- Lipid solubility
- Degree of vascularity of the tissue
- Presence of vasoconstrictors that prevent vascular uptake
STATES LEAST LIKELY TO EXERCISE
THE GREATER THE LIPID SOLUBILITY, THE GREATER THE DURATION OF ACTION.
THE MORE LIPID SOLUBLE AN LA, THE MORE TOXIC IT CAN BE AT LARGER DOSES
An interplay between sodium and potassium
Dr. David Lyness
The pharmacology of how they block pain
- 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, the 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.