Anesthetics (Ophthalmic)

This monograph includes information on the following:

1) Proparacaine
2) Tetracaine


INN:
Proparacaine— Proxymetacaine. {03}

BAN:
Proparacaine—Proxymetacaine. {03}
Tetracaine—Amethocaine. {03}

VA CLASSIFICATION
Primary: OP700

Commonly used brand name(s): Ak-T-Caine2; Ak-Taine1; Alcaine1; Diocaine1; Minims Tetracaine2; Ocu-Caine1; Ophthaine1; Ophthetic1; Opticaine2; Pontocaine2; Spectro-Caine1.

Other commonly used names are:
Amethocaine —Tetracaine
Proxymetacaine —Proparacaine

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Anesthetic, local (ophthalmic)—

Indications

Accepted

Anesthesia, local—Proparacaine and tetracaine are indicated to produce local anesthesia of short duration for ophthalmic procedures including measurement of intraocular pressure (tonometry), removal of foreign bodies and sutures, and conjunctival and corneal scraping in diagnosis and gonioscopy. {07} {08}
—Proparacaine and tetracaine are also indicated to produce local anesthesia prior to surgical procedures such as cataract extraction and pterygium excision, usually as an adjunct to locally injected anesthetics. {14}
—Ophthalmic solutions used for intraocular procedures should be preservative-free. Preservatives may cause damage to the corneal epithelium if a significant quantity of solution enters the eye through the incision. {17}

Unaccepted
Proparacaine and tetracaine are not indicated for chronic or repeated use because of the potential for severe corneal damage. {07} {08} {13} Severe keratitis and opacification and scarring of the cornea resulting in loss of vision have occurred with repeated use of these medications. {07} {08} {09}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    Ester-type local anesthetics. Proparacaine is a meta-aminobenzoic acid derivative; {03} tetracaine is an aminobenzoic acid (para-aminobenzoic acid; PABA) {08} derivative
Molecular weight—
{03}    Proparacaine hydrochloride: 330.85
    Tetracaine: 264.37
    Tetracaine hydrochloride: 300.83

pKa—
    Tetracaine: 8.4 {10}

Mechanism of action/Effect:

After topical application to the eye, local anesthetics penetrate to sensory nerve endings in the corneal tissue. {11} These medications block both the initiation and conduction of nerve impulses by decreasing the neuronal membrane's permeability to sodium ions. This reversibly stabilizes the membrane and inhibits depolarization, resulting in the failure of a propagated action potential and subsequent conduction blockade. {12}


Other actions/effects:

Following topical application to the eye, local anesthetics may retard epithelial regeneration by inhibiting mitosis, cellular migration, and corneal epithelial uptake and oxidation of glucose and pyruvate. {13} With repeated or prolonged use, these agents may retard healing of existing corneal injury or cause new corneal damage. {07} {08} {09} {13}

If significant quantities of local anesthetics are absorbed, they may act on the central nervous system (CNS) to produce CNS stimulation followed by CNS depression, and on the cardiovascular system to produce depression of cardiac conduction and excitability. {07} {08}

Absorption:

Rapidly absorbed {13} via conjunctival capillaries. {15}.

Protein binding:

Tetracaine—High. {10}

Biotransformation:

Proparacaine—Hydrolyzed by plasma esterases. {15}

Tetracaine—Hydrolyzed by cholinesterases, primarily in the plasma {08} {12} and to a much lesser extent in the liver, {12} to an aminobenzoic acid (PABA)–containing metabolite and diethylaminoethanol. {08}

Onset of action:

Proparacaine—Within 20 seconds. {13}

Tetracaine—Approximately 15 seconds. {13}

Duration of action:

Proparacaine—15 minutes or longer. {07}

Tetracaine—10 to 20 minutes; average 15 minutes. {13}

Note: For topical application to the eye, the duration of action is not prolonged by use of concentrations greater than 0.5% of proparacaine or 1% of tetracaine, or by concurrent use of a vasoconstrictor. {13} However, the duration of action increases with repeated applications. {11} {13}


Elimination:
    Tetracaine—Renal; as metabolites. {10}


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to other ester-type local anesthetics (such as benzocaine, butacaine, butamben, chloroprocaine, procaine, or propoxycaine) or to aminobenzoic acid (para-aminobenzoic acid; PABA) or parabens may be sensitive to tetracaine also. {08}

Cross-sensitivity between proparacaine and tetracaine or other local anesthetics has not been reported. {13}

Carcinogenicity/Tumorigenicity/Mutagenicity

Studies with proparacaine or {01} {07} tetracaine {02} {08} have not been done.

