The factor that is LEAST likely to affect the onset of a local anesthetic is?

Answer: Protein binding.

pKa has a direct effect on the onset of local anesthetics.  pKa determines the amount of base present in a solution, which also depends on the pH of the solution.  When the pH is equal to the pKa of a local anesthetics, then equal amounts of base and ionized species of the local anesthetic exist in solution.  Local anesthetics whose pKa is far removed from physiologic pH (e.g., procaine) have slow onset of action than local anesthetics whose pKa is close to physiologic pH.

Some local anesthetics agents (such as prilocaine) diffuse through tissues better than some other local anesthetics and therefore have more rapid onset of action.

Protein binding is more associated with duration of anesthesia than with onset.  Because the local anesthetic receptors contain proteins, it may seem intuitive that the ability of a local anesthetic to bind to proteins would influence onset of action, but this is not the case.

Addition of sodium bicarbonate to bring the pH of the local anesthetic solution closer to the local anesthetic's pKa, statistically significantly speeds the onset of action of some local anesthetics with certain types of regional blocks.  This effect is influenced by many other factors, such as the concentration of the local anesthetic injected.  The rate at which the onset of action is hastened may not be clinically significant.

Ref.  1. Lambert DH: Clinical value of adding sodium bicarbonate to local anesthetics. Reg Anesth Pain Med 2002; 27: 328-9; author reply 329-30.

As long as the volume of local anesthetic is kept constant, increasing the concentration of the local anesthetic that is injected, will hasten the onset of anesthesia because there will be more local anesthetic molecules to interact with the receptor.

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