Handbook of Clinical Anesthesia

Chapter 21

Local Anesthetics

Local anesthetics block the conduction of impulses in electrically excitable tissues (Liu SS, Lin Y: Local anesthetics. In Clinical Anesthesia. Edited by Barash PG, Cullen BF, Stoelting RK, Cahalan MK, Stock MC. Philadelphia: Lippincott Williams & Wilkins, 2009, pp 531–548). One of the important uses of local anesthetics is to provide anesthesia and analgesia by blocking the transmission of pain sensation along nerve fibers.

  1. Mechanism of Action of Local Anesthetics
  2. Anatomy of Nerves
  3. Nerves in both the central nervous system (CNS) and peripheral nervous system are differentiated by the presence or absence of a myelin sheath that is interrupted at short intervals by specialized regions called nodes of Ranvier.
  4. Nerve fibers are commonly classified according to their size, conduction velocity, and function (Table 21-1).
  5. Electrophysiology of Neural Conduction and Voltage-Gated Sodium Channels
  6. Transmission of electrical impulses along cell membranes is the basis of signal transduction. Energy necessary for the propagation and maintenance of the electric potential is maintained on the cell surface by ionic disequilibria across the permeable cell membrane. The resting membrane potential (about -60 to -70 mV) is predominantly attributable to a difference in the intracellular and extracellular concentrations of potassium and sodium ions.
  7. The flow of ions responsible for action potentials is mediated by a variety of channels and pumps, the

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most important of which are the voltage-gated sodium channels. (Nine isoforms of voltage-gated sodium channels have been identified.)

Table 21-1 Classification of Nerve Fibers

Classification

Diameter (µ)

Myelin

Conduction (m/sec)

Location

Function

A-α

6–22

+

30–120

Afferents/efferents for muscles and joints

Motor

A-β

Proprioception

A-γ

3–6

+

15–35

Efferent to muscle spindle

Muscle tone

A-δ

1–4

+

5–25

Afferent sensory nerve

Pain Touch Temperature

A

B

<3

+

3–15

Preganglionic sympathetic

Autonomic function

C

0.3–1.3

-

0.7–1.3

Postganglionic sympathetic
Afferent sensory nerve

Autonomic function
Pain Temperature

  1. Molecular Mechanisms of Local Anesthetics
  2. It is widely accepted that local anesthetics induce anesthesia and analgesia through direct interactions with the sodium channels (they reversibly bind the intracellular portion of voltage-gated sodium channels).
  3. Application of local anesthetics typically produces a concentration-dependent decrease in the peak sodium current.
  4. Mechanism of Nerve Blockade
  5. Local anesthetics block peripheral nerves by disrupting the transmission of action potentials along nerve fibers. Only about 1% to 2% of the injected local anesthetics ultimately penetrate into the nerve to

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reach the site of action (voltage-gated sodium channels).

  1. The degree of nerve blockade depends on the local anesthetic's concentration and volume (needed to suppress the regeneration of nerve impulses over a critical length of nerve fiber).
  2. Not all sensory and motor modalities are equally blocked by local anesthetics (sequential disappearance of temperature sensation, proprioception, motor function, sharp pain, and last light touch). This differential blockade had been thought to be simply related to the diameter of the nerve fiber (smaller fibers are inherently more susceptible to drug blockade than large fibers), but this does not appear to be universally true. In this regard, small nerve fibers require a shorter length (<1 cm) exposed to local anesthetic for block to occur than do large fibers.
  3. Pharmacology and Pharmacodynamics
  4. Chemical Properties and Relationship to Activity and Potency
  5. Most clinically relevant local anesthetics are made up of a lipid-soluble, aromatic benzene ring connected to an amide group via either an amide or ester moiety.
  6. The type of linkage divides the local anesthetics into aminoesters (metabolized in the liver or by plasma cholinesterase) and aminoamides (metabolized in the liver).
  7. All clinically used local anesthetics are weak bases that can exist as either the lipid-soluble, neutral form or as the charged, hydrophilic form. The combination of pH and pKa of the local anesthetic determines how much of the compound exists in each form (Table 21-2).
  8. A ratio with high concentration of the lipid-soluble form favors entry into cells because the main pathway for entry is by passive absorption of lipid-soluble form through the cell membrane. Clinically, alkalization of the anesthetic solution increases the ratio of the lipid-soluble form to the cationic form, thereby facilitating drug entry.

