LOCAL ANESTHETICS - Study Notes

1. Definition

• Drugs that reversibly block impulse conduction along nerve axons and other excitable membranes
• Block pain impulses or undesirable autonomic responses (e.g., sympathetic vasoconstriction)
• Produce temporary but complete analgesia of well-defined body regions

2. Basic Chemistry

• Optimal activity requires a balance between the lipophilic and hydrophilic ends
• Available as hydrochloride salts for solubility and stability
• Weak bases; exist as protonated or non-protonated species in tissues (ratio determined by pKa and tissue pH)
• Most drugs have pKa 8-9 → predominantly protonated at physiologic pH

Protonated vs. Non-protonated forms:

3. Classification

Amides

• Lignocaine (lidocaine)
• Mepivacaine
• Bupivacaine
• Prilocaine
• Ropivacaine
• Etidocaine

Esters

• Benzocaine - topical only (low solubility; risk of methemoglobinemia)
• Procaine
• Tetracaine - good for nerve blocks (long intracellular t½)
• Cocaine - topical only (significant systemic side effects)

4. Mechanism of Action

• Bind to intracellular sites on voltage-gated Na⁺ channels → blockade
• Binding only possible in active (open) and inactivated (closed) states - NOT in the resting state
• More nerve stimulation = more channels blocked (use-dependence)
• Binding/unbinding is noncovalent

Progressive effects of Na⁺ channel blockade:

1. Stimulation threshold increases
2. Action potential amplitude decreases
3. Impulse conduction slows
4. Action potential generation is ultimately blocked

Additional channel dynamics:

• Recovery from LA-induced block is up to 1000x slower than normal inactivation → refractory period greatly increased
• Blockade is voltage- and time-dependent
  • More negative membrane potential → channels mostly closed → low LA affinity
  • More positive membrane potential → channels open or inactivated → high LA affinity
• Effect more marked on rapidly firing axons than resting nerve fibers
• Resting membrane potential is not significantly altered (K⁺ efflux counteracts Na⁺ influx)

Modifiers of blockade:

• Elevated extracellular Ca²⁺ → partially antagonizes LA (favors resting/closed channel state)
• Elevated extracellular K⁺ → potentiates LA (favors depolarized/inactivated channel state)

5. Effects on Different Nerve Types

• Affects all nerve types: sensory, somatic motor, autonomic
• Myelinated > non-myelinated nerves: easier to block
• Smaller diameter = faster blockade: order of susceptibility:

  Pain > Autonomic > Motor

Spinal anesthesia-specific risks:

• Motor impairment → paralysis of respiratory muscles
• Autonomic impairment → hypotension

Fiber position in nerve bundle:

• Large nerve trunks: Motor fibers are outermost → motor block may precede sensory block
• Extremities: Proximal sensory fibers outermost; distal fibers innermost → anesthesia develops proximally first, spreads distally

6. Local Anesthetics in Infected Tissue

• Problem: Infected tissue is acidic (low pH) → protonated form predominates → poor cell penetration → reduced efficacy of infiltration anesthesia
• Solution: Use a regional nerve block instead (drug deposited away from the acidic area)

7. Routes of Administration

8. Drug Selection by Duration

• Topical: benzocaine (powder or gel formulations)
• Short/intermediate-acting drugs can be extended with vasoconstrictors
• Short-acting drugs (procaine, chlorprocaine) preferred for regional (IV) blocks to limit systemic effects

9. Pharmacokinetics

Absorption

• Systemic absorption is undesirable (risk of CVS and CNS toxicity)
• Factors affecting systemic absorption:
  1. Dose administered
  2. Vascularity of injection site
  3. Presence/absence of vasoconstrictor
  4. Drug-tissue binding
  5. Physicochemical properties of drug
• Greater drug-tissue binding → longer t½, slower onset
• Smaller + more lipophilic molecules → faster interaction with Na⁺ channels

Metabolism & Excretion

• Metabolized in liver and plasma → water-soluble metabolites → excreted in urine
• Esters: Hydrolyzed rapidly in plasma/tissues by pseudocholinesterase
• Amides: Metabolized by hepatic CYP450 enzymes
• Liver disease increases systemic toxicity risk for amides (lignocaine t½: 2 hrs → 8 hrs in liver disease)
• Urinary acidification promotes excretion of non-protonated drug

10. Vasoconstrictors

How they help:

• Prolong LA effect by up to 50% by limiting systemic escape of drug
• Increase local tissue drug concentration → enhanced nerve cell diffusion
• Reduce systemic toxicity
• Allow use of lower total drug dose (improved safety margin)
• Adrenaline in spinal LA also stimulates α₂ adrenoceptors → inhibits release of substance P (neurokinin-1) → reduces sensory neuronal firing
• Other α₂ agonists (e.g., clonidine) can augment LA by the same mechanism

Limitations:

• Little effect on reducing systemic effects of long-acting drugs (bupivacaine, prilocaine)

11. Adverse Effects

CNS (dose-dependent, in order of increasing severity):

• Sleepiness
• Light-headedness
• Visual disturbances
• Auditory disturbances
• Nystagmus
• Restlessness, anxiety
• Convulsions (tonic-clonic) ← higher drug levels
• CNS depression, coma, death ← highest drug levels

Cardiovascular:

• Cardiac arrhythmias, bradycardia
• Vasodilation and hypotension (autonomic nerve effects)
• Methemoglobinemia - with benzocaine
• Vasoconstriction, tachycardia, euphoria - cocaine-specific
• Pregnancy increases susceptibility → use decreased dose + vasoconstrictor
• Mepivacaine - particularly toxic to newborns → contraindicated in pregnancy

Key rule: Always use the lowest effective dose to minimize systemic toxicity