharge.

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• Epinephrine used other than intrathecally is
  absorbed systemically and may produce adverse
  cardiovascular effects.
• In small doses the beta-adrenergic effects
  predominate with increased cardiac output and
  heart rate. Dose larger than 0.25 mg (250 ug) may
  be associated with arrhythmias or other
  undesirable cardiac effects.
• Lately concerns have been raised about potential
  neural ischemia caused by epinephrine acting on
  epineural vessels and vaso nervorum. This
  potential risk has to be balanced against lower
  risk of systemic toxicity, marker for
  intravascular injection and prolongation of
  action.
• Neal in 2003
• adding 5 ug/mL (1200,000 dilution) prolongs the
  duration of lidocaine for peripheral nerve blocks
  from 186 minutes to 264 minutes.
• Adding only 2.5 ug/mL (1400,000 dilution)
  prolongs the block to 240 minutes (almost the
  same prolongation) without apparent effect on
  nerve blood flow.
• Patients with micro angiopathy (e.g., diabetics)
  who could be at increase risk for neural ischemia
  secondary to vasoconstriction potentially could
  benefit from the use of more diluted epinephrine
  (1400,000).

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LOCAL ANESTHETICS ADDITIVES

• Opioids
• The addition of short-acting opioids such as
  fentanyl and sufentanil to spinal anesthetics
  appears to intensify the block and prolong the
  duration of anesthesia similar to epinephrine
  without affecting urination. They also prolong
  analgesia beyond the duration of local
  anesthetics. When used epidurally they usually
  produced pruritus. Their usefulness in peripheral
  nerve blocks is not clear

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LOCAL ANESTHETICS ADDITIVES

• Clonidine
• Alpha 2-agonists have analgesic effects when
  injected on nerves or in the subarachnoid space.
  Side effects (hypotension, bradycardia) limit its
  use but small doses (50-75 ucg) have shown to
  significantly prolong analgesia in spinal,
  epidural, intravenous regional, and peripheral
  nerve blocks both when injected with the local
  anesthetics and when given orally.
• Hyaluronidase
• It breaks down collagen bonds potentially
  facilitating the spread of local anesthetic
  through tissue planes. The evidence however shows
  at least in the epidural space to decrease the
  quality of anesthesia. Its use seems limited to
  retrobulbar blocks.
• Dextran
• Dextran and other high-molecular-weight compounds
  have been advocated to increase the duration of
  local anesthetics. The evidence is lacking.

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METABOLISM OF LOCAL ANESTHETICS

• Ester local anesthetics
• They are hydrolyzed at the ester linkage by
  plasma pseudocholinesterase (also hydrolyses
  acetylcholine and succinylcholine). The
  hydrolysis of 2-chloroprocaine is about four
  times faster than procaine, which in turn is
  hydrolyzed about four times faster than
  tetracaine. In individuals with atypical plasma
  pseudocholinesterase the half-life of these drugs
  is prolonged and potentially could lead to plasma
  accumulation.
• The hydrolysis of all ester anesthetics leads to
  the formation of para-aminobenzoic acid (PABA),
  which is associated with a low potential for
  allergic reactions. Allergic reactions may also
  develop from the use of multiple dose vials of
  amide local anesthetics that contain PABA as a
  preservative.

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METABOLISM OF LOCAL ANESTHETICS

• Amide local anesthetics
• They are transported into the liver before their
  biotransformation. The two major factors
  controlling the clearance of amide local
  anesthetics by the liver are hepatic blood flow
  and hepatic function.
• The metabolism of local anesthetics as well as
  that of many other drugs occurs in the liver by
  the cytochrome P-450 enzymes. Because the liver
  has a large capacity for metabolizing drugs it is
  unlikely that drug interaction would affect the
  metabolism of local anesthetics.
• Drugs such as general anesthetics,
  norepinephrine, cimetidine, propranolol and
  calcium channel blockers (e.g., diltiazem) can
  decrease hepatic blood flow and increase the
  elimination half-life of amides. Similarly
  decreases in hepatic function caused by a
  lowering of body temperature, immaturity of the
  hepatic enzyme system in the fetus, or liver
  damage (e.g., cirrhosis) lead to a decreased rate
  of hepatic metabolism of the amides. Renal
  clearance of unchanged local anesthetics is a
  minor route of elimination (lidocaine is only 3
  to 5 recovered unchanged in the urine of adults
  while for bupivacaine is 10 to 16).

