1. Local Anesthetics Ed Bilsky, Ph.D. Department of Pharmacology University of New England

2. 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

3. Effects on Different Fibers Fiber typeFunctionDiameter (  m)MyelinationVelocity (m/s)Sensitivity Type A AlphaProprioception, Motor12-20Heavy70-120+ BetaTouch, Pressure5-12Heavy30-70++ GammaMuscle Spindles3-6Heavy15-30++ DeltaPain, Temperature2-5Light12-30+++ Type BPreganglionic<3Light3-15++++ Type C Dorsal rootPain0.4-1.2None0.5-2.3++++ SympatheticPostganglionic0.3-1.3None0.7-2.3++++

4. Pharmacokinetics OnsetDuration Esters ProcaineSlowShort ChloroprocaineFastShort TetracaineSlowLong Amides Lidocaine Fast Moderate MepivacaineFast Moderate BupivacaineModerateLong RopivacaineModerateLong EtidocaineFastLong

5. 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 Lidocaine

6. Amides Versus Esters Lidocaine (amide) Procaine (ester)

7. 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

8. 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

10. 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?

11. 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

12. 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

13. Types of Anesthesia Surface anesthesia –liquid spray or drops –lotions, creams or ointments Localized injection –infiltration anesthesia –nerve block anesthesia –epidural anesthesia –spinal anesthesia

14. 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

15. Adverse Reactions and Toxicity Allergic reactions (ester containing drugs) –anaphylaxis (rare) –contact dermatitis Spinal anesthetic effects –variable hypotension –spinal headache