log = pk a -ph log = = 0.2 log = = 1.1 log [1.5] = 0.2 log [12.6] = 1.1 Local anesthetics act in a frequency-dependent manner
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1 Local Anesthetics MII 2008 Susan E. Robinson 2 N 2 2 N N duration of action potency 2 2 N N 2 2 N metabolism chemical stability hypersensitivity N 2 2 N 2 2 mechanism onset of action Local anesthetics block action potential without affecting resting potential 1
2 1 2 Local Anesthetic Sites of Action Extracellular fluid K + Gate + Membrane Local anesthetics act in a frequency-dependent manner Resting membrane potential 3 K + K + K+ K+ K+ Axoplasm inactive closed depolarization open Membrant site 1. Receptor at external surface 2. Expansion of axonal membrane 3. Receptor at internal surface 4. ombination of (3) and (4) Representative agent(s) Tetrodotoxin, saxitoxin Benzocaine Quaternary ammonium compounds Amide and ester local anesthetics (e.g. lignocaine, procaine) Local anesthetics act in a frequency-dependent manner Local anesthetics bind with greater affinity to the inactived state of the sodium channel. ence, rapidly firing neurons are blocked more rapidly. [ + LA] log = pk a -p enderson-asselbach equation [ + LA] log = = 0.2 log [1.5] = 0.2 [ + LA] log = = 1.1 log [12.6] = 1.1 2
3 3 N N 3 3 N N N N N N N N 3 N N N N N N 3 3 N 3 N N 3 N 3 3 N 3 3 N N 3 N onduction blockade occurs after Diffusion of the base form across nerve sheath and membrane Re-equilibration between base and cationic forms in the axoplasm Penetration of cation into and attachment to receptor at site within the sodium channel (continued) Blockade of sodium channel Inhibition of sodium conductance Decrease in rate and degree of depolarization phase of the action potential Failure to achieve threshold potential Lack of development of a propagated action potential onduction blockade Local Anesthetics: Effect of Fiber Diameter Small diameter fibers blocked first Myelinated nerves blocked before unmyelinated (of the same diameter) rder of Susceptibility to Local Anesthetics autonomic pain temperature pressure proprioception motor Local Anesthetics: Effect of Fiber Position In general, local anesthetics are very safe if used correctly. Toxicity results from bad technique. 3
4 Major cause of systemic toxicity is high blood concentration Plasma levels of tetracaine after several routes of administration 100 Use least volume of the most dilute solution Include a vasoconstrictor Topical use is not necessarily safe RAPID INTRAVENUS 30 MG TPIAL 2% 30 MG SLW INTRAVENUS 30 MG SUBUTANEUS INFILTRATIN 30 MG TIME (minutes) cocaine Esteratic Recreational drug Blocks reuptake of catecholamines Topical use orneal damage short-acting local anesthetics procaine - esteratic, metabolized to PABA chloroprocaine - esteratic, extremely short duration of action intermediate-acting local anesthetics lidocaine - amide, rapid onset of action, high intrinsic activity to vasodilate, very widely used mepivacaine - amide, very rapid onset of action prilocaine - amide, methemoglobinemia long-acting local anesthetics tetracaine - esteratic, slow onset of action etidocaine - amide, rapid onset of action bupivacaine - amide ; available as S- enantiomer, levobupivacaine (hirocaine) ropivacaine - amide, marketed as S-enantiomer dibucaine - amide, potent, toxic, and long-acting 4
5 ropivacaine Long-acting Amide Marketed as the S-enantiomer Less cardiotoxicity Greater separation between sensory and motor blockade EMLA Eutectic Mixture of Local Anesthetics lidocaine and prilocaine used topically prior to painful procedures Spinal Anesthesia Injected into subarachnoid space Potential for hypotension and respiratory arrest Neurological complications Less potential for physiological perturbations Low probability of systemic toxicity Epidural Anesthesia Injected into epidural space Requires injection of large amounts of drug igher probability of systemic toxicity Lower occurrence of headaches 5
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