Ophthalmic Atropine Research Articles

Compounded 0.01% Atropine-What's in the Bottle?

To describe the labeling, packaging practices, and characteristics of compounded 0.01% ophthalmic atropine. A convenience sample of parents of children who had previously been prescribed low-concentration atropine for myopia management were randomized to obtain 0.01% atropine ophthalmic solution from one of nine compounding pharmacies. The products were analyzed for various important quality attributes. The main outcomes were labeling practices, concentration of atropine and degradant product tropic acid, pH, osmolarity, viscosity, and excipients in 0.01% atropine samples obtained from nine US compounding pharmacies. Twenty-four samples from nine pharmacies were analyzed. The median bottle size was 10 mL (range 3.5-15 mL), and eight of nine pharmacies used clear plastic bottles. Storage recommendations varied and were evenly split between refrigeration (33%), room temperature (33%), and cool, dark, dry location (33%). Beyond use dates ranged from 7 to 175 days (median, 91 days). Median pH of samples was 7.1 (range, 5.5-7.8). Median measured concentration relative to the prescribed concentration was 93.3% (70.4%-104.1%). One quarter of samples were under the 90% minimum target concentration of 0.01%. An inconsistent and wide variety of formulation and labeling practices exist for compounding 0.01% atropine prescribed to slow pediatric myopia progression.

Validation of a preclinical dry eye model in New Zealand white rabbits during and following topical instillation of 1% ophthalmic atropine sulfate.

BackgroundThe objective of this study was to validate an animal model for dry eye during and after the administration of 1% ophthalmic atropine sulfate (OAS) in New Zealand white (NZW) rabbits.MethodsOAS (1%) was applied three times per day to 30 eyes of 15 healthy NZW rabbits. Sacrifice, enucleation, and lacrimal gland removal took place on days 15, 21, and 30 (OAS group). A second group (n = 5) was used as control. Clinical evaluations took place on days 3, 10, 15, 18, 21, 24 and 30. The primary endpoints were: Schirmer I test, tear break‐up time (TBUT), and corneal fluorescein staining. As secondary endpoints, clinical changes including intraocular pressure, and histopathology were evaluated.ResultsWhile OAS was administered, the Schirmer I test showed a statistically significant reduction for OAS group versus control (p < 0.001), and versus basal production (p < 0.001). TBUT showed statistically significant differences between groups (days 3 and 10; p = 0.001) and versus basal values (day 3; p < 0.001). Fluorescein staining showed a statistically significant difference (day 3; p = 0.001). The most frequent clinical finding was conjunctival hyperemia (76.9% OAS vs. 20% control). For histopathology, all OAS subjects presented some degree of inflammation (86.7% minimal; 13.3% mild) whereas the control presented only 30% minimal inflammation. Goblet cell density showed no difference.ConclusionsThe effectiveness of the OAS dry eye model in NZW rabbits as reported in previous studies was confirmed, provided that the application of the drug is maintained throughout the intervention; it is not a viable model after OAS administration is suspended.

Topical ophthalmic atropine in horses, pharmacokinetics and effect on intestinal motility

BackgroundTopical ophthalmic atropine sulfate is an important part of the treatment protocol in equine uveitis. Frequent administration of topical atropine may cause decreased intestinal motility and colic in horses due to systemic exposure. Atropine pharmacokinetics are unknown in horses and this knowledge gap could impede the use of atropine because of the presumed risk of unwanted effects. Additional information could therefore increase safety in atropine treatment.ResultsAtropine sulfate (1 mg) was administered in two experiments: In part I, atropine sulfate was administered intravenously and topically (manually as eye drops and through a subpalpebral lavage system) to six horses to document atropine disposition. Blood-samples were collected regularly and plasma was analyzed for atropine using UHPLC-MS/MS. Atropine plasma concentration was below lower limit of quantification (0.05 μg/L) within five hours, after both topical and IV administration. Atropine data were analyzed by means of population compartmental modeling and pharmacokinetic parameters estimated. The typical value was 1.7 L/kg for the steady-state volume of distribution. Total plasma clearance was 1.9 L/h‧kg. The bioavailability after administration of an ophthalmic preparation as an eye drop or topical infusion were 69 and 68%, respectively. The terminal half-life was short (0.8 h). In part II, topical ophthalmic atropine sulfate and control treatment was administered to four horses in two dosing regimens to assess the effect on gastro-intestinal motility. Borborygmi-frequency monitored by auscultation was used for estimation of gut motility. A statistically significant decrease in intestinal motility was observed after administration of 1 mg topical ophthalmic atropine sulfate every three hours compared to control, but not after administration every six hours. Clinical signs of colic were not observed under any of the treatment protocols.ConclusionsTaking the plasma exposure after topical administration into consideration, data and simulations indicate that eye drops administrated at a one and three hour interval will lead to atropine accumulation in plasma over 24 h but that a six hour interval allows total washout of atropine between two topical administrations. If constant corneal and conjunctival atropine exposure is required, a topical constant rate infusion at 5 μg/kg/24 h offers a safe alternative.

