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Local Anesthetics

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

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Title: Local Anesthetics


1
Local Anesthetics LA
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  • 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).

3
  • 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 onset,
  • 2- Long Duration of Action,
  • 3- Reversible selective blockade of sensory
    nerves without motor blockade,
  • 4- Minimal local tissue irritation no systemic
    toxicities.

4
Chemistry of LA
  • 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 esp systemic depends on
  • 1- dosage,
  • 2- site of inj, (VASCULARITY) IV gt tracheal gt
    intercostals gt paracervical gt epidural gt brachial
    plexus gt sciatic gt SC
  • 3- drug-tissue binding,
  • 4- local bld flow,
  • 5- use of Vasoconstrictors (epinephrine/
    phenylephrine)
  • 6- ! physiochemical property of ! drug.
  • Absorption in highly vascular area is gt poor
    perfused tissue.

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  • Epinephrine/ VC
  • Slow ! removal reduce systemic absorption of LA
    from inj site by decreasing bld flow
  • 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 lt effective in prolonging anesthetic
    action of more lipid-soluble, long-acting drugs
    (bupivacaine ropivacaine) which are highly
    tissue-bound.

10
  • Distribution
  • ! Amide LAs are widely distributed after IV bolus
    inj.
  • Initial rapid phase into highly perfused organs,
  • then a slower phase to moderately perfused organs.

11
Metabolism Excretion
  • Acidification of urine ionization excretion of
    LA
  • Ester-type hydrolyzed rapidly in ! bld (by
    pseudo-choline-sterase) to inactive metabolite
    short plasma t1/2 (lt 1 min).
  • ! amide linkage is hydrolyzed by liver cyto P450
    with diff rate (prilocaine (fastest) gt Lid gt
    mepivacaine gt ropivacaine gt bupivacaine
    (slowest).
  • All converted to water-soluble metabolites
    excreted in urine.

12
  • Toxicity from amide-type LA occur in hepatic D.
    Ex elimination
    t1/2 of Lid from 1.6 hr in normal pat to gt 6 hr
    in liver disease pat.
  • amide LA also affected by enz inhibitors.
  • Reduced hepatic bld flow decrease their
    elimination.

13
MOA
  • Block ! Initiation propagation of AP by
    preventing voltage-gated Na channels.
  • Activity is PH-dependent, increased at alkaline
    PH. Its penetration to Na chs is very poor at
    acid PH. Inflamed tissues (acidic) resis to LA.
  • Elevated extracellular Ca2 antagonizes ! action
    of LA by Ca2 w increase! surface potential on !
    membrane.

14
Structure- Activity Characteristics of LA
  • Smaller more lipophilic LA ! Faster rate of
    interaction with Na chs.
  • Potency is vely correlated with lipid
    solubility.
  • Lid, procaine, mepivacaine are gt
    water-soluble than tetracaine, bupivacaine,
    ropivacaine that are more potent have longer
    DOA.
  • Long acting (bupivacaine ) also bind more
    extensively to plasma proteins can be displaced
    by other drugs.

15
  • Other actions on nerves
  • 1- Loss of sensation from site of painful stimuli
  • 2- Motor paralysis during surgery
  • Disadvantages
  • In Spinal anesthesia, motor paralysis impair
    respiratory activity
  • AN blockade hypotension urinary retention
    (catheterization).

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  • 1- Effect on fiber diameter
  • LA block conduction in small-diameter nerve
    fibers gt readily than in large fibers.
  • Pain sensation is blocked gt readily than other
    sensory modalities.
  • Motor axons (large diameter), are relatively
    resistance.
  • LAs block conduction in ! following order
  • small myelinated (nociceptive impulses), non-
    myelinated (C-fibers), large myelinated axons.

17
  • 2- Effect on firing frequency
  • Blockade by LA is gt 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.

18
Properties of LAs
Drug Onset Duration Plasma t1/2 SE Notes
Coc- M M 1 hr CV CNS Rarely used, only as spray for URT
Pro- M Short lt 1hr CNS restlessness, shivering, anxiety CVS B.cardia decrease COP No longer used
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Lid Rapid M 2 hr As procaine but lt tendency to CNS Widely used IV in ventricular arrhythmia. Mepivacaine is similar
Amethoc- (tetrac V. Slow Long 1 hr As Lid spinal corneal anesthesia.
Bupivac- Slow Long 2 hr As Lid but gt CVS Widely used (long DOA). Ropivacine is similar, with less cardioTox.
Priloc- M M 2 hr No VD MetHgemia Widely used, not for obstetric (neonatal metHgemia.
20
Classification Six Placement Sites
  • Surface/topical anesthesia
  • Local infiltration 
  • Peripheral nerve block 
  • Bier block (IV regional anesthesia)
  • Epidural anesthesia 
  • Spinal anesthesia (subarachnoid)

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Epidural
Spinal
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Clinical pharm
  • 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 lt 60 min in limbs.

24
  • Local Infiltration
  • Extravascular placement of ! LA in ! region to be
    anesthetized
  • Peripheral Nerve Block
  • LA inj into tissues around individual nerves or
    nerve plexuses (e.g. brachial plexus).

25
DOA
  • Short proc- chloropro- caine
  • Intermediate Lid, mepiva- prilo- caine
  • Long-acting tetra-, bupiva-, ropiva- caine.
  • DOA can be prolonged by increasing ! Dose/ adding
    VC agent.

26
  • To increase onset of LA Na-bicarbonate to LA
    sol.
  • 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, pramoxine,
    dibucaine, benzocaine, dyclonine.

27
  • OTHER USES
  • LAs have membrane-stabilizing effects Both IV
    Lid po (mexiletine, tocainide) used to Tr pat
    with neuropathic pain syndrome (uncontrolled,
    rapid, sensory fiber firing).
  • Systemic LA as adjuncts to
    TCA (amitriptyline)
    anticonvulsant (carbamazepine) combination.
  • Systemic toxicity CNS CV system. 

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Toxicity
  • 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).

29
  • 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 gt neurotoxic
    than others in spinal anes., transient
    irritation (neuropathic symptoms).

30
  • C- CVS direct effect on ! hrt smooth muscle
    indirect effect on ! ANS.
  • Depress strength of cardiac contraction, ECG
    changes cause arteriolar dilatation
    hypotension.
  • Cocaine blocks Norepinephrine uptake VC HTN
    cardiac arrhythmia ischemia.
  • Bupivacaine is gt cardiotoxic than other
    long-acting LA.
  • Ropivaciane CV CNS tox, but lt than Bupivacaine.

31
  • 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 e amides)
  • Ester-type LAs are metabolized to P-ABA
    derivatives allergic rxs.
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