Table 2: Relationships Among pKa, Ionization, and Local Anesthesia Onset at pH 7.4
Table 4: Average Duration of Local Anesthesia After Intraoral Injection (Minutes)
Onset Time (min)
Maxillary Infiltration
Inferior Alveolar Block
% Cationic
% Free Base
Medication
pKa
Medication
Soft Tissue Pulpal
Soft Tissue
Pulpal
Articaine
7.8
71
29
2-4
Bupivacaine
8.1
83
17
5-8
4% Articaine with 1:100,000 or 1:200,000 epinephrine 0.5% Bupivacaine with 1:200,000 epinephrine 1.5% Etidocaine with 1:200,000 epinephrine
60
170
90
220
Etidocaine
7.9
76
24
2-4
Lidocaine
7.8
71
29
2-4
40
340
240
440
Mepivacaine 7.7
67
33
2-4
Prilocaine
7.8
71
29
2-4
30
280
240
470
Procaine
8.9
90
10
5-8
Tetracaine 2-4 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 8.4 87 13 Considerations,” by D. J. Orr, II, 2021, in S. F. Malamed (Ed.), Handbook of Local Anesthesia (7th ed.), Elsevier Mosby, p. 412. Protein binding Increased protein binding allows local anesthetic molecules to be more firmly attached to proteins at receptor sites. The general rule is that increased protein binding leads to a longer duration of action (Table 3). Although this may be true in general, it is important to remember that duration of action of local anesthesia is dependent on other factors as well: affinity for the nerve membrane, type of injection, the presence or absence of a vasoconstrictor, and whether the goal is pulpal versus soft tissue anesthesia (Table 4). Table 3: Relationships Between Protein Binding Characteristics and Local Anesthetic Duration of Action Approximate Protein Binding (%) Duration of Action (minutes) Articaine 95 60-220 Bupivacaine 95 40-440 Etidocaine 94 30-470 Lidocaine 65 60-190 Mepivacaine 75 25-165 Prilocaine 55 40-220 Procaine 6 14-45 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 Considerations,” by D. J. Orr, II, 2021, in S. F. Malamed (Ed.), Handbook of Local Anesthesia (7th ed.), Elsevier Mosby, p. 412.
2% Lidocaine with 1:50,000 or 1:100,000 epinephrine
60
170
85
190
3% Mepivacaine
25
90
40
165
4% Prilocaine 190 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 20 105 55 Considerations,” by D. J. Orr, II, 2021, in S. F. Malamed (Ed.), Handbook of Local Anesthesia (7th ed.), Elsevier Mosby, p. 412. Vasodilator activity With the exception of cocaine, all local anesthetics are vasodilators. Vasodilation is the direct result of relaxation of peripheral arteriolar smooth muscle fibers. The greater the vasodilator activity of a local anesthetic, the faster the drug is absorbed and therefore the shorter the duration of action. A vasoconstrictor such as epinephrine or levonordefrin is often added to the local anesthetic solution to counteract this vasodilation, which in turn will increase the drug’s duration of action. To summarize the structure-activity relationship among local anesthetics: ● The aromatic portion is responsible for lipophilicity of the local anesthetic (i.e., the lipid/water distribution). Lipophilicity is the major determinant of potency for local anesthetics, and the general rule is that higher lipid solubility equates to higher potency. As a result, agents with lower lipid solubility are generally marketed at higher concentrations. The aromatic portion also determines the protein binding, or affinity of the molecule to bind to proteins. Increased protein binding allows anesthetic molecules to attach more firmly to proteins at receptor sites. The general rule is that increased protein binding equates to a longer duration of action. ● The amine portion is usually a secondary or tertiary amine and is associated with water solubility of the compounds, but is not necessary for local anesthetic activity. However, compounds lacking the amine portion are insoluble in water and useful only topically. ● The intermediate chain connects the aromatic and amine portions via an ester or amide linkage. The type of linkage is important in determining which class of local anesthetics the drug belongs to and therefore the route of metabolism and the allergic potential of the compounds.
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