• Lipid solubility
  
• Degree of vascularity of the tissue
  
• Presence of vasoconstrictors that prevent vascular uptake
  

Dr. David Lyness

@Gas_Craic

• Sodium is high extracellularly and low intracellularly
• Potassium is low extracellularly and high intracellularly
  
• Conduction is caused by a sudden shift in Na and K ions across the cell membrane
  
• Na/K/ATP Pump mechanism keeps this gradient in a resting nerve
  
• In a resting state, the membrane is more permeable to potassium
  
• Because of this shift of positive ions out of the centre, the centre is now negative
  
• There is a 60-70mV potential across the cell membrane due to these ions
  
• Stimuli like a surgeon’s cut are converted into minuscule electric currents -                  
  making the area around receptor sites LESS negative
  
• If these currents cause the threshold potential to be met, will cause an action potential to be propagated down the nerve
   
• This works via the cell membrane suddenly becoming more permeable to positive sodium ions, that flood in to a -ve area (it being a positive ion)
   
• This generates a current that sequentially depolarizes the adjacent segment of the nerve, thus "activating" the nerve and sending a wave of sequential polarization down the nerve membrane.
   
• Because the rapid influx of Na+ ions occurs in response to a change in the transmembrane potential, Na+ channels in the nerve are characterized as "voltage gated" - large, three subunit protein structures that cross the membrane layer connecting the exterior of the cell to the axoplasm (interior).
  

• LA’s bind to the alpha part of this subunit and block sodium from going back in
  
• If sodium can’t flow back in, then the wave of depolarisation/transmission is blocked
  
• A resting nerve is less sensitive to a LA than a nerve that is repeatedly stimulated
  
  
• A higher frequency of stimulation and a more positive membrane potential cause a greater degree of transmission block
  
• The more an area around the nerve is depolarised, the more likely that an LA will find an open/activated sodium subunit!
  

• LA’s have a hydrophilic and a hydrophobic section.
  
• Ester & Amide LA’s - basically describing the molecule that connects the hydrophilic/phobic sections.
  
  
• Ester-linked LAs are metabolized in plasma by pseudocholinesterase
  
• Amide-linked drugs undergo metabolism in the liver.
  
• The more lipid soluble, the larger the potency and duration of action - (more dissolvable at lipid membranes)
  
• Greater lipid solubility also increases toxicity, decreasing the therapeutic index for more hydrophobic drugs.
  
• Block duration is not related to protein binding!
  

THREE DEPENDANT FACTORS THAT AFFECT BLOCK LENGTH

• The pKa generally correlates with the speed of onset of action of most amide LA drugs (lignocaine)
• The closer the pKa to the body pH, the faster the onset
• The pKa is the pH at which 50% of the drug is ionized and 50% is present as base
• pKa of the LA is related to pH and the concentrations of the cationic and base forms by the Henderson-Hasselbalch equation:
  pH = pKa + log ([base]/ [cation]).
  
• The pKa generally correlates with the speed of onset of action of most amide LA drugs; the closer the pKa to the body pH= faster the onset.
  
• The coexistence of the two forms of the drug - the charged cation and the uncharged base-is important because drug penetration of the nerve membrane by the LA requires the base (unionized) form to pass through the nerve lipid membrane
  
• Once in the axoplasm (centre) of the nerve, the base form can accept a hydrogen ion and equilibrate into the cationic form.
  
• The cationic form is predominant and produces a blockade of the Na+ channel.
  
• The amount of base form that can be in solution is limited by its aqueous solubility.
  
• It is generally accepted the closest you can infiltrate to the nerve itself, the quicker its onset - due to distance.
  
• Direct injection into the nerve is not recommended - it can cause injury.
  

http://www.nysora.com/regional-anesthesia/foundations-of-ra/3492-local-anesthetics-clinical-pharmacology-and-rational-selection.html

LOCAL ANAESTHETICS

propofology.com

THE GREATER THE LIPID SOLUBILITY, THE GREATER THE DURATION OF ACTION.