Chronopharmacology and circadian drug interactions

Question 1

Give 4 examples of drug-metabolising enzymes which are under direct clock control

Answer 1

o	CYP450
o	SULT
o	UGT
o	NQI
o	EPH
o	GSTH
o	NAT

Question 2

Give 5 examples of diseases with known circadian rhythms

Answer 2

Peptic ulcer exacerbation (24:00)
Epileptic seizure (~20:00-24:00)
Osteoarthritis (18:00)
Epileptic seizure (06:00-12:00)
Migraine headache (06:00-12:00)

Question 3

How do pharmacokinetics and pharmacodynamics vary with time? Give examples

Answer 3

o Gastric motility: is doubled in day time than at night
o Plasma protein concentrations are higher in the day time that at night
o Hepatic blood flow is greatest at 8 am and metabolism is reduced at night When symptoms of a disease are circadian phase-dependent (e.g. nocturnal asthma)
o Drug toxicity can be avoided/minimised by administration at a particular time of the circadian day

Question 4

Give 2 examples of drugs undergoing chronokinetics

Answer 4

o Antibiotics: aminoglycosides such as gentamycin, tobramyrin, amikacin
o Renal toxicity of aminoglycosides can be reduced by giving the drug as a single daily injection when patients are active (ie during the day)

Question 5

How are antiepileptic drugs affected by time?

Answer 5

Cmax tends to be higher, tmax shorter and absorption rate constant (Ka) tended to be larger in the morning than in evening

Question 6

What are metabolism and elimination?

Answer 6

o Metabolism: liver enzyme activity, hepatic blood flow

o Elimination: urinary pH, tubular reabsorption

Question 7

How are ACE-inhibiting drugs affected by time?

Answer 7

Safer and effective when administered at bed time when compared to morning

Question 8

Give 4 examples of clock proteins known to directly regulate the activity of drug-metabolising enzymes

Answer 8

o CLOCK
o BMAL1
o REV-ERB
o ROR

Question 9

What is chronotherapy? What has it led to?

Answer 9

• Chronotherapy: Attempts to cure or prevent disease, with proper regards to disease temporal characteristics
• –> cancer chronotherapy

Question 10

Define chronopharmacology

Answer 10

• The science of the biological rhythm-dependency of medication
• Time of day affects: pharmacological efficacy, side/toxic effects, and circadian effects of drugs

Question 11

What happens if there is not a master clock?

Answer 11

The numerous rhythmic biological systems are why we require a master clock; otherwise they would operate asynchronously to potentially pathogenic effect

Question 12

How does the endogenous clock work?

Answer 12

• The endogenous clock works through “genetic cogs”, engaged in a transcription-translation feedback loop

Question 13

Over what durations could these delivery systems work?

Answer 13

• Delivery systems can be over 24hrs, 12hrs, or once-a-day

Question 14

How does time of day affect drug activity? Give an example.

Answer 14

• Time of day affects drug activity and drugs affect the biological clock
o Chlorpromazine is most effective in producing sedative and antipsychotic effects when given at midnight and immediately after rising, respectively

Question 15

How does the zeitgeber affect circadian rhythms?

Answer 15

 Cells become most active during daylight hours and least active during night-time hours; this is regulated by light intensity.

Question 16

Give 3 characteristics of an ideal chronotherapeutic drug

Answer 16

o Delivers the drug after a time interval
o Delivers the drug when its needed most
o Reduce drug release when the drug isn’t needed – reduces toxicity and side effects

Question 17

On the physiological level, what do biological clocks regulate?

Answer 17

o	Memory
o	Reward
o	Sleep-wake cycles
o	Body temperature
o	Metabolism
o	Feeding behaviour
o	Immune response
o	Detoxification
o	Liver
o	Heart 
o	Lungs
o	Spleen
o	Fat tissue
o	Muscle
o	Intestine

Question 18

Define chronopharmacokinetics

Answer 18

Chronopharmacokinetics: The biological time-related changes in the absorption, distribution, metabolism and elimination (ADME) of an agent (drugs)

Question 19

How are opioid analgesics affected by time?

Answer 19

Stronger analgesic effects when tramadol and dihydrocodeine were given in the evening to relieve painful stimuli.

Question 20

How are corticosteroids affected by time?

Answer 20

a single daily dose of inhaled corticosteroids, when administered at 17:30 rather than 08:00, was nearly as effective as four doses a day

Question 21

How are general anaesthetics affected by time?

