Chapter 11 Local Anesthetics

Chapter LOCAL ANESTHETICS 11 Kenneth Drasner HISTORY MECHANISMS OF ACTION AND FACTORS ocal anesthesia can be defined as loss of sensation in AFFECTING BLOCK L a discrete region of the body caused by disruption of Nerve Conduction impulse generation or propagation. Local anesthesia can Anesthetic Effect and the Active Form of the be produced by various chemical and physical means. Local Anesthetic However, in routine clinical practice, local anesthesia is Sodium Ion Channel State, Anesthetic produced by a narrow class of compounds, and recovery Binding, and Use-Dependent Block is normally spontaneous, predictable, and complete. Critical Role of pH Lipid Solubility Differential Local Anesthetic Blockade Spread of Local Anesthesia after Injection HISTORY PHARMACOKINETICS Cocaine’s systemic toxicity, its irritant properties when Local Anesthetic Vasoactivity placed topically or around nerves, and its substantial Metabolism potential for physical and psychological dependence gene- Vasoconstrictors rated interest in identification of an alternative local 1 ADVERSE EFFECTS anesthetic. Because cocaine was known to be a benzoic Systemic Toxicity acid ester (Fig. 11-1), developmental strategies focused Allergic Reactions on this class of chemical compounds. Although benzocaine was identified before the turn of the century, its SPECIFIC LOCAL ANESTHETICS poor water solubility restricted its use to topical anesthe- Amino-Esters sia, for which it still finds some limited application in Amino-Amide Local Anesthetics modern clinical practice. The first useful injectable local Single-Enantiomer Local Anesthetics anesthetic, procaine, can be considered the prototype on Eutectic Mixture of Local Anesthetics which all commonly used local anesthetics are based. FUTURE LOCAL ANESTHETICS The procaine molecule is derived from an aromatic acid (para-aminobenzoic acid) and an amino alcohol, yielding QUESTIONS OF THE DAY a structure with three distinct regions: an aromatic head, which imparts lipophilicity; a terminal amine tail, a pro- ton acceptor that imparts hydrophobicity; and a hydrocarbon chain attached to the aromatic acid by an ester linkage (Fig. 11-2). Several other derivatives of para- aminobenzoic acid were developed as local anesthetics during the first half of the past century, most notably tetracaine and chloroprocaine, both embodying modifi- cations of the aromatic ring (Fig. 11-3). In 1948, lidocaine was introduced, and it was the first departure from the amino-ester series. Being derived from an aromatic amine (i.e., xylidine) and an amino acid, the hydrocarbon chain and the aromatic head of 130 Chapter 11 Local Anesthetics biotransformation in the liver rather than undergoing CH3 ester hydrolysis in plasma, as is the case for the amino- esters. O NH2 COH CH3 Benzoic Acid Xylidine MECHANISMS OF ACTION AND FACTORS AFFECTING BLOCK CH3 Nerve Conduction N Local anesthetics block the transmission of the action H2N O potential by inhibition of voltage-gated sodium ion COH channels. Under normal or resting circumstances, the Para-aminobenzoic Acid Piperidine neural membrane is characterized by a negative potential of roughly –90 mV (the potential inside the nerve fiber is negative relative to the extracellular fluid). This negative Figure 11-1 Important components of local anesthetics: potential is created by active outward transport of benzoic acids, xylidine, para-aminobenzoic acid, and piperidine. sodium and inward transport of potassium ions, com- bined with a membrane that is relatively permeable to potassium and relatively impermeable to sodium ions. With excitation of the nerve, there is an increase in the membrane permeability to sodium ions, causing a decrease in the transmembrane potential. If a critical H2N C2H5 potential is reached (i.e., threshold potential), there is a CO OCH2CH2 N rapid and self-sustaining influx of sodium ions resulting O C2H5 in depolarization, after which the resting membrane Lipophilic Hydrocarbon chain Hydrophilic potential is reestablished. From an electrophysiologic standpoint, local anesthetics block conduction of neural transmission by decreasing the rate of depolarization in Figure 11-2 Local anesthetics consist of a lipophilic and response to excitation, preventing achievement of the hydrophilic portion separated by a connecting hydrocarbon threshold potential. They do not alter the resting trans- chain. membrane potential, and they have little effect on the threshold potential. the lidocaine molecule are linked by an amide bond Anesthetic Effect and the Active Form of the (rather than an ester), imparting greater stability. This Local Anesthetic molecular structure also averts the allergic reactions commonly associated with ester anesthetics (which result Local anesthetics exert their