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Table 21-2 Physiochemical Properties of Clinically Used Local Anesthetics

Local Anesthetic

pKa

% Ionized (at pH 7.4)

Partition Coefficient (Lipid Solubility)

% Protein Binding

Amides

Bupivacaine*

8.1

83

3420

95

Etidocaine

7.7

66

7317

94

Lidocaine

7.9

76

366

64

Mepivacaine

7.6

61

130

77

Prilocaine

7.9

76

129

55

Ropivacaine

8.1

83

775

94

Esters

Chloroprocaine

8.7

95

810

NA

Procaine

8.9

97

100

6

Tetracaine

8.5

93

5822

94

*Levo-bupivacaine is the same as bupivacaine.
NA = not applicable.

  1. Anesthetic activity and potency are affected by the stereochemistry of local anesthetics.
  2. Ropivacaine and levo-bupivacaine are single enantiomers that were initially developed as less cardiotoxic alternatives to bupivacaine.
  3. The desired improvement in the safety index seems to be present, but it comes at the expense of a slight decrease in potency and shorter duration of action compared with the racemic mixtures.
  4. Additives to Increase Local Anesthetic Activity(Table 21-3)
  5. Epinephrineadded to the local anesthetic solution may prolong the local anesthetic block, increase the intensity of the block and decrease systemic absorption of the local anesthetic.
  6. Vasoconstrictive effects produced by epinephrine augment local anesthetics by antagonizing inherent vasodilating effects of local anesthetics, thus decreasing systemic absorption and intraneural clearance, and perhaps by redistribution of intraneural local anesthetic.

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Table 21-3 Effects of the Addition of Epinephrine to Local Anesthetics

 

Increase Duration

Decrease Blood Levels (%)

Dose or Concentration of Epinephrine

Nerve Block

Bupivacaine

Inconsistent

10–20

1:200,000

Lidocaine

Yes

20–30

1:200,000

Mepivacaine

Yes

20–30

1:200,000

Ropivacaine

Doubtful

0

1:200,000

Epidural

Bupivacaine

Inconsistent

10–20

1:300,000–1:200,000

 

Levobupivacaine

Inconsistent

10

1:200,000–1:400,000

 

Chloroprocaine

Yes

 

1:200,000

 

Lidocaine

Yes

20–30

1:600,000–1:200,000

 

Mepivacaine

Yes

20–30

1:200,000

 

Ropivacaine

Doubtful

 

1:200,000

 

Spinal

Bupivacaine

Inconsistent

 

0.2 mg

 

Lidocaine

Yes

 

0.2 mg

 

Tetracaine

Yes

 

0.2 mg

 
  1. Analgesic effects of epinephrine via interaction with α2-adrenergic receptors in the spinal cord and brain may play a role in the effects of epinephrine added to the local anesthetic solution.
  2. The effectiveness of epinephrine depends on the local anesthetic administered, the type of regional block performed, and the amount of epinephrine added to the local anesthetic solution.
  3. Opioidsadded to the local anesthetic solution placed into the epidural or subarachnoid space result in synergistic analgesia and anesthesia without increasing the risk of toxicity.
  4. α2-Adrenergic agonistssuch as clonidine produce synergistic analgesia via supraspinal and spinal adrenergic receptors. Clonidine also has direct inhibitory effects on peripheral nerve conduction (A and C nerve fibers).

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III. Pharmacokinetics of Local Anesthetics (Tables 21-4 and 21-5)

Plasma concentration of local anesthetics is a function of the dose administered and the rates of systemic absorption, tissue distribution, and drug elimination.

Table 21-4 Typical Peak Plasma Concentrations (Cmax) After Regional Anesthetics

Local Anesthetic or Technique

Dose (mg)

Peak Plasma Concentration (µg/mL)

Time to Peak Plasma Concentration (µg/mL)

Toxic Plasma Concentration (µg/mL)

Bupivacaine

Brachial plexus

150

1.0

20

3

Celiac plexus

100

1.5

17

 

Epidural

150

1.26

20

 

Intercostal

140

0.90

30

 

Lumbar sympathetic

52.5

0.49

24

 

Sciatic/Femoral

400

1.89

15

 

Levo-bupivacaine

Epidural

75

0.36

50

4

Brachial plexus

250

1.2

55

 

Lidocaine

Brachial plexus

400

4.0

25

5

Epidural

400

4.27

20

 

Intercostal

400

6.8

15

 

Mepivacaine

Brachial plexus

500

3.68

24

5

Epidural

500

4.95

16

 

