Book Reading

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Book Reading

• MILLERS ANESTHESIA
• Sixth Edition

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Chapter 14  Local Anesthetics
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BASIC PHARMACOLOGY
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Chemistry
1. Local anesthetics can be classified as
aminoester or aminoamide compounds 2. The
aromatic ring system gives a lipophilic
(membrane-liking) character 3. The tertiary
amine end is relatively hydrophilic
-amide
  
-ester
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Category

• Esters
• Cocaine, Procaine, Chloroprocaine, Tetracaine
• Amides
• Lidocaine, Mepivacaine, Bupivacaine, Etidocaine,
  Ropivacaine

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pKa

• The fraction of local anesthetic in the
  protonated, cationic form in aqueous solution at
  physiologic pH (7.4) as a function of the pKa of
  the drug
• The drug with the lowest pKa, lidocaine, has the
  smallest fraction of its molecules protonated and
  the largest in the neutral form
• The pH is lower than normal, and local
  anesthetics are more protonated

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Lipophilic-Hydrophilic Balance

• depends on the size of the alkyl substituents
• "Lipophilicity" expresses the tendency of a
  compound to associate with membrane lipids
• Hydrophobicity

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Table 14-2   -- Relative in vitro
conduction-blocking potency and physicochemical
properties of local anesthetics
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ANATOMY OF THE PERIPHERAL NERVE
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Table 14-3   -- Classification of peripheral
nerves according to anatomy, physiology, and
function
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Physiology of Nerve Conduction
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Neurophysiologic Aspects of Phasic Inhibition

• Small myelinated axons are the most susceptible
  to impulse annihilation
• The least susceptible are the small,
  nonmyelinated C fibers
• A? and Adgt Aa and Aßgt C

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CLINICAL PHARMACOLOGY
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General Considerations

• Anesthetic Potency
• Hydrophobicity is a primary determinant of
  intrinsic anesthetic potency
• Onset of Action
• Its pKa determines the speed of onset
• Lower pH of the drug solution results in a slower
  onset time
• The dose or concentration of local anesthetic is
  an another important factor
• Duration of Action
• Hydrophobicity
• Markedly influenced by the peripheral vascular
  effects
• Differential Sensory/Motor Blockade
• Bupivacaine and etidocaine provide an interesting
  contrast

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Factors Influencing Anesthetic Activity in Humans

• Dosage of Local Anesthetic
• ?dosage, then ? duration and ?onset time
• Addition of Vasoconstrictors
• Epinephrine prolongs the duration
• Site of Injection
• The longest latencies and durations are observed
  after brachial plexus blocks
• Carbonation and pH Adjustment of Local
  Anesthetics
• The addition of sodium bicarbonate to local
  anesthetic solutions has also been reported to
  decrease the time of onset
• Mixtures of Local Anesthetics
• Pregnancy
• The spread and depth of epidural and spinal
  anesthesia are greater in pregnant than
  nonpregnant women

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PHARMACOKINETICS

• The amount injected, the rate of absorption, the
  rate of tissue distribution, the rate of
  biotransformation, excretion

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Absorption

• Absorbed into the blood
• Sites of administration
• Volume
• Use of epinephrine
• Highest after intercostal nerve blockade? caudal
  epidural space ? lumbar epidural space ? brachial
  plexus ?subcutaneous tissue

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Distribution

• The rapid disappearance phase
• rapidly equilibrating tissues
• The slow disappearance phase
• the particular compound
• Rapidly extracted by lung tissue
• The mass of skeletal muscle is the largest
  reservoir for local anesthetics
• Etidocaine has a more rapid rate of tissue
  redistribution and biotransformation than
  bupivacaine does

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Table 14-10   -- Pharmacokinetic properties of
various amide local anesthetics
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Biotransformation and Excretion

• Ester, drugs undergo hydrolysis in plasma by
  pseudocholinesterase
• 4.7 mol/mL/hr for Chloroprocaine, fastest rate
• 1.1 mol/mL/hr for procaine
• 0.3 mol/mL/hr for tetracaine
• Aminoamide drugs undergo enzymatic degradation in
  the liver
• Some degradation of lidocaine take place in
  tissues other than liver
• Excretion of the metabolites of amide-type local
  anesthetics occurs through the kidney

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Pharmacokinetic Alterations by Patient Status

• Patient age
• Newborn infants with immature hepatic enzyme
  systems prolonge elimination of aminoamide local
  anesthetics
• Chloroprocaine may offer unique advantages
• Decreased hepatic blood flow or impaired hepatic
  enzyme function (-amide)
• Markedly prolonged in patients with congestive
  heart failure