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LOCAL ANESTHETIC TOXICITY

• Systemic local anesthesia toxicity is related to
  plasma levels. Plasma concentration depends on
• The total dose
• The net absorption, which depends on
  vasoactivity of the drug, site vascularity and
  use of a vasoconstrictor.
• Biotransformation and elimination of the drug
  from the circulation
• Peak local anesthetic blood levels are directly
  related to the dose administered at any given
  site. Generally the administration of a 100-mg
  dose of lidocaine in the epidural or caudal space
  results in approximately a 1 ucg/mL peak blood
  level in an average adult. The same dose injected
  into less vascular areas (e.g., brachial plexus
  axillary approach or subcutaneous infiltration)
  produces a peak blood level of app 0.5 ucg/mL.
  The same dose injected intercostal produces a 1.5
  ucg/mL plasma level.

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LOCAL ANESTHETIC TOXICITY

• Systemic local anesthesia toxicity
• Peak blood levels may also be affected by the
  rate of biotransformation and elimination. In
  general this is the case only for very actively
  metabolized drugs such as 2-chloroprocaine, which
  has a plasma half-life of about 45 seconds to1
  minute.
• For amide local anesthetics like lidocaine peak
  plasma level after regional anesthesia primarily
  result from absorption. Lidocaine
  biotransformation half-life is approximately 90
  minutes. Local anesthetics interfere with the
  functions of all organs in which transmission of
  impulses occurs, among others the CNS and
  cardiovascular systems.

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LOCAL ANESTHETIC TOXICITY

• Central nervous system
• Toxic levels are usually produced by inadvertent
  intravascular injection.
• It can also result from the slow absorption
  following peripheral injection.
• A sequence of symptoms can include
• Numbness
  of the tongue
• 
  Lightheadedness
• Tinnitus
  
• 
  Restlessness
• 
  Tachycardia
• 
  Convulsions
• 
  Respiratory arrest

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LOCAL ANESTHETIC TOXICITY

• Cardiovascular system
• The cardiovascular manifestations usually follow
  the CNS effects (therapeutic index). The
  exception is bupivacaine, which can produce
  cardiac toxicity at subconvulsant concentrations.
• Rhythm and conduction are rarely affected by
  lidocaine, mepivacaine and tetracaine but
  bupivacaine and etidocaine can produce
  ventricular arrhythmias.
• EKG shows a prolongation of PR and widening of
  the QRS
• Higher incidence in pregnancy
• CV toxicity is increased under hypoxia and
  acidosis.

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Treatment of systemic toxicity

• ABC (Airway, Breathing and Circulation) is the
  mainstay of treatment.
• Administration of O2 by mask or bag and mask is
  often all that is necessary to treat seizures. If
  seizures interfere with ventilation
  benzodiazepines, thiopental or propofol can be
  used. The use of succinylcholine effectively
  facilitates ventilation and by abolishing
  muscular activity decreases the severity of
  acidosis. However neuronal seizure activity is
  not inhibited and thus cerebral metabolism and
  oxygen requirements remain increased.
• .

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Treatment of systemic toxicity

• Little information is available regarding the
  treatment of cardiovascular toxicity of local
  anesthetics in humans. Animal data suggest that
  (1) high doses of epinephrine may be necessary to
  support heart rate and blood pressure (2)
  atropine may be useful for bradycardia (3) DC
  cardioversion is often successful and (4)
  ventricular arrhythmias are probably better
  treated with amiodarone than with lidocaine.
  Amiodarone is used as for ACLS, 150 mg over 10
  min, followed by 1 mg/min for 6 hrs then 0.5
  mg/min. Supplementary infusion of 150 mg as
  necessary up to 2 g. For pulseless VT or VF,
  initial administration is 300 mg rapid infusion
  in 20-30 mL of saline or dextrose in water.
  Vasopressin (40 U IV, single dose, one time only)
  is more frequently used now before epinephrine (1
  mg IV every 3-5 minutes). The best treatment for
  toxic reactions is prevention

