More evidence has been discovered by CU Anschutz researchers to back up the idea that timing is important when giving drugs.
According to a study conducted by researchers at the University of Colorado Anschutz Medical Campus, a popular drug that makes patients sleepy and less anxious before surgery is associated with an increased risk of heart damage when surgeries are performed at night.
The results provide further proof that a drug’s effectiveness might vary depending on the time it is administered.
“We performed a large dataset analysis and demonstrated that administering midazolam is associated with an increased risk of myocardial injury in non-cardiac surgery when surgeries occurred at night and in healthier patients,” said the study’s senior author Tobias Eckle, MD, Ph.D., professor of anesthesiology at the University of Colorado School of Medicine. “This is significant because these findings could have tremendous implications for patient mortality.”
The findings were recently published in the journal Frontiers of Cardiovascular Medicine.
Eckle is one of a select group of experts in chronotherapy, the practice of giving drugs at specific times of day to better align with circadian rhythms. Previous research conducted by him has shown that intense light can aid in the healing of damaged hearts and that certain proteins that are favorable to health are expressed more strongly at certain times of the day.
In this study, researchers used the vast Multicenter Perioperative Outcomes Group to evaluate 1,773,118 instances in which the sedative midazolam was given to 951,345 patients.
16,404 of the patients satisfied the criteria for myocardial injury (MINS). Although there was no connection between giving the drug and the risk of heart damage in the overall study population, researchers determined that the time the drug was administered was significant.
“We found a strong association between midazolam administration and risk of MINS when surgery occurred at night or with healthier patients,” said Eckle.
The reasons are unclear but may lie within the PER2 gene, a light-regulated protein that Eckle said helps protect the heart from injury. In mouse studies, investigators found a link between midazolam, circadian protein expression, and heart ischemia.
“That suggests midazolam interferes with the circadian system in humans,” Eckle said.
The drug increases the neurotransmitter GABA which inhibits certain brain signals to produce a calming effect. That in turn can lessen the expression of higher nighttime levels of PER2. As the levels decrease, the heart may become more susceptible to injury when the midazolam is given at night rather than during the day.
“This is the major focus of chronotherapy. Drugs can have different effects depending on when they are given,” Eckle said. “If you separate day and night there is a huge effect. For example, maybe we should not give anyone midazolam at night if it increases the risks of myocardial infarcts.”
Eckle said the entire field of chronotherapy is understudied and may hold clues to more effective use of routine therapies. He believes new drugs should be tested for the best time of day to be used. Blood pressure drugs, for example, tend to work best at night.
“Drugs are often administered according to what’s most efficient,” he said. “But what is most efficient, may in the end cause damage.”
Reference: “Time-of-day dependent effects of midazolam administration on myocardial injury in non-cardiac surgery” by Meghan Prin, Jack Pattee, David J. Douin, Benjamin K. Scott, Adit A. Ginde and Tobias Eckle, 28 October 2022, Frontiers in Cardiovascular Medicine.