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Chapter: Modern Pharmacology with Clinical Applications: Local Anesthetics

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Properties of Local Anesthetics

Properties of Local Anesthetics
An important property of the ideal local anesthetic is low systemic toxicity at an effective concentration.

The first clinical uses of a local anesthetic agent oc-curred in 1884, when cocaine was employed as a topical agent for eye surgery and to produce a nerve block. These events inaugurated a new era, that of regional anesthesia. New applications were developed, including spinal, epidural, and caudal anesthesia. The search for a better local anesthetic led to chemical synthesis of a number of other compounds that have more selective local anesthetic properties and few systemic side effects.


An important property of the ideal local anesthetic is low systemic toxicity at an effective concentration. Onset of action should be quick, and duration of action should be sufficient to allow time for the surgical proce-dure. The local anesthetic should be soluble in water and stable in solution. It should not deteriorate by the heat of sterilization, and it should be effective both when in-jected into tissue and when applied topically to mucous membranes. Its effects should be completely reversible.

Although the characteristics of an ideal local anes-thetic are easily identifiable, synthesis of a compound possessing all these properties has not been accom-plished. The compounds discussed in the following sec-tions fall short of the ideal in at least one aspect. However, the judicious choice of a particular agent for a particular need will permit the practitioner to employ local anesthesia effectively and safely.


The basic components in the structure of local anes-thetics are the lipophilic aromatic portion (a benzene ring), an intermediate chain, and the hydrophilic amine portion (Fig. 27.1). The intermediate chain has either an ester linkage from the combination of an aromatic acid and an amino alcohol or an amide linkage from the combination of an aromatic amine and an amino acid. The commonly used local anesthetics can be classified as esters or amides based on the structure of this inter-mediate chain.

Mechanism of Action

The application of a local anesthetic to a nerve that is actively conducting impulses will inhibit the inward mi-gration of NA+ . This elevates the threshold for electrical excitation, reduces the rate of rise of the action poten-tial, slows the propagation of the impulse, and if the drug concentration is sufficiently high, completely blocks conduction. The local anesthetics interfere with the process fundamental to the generation of the action potential, namely, the large, transient voltage-dependent rise in the permeability of the membrane to NA+ .

While the physiological basis for the local anesthetic action is known, the precise molecular nature of the process is not completely clear. Almost all local anes-thetics can exist as either the uncharged base or as a cation. The uncharged base is important for adequate penetration to the site of action, and the charged form of the molecule is required at the site of action. The cation forms of local anesthetics appear to be required for binding to specific sites in or near the NA+ channels. The presence of the local anesthetic at these sites inter-feres with the normal passage of NA+ through the cell membrane by stopping a conformational change in the subunits of the voltage-gated NA+ channel.

Studies suggest that the receptor for the local anes-thetic is near the inner (axoplasmic) surface of the cell membrane, because quaternary analogues of local anes-thetics are quite effective when applied to the inside of the axonal membrane but are inactive when placed on the outside of the membrane. These permanently charged molecules cannot penetrate to the receptor sites.

Nerves that are rapidly depolarizing are inherently particularly susceptible to the effects of local anesthet-ics. This is termed frequency-dependent blockade and is thought to occur because the local anesthetics get totheir receptor sites only when the NA+ channel is open (depolarizing).

Differential Blockade

Peripheral nerve functions are not affected equally by local anesthetics. Loss of sympathetic function usually is followed by loss of temperature sensation; sensation to pinprick, touch, and deep pressure; and last, motor function. This phenomenon is called differential block-ade. Differential blockade is the result of a number of factors, including the size of the nerve, the presence and amount of myelin, and the location of particular fibers within a nerve bundle. For conduction to be ef-fectively blocked, the local anesthetic must exert its ef-fects over the distance between several nodes of Ranvier. Since the smallest nerves (C fibers) have no myelin, they can be most easily blocked; thus, sympa-thetic functions often are blocked soon after a local anesthetic is applied to a particular nerve bundle. Small myelinated nerves have correspondingly short distances between nodes of Ranvier and therefore are often blocked next. These nerves subserve tempera-ture and sharp pain sensation. Larger nerves then be-come blocked, accounting for the loss of function up to and including motor innervation.