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Maximum dose

• Regional anesthesiologists perform peripheral
  nerve blocks with an amount of local anesthetic
  that usually exceeds the maximum recommended
  doses.
• The common recommendations for maximum doses as
  suggested by the literature are not evidence
  based (14) and have proven to be poor
  approximation of safety (15).
• Many practitioners have called to review these
  guidelines to better reflect the reality of
  clinical practice. The American Society of
  Regional Anesthesia convened a Conference in
  Local Anesthetic Toxicity with a panel of
  experts in 2001 to discuss the subject. Many
  papers related to that conference have been
  published.
• In a review article by Rosenberg et al (14) the
  authors propose that the safe ranges should be
  block specific and related to patients age
  (e.g., epidural), organ dysfunction (especially
  for repeated doses) and pregnancy. They suggest
  also adding epinephrine 2.5 to 5 µg/ml when not
  contraindicated.
• The fact is that most of the systemic toxicity
  occurs with unintentional direct intravascular
  injection

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Methgemoglobinemia

• Prilocaine and benzocaine can oxidize the ferric
  form of the hemoglobin to the ferrous form,
  creating methemoglobin. When this exceeds 4 g/dL
  cyanosis can occur. Depending on the degree
  Methemoglobinemia can lead to tissue hypoxia. The
  oxyHb curve shifts to the left (P50 lt 27 mmHg).
  MetHb has a larger absorbance than Hb and 02Hb at
  940 nm but simulates Hb at 660 nm. Therefore at
  high SaO2 levels (more than 85) the reading
  underestimates the true value of it or
  overestimates the O2Hb. At low SaO2 (lt85) the
  value is falsely high. In the presence of high
  MetHb concentrations the SaO2 approaches 85
  independent of the actual arterial oxygenation.
• Methemoglobinemia is easily treated by the
  administration of methylene blue (1-5mg/kg) or
  less successfully of ascorbic acid (2 mg/kg).

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Allergy

• True allergy to local anesthetics is rare. It is
  relatively more frequent with esters, which are
  metabolized to para-amino-benzoic acid (PABA).
  PABA is frequently used in the pharmaceutical and
  cosmetic industries. Allergy to amide local
  anesthetics is exceedingly rare. There is no
  cross allergy between esters and amides. However
  use of methylparaben as a preservative in
  multidose vials of lidocaine can elicit allergy
  in patients allergic to PABA

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Procaine

• Esterpka 8.9slow onsetvery short half life (20
  sec)protein binding 5
• duration short

39
2-chloroprocaine

• Esterpka 9.0rapid onsetshort duration (it has
  30 minutes 2-segment regression in epidural)
• serious neurological deficits have occurred after
  massive intrathecal injection planned for spinal
  possible associated with the antioxidant
  bisulfite.The next preservative used
  ethylenediamine tetraacetic acid (EDTA) was
  associated with severe muscle spasm after
  epidural in ambulatory patients. The present
  solution is prepared without preservative and no
  back spasms have been reported

40
Tetracaine

• Esterpka 8.6slow onsetshort plasma half life
  (2.5 to 4 min) and long duration of action

41
Cocaine

• esterpka 8.5slow onsetshort durationvasoconstr
  ictorinterferes with the reuptake of
  cathecolamines resulting in hypertension,
  tachycardia, arrhythmia and myocardial
  ischemia.Can potentiate cathecolamine-induced
  arrhythmia by halothane, theophylline or
  antidepressants

42
Benzocaine

• ester (only secondary amine). It limits its
  ability to pass through membranes.pka 3.5slow
  onsetshort durationTopical anestheticexcessive
  use is associated with Methemoglobinemia

43

• Lidocaineamidepka 7.7intermediate onset and
  durationhalf-life 45-60 min

44

• Mepivacaineamidepka 7.6intermediate onset and
  duration

45

• Bupivacaineamidepka 8.1Slow onset, long
  durationCardiac arrest associated with
  bupivacaine is difficult to treat possibly due to
  its high protein binding and high lipid
  solubility

46

• Ropivacaineamidepka 8.2chemical analog of
  mepivacaine and bupivacainePrepared as L
  enantiomerOnset and duration as well as potency
  similar to bupivacaine Cardiac toxicity higher
  than mepivacaine but lower than bupivacaine

47

• LevobupivacaineamideL enantiomer of
  bupivacainesimilar to ropivacaine