11

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LA: Reversibly block impulse conduction LA: Reversibly block impulse conduction along nerve axons & other excitable along nerve axons & other excitable membrane that utilize Namembrane that utilize Na++ channels for channels for Action Potential generation.Action Potential generation.

UsesUses: block pain sensation (: block pain sensation (nociceptionnociception) ) from specific area of ! body.from specific area of ! body.

CocaineCocaine was ! 1 was ! 1stst LA isolated from Coca LA isolated from Coca plant as an ophthalmic anesthetic; Its plant as an ophthalmic anesthetic; Its chronic use: psychological dependence chronic use: psychological dependence (addiction).(addiction).

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Followed by Followed by procaineprocaine & & then then LidocaineLidocaine (Lid) which is ! most (Lid) which is ! most

widely used LA.widely used LA.

What characteristics of LAs make What characteristics of LAs make them ideal agents for anesthesiathem ideal agents for anesthesia?? As As ropivacaineropivacaine

1- Rapid onset, 1- Rapid onset, 2- Long Duration of Action,2- Long Duration of Action,3- Reversible & selective blockade of 3- Reversible & selective blockade of

sensory nerves without motor blockade, sensory nerves without motor blockade, 4- Minimal local tissue irritation & no 4- Minimal local tissue irritation & no

systemic toxicities.systemic toxicities.

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Chemistry of LAChemistry of LA Weak base & available as salts to Weak base & available as salts to

increase solubility & stability.increase solubility & stability. Consist of lipophilic gp (aromatic ring):Consist of lipophilic gp (aromatic ring):

memb penetrationmemb penetration ++ intermediate ++ intermediate chain via an chain via an esterester or or amideamide to ionizable to ionizable gp:gp: for channel blockade for channel blockade . .

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•• AbsorptionAbsorption esp systemic esp systemic: depends on:: depends on:1- dosage, 1- dosage, 2- site of inj, (VASCULARITY): IV > tracheal 2- site of inj, (VASCULARITY): IV > tracheal

> intercostals > paracervical > epidural > intercostals > paracervical > epidural > brachial plexus > sciatic > SC> brachial plexus > sciatic > SC

3- drug-tissue binding, 3- drug-tissue binding, 4- local bld flow, 4- local bld flow, 5- use of Vasoconstrictors (epinephrine/ 5- use of Vasoconstrictors (epinephrine/

phenylephrine) &phenylephrine) &6- ! physiochemical property of ! drug.6- ! physiochemical property of ! drug.Absorption in highly vascular area is > Absorption in highly vascular area is >

poor perfused tissue. poor perfused tissue.

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Epinephrine/ VC:Epinephrine/ VC:

SlowSlow ! removal & ! removal & reducereduce systemic absorption of systemic absorption of LA from inj site by decreasing bld flow &LA from inj site by decreasing bld flow &

cause higher local tissue conc of ! drug & cause higher local tissue conc of ! drug & prolong conduction blockade. prolong conduction blockade.

+ reduce CNS & systemic tox.+ reduce CNS & systemic tox.

Used with Used with short/ intermediateshort/ intermediate duration of duration of action: (procaine, Lid & mepivacaine).action: (procaine, Lid & mepivacaine).

VCs are < effective in prolonging anesthetic VCs are < effective in prolonging anesthetic action of more lipid-soluble, long-acting drugs action of more lipid-soluble, long-acting drugs (bupivacaine & ropivacaine) which are highly (bupivacaine & ropivacaine) which are highly tissue-bound. tissue-bound.

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DistributionDistribution

! ! AmideAmide LAs are widely distributed LAs are widely distributed after IV bolus inj.after IV bolus inj.

Initial rapid phase into highly Initial rapid phase into highly perfused organs, perfused organs,

then a slower phase to moderately then a slower phase to moderately perfused organs.perfused organs.

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MetabolismMetabolism & & ExcretionExcretion Acidification of urine: ionization & Acidification of urine: ionization &

excretion of LAexcretion of LA Ester-typeEster-type hydrolyzed rapidly in ! hydrolyzed rapidly in ! bldbld

(by pseudo-choline-sterase) to inactive (by pseudo-choline-sterase) to inactive metabolite; short plasma tmetabolite; short plasma t1/2 1/2 (< 1 min).(< 1 min).

