STRUCTURE ACTIVITY RELATIONSHIPS
Local anesthetics consist of a lipophilic group (usu-ally an aromatic benzene ring) separated from a hydrophilic group (usually a tertiary amine) by an intermediate chain that includes an ester or amide linkage. Articaine, the most popular local anes-thetic for dentistry in several European countries, is an amide but it contains a thiophene ring rather than a benzene ring. Local anesthetics are weak bases that usually carry a positive charge at the ter-tiary amine group at physiological pH. The nature of the intermediate chain is the basis of the classifi-cation of local anesthetics as either esters or amides (Table 16–2). Physicochemical properties of local anesthetics depend on the substitutions in the aro-matic ring, the type of linkage in the intermediate
chain, and the alkyl groups attached to the amine nitrogen. Potency correlates with octanol solubility, which in turn reflects the ability of the local anesthetic molecule to permeate lipid membranes. Potency is increased by adding large alkyl groups to a parent molecule (compare tetracaine to procaine or bupivacaine to mepivacaine). There is no measure-ment of local anesthetic potency that is analogous to the minimum alveolar concentration (MAC) of inha-lation anesthetics. The minimum concentration of local anesthetic that will block nerve impulse conduction is affected by several factors, including fiber size, type, and myelination; pH (acidic pH antagonizes block); frequency of nerve stimulation; and electrolyte concentrations (hypokalemia and hypercalcemia antagonize blockade).Onset of local anesthetic action depends on many factors, including lipid solubility and the relative concentration of the nonionized lipid-soluble form (B) and the ionized water-soluble form (BH+), expressed by the pKa. The pKa is the pH at which the fraction of ionized and nonionized drug is equal. Less potent, less lipid-soluble agents generallyhave a faster onset than more potent, more lipid-soluble agents.
Local anesthetics with a pKa closest to physi-ological pH will have (at physiological pH) a greater fraction of nonionized base that more read-ily permeates the nerve cell membrane, generally facilitating a more rapid onset of action. It is the lipid-soluble form that more readily diffuses across the neural sheath (epineurium) and passes through the nerve membrane. Curiously, once the local anes-thetic molecule gains access to the cytoplasmic side of the Na channel, it is the charged cation (rather than the nonionized base) that more avidly binds the Na channel. For instance, the pKa of lidocaine exceeds physiological pH. Thus, at physiological pH (7.40) more than half the lidocaine will exist as the charged cation form (BH+).
It is often stated that the onset of action of local anesthetics directly correlates with pKa. This asser-tion is not supported by actual data; in fact, the agent of fastest onset (2-chloroprocaine) has the greatest pKa of all clinically used agents. Other factors, such as ease of diffusion through connective tissue, can affect the onset of action in vivo. Moreover, not all local anesthetics exist in a charged form (eg, benzocaine).
The importance of the ionized and nonion-ized forms has many clinical implications, at least for those agents that exist in both forms. Local anesthetic solutions are prepared commercially as water-soluble hydrochloride salts (pH 6–7). Because epinephrine is unstable in alkaline envi-ronments, commercially formulated, epinephrine-containing, local anesthetic solutions are generally more acidic (pH 4–5) than the comparable “plain” solutions lacking epinephrine. As a direct conse-quence, these commercially formulated, epineph-rine-containing preparations may have a lower concentration of free base and a slower onset than when the epinephrine is added by the clinician at the time of use. Similarly, the extracellular base-to-cation ratio is decreased and onset is delayed when local anesthetics are injected into acidic (eg, infected) tissues. Tachyphylaxis—the decreased efficacy of repeated doses—could be partly explained by the eventual consumption of the local extracellular buffering capacity by repeat injections of the acidic local anesthetic solution, but data are lacking. Some researchers have found that alkalini-zation of local anesthetic solutions (particularly commercially prepared, epinephrine-containing ones) by the addition of sodium bicarbonate (eg, 1 mL 8.4% sodium bicarbonate per 10 mL local anesthetic) speeds the onset and improves the quality of the block by increasing the amount of free base available. Interestingly, alkalinization also decreases pain during subcutaneous infiltration.Duration of action correlates with potency and lipid solubility. Highly lipid-soluble localanesthetics have a longer duration of action, pre-sumably because they more slowly diffuse from a lipid-rich environment to the aqueous bloodstream. Lipid solubility of local anesthetics is correlated with plasma protein binding. Local anesthetics are mostly bound by α1-acid glycoprotein and to a lesser extent to albumin. Sustained-release systems using liposomal encapsulation or microspheres for deliv-ery of local anesthetics can significantly prolong their duration of action, but these approaches are not yet being used for prolonged anesthesia in the way that extended-duration epidural morphine is being used for single-shot, prolonged epidural analgesia.
Differential block of sensory rather than motor function would be desirable. Unfortunately, only bupivacaine and ropivacaine display some selectively (mostly during onset and offset of block) for sen-sory nerves; however, the concentrations required for surgical anesthesia almost always result in some motor blockade.