Pharmacokinetic Properties

Absorption and Distribution

The rate of absorption of a local anesthetic into the bloodstream is affected by the dose administered, the vascularity at the site of injection, and the specific physicochemical properties of the drug itself. Local anesthetics gain entrance into the bloodstream by ab-sorption from the injection site, direct intravenous in-jection, or absorption across the mucous membranes af-ter topical application. Direct intravascular injection occurs accidentally when the needle used for infiltration of the local anesthetic lies within a blood vessel, or it oc-curs intentionally when lidocaine is used for the control of cardiac arrhythmias.

All tissues will be exposed to local anesthetics after absorption, but concentrations will vary among the or-gans. Although the highest concentrations appear to oc-cur in the more highly perfused organs (i.e., brain, kid-ney, and lung), factors such as degree of protein binding and lipid solubility also affect drug distribution. The lung can absorb as much as 90% of a local anesthetic during the first pass. Consequently, the lungs can act as a buffer to prevent higher and therefore more toxic concentrations.

Placental transfer of local anesthetics is known to occur rapidly, fetal blood concentrations generally re-flecting those found in the mother. However, the quan-tity of drug crossing to the fetus is also related to the time of exposure, that is, from the time of injection to delivery. Subtle neurobehavioral changes in the neonate are detectable for as long as 8 hours after mepivacaine administration to the mother but are absent following the use of bupivacaine, lidocaine, and chloroprocaine. In general, minimal amounts of chloroprocaine reach the fetus because of its rapid hydrolysis by serum cholinesterase; this feature is its principal advantage in obstetrics.


The metabolic degradation of local anesthetics depends on whether the compound has an ester or an amide link-age. Esters are extensively and rapidly metabolized in plasma by pseudocholinesterase, whereas the amide link-age is resistant to hydrolysis. The rate of local anesthetic hydrolysis is important, since slow biotransformation may lead to drug accumulation and toxicity. In patients with atypical plasma cholinesterase, the use of ester-linked compounds, such as chloroprocaine, procaine and tetracaine, has an increased potential for toxicity. The hy-drolysis of all ester-linked local anesthetics leads to the formation of paraaminobenzoic acid (PABA), which is known to be allergenic. Therefore, some people have al-lergic reactions to the ester class of local anesthetics.

Local anesthetics with an amide linkage (and one ester-lined anesthetic, cocaine) are almost completely metabolized by the liver before excretion. However, the total dose administered and the degree of drug accu-mulation resulting from the initial and subsequent doses are still a concern.

Clinical Uses

Local anesthetics are extremely useful in a wide range of procedures, varying from intravenous catheter inser-tion to extensive surgery under regional block. For mi-nor surgery, the patients can remain awake; this is an advantage in emergency surgery, because protective air-way reflexes remain intact. Many operative procedures in the oral cavity are facilitated by regional block of specific nerves. If surgery permits, the patient can return home, because he or she is less sedated than would be the case after general anesthesia.

Topical Anesthesia

Local anesthetics are used extensively on the mucous membranes in the nose, mouth, tracheobronchial tree, and urethra. The vasoconstriction produced by some lo-cal anesthetics, cocaine especially, adds a very important advantage to their use in the nose by preventing bleed-ing and inducing tissue shrinkage. Topical anesthesia permits many diagnostic procedures in the awake pa-tient, and when it is combined with infiltration tech-niques, excellent anesthesia may be obtained for many surgical procedures in the eye and nose. The practi-tioner should be cautious when higher volumes are re-quired, since overdosage may cause systemic reactions. Additionally, when the tracheobronchial tree and lar-ynx are anesthetized, normal protective reflexes, which prevent pulmonary aspiration of oral or gastric fluids and contents, are lost.


Infiltration (i.e., the injection of local anesthetics under the skin) of the surgical site provides adequate anesthe-sia if contiguous structures are not stimulated. Since the onset of local anesthesia is rapid, the surgical proce-dures can proceed with little delay. Minimally effective concentrations should be used, especially in extensive procedures, to avoid toxicity from overdosage.