Intercostal

500

8.06

9

 

Sciatic/Femoral

500

3.59

31

 

Ropivacaine

Brachial plexus

190

1.3

53

4

Epidural

150

1.07

40

 

Intercostal

140

1.10

21

 

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Table 21-5 Pharmacokinetic Parameters of Local Anesthetics

Local Anesthetic

Volume of Distribution at Steady State (VDss) (L/kg)

Clearance (L/kg/hr)

Elimination Half-Time (hr)

Bupivacaine

1.02

0.41

3.5

Levo-bupivacaine

0.78

0.32

2.6

Chloroprocaine

0.50

2.96

0.11

Etidocaine

1.9

1.05

2.6

Lidocaine

1.3

0.85

1.6

Mepivacaine

1.2

0.67

1.9

Prilocaine

2.73

2.03

1.6

Procaine

0.93

5.62

0.14

Ropivacaine

0.84

0.63

1.9

  1. Systemic Absorption(Table 21-6)
  2. Decreasing systemic absorption of local anesthetics increases their safety margin in clinical uses. The rate and extent of systemic absorption depends on the site of injection, the dose, the drug's intrinsic pharmacokinetic properties, and the addition of a vasoactive agent.
  3. Distribution
  4. Regional distribution of local anesthetics after systemic absorption depends on organ blood flow, the partition coefficient of the local anesthetic between compartments, and protein binding.
  5. Organs that are well perfused, such as the heart and brain, have higher drug concentrations.

Table 21-6 Determinants of the Rate and Extent of Systemic Absorption of Local Anesthetics

Site of injection (intercostal > caudal > brachial plexus > sciatic or femoral)
Dose

Physiochemical properties (lipid solubility, protein binding)
Addition of epinephrine

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  1. Elimination
  2. Clearance of aminoester local anesthetics primarily depends on clearance by plasma cholinesterase.
  3. Aminoamides are transformed by hepatic carboxylesterases and cytochrome P450 enzyme.
  4. Clinical Pharmacokinetics
  5. The primary benefit of knowledge of the systemic pharmacokinetics of local anesthetics is the ability to predict Cmax(maximum plasma concentration) after the drugs are administered, thus reducing the likelihood of administration of toxic doses.
  6. Pharmacokinetics are difficult to predict in any given circumstance because both physical and pathophysiologic characteristics affect individual pharmacokinetics.
  7. Clinical Use of Local Anesthetics

(Tables 21-7 and 21-8)

  1. Toxicity of Local Anesthetics
  2. Central Nervous System Toxicity
  3. Local anesthetics readily cross the blood–brain barrier, and generalized CNS toxicity may occur from systemic absorption or direct vascular injection.
  4. Development of CNS toxicity is more likely with certain local anesthetics (Table 21-9), and the signs of generalized CNS toxicity from local anesthetics are dose dependent (Table 21-10).
  5. Factors that increase CNS toxicity include decreased protein binding, acidosis, vasoconstriction, and hyperdynamic circulation caused by epinephrine being added to the local anesthetic solution.
  6. Factors that decrease CNS toxicity include drugs (barbiturates, benzodiazepines) and decreased systemic absorption caused by epinephrine being added to the local anesthetic solution.

Table 21-7 Clinical Use of Local Anesthetics

Regional anesthesia and analgesia
Intravenous regional anesthesia
Peripheral nerve blocks (single injection or continuous infusion)
Topical (airway, eye, skin)
Blunt responses to tracheal intubation

  1. P.316
  2. P.317

Table 21-8 Clinical Profile of Local Anesthetics

Local Anesthetic

Concentration (%)

Clinical Use

Onset

Duration (hr)

Recommended Maximum Single Dose (mg)

Amides

Bupivacaine (levobupivacaine)

0.25

Infiltration

Fast

2–8

175/225 + epinephrine

 

0.25–0.5

Peripheral nerve block

Slow

4–12

175/225 + epinephrine

 

0.5–0.75

Epidural anesthesia

Moderate

2–5

175/225 + epinephrine

Lidocaine

0.5–1

Infiltration

Fast

2–8

300/500 + epinephrine

 

0.25–0.5

Intravenous regional

Fast

0.5–1.0

300

 

1.0–1.5

Peripheral nerve block

Fast

1–3

300/500 + epinephrine

 

1.5–2.0

Epidural anesthesia

Fast

1–2

300/500 + epinephrine

 

1.5–2.0

Topical

Fast

0.5–1.0

100

 

