What is the pharmacology of local anesthetics?

From the Guidelines

Local anesthetics work by temporarily blocking nerve conduction to prevent pain sensation, and their pharmacology is characterized by inhibiting sodium channels in nerve cell membranes, preventing the generation and propagation of action potentials, as seen with lidocaine, an amide local anesthetic, which blocks sodium ion channels required for the initiation and conduction of neuronal impulses, resulting in local anesthesia after topical application 1.

Key Characteristics of Local Anesthetics

• They are classified as either amide-type (lidocaine, bupivacaine, ropivacaine) or ester-type (procaine, tetracaine) 1.
• Amides are metabolized in the liver while esters are broken down by plasma cholinesterases.
• The onset, potency, and duration vary among agents:
  • Lidocaine works quickly (2-5 minutes) with moderate duration (1-2 hours) 1.
  • Bupivacaine has a slower onset (5-10 minutes) but longer duration (4-8 hours) 1.

Administration Routes and Effects

• Local anesthetics can be administered through various routes including topical application, infiltration, peripheral nerve blocks, and neuraxial techniques.
• The addition of epinephrine (typically 1:100,000 or 1:200,000) to local anesthetics causes vasoconstriction, which reduces systemic absorption, prolongs duration of action, and decreases bleeding at the site.

Potential Adverse Effects

• Systemic toxicity (causing CNS excitation followed by depression, and cardiovascular effects like hypotension and arrhythmias) 1.
• Allergic reactions (more common with ester-type) 1.
• Tissue toxicity with prolonged exposure.

Maximum Recommended Doses

• The maximum recommended doses for local anesthetics vary by agent and are influenced by factors such as the presence of epinephrine and the patient's age and weight 1.
• For example, the maximum dose of lidocaine with epinephrine is 7.0 mg/kg, while the maximum dose without epinephrine is 4.4 mg/kg 1.

Recent Guidelines and Recommendations

• Recent guidelines recommend careful consideration of the risks and benefits of local anesthetic use, particularly in pediatric patients 1.
• The use of long-acting local anesthetics, such as bupivacaine and ropivacaine, is recommended for postoperative pain management in children, with maximum doses of 1 ml/kg (= 2.5 mg/kg) and 1.5 ml/kg (= 3 mg/kg), respectively 1.

From the FDA Drug Label

Local anesthetics block the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential

In general, the progression of anesthesia is related to the diameter, myelination, and conduction velocity of affected nerve fibers.

Clinically, the order of loss of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone.

The pharmacology of local anesthetics involves blocking nerve impulses by increasing the threshold for electrical excitation, slowing nerve impulse propagation, and reducing the rate of rise of the action potential. The order of loss of nerve function is:

• Pain
• Temperature
• Touch
• Proprioception
• Skeletal muscle tone 2 3

From the Research

Mechanism of Action

• Local anesthetics act on nerve endings or around nerve trunks, combining with specific sodium ion (Na+) channel sites on the nerve membrane 4.
• They affect the membrane potential by reducing Na+ passage through sodium ion channels, thus blocking the generation and conduction of nerve impulses 4.
• Local anesthetics reversibly block the generation and conduction of sensory nerve impulses 4.

Classification and Potency

• Local anesthetic agents can be classified according to their intrinsic anesthetic potency and duration of activity 5.
• Agents can be categorized as:
  • Low potency and short duration of action (e.g., procaine and chloroprocaine) 5, 6.
  • Intermediate potency and duration of action (e.g., lidocaine, mepivacaine, and prilocaine) 5, 6.
  • High potency and long duration of action (e.g., tetracaine, bupivacaine, and etidocaine) 5, 6.

Pharmacokinetics

• The blood level of local anesthetics is determined by the rate of uptake, tissue redistribution, metabolism, and excretion 6.
• The rate of vascular absorption is a function of the site of injection, dosage, inclusion of a vasoconstrictor in the local anesthetic solution, and the specific drug employed 6.
• Amino esters are eliminated by means of enzymatic hydrolysis in blood, while amino amides are metabolized primarily in the liver 6.

Toxicity

• The toxicity of local anesthetic drugs is usually due to inadvertent rapid intravascular injection or extravascular administration of an excessive amount 5.
• Intravascular toxicity is correlated with intrinsic anesthetic potency, whereas toxicity following extravascular injections is a function of physiological disposition characteristics of the various agents 5.
• The central nervous system is most susceptible to the toxic effects of local anesthetic agents, with signs and symptoms of CNS excitation followed by depression being the most common manifestations of local anesthetic toxicity 5.

Drug Delivery Systems

• Local anesthetics have been widely used in clinical practice, but their neurotoxicity and short half-lives have significantly limited their clinical applications 7.
• Numerous drug delivery systems have been designed to encapsulate local anesthetic agents, allowing for slow release and prolonged analgesia 7.
• Polymer-based delivery platforms are the most extensively explored, especially in the form of polymeric nanoparticle carriers, due to their excellent biocompatibility, biodegradability, and versatility 7.