Structural Features
With the exception of cocaine, all local anesthetics in current clinical use are synthetic and are poorly water- soluble, weakly basic, aromatic amines (Figure 6-1). The structural components consist of an aromatic hydrophobic portion, an intermediate linkage site, and a hydrophilic amine. Each of these three components confers different properties to the molecule. The hydrophobic portion must be an aromatic ring and is essential for anesthetic activity. As the hydrophobicity of the molecule increases, potency and duration of action increase. This is because increasing lipid solubility leads to greater access to the site of anesthetic action and to a decreased rate of metabolism. Increasing hydrophobicity also increases toxicity, therefore decreasing the therapeu- tic index.The intermediate chain, usually of two to three carbons, is linked to the aromatic ring by either an ester (—C—O—) or amide (—N—C—) linkage (see Figure 6-1), the nature of which determines certain pharmacologic properties of the molecule, including its metabolism. Esters are unstable compounds that are rapidly hydrolyzed by plasma pseudocholinesterase, whereas the amides are very stable and must be metabolized in the liver. All commonly used topical ocular anesthetics are of
the ester type, whereas most injectable anesthetics have an amide linkage (Box 6-1).
Physiochemical Characteristics
All local anesthetics exist in solution either as the uncharged amine or as the positively charged substituted ammonium cation. Because amines are only slightly solu- ble in water, they are formulated in solution as hydrochlo- ride salts. This enhances water solubility and stability in solution and prolongs their shelf life.The degree of ioniza- tion is also important in the distribution of the anesthetic to its site of action, because only the nonionized form readily crosses cell membranes. Because the local anes- thetics are weak bases, with a pKabetween 8 and 9, they
tend to ionize in acidic solutions. However, on contact with neutral or alkaline environments, such as tears, the uncharged fraction of the drug molecule increases, which allows more anesthetic to enter the nerve cell membrane. If a local anesthetic is applied or injected into an acidic environment, such as in the presence of infection, the ionized fraction of the drug increases.Thus, the pH of the medium may alter how much anesthetic reaches the site of action.
Mechanism of Action
Local anesthetics prevent both generation and conduc- tion of nerve impulses.Their main site of action appears to be the cell membrane, where they block the transient increase in membrane permeability to sodium ions that normally occurs with depolarization of the membrane. Blockade of sodium transport is thought to occur through binding of the local anesthetic to a specific bind- ing site located within a voltage-gated sodium channel present in the cell membrane. A large (300 kDa) heterotrimeric protein containing numerous transmem- brane segments forms this sodium channel. Several hydrophobic amino acid residues on a small portion of one of the transmembrane segments serve as the binding site.The greater the hydrophobicity of the local anesthetic,
the greater the affinity for binding. After application, anes- thetics diffuse across the cell membrane in the uncharged (lipid-soluble) amine form, but at the site of action the charged substituted ammonium cation preferentially interacts with the receptor that is only accessible from the inner membrane surface.
The duration of action of local anesthetics is propor- tional to the time they are in contact with the nerve tissue. Consequently, any agent or procedure that keeps anesthetics at their site of action prolongs the period of anesthesia. In clinical practice formulation of injectable local anesthetics with vasoconstrictors helps to localize the anesthetic at the desired site. Local vasoconstriction may also offer the advantage of slowing absorption into the systemic circulation, which reduces the potential for
systemic anesthetic toxicity. However, use of vasocon- strictors can cause tissue hypoxia and subsequent cell damage.
In addition, the intrinsic vasodilator activity and degree of plasma protein binding of anesthetics can influence their clinical potency and duration of action. Compared with mepivacaine, lidocaine exhibits enhanced vasodila- tor action, which results in a clinically shorter duration of action. Although protein binding generally reduces the amount of free drug available for receptor interaction, it can provide a drug depot for maintenance of anesthetic effect. This may partly explain the prolonged duration of action of highly protein-bound anesthetics, such as bupivacaine and etidocaine.
