Pharmacology of Local Anesthetics

Homeostatic mechanisms in excitable neuronal cells maintain a chemical gradient with high extracellular sodium and high intracellular potassium concentrations such that the inside of neuronal cells is electronegative (-50 to -90 mV) and the outside is electropositive.12-14 Nociceptive signals alter the distribution of these ions and briefly reverse electrical polarity, which leads to neuronal membrane depolarization that provides the energy to activate voltage-gated sodium channels.

If the threshold for activation of voltage-gated sodium channels is reached, sodium ions flow into the cell and an action potential is generated.12-14 The duration of this inward sodium current is limited as the voltage-gated sodium channels close spontaneously behind the passing action potential. Following inactivation of voltage-gated sodium channels, Na/K ATPase pumps sodium out of the cells and the leak of potassium ions through passive ion channels restore the resting membrane potential.

Local anesthetics (LAs) reduce the amplitude and conduction velocity of action potentials in a reversible, dose-dependent manner.12-14 LAs’ sites of action are the voltage-gated sodium channels. They are large membrane proteins, which consist of a pore forming α-subunit and one or two β-subunits. The receptors for LAs are on the intracellular α-subunits. Consequently, to gain access to their receptors, LAs must diffuse across lipophilic neuronal membranes at the site of administration.

LAs cross biological membranes by passive diffusion. Since LAs are weak bases, in an aqueous environment they exist as a mixture of protonated or positively charged (ionized) and deprotonated or neutral (unionized) molecules. The ratio of ionized to unionized forms of a LA is predicated on its dissociation constant or pKa and the pH of the drug’s milieu, i.e., the environment at the site of drug administration. The pKa is that pH at which a drug is 50% ionized and 50% unionized.

Since only unionized molecules of drugs can translocate across biological membranes, the ionized LA molecules will be unable to reach their receptors or diffuse into the circulation and become trapped at the site of administration. This phenomenon is known as ion trapping. For example, when lidocaine with a pKa of 7.9 is deposited into an infected/inflamed site with a pH less than 7.9, more than 50% of its molecules become protonated and will be unable to diffuse across biological membranes.

If, however, sufficient numbers LA molecules can interact with voltage-gated sodium channels, the action potentials will be temporarily halted.12-14 Because of differential functional blockade predicated on the degree of myelination of the nerve fibers and the LAs’ concentration gradient, different fiber-types are blocked at different times. The general order of functional deficit progresses sequentially as follows: first pain, second pain, temperature, touch, proprioception, and finally motor functions.

Cocaine was the first recognized LA. Its addictive properties and toxicity, i.e., psychological and physical dependence, mood alteration, CNS and cardiac excitation, and intense vasoconstriction preclude its clinical use in dentistry.17 Procaine, an analog of cocaine, has short duration of action, high allergenicity, and it is no longer available in dental cartridges. Today, the gold standard for LAs is lidocaine; other available LAs include mepivacaine, prilocaine, articaine and bupivacaine.

LAs consist of three structural domains: an aromatic group connected by an ester- or an amide-linkage to an aliphatic chain containing a secondary or a tertiary amine group (Figure 2).14,18-25 For example, procaine has an ester-linkage connecting the aromatic group to the amine group and is referred to as an ester or aminoester LA. The other agents have an amide-linkage and are called amide or aminoamide LAs. These structural components affect pharmacodynamic and pharmacokinetic processes.14,18-25

Figure 2. Structural Domains of Local Anesthetic Agents.

Image showing structural domains of local anesthetic agents.

The rate of LAs’ absorption into the systemic circulation is also modulated by the determinants of passive diffusion, i.e., the drug’s molecular weight, pKa, lipid solubility, formulation, concentration gradient, and the pH and vascularity of the environment.14,18-25 LAs in plasma bind to albumin, α-1 acid glycoproteins, and erythrocytes. The primary determinant of a LA’s ability to distribute from the vascular compartment to other body fluids or tissues is its protein-binding capacity (Table 1).14,18-25

There are three distinct phases of drug distribution from the vascular compartment to other body fluids and tissues.18-20 Phase 1 is characterized by rapid fall in plasma concentration as the drug is distributed to well-perfused tissues such as the brain, liver, heart, kidneys, and lungs. Phase 2 is associated with a slower decline in plasma levels as the drug is distributed to less well-perfused tissues such as skeletal muscles and fat. Phase 2 mirrors the distribution half-life or T1/2α of LAs.

The degree of tissue uptake of LAs is expressed as their volume of distribution (Vd).18-20 LAs with lower plasma protein-binding capacity and greater lipid solubility have a greater Vd. Phase 3 of drug distribution reflects the decline in LAs’ plasma concentration due to clearance, i.e., metabolism and excretion of LAs and represents their elimination half-life or T1/2β.18-25 Therefore, the primary determinant of a LA’s elimination half-life (T1/2β) is its Vd (Table 1).18-25

Table 1. Plasma-protein Binding Capacity, Lipid Solubility, and T1/2β of LAs.17-24
Percent plasma-protein binding capacity60-80755560-8095
Lipid solubility43212517346
Elimination half-life or T1/2β≈2.0≈1.9≈2.0≈1.8≈5.5

The metabolism of aminoamide-type LAs takes place primarily in the liver by cytochrome P450 isoenzymes CYP3A4 and CYP1A2.14,18-25 With some exceptions, the excretion of metabolites and any unchanged LA takes place in the kidneys. Prilocaine is metabolized both in the liver and the kidneys. The metabolites and any unchanged drug are exerted via the kidneys. As a general rule, aminoamide-type LAs require 5 half-lives, i.e., T1/2β x 5, for systemic clearance (Table 1).

While articaine is a member of the aminoamide group of LAs, it is unique in that it contains a thiophene-based nucleus as well as an ester-linkage connecting a second side chain (Figure 3). As a result, articaine is rapidly inactivated via hydrolysis of the ester side-chain by plasma carboxyesterase. Only about 5 to 10% of articaine is metabolized by hepatic microsomal CYP450 isoenzymes. The metabolites and any unchanged drug are excreted by the kidneys.

Figure 3. Structural Domains of Articaine.

Image showing structural domains of articaine.