Understanding medication circadian efficacy could improve care

By Cheryl Guttman Krader

Knowledge about the circadian pattern of IOP and the 24-hour efficacy of glaucoma medications is increasing and is expected to contribute to better medical management of glaucoma in the future, reported Sunita Radhakrishnan, MD.

Sunita Radhakrishnan, MD, said ophthalmologists need to consider that the results of circadian IOP studies are conducted under rigorous conditions, so the results may not be applicable to the average patient. (Photo by Stevan Nordstrom)

“IOP is not a static parameter and glaucoma is not a 9-to-5 disease,” said Dr. Radhakrishnan, who is in private practice at the Glaucoma Center of San Francisco. “However, we typically assess IOP in our patients by measuring it only in the daytime and at best during a handful of visits throughout the year.

“This approach seems to be adequate for many patients, since glaucoma progression is typically very slow,” Dr. Radhakrishnan explained. “However, more often than not, clinicians are confronted with cases that bring to light how little data we actually have to guide our management decisions. In the future, technology for self-tonometry and 24-hour IOP-monitoring may be used to obtain information on individual IOP circadian patterns and response to intervention in order to guide our decisions on patient care.”

Research conducted at specialized sleep laboratories has provided information demonstrating that IOP varies depending on time of day and body position. The results of these studies show that IOP is higher during the night than during the day and when subjects are in a supine versus upright (lying down versus sitting) position. However, while the change in body position is an important contributor to the nocturnal rise in IOP, it does not explain the entire increase, Dr. Radhakrishnan said.

24-hour efficacy of IOP meds

The research has also generated information about the 24-hour efficacy of IOP-lowering medications. Results from multiple studies show the prostaglandin analogues are effective in reducing IOP during the day and at night, and a study comparing bimatoprost, latanoprost, and travoprost found no statistically significant differences between the three prostaglandin analogues in their 24-hour efficacy.

In contrast, studies investigating beta-blockers found they were effective in lowering IOP during the day but not at night. The finding is consistent with the fact that aqueous humor production, which is inhibited by beta-blockers, is already decreased during the night.

Like the beta-blockers, the alpha-agonist brimonidine was also shown to reduce IOP during the daytime only, whereas the carbonic anhydrase inhibitors dorzolamide and brinzolamide demonstrated efficacy for lowering IOP during the day and at night.

“The beta-blockers, carbonic anhydrase inhibitors, and alpha-agonists have all been shown to be effective for additional IOP-lowering when added to a prostaglandin analogue,” noted Dr. Radhakrishnan. “However, in most of the studies investigating adjunctive therapy, IOP was measured only during the day.

“In one 24-hour IOP study, evaluating the effect of adjunct treatment in patients receiving latanoprost, nocturnal IOP was lower in patients treated with brinzolamide 3 times a day compared with timolol every morning,” Dr. Radhakrishnan said. “In another study, both dorzolamide and brimonidine seemed to perform well when either was used twice daily in addition to a prostaglandin analogue.”

Translating to the real world

When trying to apply the findings from these studies to clinical practice, ophthalmologists need to consider that the circadian IOP studies are conducted under rigorous conditions, and so the results may not be applicable to the average patient. Furthermore, in some studies, the carbonic anhydrase inhibitors and brimonidine were administered three times daily rather than on the twice-daily schedule that is often prescribed for patients.

However, the most basic issue to consider is the lack of understanding about the clinical relevance of avoiding nocturnal IOP elevations.

“It makes intuitive sense to decrease IOP around the clock,” Dr. Radhakrishnan explained. “However, it remains to be determined what role nocturnal IOP elevation has on the onset or progression of glaucoma.”

In addition, the goal of achieving 24-hour IOP control must be considered in the context of several other factors. “Although it seems ideal to achieve diurnal and nocturnal IOP-lowering for every patient, there is no ‘one-size-fits-all’ algorithm for managing glaucoma,” Dr. Radhakrishnan said. “Treatment decisions need to be individualized taking into account safety, tolerability, efficacy, and cost.”