13

Local Anesthetic Agents

Ashok Garg

Introduction

In modern ophthalmology with the preponderance of elderly patients (due to increased life expectancy) and the move towards high-tech outpatient surgical care, there is a growing emphasis and need of local anesthesia

Local anesthesia is the lifeline of modern ophthalmic surgery and is safer and should always be used unless there are specific indications for general anesthesia. Local anesthesia in the eye may be achieved by topical application of anesthetic drops or by infiltration of the sensory nerves with anesthetic solution (injectables).

Local Anesthetics (Injectables)

Local anesthetics prevent the generation and conduction of nerve impulses by reducing sodium permeability increasing the electrical excitation threshold, slowing the nerve impulses propagation, and reducing the rate of rise of the action potential.

Indications

Local injectable anesthetics are indicated for infiltration anesthesia in any kind of intraocular surgery.

Contraindications

Hypersensitivity to local anesthetics, para-amino benzoic acid or parabens. Do not use large doses of local anesthetics in patients with heart block.

Precautions during Local Injectable Anesthesia

•Use local anesthetic with caution when there is inflammation or sepsis in the region of proposed injection.

•Monitor cardiovascular respiratory vital signs and state of consciousness after each injection.

•Local anesthetic should be injected with great care in debilitated or elderly patients, acutely ill patients, children and patients with increased intraabdominal pressure or patients with severe shock or heart block.

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•Many drugs used during local anesthesia are considered potential triggering agents for familial malignant hyperthermia, hence the arrangement for supplemental general anesthesia should be there.

•Use solutions containing a vasoconstrictor with great caution in patients with history of hypertension, peripheral vascular disease, arteriosclerotic heart disease, cerebral vascular insufficiency, heart block, thyrotoxicosis, diabetes. These patients may exhibit exaggerated vasoconstrictor response.

•Watch for hypersensitivity reactions including anaphylaxis to any component of local anesthetics.

•Administer ester type local anesthetics cautiously to patients with abnormal or reduced levels of plasma esterases.

•Some of these anesthetic products contain sulfites which may cause allergic type reactions in certain susceptible patients. Although prevalence of sulfite sensitivity is low.

•Use amide type local anesthetics with care in patients with impaired hepatic function.

•Use local anesthetics with caution in patients with renal disease.

•Exercise caution regarding toxic equivalence when mixtures of local anesthetics are employed.

•Do not use disinfecting agents containing heavy metals for skin (periorbital area) disinfection.

•Do not use local anesthetics in any condition in which a sulfonamide drug is employed.

•Patients should be asked to avoid touching or rubbing the eye until the anesthesia is worn off.

Adverse Reactions of Local Injectable Anesthetics

The most common acute adverse reactions are related to the CNS and cardiovascular systems. These are generally dose related and may result from rapid absorption from the injection site, from diminished tolerance or from unintentional intravascular injections.

CNS Adverse Reactions

Restlessness, anxiety, dizziness, tinnitus, blurred vision, tremors, convulsions, nausea, vomiting, chills, pupil constriction, excitement may be transient or absent.

Depressive effects These may or may not be preceded by the excitatory symptoms. These are: drowsiness, sedation, generalized CNS depression, unconsciousness, coma, apnea and respiratory depression and even death from respiratory arrest.

Cardiovascular Symptoms of Toxicity

•Peripheral vasodilation

•Hypertension and tachycardia

•Decreased cardiac output

•Hypotension

•Bradycardia

•Methemoglobinemia

•Heart block, ventricular arrhythmias

•Circulatory collapse.

Allergic Adverse Reactions

•Cutaneous lesions of late onset

•Erythema, angioneurotic edema

•Sneezing, syncope

•Excessive sweating

•Elevated temperature and anaphylactoid symptoms.

Overdosage

Acute emergencies from local injectable anesthetics are generally related to high plasma levels encountered during therapeutic use or to unintended injection overdosage can lead to

•Convulsions, apnea and under ventilation

•Circulatory depression.

If not treated promptly, convulsions and cardiovascular depression can result in hypoxia, acidosis, bradycardia, arrhythmias and cardiac arrest. Various local injectable anesthetics used in ophthalmology are classified as follows.

Esters

•Procaine

•Chloroprocaine

•Tetracaine

Amides

•Lidocaine

•Prilocaine

•Mepivacaine

•Bupivacaine

•Etidocaine

•Centbucridine

Individual drug monographs are described as follows.