Atropine-induced toxicity after off-label sublingual administration of eyedrop for sialorrhoea treatment in neurological disabled patients.

Sialorrhea is a troublesome and disabling symptom defined by the unintentional loss of saliva from the mouth, usually associated with swallowing disorders. Today there is no consensus about the management of sialorrhoea, but off-label use of ophthalmic atropine eyedrop administered sublingually may offer benefits, despite limited safety data. We report 2 cases of atropine overdose after sublingual administration illustrating that atropine can expose to severe adverse effects when administered sublingually. The noncompartmental pharmacokinetic study of atropine performed in 1 patient highlighted that systemic absorption of sublingual atropine was effective (Cmax [1 h] = 2.2 ng mL-1 ; approximately) after a single dose of 1 mg.

Stability of Ophthalmic Atropine Solutions for Child Myopia Control.

Myopia is an ophthalmic condition affecting more than 1/5th of the world population, especially children. Low-dose atropine eyedrops have been shown to limit myopia evolution during treatment. However, there are currently no commercial industrial forms available and there is little data published concerning the stability of medications prepared by compounding pharmacies. The objective of this study was to evaluate the stability of two 0.1 mg/mL atropine formulations (with and without antimicrobiobial preservatives) for 6 months in two different low-density polyethylene (LDPE) multidose eyedroppers. Analyses used were the following: visual inspection, turbidity, chromaticity measurements, osmolality and pH measurements, atropine quantification by a stability-indicating liquid chromatography method, breakdown product research, and sterility assay. In an in-use study, atropine quantification was also performed on the drops emitted from the multidose eyedroppers. All tested parameters remained stable during the 6 months period, with atropine concentrations above 94.7% of initial concentration. A breakdown product (tropic acid) did increase slowly over time but remained well below usually admitted concentrations. Atropine concentrations remained stable during the in-use study. Both formulations of 0.1 mg/mL of atropine (with and without antimicrobial preservative) were proved to be physicochemically stable for 6 months at 25 °C when stored in LDPE bottles, with an identical microbial shelf-life.

Eye Injury- Baseball

HISTORY: A 12 year-old male sustained an injury to left eye during a baseball game. While playing first base, the outfielder threw a ball to him so patient could tag the runner out. When catching the ball, he missed, and instead the ball struck him in the face in the area of the left eye. There was no loss of consciousness, vomiting, hematoma or altered mental status. He initially had difficulty seeing out of the eye, but vision returned soon after and appeared blurry. PHYSICAL EXAMINATION: Normocephalic. With the exception of limitation in upward gaze of left eye, the remaining extraocular movements were intact. Hyphema of left eye noted. Pupils equal, round and reactive to light bilaterally. Moderate left periorbital edema and ecchymosis. Vision intact to left eye. Sensation intact in V1-V3 distribution, facial nerve function intact bilaterally. Normal occlusion, midface stable. Hearing to spoken voice intact and TM’s clear with no evidence of hemotympanum. Remainder of examination was normal. DIFFERENTIAL DIAGNOSIS: 1. Orbital Ridge Fracture 2. Orbital Blowout Fracture 3. Hyphema 4. Retinal detachment 5. Commotio Retinae 6. Globe Rupture TEST AND RESULTS: CT facial bones: -Blowout fracture of left inferior and medial wall of left orbit -Left orbital emphysema with small contusion vs hematoma within the retrobulbar fat -Minimal blood within the left ethmoid and maxillary sinus Ophthalmology Consult: -Visual Acuity 20/30 Right, 20/200 Left -3 mm Hyphema of left eye -Commotio Retinae of left macula -Normal intraocular pressure FINAL/WORKING DIAGNOSIS: Left orbital floor fracture, Traumatic Hyphema, Commotio Retinae involving the macula TREATMENT AND OUTCOMES: 1. CT scan without significant displacement and no ocular muscle entrapment on repeat exam, no operative repair needed; follow-up with plastic surgery 1-2 weeks 2.Per ophthalmology recommendations: a. Ongoing observation for cataract, retinal detachment, and glaucoma due to increased risk from blunt ocular trauma b. Bed rest with bathroom privileges 3-4 days c. Ophthalmic prednisolone and ophthalmic atropine for hyphema with monitoring for absorption and rebleed d. Monitor for macular hole as increased risk secondary to commotio retinae e. Follow-up in 1-2 days

