Local Anesthetics

Local anesthetics are a group of pharmacological agents that reversibly block the conduction of impulses in electrically excitable tissues. Local anesthetics are used in clinical practice to induce a state of local or regional anesthesia by blocking sodium channels and inhibiting the conduction of painful stimuli via afferent nerves. The effects of local anesthetics are influenced by their physicochemical properties such as lipid solubility and protein binding, as well as nerve anatomy and local tissue conditions. Adverse events, interactions, and contraindications vary depending on the agent that is used.

Last update:

Table of Contents

Share this concept:

Share on facebook
Share on twitter
Share on linkedin
Share on reddit
Share on email
Share on whatsapp

Chemistry and Pharmacodynamics

Chemical structure

  • Weak bases available as salts
  • Basic components of most agents:
    • Lipophilic group (e.g., an aromatic ring)
    • An intermediate chain
    • An ionizable group (e.g., tertiary amines) 
  • Cocaine: a naturally occurring tropane alkaloid
  • Benzocaine: the benzoate ester of para-aminobenzoic acid

Mechanism of action

  • Polar compounds are held together by covalent bonds and have distinct regions of positive and negative charges that result from bonding with atoms including nitrogen, oxygen, and sulfur.
  • Polar compounds are water soluble.
  • Local anesthetics are polar compounds that can acquire nonpolar properties and cross cell membranes. 
  • Once the nonpolar molecule crosses the cell membrane, it reverts to its polar form and binds to the receptor in the sodium channels.
  • Local anesthetics bind to sodium channels and block sodium influx.
  • Blocking sodium influx into the cell prevents membrane depolarization and the conduction of painful stimuli.

Physiologic effects

  • Interruption of sodium influx into neuronal membranes prevents the sudden change in membrane voltage that is necessary for signaling.
  • Rapid-firing autonomic nerve fibers are most susceptible to local anesthetics.
  • Reduction in the sensation of pain without causing a loss of consciousness
  • Paralysis (local nerve block)
  • Nerve fibers transmitting pain are more sensitive than other fibers that carry sensations such as pressure and proprioception, which may remain partially intact.

Pharmacokinetics

Absorption

  • Most local anesthetics are rapidly absorbed into the blood (e.g., lidocaine):
    • Often administered with a vasoconstrictor (e.g., epinephrine) to retard the rate of absorption
    • Longer-acting agents are less dependent on vasoconstrictors.
  • Cocaine is a potent vasoconstrictor owing to its intrinsic sympathomimetic effects:
    • Vasoconstriction results in decreased local blood flow.
    • Decreased blood flow prolongs the local concentration and effect of the anesthetic.

Distribution

  • Phases of absorption and distribution of local anesthetics are the highest in highly vascularized tissues followed by less vascularized tissues and fat.
  • Esters are protein bound to a lesser extent than amides.
  • Renal failure increases the accumulation of local anesthetics.

Metabolism

  • Esters are rapidly hydrolyzed by pseudocholinesterase to para-aminobenzoic acid.
  • Half-life is between 1 and 8 minutes.
  • Amide anesthetics undergo a metabolic pathway that involves aromatic hydroxylation, hydrolysis, and dealkylation.
  • The half-life of amides is longer than that of esters.

Excretion

  • Excreted by the kidneys
  • Amide excretion relies on hepatic metabolism:
    • Reduced hepatic blood flow results in the accumulation of metabolites.
    • Critical illnesses may reduce blood flow to the liver and result in the accumulation of metabolites.
  • Metabolites accumulate in individuals with renal dysfunction.

Pharmacokinetics of commonly used local anesthetics

Table: Pharmacokinetics of commonly used local anesthetics
AgentHalf-life (adults)Onset of actionMetabolismExcretion
Cocaine30 minutes to 1.5 hours15–30 secondsHydrolysis: spontaneous and by plasma pseudocholinesterase; hepaticRenal
Benzocaine11 h15–30 secondsHydrolysis by plasma cholinesterase; hepaticRenal
Procaine7–8 minutes5–10 minutesHydrolysis by plasma cholinesteraseRenal
Lidocaine2 hours45–90 secondsHepatic (CYP1A2 and CYP3A4)Renal
Bupivacaine2–3 hours
  • Infiltration: 2–10 minutes
  • Epidural: 17 minutes
  • Spinal: 1 minute
HepaticRenal
CYP: cytochrome P450

Classification

Classification by structural group

Local anesthetics can be classified into 2 structural groups:

  • Aminoamides (amides):
    • Metabolized in the liver
    • Should be used judiciously in individuals with liver failure
  • Aminoesters (esters):
    • Often cause allergic reactions
    • Metabolized by pseudocholinesterase

Classification by route of administration

Local anesthetics can be classified on the basis of how they are administered.