When applied topically to the eye, the anesthetics in current clinical use have relatively low systemic and ocular toxicity. Their sufficiently long duration of action, low cost, stability in solution, and general lack of interfer- ence with actions of other drugs make them useful agents for such ocular procedures as tonometry, corneal pachymetry, foreign body and suture removal, gonioscopy, nasolacrimal duct irrigation and probing, and even cataract surgery. When injected to provide local anesthe- sia, these agents present greater risks of toxicity. However, compared with general anesthesia, the local anesthetics offer many advantages.
Injectable Anesthetics
When more extensive ophthalmic procedures are to be undertaken, such as incision and curettage of chalazion, administration of anesthetics by injection is necessary (Table 6-1). Xylocaine, a common trade name of lidocaine, is no longer available in the United States, although lido- caine is readily available and widely used. Although lido- caine is most frequently administered via an injectable route, it is also used intracamerally during cataract surgery. Preservative-free 1% lidocaine is often injected into the anterior chamber during cataract surgery to supplement topical anesthesia to minimize perioperative pain and light sensitivity. Most studies have indicated that intracameral lidocaine does not cause morphologic or functional changes in the corneal endothelium.
The duration of the anesthetic effect is determined by the length of time the drug stays bound to the nerve protein.This is dictated by the chemical structure of the drug, the concentration, the amount administered, and the rate of removal by diffusion and circulation.
The addition of epinephrine, a vasoconstrictor, to an injectable anesthetic prolongs the duration of anesthesia and decreases the rate of systemic absorption, thereby decreasing the risk of systemic toxicity. The duration of some anesthetics, such as bupivacaine, a long-acting anes- thetic, cannot be significantly extended by adding epinephrine. Epinephrine also decreases local bleeding. Effective vasoconstriction is obtained with a concentra- tion of 1 to 100,000 or even 1 to 200,000. The usual
H H N H H HYDROPHOBIC AROMATIC RING LINKAGE SITE AMIDE LINK + ESTER LINK INTERMEDIATE CHAIN HYDROPHILIC IONIZABLE AMINE O C O H H C H N H C R4 H + R3 R2 R1
Figure 6-1 Generalized molecular structure of a local anes- thetic, consisting of a hydrophobic aromatic residue, the linkage site, an intermediate alkyl chain, and a hydrophilic amino group. (Adapted from Lesher GA. General principles of local anesthetics. In: Onofrey BE, ed. Clinical optometric pharmacology and therapeutics. Philadelphia: JB Lippincott, 1991; Chapter 53.)
Box 6-1 Classification of Local Anesthetics Ester linkage
Esters of benzoic acid Cocaine
Esters of meta-aminobenzoic acid Proparacaine
Esters of para-aminobenzoic acid Procaine
Chloroprocaine Tetracaine Benoxinate
Amide linkage (amides of benzoic acid) Lidocaine
Mepivacaine Bupivacaine Etidocaine
concentrations of epinephrine used for ophthalmic procedures range from 1:50,000 to 1:200,000. When epinephrine is subjected to heat, its potency is destroyed. Consequently, solutions containing epinephrine should not be subjected to heat sterilization. Use of epinephrine as an adjunctive agent can result in undesirable effects on local tissue, such as delayed wound healing and occa- sional necrosis and intense vasoconstriction. It may also produce adverse systemic reactions, such as apprehen- sion, anxiety, restlessness, tremor, pallor, tachycardia, dys- pnea, hypertension, palpitation, headaches, and precordial distress. When subjective palpitation occurs with or without a throbbing headache, tachycardia, and hypertension, a diagnosis of reaction to epinephrine rather than to the local anesthetic is indicated. Although these reactions are temporary, patients with cardiovascu- lar disease may suffer cardiac arrhythmias, angina attacks, or cerebral ischemia.
Topical Anesthetics
The efficacy of topical ocular anesthetics is usually deter- mined by their ability to suppress corneal sensitivity. When a dose–response relationship is determined for various anesthetics, a concentration for each drug is obtained beyond which no further increase in activity occurs. The concentration at which this maximum effi- cacy occurs is termed the maximum effective concentra- tion.Thus, increasing the concentration of the anesthetic beyond the maximum effective concentration serves no useful purpose but increases the risk of local and systemic toxicity.
