Biological Clock And Their Significance Leading To 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. 

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. 

Chronotherapy in various diseases

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. 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 glucocorticosteroid ciclesonide, sustained-release theophylline, 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 fibrinolytic 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 chronotherapeutic 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. 

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 short-term rhythmicity and complex secondary circadian rhythm is variable early-morning and late-afternoon insulin resistance. 

9. Alzeimer’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.

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