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Prepared by : Dr Alia Alshanawani

College of Medicine, KSU.

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

Uses: block pain sensation (nociception) from specific area of ! body.

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

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Followed by procaine & then Lidocaine (Lid) which is ! most

widely used LA.

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

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

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

systemic toxicities (cardiac & CNS).3

Weak base & available as salts to increase solubility & stability.

Consist of lipophilic gp (aromatic ring): memb penetration ++ intermediate chain via an ester or amide to ionizable gp: for channel blockade .

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• Absorption of injected LA, esp systemic: depends on:

1- dosage, 2- site of inj, (VASCULARITY): IV > tracheal >

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

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

&6- ! physiochemical property of ! drug.

Absorption in highly vascular area (trachea, intercostal) is > poor perfused tissues (dermis & SC fat).

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Epinephrine/ VC:Slow ! removal & reduce systemic absorption of

LA from inj site by decreasing blood flow (upto 30%) &

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

+ reduce CNS & systemic tox.Used with short/ intermediate duration of

action: (procaine, Lid & mepivacaine).

VCs are < effective in prolonging anesthetic action of more lipid-soluble, long-acting drugs (bupivacaine & ropivacaine) which are highly tissue-bound. 9

Distribution

! Amide LAs are widely distributed after IV bolus inj.

Initial rapid phase into highly perfused organs (brain, kidney, liver & heart),

then a slower phase to moderately perfused organs (Muscle, GIT).

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Acidification of urine: ionization & excretion of LA

Ester-type hydrolyzed rapidly in ! blood (by pseudo-choline-sterase) to inactive metabolites; short plasma t1/2 (< 1 min).

! amide linkage is hydrolyzed by liver cytochrome P450 with different rates order (prilocaine (fastest) > Lid > bupivacaine (slowest).

All ester & amide LAs converted to more water-soluble metabolites & excreted in urine.

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

amide LA also affected by enz inhibitors.

Reduced hepatic bld flow: decrease their elimination. 12

Block ! Initiation & propagation of action potential (AP) by preventing voltage-gated Na+ channels.

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

Elevated extracellular Ca2+ antagonizes ! action of LA by Ca2+ which increase ! surface potential on ! membrane.

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

Potency is +vely correlated with lipid solubility.

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

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

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Structure- Activity Characteristics of LA:

Other actions of LA on nerves:1- Loss of sensation from site of painful

stimuli2- Motor paralysis during surgery;

desirable; but also limit ! ability of patient to cooperate in obstetric delivery.

Disadvantages In Spinal anesthesia, motor paralysis:

impair respiratory activity & AN blockade: hypotension & urinary

retention (catheterization).15

1- Effect on fiber diameter: LA block conduction in small-diameter

nerve fibers > readily than in large fibers. (bec electrical impulse is shorter)

Pain sensation is blocked > readily than other sensory modalities.

Motor axons (large diameter), are relatively resistance.

LAs block conduction in ! following order:

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

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2- Effect on firing frequency

Blockade by LA is > at higher frequencies of depolarization.

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

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

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DrugDrugOnseOnsett

DuraDura-tion-tion

PlasPlas-ma -ma tt1/21/2

SESENotesNotes

CocCoc--MediMediumum

MM11 hrhrCV & CNS, CV & CNS, due to block due to block

of amine of amine uptakeuptake

Rarely used, Rarely used, only as spray only as spray for URTfor URT

ProPro--MMShortShort < <1hr1hr

CNSCNS: : restlessnessrestlessness, shivering, , shivering, anxietyanxiety

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

No longer No longer usedused

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LidLidRapidRapidMM22 hrhrAs 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

LongLong11 hrhrAs LidAs Lidspinal & corneal spinal & corneal anesthesiaanesthesia..

BupivacBupivac--

SlowSlowLongLong22 hrhrAs 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--MMMM22 hrhrNo VDNo VD

MetHgemiMetHgemiaa

Widely used, Widely used, not for obstetric not for obstetric (neonatal (neonatal metHgemiametHgemia.. 19

Surface/topical anesthesia Local infiltration  Peripheral nerve block  Bier block (IV regional anesthesia) Epidural anesthesia  Spinal anesthesia (subarachnoid)

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SpinalSpinal

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Effective analgesia in specific regions of ! body.

Route of administration:1- Topical/ surface application (nasal

mucosa, wound margins)2-Inj in ! vicinity of peripheral nerve endings

(infiltration) & major nerve trunks (blocks)3- Inj into ! epidural or subarachnoid spaces

surrounding ! spinal cord.4- IV regional anesthesia (Bier block) for

surgery < 60 min in limbs. 23

Short: proc- & chloropro- caine Intermediate: Lid, mepiva- & prilo- caine Long-acting: tetra-, bupiva-, & ropiva-

caine.

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

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To increase onset of LA: + Na-bicarbonate to LA sol; LA become > lipid soluble.

Repeated inj of LA: tachyphylaxis (extracellular acidosis)

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

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

application. Cocaine bec of excellent penetration & local

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

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

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OTHER USES: LAs have membrane-stabilizing effects;

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

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

Systemic toxicity: CNS & CV system. 

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A- CNS:1- All LAs at low conc: sleepiness, light

headiness, visual & auditory disturbances & restlessness.

Early symp: tongue numbness + metallic taste.

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

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

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

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

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

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

Bupivacaine is > cardiotoxic than other long-acting LA.

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

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

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D- Hematologic effects:Large dose of prilocaine: accumulation of

Oxidizing Agent (o- toluidine) that convert Hg to metHg.;; cyanosis & chocolate-colored. Not recommended in infants. (Benzocaine can also cause metHg).

Rx: IV methylene blue/ ascorbic acid.

E- Allergic rxs: (Not with amides)Ester-type LAs are metabolized to P-ABA

derivatives; allergic rxs.30