! ! amideamide linkage is hydrolyzed by linkage is hydrolyzed by liverliver cyto Pcyto P450450 with diff rate (prilocaine with diff rate (prilocaine ((fastestfastest) > Lid > mepivacaine > ) > Lid > mepivacaine > ropivacaine > bupivacaine (ropivacaine > bupivacaine (slowestslowest). ).

All converted to water-soluble All converted to water-soluble metabolites & excreted in urine.metabolites & excreted in urine.

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Toxicity from Toxicity from amide-typeamide-type LA LA occur in occur in hepatic Dhepatic D. . Ex: elimination t Ex: elimination t1/21/2 of Lid of Lid from 1.6 hr in normal pat to > 6 from 1.6 hr in normal pat to > 6 hr in liver disease pat.hr in liver disease pat.

amideamide LA also affected by LA also affected by enz enz inhibitorsinhibitors..

Reduced hepatic Reduced hepatic bld flowbld flow: : decrease their elimination.decrease their elimination.

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MOAMOA Block ! Initiation & propagation of AP Block ! Initiation & propagation of AP

by preventing by preventing voltage-gated Navoltage-gated Na++ channelschannels..

Activity is PH-dependent, increased Activity is PH-dependent, increased at at alkalinealkaline PH. Its penetration to Na PH. Its penetration to Na++ chs is very poor at acid PH. Inflamed chs is very poor at acid PH. Inflamed tissues (acidic): resis to LA.tissues (acidic): resis to LA.

Elevated extracellular CaElevated extracellular Ca2+ 2+

antagonizesantagonizes ! action of LA by Ca ! action of LA by Ca2+2+ w w increase! surface potential on ! increase! surface potential on ! membrane.membrane.

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Smaller & more lipophilic LA: ! Faster Smaller & more lipophilic LA: ! Faster rate of interaction with Narate of interaction with Na++ chs. chs.

Potency is +vely correlated with lipid Potency is +vely correlated with lipid solubility. solubility.

Lid, procaine, & mepivacaine are > Lid, procaine, & mepivacaine are > water-solublewater-soluble than tetracaine, than tetracaine, bupivacaine, & ropivacaine that are bupivacaine, & ropivacaine that are more potent & have longer DOA.more potent & have longer DOA.

Long acting (bupivacaine ) also bind Long acting (bupivacaine ) also bind more extensively to plasma proteins & more extensively to plasma proteins & can be displaced by other drugs.can be displaced by other drugs.

Structure- Activity Characteristics of LA:

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Other actions on nerves:Other actions on nerves:

1- Loss of sensation from site of painful 1- Loss of sensation from site of painful stimulistimuli

2- Motor paralysis during surgery2- Motor paralysis during surgery

DisadvantagesDisadvantages In In Spinal anesthesiaSpinal anesthesia, motor paralysis: , motor paralysis:

impair respiratory activity &impair respiratory activity &

AN blockade: hypotension & urinary AN blockade: hypotension & urinary retention (catheterization).retention (catheterization).

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1- Effect on fiber diameter1- Effect on fiber diameter::

LA block conduction in LA block conduction in small-diametersmall-diameter nerve fibers > readily than in large nerve fibers > readily than in large fibers.fibers.

PainPain sensation is blocked > readily than sensation is blocked > readily than other sensory modalities.other sensory modalities.

Motor axons (large diameter), are Motor axons (large diameter), are relatively resistance.relatively resistance.

LAs block conduction in ! following order: LAs block conduction in ! following order:

small myelinated (small myelinated (nociceptive nociceptive impulses)impulses), non- myelinated (C-fibers), , non- myelinated (C-fibers), large myelinated axons. large myelinated axons.

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2- Effect on firing frequency2- Effect on firing frequency

Blockade by LA is > at higher Blockade by LA is > at higher frequencies of depolarization.frequencies of depolarization.

Sensory (esp pain)Sensory (esp pain) fibers have High fibers have High firing rate & long AP duration. whilefiring rate & long AP duration. while

Motor fibers fire at a slower rate & have Motor fibers fire at a slower rate & have shorter AP duration.shorter AP duration.

