Chrono-Pharmacology Reveals That “When” You Take Your Medication Can Make A Life-Saving Difference

For drugs meant to avert heart attack and stroke, the insights of ‘chronopharmacology’ can make a life-saving difference. Chrono-Pharmacology Reveals That “When” You Take Your Medication Can Make A Life-Saving Difference

Our physiology and biochemistry change profoundly over the course of a 24-hour day, so it’s not surprising that medicines show variable levels of effectiveness depending on when we take them.

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The concept of “chronopharmacology” says that medications and treatments should be delivered at a time of day when they are most needed and most effective. Now researchers are finding that chronopharmacology is especially important in the case of heart attacks and strokes, two of the leading causes of death in the U.S., responsible for almost 900,000 deaths annually.

A stroke occurs when a blood vessel in the brain ruptures and bleeds, or when there’s a blockage in the blood supply to the brain; a heart attack occurs when the supply of blood to the heart is suddenly blocked.

The blockage or rupture of a blood vessel in the brain or heart prevents glucose and oxygen from sustaining these highly metabolically active organs.

Such life-changing events show a circadian variation, meaning that they are more likely to happen at certain times of day. A major review of 31 studies based on 11,816 stroke patients, published in the journal Stroke in 1998, found that there was a 49% increase in the chance of a stroke between 6 a.m. and noon compared with the rest of the day.

A study published in the journal Heart in 2011 documented similar results for heart attacks. Collectively, these data show unambiguously that you are most likely to die from a stroke or heart disease first thing in the morning.

A key contributor to this 6 a.m. to noon “window” in risk and death is the circadian-driven rise in heart rate and blood pressure.

This occurs because the body anticipates the demands of activity in the morning—the switch from sleep to consciousness and an increased need for oxygen and nutrients.

The rise in blood pressure is in large part mediated by the autonomic nervous system, the part of the nervous system responsible for the unconscious control of bodily functions.

Altered behavior, in the form of a major change in activity and posture after waking up, also acts to increase blood pressure.

Increased physical activity is accompanied by physiological changes, including a rise in cortisol, testosterone, insulin and glucose, all of which help drive a higher metabolic rate and increased activity. Raised metabolism requires more oxygen and glucose, and increased blood pressure delivers these essentials.

Significantly, there is also an increase in pro-clotting factors in the blood in the morning, including the activation of platelets.

Platelets normally act to clump together to form blood clots and prevent blood loss following injury. But they can also work against us by producing clots that block blood vessels, resulting in a stroke.

Blood clotting peaks in the morning hours, corresponding to the greatest chance of having a stroke or heart attack. If you are healthy, these dynamic changes are not a problem, but poor health can make them lethal.

Anything that keeps our rhythmic physiology from getting the correct materials in the right place, in the right amount, at the right time of day will increase our health risks.

Sustained night-shift work, jet lag or marked sleep/wake disruption is associated with an increased chance of stroke and heart attack.

The syndrome called SCRD, for sleep and circadian rhythms disruption, is clinically linked to elevated blood pressure and higher triglyceride levels. High triglycerides contribute to the hardening and thickening of the artery walls, which increases the risk of stroke, heart attack and heart disease.

Individuals who have a heart attack during the morning risk window also experience more heart damage and a poorer chance of recovery compared with heart attacks at other times of the day.

German physicians refer to this time period as the Todesstreifen or “death zone,” a word originally used to describe the strong likelihood of death by sniper fire if you entered the buffer zone between West and East Germany.

These daily changes in stroke and cardiovascular risk are now being considered in both the development of new drugs and the delivery of existing medications.

When blood-pressure medications known as antihypertensives are taken before bedtime, rather than in the morning, they are more effective in regulating blood pressure levels and in reducing stroke and heart attack.

In the most extensive study to date, published in the European Heart Journal in 2019, taking antihypertensive medicine at bedtime was associated with both improved blood pressure regulation and a near halving of cardiovascular problems and deaths when compared with morning medication.

Researchers led by Ramón Hermida of the University of Vigo in Spain randomly assigned nearly 20,000 hypertensive individuals with an average age of 60.5 years to take their entire daily dose of one or more anti-hypertensive drugs at bedtime or on waking in the morning. The researchers followed up with the patients annually, performing detailed health checks, for over six years.

Those who took their antihypertensives in the evening nearly halved their risk of cardiovascular death, including heart failure and stroke.

Why take antihypertension medication at night if the danger is most acute in the morning? The answer relates to how the drugs are absorbed and distributed in the body, metabolized, and then finally broken down and excreted. These processes take time.

Taking antihypertensive medication at bedtime means that the drug levels rise and remain in the body at relatively high levels, acting to reduce blood pressure across the time window when the sharp rise in blood pressure normally occurs, between 6 a.m. and noon.

If antihypertensive medication is taken in the morning, drug effectiveness will have risen and then peaked after the critical surge in blood pressure.

Evening also appears to be the best time to take aspirin, which “thins the blood” by inhibiting pro-clotting factors and reducing platelet activation. Aspirin levels in the blood rise rapidly when the medicine is taken and then decline fairly quickly, within a few hours.

So how does bedtime aspirin reduce platelet “stickiness” in the morning? It prevents platelets from clumping together to form clots for the lifetime of the platelet, which is around 10 days: Platelets are permanently “turned off” after exposure to aspirin.

A hundred billion new platelets are made freshly each day, and they are made in the evening. Taking aspirin in the evening thus ensures that new platelets will be effectively deactivated before the dangerous window for stroke the following morning.

There is a downside to taking these medicines in the evening. Taking aspirin before bed may increase the chances of damaging the stomach or intestinal lining, leading to the development of ulcers that can bleed or perforate. But the use of proton-pump inhibitors (PPIs) and drugs that protect the gastrointestinal system can resolve this problem.

As for antihypertensives, some are diuretics that stimulate the kidneys to remove water and salt from the blood into the urine. This reduces blood pressure but increases urine production, making it necessary to go to the bathroom more at night.

Currently, there are no formal guidelines regarding when patients should take blood pressure tablets, vitamin supplements or aspirin. New studies are under way in an attempt to support the findings of Dr. Hermida and colleagues. If confirmed, they will provide important guidance for general practitioners.

Chrono-Pharmacology Reveals That “When” You Take Your Medication Can Make A Life-Saving Difference

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