Local anesthetics

Local anesthetics

Clinical data
Pharmacodynamics
Pharmacokinetics
Physical and chemical data
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Local anesthetics are the defining medication class for regional and local anesthesia. They transiently inhibit sensory, motor, and autonomic nerve function depending on location/route of administration and dosage.

Uses

Provide anesthesia and analgesia by disrupting the conduction of impulses along nerve fibers

Contraindications

Absolute contraindications

• Local anesthetic allergy:
  • True hypersensitivity reactions to local anesthetics (due to IgG or IgE antibodies) are rare
  • Esters are more likely to induce allergic reactivity, especially if compound (procaine or benzocaine) is a derivative of p-aminobenzoic acid (PABA), a known allergen.

Precautions

Drug interactions:

• Succinylcholine and ester local anesthetics both depend on pseudocholinesterase for metabolism, but there is no evidence that this competition has clinical importance. However, pseudocholinesterase inhibitors (organophosphate poisons) and patients with low pseudocholinesterase activity (low dibucaine number) may have decreased metabolism of ester local anesthetics.
• Drugs that decrease hepatic blood flow (H2 receptor blockers, b-blockers) may decrease amide local anesthetic clearance.

Pharmacology

Pharmacodynamics

Mechanism of action

Local anesthetics target voltage-gated sodium channels. Local anesthetic binding to the intracellular α subunit prevents channel activation and inhibit sodium influx through the channel, resulting in decreased sodium conductance across the membrane.

• Thus, the threshold for excitation and impulse conduction in the nerve increases, and the rate of rise and magnitude of the action potential decreases. Impulse conduction velocity is also slowed.
• Of note, this does not alter the resting membrane potential.

Local anesthetics have greatest affinity for the Na channel in the open or inactivated state as opposed to the resting state. Thus, depolarization favors local anesthetic binding.

Sensitivity of nerve fibers to local anesthetics depends on axonal diameter and myelination.

• Larger, faster-conducting fibers (Aα) are less sensitive to local anesthetics than smaller, slower fibers (Aδ)
• Additionally, small, unmyelinated C fibers are more resistant than larger myelinated fibers.

Adverse effects

Local Anesthetic Systemic Toxicity (LAST)

• More vascular injection sites, dose, the local anesthetic's intrinsic pharmacokinetic properties, and the addition of a vasoactive agent all affect the risk for LAST
• CNS toxicity:
  • Local anesthetics readily cross the blood brain barrier
  • Clinical manifestations: lightheadedness, tinnitus, tongue numbness, metallic taste → CNS excitation (block inhibitory pathways) → CNS depression, seizure → coma
• Cardiovascular toxicity
  • Dose dependent blockade of Na channels → disruptions of cardiac conduction system → bradycardia, ventricular dysrhythmias, decreased contractility, cardiovascular collapse/circulatory arrest
  • Bupivacaine has higher risk of CV toxicity
  • Approximately 3x the amount of local anesthetics are required to produce cardiovascular toxicity than CNS toxicity
  • Addition of epi allows for early detection of intravascular injection and also increases the max allowable dose
• Treatment of LAST:
  • Initial management:
    • Call for intralipid kit
    • ABCs: do you need to support circulation/airway?
    • Stop local anesthetic
    • Give benzodiazepines for seizure
    • Reduce individual epinephrine doses to <1 mcg/kg
    • AVOID: vasopressin, Ca channel blockers, Beta blockers, local anesthetics, and propofol (can further decrease cardiac contractility)
  • Initiate early intralipid (IL) therapy
    • Rapidly give 1.5 cc/kg bolus of 20% intralipid IV (*max 3 doses)
    • Start infusion at 0.25 cc/kg/min (*max rate 0.5 cc/kg/min)
    • If patient remains unstable, may repeat bolus and increase infusion rate

Pharmacokinetics

Absorption of local anesthetics depends on route of administration. The rate of systemic absorption and rise of blood local anesthetic concentration is highly dependent on the vascularity of the site of infection.

In general, IV > tracheal > intercostal > paracervical > epidural > brachial plexus > sciatic > subcutaneous.

Presence of additives, such as epinephrine, can decrease amount of systemic absorption and prolong the duration of the effect at the intended site. Lastly, absorption is affected by lipid solubility of the local anesthetic; more lipid-soluble agents (also highly tissue bound) are more slowly absorbed than less lipid-soluble agents.

Chemistry and formulation

Local anesthetics consist of a lipophilic group and a hydrophilic group connected by an ester or amide linkage. Thus, there are two major classifications of local anesthetics: esters and amides.

• Esters are predominantly rapidly metabolized by pseudocholinesterases and their water soluble metabolites are excreted in the urine.
• Amides are metabolized by p450s in the liver, and the rate depends on the agent but is overall slower than ester hydrolysis. Decreases in hepatic function or liver blood flow will reduce rate of amide metabolism and predispose these patients to risk of systemic toxicity.

Local anesthetics are weak bases. Their onset depends on their lipid solubility and their pKa. Local anesthetics with a pKa closest to physiologic pH will have a greater fraction of nonionized base that more readily permeates the nerve sheath membrane to bind to the Na channel, hence facilitating a more rapid onset of action. Duration of action correlates with potency and lipid solubility. Highly lipid-soluble local anesthetics have longer duration of action as they more slowly diffuse from a lipid-rich environment to the aqueous bloodstream. In general, less potent, less lipid-soluble agents also have faster onset than more potent, more lipid-soluble agents.

ITE tips

Nerves in order of sensitivity to local anesthetics:

• Most sensitive → least sensitive: B fibers > A fibers > C fiber
• Small myelinated fibers (B) are easiest to block, and have least surface area.
• Unmyelinated nerves (C) are the most resistant because surface area of available channels to block is largest.

The correct arrangement of local anesthetics in order of their ability to produce cardiotoxicity from most to least is:

• a. Bupivacaine, lidocaine, ropivacaine
• b. Bupivacaine, ropivacaine, lidocaine
• c. Ropivacaine, bupivacaine, lidocaine
• d. Lidocaine, ropivacaine, bupivacaine