Local anesthetic agents

Local anesthetics (LAs) are drugs that block the sensation of pain in the region where they are administered. LAs act by reversibly blocking the sodium channels of nerve fibers, thereby inhibiting the conduction of nerve impulses. Nerve fibers that carry pain sensation have the smallest diameter and are the first to be blocked by LAs. Loss of motor function and sensation of touch and pressure follow, depending on the duration of action and dose of the LA used. LAs can be infiltrated into skin/subcutaneous tissues to achieve local anesthesia or into the epidural/subarachnoid space to achieve regional anesthesia (e.g., spinal anesthesia, epidural anesthesia). Some LAs (lidocaine, prilocaine, tetracaine) are effective on topical application and are used before minor invasive procedures (venipuncture, bladder catheterization, endoscopy/laryngoscopy). LAs are divided into two groups based on their chemical structure. The amide group (lidocaine, prilocaine, mepivacaine, etc.) is safer and, hence, more commonly used in clinical practice. The ester group (procaine, tetracaine) has a higher risk of causing allergic reactions or systemic toxicity and is, therefore, reserved for patients with known allergies to drugs of the amide group. Overdose or inadvertent injection of an LA into a blood vessel can cause systemic toxicity, which mainly affects the CNS (tinnitus, seizures, etc.) and the CVS (bradycardia, arrhythmias, etc.).

• LAs have a lipophilic group linked with a hydrophilic group
• Ester group
  • Metabolized in the serum by esterases
  • Have a higher risk of causing allergic reactions or systemic toxicity
• Amide group
  • Metabolized in the liver
  • Safer than the ester agents
  • Should be used when patients are allergic to esters

Ester LAs do not contain an “i” in their name preceding “-caine.” Amide LAs contain an "i" in their name preceding “-caine.”

References:^[1][2][3]

• Pain pathway: thermal, mechanical, or chemical stimuli → nociceptor stimulation → conversion of stimulus to an electric signal (action potential) → neural conduction of electric signal to the CNS → perception of pain
• LAs bind to the inner portion of voltage-gated sodium channels of the nerve fibers; → reversible blockage of sodium channels → inhibition of nerve excitation and impulse conduction (pain signals) → local anesthesia in the area supplied by the nerve
• LAs with 3° amine structure infiltrate membranes in their uncharged form, then bind to ion channels in their charged form.
• The susceptibility of nerve fibers to LA depends on their firing rate, size, and myelination.
  • Rapidly firing neurons are blocked more effectively than slow-firing neurons.
  • Small diameter nerves are the first to be anesthetized.
  • Myelinated nerves are blocked faster than unmyelinated nerves.
  • Because size is thought to outweigh myelination, nerve fibers are blocked in the following order:
    1. Small myelinated fibers
    2. Small unmyelinated fibers
    3. Large myelinated fibers
    4. Large unmyelinated fibers
  • Loss of sensation occurs in the following order:
    1. Pain
    2. Temperature
    3. Touch
    4. Pressure
• Factors that affect the efficacy of LA
  • Use of vasoconstrictors (e.g., adrenaline) reduces bleeding and systemic absorption of LAs, leading to a prolonged anesthetic effect.
  • Inflamed/infected tissue: decreased efficacy of LAs
    • LAs are composed of a lipophilic group and a hydrophilic group, and permeability depends on which group is predominant.
    • Because inflamed tissue has an acidic environment, alkaline anesthetics are charged; and the hydrophilic group predominates → ↓ ability to penetrate the nerve cell membranes → ↓ efficacy

References:^{[4][5][6][7][8][9]}

• Complications are uncommon
• Allergy
  • Acute: anaphylaxis (rare)
  • Delayed: pruritic rash with blisters at site of LA injection within 72 hours of administration
• Vasovagal syncope
• Systemic toxicity
  • Central nervous system
    • Tinnitus, metallic taste, perioral paresthesia
    • Seizures
  • Cardiovascular system (especially with bupivacaine)
    • Bradycardia; , decreased cardiac contractility; , atrioventricular block
    • Ventricular arrhythmias (especially cocaine)
    • Can cause hypertension or hypotension
    • Cardiogenic shock
  • Hematologic: methemoglobinemia (especially benzocaine) → cyanosis, gray skin color, fatigue

References:^[5][9][10]

We list the most important adverse effects. The selection is not exhaustive.

• Local anesthetic agents have a wide range of clinical uses
• Topical application (lidocaine, tetracaine, prilocaine)
  • Useful in children, e.g., in form of a lidocaine patch, before performing minor invasive procedures, such as venipuncture or intravenous catheter placement
  • As a gel: prior to catheterizing the bladder (as a lubricant and as an LA)
  • As a mouth gargle/spray: prior to performing indirect laryngoscopy, endoscopy, etc.; in pharyngitis with odynophagia
• Infiltration
  • Into the skin/subcutaneous tissue: for skin surgery (skin biopsy, suturing, foreign body extraction, etc.)
  • Into the epidural space for epidural anesthesia
  • Into the subarachnoid space for spinal anesthesia

References:^[9]