Answer 21

 Barbiturates – dark phase
 Benzodiazepines: The elimination half-life of midazolam was found to be at its shortest at 14:00 and at its longest at 02:00
 Ketamine: action longer during the night that during the day
 Halothane: Greatest efficacy between 24:00 and 06:00

Question 22

What is the objective of chonotherapy?

Answer 22

o Delivery of drugs to targeted sites in higher concentrations when they are needed most

Question 23

Define chronotoxicology

Answer 23

• Undesired or harmful effects from chemical, physical or other agents (poisons, pollutants and overdoses of drugs) on biological temporal characteristics and as a function of biological timing

Question 24

Why is a circadian rhythm necessary?

Answer 24

• Living in a cyclical environment necessitates a biological clock. Cycles include:
o Day/night (light/dark) cycle
o Weather patterns
o Food availability – there are flowers which open during the day and close during the night

Question 25

Describe photic input.

Answer 25

• Originates from the retina
o Fires along the retino-hypothalamic tract to the SCN
o Glutamatergically signals to the intergeniculate leaflet, which it turn fires down the geniculohypothalamic tract (using neuropeptide Y) to the SCN
o Retinohypothalamic tract uses glutamate and PACAP signalling to pass information to the SCN

Question 26

What is absorption?

Answer 26

o Absorption: GI blood flow, drug-protein binding
 Depends on pH, gastric emptying, motility and gastrointestinal blood flow.
 Lipophilic drugs are better absorbed in the morning because of faster gastric emptying time and a higher GI perfusion in the morning.
 Valproic acid, Indomethacin, Ketoprofen are better absorbed in the morning.
 Skin penetration of lidocaine and prilocaine is better in the evening.

Question 27

Can the SCN be influenced by the zeitgeber?

Answer 27

Yes - this is how the SCN is responsible for synchronising physiology and behaviour with the day/night cycle

Question 28

Which organisms have biological clocks?

Answer 28

all organisms have a biological clock:
o	Bacteria
o	Plants
o	Fungi
o	Animals

Question 29

How do you establish if biological activity has an endogenous circadian rhythm?

Answer 29

eliminate light input – when you’ve done this, if the behaviour still occurs cyclically, it’s a circadian rhythm

Question 30

What does zeitgeber mean?

Answer 30

time giver

Question 31

How are antihypertensive drugs affected by time?

Answer 31

o Antihypertensive drugs: Cmax higher and/or tmax shorter after morning that evening dosing of lipophilic drugs (nifedipine, oral nitrates, propranolol etc.).

Question 32

Name the 4 components of the endogenous clock

Answer 32

o The main components are BMAL1, CLOCK, PER, and CRY

Question 33

How are anti-migraine drugs (e.g. sumatriptan) affected by time?

Answer 33

Mean peak serum concentration significantly higher following 7:00 administration than after 19:00

Question 34

The master circadian clock is found in which area of the brain?

Answer 34

the suprachiasmatic nucleus
o Part of the hypothalamus consisting of ~35,000 cells
 Patterns of neuronal activity and firing change throughout the day in response to light levels, thereby regulating the activity of the hypothalamus and other brain areas to control physiological processes and behaviours (e.g. sleep)
o Found above the optic chiasm

• Responsible for synchronising physiology and behaviour with the day/night cycle

Question 35

Explain how the endogenous clock works on a molecular level.

Answer 35

BMAL and CLOCK form a dimer, then translocates to the nucleus to stimulate the production of a PER-CRY dimer; this in turn inhibits the production of the BMAL-CLOCK dimer.

Protein production varies throughout the day and night, and this in turn affects cell activity.

Hall, Rosbash, and Young won the 2017 Nobel Prize in Physiology or Medicine for determining this.

You can track these changes over time (day and night); in an animal without a clock, this doesn’t occur – this animal cannot endogenously tell time. Oscillation of protein levels changes neuronal activity during the day and night

Question 36

What is distribution?

Answer 36

o Distribution: gastric acid secretion and pH, motility, gastric emptying time
 Blood flow: Depends on several regulatory factors, including sympathetic and parasympathetic systems whose activities are known to be circadian time dependent
 A diurnal increase and nocturnal decrease of blood flow and local tissue blood flows may explain a possible difference in drug distribution depending on the dosing time
 Plasma concentration of albumin and alpha 1 glycoprotein is circadian time dependent: show peak activity around noon. Therefore drugs bound to plasma proteins like valproic acid, carbamazepine, diazepam, and prednisolone etc, show increase in free fraction at night

Question 37

Give an example of a chronotherapeutic drug

Answer 37

o The first anti-cancer drug to undergo chronotherapeutic development was oxalpatin
 Studies investigated circadian vs constant rate
 Constant rate had 10x higher incidence of neutropenia and distal paraesthesia and 55% higher vomiting
 Time of best tolerability coincided with time of best efficacy
 Some anticancer drugs are ore tolerable between 00:00 and 04:00

Question 38

What do these inputs lead to?

