Lipid solubility appears to be the most significant property of local anesthetic molecules in determining anesthetic potency. The lipid nature of the nerve cell membrane probably explains this relationship between lipid solubility and potency. Local anesthetic molecules which are highly lipophilic, easily penetrate nerve cell membranes and become intracellular, resulting in more blockade. Graphs of the potency of local anesthetics against the oil/water partition coefficients demonstrates the clear relationship between potency and lipid solubility. Lipid studies involving exposed, intact nerves demonstrate the relationship between the minimal effective concentration required to interrupt conduction block and lipid solubility of the agents.
Clinically, this phenomenon is demonstrated by bupivacaine and etidocaine which are considerably more lipid soluble and more potent (40 times for etidocaine and 10 times for bupivacaine) than lidocaine. The potency of these agents correspond directly to the lipid solubility. A clinical example is the relationship of procaine to tetracaine. When a hydrophobic butyl group is added to the aromatic ring of procaine, tetracaine is created. The 40 times increase in potency which results establishes the hydrophobic (lipophilic) properties of the molecules as the principal determinant of potency. If this same butyl group is conjugated with a hydrophilic group, the resultant molecule has potency lower than procaine. It may be that there is a hydrophobic region near the sodium channel which orients the local anesthetic molecule with the amine group in the receptor area of the sodium channel.
The protein binding capacity of a local anesthetic determines the duration of conduction block . Protein binding is related to lipid solubility. In general, agents with greater protein binding have a greater attraction for receptor sites and remain within sodium channels for a longer period of time. This means that agents with higher protein binding capacity are associated with a longer duration of action.
Again, this is confirmed by both in vitro as well as clinical experience. Poorly protein bound agents, such as procaine, are readily washed out in vitro experiments, and duration of local anesthetic blockade can be extremely short whereas those which are highly protein bound, such as bupivacaine, are less easily washed out in vitro experiments and conduction blockade is interrupted for a longer period of time. The clinical activity of the agents which are more protein bound such as bupivacaine and etidocaine, are associated with a longer duration of clinical anesthesia. The less well protein bound agents such as procaine and chloroprocaine, are associated with short duration of clinical activity.
A major determinant of local anesthetic onset is pKa. The pKa of a local anesthetic molecule is that pH at which 50% of the agent exists in the ionic and 50% non-ionic form. The pKa determines a number of the agents clinical actions, most importantly, onset of conduction blockade. The onset is related to the concentration of the local anesthetic molecule present in the non-ionic form. The non-ionic form is the form which extracellularly is associated with penetration of the nerve cell membrane. The pKa of most local anesthetic agents is higher than physiologic (7.7 to 9.0). Local anesthetic molecules are prepared and sold at a pH lower than physiologic meaning that a majority of the molecules exist in the solution in the ionic form. The higher the pKa, the higher the percentage of ionic form of the molecule present in the solution, and hence, the lower the concentration of the non-ionic form and the slower speed of onset of the local anesthetic agent.
One of the properties of the local anesthetic molecules which determines their level of activity is their effect on blood vessels in the areas where they are injected. All local anesthetics, with the exception of cocaine, are associated with vasodilation, and the blood levels and duration of action and the systemic effects are modulated by the proportion of vessel dilation associated with each agent. Vasodilation decreases the duration of action of local anesthetic molecules as well as prolonging onset time.
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