- Lipid solubility
- Degree of vascularity of the tissue
- Presence of vasoconstrictors that prevent vascular uptake
Dr. David Lyness
- 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.
THE GREATER THE LIPID SOLUBILITY, THE GREATER THE DURATION OF ACTION.