Circadian Medicine Part 2 Flashcards
Cholesterol
- A component of cell membranes
○ determine cell membrane fluidity
○ stabilize the cell membrane = otherwise can tear or be disrupted more readily - Needed to make vitamin D, hormones (testosterone, estrogen), bile acids (fat dissolving)
- Synthesis:
○ 80% take place de novo in liver + small intestine (+ all cell types)
○ 20% from foods - If consume only 1 egg yolk = 200 mg cholesterol/ day Liver will produce 800 mg/ day from fat, sugars, + proteins
High cholesterol
Cholesterol
* High cholesterol levels –> fatty deposits in blood vessels (aperture become narrow) –> break-away deposits form a clot –> heart attack/ stroke
○ poor lifestyle choices
○ can be inherited
First cholesterol screening:
* B/w 9 + 11 y + repeated every five yrs after that
* For men ages 45 to 65 + for women ages 55 to 65:
○ screenings every one to two years
* For those over 65:
○ annual testing
LDL + HDL
Low-density lipoprotein (LDL)
* “bad” cholesterol - can build up in arteries + form fatty, waxy deposits called plaques –> ↑risk for heart disease + stroke
High-density lipoprotein (HDL)
* “good” cholesterol - transports excess cholesterol out of arteries to liver, which removes it from body –> lower the risk for heart disease + stroke
Statin therapy
- Lowers LDL cholesterol biosynthesis in the liver
○ Inhibit (HMGCoA) reductase activity - Efficacy:
○ For 1 mmol/l (38.7 mg/dl) reduction in LDL cholesterol by statins –> ↓ all-cause mortality + coronary artery disease death by 10 + 20%
○ –> primary + secondary prevention of cardiovascular disease
(Awad & Banach, 2018)
Optimal time-of-day for statin administration - cholesterol biosynthesis
- Cholesterol biosynthesis peaks at night (b/w midnight + 0500)
- If want to apply statin = would want to inhibit the synthesis of LDL –> the enzyme HMG CoA that targets the LDL
- (HMG CoA) reductase peaks in the night-time hrs
○ –> synchronize delivery of the drug to the abundance of cholesterol + active enzyme –> optimise treatment
○ –> statins be given in the evening = to target the reduction in LDL
Time of administration + patients’ adherence:
○ Drug concomitantly taken w/ other drugs (e.g. antiplatelet + antihypertensive agents) –> difficulty w/ drug adherence to taking meds at different times of day
(Awad & Banach, 2018)
SA + LA statins time of delivery
- Short-acting statins should be given in the evening
- Long-acting statins could be given at any time of day, allowing more patient-based choice –> better adherence especially in polypharmacy
(Awad & Banach, 2018)
meds better evening + why time of delivery is bad for companies
Medicines that work better in the evening:
* Hydralazine for high BP
* Morphine for analgesia
○ pain is worse at night
More research required in chronomedicine:
- Investigation of optimal time-of-day of drug delivery:
* Low incentive for drug companies
* better timing won’t increase sales
* reduce amount of drugs given to patients ↓ sales
Prevalence of mental health symptoms in Australian elite athletes (Purcell et al., 2020)
- High to very high psychological distress (17.15%) compared to general community norms (9.5%)
- Reported symptoms of:
○ Depression
○ Anxiety - Reported better (compared to other Australians):
○ Life satisfaction, self-esteem, body satisfaction
○ Lower rates of risky alcohol consumption, problem gambling
Mood
- About emotion, feeling or affect
○ Emotion - bodily reactions activated through neurotransmitters + hormones released by the brain
§ 7 universal facial expressions of emotions
§ An emotion that persists for an extended period of time w/o interruption –> categorised as a mood or disorder
○ Feeling - conscious experience of emotional reactions (e.g., disappointed, hopeless, grieved, lonely, bitterness, love)
○ Affect - one’s immediate expression of emotion
Measures of mood scores
Measures of mood scores
* Visual analogue scale (VAS)
* Affect (one’s immediate expression of emotion)
Positive affect (behavioural approach)
* enthusiasm, interest, + satisfaction
Negative affect (behavioural withdrawal)
* subjective distress incorporating aversive effects of anxiety, nervousness, tension, + guilt
(Peeters et al., 2006)
What can we glean from the literature?
- Patients unable to control mood in mood disorders
- Need conduct ambulatory mood measures for tracking severity + perhaps clinical course
- Mood has a biological basis:
○ an imbalance in neurotransmitters (norepinephrine + serotonin) = why some people w/ mood disorders have been prescribed w/ meds that counteract these NTs = bring them back into balance - Circadian disruption/ misalignment: sleep-wake cycles not synced to the light-dark cycle potentially a “trigger” for mood disorders?
○ E.g. someone w/ a sleep-wake disruption over a very long period of time, they can suffer from major depressive disorder = to treat MDD one of the things to look at is there sleep pattern (sleep-wake timing)
Circadian disruption is strongly associated with psychiatric disorders
- Disrupting factors:
○ social zeitgebers
○ genetic variants - Healthy adults: phase advance worsened mood (Wirz-Justice 2022)
- A subgroup of depressed patients (20– 30%) displayed dysregulated 24h rhythms (sleep, core body temp, cortisol & melatonin, + mood (Sato et al, 2021)
Timing of antidepressant drugs - tricyclic antidepressants
- Lofepramine (not available in US, Australia, NZ, Canada)
○ Midnight dosing the most favourable administration time
○ Side effects: Sleep disturbances, agitation, confusion, nightmares, hallucinations, hypomania, mania, psychoses, delirium - Clomipramine
○ The highest antidepressant effect verified at noon
○ Fewer side effects: tremors + mouth dryness at noon compared w/ before bedtime - Amitriptyline
○ Lower side effects (drowsiness, confusion, mental slowness) w/ evening than morning doses
○ Taken at evening = around 9:00pm
