LOCAL ANESTHETICS

LOCAL ANESTHETICS

• Local anesthetics are drugs which upon topical application or local injection cause reversible loss of sensory perception, especially of pain in a localized area of the body.
• It blocks generation and conduction of nerve impulses at a localized site of contact without structural damage to neurons.
• Loss of sensory as well as motor impulses.
• LAs, do not cause the loss of consciousness when administered correctly.

HISTORY OF LOCAL ANESTHETICS

• Albert Niemann (1860) isolated crystals from the coca shrub – and called it “COCAINE”, he found that it reversibly numbed his tongue.
• German chemist Alfred Einhorn (1905) produced the first synthetic ester type local anesthetic Novocain (procaine) which retained the nerve blocking properties but lacked the powerful CNS actions of cocaine.
• Swedish chemist Nils Lofgren (1943) synthesized the first amide-type local anesthetic – marketed under the name of Xylocaine (Lidocaine).

CHEMISTRY OF LOCAL ANESTHETICS

• Three major parts of any Local Anesthetics:
  • Aromatic Ring (Lipophilic Moiety).
  • Intermediate Chain is of Amide or Ester (basis of classification).
  • Amine Group (Hydrophilic Group).
• Potency = Lipid Solubility
• Higher solubility = Can use a lower concentration and reduce potential for toxicity.

CLASSIFICATION OF LOCAL ANESTHETICS

           1.Based on duration of action

            Duration = Protein Binding

• Short Acting (20-25 Min.):
  • Procaine
  • Chloroprocaine.
• Intermediate Acting (45-60 Min.):
  • Lidocaine (Lignocaine)
  • Prilocaine
  • Lignocaine
  • Cocaine
• Long Acting (2-3 Hours):
  • Bupivacaine
  • Etidocaine
  • Ropivacaine       
  • Tetracaine

          2. Based on chemical nature:

1.Esters:

• Cocaine
  • Procaine
  • Tetracaine
  • Benzocaine
• Produce more intense & longer lasting anesthesia.
• Not hydrolyzed by plasma esterase’s.
• Rarely cause hypersensitivity reactions.

2.Amides:

• Lidocaine
  • Mepivacaine
  • Bupivacaine
  • Etidocaine
• Short duration of action and less analgesia.
• Hydrolyzed by plasma esterase’s.
• High risk of hypersensitivity.

PROPERTIES OF LOCAL ANESTHETICS

• Reversible in action
• Nonirritant
• No allergic reaction
• No systemic toxicity
• Rapid onset of action
• Sufficient duration of action
• Potent
• Stable in solution
• No interfere with healing of tissues
• Should have Vaso-constrictive action
• Not expensive

MECHANISM OF ACTION

• The primary target of the LA, Voltage Activated Sodium Channels (VASA) is one the numerous membrane proteins which reside in phospholipids bilayer encapsulating the neurons.
• LAs block VASA → Reduce Na⁺ influx → No depolarization → No Conduction of Active Potential (PA).
• Local anesthetics gain access to the inner axonal membrane by:
  • Traversing sodium channels while they are more often in an open configuration.
  • Pass directly through the plasma membrane.
• More lipid soluble (Unionized/Uncharged) form → More effective intracellular conc.
• Inside the neuron → Ionized form is more effective blocking entity.
• Both ionized & unionized forms play significant role in
  • First in reaching the receptor site.
  • Second in causing the effect.

   PHARMACOKINETICS OF LOCAL ANESTHETICS

1. ABSORPTION:
   • Absorption is determined by:
     • Absorption site
     • Dose
     • Rate of injection
     • Pharmacological properties.
   • Plasma Conc. After injection at various sites is:
     • Intrapleural > Intercostal > Lumbar Epidural > Brachial Plexus > Sciatic > Femoral.
     • First pass Pulmonary Metabolism limits the Conc. Of Local Anesthetics that reaches to Systemic Circulation.

    FACTORS AFFECTING THE ABSORPTION OF LAs:

1. Site of Injection (Intrapleural > Intercostal > Lumbar Epidural > Brachial Plexus > Sciatic > Femoral).
2. Dose
3. Physicochemical Properties (Lipid Solubility & Protein Binding).
4. Addition of Epinephrine.

     2.DISTRIBUTION:

• Tissue distribution of LA is proportional to:
  • Lipid solubility of drug
  • Blood supply to that tissue
• LA drugs are distributed rapidly in:
  • Brain, Heart, Liver, Lung.
• But more slowly distributed…. which have lower blood supply:
  • Muscles & Adipose Tissues.
• Patient age, cardio-vascular status and hepatic function influence the tissue blood flow.

      3.METABOLISM:

• Amide:
  • Metabolism is dependent on hepatic blood flow.
  • Toxicity of amides is more likely with:
  • Prolonged infusions in sick, elderly patients.
  • Postoperative increase in AAG (Acute Angle Glaucoma) attenuates the rise in plasma concentrations
• Esters:
  • Hydrolyzed rapidly in plasma by pseudo cholinesterase to the metabolite
  • Para-aminobenzoic acid (PABA), which can generate an allergic reaction.

      4.EXCRETION:  

• Kidneys are primary excretory organs of LA drugs & their metabolites.
  • Esters appears in very small conc. of parent compound in urine.
  • Excretion of amide local anesthetics is dependent on         hepatic metabolism metabolites may accumulate in renal failure.
  • Metabolism is fastest in the rank order:
    • Prilocaine > Lidocaine > Bupivacaine.
  • Most of the LA drugs cross the placenta.

     IMPORTANCE OF ADDING VASOCONSTICTORS TO LOCAL ANESTHETICS

• Vasoconstrictors Constrict blood vessels
• Decrease blood flow
• Decrease the blood level of the drug
• Increase the concentration of drug at the site
• Decrease bleeding at site
• Increase the duration of drug.