The maximum effective concentrations of propara- caine, tetracaine, and cocaine are 0.5%, 1%, and 20%, respectively. In clinical practice, however, the optimum effective concentration of the drug may be less than the
maximum effective concentration. For instance, 0.5% tetracaine is less irritating to the eye than the maximum effective concentration of 1% and thus is better suited for clinical use. The topical application of a combination of two or more local anesthetics does not produce an additive effect, but it does increase the risk of side effects and so is contraindicated. The commonly used topical anesthetics are listed in Table 6-2.
Cocaine
Cocaine is unique among local anesthetics because it exhibits both anesthetic and adrenergic agonist activity. It is not commercially available in an ophthalmic solution. For clinical use the salt form of cocaine, cocaine hydrochloride, must be specially formulated in aqueous solution. Although not approved by the U.S. Food and Drug Administration for ophthalmic use, solutions of cocaine intended for otolaryngologic purposes are commercially available. Clinical experience indicates an apparent effective and safe for ocular use. The usual concentration for topical ocular use is 1% to 4%, but the 10% solution is often used, due to its adrenergic stimula- tory effects, for the diagnosis of Horner’s syndrome (see Chapter 22). One drop of a 2% solution produces excellent corneal anesthesia within 5 to 10 minutes. Complete anesthesia lasts approximately 20 minutes, with incomplete surface anesthesia lasting for approxi- mately 1 to 2 hours. Cocaine is used as a nasal spray or in a nasal pack during dacryocystorhinostomy. When applied to the nasal mucosa in a gauze pack, cocaine anesthetizes the contact area for an hour or longer. Cocaine, due to its adrenergic effects, causes vasocon- striction, thus retarding its own absorption. Hence, cocaine constricts the conjunctival and nasal vasculatures when applied topically to these mucous membranes. Because of this vasoconstrictor action, use of epinephrine
Table 6-1
Local Anesthetics for Regional Infiltration and Peripheral Nerve Block
Anesthetic Formulation Onset of Duration of
(Trade Name) (% Solution)a Action (min) Action (hr) Maximum Dose (mg)b
Procaine (Novocain) 1, 2, 10 7–8 1⁄ 2– 3⁄4 600 (10.0 mg/kg) Lidocaine 0.5, 1, 1.5, 2, 4 4–6 2 ⁄ 3– 1 (1–2 with epinephrine) 300 (4.5 mg/kg) 500 (7.0 mg/kg) with epinephrine Mepivacaine (Carbocaine) 1, 1.5, 2 3–5 2–3 400 Bupivacaine (Marcaine, 0.25, 0.50, 0.75 5–10 4–12 175 Sensorcaine) Etidocaine (Duranest) 1, 1.5 3–5 5–10 400 (8.0 mg/kg)
a1% solution = 10 mg/ml. Some concentrations are commercially available with epinephrine. bFor healthy adults. Use lowest dosage that provides effective anesthesia.
Adapted from Raj PP. Handbook of regional anesthesia. New York: Churchill Livingstone, 1985; Bartlett JD, Fiscella R, Jaanus SD, et al., eds. Ophthalmic drug facts. St. Louis: Facts and Comparisons, 2005; Crandall DG. Pharmacology of ocular anesthetics. In: Duane TD, Jaeger EA, eds. Biomedical foundations of ophthalmology. Philadelphia: J.B. Lippincott, 1994; and Sobol WM, McCrary JA. Ocular anesthetic properties and adverse reactions. Int Ophthalmol Clin 1989;29:195–199.
with cocaine is not only unnecessary but may be harmful, because cocaine causes sensitization to exogenous epinephrine. Cocaine may loosen the corneal epithelium to a greater extent than other topically applied anes- thetics, thus facilitating debridement of the corneal epithelium.
Because cocaine blocks reuptake of norepinephrine and has an adrenergic potentiating effect, its use is contraindicated in patients with systemic hypertension or patients taking adrenergic agonists. The interaction between cocaine and catecholamines contraindicates the use of cocaine in patients taking drugs that modify adrenergic neuronal activity, such as guanethidine, reser- pine, tricyclic antidepressants, methyldopa, or monoamine oxidase inhibitors. Additionally, drugs that act directly on adrenergic receptors, such as phenylephrine, are contraindicated with use of cocaine. Because cocaine has a mydriatic effect, it is contraindicated in patients predisposed to angle-closure glaucoma.