Esters

Procaine

Procaine is paraaminobenzoic acid ester of diethylaminoethanol. It was first prepared in 1905. The chemical structure is depicted in Figure 13.1

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FIGURE 13.1 Chemical structure of procaine

Indication Procaine is used for infiltration anesthesia prior to any intraocular surgery. It is not used topically.

Dosage Procaine is available as 1 percent (2 ml) ampoules. It has rapid onset of action (2–5 minutes) with an average duration of action one hour.

Concentration of 0.5 to 2 percent are used with a maximum dose of 14 mg/kg body weight.

Detoxification occurs by hydrolysis to para-amino benoic acid and diethylaminoethanol through the enzyme pseudocholinesterase in the plasma.

Solution for infiltration anesthesia is freshly prepared. To prepare 60 ml of 0.5 percent solution (5 mg/ml) dilute 30 ml of 1 percent solution with 30 ml sterile distilled water.

Add 0.5 to 1 ml of epinephrine (1:1000 per 100 ml) anesthetic solution for vasoconstrictive effect (1:200000 to 1:100000).

Precautions and adverse reactions have already been described in general monograph section of local injectable anesthetics.

Chloroprocaine

Chloroprocaine is a 2 chloro—4 aminobenzoate ester of B-diethylaminoethanol. It was introduced in 1952 as an analog of procaine. The chemical structure is depicted in Figure 13.2.

FIGURE 13.2 Chemical structure of

Chloroprocaine

Chloroprocaine is used for infiltration anesthesia in concentrations of 0.5 to 2 percent. Onset of anesthesia is very rapid (2–5 minutes) and the average duration of action lasts for 1½ hours. It is twice as potent as procaine and has similar

FIGURE 13.3 Chemical structure of tetracaine

pharmacological properties. Metabolism is largely through hydrolysis by pseudocholinesterase in the plasma.

Tetracaine (Amethocaine)

Tetracaine is a parabutylaminobenzoic acid ester of dimethylaminoethanol. It was first prepared in 1933. The chemical structure is depicted in Figure 13.3.

Tetracaine is used for infiltration as well as topical anesthesia.

Dosage Tetracaine is available in concentration of 0.25 to 2 percent solutions. Tetracaine is a potent and toxic local anesthetic and dangerous overdosage may occur if it is given in doses higher than 1.5 mg/ kg body weight.

It should be given with caution for infiltration anesthesia purpose.

Amides

Lidocaine

Lidocaine is one of the most common local injectable anesthetic agent used in ophthalmic surgery worldwide.

Lidocaine is 2-diethylamino-2′-6′-acetoxylidine. It was first prepared in 1948. The chemical structure is depicted in Figure 13.4.

Indication Lidocaine 2 percent is used for infiltration anesthesia prior to any type of intraocular surgery.

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FIGURE 13.4 Chemical structure of lidocaine

Dosage Lidocaine is available in concentration of 0.5 to 4 percent as lidocaine hydrochloride (2, 5 ml ampoules and 30 ml and 50 ml vials). For infiltration anesthesia generally 1 percent and 2 percent solutions are used (In 2 ml, 5 ml and 10 ml ampoules; 30 and 50 ml vials). It has rapid onset of action (0.5–2 minute) and average duration of action lasts for 1½ to 2 hours.

Lidocaine is metabolized in the liver to xylidine and diethylaminoacetic acid or is directly excreted into the urine and bile.

For infiltration anesthesia it is generally given with mixture of adrenaline and hyaluronidase to prolong the anesthetic effect and better diffusion to the ocular tissue. Hyaluronidase is an enzyme capable of depolymerizing hyaluronic acid found in interstitial spaces and when it gets depolymerized, fluid passes more easily between the tissues. Preferable 1:100,000 solution of adrenaline concentration is used and it causes sufficient vasospasm to reduce significantly the rate of removal of local anesthetic agent. A correctly placed retrobulbar or peribulbar injection of this solution causes complete akinesia and anesthesia of the globe. Hyaluronidase is also mixed with 2 percent lidocaine and adrenaline injection for better diffusion of solution into the tissues. It increases the effective area of anesthesia by 40 percent though inevitably of shorter duration.

Various Lidocaine combinations available commercially are

•Lidocaine HCl 0.5–2 percent with 1:100000 to 1:200000 epinephrine (in 5 ml and 10 ml ampoules, 20, 30 and 50 ml vials).

•Lidocaine HCl 1.5–5 percent with 7.5 percent Dextrose (in 2 ml ampoules).

Safe dose for lidocaine HCl is—7 mg/kg body weight with vasoconstrictors and 2.9 mg/kg body weight without vasoconstrictors. Recently preservative free 1 percent lidocaine hydrochloride (0.5 ml) ampoules have been available commercially for intracameral use during intraocular surgery.

