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Local Anesthetics: Overview

Local Anesthetics: Overview. Important structural features: lipophilic weak bases Mechanism of action: stabilization of inactivated Na channels Use-dependent ( Frequency- dependent) Nerve fiber-type sensitivity Uses Adverse effects. -First Local Anesthetic-

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Local Anesthetics: Overview

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  1. Local Anesthetics: Overview • Important structural features: lipophilic weak bases • Mechanism of action: stabilization of inactivated Na channels • Use-dependent (Frequency-dependent) • Nerve fiber-type sensitivity • Uses • Adverse effects

  2. -First Local Anesthetic- • Cocaine: isolated from Coca leaves • in 1859 by Niemann • Introduced into ophthalmology & dentistry in 1880s • Widely available in the early 1900s; • Coca-Cola allegedly contained ~ 25μg/ml • Also found to have strong vasoconstrictive action • First analog of cocaine synthesized for use as • a local anesthetic: procaine (1905)

  3. Local Anesthetics: relevant structural features Amides: Lidocaine inactivated via P450 CH O C2H5 NH-C-CH2-N C2H5 CH Esters: Tetracaine inactivated by plasma esterase O C2H5 HN -C-O-CH-CH-N C2H5 C4H9

  4. Mechanism of Action of Local Anesthetics • * Ionized form of weak base blocks Na+ channels by binding to an internal sequence involved in channel inactivation • to gain access to intracellular face of the Na+ channel, local anesthetics must penetrate the nerve in the un-ionized, or neutral, form; hence, action is strongly dependent upon local pH (alkaline – good; acidic – bad) Na+ -NH3+ ↔ -NH2 + H+ inactivation gate -NH2 ↔ -NH3+ Na channel

  5. Mechanism of Action of Local Anesthetics • * Ionized form of weak base blocks Na+ channels by binding to an internal sequence involved in channel inactivation • to gain access to intracellular face of the Na+ channel, local anesthetics must penetrate the nerve in the un-ionized, or neutral, form; hence, action is strongly dependent upon local pH (alkaline – good; acidic – bad) Na+ -NH3+↔ -NH2 + H+ inactivation gate -NH2↔ -NH3+ Na channel Na+ enters

  6. Mechanism of Action of Local Anesthetics • * Ionized form of weak base blocks Na+ channels by binding to an internal sequence involved in channel inactivation • to gain access to intracellular face of the Na+ channel, local anesthetics must penetrate the nerve in the un-ionized, or neutral, form; hence, action is strongly dependent upon local pH (alkaline – good; acidic – bad) Na+ -NH3+↔ -NH2 + H+ inactivation gate -NH2↔ -NH3+ Na channel Na channels close (inactivate) Na+ enters K+ exits

  7. Mechanism of Action of Local Anesthetics • * Ionized form of weak base blocks Na+ channels by binding to an internal sequence involved in channel inactivation • to gain access to intracellular face of the Na+ channel, local anesthetics must penetrate the nerve in the un-ionized, or neutral, form; hence, action is strongly dependent upon local pH (alkaline – good; acidic – bad) Na+ -NH3+↔ -NH2 + H+ inactivation gate -NH2↔ -NH3+ Na channel Prolong the refractory period  Size of the action potential

  8. Mechanism of Action of Local Anesthetics • * Ionized form of weak base blocks Na+ channels by binding to an internal sequence involved in channel inactivation • to gain access to intracellular face of the Na+ channel, local anesthetics must penetrate the nerve in the un-ionized, or neutral, form; hence, action is strongly dependent upon local pH (alkaline – good; acidic – bad) • action of local anesthetics is dependent upon Na+ channel activity = use-dependent (frequency-dependent) blockade via high affinity binding to inactivated state of channel (very important for antiarrhythmic activity of some l.a.s)

  9. * Mechanism of Action of Local Anesthetics • * Ionized form of weak base blocks Na+ channels by binding to an internal sequence involved in channel inactivation • to gain access to intracellular face of the Na+ channel, local anesthetics must penetrate the nerve in the un-ionized, or neutral, form; hence, action is strongly dependent upon local pH (alkaline – good; acidic – bad) • action of local anesthetics is dependent upon Na+ channel activity = use-dependent (frequency-dependent) blockade via high affinity binding to inactivated state of channel (very important for antiarrhythmic activity of some l.a.s)

