Local Anesthetic Pharmacology

Local anaesthetic agents can be defined as drugs used clinically to produce a reversible loss of sensation in a circumscribed area of the body.

Most of the clinically useful local anaesthetic agents consist of an aromatic ring linked by a carbonyl-containing moiety through a carbon chain to a substituted amino group.

• Incas used cocaine as a topical anesthetic, dating back to 3000 B.C.
• 1860: Cocaine isolated from coca leaves by Paolo Mantegazza, who tested it on himself.
• 1860: Cocaine formulated into "Dr. Mariani's French Tonic," for which Dr. Mariani received a gold medal from Pope Leo XIII.
• 1884: Cocaine used for topical ophthalmic anesthesia by Carl Koller (at the suggestion of Freud).

• 1984: Cocaine used for peripheral nerve block (Halstead)
• 1886: John S. Pemberton invented Coca Cola, combining cocaine with Cola nitida extract (kola nut).
• 1898: Cocaine first used for spinal anesthesia (Bier) - He personally developed PDPH, which he correctly diagnosed!
• By 1900, the addictive properties of cocaine were well recognized.
• 1904: Fourneau develops stovaine, promptly forgotten
• 1905: Einhorn develops procaine, introduced into clinical practice by Braun. Einhorn called it novocaine, for "new cocaine." He demonstrated that it had all the anesthetic effects, and none of the addictive potential.

The local anesthetic molecule consists of three parts:

1. Aromatic group
2. Linking chain
3. Tertiary amine

There are 2 classes of local anesthetic drugs defined by the nature of the carbonyl-containing linkage group:

• Amide link (NH.CO-)
• Ester link (-COO-)

Amides:

• Lignocaine
• Prilocaine
• Mepivacaine
• Bupivacaine

Relatively stable in solution, are slowly metabolized by hepatic amidases and hypersensitivity reactions to amide local anesthetics are extremely rare.

Esters:

• Cocaine
• Procaine
• Amethocaine
• Chloroprocaine

Relatively unstable in solution and are rapidly hydrolyzed in the body by plasma cholinesterase (and other esterases). One of the main breakdown products is para-amino benzoate (PABA), which is associated with allergic phenomena and hypersensitivity reactions.

Intrinsic Properties Affecting Local Anesthetic Action

• Lipid Solubility: Correlates with potency
• pKa (Acid Dissociation Constant): Correlates with the onset of action
• Protein Binding: Correlates with the duration of action

Nerves

• Small Diameter Nerves: Small diameter nerves are more easily blocked than large diameter nerves.
• Myelinated Nerves: For nerves of the same diameter, myelinated nerves will be blocked before unmyelinated nerves.

Why Preganglionic Nerves: Preganglionic nerves are blocked before the smaller unmyelinated C fibers (pain nerves) in spinal anesthesia.

• Nerves that Fire Frequently: Nerves that fire frequently are preferentially blocked over nerves that fire infrequently.

Rate of Onset

• Potency: Correlates closely with lipophilicity, with more lipophilic local anesthetics being more potent.
• Dose: Increased dose, either by increasing volume or increasing concentration, accelerates the rate of onset.
• Un-ionized Fraction: Adding bicarbonate accelerates the rate of onset.
• Epinephrine: Reduces the rate at which the drug washes away.
• Elimination Pharmacokinetics: Rapidly eliminated drugs demonstrate rapid onset because they are given in relatively higher doses. For example, the intrinsic rate of onset of succinylcholine is fairly slow, but the rapid clearance permits administration of a huge overdose, which clinically results in the rapid onset of drug effect.