The major ocular side effect of cocaine is significant corneal epithelial toxicity. Grossly visible grayish pits and irregularities are readily produced by this drug.These are followed by loosening of the corneal epithelium, which may result in large erosions. Although this characteristic is generally considered to be an adverse effect, it is clini- cally useful in cases requiring corneal epithelial debride- ment. However, the corneal epithelial effects of cocaine contraindicate its use in any procedure requiring good visualization through the cornea, such as in retinal detachment surgery or in routine ophthalmoscopy or gonioscopy.
Acute systemic cocaine toxicity may result from as little as 20 mg (10 drops of a 4% solution) of drug. The total dose of cocaine should not exceed 3 mg/kg of
body weight. Typical manifestations of systemic toxicity include excitement, restlessness, headache, rapid and irregular pulse, dilated pupils, nausea, vomiting, abdomi- nal pain, delirium, and convulsions.
Because of the strong abuse potential of cocaine, its distribution and clinical use are subject to federal and state controlled substance regulations under supervision of the Drug Enforcement Administration. Because of its potential ocular and systemic toxicity, cocaine has gener- ally been replaced by the safer synthetic local anesthetics. Tetracaine
Tetracaine, an ester of para-aminobenzoic acid (PABA), has been widely used for topical anesthesia of the eye. It is currently available in a 0.5% solution. Its onset, inten- sity, and duration of anesthesia are comparable with those of proparacaine and benoxinate (Figure 6-2). Onset of anesthesia sufficient to permit tonometry or other minor procedures involving the superficial cornea and conjunc- tiva is 10 to 20 seconds, and duration of anesthesia is 10 to 20 minutes. It has been reported, however, that the 1% solution produces anesthesia lasting nearly an hour. Tetracaine 1% has also been used successfully to provide anesthesia during phacoemulsification cataract surgery and intraocular lens implantation.
Tetracaine causes rapid surface anesthesia, but even repeated applications to the conjunctival surface may fail to achieve effective scleral anesthesia. Preparations of local anesthetics for topical use that include tetracaine should never be injected. Practitioners are cautioned to consider tetracaine a potent and potentially toxic local anesthetic. Dangerous overdoses may occur if it is administered in doses higher than 1.5 mg/kg of body weight.
Table 6-2
Topical Anesthetics
Anesthetic Trade Name Formulation Preservative
Cocaine hydrochloride Schedule II controlled 1–10% solution prepared
substance from bulk powder
Tetracaine hydrochloride Opticaine 0.5% solution 0.4% chlorobutanol
Tetcaine
Benoxinate hydrochloride with Fluress 0.4% solution combined 1% chlorobutanol
fluorescein sodium with 0.25% fluorescein
sodium
Benoxinate hydrochloride with Flurasafe 0.4% solution combined 0.5% chlorobutanol
fluorexon disodium with 0.35% fluorexon
disodium
Proparacaine hydrochloride AK-Taine 0.5% solution 0.01% benzalkonium chloride
Alcaine Ophthetic Parcaine
Proparacaine hydrochloride Fluoracaine 0.5% solution combined 0.1% thimerosal
with fluorescein sodium Flucaine with 0.25% fluorescein
A variety of side effects often accompany the use of topical tetracaine. Tetracaine appears to produce greater corneal compromise than proparacaine, including ultra- structural damage to the cell membrane, loss of microvilli, and desquamation of superficial epithelial cells. Perhaps the greatest objection to the use of tetracaine, however, is the moderate stinging or burning sensation that almost always occurs immediately after its topical instillation. This typically lasts 20 to 30 seconds after drug applica- tion. Another problem associated with use of tetracaine is allergic reactions. Local allergy to tetracaine may develop because of repeated use (e.g., in tonometry of glaucoma patients), but this is uncommon. Rarely, tetracaine can exhibit cross-sensitivity with proparacaine.