  • Topical:
    • Lidocaine
    • Prilocaine
    • Benzocaine
    • Cocaine
  • Subcutaneous infiltration:
    • Cocaine
    • Benzocaine
    • Procaine
    • Lidocaine
    • Bupivacaine
    • Ropivacaine
  • Ophthalmologic: tetracaine
  • Neuraxial:
    • Procaine
    • Tetracaine
    • Lidocaine
    • Bupivacaine
    • Ropivacaine

Summary

Table: Classification of local anesthetics
EstersAmides
Topical agentsParenteral agentsIntermediate actingLong acting
  • Cocaine
  • Benzocaine
  • Procaine (short acting)
  • Tetracaine (long acting)
Lidocaine
  • Bupivacaine
  • Ropivacaine

Indications

Local anesthetics are chosen because of their onset of action, potency, and duration of action. The choice of a local anesthetic depends on the clinical needs, tolerance of the individual, and physician preference. Local anesthetics are often used in combination with nonsteroidal anti-inflammatory drugs, opioids, and anticonvulsants.

  • Pain:
    • Used to manage acute pain during or after surgery, trauma, and labor
    • Used in the management of chronic pain resulting from medical conditions
  • Surgery: Anesthesia is necessary during surgery. Local anesthetics play an important role during surgery and may be used in combination with general anesthetics:
    • Dental procedures
    • Eye surgery
    • Rectal surgery
    • Orthopedic surgery
    • Dermatologic surgery
  • Painful medical procedures that may require the use of local anesthetics:
    • Lumbar puncture
    • Bone marrow aspiration and biopsy
    • Intravenous device placement

Adverse Effects and Contraindications

Adverse effects

  • Local side effects include edema and skin blanching.
  • Nervous system:
    • Nerve damage: Temporary or permanent nerve damage is possible.
    • Vasovagal episode due to overactivity of the parasympathetic nervous system
    • Dizziness
    • Tinnitus
    • Metallic taste in the mouth
    • Changes in sensation: tingling, numbness
    • Seizures: mostly associated with the use of bupivacaine 
  • Respiratory:
    • Respiratory depression
    • Coma
  • Hematologic: hematoma
  • Cardiovascular:
    • Hypotension
    • Atrioventricular (AV) conduction delay
    • Arrhythmias
  • Allergy
Table: Adverse effects of some local anesthetics
AgentEffects
Cocaine
  • Cardiovascular:
    • Sympathomimetic
    • Severe hypertension
    • Arrhythmia
  • Cerebrovascular:
    • Intracranial hemorrhage
    • Stroke
  • Psychiatric:
    • Euphoria
    • Hyperexcitability
    • Mania
    • Psychoses
  • High addictive potential
Benzocaine
  • Methemoglobinemia
  • Hypersensitivity
ProcaineHypersensitivity
Tetracaine
  • CNS toxicity
  • Hypersensitivity
Lidocaine
  • Cardiovascular:
    • Bradycardia
    • Arrhythmia
    • Hypotension and shock
    • Coronary artery vasospasm and MI
  • Respiratory:
    • Bronchospasm and dyspnea
    • Respiratory depression and failure
  • Neurotoxicity (e.g., agitation, anxiety, confusion, disorientation, dizziness, euphoria, hallucination, hyperesthesia/hypoesthesia, lethargy, loss of consciousness)
  • Methemoglobinemia
  • Hypersensitivity
  • Cauda equina syndrome
  • Nausea/vomiting
  • Tremor and muscle weakness
  • Tinnitus
Bupivacaine
  • Nausea/vomiting
  • Headache
  • Lumbalgia
  • Sexual dysfunction
  • Restlessness
  • Anxiety
  • Vertigo
  • Tinnitus
  • Tremor, convulsions, myoclonic jerks
  • Cardiovascular collapse
  • Coma
  • Methemoglobinemia
Ropivacaine
  • Hypotension
  • Nausea/vomiting
  • Bradycardia
  • Headache

Contraindications

  • History of allergies
  • Arrhythmia (e.g., Wolff-Parkinson-White syndrome)
  • Methemoglobinemia
  • Glucose-6-phosphate-dehydrogenase (G6PD) deficiency
  • Septicemia and cerebrospinal disease