Usual dosage is to inject 0.25 cc of 1 percent preservative free lidocaine into the anterior chamber through the cannula though 1 mm stab incision made in the peripheral cornea, 5 seconds later eye is anesthetized.

Advantages of intracameral injection of lidocaine

•It relieves all discomfort and apprehension of the patient.

•It decreases the need of sedation.

•Surgery is quicker and less tense and patient responds faster with no complications or adverse effects.

•Has an excellent deeper depth of anesthesis.

•Eliminates blocks and their potential complications.

•Has good effect in conjunction with topical anesthesia.

Prilocaine

Prilocaine is α-propylamino 2 methylproprionanilide. It was first prepared in 1960. The chemical structure is depicted in Figure 13.5.

Its pharmacological properties are similar to those of lidocaine and its onset of action takes 5 to 15 minutes and duration of action lasts for 1 to 3 hours.

Prilocaine is used for infiltration and regional nerve block anesthesia. It is available in concentration of 0.5 to 3 percent. The suggested maximum dose is 10 mg/kg body weight.

FIGURE 13.5 Chemical structure of prilocaine

Unusual toxic effect seen after administration of large doses (more than 800 mg) is cyanosis due to methemoglobinemia.

Mepivacaine

Mepivacaine is N-methyl pipecolic acid 2,6 dimethyl anilide. It was first prepared in 1956. The chemical structure is depicted in Figure 13.6. Mepivacaine has pharmacological properties similar to those of lidocaine. Notable exception is its effect on blood vessels. It is shown to have mild vasoconstrictor effect which reduces its absorption. The effect of mepivacaine on the peripheral circulation is a potentiation of the action of norepinephrine on nerve endings. The onset of action starts within 3 to 5 minutes and duration of action is from 2 to 2½ hours (with epinephrine). The suggested maximum dose is 7.0 mg/kg body weight.

It is used for infiltration and nerve block anesthesia.

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FIGURE 13.6 Chemical structure of mepivacaine

Dosage Mepivacaine is commercially available as mepivacaine HCl 1 to 2 percent injectable solutions (in 20, 30 and 50 ml vials). For infiltration anesthesia, 1 percent concentration is used.

Bupivacaine

Bupivacaine is structurally similar to mepivacaine and is one of the common anesthetic agents used in the ophthalmology for infiltration anesthesia. It was first prepared in 1963. The chemical structure is depicted in Figure 13.7.

Bupivacaine is 3 to 4 times more potent than lidocaine. Its onset of action starts within 5 to 10

FIGURE 13.7 Chemical structure of bupivacaine

minutes and duration of action lasts for 3 to 5 hours (with epinephrine).

Dosage Bupivacaine is available as bupivacaine HCl injectable solution in concentration of 0.25 to 0.75 percent (in 2 ml ampoules and 10, 30 and 50 ml vials). For retrobulbar or peribulbar injection 0.75 percent strength solution is used.

Bupivacaine is also available in combination with epinephrine commercially. Bupivacaine HCl 0.25 to 0.75 percent (in 2 ml ampoules, 10 ml, 30 ml and 50 ml

vials).

The maximum safe dose is 2.0 mg/kg body weight.

Practically for infiltration anesthesia prior to intraocular surgery it is used in combination of 2 percent lidocaine to produce complete akinesia and anesthesia of globe for more than 2 hours. Usually 50:50 percent of both solutions (0.5% bupivacaine HCl and 2% lidocaine HCl in addition to adrenaline and hylase) are used to produce anesthesia for major ocular surgeries.

Etidocaine

Etidocaine is used for infiltration anesthesia in ophthalmic surgery. It is available as 0.5 to 1 percent injectable solutions (in 30 ml vials and 20 ml ampoules). Its onset of action start in 5 to 15 minutes and duration of action lasts for 3 to 5 hours. It is also available commercially with epinephrine. Etidocaine HCl 1.0 to 1.5 percent with 1:20000 epinephrine (30 ml vials).

Centbucridine

Centbucridine is 4-N-butylamino-1, 2, 3, 4, tetrahydroacridine hydrochloride. It is recently introduced anesthetic agent. It has been shown 5 to 8 times more potent than lidocaine.

It is used for infiltration anesthesia and topical anesthesia.

Dosage Centbucridine is available as 0.5 percent Centbucridine injectable solution (in 10 ml and 30 ml vials). Its onset of action starts in 2 to 5 minutes and duration of action lasts for 1 to 1½ hours.