Benoxinate
Benoxinate is commercially available only in combination with a vital dye solution. It is most commonly combined with sodium fluorescein 0.25%, but recently it was combined with 0.35% disodium fluorexon (Flurasafe by Accutome). Fluorexon is a high-molecular-weight fluores- cein that does not stain hydrogel contact lenses; therefore the use of Flurasafe is intended to allow contact lens patients to resume wear sooner without concern of contact lens staining. Benoxinate 0.4%, an ester of PABA, has an onset, intensity, and duration of anesthesia similar to those of tetracaine 0.5% and proparacaine 0.5% (see Figure 6-2). Because benoxinate is available only in combination with a vital dye, its primary clinical use is for applanation tonometry.Although solutions of fluorescein serve as good culture media for Pseudomonas aerugi- nosa, the benoxinate–sodium fluorescein combination has been shown to have substantial bactericidal proper- ties. Thus, the benoxinate–sodium fluorescein combina- tion is ideal for use in applanation tonometry, because it does not have the same risk for Pseudomonas contami- nation characteristic of sodium fluorescein solutions.
Relatively few side effects are associated with the clin- ical use of benoxinate as an ocular anesthetic. Topical instillation typically produces a sensation of stinging or burning that is greater than that produced by the instilla- tion of proparacaine but less than that produced by tetra- caine. In addition, benoxinate appears to cause less corneal epithelial desquamation than proparacaine, but this has not been substantiated by controlled clinical studies. Local allergic reactions to benoxinate are rare. Benoxinate may be safely administered to some patients who are allergic to tetracaine, another ester of PABA, without causing allergic reactions, which suggests that the allergenic potential of benoxinate is extremely low. There is no apparent cross-sensitivity between this agent and proparacaine.
Some individuals demonstrate significant increases or decreases (±10 mcm) in corneal thickness after the instil- lation of topical benoxinate. This effect must be consid- ered when performing preoperative pachymetry before corneal refractive surgery.
Proparacaine
Proparacaine is commercially available in a 0.5% solution, both with and without sodium fluorescein 0.25% (see Table 6-2).The onset, intensity, and duration of anes- thesia from these preparations are similar to those of tetracaine 0.5% and benoxinate 0.4% (see Figure 6-2). Proparacaine, however, does not appear to penetrate into the cornea or conjunctiva as well as tetracaine.
When used without sodium fluorescein, proparacaine is widely used as a general-purpose topical anesthetic. It produces little or no discomfort or irritation on instilla- tion and is therefore readily accepted by most patients. When compared directly with tetracaine, 86% of patients reported that proparacaine caused less pain on adminis- tration. Unopened bottles may be stored at room temper- ature, but once opened the bottles should be tightly capped and, ideally, refrigerated to retard discoloration. Discolored solutions of proparacaine should be discarded.
Proparacaine has few side effects. Although localized allergic hypersensitivity reactions may develop, these are rare and occur less frequently with proparacaine than with tetracaine. Allergic reactions may be characterized by conjunctival hyperemia and edema, edematous eyelids, and lacrimation. After topical ocular instillation in recommended doses, allergic systemic manifestations are extremely rare. Topically instilled proparacaine was reported to have a possible role in the development of a hypersensitivity reaction that resulted in exacerbation of an existing case of Stevens-Johnson syndrome. Proparacaine was also reported to cause allergic contact dermatitis on the fingertips.This rare work-related hazard was confirmed by skin-patch testing. Rarely, proparacaine can exhibit cross-sensitivity with tetracaine.
As with benoxinate, corneal thickness instability can occur for about 5 minutes after proparacaine administration.
0 1 2 3 4 5 5 10 15 MINUTES ESTHESIOMETER 20 25 30 Benoxinate Proparacaine Tetracaine
Figure 6-2 Comparison of onset, intensity, and duration of anesthesia obtained with tetracaine 0.5%, proparacaine 0.5%, and benoxinate 0.4%. (Reprinted with permission from Am J Ophthalmol 1955;40:697–704. Copyright, The Ophthalmic Publishing Company.)
These changes in corneal thickness should be considered when obtaining measurements for refractive surgery or when performing pachymetry in glaucoma patients.