electrophysiologic effects from sensitivity to the cleaved aromatic acid). Because of by blocking sodium ion conductance. This effect is pri- these favorable properties, lidocaine became the template marily mediated by interaction with specific receptors for the development of a series of amino-amide anes- that are within the inner vestibule of the sodium ion thetics (see Fig. 11-3). channel. The commonly used injectable local anesthetics Most amino-amide local anesthetics are derived from exist in two forms that are in dynamic equilibrium, an xylidine, including mepivacaine, bupivacaine, ropiva- uncharged base or a protonated quaternary amine. Most caine, and levobupivacaine (see Fig. 11-1). In contrast likely, the charged form of the local anesthetic molecule to lidocaine, the terminal amino portion of these newer binds to the receptor and is responsible for the predomi- compounds is contained within a piperidine ring (see nant action of these drugs. However, the pharmacology Fig. 11-1), and the series is commonly referred to as pipe- is a bit more complex, as the charged structure is highly cholyl xylidines. Ropivacaine and levobupivacaine share hydrophilic, and relatively incapable of penetrating the an additional distinctive characteristic: they are single nerve membrane to reach its site of action. The neutral enantiomers rather than racemic mixtures. They are pro- base plays a critical role in the local anesthetic effect ducts of a developmental strategy that takes advantage of by permitting the anesthetic to penetrate the nerve the differential stereoselectivity of neuronal and cardiac membrane to gain access to the receptor (Fig. 11-4).2 sodium ion channels in an effort to reduce the potential After penetration, re-equilibration occurs, permitting for cardiac toxicity (see “Adverse Effects”). Because they the charged form of the local anesthetic to bind. These are amides, all of the newer local anesthetics require drugs also may reach the sodium channel laterally 131 Section II PHARMACOLOGY AND PHYSIOLOGY Figure 11-3 Chemical structures of ester (i.e., H2N O C2H5 H2N O C2H5 procaine, chloroprocaine, COCH2CH2N COCH2CH2N tetracaine, and cocaine) C2H5 C2H5 and amide (i.e., lidocaine, CI mepivacaine, Procaine Chloroprocaine bupivacaine, etidocaine, prilocaine, and H CO ropivacaine) local 3 O H9C4 anesthetics. C N CH3 N O CH3 O H COCH2CH2N CO CH3 H Tetracaine Cocaine CH3 CH3 CH3 O O C2H5 N NHCCH2N NHC CH3 C2H5 CH3 Lidocaine Mepivacaine CH2CH2CH2CH3 CH3 CH3 O O N C2H5 NHC NHCCHN CH3 CH3 C2H5 C2H5 Bupivacaine Etidocaine O CH3 NHCCHNHCH2CH2CH3 H NH CO CH3 N CH3 C3H7 Prilocaine Ropivacaine (i.e., hydrophobic pathway). Yet this mechanism cannot conformational states with different affinities. During completely account for all of the local anesthetic effect. excitation, the sodium channel moves from a resting- For example, benzocaine exists only in an uncharged closed state to an activated-open state, with passage of form, and it is not affected by pH, but it still possesses sodium ions and consequent depolarization. After depo- local anesthetic activity. larization, the channel assumes an inactivated-closed conformational state. Local anesthetics bind to the activated and inactivated states more readily than the resting Sodium Ion Channel State, Anesthetic Binding, state, attenuating conformational change. Drug dissocia- and Use-Dependent Block tion from the inactivated conformational state is slower According to the modulated receptor model, sodium ion than from the resting state. Thus, repeated depolarization channels alternate between several conformational produces more effective anesthetic binding. The electro- states, and local anesthetics bind to these different physiologic consequence of this effect is progressive 132 Chapter 11 Local Anesthetics injectable anesthetics are between 7.6 and 8.9, less than one half of the molecules are un-ionized at physio- + + LA + H LAH logic pH (Table 11-1). Because local anesthetics are poorly soluble in water, they are generally marketed as water-soluble hydrochloride salts. These hydrochloride LA LAH+ salt solutions are acidic, contributing to the stability of local anesthetics but potentially impairing the onset of a block. Bicarbonate is sometimes added to local anesthetic solutions to increase the un-ionized fraction in an LA + H+ LAH+ effort to hasten the onset of anesthesia. Other conditions that lower pH, such as tissue acidosis produced by infec- tion, may likewise have a negative impact on the onset and quality of local anesthesia. II Lipid Solubility Lipid solubility of a local anesthetic affects its tissue penetration and its uptake in the nerve membrane. Figure 11-4 During diffusion of local anesthetic across the This physiochemical property impacts

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