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- 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)

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

Mechanism of Action of Local Anesthetics * Ionized form of weak base blocks Na + channels by binding to an internal sequence involved in channel inactivation L 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 + -NH 3 + ↔ -NH 2 + H + inactivation gate -NH 2 ↔ -NH 3 + Na channel

Mechanism of Action of Local Anesthetics * Ionized form of weak base blocks Na + channels by binding to an internal sequence involved in channel inactivation L 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 + -NH 3 + ↔ -NH 2 + H + inactivation gate -NH 2 ↔ -NH 3 + Na channel Na + enters

Mechanism of Action of Local Anesthetics * Ionized form of weak base blocks Na + channels by binding to an internal sequence involved in channel inactivation L 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 + -NH 3 + ↔ -NH 2 + H + inactivation gate -NH 2 ↔ -NH 3 + Na channel Na channels close (inactivate) Na + enters K + exits

Mechanism of Action of Local Anesthetics * Ionized form of weak base blocks Na + channels by binding to an internal sequence involved in channel inactivation L 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 + -NH 3 + ↔ -NH 2 + H + inactivation gate -NH 2 ↔ -NH 3 + Na channel Prolong the refractory period  Size of the action potential

Mechanism of Action of Local Anesthetics * Ionized form of weak base blocks Na + channels by binding to an internal sequence involved in channel inactivation L 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) L 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)

Mechanism of Action of Local Anesthetics * Ionized form of weak base blocks Na + channels by binding to an internal sequence involved in channel inactivation L 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) L 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) *

Mechanism of Action of Local Anesthetics * Ionized form of weak base blocks Na + channels by binding to an internal sequence involved in channel inactivation L 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) L 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) *

Mechanism of Action of Local Anesthetics * Ionized form of weak base blocks Na + channels by binding to an internal sequence involved in channel inactivation L 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) L 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) *

Mechanism of Action of Local Anesthetics * Ionized form of weak base blocks Na + channels by binding to an internal sequence involved in channel inactivation L 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) L 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

Mechanism of Action of Local Anesthetics * Ionized form of weak base blocks Na + channels by binding to an internal sequence involved in channel inactivation L 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) L 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

Mechanism of Action of Local Anesthetics * Ionized form of weak base blocks Na + channels by binding to an internal sequence involved in channel inactivation L 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) L 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) * * * *

Mechanism of Action of Local Anesthetics * Ionized form of weak base blocks Na + channels by binding to an internal sequence involved in channel inactivation L 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) L 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

Mechanism of Action of Local Anesthetics * Ionized form of weak base blocks Na + channels by binding to an internal sequence involved in channel inactivation L 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) L 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

Mechanism of Action of Local Anesthetics * Ionized form of weak base blocks Na + channels by binding to an internal sequence involved in channel inactivation L 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) L 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) L 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 FibersMost susceptible to local anesthetics Medium Type B Autonomic FibersSome effect (basis for local vasodilation) Largest Type A Motor FibersLittle if any effect (by only a few of the long- duration amides)

Mechanism of Action of Local Anesthetics * Ionized form of weak base blocks Na + channels by binding to an internal sequence involved in channel inactivation L 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) L 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) L 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 FibersMost susceptible to local anesthetics Medium Type B Autonomic FibersSome effect (basis for local vasodilation) Largest Type A Motor FibersLittle if any effect (by only a few of the long- duration amides) Leffect 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

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

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

Uses and Issues for Local Anesthetics: DrugTypePKUsesIssues Lidocaine (Xylocaine)amidemedium (1-2hr)everything:potent (most widely used)rapid onsettopical, spinal(also for preventricular PNB, epi, infl. contractions=PVCs) RopivacaineamidelongEpidural, PNB, less potent (3->10hr)infiltration(sub for bupiv*) Tetracaineesterlong (3hr)spinal,highest risk very slowtopicalof toxicity onset Mepivacaineamidemedium but rapid onsetinfiltration, less vasodilation (Carbocaine)(2-3hr)PNB (#1) (not for OB: toxic to fetus) Etidocaineamidelonginfiltration, PNB preferential (discontinued in US)(5->10hr)epidural motor block Benzocaineester -topical(sprays) PrilocaineamidemediumPNB (dental) less vasodilation (infiltration) lower CNS tox topical (w lidocaine)(not for OB) ** Cocaineestershorttopical-abuse nasomucosal vasoconstrictor Dibucaineamidelongtopicalvery potent too toxic for inj Bupivacaine (Marcaine)amideslow but longtopicalnot for inj* Procaine (Novocain)estershort(limited)too short 2-Chloroprocaineestervery shortEpiduralOB: at delivery PK = (pharmacokinetics) duration of action, and for lidocaine and tetracaine, onset.

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