References

  1. National Center for Biotechnology Information. (2021). PubChem Compound Summary for CID 2337, Benzocaine. Retrieved July 1, 2021, from https://pubchem.ncbi.nlm.nih.gov/compound/Benzocaine 
  2. National Center for Biotechnology Information. (2021). PubChem Compound Summary for CID 4914, Procaine. Retrieved July 1, 2021, from https://pubchem.ncbi.nlm.nih.gov/compound/Procaine
  3. National Center for Biotechnology Information. (2021). PubChem Compound Summary for CID 5411, Tetracaine. Retrieved July 1, 2021, from https://pubchem.ncbi.nlm.nih.gov/compound/Tetracaine
  4. National Center for Biotechnology Information. (2021). PubChem Compound Summary for CID 3676, Lidocaine. Retrieved July 1, 2021, from https://pubchem.ncbi.nlm.nih.gov/compound/Lidocaine
  5. National Center for Biotechnology Information. (2021). PubChem Compound Summary for CID 2474, Bupivacaine. Retrieved July 1, 2021, from https://pubchem.ncbi.nlm.nih.gov/compound/Bupivacaine
  6. Benzocaine: Drug information. (2021). UpToDate, Waltham, MA. Retrieved July 1, 2021, from https://somepomed.org/articulos/contents/mobipreview.htm?14/45/15071?source=see_link
  7. Singh, R., Al Khalili, Y. (2021). Benzocaine. StatPearls. Treasure Island (FL): StatPearls Publishing. http://www.ncbi.nlm.nih.gov/books/NBK541053/ 
  8. Sheikh, N.K., Dua, A. (2021). Procaine. StatPearls. Treasure Island (FL): StatPearls Publishing. http://www.ncbi.nlm.nih.gov/books/NBK551556/ 
  9. Hsu, D.C. (2021). Subcutaneous infiltration of local anesthetics. UpToDate, Waltham, MA. Retrieved July 1, 2021, from https://www.uptodate.com/contents/subcutaneous-infiltration-of-local-anesthetics
  10. Stringer, C.M., Lopez, M.J., Maani, C.V. (2021). Tetracaine. StatPearls. Treasure Island (FL): StatPearls Publishing. Retrieved from http://www.ncbi.nlm.nih.gv/books/NBK535437/
  11. UpToDate. (2021). Tetracaine: Drug information. UpToDate, Waltham, MA. Retrieved July 1, 2021, from https://www.uptodate.com/contents/clinical-use-of-topical-anesthetics-in-children
  12. Beecham, G.B., Bansal, P., Nessel, T.A., Goyal, A. (2021). Lidocaine. StatPearls. Treasure Island (FL): StatPearls Publishing. http://www.ncbi.nlm.nih.gov/books/NBK539881/ 
  13. George, A.M., Liu, M. (2021). Ropivacaine. StatPearls. Treasure Island (FL): StatPearls Publishing. http://www.ncbi.nlm.nih.gov/books/NBK532924/ 
  14. Garmon, E.H., Huecker, M.R. (2021). Topical, local, and regional anesthesia and anesthetics. StatPearls. Treasure Island (FL): StatPearls Publishing. http://www.ncbi.nlm.nih.gov/books/NBK430894/ 
  15. Richards, J.R., Laurin, E.G. (2021). Cocaine. StatPearls. Treasure Island (FL): StatPearls Publishing. http://www.ncbi.nlm.nih.gov/books/NBK430769/ 
  16. Gallelli, L., Gratteri, S., Siniscalchi, A., Cione, E., Sirico, S., Seminara, P., Caroleo, M.C., De Sarro, G. (2017). Drug-Drug interactions in cocaine-users and their clinical implications. Current Drug Abuse Reviews, 10, 25–30. https://doi.org/10.2174/1874473710666170920143344 
  17. Mahajan, A., Derian, A. (2021). Local anesthetic toxicity. StatPearls. Treasure Island (FL): StatPearls Publishing. http://www.ncbi.nlm.nih.gov/books/NBK499964/

Study on the Go

Lecturio Medical complements your studies with evidence-based learning strategies, video lectures, quiz questions, and more – all combined in one easy-to-use resource.

Learn even more with Lecturio:

Complement your med school studies with Lecturio’s all-in-one study companion, delivered with evidence-based learning strategies.

🍪 Lecturio is using cookies to improve your user experience. By continuing use of our service you agree upon our Data Privacy Statement.

Details