2. Application of local anesthetics typically produces a concentration-dependent decrease in the peak sodium current.

D. Mechanism of Nerve Blockade

1. Local anesthetics block peripheral nerves by disrupting the transmission of action potentials along nerve fibers. Only about 1% to 2% of the injected local anesthetics ultimately penetrate into the nerve to reach the site of action (voltage-gated sodium channels).

2. The degree of nerve blockade depends on the local anesthetic’s concentration and volume (needed to suppress the regeneration of nerve impulses over a critical length of nerve fiber).

3. Not all sensory and motor modalities are equally blocked by local anesthetics (sequential disappearance of temperature sensation, proprioception, motor function, sharp pain, and last light touch). This differential blockade had been thought to be simply related to the diameter of the nerve fiber (smaller fibers are inherently more susceptible to drug blockade than large fibers), but this does not appear to be universally true. In this regard, small nerve fibers require a shorter length (<1 cm) exposed to local anesthetic for block to occur than do large fibers.

II. PHARMACOLOGY AND PHARMACODYNAMICS

A. Chemical Properties and Relationship to Activity and Potency

1. Most clinically relevant local anesthetics are made up of a lipid-soluble, aromatic benzene ring connected to an amide group via either an amide or ester moiety.

2. The type of linkage divides the local anesthetics into aminoesters (metabolized in the liver or by plasma cholinesterase) and aminoamides (metabolized in the liver).

3. All clinically used local anesthetics are weak bases that can exist as either the lipid-soluble, neutral form or as the charged, hydrophilic form. The combination of pH and pKa of the local anesthetic determines how much of the compound exists in each form (Table 21-2).

4. A ratio with high concentration of the lipid-soluble form favors entry into cells because the main pathway for entry is by passive absorption of lipid-soluble form through the cell membrane. Clinically, alkalization of the anesthetic solution increases the ratio of the lipid-soluble form to the cationic form, thereby facilitating drug entry.

5. Anesthetic activity and potency are affected by the stereochemistry of local anesthetics.

a. Ropivacaine and levo-bupivacaine are single enantiomers that were initially developed as less cardiotoxic alternatives to bupivacaine.

b. The desired improvement in the safety index seems to be present, but it comes at the expense of a slight decrease in potency and shorter duration of action compared with the racemic mixtures.

B. Additives to Increase Local Anesthetic Activity (Table 21-3)

1. Epinephrine added to the local anesthetic solution may prolong the local anesthetic block, increase the intensity of the block and decrease systemic absorption of the local anesthetic.

a. Vasoconstrictive effects produced by epinephrine augment local anesthetics by antagonizing inherent vasodilating effects of local anesthetics, thus decreasing systemic absorption and intraneural clearance, and perhaps by redistribution of intraneural local anesthetic.

b. Analgesic effects of epinephrine via interaction with α₂-adrenergic receptors in the spinal cord and brain may play a role in the effects of epinephrine added to the local anesthetic solution.

c. The effectiveness of epinephrine depends on the local anesthetic administered, the type of regional block performed, and the amount of epinephrine added to the local anesthetic solution.

2. Opioids (especially buprenorphine) added to the local anesthetic solution placed into the epidural or subarachnoid space result in synergistic analgesia and anesthesia without increasing the risk of toxicity.

3. α2-Adrenergic agonists such as clonidine produce synergistic analgesia via supraspinal and spinal adrenergic receptors. Clonidine also has direct inhibitory effects on peripheral nerve conduction (A and C nerve fibers).

4. Steroids. Combined with intermediate- to long-acting local anesthetics, dexamethasone extends the duration of analgesia by approximately 50% after utilization of the supraclavicular or interscalene approach for brachial plexus block (Fig. 21-1).

III. PHARMACOKINETICS OF LOCAL ANESTHETICS (Tables 21-4 and 21-5). Plasma concentration of local anesthetics is a function of the dose administered and the rates of systemic absorption, tissue distribution, and drug elimination.

A. Systemic Absorption (Table 21-6)

1. Decreasing systemic absorption of local anesthetics increases their safety margin in clinical uses. The rate and extent of systemic absorption depend on the site of injection, the dose, the drug’s intrinsic pharmacokinetic properties, and the addition of a vasoactive agent.

B. Distribution

1. Regional distribution of local anesthetics after systemic absorption depends on organ blood flow, the partition coefficient of the local anesthetic between compartments, and protein binding.

2. Organs that are well perfused, such as the heart and brain, have higher drug concentrations.

C. Elimination

1. Clearance of aminoester local anesthetics primarily depends on clearance by plasma cholinesterase.

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