Potency, pKa, Lipophilicity

Addition of Bicarbonate

• Lidocaine: 1 cc bicarb / 10 cc drug
• Mepivacaine: 1 cc bicarb / 10 cc drug
• Bupivacaine: 0.1 cc / 10 cc (Note: Hard to not get precipitation)
• Levobupivacaine: Same as bupivacaine

Duration of Action

• Rate of Systemic Absorption:
• Tissue Vascularity
• Use of Epinephrine
• Rate of Elimination:
• Particularly for esters, which are metabolized locally
• General Groups:
• Short: Procaine, chloroprocaine
• Intermediate: Lidocaine, mepivacaine, prilocaine
• Long Acting: Tetracaine, bupivacaine, etidocaine, ropivacaine, levobupivacaine

• Amides:
• Primarily hepatic
• Plasma concentration may accumulate with repeated doses
• Toxicity is dose-related and may be delayed by minutes or even hours from the time of the dose.
• Esters:
• Ester hydrolysis in the plasma by pseudocholinesterase
• Almost no potential for accumulation
• Toxicity is either from direct IV injection (e.g., tetracaine, cocaine) or persistent effects of exposure (e.g., benzocaine, cocaine).

• Dose
• Vascularity:
• Intercostal > Caudal > Epidural > Brachial > Infiltration
• pH:
• Slower absorption if the solution is alkaline because more is bound into the tissues.
• Lipophilicity:
• Slower absorption for more lipophilic drugs because more is bound in the tissues.
• Epinephrine:
• Decreases local blood flow, decreasing absorption.

• Local Anaesthetic Agents: Are relatively free from side effects if administered in an appropriate dosage and in the correct anatomical location.
• Systemic and Localized Toxic Reactions: May occur, usually from:
• Accidental Injection:
• Into blood vessels (Intravascular)
• Into the spinal canal (Intrathecal)
• Administration of an excessive dose of the local anaesthetic agent.
• Main Concern: CNS (Central Nervous System) and Cardiac Toxicity
• CNS:
• Early Signs:
• Lightheadedness
• Dizziness
• Circumoral Paraesthesia
• Visual and/or Auditory Disturbances:
• Difficulty focusing
• Tinnitus
• Progression:
• Anxiety → Disorientation → Drowsiness → Loss of Consciousness
• Shivering, Muscular Twitching, and Tremors → Seizures → Respiratory Arrest
• CNS Toxicity is Exacerbated by Hypercarbia and Acidosis
• Cardiac:
• Hypotension
• All local anaesthetics are negative inotropes
• Cardiac Arrhythmias:
• PVC → Wide QRS → Multiform V-tach → V-fib, or
• Pattern with bupivacaine
• Bradycardia → Asystole
• Pattern with bupivacaine + lidocaine
• With Most Drugs: CNS toxicity precedes cardiac toxicity, providing a warning of impending disaster.
• Key Response: Maintain oxygenation and normal CO2!
• With Bupivacaine: CNS toxicity rapidly progresses to cardiovascular collapse.
• Pregnancy Enhances the Risk of Cardiac Toxicity.
• Risk of Seizure and/or Cardiovascular Collapse is Increased by:
• Cold Temperature (Slows Metabolism)
• Metabolic or Respiratory Acidosis
• Hypoxia

Treatment of Overdose

• Airway:
• 100% oxygen
• Intubate if necessary to ventilate
• CNS:
• Break seizure with propofol, thiopental, or midazolam
• Cardiovascular:
• Amiodarone has demonstrated efficacy. Use 300 mg
• Lidocaine would be a particularly poor choice!
• Resuscitation difficult with bupivacaine, more frequently successful in animal studies following ropivacaine and levobupivacaine overdose.

Neurotoxicity

• Chloroprocaine:
• Low pH and presence of metabisulfite
• Not recommended for spinal anesthesia
• Lidocaine:
• Initially seen with formulation in 10% dextrose
• Now seen with all formulations
• No longer used for spinal anesthesia
• Bupivacaine: Appears free of neurotoxicity

Methemoglobinemia

• 10%: Clinical anoxia
• 60%: Stupor, coma, and death.
• Documented with benzocaine, prilocaine
• Associated with benzocaine and prilocaine
• Treat with methylene blue:
• 1-2 mg/kg given over 5 minutes
• Faster administration may exacerbate methemoglobinemia

• Esters:
• Metabolized by pseudocholinesterase
• Compete with succinylcholine for metabolism, so when given together, each lasts longer
• Metabolism slowed by administration of anticholinesterase (e.g., neostigmine)
• Local Anaesthetic Toxicities are ADDITIVE
• Divide lidocaine dose by 4 to convert to bupivacaine equivalents
• Keep lidocaine/4 + bupivacaine less than 3 mg/kg