Local Anesthetics: Overview Important structural features: lipophilic weak bases Mechanism of...
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Transcript of Local Anesthetics: Overview Important structural features: lipophilic weak bases Mechanism of...
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
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