Case 2: Feeding Intolerance Following Topical Atropine Instillation in a Premature Infant

An extremely low-birthweight female newborn, weighing 545 g, is born at 23 weeks of gestation via cesarean section. Following a pregnancy complicated by preterm labor with prolonged rupture of membranes and positive maternal group B Streptococcus status, the newborn requires positive pressure ventilation, chest compressions, intubation, and surfactant administration in the delivery room. After initial stabilization, she is admitted to the NICU. She receives continuous positive pressure ventilation on day 37 after birth and is ultimately weaned to room air. She initially receives enteral feeds with breast milk and gradually advances to full enteral feeds by day 40 after birth. Within a week of tolerating full enteral feeds, she makes a transition to 24 kcal/oz of formula because of insufficient maternal breast milk supply. Her eyes are regularly screened for retinopathy of prematurity (ROP) from 31 weeks’ postmenstrual age (PMA). Before each ROP screening, she receives cyclopentolate/phenylephrine and proparacaine ophthalmic eye drops. Her initial eye examination reveals bilateral zone 1 stage 1 ROP. After the diagnosis of bilateral zone 2 stage 3 ROP with plus disease is made at PMA of 36 weeks, she is successfully treated with laser ablation therapy to the peripheral avascular retina of both eyes after a brief period of having nothing orally for 4 hours. Her enteral feeds are resumed later on the same day after laser surgery. She is subsequently started on daily ophthalmic 0.5% atropine drops and tobramycin/dexamethasone ophthalmic drops 4 times a day. On postoperative day 1, she is noted to have tachycardia with pulses ranging from 190 to 200 beats/min 1 hour after ophthalmic atropine is applied. She continues to have intermittent tachycardia, but enteral feeds are continued as she continues to have normal physical examination …

Physostigmine Reversal of Dysarthria and Delirium After Iatrogenic Atropine Overdose From a Dental Procedure

BackgroundSublingual atropine, dosed at 0.4–0.8 mg, is used by dentists as an antisialogogue to facilitate and increase the speed of procedures. Concentrated ophthalmic atropine drops (10 mg/mL) are commonly used off-label for this purpose. These highly concentrated drops may result in medication errors, atropine toxicity, and the antimuscarinic toxidrome. We report a case of a man who suffered acute delirium and dysarthria (from dry mouth) after an iatrogenic overdose from a dental procedure. His symptoms were initially interpreted as a stroke, but they completely resolved with physostigmine. Case ReportA 57-year-old man presented with acute dysarthria and delirium after a dental procedure; 4 hours earlier he was fitted for a temporary replacement of some premolar/molar teeth. He received sublingual atropine to assist in gingival drying for molding of his prosthesis, but a calculation error resulted in the administration of approximately 113 mg. A stroke evaluation was initially planned; however, 2.5 mg of intravenous physostigmine completely reversed his symptoms. His symptoms reoccurred and were successfully treated twice more with physostigmine; the patient was observed overnight with no additional symptoms and safely discharged the next morning. Why Should an Emergency Physician be Aware of This?Ophthalmic atropine drops are highly concentrated and may cause an overdose after ingestion of small amounts. This novel case highlights the importance of considering antimuscarinic poisoning in cases of acute delirium or dysarthria after dental procedures and stands as a reminder to inquire about the use of atropine drops in such cases. Timely recognition of the antimuscarinic toxidrome and appropriate use of physostigmine may prevent unnecessary testing while providing an effective therapy. This case also highlights the need for observation after resolution of delirium treated with physostigmine.