Pregnancy/Reproduction

Pregnancy—
Problems in humans have not been documented.

Studies of the teratogenic potential of proparacaine {01} {07} or tetracaine {02} {08} have not been done in animals.

FDA Pregnancy Category C. {01} {02} {07} {08}

Breast-feeding

It is not known whether proparacaine {07} or tetracaine {02} {08} is distributed into breast milk. However, problems in humans have not been documented.

Pediatrics

Proparacaine—Appropriate studies on the relationship of age to the effects of proparacaine have not been performed in the pediatric population. However, pediatrics-specific problems that would limit the usefulness of this medication in children are not expected.

Tetracaine —Appropriate studies on the relationship of age to the effects of tetracaine have not been performed in the pediatric population. However, the stinging that frequently occurs after application of tetracaine may upset small children. {13}


Geriatrics


Appropriate studies on the relationship of age to the effects of ophthalmic anesthetics have not been performed in the geriatric population. However, geriatrics-specific problems that would limit the usefulness of this medication in the elderly are not expected.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


For tetracaine {16}
Cholinesterase inhibitors, especially demecarium, echothiophate, and isoflurophate    (metabolism of tetracaine may be inhibited, leading to prolonged ocular anesthetic effect and increased risk of toxicity, if administered to a patient receiving therapy with a cholinesterase inhibitor)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Cultures (24-hour) for detection of infection    (topical ocular anesthetics and preservatives present in the formulations may inhibit growth of organisms, including Staphylococcus albus , Pseudomonas , and Candida albicans {13})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist

For proparacaine or tetracaine:
Ocular inflammation and/or infection    (may alter pH and/or increase blood circulation at site of application, leading to decrease or loss of anesthetic effect {13})


For proparacaine {01} {07}:
Allergic reaction to proparacaine, history of
Allergies    (proparacaine may cause an allergic reaction)


For tetracaine {08}:
Allergic reaction to tetracaine, history of
Plasma cholinesterase deficiency    (increased risk of toxicity because of decreased metabolism)




Side/Adverse Effects

Note: Allergic contact dermatitis with drying and fissuring of the fingertips has been reported with these medications. {01} {07}
Prolonged use of topical ophthalmic anesthetics may produce severe keratitis, permanent corneal opacification, and scarring, with loss of visual acuity. {01} {02} {07} {08} {09} Also, prolonged use of topical ophthalmic anesthetics may cause delay in corneal epithelial healing. {07} {08} {13}
Proparacaine may rarely cause a severe, immediate hypersensitivity reaction that may include acute intense and diffuse epithelial keratitis; a gray, ground-glass appearance; sloughing of large areas of necrotic epithelium; corneal filaments and, sometimes, iritis with descemetitis. {01} {07} Rarely, proparacaine also causes a delayed hypersensitivity reaction {09} characterized by softening and erosion of the corneal epithelium, conjunctival congestion, and hemorrhage. {01} {07} {09} Tetracaine may also rarely cause local hypersensitivity reactions. {08} {13} In addition, sensitivity reactions to the preservatives present in ophthalmic formulations may occur. {14}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Signs and/or symptoms of systemic toxicity—very rare {15} {16}
    
CNS depression (drowsiness; shortness of breath or troubled breathing)—may follow CNS stimulation
    
CNS stimulation (blurred vision; convulsions; dizziness; muscle twitching or trembling; nausea or vomiting; unusual excitement, nervousness, or restlessness)
    
increased sweating
    
irregular heartbeat
    
unusual paleness
    
unusual tiredness or weakness



Those indicating need for medical attention only if they are severe or if they continue or are bothersome
Incidence less frequent {01} {02} {07} {08}
    
Burning, stinging, redness, or other irritation of eye, mild
Note: These effects may occur upon application of tetracaine, or up to several hours after application of proparacaine. Ocular discomfort characterized by a burning sensation occurs more frequently, and is more severe, with tetracaine than with proparacaine. {13} Closing the eyes immediately after application may decrease the discomfort. {13}



