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Local anesthetics (LAs) are used in many clinical scenarios that require the pain practitioner to be intimately familiar with their pharmacokinetic and pharmacodynamic properties. They are used in the prevention of acute, inflammatory, nociceptive, cancer-related, neuropathic, and chronic pain, for diagnostic and prognostic purposes, and in the possible prevention of chronic pain.1


Operating primarily by their interaction with sodium voltage dependent channels (NaVs) to block sodium (Na+) entry into the neuron, LAs interrupt nerve impulse conduction and propagation. However, in recent years, other actions, such as LA interaction with other non-Na+ ion channels and G-protein receptors, which may be important in their ability to prevent and treat pain, have been described.2 These interactions take place in both the central and peripheral nervous system. In a concentration dependent fashion, LAs interrupt autonomic, sensory, and motor impulses, giving rise to autonomic system blockage, sensory analgesia, and muscle paralysis. With a deeper understanding of both the pharmacokinetics and pharmacodynamics of LAs, a higher rate of treatment success can be achieved, with a reduction in side effects. This chapter aims to focus on the newest information regarding LA mechanisms, pharmacodynamics, and toxicity.




LAs, being poorly soluble in water, are mixed with hydrochloride salts. If epinephrine is added to the solution, sodium bisulfate is often added to further lower the pH to about 4 to prevent its oxidative decomposition.


LAs such as lidocaine, tetracaine, and bupivacaine are also manufactured in liposomal vesicles. Such a formulation provides for a prolongation of action and a decrease in toxicity.3 Such a formulation allows for the slow continuous subcutaneous infiltration of the drug providing analgesia for up to 96 hours to decrease toxicity.4


Since the pKa of most LAs is approximately 8, within the acidic carrier medium they are dissolved in, pH 3.9 to 6.5, only approximately 3% of the drug exists in the lipid-soluble form. Because the lipid-soluble form is felt important for LA mechanism of action, alkalinization, via addition of sodium bicarbonate, is used by some practitioners. This process shifts the pH of the medium to become closer to the pKa of the drug, allowing for more of the drug to exist in the lipid-soluble form. The result is a hastening of the onset of LAs in peripheral nerve and neuraxial blocks by 3 to 5 minutes, a deepening of the depth of sensory and motor block, and an increase in the epidural spread of the drug.5 However, prolonged or excessive alkalinization can cause LA molecules to precipitate from suspension. Additionally, the value of adding sodium bicarbonate to solutions to enhance speed of onset also depends on the injection site and the specific physiochemical properties of the individual LA used.6




LAs consist of 4 portions:


  1. Aromatic ring

  2. Ester or amide linkage

  3. Hydrocarbon ...

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