Can ocular administration of atropine cause colic?

Can ocular administration of atropine cause colic?

Ophthalmic atropine for sublingual use: A novel treatment for excessive respiratory secretions

We describe a novel case of utilizing ophthalmic atropine suspension via sublingual route to control excessive secretions in a critically ill patient. In addition, a medication event related to a labeling and administration event is described where the patient received the drug via ophthalmic route. A 32-year-old Hispanic female presenting with NMDA-receptor antibody mediated encephalitis experienced a prolonged intensive care unit (ICU) stay secondary to hypercarbic respiratory failure complicated by excessive respiratory secretions. After one week on mechanical ventilation, the patient was set to undergo a percutaneous endoscopic gastrostomy (PEG) tube placement and tracheotomy. The patient’s respiratory status was compromised by copious secretion production, preventing the patient from being transitioned to the general care floor. For secretion control, pharmacological interventions such as scopolamine transdermal patches and glycopyrrolate oral tablets were trialed, however systemic exposure to these agents resulted in urinary retention requiring catherization with a mild and persistent tachycardia. Ophthalmic atropine was administered sublingually at a dose of 1 mg every six hours to provide local relief of the patient's secretion production. Secretion production improved within 72 hours and the patient’s urinary retention resolved at the time of scopolamine and glycopyrrolate discontinuation. Previously in the literature the use of sublingual atropine was only described for secretion control in patients receiving end of life care, drug induced sialorrhea and neuro-developmental disorders. As observed in this case report, sublingual atropine may be an effective treatment to control respiratory secretions in critically ill patients who are unable to tolerate other therapies.

The effect of topical ophthalmic 1% atropine on heart rate and rhythm in normal dogs

To determine if topically administered ophthalmic atropine affects heart rate or rhythm in clinically normal dogs. Two groups of 15 healthy dogs were evaluated, one consisting of dogs weighing <15 kg, the other consisting of dogs weighing >15 kg. Each dog was suited with a Holter monitor. At start time 0, dogs received one drop of ophthalmic 1% atropine solution, or one drop of sterile saline solution as a control in each eye, via random assignment. Each dog served as their own control. This procedure was repeated two more times, at 6-h intervals, for a total of three treatments over a 12-h period. Holter monitors recorded heart rate and rhythm for 24 h. Statistical analysis was performed to compare values between the groups. Dose dependent changes in cardiac parameters were evaluated. The mean heart rate and average minimum heart rate was significantly higher during the treatment period compared to the control period (8% and 13%, respectively). The mean number of hours with a heart rate <50 bpm decreased by 47% in the treatment vs. the control period. The mean maximum heart rate and number of h with a heart rate > 180 bpm did not differ significantly between the two groups. There was no evidence of dose dependence on heart rate when comparing small and large dogs. No significant differences in heart rhythm were noted between groups for measurable parameters. Topically administered atropine causes a small but significant increase in heart rate in healthy dogs.

Pharmaceutical intervention for myopia control

Myopia is the result of a mismatch between the optical power and the length of the eye, with the latter being too long. Driving the research in this field is the need to develop myopia treatments that can limit axial elongation. When axial elongation is excessive, as in high myopia, there is an increased risk of visual impairment and blindness due to ensuing pathologies such as retinal detachments. This article covers both clinical studies involving myopic children, and studies involving animal models for myopia. Atropine, a nonselective muscarinic antagonist, has been studied most extensively in both contexts. Because it remains the only drug used in a clinical setting, it is a major focus of the first part of this article, which also covers the many shortcomings of topical ophthalmic atropine. The second part of this article focuses on in vitro and animal-based drug studies, which encompass a range of drug targets including the retina, retinal pigment epithelium and sclera. While the latter studies have contributed to a better understanding of how eye growth is regulated, no new antimyopia drug treatments have reached the clinical setting. Less conservative approaches in research, and in particular, the exploration of new bioengineering approaches for drug delivery, are needed to advance this field.

