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.2,11,12 Nociceptive or painful stimuli alter the distribution of these ions and briefly reverse electrical polarity, which may lead to neuronal membrane depolarization. The energy generated by neuronal depolarization may activate voltage-gated sodium channels (Figure 2).

Figure 2. Activation of Peripheral Sensory Terminals.
Diagram showing the activation of peripheral sensory terminals.

If the threshold energy level for the activation of voltage-gated sodium channels is reached, sodium ions flow into neuronal cells and an action potential is generated.2,11,12 LAs, reversibly and in a dose-dependent manner, reduce the amplitude and conduction velocity of action potentials by interacting with their receptors located on the voltage-gated sodium channels. Since the sites of action of LAs are located on the cytosolic side of these large membrane proteins, following administration, LAs must diffuse across lipophilic neuronal membranes.2,11,12

LAs cross neuronal 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 pKa or dissociation constant 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.

Only unionized LA molecules can translocate across biological membranes. 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. Predictably, 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.

When a threshold number of LA molecules interact with their receptors, the action potentials will be temporarily blocked.2,11,12 Because of differential functional blockade is 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: pain, temperature, touch, proprioception, and finally motor functions.

The rate of LAs’ absorption from the site of administration into the systemic circulation is also predicated on passive diffusion.2-10 Once in the vascular compartment, LAs bind to albumin, α-1 acid glycoproteins, and erythrocytes. Consequently, the protein-binding capacity of a LA affects drug distribution from the vascular compartment to other body fluids or tissues, including LAs’ ability to reach their receptors on the voltage-gated sodium channels (Table 1).2-10

The distribution of a drug from the vascular compartment has three distinct phases. Phase 1 reflects the rapid decline in drug plasma levels due to the drug’s distribution to well-perfused tissues (i.e., brain, liver, heart, kidneys, and lungs). Phase 2 reflects the decline in drug plasma levels due to the drug’s slow distribution to less well-perfused tissues (i.e., skeletal muscles and fat) and mirrors a drug’s distribution half-life (T1/2α).3-10

Phase 3 of drug distribution reflects the decline in drug plasma levels due to clearance, i.e., metabolism and excretion of the drug and mirrors the drug’s elimination half-life or T1/2β.3-10 The degree of tissue uptake of LAs is expressed as their volume of distribution (Vd).3-10 LAs with greater lipid solubility and lower plasma protein-binding capacity have a greater Vd. Therefore, a drug’s Vd is the primary determinant of the drug’s elimination half-life (T1/2β) (Table 1).3-10

Table 1. The elimination half-life of LAs is predicated on their lipid solubility and protein-binding capacity.
  Lidocaine Mepivacaine Prilocaine Articaine Bupivacaine
Lipid solubility 43 21 25 17 346
Plasma protein-bound fraction 60-80 75 55 60-80 95
Elimination half-life (T1/2β) ≈2.0 ≈1.9 ≈2.0 ≈1.8 ≈5.5

The metabolism of most aminoamide-type LAs takes place primarily in the liver by cytochrome P450 isoenzymes CYP3A4 and CYP1A2.2‑10 The excretion of their metabolites and any unchanged drugs takes place in the kidneys.2‑10 Prilocaine is metabolized both in the liver and the kidneys, its metabolites and any unchanged drug molecules are also exerted in the kidneys. As a rule, aminoamide-type LAs require 5 elimination half-lives, i.e., T1/2β x 5, for systemic clearance.

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 sidechain by plasma carboxylesterases. 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.
Diagram showing the structural domains of articaine.
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