When you take the aspirin also matters

There is a developing field of circadian physiology/chronobiology/chronotherapeutics finding dramatic differences in gene expression at different times of the day and quite variable differences in drug function depending on when these drugs are taken. A recent blog looked at concerns about aspirin dosing and its effectiveness in cardiac protection (seehttp://gmodestmedblogs.blogspot.com/2018/07/aspirin-one-dose-does-not-fit-all.html​ ). In looking at some of this literature, I was struck by a not-so-frequently-looked-at issue, the timing of aspirin taking.

-- In brief,

    -- transcription factors stimulate genes to make proteins by attaching directly to the DNA

    -- there exist “clock proteins”(eg CLOCK, which stands for Circadian Locomotor Output Cycles Kaput (!!), and BMAL1), present in almost all cells in the body, which vary in their quantity depending on the time of day (circadian rhythm), and seem to be the major activators of transcription

    -- a very large percentage of genes may well be turned on or off depending on circadian rhythms

    -- animal studies of the frequency of proteins with circadian rhythm:

        --more than 80% of cyanobacteria genes are produced according to a specific circadian rhythm (not so surprising given that they are photosynthetic bacteria)

        -- 43% of 20,000 mouse genes are expressed variably during the day, largely just before dawn and just before dusk

        --And, 82% of genes in baboons have daily rhythms, as found from sampling genes from 64 tissues, including 22 brain regions, noting rhythmic expression in a tissue-specific manner (see doi.org/10.1126/science.aao0318)

Effects of circadian rhythm on drug metabolism in humans and comments:

-- aspirin (see aspirin chronotherapy systemreviews2015 in dropbox, or DOI 10.1186/s13643-015-0078-3):

    -- the half-life of aspirin in circulating blood is short, with the peak level 3.5 to 4 hours after intake

    -- we know that the benefit of aspirin varies significantly from person-to-person

    -- there are studies suggesting that accelerated platelet function recovery after aspirin might play a role in this variability

    -- acute myocardial infarctions, strokes, sudden cardiac death, ruptured aortic aneurysms frequently occur in the morning hours (between 6 and 12 AM) when platelet aggregability is highest

    --a recent systematic review cited several observations (see aspirin better at night kardiochirugia2018 in dropbox, or DOI: https://doi.org/10.5114/kitp.2018.76479):

        --aspirin seems to have both COX-1 dependent (inhibition of cyclooxygenase/increase of prostacyclin) and non-COX-1 dependent (effect on improving endothelial function/activation of nitric oxide synthetase and production of platelet nitric oxide)

        --there are several studies finding that nocturnal (vs morning dosing) of low-dose aspirin leads to decreases in blood pressure, on the order of 6/4 mmHg, suggesting a shorter-term effect on endothelial function

        --a randomized cross-over trial found evening vs morning dose of aspirin had beneficial effects on platelet aggregation

    --all of this suggests that evening dosing may be  more beneficial, and raises the further question of the potential benefit of split-doses of aspirin

--statins:

    --the short half-life statins should be taken at night, since cholesterol synthesis peaks during sleep, and the documented effects of them on lipids is greatest. This does not apply to the long-acting statins, such as atorvastatin

--hypertension:

    --2 studies found that taking antihypertensives at night led to lower risk of diabetes (see https://blogs.bmj.com/bmjebmspotlight/2015/10/14/primary-care-corner-with-geoffrey-modest-md-take-blood-pressure-meds-at-night-to-prevent-diabetes/ ). Most patients were on ACE-I/ARBs (which have shorter half-lives, though are typically taken once a day)

    --many drugs have been studied in animals, finding, for example:

        --nifedipine has better bioavailability in the morning

        -- propranolol is better absorbed after a morning dose (overall, lipophilic drugs generate a higher concentration or time to the peak concentration when meds taken in the morning)

--valproic acid:

    --higher levels if taken during the daytime, with reduced clearance of the drug (this was confirmed in mice with laboratory-induced changes in the light-dark cycles)

--acetaminophen overdosing:

    --(a mouse study): a cascade of proteins are affected by diurnal variation, leading to increased expression of CYP2E1 (these variations in the nocturnal mice is in the evening; likely in humans in the morning) as well as antioxidants, leading to a higher levels of acetaminophen breakdown to the toxic N-acetyl-p-benzoquinoneimine (NAPQI) and increased hepatotoxicity.  In mice, poisoning the clock proteins eliminates the differences in acetaminophen toxicity between day and night. See https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4346587/pdf/nihms-664139.pdf 

--diabetes:

    --studies have suggested that shift work is associated with increased risk of diabetes in humans. An intriguing study found that rats (diabetes-prone human islet amyloid polypeptide transgenic ones) exposed to a normal light regimen vs an experimental disruption of the circadian rhythm had accelerated development of diabetes (see J Biol Rhythms. 2011 Oct;26(5):423-33, or doi: 10.1177/0748730411416341 )

--cancer:

    --and several cancer drugs are metabolized more at different times of the day, including fluorouracil (the enzyme which breaks it down) spikes around midnight, and

 doxorubicin (clearance decreased with given at 9pm vs 9am), and no doubt several others.

So, lots of information. Much of it in animal studies.  But really does bring up the big issue that there seem to be lots of effects of circadian variation in potentially all of: disease, metabolism, and therapeutics.  Some relates to the half-life of the drug and optimizing the timing for that. some to newer insights into the circadian rhythm actually turning on or off the genes which affect the metabolism. And that this all really should be studied more in humans (it would be interesting to know, for example, if acetaminophen toxicity happened more in the morning hours…). and perhaps this should be a requirement of new drug testing prior to FDA approval.

In terms of current knowledge in humans, I do think it might make sense to dose ACE-inhibitors in the evening (several of the ACE-I studies for hypertension did find an increase in strokes, which often happen in the wee hours), and there really is not much down-side to taking aspirin at night (all assuming equal medication adherence).

There is also the rather difficult situation of patients with variable work schedules. Should they take their meds at a different time depending on when they are up/go to sleep? And, how quickly do their clock proteins reprogram with varying sleep schedules (even if they are awake for a week of night-shifts, when do their proteins change enough to make sense to change their medication-taking schedules?? And does this vary depending on the specific clock proteins which affect the metabolism of the different meds they are taking??)

also, this does bring up that oh-so-common occurence of our being a bit blind-sided by new findings which challenge our accepted presumed model of how things work: i/we certainly seemed to have assumed that the irreversible effects of aspirin on platelets meant that we really didn't have to pay attention to the timing of the dose, and even considered an every other day dosing as in some studies. and, as happens all too frequently, this was wrong. or at least not the complete picture.  reinforces the importance of always questioning our assumptions...

also, see http://gmodestmedblogs.blogspot.com/2017/10/simplified-iron-supplementation-regimen.html​ , a blog which also questions the oft-held approach of iron therapy for anemia, suggesting that lower doses every other day are actually optimal