Sublingual Atropine Drops for the Treatment of Pediatric Sialorrhea

Excess oral secretions or sialorrhea is a common problem affecting children and adults with neurological disorders, as well as those approaching the end of life because of a variety of underlying illnesses. Systemic anticholinergic medications are often prescribed in an attempt to improve quality of life and reduce complications; yet, response rates are variable, and a sizable proportion of patients discontinue these drugs as a result of intolerable side effects. This report describes the successful use of a local treatment, sublingually delivered ophthalmic atropine drops, to reduce sialorrhea in a child receiving palliative care. In addition, medical evidence for the safety and efficacy of traditionally prescribed systemic medications for the treatment of pediatric sialorrhea is reviewed.

Pretreating Rats with Parenteral Ophthalmic Antimuscarinic Agents Decreases Mortality from Lethal Organophosphate Poisoning

In the event of a large scale organophosphate (OP) or nerve agent exposure that depletes a hospital's atropine stores, alternative antidotes should be considered. To test the effects of parenteral administration of ophthalmic antimuscarinic agents on survivability in a rat model of acute, lethal OP poisoning. After determining appropriate dosing for comparison, rodents were randomized to receive one of four intraperitoneal antidotes (n = 10 per group): 1) normal saline (0.3 mL), 2) atropine sulfate (10 mg/kg), 3) ophthalmic atropine sulfate (1%; 10 mg/kg), or 4) ophthalmic homatropine (5%; 20 mg/kg). Five minutes after pretreatment, dichlorvos (10 mg/kg) was administered subcutaneously. Mortality rates and time to death were compared by using Fisher's exact test and the Kaplan-Meier method with log rank test, respectively. If the animal was alive at 120 minutes, survival was assumed. Survival in rats pretreated with standard atropine was 100%. Survival in rats pretreated with ophthalmic homatropine and atropine sulfate were 100% (p < 0.001; 95% CI = 0.98 to 1.02) and 90% (p < 0.01; 95% CI = 0.71 to 1.09), respectively, compared with controls (20% survival; 95% CI = 0.04 to 0.45). Time of death ranged between 7 and 19 minutes. Comparison of survival times revealed a statistically significant improvement in experimental groups compared with controls (p < 0.0001). Parenteral pretreatment with ophthalmic preparations of homatropine or atropine sulfate was equal to standard atropine in preventing lethality in this rat model of acute, lethal OP poisoning.

Systemic effects of topical and subconjunctival ophthalmic atropine in the horse

Abstract Objective To identify any systemic effects of topical and subconjunctival administration of atropine sulfate in the horse. Animals studied Six mature grade horses were treated hourly in one eye with topical ophthalmic atropine drops for 24 h. Five horses were treated subconjunctivally in one eye with 3 mg of atropine sulfate. Procedures Pupillary light reflexes, pupil size, electrocardiographic parameters, girth measurements, intestinal motility, and clinical signs of abdominal pain were monitored. Results Alteration in ausculated gut motility and clinical signs of abdominal pain were the most sensitive indicators of the systemic manifestations of the topically applied atropine. Gut motility was absent in all horses for periods of 2–18 h in all four abdominal quadrants in horses given topically administrated atropine. Sings of abdominal pain were observed in four of six horses that received topical atropine. In the subconjunctival test study, gut motility was absent in three horses for periods of 3–7 h. Uniocular subconjunctival injection of 3 mg atropine sulfate produced signs of abdominal pain in one of six horses. Conclusion The ophthalmic administration of atropine can affect gut motility and induce signs of colic in selected horses.

Systemic effects of topical and subconjunctival ophthalmic atropine in the horse

OBJECTIVE: To identify any systemic effects of topical and subconjunctival administration of atropine sulfate in the horse. Animals studied Six mature grade horses were treated hourly in one eye with topical ophthalmic atropine drops for 24 h. Five horses were treated subconjunctivally in one eye with 3 mg of atropine sulfate. Procedures Pupillary light reflexes, pupil size, electrocardiographic parameters, girth measurements, intestinal motility, and clinical signs of abdominal pain were monitored. RESULTS: Alteration in auscultated gut motility and clinical signs of abdominal pain were the most sensitive indicators of the systemic manifestations of the topically applied atropine. Gut motility was absent in all horses for periods of 2-18 h in all four abdominal quadrants in horses given topically administered atropine. Signs of abdominal pain were observed in four of six horses that received topical atropine. In the subconjunctival test study, gut motility was absent in three horses for periods of 3-7 h. Uniocular subconjunctival injection of 3 mg atropine sulfate produced signs of abdominal pain in one of six horses. Conclusion The ophthalmic administration of atropine can affect gut motility and induce signs of colic in selected horses.