Local Anesthetics (Topical)

Topical anesthesia is the mainstay of modern ophthalmic surgery. Topical anesthesia is now widely used from superficial minor surgery of conjunctiva and cornea to high-tech phacoemulsification, excimer laser PRK and LASIK surgery. Topical anesthetic agents produce their effect by blocking nerve conduction in the superficial cornea and conjunctiva. The physiological effect of all topical anesthetic agents occur in a similar fashion. They work at the level of cell membrane by preventing the sodium flux by closing the pores through which the ions migrate in the lipid layer of nerve cell membrane. The anesthetic agents block conduction of afferent nerve impulses thereby abolishing sensation and producing local anesthetic action.

Indications

Corneal anesthesia of short duration for any diagnostic and surgical procedure on the eye.

Contraindications

Known hypersensitivity to the drug or to any other ingredient in these preparations. Prolonged used specially for self-medication is not recommended.

Precautions

These anesthetic agents are for topical ophthalmic use only. Prolonged use is not recommended as it may diminish duration of anesthesia, retard would healing and cause epithelial erosions. It may produce permanent corneal opacification with accompanying

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visual loss, severe keratitis, scarring or corneal perforation, if signs of sensitivity develops discontinue the use.

•Tolerance varies with the status of the patient. Give debilitated, elderly or acutely ill patients reduced doses commensurate with their weight, age and physical status.

•Use with caution in patients with abnormal or reduced levels of plasma esterases.

•Use with caution in patients with known allergies, cardiac disease or hyperthyroidism.

•Protection of the eye from irritating chemicals, foreign bodies and rubbing during the period of anesthesia is important.

Adverse Reactions

On topical use these anesthetic agents may cause

•Mild stinging and burning sensation, vasodilation

•Shortening of tear break-up time

•Decreased blinking

•Corneal edema

•Decreased epithelial mitosis and migration

•Slow epithelial healing

•Punctate epithelial keratitis

•Epithelial desquamation

•Allergic reactions of lid and conjunctiva

•Iritis

Various anesthetic agents used in ophthalmology as topical agents are

•Benoxinate

•Proparacaine

•Tetracaine

•Lidocaine

•Centbucridine

•Cocaine

•Phenacaine

•Dimethocaine

•Piperocaine

•Dibucaine

•Naepaine

•Butacaine

In today ophthalmic surgery and in diagnostic procedures, proparacaine, benoxinate and tetracaine are commonly used. Their action starts within 15 to 20 seconds and effects last for 15 to 20 minutes.

Other topically applied anesthetic agent is 4 percent Xylocaine, its use is becoming lesser and lesser due to problems with irritation, allergy, etc.

Individual drug monograph of topical anesthetic agent is as follows.

Benoxinate HCl (Oxybuprocaine)

Benoxinate HCI is a paraaminobenzoic acid ester. The chemical structure is depicted in Figure 13.8.

It is available as 0.4 percent topical solution. Its action starts within 10 seconds of topical instillation and effect lasts for 15 minutes. 1 to 2 drops of 0.4 percent solution is sufficient to anesthetize the cornea. For deep anesthesia 3 instillations at 90 second interval is sufficient. Because of high degree of safety it is most suitable for topical use.

It is also available as 0.4 percent benoxinate HCI solution with 0.25 percent fluorescein sodium (in 5 ml pack). It is associated with less irritation on instillation.

Another topical anesthetic agent having properties and uses similar to benoxinate is proxymetacaine (0.5%).

Proparacaine

Proparacaine is one of the most common topical anesthetic agents for topical anesthesia in intra-ocular surgery (phacoemulsification, cataract surgery, excimer laser PRK and LASIK surgery)

It is a benzoic acid ester. The chemical structure is depicted in Figure 13.9.

FIGURE 13.8 Chemical structure of benoxinate

FIGURE 13.9 Chemical structure of proparacaine

It is available as 0.5 percent and 0.75 percent topical solution. It is used 2 to 5 minutes prior to intraocular surgery.

Its effect starts within 15 to 20 seconds and lasts for 15 minutes. Potency is similar to that of tetracaine. Maximum dose is 10 mg (about 20 crops of 0.5 percent solution on topical instillation).

Due to higher degree of potency and safety it is most appropriate choice for topical ocular anesthesia. It is available as 0.5 percent proparacaine HCl solution and 0.25 percent fluorescein sodium.

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Tetracaine

Tetracaine is para-butylaminobenzoic acid ester of dimethylaminoethanol. It is one of the most popular topical anesthetic agents currently used in ophthalmology.

It is available as 0.25 to 1 percent topical solution usually 0.5 percent strength is used for topical anesthesia.