  10. * Mechanism of Action of Local Anesthetics • * Ionized form of weak base blocks Na+ channels by binding to an internal sequence involved in channel inactivation • to gain access to intracellular face of the Na+ channel, local anesthetics must penetrate the nerve in the un-ionized, or neutral, form; hence, action is strongly dependent upon local pH (alkaline – good; acidic – bad) • action of local anesthetics is dependent upon Na+ channel activity = use-dependent (frequency-dependent) blockade via high affinity binding to inactivated state of channel (very important for antiarrhythmic activity of some l.a.s)

  11. * Mechanism of Action of Local Anesthetics • * Ionized form of weak base blocks Na+ channels by binding to an internal sequence involved in channel inactivation • to gain access to intracellular face of the Na+ channel, local anesthetics must penetrate the nerve in the un-ionized, or neutral, form; hence, action is strongly dependent upon local pH (alkaline – good; acidic – bad) • action of local anesthetics is dependent upon Na+ channel activity = use-dependent (frequency-dependent) blockade via high affinity binding to inactivated state of channel (very important for antiarrhythmic activity of some l.a.s)

  12. * Mechanism of Action of Local Anesthetics • * Ionized form of weak base blocks Na+ channels by binding to an internal sequence involved in channel inactivation • to gain access to intracellular face of the Na+ channel, local anesthetics must penetrate the nerve in the un-ionized, or neutral, form; hence, action is strongly dependent upon local pH (alkaline – good; acidic – bad) • action of local anesthetics is dependent upon Na+ channel activity = use-dependent (frequency-dependent) blockade via high affinity binding to inactivated state of channel (very important for antiarrhythmic activity of some l.a.s) XX

  13. * Mechanism of Action of Local Anesthetics • * Ionized form of weak base blocks Na+ channels by binding to an internal sequence involved in channel inactivation • to gain access to intracellular face of the Na+ channel, local anesthetics must penetrate the nerve in the un-ionized, or neutral, form; hence, action is strongly dependent upon local pH (alkaline – good; acidic – bad) • action of local anesthetics is dependent upon Na+ channel activity = use-dependent (frequency-dependent) blockade via high affinity binding to inactivated state of channel (very important for antiarrhythmic activity of some l.a.s) XX

  14. * * * * Mechanism of Action of Local Anesthetics • * Ionized form of weak base blocks Na+ channels by binding to an internal sequence involved in channel inactivation • to gain access to intracellular face of the Na+ channel, local anesthetics must penetrate the nerve in the un-ionized, or neutral, form; hence, action is strongly dependent upon local pH (alkaline – good; acidic – bad) • action of local anesthetics is dependent upon Na+ channel activity = use-dependent (frequency-dependent) blockade via high affinity binding to inactivated state of channel (very important for antiarrhythmic activity of some l.a.s)

  15. * * XX XX XX * * Mechanism of Action of Local Anesthetics • * Ionized form of weak base blocks Na+ channels by binding to an internal sequence involved in channel inactivation • to gain access to intracellular face of the Na+ channel, local anesthetics must penetrate the nerve in the un-ionized, or neutral, form; hence, action is strongly dependent upon local pH (alkaline – good; acidic – bad) • action of local anesthetics is dependent upon Na+ channel activity = use-dependent (frequency-dependent) blockade via high affinity binding to inactivated state of channel (very important for antiarrhythmic activity of some l.a.s)

  16. * * * * Mechanism of Action of Local Anesthetics • * Ionized form of weak base blocks Na+ channels by binding to an internal sequence involved in channel inactivation • to gain access to intracellular face of the Na+ channel, local anesthetics must penetrate the nerve in the un-ionized, or neutral, form; hence, action is strongly dependent upon local pH (alkaline – good; acidic – bad) • action of local anesthetics is dependent upon Na+ channel activity = use-dependent (frequency-dependent) blockade via high affinity binding to inactivated state of channel (very important for antiarrhythmic activity of some l.a.s) XX XX XX