Answer 38

rhythmic outputs from the SCN, regulating cell firing and chemical release

Question 39

Name the 5 types of circadian rhythm, their time durations, and give an example of each.

Answer 39

o	Circadian = 20-28hour cycles
	Daily cycles – sleep/wake
o	Ultradian = <20hour cycles
	Sleep stages
o	Infradian = >28hour cycles
	Pre-menstrual syndrome
o	Circamensual = ~30 day cycle
	Menstrual cycle
o	Circannual = annual/seasonal
	Hibernation period, migration patterns

Question 40

Define chronopharmacodynamics and give 3 examples of its effects

Answer 40

Chronopharmacodynamics: Rhythmic differences in the susceptibility or sensitivity of a biological target to an agent
o	Receptors: number, conformation 
o	Membrane permeability 
o	Second messengers, metabolic pathways
o	Free-to-bound fraction of medications 
o	Cell, tissue, organ rhythms

Question 41

What is chronodisruption and how can it impact health?

Answer 41

Disruption of biological clocks is linked to disease:
o Seasonal affective disorders
o Sleep disorders
o Shift work disorders
o Neurodegenerative disease e.g. Alzheimer’s
o Obesity/metabolic syndromes
o Inflammation (asthma/COPD)
o Cancer
o Most heart attacks and strokes occur between 6am-noon, when blood pressure increases to wake you up
• Chronic sleep loss –> social jetlag – misalignment of biological and social time –> potential to cause health problems
• The SCN and hypothalamus can drive circadian rhythms in hormonal secretion – altering melatonin secretion (sleep hormone) by interacting with the pineal gland.
o This can also be affected by changes in seasons

Question 42

How are anti-inflammatory drugs affected by time?

Answer 42

Have greater rates and extents of bioavailability when administrated in the morning than evening e.g. Indomethacin, ketoprofen

Question 43

Why do cells need to be in-phase? Which neurotransmitters and cells are important for this?

Answer 43

• Cells need to be in-phase (ensemble) to effectively tell time
o Important neurotransmitters for this are:
 GABA
 AVP (arginine vasopressin)
 VIP – ventral cells
o This is what breaks down during old age and disease

Question 44

How could chronotherapeutics be made practical?

Answer 44

by developing a pulsatile drug delivery system; this would be good for diseases which have a predictable cyclic rhythm - timing of medication can improve the outcome of desired effects

Question 45

Describe non-photic input

Answer 45

• Mainly comes from the median raphe nucleus, serotonergically firing to the SCN
• Dorsomedial hypothalamic nucleus is involved too

Question 46

How can circadian rhythms vary between people?

Answer 46

Larks:
o Morning people
o Early risers, early to bed

Owls:
o Later start
o Later to bed

True larks and owls are rare (5% of the population at most); most people are simply variations on normality

Question 47

Which external factors can influence a circadian rhythm?

Answer 47

o Light-dark exposure, regular eating patterns, and scheduled exercise –> synchronised mechanics –> synchronised internal clock
o These mechanics may need to be adjusted and in synchrony with the environment around us

Question 48

Give an example of a drug which shows chronotoxicology

Answer 48

Ouabain - cardioactive drug; effects are strongly time-gated - at 18:00 clock hours, 80% survive; at 06:00 clock hours, 74% day AT THE SAME DOSAGE

Question 49

On the cellular level, what do biological clocks regulate?

Answer 49

o	Cell cycle progression
o	DNA damage repair
o	Cellular energy metabolism
o	Cell detoxification
o	Neuronal excitability

Question 50

Outline a study into circadian rhythms and its results

Answer 50

• Early studies into circadian rhythms are best exemplified by the Munich bunker experiments in 1961; 28 days of isolation led to:
o No time cues
o No social interaction
o PPs set up their own day-night cycle
 This allowed us to conclude that circadian rhythms are endogenous and not intrinsically driven by the light-dark cycle
 Showed that biological clocks are important for regulating:
• Being awake
• Eating
• Sleeping
• An animal that doesn’t have a biological clock doesn’t know what time it is

Question 51

Define chronergy

Answer 51

• Chronergy: rhythmic differences in effects of drugs on the organisms as a whole, which includes both desired and undesired effects

Question 52

Which other inputs to the circadian system are there?

Answer 52

• Circulating factors such as glucose and leptin impact on SCN signalling