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Properties of LAsProperties of LAs

DrugDrug OnseOnsett

DuraDurationtion

PlasPlasma ma tt1/21/2

SESE NotesNotes

CocCoc-- MM MM 11 hrhr CV & CNSCV & CNS Rarely used, Rarely used, only as spray only as spray for URTfor URT

ProPro-- MM ShortShort < <1hr1hr

CNSCNS: : restlessnessrestlessness, shivering, , shivering, anxietyanxiety

CVSCVS: : B.cardia & B.cardia & decrease decrease COPCOP

No longer No longer usedused

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LidLid RapidRapid MM 22 hrhr As As procaine procaine but < but < tendency tendency to CNSto CNS

Widely used + Widely used + IV in ventricular IV in ventricular arrhythmia. arrhythmia. MepivacaineMepivacaine is is similarsimilar

AmethoAmethoc- c- (tetrac(tetrac

V. V. SlowSlow

LongLong 11 hrhr As LidAs Lid spinal & corneal spinal & corneal anesthesiaanesthesia..

BupivacBupivac--

SlowSlow LongLong 22 hrhr As Lid but As Lid but > CVS> CVS

Widely used Widely used (long DOA). (long DOA). RopivacineRopivacine is is similar, with similar, with less cardioToxless cardioTox..

PrilocPriloc-- MM MM 22 hrhr No VDNo VD

MetHgemiMetHgemiaa

Widely used, Widely used, not for obstetric not for obstetric (neonatal (neonatal metHgemiametHgemia..

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ClassificationClassification: : Six Placement SitesSix Placement Sites

SurfaceSurface//topical anesthesiatopical anesthesia Local infiltrationLocal infiltration   Peripheral nerve blockPeripheral nerve block   Bier block Bier block ((IV regional anesthesia)IV regional anesthesia) Epidural anesthesiaEpidural anesthesia   Spinal anesthesia Spinal anesthesia ((subarachnoid)subarachnoid)

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EpiduralEpidural SpinalSpinal

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Clinical pharmClinical pharmEffective analgesia in specific regions of ! Effective analgesia in specific regions of !

body.body.

Route of administrationRoute of administration::

1- Topical/ surface application (nasal 1- Topical/ surface application (nasal mucosa, wound margins)mucosa, wound margins)

2-Inj in ! vicinity of peripheral nerve endings 2-Inj in ! vicinity of peripheral nerve endings (infiltration) & major nerve trunks (blocks)(infiltration) & major nerve trunks (blocks)

3- Inj into ! epidural or subarachnoid spaces 3- Inj into ! epidural or subarachnoid spaces surrounding ! spinal cord.surrounding ! spinal cord.

4- IV regional anesthesia (Bier block) for 4- IV regional anesthesia (Bier block) for surgery < 60 min in limbs.surgery < 60 min in limbs.

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Local Infiltration:Local Infiltration:

Extravascular placement of ! LA in ! Extravascular placement of ! LA in ! region to be anesthetizedregion to be anesthetized

Peripheral Nerve Block:Peripheral Nerve Block:

LA inj into tissues around individual LA inj into tissues around individual nerves or nerve plexuses (e.g. brachial nerves or nerve plexuses (e.g. brachial plexus). plexus).

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DOADOA

ShortShort: proc- & chloropro- : proc- & chloropro- cainecaine IntermediateIntermediate: Lid, mepiva- & prilo- : Lid, mepiva- & prilo- cainecaine Long-actingLong-acting: tetra-, bupiva-, & ropiva- : tetra-, bupiva-, & ropiva-

cainecaine..

DOA can be prolonged by increasing ! DOA can be prolonged by increasing ! Dose/ adding VC agent. Dose/ adding VC agent.

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To increase To increase onsetonset of LA: + Na-bicarbonate to of LA: + Na-bicarbonate to LA sol.LA sol.

Repeated inj of LA: tachyphylaxis (extracellular Repeated inj of LA: tachyphylaxis (extracellular acidosis)acidosis)

Pregnancy increase LA tox.Pregnancy increase LA tox. Topical LATopical LA: eye, ENT & for cosmetic surgery. : eye, ENT & for cosmetic surgery.

Properties: Properties: 1- rapid penetration across ! skin/ mucosa &1- rapid penetration across ! skin/ mucosa & 2- low tendency to diffuse away from ! site of 2- low tendency to diffuse away from ! site of

application.application. Cocaine bec of excellent penetration & local Cocaine bec of excellent penetration & local

VC used for (ENT) procedures. Has irritating VC used for (ENT) procedures. Has irritating effect so NOT used in ophthalmic procedure.effect so NOT used in ophthalmic procedure.