  17. Mechanism of Action of Local Anesthetics • * Ionized form of weak base blocks Na+ channels by binding to an internal sequence involved in channel inactivation • to gain access to intracellular face of the Na+ channel, local anesthetics must penetrate the nerve in the un-ionized, or neutral, form; hence, action is strongly dependent upon local pH (alkaline – good; acidic – bad) • action of local anesthetics is dependent upon Na+ channel activity = use-dependent (frequency-dependent) blockade via high affinity binding to inactivated state of channel (very important for antiarrhythmic activity of some l.a.s) • small, unmyelinated fibers, such the type C fibers that carry nociceptive signals (pain), are more susceptible to local anesthetic block than are larger fibers. Smallest Type C Pain Fibers Most susceptible to local anesthetics • Medium Type B Autonomic Fibers Some effect (basis for local vasodilation) • Largest Type A Motor Fibers Little if any effect (by only a few of the long- duration amides)

  18. Mechanism of Action of Local Anesthetics • * Ionized form of weak base blocks Na+ channels by binding to an internal sequence involved in channel inactivation • to gain access to intracellular face of the Na+ channel, local anesthetics must penetrate the nerve in the un-ionized, or neutral, form; hence, action is strongly dependent upon local pH (alkaline – good; acidic – bad) • action of local anesthetics is dependent upon Na+ channel activity = use-dependent (frequency-dependent) blockade via high affinity binding to inactivated state of channel (very important for antiarrhythmic activity of some l.a.s) • small, unmyelinated fibers, such the type C fibers that carry nociceptive signals (pain), are more susceptible to local anesthetic block than are larger fibers. Smallest Type C Pain Fibers Most susceptible to local anesthetics • Medium Type B Autonomic Fibers Some effect (basis for local vasodilation) • Largest Type A Motor Fibers Little if any effect (by only a few of the long- duration amides) • effect dependent to some degree on position of fibers in nerve bundle: in the extremities nerves innervating proximal sites are on outside, while nerve innervating distal sites are on the inside of the bundle distal

  19. Basic Administration of Local Anesthetics Topical (Surface)- skin and mucosa Infiltration – direct injection (eg. knee) for: joint pain Peripheral Nerve Block – injected close to nerve trunks (eg. brachial) for: surgical procedures severe, chronic pain (eg. cancer) Spinal – injection into subarachnoid space near spinal cord for: surgery Epidural – injection just above dura surrounding spinal cord, near spinal nerve roots for: OB surgery

  20. Basic Administration of Local Anesthetics spinal cord dura arachnoid Spinal: Epidural: Nerve Roots

  21. Uses and Issues for Local Anesthetics: DrugTypePKUsesIssues Lidocaine(Xylocaine) amide medium (1-2hr) everything: potent (most widely used) rapid onset topical, spinal (also for preventricular PNB, epi, infl. contractions=PVCs) Ropivacaine amide long Epidural, PNB, less potent (3->10hr) infiltration (sub for bupiv*) Tetracaine ester long (3hr) spinal, highest risk very slow topical of toxicity onset Mepivacaine amide medium but rapid onset infiltration, less vasodilation (Carbocaine) (2-3hr) PNB (#1) (not for OB: toxic to fetus) Etidocaine amide long infiltration, PNB preferential (discontinued in US) (5->10hr) epidural motor block Benzocaine ester - topical (sprays) Prilocaine amide medium PNB (dental) less vasodilation (infiltration) lower CNS tox topical (w lidocaine) (not for OB) ** Cocaine ester short topical- abuse nasomucosal vasoconstrictor Dibucaine amide long topical very potent too toxic for inj Bupivacaine (Marcaine) amide slow but long topical not for inj* Procaine (Novocain) ester short (limited) too short 2-Chloroprocaine ester very short Epidural OB: at delivery PK = (pharmacokinetics) duration of action, and for lidocaine and tetracaine, onset.

  22. Adverse Effects • Major concerns with local anesthetics results from their escape into the circulation. Distribution of locals into the circulation occurs slowly with most applications (except topical); however, risk of adverse effects is dose- and age-dependent. •  CNS: • low doses: tremors and oral numbness, with possible dizziness, confusion and agitation (exception = cocaine) • mod. doses: convulsions (immediately preceded by muscle twitching); prevented by injection of anti-convulsant • high doses: possible respiratory depression • Cardiovascular: • vasodilation • (exception = cocaine) • less often, myocardial depression ( ventricular contraction), possibly leading to reduced cardiac output, and, in the worst case, ventricular arrhythmias and cardiac arrest (unintentional high plasma levels of LAs, but can occur with normal IV doses of bupivacaine) • Hypersensitivity: • - local dermatitis with some topicals; rare systemic allergic response with injected esters (due to metabolite) • Drug interactions: potentiate the action of non-depolarizing NMJ blockers

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