Local Anaesthesia Introduction & Pharmacology

• Local anaesthesia is a loss of sensation in a circumscribed area of the body by a depression of excitation in nerve endings or an inhibition of the conduction process in peripheral nerves.
• Uses of LA in dentistry:

  • Operative pain management
  • Post-operative pain management
  • Diagnosis (not as much any more because better techniques now available, eg pulp testing)
  • Haemostasis (because it contains vasoconstrictors to reduce bleeding in the local area)
• LA mechanism of action = a chemical roadblock between the tooth and the brain. It stops messages from tooth getting to brain.
• There are 2 theories of LA action:

  • Membrane expansion
  • Specific receptor (currently more accepted theory)
• Action potential is how a pain message gets from a tooth to the brain so that the brain can interpret it as pain. When a nerve is stimulated, it will undergo a period of depolarisation, a period of repolarisation and then a refractory period. During the refractory period the nerve can't fire off any more action potentials; it's in a state of 'recovery'. This is governed by shifts in the electrochemical gradients within the nerves - voltage gated sodium channels allow this process to work. Therefore voltage-gated sodium channels are where LAs work.

  
• M gate = the activation gate

  H gate = the deactivation gate

  When the nerve is at rest, the outside of the cell is positive and the inside is negative.

  
• If the cell is stimulated (eg if drill hits dentine) then the m gate will open, which allows sodium to move into the cell. This causes the electrochemical gradient to shift, so that the outside becomes negative and the inside becomes positive.

  
• During repolarisation, the h gate (the deactivation gate) closes to stop any further sodium from entering the cell. Potassium then moves from the inside of the cell to outside the cell across the cell membrane, which allows the electrochemical gradient to shift back.

  
• Membrane expansion theory: LA simply diffuses into the cell membrane and causes the nerve cell membrane to expand, so that it physically blocks off the sodium channel, meaning that sodium can't move into the cell to create an action potential.

  
• Specific receptor theory:

  • There's a binding site for local anaesthetic on the inside of the h gate (the deactivation gate)
  • The LA binds to that site and holds it closed
  • By doing this, it keeps the cell membrane in the refractory period, meaning that it can't fire new action potentials

  
• Sodium channels:

  • Composed of 3 subunits: α, β₁, β₂
  • Alpha subunit where sodium passes
  • Composed of Na channel surrounded by four protein domains (I-IV)
  • Each domain contains six segments (S1-S6)
  • S4 - m gate

  
• LA molecule:

  • Aromatic group (lipophilic)
  • Intermediate chain (ester or amide link)
  • Substituted amino terminal (hydrophilic)
• Intermdiate chain:

  • Allows spatial separation of lipid and water soluble components
  • Allows classification of LA into 2 major groups
  • 2 major groups are esters and amides

  The intermediate chain is the part that determines whether it's an ester or an amide (specifically the bits in the circles)

  
• Classification of amides and esters:

  • Amides
  • Lidocaine
  • Prilocaine
  • Mepivicaine
  • Articaine
  • Esters
  • Benzocaine (commonly used in topical anaesthetics, but problems with allergies)
  • Amethocaine
  • Procaine
• Amides vs esters:

  • Allergic potential
  • Lots of people used to be allergic to esters in LA, so moved away from using them - pretty much exclusively use amides now except for benzocaine
  • Metabolism
• Dilemma:

  • LA binding site is intracellular
  • Therefore LA needs to be lipophilic and uncharged across the cell membrane and get to the binding site
  • Specific binding to achieve LA requires a charged molecule
  • Therefore the LA needs to be in charged form
  • How can LA be uncharged (lipophilic) and charged at the same time
• Chemistry:

  • LAs are weak bases
  • So in solution the LA molecule will exist as:
  • Uncharged base
  • Charged cation
  • Important as LA is then:
  • Lipid soluble to enter cells to work
  • Charged form for specific bonding once in cell

  
• When you inject the LA solution, you'll have the two different types. The uncharged molecules will cross the nerve cell membrane to reach the inside. Once inside, the LA will dissociate again, giving charged and uncharged forms. The charged forms can then bind to the site on the h gate (the deactivation gate).