Other topical: Lid + VC, tetracaine, pramoxine, Other topical: Lid + VC, tetracaine, pramoxine, dibucaine, benzocaine, & dyclonine.dibucaine, benzocaine, & dyclonine.

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OTHER USES:OTHER USES: LAs have membrane-stabilizing effects; LAs have membrane-stabilizing effects;

Both IV Lid & po (mexiletine, tocainide) Both IV Lid & po (mexiletine, tocainide) used to Tr pat with neuropathic pain used to Tr pat with neuropathic pain syndrome: (uncontrolled, rapid, sensory syndrome: (uncontrolled, rapid, sensory fiber firing).fiber firing).

Systemic LA: as adjuncts to Systemic LA: as adjuncts to TCA (amitriptyline) & TCA (amitriptyline) & anticonvulsant (carbamazepine) anticonvulsant (carbamazepine) combination.combination.

Systemic toxicity: CNS & CV system. Systemic toxicity: CNS & CV system. 

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ToxicityToxicity

A- CNSA- CNS::

1- All LAs at low conc: sleepiness, light 1- All LAs at low conc: sleepiness, light headiness, visual & auditory headiness, visual & auditory disturbances & restlessness.disturbances & restlessness.

Early symp: tongue numbness + metallic Early symp: tongue numbness + metallic taste.taste.

Rare, but High plasma conc.: nystagmus & Rare, but High plasma conc.: nystagmus & muscular twitching, then tonic-clonic muscular twitching, then tonic-clonic convulsions. Followed by generalized convulsions. Followed by generalized CNS depression (apnea).CNS depression (apnea).

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Convulsions: excessive LA level in ! bld. Convulsions: excessive LA level in ! bld. If large dose of LA is required: RIf large dose of LA is required: Rxx pre- pre-medication with BDZs prophylaxis.medication with BDZs prophylaxis.

2- For 2- For cocainecocaine: widely abuse drug, : widely abuse drug, severe CV toxicity; HTN, arrhythmia, & severe CV toxicity; HTN, arrhythmia, & myocardial Failure.myocardial Failure.

B- NeurotoxB- Neurotox: direct neuronal tox. With : direct neuronal tox. With excessive high conc. Chloroprocaine & excessive high conc. Chloroprocaine & Lid are > neurotoxic than others in Lid are > neurotoxic than others in spinal anes.,: transient irritation spinal anes.,: transient irritation (neuropathic symptoms).(neuropathic symptoms).

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C- CVSC- CVS: direct effect on ! hrt & smooth : direct effect on ! hrt & smooth muscle & indirect effect on ! ANS.muscle & indirect effect on ! ANS.

Depress strength of cardiac contraction, Depress strength of cardiac contraction, ECG changes & cause arteriolar ECG changes & cause arteriolar dilatation;; hypotension.dilatation;; hypotension.

Cocaine blocks Norepinephrine uptake: Cocaine blocks Norepinephrine uptake: VC & HTN + cardiac arrhythmia & VC & HTN + cardiac arrhythmia & ischemia.ischemia.

Bupivacaine is > cardiotoxic than other Bupivacaine is > cardiotoxic than other long-acting LA.long-acting LA.

Ropivaciane: CV & CNS tox, but < than Ropivaciane: CV & CNS tox, but < than Bupivacaine.Bupivacaine.

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D- Hematologic effectsD- Hematologic effects::

Large dose of prilocaine: accumulation of Large dose of prilocaine: accumulation of Oxidizing Agent (o- toluidine) that Oxidizing Agent (o- toluidine) that convert Hg to metHg.;; cyanosis & convert Hg to metHg.;; cyanosis & chocolate-colored. Nchocolate-colored. Not recommended in ot recommended in infants. infants. (Benzocaine can also cause (Benzocaine can also cause metHg).metHg).

Rx: IV methylene blue/ ascorbic acid.Rx: IV methylene blue/ ascorbic acid.

E- Allergic rxsE- Allergic rxs:: (Not e amides) (Not e amides)

Ester-type LAs are metabolized to P-ABA Ester-type LAs are metabolized to P-ABA derivatives; allergic rxs.derivatives; allergic rxs.