Local Anesthetics: Lidocaine, Prilocaine and Bupivacaine

Mechanism

Pharmacological Class and Group

Local anesthetics belonging to the class of Aminoamides (Lidocaine, Prilocaine and Bupivacaine).

Mechanism of Action

Local anesthetics prevent the generation and conduction of nerve impulses in the peripheral sensory axons of the dermis.

Blocking of Voltage Dependent Sodium Channels

1. Diffusion of the Non-Ionized Form: At a physiological dermoepidermal pH of 7.4, a fraction of the local anesthetic molecule is in its free non-ionized (lipophilic) form, which allows it to passively cross the axonal lipid cell membrane of the afferent neurons.

2. Intracellular Protonation and Channel Binding: Once in the cellular axoplasmic cytoplasm, the slightly more acidic pH promotes reionization of the molecule to its positively charged active cationic form.

3. NaV Channel Central Pore Blocking: The cation binds specifically and with high affinity to a receptor site located in the intracellular vestibule of the S6 segment of Domain IV of the voltage-gated sodium channel (NaV):

Anesthetic Amide Binding to the NaV channel Blocking of the Na current⁺ Absence of Action Potential

4. Interruption of Membrane Depolarization: This mechanically blocks the inward sodium current, preventing the electrical depolarization threshold from being reached. The propagation of the sensory action potential through the fast-conducting C and A-δ subgroup pain fibers is stopped.

Pharmacokinetics

High Resolution Pharmacokinetics

• Systemic Absorption: Highly dependent on the vascularization of the injected bed, the total dose administered and the presence of a vasoconstrictor agent (epinephrine). The addition of epinephrine induces local vasoconstriction, decreasing the capillary clearance of the anesthetic, which prolongs the duration of the block by twofold and reduces the systemic plasma peak of toxicity by half.
• Metabolism: Exclusive phase I hepatic metabolism via deakilation and conjugation mediated by cytochrome P450 enzymes (mainly CYP1A2 and CYP3A4 for lidocaine). The metabolism of prilocaine generates the active metabolite o-toluidine.
• Excretion: Elimination by renal filtration in the form of water-soluble metabolites.
• Half-life (t_1/2): Short for lidocaine (1.5-2 hours) and prilocaine (1.6 hours); prolonged for bupivacaine (2.7-3.5 hours), making it ideal for long-term postoperative pain control.

Indicators and dose

Clinical Indications and Off-Label Uses

• Local Infiltration Anesthesia: For performing diagnostic skin biopsies (punch, scraping), removal of skin tumors (basal cell or squamous cell carcinomas, nevi, sebaceous cysts).
• Topical Cutaneous Anesthesia (EMLA Cream): Prior to venipuncture, botulinum toxin injections or hyaluronic acid fillers, photodynamic therapy or curettage of molluscum contagiosum in pediatrics.
• Field Block or Peripheral Nerve Block: Digital nerve block for ingrown toenail surgery (onychocryptosis), supraorbital nerve block for forehead procedures.

Dosage and Clinical Adjustment

Lidocaine 1% or 2% (with or without epinephrine 1:100,000):

• Maximum Dose of Plain Lidocaine (without epinephrine): 4.5 mg/kg (approximately 20-30 mL of 1% solution in an average 70 kg adult).
• Maximum Dose of Lidocaine with Epinephrine: 7 mg/kg (approximately 50 mL of 1% solution, epinephrine slows systemic absorption).

Bupivacaine 0.25% or 0.5%:

• Maximum dose: 2 mg/kg single; 2.5 mg/kg with epinephrine.

EMLA Cream (Lidocaine/Prilocaine):

• Apply a thick layer (approximately 1-2 g per 10 cm² of skin surface) on the area to be operated on and cover with a transparent occlusive adhesive dressing for a minimum of 60 to 120 minutes prior to the procedure.

Adjustment in Renal and Hepatic Failure: No adjustment is required for single doses of minor local infiltration in renal failure; reduce the dose by 50% in Child-Pugh C end-stage liver failure if multiple or repeated infiltrations are planned.

Security

Absolute and Relative Contraindications

Absolute Contraindications

• Known hypersensitivity to amide-type local anesthetics.
• Epinephrine injection in acral territories: Fingers and toes, ear lobe, tip of the nose or penis (due to severe risk of irreversible digital ischemia and gangrene due to terminal vasoconstriction).
• Congenital or idiopathic methaemoglobinemia (for prilocaine).

Relative Contraindications

• Second or third degree heart block or severe untreated arrhythmias (lidocaine is a class Ib antiarrhythmic that slows cardiac conduction).
• Severe liver dysfunction or Child-Pugh C cirrhosis (delays plasma clearance).

Adverse Effects (ADR) and Specific Toxicity

• Very common (topical EMLA): Transient local skin erythema or pallor (due to the direct vasoconstrictor effect of dermoepidermal prilocaine).
• Common: Burning sensation upon injection (mitigated by alkalinizing the solution with sodium bicarbonate in a 1:9 ratio).
• Rare (<0.1%): Local Anesthetic Systemic Toxicity Syndrome (LAST), Acute o-toluidine-induced methaemoglobinemia (associated with the use of prilocaine in large topical doses).

Critical Toxicity: LAST Syndrome and Intravascular Injection Toxicity

Accidental intravascular injection or systemic absorption of massive doses of amide-type anesthetics (especially bupivacaine or lidocaine) triggers severe acute biphasic poisoning with imminent neurological and cardiovascular involvement:

1. Initial Neurological Phase: Metallic taste in the mouth, perioral paresthesias, pulsating tinnitus, slurred speech, progressive psychomotor agitation, muscle tremor and, finally, generalized tonic-clonic seizures.

2. Terminal Cardiovascular Phase (LAST): Bupivacaine persistently blocks cardiac sodium channels in systole, abruptly depressing contractility. It induces refractory bradycardia, extreme prolongation of the PR interval and the QRS complex, ventricular tachycardia, torsades de pointes and asystole.

Severe LAST Refractory Cardiorespiratory Arrest Immediate infusion of 20% Lipid Emulsion

The priority emergency treatment is advanced life support, intubation and immediate administration of 20% lipid emulsion (Intralipid) intravenously (1.5 mL/kg bolus followed by infusion of 0.25 mL/kg/min), which acts as a lipid sink by capturing and extracting anesthetic molecules from the membranes of the myocardium.

Drug Interactions of Clinical Relevance

• Antiarrhythmics (Amiodarone, Sotalol): Synergistic depressant effect on atrioventricular conduction and cardiac contractility.
• Methemoglobinemia Inducing Drugs (Dapsone, Sulfonamides): Co-administered with prilocaine, they substantially increase the risk of refractory cyanosis due to methemoglobin formation.

Safety in Pregnancy and Breastfeeding

• Pregnancy: Compatible with precautions. Lidocaine is the local infiltration anesthetic of choice and is safe in pregnant women (it crosses the placenta but is not associated with teratogenicity at usual doses). Avoid the use of bupivacaine if extensive blocks are planned due to the risk of progesterone-induced cardiotoxicity in pregnant women.
• Breastfeeding: Compatible. It is excreted in clinically negligible quantities in breast milk, and is considered safe for the infant after minor anesthesia of the mother.