Biological circadian rhythms and its applications in various systems and with a note on disease treatment patterns

1. CHRONOTHERAPY
&
IT’S ROLE IN
DISEASE TREATMENT
By
Koppala RVS Chaitanya
Department of Pharmacology

2. CHRONOTHERAPY:
Almost all functions of the body, including drug absorption and distribution, drug metabolism,
and renal elimination, show significant daily variations. These include liver metabolism, hepatic
blood flow and the first-pass effect, glomerular filtration, renal plasma flow, urine volume and
pH; blood pressure, heart rate and organ perfusion rates; acid secretion in the gastrointestinal
tract and gastric emptying time. The onset and symptoms of diseases such as asthma attacks,
coronary infarction, angina pectoris, stroke and ventricular tachycardia are circadian phase
dependent. An example is a morning-time risk of angina, myocardial infarction, and stroke. In
humans, variations during the 24 hours day in pharmacokinetics (chrono-pharmacokinetics) have
been shown for drugs like Propranolol, nifedipine, Verapamil, enalapril, isosorbide 5-
mononitrate and digoxin, anti-asthmatics (theophylline and terbutaline), anticancer drugs,
psychotropics, analgesics, local anaesthetics and antibiotics. The circadian rhythm regulates
many functions in the body like the production of hormones, sleeping patterns, behaviour and
physiology.

3. Chronotherapy: Chronotherapy refers to the use of circadian, ultradian, infradian and seasonal
or other rhythmic cycles in the application of therapy and minimising the side effects of the
drugs. Chronotherapeutics is concerned with the delivery of drugs according to the intrinsic
activities of a disease over a certain period because the biochemical, physiological and
pathological variations over 24 hours in humans have occurred.
Advantages of Chronopharmacotherapy:
1. It counteracts an overdosing of any class of medication.
2. It makes the use of the medication progressively proper, and in this manner, the estimation of
a medication is expanded.
3. It decreases the symptoms of medication and aides in minding out the treatment for just a
specific or constrained timeframe.
Disadvantages of Chronopharmacotherapy:
1. It builds up a non 24 h rest wake disorder after the treatment as the individual doses for more
than 24 h during the treatment. It's not exactly normal, but rather, the level of hazard is not
known.
2. An individual may likewise be denied of rest now and then.
3. The individual turns out to be less profitable during Chronotherapy and remaining alert till
the other timetable may be a bit awkward.
4. The patient should take a break from the busy schedule calendar as its time taking treatment.
5. Therapeutic supervision is compulsory for this treatment, and customary counseling of rest
pros is prescribed.
6. Individual needs to keep himself wakeful till the following rest plan so he needs to get
Role of Chronotherapy in disease treatment:
1. Asthma: It is characterized by airway inflammation resulting in hyper responsiveness of the
lower respiratory tract to various environmental stimuli. Airway resistance increases
progressively at night in a patient with asthma. There is an increased incidence of asthma
during the early-morning hours. The symptoms of asthma occur 50 to 100 times more at night.

4. The exacerbation of asthma during the night represents the changing status of biological
functioning due to circadian rhythms in the airway’s hyper reactivity to acetylcholine, histamine,
plasma cortisol, epinephrine, histamine, and cyclic AMP. Once daily dosing of inhaled
Glucocorticosteroids ciclesonide, sustained-release theophylline, and transdermal tulobuterol
patch was found to be effective in case of nocturnal asthma.
2. Cardiovascular disease: Capillary resistance and vascular reactivity are more in the
morning. Increased platelet aggregation and decreased fibrinolytics activity in the morning lead
to relative hypercoagulability of the blood. BP is at its lowest during the sleep cycle and rises
steeply during the early morning. These observations show that myocardial ischemia, angina
pectoris, acute myocardial infarction, congestive cardiac failure and sudden cardiac death are
greater during the initial hours of the day. External factors affecting ANS including physical
activity, emotional state, meal and sleep/wake routine also contribute to variations. Currently,
there are Chronotherapeutics antihypertensive products like oral nitrates, calcium channel
blockers and β-adrenoceptor antagonists whose both pharmacokinetics and Pharmacodynamics
get influenced by circadian rhythm are available with novel drug delivery systems, releasing
drugs during the vulnerable period of 6 am to noon upon administration of medications at 10
pm
.

5. 3. Cancer: Chemotherapy was found to be more effective and less toxic if they are administered
at selected times. Circadian chemotherapy timing affects drug toxicity patterns and severity,
maximum tolerated dose, average dose intensity, tumour response quality and frequency and the
survival of patients with cancer. Pharmacologic and pharmacokinetic properties of the drug,
rhythmic changes in DNA and RNA synthesis, RNA translational activity and mitotic activity
may influence tumour cell susceptibility. The cancer chromogenic therapy was found to be
effective in tumour suppression in-vivo.
4. Peptic ulcer: Functions of the gastrointestinal tract like gastric acid secretion is highest at
night, while bowel motility and gastric emptying are all slower at night. Suppression of
nocturnal acid is an important factor in duodenal ulcer healing. Therefore, H2 antagonists are
recommended once daily at bedtime for active duodenal ulcers which overcomes problems of
sustained or profound decrease of 24 hours intra-gastric acidity including the threat of enteric
infection and infestation, potential bacterial overgrowth with possible N-nitrosamine formation.
5. Arthritis: Morning stiffness is more in rheumatoid arthritis that can be distinguished from
osteoarthritis when the patient’s joints are most painful and is the characteristic feature of
rheumatoid arthritis, whereas symptoms are often worse in the afternoon and worse in the
evening in osteoarthritis. Cyclooxygenase-2 inhibitors are effective to relieve osteoarthritis
symptoms when taken in the morning and better results are obtained in rheumatoid arthritis when
a small part of the dose is taken in the evening.
6. Allergic Rhinitis: Symptoms of allergic rhinitis (nasal congestion, sneezing, running nose)
are typically more severe in the early morning hours. If the administration of the drug can be
matched with the biological time structure optimum relief may be provided at the time when it is
needed most by the patient.
7. Mood Disorders: Deprivation of sleep in half of the night and timed exposure to day light-
intensity and artificial light still experimental therapies, may ease the depression premenstrual
or during menopause and benefit both women and men with seasonal and other mood disorders
8. Diabetes: Insulin is released in a pulsatile manner but sometimes irregularly. The modulators
of insulin release and action are secreted in a circadian pattern and impress the mode of insulin
release. So the difference between the maximum and minimum plasma insulin concentration has

6. short-term rhythmicity and complex secondary circadian rhythm is variable early-morning and
late-afternoon insulin resistance.
9. Alzheimer’s Disease: A change of circadian rhythm is seen in patients with Alzheimer’s
disease. Individuals with Alzheimer’s symptoms show a higher percentage of nocturnal
activity which shows the lower inter-daily stability of motor activity and activity of macrophages
peak time than normal healthy individuals. Body temperature is also higher in patients and
circadian abnormalities are seen together with cognitive and functional deterioration in this
disease.
10. Parkinson’s Disease: Parkinson’s disease discloses many alterations in the circadian
rhythm of blood pressure; amplified diurnal blood pressure variability and postprandial
hypotension due to autonomic dysfunction