conductance increases, causing the nerve to become less electronegative compared to the outside environment. Sufficient neuronal stimulation pushes depolarization over a threshold that leads to a nerve impulse being propagated down the nerve and on to the next. The action potential is very transient, and the Pharmacodynamics Pharmacodynamics focuses specifically on the relationship between drug concentration at the site of action and the resulting effect; it further includes the time course and intensity of therapeutic and adverse effects. The typical local anesthetic molecular structure can be divided into three parts: an aromatic group, an intermediate chain, and a secondary or tertiary amino terminus. The overall pharmacodynamic activity of the local anesthetic is determined by the combination of these three components. The aromatic portion of the molecule confers lipophilic properties, while the amino group determines the water solubility. The intermediate chain provides for the appropriate spatial separation between the lipophilic and hydrophilic ends and typically contains either an ester or amide moiety that helps to catalogue the local anesthetic’s class. Figure 1 presents the structure of procaine (Novocain) in the ester class and lidocaine (Xylocaine) in the amide class. Figure 1: Local Anesthetic Structure and Classes
sodium ion channels close rapidly in response to an outward flow of potassium ions. Local anesthetics interact directly with neuronal sodium channels, preventing the gating mechanism that underlies the opening of sodium channels, and thereby inhibiting nerve conduction. metabolism, and excretion (i.e., each drug’s unique pharmacokinetic profile). It is their unique pharmacodynamic profile (i.e., lipid solubility, pKa, protein binding, and vasodilator activity) that determines each local anesthetic’s potency and onset and duration of activity. Lipid solubility Lipid solubility significantly affects the activity of local anesthetics. Alterations of any portion of the local anesthetic molecule can significantly influence a drug’s action. For example, the addition of a chlorine atom to the ortho position of the aromatic ring of procaine creates chloroprocaine, a more lipophilic local anesthetic with four times the potency but only half the toxicity of procaine. Agents with lower lipid solubility are generally marketed at higher concentrations (Table 1). Table 1: Relationships Between Lipid Solubility and Clinically Effective Local Anesthetic Concentration Medication Lipid Solubility
Articaine
40
4
Bupivacaine
560
0.5
Etidocaine
1,853
1.5
Lidocaine
110
2
Mepivacaine
42
2-3
Prilocaine
55
4
Procaine 2 Note . Adapted from “The ADA/PDR Guide to Dental Therapeutics” (5th ed.), by the American Dental Association and the Physicians’ Desk Reference, 2009, PDR Network, pp. 11-13; “Local Anesthetics: Review of Phar Anesthesia Progress, 59(2), pp. 90-102; “An Update on Local Anesthetics in Dentistry,” by D. A. Haas, 2002, Journal of the Canadian Dental Association, 68(9), pp. 546-551; “Local Anesthetics: Pharmacology and Toxic 54(4), pp. 587-599; and “Legal 80 Considerations,” by D. J. Orr, II, 2021, in S. F. Malamed (Ed.), Handbook of Local Anesthesia (7th ed.), Elsevier Mosby, p. 412. pKa At physiological pH of 7.4, all local anesthetic molecules exist in two states: a free base (uncharged) that readily penetrates tissues and lipid-rich membranes and a cation (positively charged species) that is unable to cross membranes. The pKa of a molecule is the pH at which the proportion of these two species is 50:50. Since all local anesthetics are weak bases, their pKa range is between 7.7 and 8.9. In other words, they prefer to be in balance at a more basic pH, above 7.4. Since physiological pH is less than the pKa of all local anesthetics (i.e., the physiological pH is more acidic), when introduced to the body, all local anesthetics exist primarily in the cationic, positively charged form and are unable to cross membranes. Differences in pKa among local anesthetics result in differences in their onset time (Table 2). As can be seen, the closer the pKa is to tissue pH (7.4), the faster the onset of the local anesthetic. This is particularly important when there is an infection present. When an infection is present, the pH of the tissue drops and it becomes more acidic. Therefore, choosing local anesthetics with the lowest pKa in these situations would be pharmacologically prudent.
This classification is important because there are significant differences in metabolism and allergenicity between these two classes of local anesthetics. The ester class of local anesthetics is metabolized in the blood and is used in dentistry solely for topical administration. The ester class includes: ● Benzocaine (Dermoplast, Orajel, Anbesol, Orabase). ● Cocaine. ● Dyclonine (Dyclone). ● Procaine (Novocain, Mericaine). ● Tetracaine (Pontocaine, Viractin, Dermocaine). The amide class of local anesthetics is metabolized in the liver and includes: ● Articaine (Septocaine, Zorcaine).
● Bupivacaine (Marcaine). ● Etidocaine (Duranest). ● Lidocaine (Xylocaine). ● Mepivacaine (Carbocaine, Polocaine). ● Prilocaine (Citanest).
Pharmacologically, the local anesthetics can be further categorized as low potency agents with a short duration of action (procaine), local anesthetics of intermediate potency and duration of action (lidocaine, prilocaine and mepivacaine), and agents of high potency and long duration (tetracaine, etidocaine and bupivacaine). The blood levels of these agents are dependent on their rate of absorption, tissue redistribution,
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