AHFS Class:

• Mydriatics 52:24

Generic Name(s):

• Atropine Sulfate

Atropine ( dl -hyoscyamine), a naturally occurring tertiary amine antimuscarinic, is a mydriatic and cycloplegic.

Atropine sulfate ophthalmic preparations are used to produce mydriasis and cycloplegia for examination of the retina and optic disk and accurate measurement of refractive errors. However, because of the long duration of action of the drug, it is seldom, if ever, used for cycloplegic refraction in adults.101 In rare cases, topical ophthalmic atropine use may be necessary to achieve maximal cycloplegia in pediatric patients, but cyclopentolate is more frequently used.102,103

Atropine sulfate also is used in the management of acute inflammatory conditions (i.e., iridocyclitis) of the iris and uveal tract (e.g., uveitis). Atropine sulfate also is used for its cycloplegic effects in the treatment of suppression amblyopia to reduce the visual acuity of the unaffected eye below that of the amblyopic one and thus force fixation with the amblyopic eye. The drug also has been used to treat patients with a functional excess of accommodation and convergence.

For other uses of atropine, see 12:08.08.

Administration

Atropine sulfate is applied topically to the eye in the form of an ophthalmic ointment or solution. To avoid excessive systemic absorption, finger pressure should be applied on the lacrimal sac during and for 1-2 minutes following topical administration of the solution or ointment. Care should be taken to avoid contamination of the ointment tube and solution container.

Dosage

To produce mydriasis and cycloplegia for refraction in adults, 1 drop of a 1% solution may be instilled onto the eye(s) 1 hour before the procedure. In children, the usual dosage for cycloplegic refraction is 1-2 drops of a 0.5% solution instilled onto the eye(s) twice daily for 1-3 days before the procedure (the 0.5% solution is no longer commercially available in the US). Alternatively, to produce mydriasis and cycloplegia for refraction in adults, 0.3-0.5 cm of a 1% ointment may be placed into the conjunctival sac 1-3 times daily. In children, the usual dosage for cycloplegic refraction is 0.3 cm of a 1% ointment placed into the conjunctival sac 3 times daily for 1-3 days before the procedure. If the ointment is used for refraction, the drug should be applied several hours before the procedure, since it may impair corneal transparency and prevent accurate measurement of refractive errors.

For pupillary dilation in the treatment of acute inflammatory conditions of the iris and uveal tract in adults (i.e., iridocyclitis, uveitis), 1 or 2 drops of a 0.5 or 1% solution may be instilled onto the eye(s) up to 4 times daily. In children, the usual dosage for the treatment of uveitis is 1 or 2 drops of a 0.5% solution up to 3 times daily. Alternatively, for pupillary dilation in the treatment of acute inflammatory conditions of the iris and uveal tract in adults and children, 0.3-0.5 cm of a 1% ointment may be placed into the conjunctival sac up to 3 times daily.

Adverse Effects

Atropine sulfate may cause increased intraocular pressure. Prolonged administration of atropine sulfate to the eye may cause local irritation, hyperemia, edema, follicular conjunctivitis, or dermatitis.

Topical application of atropine sulfate to the eye may cause adverse systemic effects. Systemic atropine toxicity may be manifested as flushing and dryness of the skin, blurred vision, rapid and irregular pulse, fever, abdominal distention in infants, mental aberration, and loss of neuromuscular coordination. Severe systemic reactions to atropine are characterized by hypotension with progressive respiratory depression. Ophthalmic atropine has been associated with cardiac arrhythmias (e.g., atrial fibrillation) in a few patients.100

For additional information on adverse systemic effects of atropine, see Cautions in the Antimuscarinics/Antispasmodics General Statement 12:08.08.

Precautions and Contraindications

Patients receiving ophthalmic atropine sulfate should be advised not to drive or engage in other hazardous activities while the mydriasis persists.104 In addition, patients may experience an increased sensitivity to light and should be advised to protect their eyes when exposed to bright illumination.104 Parents should be advised to ensure that atropine sulfate ophthalmic preparations do not get into a child's mouth and to wash their hands following administration.104 Care should be taken to avoid contamination of the ophthalmic ointment tube and solution container.

Atropine sulfate ophthalmic preparations are contraindicated in patients with known or suspected angle-closure glaucoma. The possibility of undiagnosed glaucoma in geriatric patients should be considered. To avoid induction of angle-closure glaucoma in susceptible patients, an estimation of the depth of the angle of the anterior chamber should be performed prior to the initiation of therapy. Atropine sulfate ophthalmic ointment and solution are also contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation.

Pediatric Precautions

Atropine sulfate should be used with extreme caution, if at all, in infants and small children, and in children with spastic paralysis or brain damage because of increased susceptibility to the systemic effects of the drug in these patients. Atropine sulfate ophthalmic ointment is generally preferred for use in children, since use of the ophthalmic solution may increase the risk of adverse systemic effects.

