APPLICATIONS OF CHRONOTHERAPY IN DIABETIS, ASTHMA AND

PEPTIC ULCER

CHRONOTHERAPY

❖ The treatment of an illness or disorder by administering a drug at a

time of day believed to be in harmony with the body’s natural rhythm.

❖ The goal is to improve our understanding of periodic and thus

predictable (e.g. circadian) changes in both desired effects (Chrono
effectiveness) and tolerance (Chrono tolerance) of medications.

❖ The challenges of modern life can be managed to be in better

alignment with our circadian rhythm.

DIABETES

➢ Diabetes mellitus is a chronic metabolic disorder characterised by a

high blood glucose concentration – hyperglycaemia.

➢ Fasting plasma glucose >7.0 mmol/L.

➢ Or plasma glucose >11.1 mmol/L, 2 h after a meal

➢ Caused by insulin deficiency, often combined with insulin resistance.

➢ The result is disordered utilization and storage of the proximate

nutrients (carbohydrates, proteins and fats) and reduced production
of ATP.

APPLICATIONS IN DIABETIS

➢ In the management of diabetes, the target is to maintain the patient

in the normoglycemia.

➢ Shift workers are more vulnerable to diabetes and obesity, worse

glucose control, cardiovascular disease and mortality.

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➢ Misalignment of behavioural and circadian cycles results in adverse
cardiometabolic endpoints including higher arterial BP, glucose,
insulin, cortisol and catecholamines.

Influence of circadian rhythm on blood glucose

• Levels of both insulin and the counterregulatory hormones, which

work against the action of insulin, are influenced by a circadian
rhythm.

• Counterregulatory hormones include glucagon, adrenaline, growth

hormone (GH) and cortisol, raise blood glucose levels when
needed.

• In the middle of the night, GH secretion increase, followed by a

surge in cortisol, which increases blood glucose production by the
liver.

• In non-diabetes, these processes are offset by increased insulin

secretion by the pancreas, so blood glucose remains stable.

• In people with Type 1 and Type 2 diabetes where pancreas and liver
functions are improper respectively, change in blood glucose levels
during sleep can cause “dawn phenomenon”.

Circadian rhythms, insulin action, and glucose homeostasis

• Circadian misalignment increases insulin resistance and decreases

pancreatic function.

• Circadian disruption caused by exposure to light at night is

associated with lower nocturnal melatonin, which in turn affect
glucose metabolism.

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• Potential therapies for circadian misalignment include entraining the
central pacemaker with timed light exposure and/or melatonin and
restricting food intake to the biological day.

Circadian rhythm and sugar metabolism

• When behaviour cycles of feeding and sleeping are not in normal

alignment with the internal body clock, it negatively affects the
regulation of blood sugar.

• An experiment was conducted to prove this, that included a group

of people who were kept in normal daily rhythm with proper food and
sleep.

• Then this schedule was reversed for 4 weeks, and the result was an
increase in post-meal blood glucose level by 17% in the evening
than in the morning.

• Hence, it is evident that when people live lives that are attuned to
the natural rhythm of their endocrine system, blood glucose level
may become unstable enough to contribute to the development of
diabetes.

• Chronotherapy of diabetes Insulin secretion by pancreatic cells and

insulin sensitivity in the insulin target organs are involved in
maintaining glucose homeostasis, hence correction of these
abnormalities is necessary for effective treatment.

• Insulin sensitizers (thiazolidinediones and biguanides) are widely

used.

• Glinides and rapid-and-long-acting insulin analogues are useful in

improving glycaemic control and for the risk reduction of prolonged
hypoglycaemia and body weight gain.

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• Circadian clock is impaired in patients with type 2 diabetes.
Therefore maintenance of circadian clock function are important for
the prevention of type 2 diabetes.

• To avoid hypoglycaemia at night take short acting insulin at dinner

time and long acting insulin dose at bed time.

CHRONOTHERAPY OF DIABETIS

• Both insulin secretion by pancreatic cells and insulin sensitivity in

the insulin target organs shows daily rhythmicity.

• It may be involved in maintaining homeostasis of glucose

metabolism.

• Because these rhythms are impaired in patients with diabetes, the

correction of these abnormalities is necessary for effective
treatment.

• There are few studies showing chronotherapy of insulin sensitizers.

• The medications which are used for the treatment of impaired insulin
secretion, including glinides and rapid and long acting insulin
analogues, have the merit of chronotherapy approach.

• These medications are used not only for improving glycaemic

control but for the risk reduction of prolonged hypoglycaemia and
body weight gain.

• It showed that circadian clock is impaired in patients with type 2

diabetes.

• Because the association between clock gene expression and

glucose tolerance is also detected in subjects without diabetes,

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 favourable lifestyle to maintain circadian clock function are
important for the prevention of type 2 diabetes.

APPLICATIONS IN ASTHMA

• ASTHMA

• Asthma is a common inflammatory disease of the airways, with a

pronounced circadian variation in symptoms.

