Medical Pharmacology Chapter 15: Local Anesthetics

Local Anesthetic Agents

• Overview --Chemical Properties:

  • Structural Aspects

    • Lipophilic component

    • Connecting chain (ester or amide)

    • Ionizable group

  • Racemates/Pure Isomers

    • Pipecoloxylidide-agents (mepivacaine (Carbocaine), ropivacaine (Naropin))

      •  Chiral agents (asymmetric carbon); left-(S), right-(R)-handed configurations

      •  Mepivacaine (Carbocaine) and bupivacaine (Marcaine) are used clinically as racemates (50:50 mixture) of enantiomers

        • S enantiomers of mepivacaine (Carbocaine) and bupivacaine (Marcaine): less toxic than racemates

      •  Ropivacaine (Naropin): pure S enantiomer

  •  Pharmacological activity (2 factors--one that considers chemical aspects alone and the second that considers interaction with receptors)

    •  Balance between lipophilic and hydrophilic characteristics

    •  Potency of stereoisomers (e.g.,ropivacaine (Naropin) and mepivacaine (Carbocaine))

  • Duration of action:

    •  Esters: shorter duration of action (compared to local anesthetics with amide linkages)

  • Properties: Local Anesthetics are weak bases:

    •  Existing as either uncharged base or cation (postiively charged)

    •  Proportions depending on pK_a and pH (as described by the Henderson-Hasselbalch equation)

      •  log ([cationic form] / [uncharged form]) = pK_a - pH

      •  Most local anesthetics have pKa's ranging from 8.0-9.0, therefore at physiological pH, most local anesthetic molecules will be positively charged (cationic form)

        • Cationic form: probably physiologically active form at the receptor

        • Uncharged form: important for penetration across biological membranes to reach site of action

        • Local anesthetic receptor localization internal side of the cell membrane {requiring penetration by uncharged form}

          •  In infected tissue, extracellular pH is lower; more drug in ionized state; less likely to diffuse into the cell; reduced local anesthetic effect

  • Esters: Cocaine Procaine (Novocain) Benzocaine (Cetacaine) Tetracaine, Chloroprocaine (Nesacaine)

    • 

  • Amides: Lidocaine (Xylocaine), Mepivacaine (Polocaine/Carbocaine), Etidocaine (Duranest), Bupivacaine (Marcaine), Prilocaine

    ,