Effect of topical 1% atropine sulfate on intraocular pressure in normal horses

Abstract Objective To determine the effect of topical 1% ophthalmic atropine sulfate on intraocular pressure (IOP) in ocular normotensive horses. Animals Studied Eleven clinically healthy horses. Procedures IOP was measured bilaterally twice daily, at 8 am and 4 pm, for 5 days. No medication was applied for the first 2 days of the study. Thereafter, one eye of each horse was treated with 0.1 mL of topical 1% atropine sulfate ointment twice daily (7 am and 7 pm) for 3 days. The contralateral eye served as a control. In eight of the horses, an additional IOP reading was taken 3 days following cessation of the atropine treatment. Results There was no significant difference in the IOP of control vs. treatment eyes in the pretreatment period, days 1 and 2 (P= 0.97 and 0.55, respectively). During the treatment period, treated eyes of 10 of the horses had significantly lower IOP than control eyes (P= 0.03). The mean IOP reduction in treated eyes, relative to untreated eyes, was 11.2%. One horse had a significant rise in IOP in the treated eye compared to the remaining study animals. The IOP of control eyes did not vary significantly over the observation period (P= 0.27). There was no significant variation in IOP between the 8 am and 4 pm measurement (P= 0.9). Conclusions Topical 1% atropine sulfate causes a small, but significant decline in IOP in most ocular normotensive horses. Because topical atropine may elevate IOP in some horses, it should be used with caution in the treatment of glaucoma in this species.

Effect of topical 1% atropine sulfate on intraocular pressure in normal horses.

OBJECTIVE: To determine the effect of topical 1% ophthalmic atropine sulfate on intraocular pressure (IOP) in ocular normotensive horses. Animals Studied Eleven clinically healthy horses. Procedures IOP was measured bilaterally twice daily, at 8 AM and 4 PM, for 5 days. No medication was applied for the first 2 days of the study. Thereafter, one eye of each horse was treated with 0.1 mL of topical 1% atropine sulfate ointment twice daily (7 AM and 7 PM) for 3 days. The contralateral eye served as a control. In eight of the horses, an additional IOP reading was taken 3 days following cessation of the atropine treatment. RESULTS: There was no significant difference in the IOP of control vs. treatment eyes in the pretreatment period, days 1 and 2 (P = 0.97 and 0.55, respectively). During the treatment period, treated eyes of 10 of the horses had significantly lower IOP than control eyes (P = 0.03). The mean IOP reduction in treated eyes, relative to untreated eyes, was 11.2%. One horse had a significant rise in IOP in the treated eye compared to the remaining study animals. The IOP of control eyes did not vary significantly over the observation period (P = 0.27). There was no significant variation in IOP between the 8 AM and 4 PM measurement (P = 0.9). CONCLUSIONS: Topical 1% atropine sulfate causes a small, but significant decline in IOP in most ocular normotensive horses. Because topical atropine may elevate IOP in some horses, it should be used with caution in the treatment of glaucoma in this species.

Anticholinergic visual hallucinosis from atropine eye drops

A 37-year-old man with type I diabetes mellitus and chronic renal failure presented to the emergency department complaining of hallucinations. He was 5 days postoperative for left pars plana vitrectomy and intra-ocular lens implantation and had been taking ophthalmic atropine, tobramycin and prednisolone. He had presented 5 months earlier, on the same ophthalmic medications, with postoperative hallucinations after a right pars plana vitrectomy. Visual hallucinations are a major side effect of anticholinergic poisoning. Ophthalmic instillation of atropine has been documented to cause many central nervous sytstem symptoms, including hallucinations.

Ophthalmic atropine in horses: is colic a serious problem?

Ophthalmic atropine in horses: is colic a serious problem?