Local Anesthetics

Ed Bilsky, Ph.D.

Department of Pharmacology

University of New England

Therapeutic Rationale

• Local anesthetics work by reversibly inhibiting nerve conduction by blocking Na+ channels

• Blockade of different peripheral nerves is dose-dependent– termed ‘differential nerve block’, a sequence of blockade of sharp pain,

cold, warmth, touch, and finally conduction in motor fibers

• Site directed injections localize the action of the drug– choice of local anesthetic depends on the site of

injection and the duration of action needed

Effects on Different Fibers

Fiber type Function Diameter (m)MyelinationVelocity (m/s)Sensitivity

Type A

Alpha Proprioception, Motor 12-20 Heavy 70-120 +

Beta Touch, Pressure 5-12 Heavy 30-70 ++

Gamma Muscle Spindles 3-6 Heavy 15-30 ++

Delta Pain, Temperature 2-5 Light 12-30 +++

Type B Preganglionic <3 Light 3-15 ++++

Type C

Dorsal root Pain 0.4-1.2 None 0.5-2.3 ++++

Sympathetic Postganglionic 0.3-1.3 None 0.7-2.3 ++++

Pharmacokinetics

Onset Duration

Esters

Procaine Slow Short

Chloroprocaine Fast Short

Tetracaine Slow Long

Amides

Lidocaine Fast Moderate

Mepivacaine Fast Moderate

Bupivacaine Moderate Long

Ropivacaine Moderate Long

Etidocaine Fast Long

Medicinal Chemistry

• Chemical Structure– Most local anesthetics consist

of a lipophilic group (aromatic ring) connected by an intermediate chain to an ionizable group (usually a tertiary amine)

• Optimal activity requires a delicate balance between the lipophilic and hydrophilic strengths of these groups

CH3

CH3

NH C

O

CH2 N

C2H5

C2H5

LipophillicGroup

IntermediateChain

AmineSubstituents

Lidocaine

Amides Versus Esters

Lidocaine (amide) NH C

O

CH3

CH3

CH2 N

C2H5

C2H5

C

O

N

C2H5

C2H5

H2N O CH2 CH2Procaine (ester)

Mechanism of Action

• Local anesthetics need to enter into nerve cells– lipophilic properties allow for membrane diffusion

• Local anesthetics need to interact with the inside of voltage gated Na+ channels– these drugs are typically weak bases: under

physiological conditions these drugs tend to carry a positive charge and are hydrophillic

– the cationic form of the drug is the most active inside sodium channels

Mechanism of Action

• A characteristic blocking effect is observed with local anesthetics

• Nearly full sized Na+ currents can be elicited during the first depolarizing impulse in the presence of a local anaesthetic

• Subsequent impulses elicit smaller and smaller peak currents

• It has been hypothesized that the drug binds cumulatively and that this block needs open channels

• This accumulation of inhibition has been called use-dependent block or phasic block

Clinical Question

Observation:

• Dentists frequently observe that local anesthetics are less effective in infected tissues

Question:

• What might be a mechanistic explanation for this observation?

Pharmacokinetics-Absorption

• Local anesthetics are usually administered by localized injection– the onset of effect is therefore typically rapid

• The systemic absorption of these drugs from the site of injection is of considerable importance– rate of offset of anesthesia– CNS toxicity– cardiac toxicity

Pharmacokinetics-Absorption

• A vasoconstrictive agent such as norepineprhine is commonly co-administered with some local anesthetics– decreases blood flow to injection site– lowers the systemic absorption of the local

anesthetic– prolongs the duration of anesthesia

• Cocaine has a unique pharmacological profile– blocks reuptake of NE --> produces

vasoconstriction

Types of Anesthesia

• Surface anesthesia– liquid spray or drops– lotions, creams or ointments

• Localized injection– infiltration anesthesia– nerve block anesthesia– epidural anesthesia– spinal anesthesia

Adverse Reactions and Toxicity

• Central Nervous System effects– all local anesthetics can act on the CNS– anxiety, paresthesias, tremors, tinnitus,

convulsions– high plasma concentrations can produce CNS

depression

• Cardiovascular effects– most local anesthetics produce vasodilation– cardiac depressant effects through Na+ channels

Adverse Reactions and Toxicity

• Allergic reactions (ester containing drugs)– anaphylaxis (rare)– contact dermatitis

• Spinal anesthetic effects– variable hypotension– spinal headache