Tetracaine HCl penetrates tissue more deeply than proparacaine and benoxinate.

Its action starts in 20 seconds and lasts for 10 to 12 minutes after topical instillation. It is instilled 2 to 5 minutes prior to the surgery. 1 to 2 drops are instilled topically 2 to 3 times at 60 second duration. Maximum dose is 5 mg (10 drops to each eye of 0.5% solution).

On topical instillation however it produces stinging sensation for 30 seconds.

Lidocaine HCl

Lidocaine is 2-diethyl amino, 2,6 aceto xylidine.

Prior to introduction of topical benoxinate, proparacaine and tetracaine anesthetic agents, 4 percent lidocaine HCl was commonly used for topical anesthesia.

One drop of 4 percent lidocaine solution renders the cornea anesthetized within 30 to 60 seconds and effect lasts for 10 minutes.

It is rapidly acting and does not cause dilation of pupil.

On topical instillation however it causes marked stinging sensation for 30 seconds. Due to its stinging sensation problem, it is now less commonly used for topical

anesthesia purpose.

Centbucridine

Centbucridine is recently introduced topical anesthetic agent. It is available as 1 percent topical solution and effect lasts for 15 minutes. It causes very less stinging than 4 percent lidocaine and is safe on topical use. Usual dosage is one drop to be instilled topically and sufficient to produce topical anesthesia.

Cocaine

Cocaine is an alkaloid of erythoxylon coca. It was first introduced in 1884. The chemical structure is given in Figure 13.10.

FIGURE 13.10 Chemical structure of cocaine

Cocaine was quite extensively used in late fifties of last century. It is available as topical solution in concentration of 1 to 10 percent as cocaine HCl. One drop of 2 percent solution renders the cornea anesthetized within 30 seconds and effect lasts for 12 minutes.

Maximum dose is 20 mg (about 10 drops to each eye of 2% solution). It is however toxic directly to corneal epithelium. It may be used to aid penetration of the other drugs (like cycloplegics) into the cornea and anterior chamber. Cocaine causes mydriasis and when absorbed systemically it may be associated with dangerous drug interactions and hypertensive crisis and CNS stimulation. Toxic doses of cocaine cause fatal circulatory and respiratory collapse. It is now not commonly used for topical purpose as better topical agents are available.

Phenocaine

Phenocaine is derivative of phenetidine. It is N, N, Bis (p-ethoxy-phenyl) acetamidine. The chemical structure is depicted in Figure 13.11.

FIGURE 13.11 Chemical structure of phenocaine

As it is not an ester, it can be considered as an alternative agent for use in patient sensitive to ester group.

It is used as 1 percent topical solution for instillation. Phenocaine is no longer used because it causes excessive irritation and highly toxic.

Dimethocaine

Dimethocaine was first prepared in 1932. It is 3-diethylamino, 2,2 dimethyl propyl p- amino benzoate. The chemical structure is depicted in Figure 13.12. It has been used in ophthalmology as topical agent in concentration of 2 to 5 percent. It is derivative of paraaminobenzoic acid.

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FIGURE 13.12 Chemical structure of dimethocaine

FIGURE 13.13 Chemical structure of piperocaine

Piperocaine

Piperocaine is benzoic acid ester of methyl piperidinopropanol. The chemical structure is depicted in Figure 13.13. It is used as topical 2 percent solution for topical anesthesia. It has effect of regeneration of corneal epithelium.

Piperocaine alongwith lidocaine are the only agents associated with normal healing of the cornea.

Dibucaine

Dibucaine is 2 butoxy-N (2-diethyl aminoethyl) cinchoninamide. It is quinolone derivative and is not an ester. The chemical structure is depicted in Figure 13.14.

Dibucaine is probably the most potent local anesthetic agent but its use has declined because

FIGURE 13.14 Chemical structure of dibucaine

of toxicity. It is used as 0.1 percent topical solution for instillation.

Naepaine

Naepaine is mono-n-amylamino ethyl-p-amino benzoate. Its chemical structure is depicted in Figure 13.15.

One topical use, it does not cause mydriasis of alteration in intraocular pressure. It is not associated with local irritation. It is derivative of paraaminobenzoic acid and is used 2 to 4 percent topical ophthalmic solution.

Butacaine

Butacaine is paraminobenzoic acid ester of dibutylaminopropanol. The chemical structure is depicted in Figure 13.16.

It is used topically as 2 percent solution.

FIGURE 13.15 Chemical structure of naepaine

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FIGURE 13.16 Chemical structure of butacaine