Local Anesthetics

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Local Anesthetics LA
Prepared by Dr Alia Alshanawani College of
Medicine, KSU.
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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).

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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).

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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 of injected LA, 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 blood flow,
• 5- use of Vasoconstrictors (epinephrine/
  phenylephrine)
• 6- ! physiochemical property of ! drug.
• Absorption in highly vascular area (trachea,
  intercostal) is gt 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 lt effective in prolonging anesthetic
  action of more lipid-soluble, long-acting drugs
  (bupivacaine ropivacaine) which are highly
  tissue-bound.

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• 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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Metabolism Excretion

• Acidification of urine ionization excretion of
  LA
• Ester-type hydrolyzed rapidly in ! blood (by
  pseudo-choline-sterase) to inactive metabolites
  short plasma t1/2 (lt 1 min).
• ! amide linkage is hydrolyzed by liver cytochrome
  P450 with different rates order (prilocaine
  (fastest) gt Lid gt 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
  gt 6 hr in liver disease pat.
• amide LA also affected by enz inhibitors.
• Reduced hepatic bld flow decrease their
  elimination.

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MOA

• 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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Structure- Activity Characteristics of LA

• Smaller more lipophilic LA ! Faster rate of
  interaction with Na channels.
• Potency is vely correlated with lipid
  solubility.
• Lid, procaine, mepivacaine are gt
  water-soluble than tetracaine, bupivacaine,
  ropivacaine that are gt 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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• Other actions of LA on nerves
• 1- Loss of sensation from site of painful stimuli
• 2- 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).

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• 1- Effect on fiber diameter
• LA block conduction in small-diameter nerve
  fibers gt readily than in large fibers. (bec
  electrical impulse is shorter)
• 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 (pain impulses), non- myelinated
  (C-fibers), large myelinated axons.

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• 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.

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Properties of LAs
Drug Onset Dura-tion Plas-ma t1/2 SE Notes
Coc- Medium M 1 hr CV CNS, due to block of amine uptake Rarely used, only as spray for URT
Pro- M Short lt 1hr CNS restlessness, shivering, anxiety CVS B.cardia, VD 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.
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Methods of administration 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.

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Duration of Action

• 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 gt 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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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).

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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 gt 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 gt cardiotoxic than other
  long-acting LA.
• Ropivaciane CV CNS tox, but lt 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.