  
• The quicker the LA enters the cell the more effective it is and the quicker it acts. Therefore LA with a high proportion of uncharged molecules after injection are most effective.
• Ratio of charged to uncharged molecules governed by pH and pKa (dissociation constant).
• Ionisation:

  • Lower pH less uncharged molecules present when LA injected
  • eg in infected tissues - so ideally don't inject LA into infected tissue because it won't work
  • Lower pKa (dissociation constant) more uncharged molecules exist (what you want)
  • So ideally, inject into an area with a high pH and a low pKa
  • LAs have different pKas, therefore have different onsets of action
  • Lidocaine - 7.9
  • Articaine - 7.8
  • Bupivicaine - 8.1
  • Procaine - 9.1
• Chemo-physical properties that influence LA action:

  • Ionisation (pH and pKa) - onset
  • Partition coefficient - onset
  • Protein binding - duration of action
  • Vasodilator ability - duration of action
• Partition coefficient:

  • Measures lipid solubility
  • Higher partition coefficient = drug is more lipid soluble
  • Therefore crosses nerve sheath quicker
  • Therefore higher partition coefficient the faster the onset of action
  • Lidocaine's partition coefficient = 3
  • Procaine's partition coefficient = 0.6
  • Therefore lidocaine has a quicker onset of action than procaine
• Protein binding:

  • Drugs have varying degrees of protein binding
  • Degree of protein binding related to duration of action
  • Bound portion acts as a reservoir from which free drug can be released to replace what has been used/metabolised
  • If it's bound to a protein - can't be used
  • Once the free drug has all been used, the bound protein will then be released
  • Lidocaine - 64% protein bound, half life 90 mins
  • Bupivicaine - 96% protein bound, half life 160 mins
  • Much more long-lasting than lidocaine - used for complex maxillofacial surgery
  • Articaine - 94% protein bound, half life 108 minutes
• Vasodilatory ability:

  • Most LAs are vasodilators
  • Exception cocaine - potent vasoconstrictor
  • Degree of vasodilation varies between types
  • More vasodilation then LA washes away quicker so short duration of action
  • Addition of vasoconstrictor to overcome this
• What is in an LA cartridge:

  • Anaesthetic agent
  • Vasoconstrictor
  • Reducing agent
  • Ringer's solution
  • Preservatives - most don't have these anymore though to try to avoid allergies
• Vasoconstrictor containing LA:

  • More profound anaesthesia
  • Longer-lasting anaesthesia
  • Better haemostasis
• Vasoconstrictors used in the UK:

  • Adrenaline (epinephrine) - a catecholamine
  • Naturally occurs in the body - therefore can't be allergic to it
  • Felypressin - (octapressin) - a synthetic peptide
  • Others available but not in the UK
• Adrenaline can affect:

  • Blood vessels
  • Heart
  • Lungs
  • Metabolism
  • Wound healing
• Vascular effects:

  • Alpha adrenoreceptors
  • Found in the skin and mucous membrane
  • Causes vasoconstriction if LA comes into contact with them
  • Beta adrenoreceptors
  • Found in skeletal muscle and liver
  • Causes vasodilation if LA comes into contact with them
  • Reduced diastolic blood pressure
  • Causes fainting with high doses
  • Peripheral vasoconstriction better than felypressin
• Metabolic effects:

  • Alpha adrenoreceptor inhibition of insulin release -> increase blood glucose
  • Beta adrenoreceptor activation of sodium-potassium pump -> potassium pumped intracellular -> decrease plasma potassium
• Cardiac effects:

  • Direct effect
  • Activation of beta-adrenoreceptors
  • Increases rate and force of contraction of heart
  • Increases cardiac output
  • Indirect effect
  • Secondary to metabolic changes - decrease in plasma potassium (hypovolaemia)
• Pulmonary effects:

  • Stimulation beta-adrenoreceptors in the lungs
  • Causes bronchiolar relaxation
  • Theoretical in LA doses (especially in dentistry)
• Wound healing:

  • Decreased oxygen tension in tissues
  • Increased fibrinolysis - decreased stability of blood clots
  • Quite theoretical based on amount used in dentistry though
• Amount of adrenaline in a cartridge - various concentrations available:

  • UK - 1:80,000
  • 1:80,000 = 12.5μg/mL
  • 2.2mL contains 27.5μg of adrenaline
• Felypressin:

  • Causes
  • Coronary artery vasoconstriction
  • Oxytocic action on uterus - therefore could potentially induce labour
  • Poorer control of haemorrhage cf adrenaline
  • Amount in cartridge:
  • 0.54μg/mL
  • 2.2mL contains 1.2μg