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Toxicity
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Systemic Toxicity Central Nervous System
Toxicity

• Subjective
• lightheadedness, dizziness, difficulty focusing
  and tinnitus, drowsiness and disorientation
• Objective
• shivering, muscular twitching, tremors, GTC,
  generalized CNS depression, respiratory
  depression and ultimately respiratory arrest
• Correlation exists between potency and
  intravenous CNS toxicity (procaine bupivacaine)
  
• Blockade of the inhibitory pathways allows
  facilitatory neurons to function
• An increase in the dose leads to inhibition of
  the activity of both inhibitory and facilitatory
  circuits
• Respiratory or metabolic acidosis increases the
  risk of CNS toxicity
• Generally be terminated by small intravenous
  doses of benzodiazepines (such as midazolam or
  thiopental)

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Systemic Toxicity Cardiovascular System Toxicity

• Direct Cardiac Effects
• Decrease in the rate of depolarization in
  Purkinje fibers and ventricular muscle
• ? the availability of fast sodium channels in
  cardiac membranes
• ?Action potential duration and the effective
  refractory period
• ?the ratio of the effective refractory period to
  the duration of the action potential
• lidocaine vs. bupivacaine
• ECG ?PR interval, ?QRS complex, sinus
  bradycardia
• All LAs exert a dose-dependent negative inotropic
  action on cardiac muscle
• by affecting calcium influx
• should be antagonized by an increase in
  extracellular Ca2

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Systemic Toxicity Cardiovascular System Toxicity

• Indirect Cardiovascular Effects
• High levels of spinal or epidural blockade can
  produce severe hypotension
• adverse outcomes is associated with delays in
  recognition of the problem, delays in instituting
  airway support ,and delays in administration of
  direct-acting combined a- and ß-adrenergic
  agonists

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Systemic Toxicity Cardiovascular System Toxicity

• Direct Peripheral Vascular Effects
• Biphasic effect
• Low concentrations produce vasoconstriction
• High concentrations produce vasodilation
• Cocaine is the only one that consistently causes
  vasoconstriction at all concentrations
• inhibit the uptake of norepinephrine and thus
  potentiate neurogenic vasoconstriction
• Increases in pulmonary vascular resistance

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Comparative Cardiovascular Toxicity

• The CC/CNS ratio ( ratio of the dosage required )
• Irreversible cardiovascular collapse (CC) and the
  dosage that will produce CNS toxicity
  (convulsions)
• Lidocaine was 7.1 1.1
• bupivacaine was 3.7 0.5
• etidocaine was4.4 0.9
• The CC/CNS blood level ratio for lidocaine was3.6
  0.3 versus 1.6 to 1.7 for bupivacaine and
  etidocaine
• Enhanced Cardiotoxicity in Pregnancy
• CC/CNS dose ratio of bupivacaine decreased
  from3.7 0.5 to 2.7 0.4

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• Ventricular Arrhythmias
• Bupivacaine and a lesser degree etidocaine may
  induce severe cardiac arrhythmias
• Ventricular arrhythmias were rarely seen with
  lidocaine, mepivacaine, or tetracaine
• Lead to a reentrant type of arrhythmia similar to
  torsades de pointes

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• Acidosis and Hypoxia
• potentiate the negative chronotropic and
  inotropic action of lidocaine and bupivacaine
• Hypercapnia, acidosis, and hypoxia occur very
  rapidly after seizure activity induced by the
  rapid accidental intravascular injection of LAs

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Methemoglobinemia

• After the use of large doses of prilocaine
• 600-mg doses are required
• The metabolism in the liver results in the
  formation of O-toluidine
• is responsible for the oxidation of hemoglobin to
  methemoglobin
• Spontaneously reversible or be treated by
  methylene blue
• The use of EMLA

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Allergies

• Aminoester drugs
• are derivatives of p-aminobenzoic acid? allergen
• Aminoamide
• are not derivatives of p-aminobenzoic acid
• allergic reactions are extremely rare
• solutions may contain methylparaben (a
  preservative
• chemical structure is similar to that of
  p-aminobenzoic acid

