Local anesthetics: classification (esters and amides), mechanism of action, and toxicity

1. Mechanism of action

LAs are weak bases (pKa 7.6–9). In tissues, they exist in two forms: uncharged (lipophilic, penetrates the membrane) and charged (hydrophilic, binds to the Na⁺ channel). They block the Na⁺ channel from the inner surface of the membrane, preferentially in the open and inactivated states → ↓ rate of depolarization → impulse conduction block.

In inflamed tissue acidosis, the fraction of the uncharged form decreases → reduced LA efficacy in the area of infection.

2. Classification

3. Key drug characteristics

Lidocaine (xylocaine)

• Amide, onset of action 2–5 min, duration 60–120 min.
• Infiltration 0.5–1%; regional block 1–2%; epidural 1.5–2%; spinal 5% is not used (neurotoxicity).
• Max dose: 4.5 mg/kg without epinephrine, 7 mg/kg with epinephrine.
• Also used as an antiarrhythmic (Class Ib).

Bupivacaine (marcaine)

• Long duration of action — 4–12 hours.
• Epidural, spinal, peripheral nerve block.
• Max dose: 2 mg/kg (maximum 175 mg per injection).
• The most cardiotoxic LA — heart-to-brain ratio of 2:1 (compared to 7:1 for lidocaine). The levorotatory isomer (levobupivacaine) is safer.

Ropivacaine

• Pure S-isomer, lower cardiotoxic potential than bupivacaine.
• Differential block: greater sensory and lesser motor block — convenient for obstetrical epidural analgesia.
• Max dose: 3 mg/kg.

Articaine

• Amide with an ester side chain (metabolized by esterases as well — faster).
• High tissue diffusion — popular in dentistry.
• Max dose: 7 mg/kg.

Procaine (novocaine)

• Ester, short duration of 30–60 min.
• High risk of allergy due to PABA.
• Declining use; obsolete.

4. Routes of administration

• Surface (topical): mucous membranes, skin — EMLA, tetracaine, lidocaine 2–5%.
• Infiltration: layered administration into tissues.
• Nerve block: blockade of a nerve trunk.
• Regional: blockade of plexuses (brachial, lumbar), intercostal, paravertebral.
• Spinal: intrathecal into the subarachnoid space (hyperbaric bupivacaine).
• Epidural: into the epidural space, continuous via catheter.
• Intravenous regional anesthesia (Bier's block): exsanguination + tourniquet placement + IV lidocaine injection.

5. Adjuvants

• Epinephrine 1:200,000 — vasoconstriction → ↑ duration, ↓ systemic absorption, ↑ maximum dose. Contraindicated in end-arterial areas (fingers, ear, nose, penis) due to risk of ischemia; modern data challenge this restriction, but it is traditionally avoided.
• Sodium bicarbonate — accelerates the onset of action and reduces injection pain (alkalinization).
• Opioids (fentanyl, morphine) — epidural/spinal to enhance analgesia.
• Clonidine, dexmedetomidine — α2-agonists, prolong the block.

6. Local anesthetic systemic toxicity (LAST)

Signs

• CNS (early): metallic taste, tongue numbness, tinnitus, dizziness, psychosis → seizures → altered mental status, coma.
• Cardiovascular (late): hypotension, bradycardia, QRS prolongation, AV block, ventricular arrhythmias, cardiac arrest.
• Bupivacaine can cause CVS toxicity without preceding CNS symptoms.

Causes

• Intravascular injection (primary cause).
• Exceeding the maximum dose.
• Rapid absorption (highly vascular areas: intercostal > caudal > epidural > brachial plexus).

Prevention

• Aspiration before each injection.
• Test dose with epinephrine (↑ HR/BP upon IV administration).
• Ultrasound guidance for blocks.
• Do not exceed maximum doses.

7. LAST Management

1. Stop injection.
2. Ensure patent airway, 100% oxygen.
3. Manage seizures: benzodiazepines (midazolam, diazepam).
4. Hemodynamics: low-dose epinephrine (10–100 mcg); avoid vasopressin, β-blockers, lidocaine.
5. 20% lipid emulsion (Intralipid): 1.5 mL/kg bolus over 2–3 min, then infusion 0.25 mL/kg/min; repeat bolus if instability persists.
6. In cardiac arrest — standard ACLS + ECMO as a bridge to LA metabolism.

8. Allergic reactions

• True IgE-mediated reactions are rare (< 1%), more commonly PABA with esters.
• Frequent cause of "allergy" — epinephrine-induced tachycardia, vasovagal reactions, parabens irritation.
• In confirmed allergy — switch to another class (from esters to amides).

9. Methemoglobinemia

• Most common with — prilocaine, benzocaine.
• Clinical presentation: cyanosis, SpO₂ 85–90% unresponsive to oxygen.
• Diagnosis: co-oximetry.
• Treatment: methylene blue 1–2 mg/kg IV.

10. Specifics in pregnant women

• Decreased protein binding → ↑ free fraction → higher toxicity.
• Bupivacaine during pregnancy is more cardiotoxic — ropivacaine or levobupivacaine are preferred.
• Spinal anesthesia — preferred technique for C-section.

11. FAQ

Why is lidocaine less effective in inflamed tissue?
Low pH → lower fraction of the uncharged form that crosses the membrane. Adding bicarbonate and injecting outside the inflammation zone improves the effect.

What is the difference between spinal and epidural anesthesia?
Spinal — into the subarachnoid space, ~2 mL LA, block in 3–5 min, duration 2–4 h. Epidural — 15–20 mL, via catheter, slower onset, adjustable duration.

Is epinephrine in end-artery areas always contraindicated?
Systematic reviews show safety with careful use. The traditional taboo is being reconsidered, but caution remains in practice.

What to do if LAST is suspected?
Immediately start ABC + lipid emulsion. Do not wait for full-blown clinical signs — time is critical.

Why is articaine better than lidocaine in dentistry?
High lipophilicity and rapid metabolism → good bone diffusion and short systemic exposure. In Russia, it is the primary LA in dentistry.

See also: Analgesics · Antiarrhythmics · Muscle relaxants · Pharmacology Catalog · Clinical Scales