4

Topical

Fast

0.5–1.0

300

Mepivacaine

0.5–1.0

Infiltration

Fast

1–4

400/500 + epinephrine

 

1.0–1.5

Peripheral nerve block

Fast

2–4

400/500 + epinephrine

 

1.5–2.0

Epidural anesthesia

Fast

1–3

400/500 + epinephrine

 

2–4

Spinal anesthesia

Fast

1–2

100

Prilocaine

0.5–1.0

Infiltration

Fast

1–2

600

 

0.25–0.5

Intravenous regional

Fast

0.5–1.0

600

 

1.5–2.0

Peripheral nerve block

Fast

1.5–3.0

600

 

2–3

Epidural

Fast

1–3

600

Ropivacaine

0.2–0.5

Infiltration

Fast

2–6

200

 

0.5–1.0

Peripheral nerve block

Slow

5–8

250

 

0.5–1.0

Epidural anesthesia

Moderate

2–6

200

Mixture

Lidocaine + prilocaine

2.5/2.5

Skin topical

Slow

3–5

20 g

Esters

Benzocaine

≤20%

Skin topical

Fast

0.5–1.0

200

Chloroprocaine

1

Infiltration

Fast

0.5–1.0

800/1000 + epinephrine

 

2

Peripheral nerve block

Fast

0.5–1.0

800/1000 + epinephrine

 

2–3

Epidural anesthesia

Fast

0.5–1.0

800/1000 + epinephrine

Cocaine

4–10

Topical

Fast

0.5–1.0

150

Procaine

10

Spinal anesthesia

Fast

0.5–1.0

1000

Tetracaine

2

Topical

Fast

0.5–1.0

20

 

0.5

Spinal anesthesia

Fast

 

20

  1. P.318

Table 21-9 Central Nervous System and Cardiovascular System Toxicity

Local Anesthetic

Relative Potency for CNS Toxicity

Ratio of Dose Needed for CVS:CNS Toxicity

Bupivacaine

4.0

2.0

Levo-bupivacaine

2.9

2.0

Chloroprocaine

0.3

3.7

Etidocaine

2.0

4.4

Lidocaine

1.0

7.1

Mepivicaine

1.4

7.1

Prilocaine

1.2

3.1

Procaine

0.3

3.7

Ropivacaine

2.9

2

Tetracaine

2.0

 

CNS = central nervous system; CVS = cardiovascular system.

  1. The incidence of CNS toxicity with epidural injection of local anesthetics is estimated to be three in 10,000; for peripheral nerve blocks, the incidence is one in 10,000.
  2. Cardiovascular Toxicity of Local Anesthetics
  3. In general, much greater doses of local anesthetics are required to produce cardiovascular toxicity than CNS toxicity (Table 21-10).
  4. Use of single-optical isomer (S/L) preparations of ropivacaine and levo-bupivacaine may improve the safety profile for long-lasting regional anesthesia.

Table 21-10 Dose-Dependent Systemic Effects of Lidocaine

Plasma Concentration (µg/mL)

Effect

1–5

Analgesia

5–10

Light-headedness
Tinnitus
Numbness of tongue

10–15

Seizures
Unconsciousness

15–25

Coma
Respiratory arrest

>25

Cardiovascular depression

  1. P.319
  2. Reduced potential for cardiotoxicity is likely because of reduced affinity for brain and myocardial tissue from their single isomer preparation.
  3. In addition to the stereoselectivity, the larger butyl side chain in bupivacaine may also have more of a cardiodepressant effect as opposed to the propyl side chain of ropivacaine.
  4. Cardiovascular toxicity (hypotension, bradycardia, arterial hypoxemia) produced by less lipid-soluble and potent local anesthetics such as lidocaine is different from that produced by more potent and lipid-soluble anesthetics such as bupivacaine (sudden cardiovascular collapse because of ventricular cardiac dysrhythmias that are resistant to resuscitation).
  5. All local anesthetics block the cardiac conduction system via a dose-dependent block of sodium channels.
  6. Compared with lidocaine cardiotoxicity, bupivacaine cardiotoxicity is enhanced by bupivacaine's stronger binding affinity to resting and inactivated sodium channels.
  7. Local anesthetics bind to sodium channels during systole and dissociate during diastole.
  8. Bupivacaine dissociates more slowly from sodium channels during cardiac diastole than lidocaine.
  9. Bupivacaine dissociates so slowly that the duration of diastole at heart rates between 60 and 180 bpm does not allow enough time for complete recovery of sodium channels, so bupivacaine conduction block increases.
  10. Lidocaine fully dissociates from sodium channels during diastole, and little accumulation of conduction block occurs.
  11. Bupivacaine may inhibit cyclic adenosine monophosphate (cAMP) production, suggesting that large doses of epinephrine (resuscitative effects modulated by cAMP) may be needed during resuscitations from bupivacaine overdose.
  12. Treatment of Systemic Toxicity From Local Anesthetics(Table 21-11)
  13. The best method for avoiding systemic toxicity from local anesthetics is through prevention, including using frequent syringe aspirations, a small local anesthetic test dose (3 mL), and slow injection or fractionation of the dose of local anesthetic.