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Local Tissue Toxicity

• Direct toxicity to nerves
• High intraneural concentrations (5 lidocaine )
• Irreversible block in desheathed nerve by
  lidocaine has a threshold of 20 mM (0.5) and a
  50 effective concentration (EC50) of 45 mM
  (1.1) versus an EC50 of 1 mM for reversible
  impulse blockade
• Combination of low pH, sodium bisulfite, and
  inadvertent intrathecal dosing is responsible in
  part for the neurotoxic reactions observed after
  the use of large amounts of chloroprocaine
• Transient neurologic symptoms (back pain,
  paresthesias, radicular pain, or hypoesthesia)
• mepivacaine and lidocaine cause more frequent
  symptoms than bupivacaine does
• lidocaine was 6.7-fold higher than with
  bupivacaine and 5.5-fold higher than with
  prilocaine
• Intraoperative positioning also appears to be a
  risk factor? lithotomy position and
  Trendelenburg position
• Skeletal muscle changes
• Reversible, and muscle regeneration occurs
  rapidly and is complete within 2 weeks after the
  injection of local anesthetics

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CHOICE OF LOCAL ANESTHETIC FOR VARIOUS REGIONAL
ANESTHETIC PROCEDURES
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Infiltration Anesthesia

• The onset of action is almost immediate for all
  agents
• Epinephrine will prolong the duration by all
  local anesthetics
• When large surface areas have to be anesthetized,
  large volumes of dilute anesthetic solutions
  should be used
• when performing infiltration anesthesia in
  infants and smaller children
• Pain immediately after the subcutaneous injection
  of local anesthetics
• acidic nature

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Table 14-4   -- Infiltration anesthesia
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Intravenous Regional Anesthesia

• Intravenous administration of a local anesthetic
  into a tourniquet-occluded limb (i.e., Bier
  block)
• The safety and efficacy depend on the
  interruption of blood flow to the involved limb
  and gradual release of the occluding tourniquet
• Primarily for surgical procedures on the upper
  limbs
• Lidocaine has been the drug used most frequently
• 3 mg/kg (40 mL of a 0.5 solution) of
  preservative-free lidocaine without epinephrine
  for upper limbs
• 50 to 100 mL of 0.25 lidocaine for lower limbs
• A safety advantage with the aminoester-linked
  compounds because of their hydrolysis in blood
• Use of bupivacaine is discouraged

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Peripheral Nerve Blockade

• Major Minor nerve blockade
• Major two or more distinct nerves or a nerve
  plexus
• Minor such as the ulnar or radial nerve
• The duration of both sensory analgesia and motor
  blockade is prolonged significantly when
  epinephrine is added
• Intrapleural regional analgesia

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Table 14-5   -- Minor nerve blocks
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Peripheral Nerve Blockade

• Brachial plexus blockade is the most common major
  peripheral nerve block technique
• Intermediate potency exhibit more rapid onset
  than the more potent compounds do
• Etidocaine may be an exception
• Epinephrine is less effective with drugs that
  have intrinsically longer durations of action

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Table 14-6   -- Major nerve blocks
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Central Neural Blockade

• Epidural anesthesia Spinal anesthesia
• The duration of short- and intermediate-acting
  drugs is significantly prolonged by the addition
  of epinephrine (1200,000)
• For EA, bupivacaine
• at 0.125 adequate analgesia with only mild motor
  deficits
• ? painless
• at 0.25 more intense analgesia with moderate
  degrees of motor blockade
• ? combined epidural-light general anesthesia
• 0.5 to 0.75 more profound degree of motor block
• ? major operation without general anesthesia

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Table 14-7   -- Epidural anesthesia
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Central Neural Blockade

• For spinal anesthesia
• Tetracaine hypobaric, isobaric, hyperbaric
• Bupivacaine hyperbaric solution(0.75 with 8.25
  dextrose) or nearly isobaric 0.5 solution
• Both sensory and motor block is significantly
  longer with tetracaine
• Bupivacaine has been reported in some studies to
  be associated with less hypotension
• Frequency of tourniquet pain in the lower limbs
  is significantly reduced with bupivacaine

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Topical Anesthesia
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Tumescent Anesthesia

• The subcutaneous injection of large volumes of
  dilute local anesthetic in combination with
  epinephrine and other agents
• Plastic surgeons during liposuction procedures
• Total doses of lidocaine ranging from 35 to 55
  mg/kg, which may peak more than 8 to 12 hours
  after infusion
• Clinicians should use great caution

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Systemic Local Anesthetics for Neuropathic Pain

• Allodynia(???), causalgia(???), and other sensory
  disturbances from nerve injury, diabetes, and
  herpes infection
• Neuropathic pain and that such impulses are
  particularly sensitive to use-dependent Na
  channel blockers
• The mechanism of this remarkable action remains a
  mystery

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Thanks for your attention!