Regional Block

Regional block, a form of anesthesia that includes spinal and epidural anesthesia, involves injection near a nerve or nerve plexus proximal to the surgical site. It provides excellent anesthesia for a variety of proce-dures. Brachial plexus block is commonly used for the upper extremity. Individual blocks of the sciatic, femoral, and obturator nerves can be used for the lower extremity. An amount that is close to the maximally tol-erated dose is required to produce blockade of a major extremity.

Spinal Anesthesia

Spinal anesthesia (subarachnoid block) produces exten-sive and profound anesthesia with a minimum amount of drug. The local anesthetic solution is introduced di-rectly into the spinal fluid, where the nerves are not pro-tected by a perineurium. This produces, in effect, a tem-porary cord transection such that no impulses are transmitted beyond the level that is anesthetized. The onset is rapid, and with proper drug selection, the anes-thesia may last 1 to 4 hours. With careful technique, neu-rological complications are extremely rare. Procedures as high as upper-abdominal surgery can be performed under spinal anesthesia. Arterial hypotension produced by the local anesthetic is proportional to the degree of interruption of sympathetic tone, and it can produce pooling of blood in the lower extremities, which leads to decreased cardiac filling pressures. Knowing this allows blood pressure to be easily controlled, and hypotension is not usually a deterrent to spinal anesthesia. The sites of action of spinal anesthesia are the spinal nerve roots, spinal ganglia, and (perhaps) the spinal cord.

Lumbar Epidural Anesthesia

Lumbar epidural anesthesia affects the same area of the body as does spinal anesthesia. As the name implies, the drug is deposited outside the dura. In contrast to spinal anesthesia, this method requires a much larger amount of drug. This procedure makes segmental anesthesia possi-ble, whereby the anesthetized area is bordered caudally and cephalad by unaffected dermatomes and myotomes.

The concentration and volume of the local anes-thetic solution will affect the extent of the cephalad and caudad spread of the block. The anesthesia can be made continuous by maintaining a small catheter in the epidural space; prolonged effects are obtained by peri-odically injecting supplemental doses through the catheter or by attaching it to a computer pump. The site of anesthetic action is on the nerves as they leave the in-tervertebral foramina. However, effective drug concen-trations may be found in the spinal fluid, probably gain-ing entrance through the arachnoid villi. Arterial hypotension occurs by the same mechanism and is man-aged as in spinal anesthesia.

Epidural anesthesia is especially useful in obstetrics. Excellent analgesia occurs and the patient remains awake. Analgesia by the epidural route can be provided for labor and delivery or for cesarean section. Bupivacaine in lower concentrations has the advantage of providing excellent analgesia while minimally reduc-ing motor strength.

Caudal Anesthesia

In the caudal form of extradural anesthesia, the agent is introduced through the sacral hiatus above the coccyx. It is particularly applicable to perineal and rectal proce-dures. Anesthetization of higher anatomical levels is not easily obtained, because the required injection volume can be excessive. Although caudal anesthesia has been used extensively in obstetrics, lumbar epidural blockade is now more commonly used because of the lower dose of drug required; in addition, the sacral segments are spared until their anesthesia is required for the delivery.

Intravenous Extremity Block

Excellent and rapid anesthetization of an extremity can be obtained easily. Following insertion of an intra-venous catheter in the limb of interest, a rubber band-age is used to force blood out of the limb, and a tourni-quet is applied to prevent the blood from reentering; a dilute solution of local anesthetic, most commonly lido-caine, is then injected intravenously. This technique fills the limb’s vasculature and carries the anesthetic solu-tion to the nerve by means of the blood supply. Because of the pain produced by a tourniquet after some time, this procedure usually is limited to less than 1 hour. The systemic blood levels of drug achieved after tourniquet release generally remain below toxic levels.

Although it is more easily and therefore more com-monly used on the upper extremity, intravenous ex-tremity anesthesia can be used on the leg and thigh.