Incidence rare {13}
    
Allergic reaction (itching, pain, redness, or swelling of eye or eyelid, severe; watering of eyes, severe and continuing)





Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Anesthetics (Ophthalmic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before receiving this medication
»   Conditions affecting use, especially:
Allergic reaction to the anesthetic considered for use, history of, and, for tetracaine only, to any other PABA-derivative anesthetic, PABA, or parabens

Proper use of this medication

Proper dosing

Precautions after receiving this medication
» Not rubbing or wiping the eye until anesthesia has worn off, to prevent damage to the eye

Possibility of rash with dryness and cracking of skin if medication comes in contact with fingers; washing hands after touching eyes following application of medication


Side/adverse effects
» Checking with physician as soon as possible if severe symptoms indicating possible hypersensitivity occur

Signs and symptoms of potential side effects, especially hypersensitivity reactions


General Dosing Information
Proparacaine is approximately equal in potency to tetracaine when used in equal concentrations, but is less irritating. {13}

It is important that the eye be protected from irritating chemicals, foreign bodies, and rubbing during the period of anesthesia since the ``blink'' reflex is temporarily eliminated. Rubbing or touching the eye during anesthesia may damage the anesthetized cornea and conjunctiva. {01} {02} {07} {08} {13}

When a local anesthetic is used for tonometry, the tonometer should be thoroughly rinsed with sterile distilled water prior to use, to remove any sterilizing or detergent solutions. {01} {07}

For treatment of allergic reactions
Topical application of ophthalmic corticosteroids or antihistamines may be helpful. {17}

For treatment of systemic toxicity
Recommended treatment includes

   • Securing and maintaining a patent airway, administering oxygen, and instituting assisted or controlled respiration as required. In some patients, endotracheal intubation may be needed. Respiratory stimulants should not be given because they are considered ineffective. {13}
   • For convulsions—Administering an anticonvulsant. Benzodiazepines are most commonly used. {18} Because intravenously administered benzodiazepines may cause respiratory {20} and circulatory {21} depression, especially when administered rapidly, {19} {22} medications and equipment needed for support of respiration and for resuscitation must be immediately available. {23}
   • Administering vasopressors and intravenous fluids, if necessary, to treat hypotension. {13}

PROPARACAINE

Summary of Differences


Pharmacology/pharmacokinetics:
See Pharmacology/Pharmacokinetics.



Precautions:
Cross-sensitivity and/or related problems—No cross-sensitivity with tetracaine or other PABA-derivative local anesthetics, PABA, or parabens.

Drug interactions and/or related problems—No interaction with cholinesterase inhibitors.

Medical considerations/contraindications—Caution also required in allergies.



Side/adverse effects:
See Side/Adverse Effects .



Ophthalmic Dosage Forms

PROPARACAINE HYDROCHLORIDE OPHTHALMIC SOLUTION USP

Usual adult and adolescent dose
Anesthetic, local
For superficial procedures (e.g., tonometry, suture removal, foreign body removal): Topical, to the conjunctiva, 1 or 2 drops of a 0.5% solution. {25}

For deeper procedures (e.g., cataract removal): Topical, to the conjunctiva, 1 drop of a 0.5% solution every five to ten minutes for five to seven doses. {25} A preservative-free solution should be used. {17}


Usual pediatric dose
See Usual adult and adolescent dose.

Strength(s) usually available
U.S.—


0.5% (Rx) [Ak-Taine] [Alcaine] [Ocu-Caine] [Ophthaine] [Ophthetic] [Spectro-Caine][Generic]

Canada—


0.5% (Rx) [Alcaine] [Diocaine] [Ophthetic]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container. Protect from freezing.

Note: Opened containers should be stored between 2 and 8 °C (36 and 46 °F).


Stability:
Opened containers of proparacaine hydrochloride solution should be refrigerated to retard discoloration of the solution.

A discolored (amber) solution should not be used.


TETRACAINE

Summary of Differences


Pharmacology/pharmacokinetics:
See Pharmacology/Pharmacokinetics .



Precautions:
Cross-sensitivity and/or related problems—Potential cross-sensitivity with other PABA-derivative local anesthetics, PABA, or parabens.

Drug interactions and/or related problems—Interaction with cholinesterase inhibitors.