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Table 21-11 Treatment of Systemic Toxicity from Local Anesthetics

Stop injection of local anesthetic
Administer supplemental oxygen
Support ventilation
Insert tracheal intubation and control ventilation if necessary
Suppress seizure activity (thiopental, midazolam, propofol)
Treat ventricular dysrhythmias (electrical cardioversion, epinephrine, vasopressin, amiodarone; 20% lipid solutions should be considered to remove bupivacaine from its sites of action)

  1. Treatment of systemic toxicity is primarily supportive.
  2. A promising treatment for cardiac toxicity from bupivacaine is intravenous administration of lipid to theoretically remove the local anesthetic from sites of action.
  3. Neural Toxicity of Local Anesthetics
  4. Although all clinically used local anesthetics can cause concentration-dependent nerve fiber damage in peripheral nerves when used in high concentrations, it is believed that clinically used concentrations are safe for peripheral nerves.
  5. Compared with peripheral nerves, the spinal cord and nerve roots are more prone to injury.
  6. Lidocaine and tetracaine may be especially neurotoxic in a concentration-dependent fashion, and this neurotoxicity may theoretically occur with clinically used concentrations.
  7. Despite laboratory findings that all local anesthetics may cause neurotoxicity, spinal administration of local anesthetics in patients has not manifested a neurotoxic potential.
  8. Transient Neurologic Symptoms After Spinal Anesthesia
  9. Transient neurologic symptoms (TNS; pain or sensory abnormalities in the lower back and extremities) may occur after administration of all local anesthetics used for spinal anesthesia (Table 21-12).
  10. Increased risk of TNS is associated with lidocaine, the lithotomy position, and ambulatory anesthesia but not the baricity of the solution or the dose of local anesthetic.

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Table 21-12 Incidence of Transient Neurologic Symptoms After Spinal Anesthesia

Local Anesthetic

Concentration (%)

Type of Surgery

Approximate Incidence of Transient Neurologic Symptoms (%)

Lidocaine

2–5

Lithotomy position

30–36

 

2–5

Knee arthroscopy

18–22

 

0.5

Knee arthroscopy

17

 

2–5

Mixed supine position

4–8

Mepivacaine

1.5–4.0

Mixed

23

Bupivacaine

0.5–0.75

Mixed

1

Levobupivacaine

0.5

Mixed

1

Prilocaine

2–5

Mixed

1

Ropivacaine

0.5–0.75

Mixed

1

  1. The potential neurologic cause of this syndrome coupled with the known concentration-dependent toxicity of lidocaine has led to concerns over a neurotoxic cause for TNS from spinal lidocaine (Table 21-13).
  2. Preservative-free 2-chloroprocaine provides an anesthetic profile similar to lidocaine's without TNS.
  3. Myotoxicity of Local Anesthetics.Local anesthetics have the potential for myotoxicity in clinically applicable concentrations (dysregulation of intracellular calcium concentrations).

Table 21-13 Possible Causes of Transient Neurologic Symptoms

Concentration-dependent neurotoxicity
Patient positioning
Early ambulation
Needle trauma
Neural ischemia
Pooling secondary to maldistribution

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  1. Allergic Reactions to Local Anesthetics
  2. True allergic reactions to local anesthetics, especially aminoamides, are rare.
  3. Increased allergenic potential with ester local anesthetics may be caused by metabolism to para-aminobenzoic acid, which is a known antigen.
  4. Preservatives such as methylparaben and metabisulfite can also provoke an allergic response.

Editors: Barash, Paul G.; Cullen, Bruce F.; Stoelting, Robert K.; Cahalan, Michael K.; Stock, M. Christine

Title: Handbook of Clinical Anesthesia, 6th Edition

Copyright ©2009 Lippincott Williams & Wilkins

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