Sympathetic Block

Blockade of the sympathetic nervous system can be more selectively accomplished than that which occurs during spinal or epidural anesthesia. Cell bodies for pre-ganglionic sympathetic nerves originate in the interme-diolateral cell column of the spinal cord, from the first thoracic to the second lumbar segments. The myelinated axons of these cells travel as white communicating rami before joining the sympathetic chain and synapsing in the ganglia. The best location for a sympathetic block is at the sympathetic ganglia, since a block at this level will affect only the sympathetic nerves. For example, local anesthetic blockade of the stellate ganglion (which in-cludes T1) blocks sympathetic innervation to all of the upper extremity and head on the injected side. A block of the sympathetic chain at L2 affects all of the lower ex-tremity. This form of local anesthesia is particularly use-ful during treatment of a variety of vasospastic diseases of the extremities and for some pain syndromes.

Control of Cardiac Arrhythmias

Procainamide and lidocaine are two of the primary drugs for treating cardiac arrhythmias. Since lidocaine has a short duration of action, it is common to adminis-ter it by continuous infusion. Procainamide, because of its amide linkage, has longer action than does its pre-cursor, procaine. Orally active analogues of local anes-thetics (e.g., mexiletine) also are used as antiarrhyth-mics .

Use of Vasoconstrictors

The most commonly used vasoconstrictors, the sympa-thomimetic drugs, are often added to local anesthetics to delay absorption of the anesthetic from its injection site. By slowing absorption, these drugs reduce the anes-thetic’s systemic toxicity and keep it in contact with nerve fibers longer, thereby increasing the drug’s dura-tion of action. Administration of lidocaine 1% with ep-inephrine results in the same degree of blockade as that produced by lidocaine 2% without the vasoconstrictor.

Many vasoconstrictors are available, but epineph-rine is by far the most commonly employed. Because epinephrine can have systemic α- and β-adrenergic ef-fects, precaution is needed when local anesthetics containing this amine are given to a patient with hyper-tension or an irritable myocardium. Sensitivity to epi-nephrine may be incorrectly diagnosed as an allergy to local anesthetics. Epinephrine-containing solutions should be used cautiously in persons taking tricyclic an-tidepressants or monoamine oxidase (MAO) inhibitors, since those drugs may enhance the systemic pressor ef-fects of sympathomimetic amines.

Levonordefrin (Neo-Cobefrin) is an active optical isomer of nordefrin that has α1-adrenergic activity and possesses little or no -agonist properties. It is used ex-clusively in some dental anesthetic cartridges as a vaso-constrictor. Its theoretical advantage is that it causes less hypertension and tachycardia than does epinephrine.

Phenylephrine hydrochloride (Neo-Synephrine) is a pure -agonist that is occasionally used for subarach-noid block and is marketed with procaine for use in dentistry. It has little direct cardiac effect.

Adverse Effects

The central nervous and cardiopulmonary systems are most commonly affected by high plasma levels of local anesthetics. Local anesthetics given in initially high doses produce central nervous system (CNS) stim-ulation characterized by restlessness, disorientation, tremors, and at times clonic convulsions. Continued ex-posure to high concentrations results in general CNS depression; death occurs from respiratory failure sec-ondary to medullary depression. Treatment requires ventilatory assistance and drugs to control the seizures. The ultra–short-acting barbiturates and the benzodi-azepine derivatives, such as diazepam, are effective in controlling these seizures. Respiratory stimulants are not effective. CNS manifestations generally occur be-fore cardiopulmonary collapse.


Cardiac toxicity is generally the result of drug-induced depression of cardiac conduction (e.g., atrioven-tricular block, intraventricular conduction block) and systemic vasodilation. These effects may progress to se-vere hypotension and cardiac arrest.

Allergic reactions, such as red and itchy eczematoid dermatitis or vesiculation, are a concern with the ester-type local anesthetics. True allergic manifestations have been reported with procaine. The amides are essentially free of allergic properties, but suspected allergic phenom-ena may be caused by methylparaben, a parahydroxyben-zoic acid derivative used as an antibacterial preservative in multiple-dose vials and some dental cartridges. Esters probably should be avoided in favor of an amide when the patient has a history of allergy to a PABA-containing preparation such as certain cosmetics or sunscreens.

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