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

Abstract

Background Topical 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. Results Atropine 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. Conclusions Taking 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.

Plasma atropine concentrations associated with decreased intestinal motility in horses

“…Borborygmi frequency has commonly been used to evaluate the equine abdomen both clinically and in experimental pharmacological studies (12-17). Borborygmi response decreased after atropine administration compared with both control treatment and 0 h, similar to what has been described in several previous studies (3,5,8,10). The measurement of borborygmi response is subjective.…”

“…The precision (relative standard deviation) was in the range of 2.1-8.3% and the recovery was 95.5-98%. The analytical method is thoroughly described in Ström et al's work (5).…”

“…The fitted PK model was adapted for extravascular administration by adding an absorption compartment. The parameter values for the absorption rate constant (k a , 5.95 h −1 ) and bioavailability (F, 0.69) were collected from Ström et al (5). The simulated atropine doses were 1.67 and 0.67 µg/kg representing 0.1 and 0.04 ml of 1% atropine sulfate solution to a 500 kg horse, respectively.…”

“…If the drug was administered every 6 h instead, clinical signs of abdominal pain were absent, suggesting a difference in systemic atropine exposure between the two dosing regimens (4). Recently, pharmacokinetic modeling and simulation indicated a short atropine plasma terminal half-life and suggested a complete washout from the circulation between administrations in the 6h protocol (5). In contrast, simulations predicted accumulation of atropine for the 1 mg per h dosing regimen.…”

Highlights of recent clinically relevant papers

“…This study by Lena Ström and co‐workers in Sweden, France and the UK investigated the administration of topical ophthalmic atropine in horses, including the pharmacokinetics and effect on intestinal motility .…”