Local Anesthetics

M.7, W.3, L.10

Define nociceptor, nociception, and noxious stimuli

• Nociceptor - specialized pain receptor that generates an AP

• Nociception - detection of noxious stimuli that actually or potentially causes damage to an organism

  • NOT THE SAME AS PAIN

• Noxious - harmful, poisonous or very unpleasant

Describe the Mechanism of Action of local anesthetics

• block voltage-gated sodium (NA+) channels in afferent nerve fibers

• This prevents:

  • initiation of APs

  • propagation/conduction of nerve impulses

• W/out NA+ influx, depolarization cannot occur, so pain signals cannot travel from the periphery to the CNS

Describe the physiological basis of Local Anesthetics

Normal pain transmission:

1. Nociceptors detect tissue damage

2. Action potentials travel along afferent fibers

3. Signals are processed in the spinal cord and brain

• Local Anesthetics interrupt this pathway by preventing nerve conduction

Weak Base Properties

LAs are weak bases:

BH+ ↔ B + H+

• The uncharged form (B) crosses lipid membranes

• The charged form (BH+) blocks sodium channels inside the neuron

Because diffusion across membranes requires the drug to be uncharged, tissue pH strongly affects efficacy

Use Dependence

Sodium channels exist in:

• open

• closed

• inactivated states

LAs bind more effectively to active/open channels, meaning rapidly firing nerves are blocked more readily (“use dependence”)

Differential Susceptibility of Fibers

Smaller fibers are blocked first:

• Aδ fibers (sharp pain)

• C fibers (dull pain)

This explains why pain sensation is lost before motor function

Side Effects and Physiological Basis

CNS Toxicity

• usually occurs after overdose or accidental IV injection:

  • initial CNS stimulation → tremors/convulsions

  • followed by CNS depression → coma/death

• This occurs because sodium channels in CNS neurons are also blocked

Cardiovascular Effects

• reduced myocardial contractility

• decreased heart rate

• peripheral vasodilation

Due to sodium channel blockade in cardiac tissue and vascular smooth muscle

List the 7 clinical uses of local anesthetics

1. Topical Anesthetics

2. Local infiltration

3. Instillation into a cavity or wound

4. Intravenous regional anesthesia (Bier’s Block)

5. Peripheral nerve blocks

6. Epidural (extradural) block

7. Systemic administration

Describe the clinical application of local anesthetic drugs

• Topical Anesthesia - desensitize mucus membranes and intact skin

• Local Infiltration - minor surgical procedures involving skin/subcutaneous tissues

• Instillation into cavities/wounds - interpleural or intra-articular anesthesia

• Intravenous regional anesthesia (Bier’s Block) - limb desensitization, e.g. digit amputation

• Peripheral Nerve Blocks - Diagnostic surgical procedures (dental, intercostal, brachial plexus, paravertebral blocks)

• Epidural blocks - desensitize perineum, hindlimbs, caudal abdomen

• Systemic Lidocaine Infusion - analgesia in severely painful patients

Chemical Structure

Local anesthetics contain:

• lipophilic aromatic group

• hydrophilic amine group

• ester or amide linkage

This structure determines lipid solubility, metabolism, and duration

pH Dependence and Clinical Significance

LAs are:

• weak bases

• mostly ionized at physiological pH

• more ionized in acidic conditions

Clinical Significance

Inflamed tissue is acidic:

• more drug becomes ionized

• less crosses membranes

• reduced anesthetic effectiveness

This explains why local anesthetics may fail in infected/inflamed tissue

Factors affecting Onset, Potency, and Duration

• Degree of ionization determines speed of onset

• Lipid solubility determines potency

• Protein binding determines duration of action

Drug Additives

Bicarbonate

• increases pH

• increases uncharged fraction

• speeds onset

Adrenaline (epinephrine)

• causes vasoconstriction

• slows systemic absorption

• prolongs duration of action

Elimination and Duration

Type → Metabolism → Half-life

• Ester-linked drugs → hydrolyzed by plasma cholinesterases → short half-life

• Amide-linked drugs → metabolized in liver → longer half-life

Clinical Implications:

• Ester drugs → shorter acting

• Amide drugs → longer duration, caution in liver disease

Overall Summary

Local Anesthetics:

• block sodium channels and prevent nerve conduction

• are weak bases whose activity depends on pH

• preferentially block small pain fibers

• are used in many local, regional, and systemic analgesic techniques

• have pharmacokinetics that determine onset, potency, route and duration

• can cause CNS and cardiovascular toxicity if overdosed