Geriatric Precautions

No overall differences in efficacy or safety of ophthalmic atropine sulfate have been observed between geriatric and younger adults.104

Mutagenicity and Carcinogenicity

Studies have not been performed to date to evaluate the mutagenic or carcinogenic potential of atropine sulfate after ophthalmic administration.104

Pregnancy, Fertility, and Lactation

Animal reproduction studies have not been performed with ophthalmic atropine sulfate, and it is not known whether the drug can cause fetal harm when administered to pregnant women.104 Atropine should be used during pregnancy only when clearly needed.104

Studies have not been conducted in animals or humans to date to determine whether atropine sulfate affects fertility, and it is not known whether the drug affects reproductive capacity.104

It is not known whether atropine sulfate is distributed into human milk following topical application to the eye.104 Because many drugs are distributed into human milk, caution should be exercised when the drug is administered to a nursing woman.104

Pharmacology

Atropine sulfate is a mydriatic and cycloplegic drug. Following topical application to the eye, atropine sulfate blocks the action of acetylcholine resulting in relaxation of the cholinergically innervated sphincter muscle of the iris. Cholinergic stimulation of the accommodative ciliary muscle of the lens is also blocked. Anticholinergic effects of atropine sulfate in the eye produce dilation of the pupil (mydriasis) and paralysis of accommodation (cycloplegia). The mydriatic, but not the cycloplegic, effect of atropine sulfate may be enhanced by concomitant administration of a sympathomimetic agent (e.g., epinephrine).

Atropine sulfate has a slower onset of mydriatic and cycloplegic action and more prolonged ocular effects than most other anticholinergic drugs. The maximum mydriatic effect of atropine sulfate occurs in about 30-40 minutes following topical application to the eye. Maximum cycloplegia occurs in several hours. Mydriasis generally lasts about 7-12 days and cycloplegia persists for up to 14 days or longer. The onset of effect may be slower and the duration more prolonged in individuals with heavily pigmented irides.

Pharmacokinetics

Following topical application to the eye, atropine sulfate is readily absorbed transconjunctivally. Following subconjunctival injection of the drug in rabbits, atropine is distributed throughout the eye with highest concentrations in the cornea and in the vitreous and aqueous humors. In these rabbits, 95% of the dose was excreted in urine within 5 hours. Unlike humans, rabbits have high concentrations of atropine esterase, which readily inactivates the drug. For additional information on the pharmacokinetics of atropine, see 12:08.08.

Chemistry and Stability

Chemistry

Atropine ( dl -hyoscyamine) is a naturally occurring tertiary amine antimuscarinic. Atropine is the prototype of the antimuscarinics. The drug may be prepared synthetically but is usually obtained by extraction from various members of the Solanaceae genus of plants including Atropa belladonna (deadly nightshade), Datura stramonium (Jimson weed), or Duboisia myoporoides.

Atropine is a racemic mixture of d - and l -hyoscyamine, a tertiary amine organic ester formed by combining tropine and tropic acid. It is not clear whether atropine occurs naturally as a racemic mixture in plant tissues or is formed during extraction, a process known to cause racemization. Atropine occurs as white crystals, usually needle-like, or a white, crystalline powder; it is optically inactive, but usually contains a slight excess of l -hyoscyamine. Atropine has solubilities of approximately 2.17 mg/mL in water and 0.5 g/mL in alcohol at 25°C. The drug has a pK_a of 9.8.

Atropine is commercially available as the sulfate salt which occurs as colorless crystals or a white, crystalline powder. Atropine sulfate has solubilities of approximately 2 g/mL in water and 0.2 g/mL in alcohol at 25°C. Atropine sulfate ophthalmic solution is a sterile, aqueous solution of the drug; hydrochloric acid and/or sodium hydroxide may be added to adjust the pH to 3.5-6. The ophthalmic solution may also contain suitable stabilizers and benzalkonium chloride or chlorobutanol as a preservative. Atropine sulfate ophthalmic ointment is a sterile preparation containing the drug in a suitable ophthalmic ointment base (e.g., white petrolatum, mineral oil, nonionic lanolin derivatives, and water). The ophthalmic ointment also may contain a preservative (e.g., chlorobutanol).

Stability

Atropine sulfate effloresces on exposure to air and is slowly affected by light.

Atropine sulfate ophthalmic ointment should be stored in collapsible ophthalmic ointment tubes kept tightly closed and protected from heat at a temperature less than 40°C, preferably between 15-30°C; freezing should be avoided. Atropine sulfate ophthalmic solution should be stored in tight containers at a temperature of 8-27°C, or as specified by the manufacturer; freezing should be avoided.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

100. Merli GJ, Weitz H, Martin JH et al. Cardiac dysrhythmias associated with ophthalmic atropine. Arch Intern Med . 1986; 146:45-7. [PubMed 3942464]

101. Zimmerman CF, Hogan RN, Le TD. Mydriatic and cycloplegic drugs. In: Zimmerman TJ, Kooner KS, Sharir M et al, eds. Textbook of ocular pharmacology. Philadelphia: Lippincott-Raven; 1997:807-26

102. Ellis FD. Cycloplegic agents. In: Zimmerman TJ, Kooner KS, Sharir M et al, eds. Textbook of ocular pharmacology. Philadelphia: Lippincott-Raven; 1997:787-89.

103. American Academy of Ophthalmology Pediatric Ophthalmology/Strabismus Panel. Preferred practic pattern guidelines. Pediatric eye evaluations. San Francisco, CA: American Academy of Ophthalmology; 2007. Available from website. Accessed 2008 Apr 24. [Web]

104. Alcon Pharmaceuticals. Isopto Atropine^® (atropine sulfate) ophthalmic solution prescribing information. Fort Worth, TX; 2003 Aug.