Local Anesthetics: Overview Important structural features: lipophilic weak bases Mechanism of action: stabilization of inactivated Na channels Use-dependent.

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 asa local anesthetic: procaine (1905)

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

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

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

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

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

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)

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)

*

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)

*

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)

*

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

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

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)

****

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

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

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 anestheticsMedium 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)

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 anestheticsMedium 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

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 cordfor: surgery

Epidural – injection just above dura surrounding spinal cord, near spinal nerve rootsfor: OB

surgery

Basic Administration of Local Anesthetics

spinal cord

duraarachnoid Spinal:

Epidural:

NerveRoots

Uses and Issues for Local Anesthetics:Drug Type PK Uses Issues 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 toxicityonset

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 vasoconstrictorDibucaine amide long topical very potent

too toxic for injBupivacaine (Marcaine) amide slow but long topical not for inj*Procaine (Novocain) ester short (limited) too short2-Chloroprocaine ester very short Epidural OB: 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-convulsanthigh 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