Medical considerations/contraindications—Caution also required in plasma cholinesterase deficiency.



Side/adverse effects:
See Side/Adverse Effects .



Ophthalmic Dosage Forms

TETRACAINE OPHTHALMIC OINTMENT USP

Note: This product is no longer being manufactured in the U.S. but may still be in circulation. {24}


Usual adult and adolescent dose
Anesthetic, local
Topical, to the lower conjunctival fornix, approximately 1.3 to 2.5 cm (approximately 1/2 to 1 inch) of a 0.5% ointment.


Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


0.5% (Rx) [Pontocaine]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing.

Note: Do not allow the tip of the tube to contact any surface that may cause contamination.



TETRACAINE HYDROCHLORIDE OPHTHALMIC SOLUTION USP

Usual adult and adolescent dose
Anesthetic, local
Topical, to the conjunctiva, 1 or 2 drops of a 0.5% or 1% solution. {02} {08}


Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


0.5% (Rx) [Ak-T-Caine] [Opticaine{27}] [Pontocaine][Generic]

Canada—


0.5% (Rx) [Minims Tetracaine] [Pontocaine][Generic]


1% (Rx) [Minims Tetracaine{26}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container. Protect from freezing.

Stability:
Do not use the solution if it contains crystals or is cloudy or discolored.



Revised: 08/25/94



References
  1. Alcaine (proparacaine) package insert (Alcon—US), Rev 1/89, Rec 5/89.
  1. Pontocaine (tetracaine) package insert (Winthrop—US), Rev 9/84, Rec 2/89.
  1. Fleeger CA, editor. USAN 1994. USAN and the USP dictionary of drug names. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1993: 551, 653.
  1. Open.
  1. Open.
  1. Open.
  1. Proparacaine Hydrochloride Ophthalmic Solution package insert (Bauch & Lomb—US), Rev 10/91, Rec 8/93.
  1. Pontocaine Hydrochloride Ophthalmic Solution package insert (Sanofi Winthrop—US), Rev 3/93; Rec 9/93.
  1. Brent MH, Slomovic AR, Easterbrook M. Keratitis associated with the use of proparacaine hydrochloride. Can Med Assoc J 1987; 186: 380-1.
  1. Miller RD, editor. Anesthesia. 3rd ed. New York: Churchill Livingstone, 1990: 437-50.
  1. Draeger J, Langenbucher H, Bannert C. Efficacy of topical anaesthetics. Ophthalmic Res 1984; 16: 135-8.
  1. Gilman AG, Rall TW, Nies AS, Taylor P, editors. Goodman and Gilman's the pharmacological basis of therapeutics. 8th ed. New York: Pergamon Press, 1990: 312-8.
  1. Havener WH. Ocular pharmacology. 5th ed. St. Louis: Mosby, 1983: 75-8.
  1. Drug evaluations subscription. Chicago: American Medical Association, Spring 1992: III 2:10-2:11.
  1. Cydulka RK, Betzelos S. Seizures following the use of proparacaine hydrochloride eye drops. J Emerg Med 1990; 8: 131-3.
  1. Panel consensus, Anesthetics (Ophthalmic) monograph, draft for USP DI 1985.
  1. Panelist comment, draft 11/93.
  1. Panel consensus, Benzodiazepines (Systemic) monograph, USP DI.
  1. Comment, treatment of convulsions information, Lidocaine and Prilocaine (Topical) monograph, ballot 6/93.
  1. Comments, treatment of convulsions information, Lidocaine and Prilocaine (Topical) monograph, draft 6/93.
  1. Ellenhorn MJ, Barceloux DG. Medical toxicology. Diagnosis and treatment of human poisoning. New York: Elsevier, 1988; 16: 1263-5, 1317-24.
  1. Comment, treatment of convulsions information, Lidocaine and Prilocaine (Topical) monograph, ballot 6/93.
  1. Comments, treatment of convulsions information, Lidocaine and Prilocaine (Topical) monograph, draft 6/93 and ballot 6/93.
  1. Personal communication, Product information specialist, Sanofi Winthrop—US, via telephone 11/1/93.
  1. Panel consensus, draft 11/93.
  1. Manufacturer comment, draft 11/93.
  1. Personal communication, 4/12/95.
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