• Increased airway narrowing at night is thought to occur as a result

of circadian variation in neurohormones and intensification of airway
inflammation.

• In addition, vagal- tone, neurogenic inflammation and airway hyper

responsiveness are increased at night.

• PATHOGENESIS

• Many cells contribute to the nocturnal inflammatory process in the

asthmatic airways, including mast cells, eosinophils, neutrophils and
lymphocytes.

• These cells are capable of secreting innumerable inflammatory

mediators, such as histamine, cytokines, leukotrienes,
prostaglandin, neutral endopeptidase and superoxides, which are
potent bronchoconstrictors and secretagogues.

• They also cause increased vascular permeability and airway

oedema.

• All these chronobiological events promote nocturnal worsening of

asthma and increased nocturnal deaths.

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 CURRENT AND EMERGING CHRONOTHERAPIES FOR
ASTHMA

• Theophylline

• Anti-asthmatic drugs such as theophylline and long acting β

sympathomimetics may/should be dosed higher in the evening than
during daytime when asthma is predominantly nocturnal.

• In asthmatic patients, theophylline inhibits the late response to

allergen, increases CD8+ cells in peripheral blood, and decreases
T lymphocytes in the airways.

• The theophylline Cmax is greater and Tmax is shorter with dosing at

8:00am than at 8.00pm.

• The chronotherapy of theophylline entails the purposeful delivery of

medication in unequal amounts during 24 hours so that an elevated
concentration is achieved during the night time, when the risk of
asthma is greatest, and a reduced concentration is achieved during
the daytime, when the risk of asthma is lowest.

2. 𝛽2 Adrenergic agonist (BAs)

• They primarily cause relaxation of airway smooth muscle and also

possess anti-inflammatory action.

• BAs are predominantly inhaled and can be short-acting BA (SABA)

with a duration of 4 hours, or long-acting (LABA) effective for 12-24
hours.

• SABAs are prescribed as “reliever” medications for immediate relief

from bronchoconstriction.

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• The majority of LABA are inhaled as aerosols. It can also be
administered orally as tablet (Terbutaline) and as a transdermal
preparation in the form of patches.

• Bambuterol is a prodrug of terbutaline and exerts a bronchodilator

effect for 24 hours. It was also found that evening dosing is more
advantageous than morning dosing.

• Neither of the Bambuterol regimens were associated with any

cardiovascular or nervous system adverse effects.

3. LABA tablet formulation

• Terbutaline is a LABA tablet formulation that was one of the first to

be assessed in chronotherapy trials.

• Daily doses were administered to asthmatics in synchrony with

biological need defined in terms of the circadian rhythm of lung
function.

4. LABA inhaler medication

• Formoterol and salmeterol are aerosol LABA medications, with few

adverse effects.

• Both medications have duration of action of about 12 hours,

although formoterol may have a more rapid onset of affect

5. Anticholinergic agents

• Cholinergic tone from vagal nerves in the parasympathetic system

increases at night and may cause bronchoconstriction and mucus
secretion.

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• It has been suggested that the vagal nerve is one of the dominant
pathways for conveying circadian signals from the suprachiasmatic
nucleus master clock to the peripheral clock in the respiratory tract.

6. Corticosteroids

• Long term oral administration of corticosteroids between 8am and

3pm is effective in controlling nocturnal asthma.

• Inhaled corticosteroids (ICS) are very effective in controlling asthma

symptoms in asthmatic patients of all ages and severity.

• The advantage of inhaled therapy is that corticosteroid is delivered

specifically to the target area.

• ICSs inhibit inflammatory cytokines and reduce airway

hyperresponsiveness. It also reduce mast cells, T lymphocytes, and
eosinophils in the bronchial epithelium and submucosa.

PEPTIC ULCER

• Peptic ulcer occurs in that part of the gastrointestinal tract (g.i.t.)

which is exposed to gastric acid and pepsin, i.e. the stomach and
duodenum.

• Ulcer is caused by eradication of the stomach mucosa, in duodenal

ulcer acid secretion is high in about half of the patients, reduction of
acid secretion which is the main approach to ulcer treatment.

• The etiology of peptic ulcer is not clearly known. It results probably

due to an Imbalance between the aggressive (acid, pepsin, bile and
H. pylori)and the defensive (Gastric mucus and bicarbonate
secretion, prostaglandins, innate resistance of the Mucosal cells)
factors

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 APPLICATIONS IN PEPTIC ULCER

PEPTIC ULCER

• Peptic ulcer is defined as the erosion happen in the lumen of

stomach.

• Under fasting conditions, acid is secreted in relatively low amount to

maintain an intragastric pH of approximately 1.5 called basal acid
secretion.

• A circadian rhythm in basal gastric acid secretion has been reported

in healthy men with active duodenal ulcer disease. The rate of basal
acid secretion is highest between 9 pm and midnight.

• Increase in acid secretion, meals are associated with a transient

elevation in intra gastric pH due to its buffering effect.

• During day time, intragastric pH fluctuates, especially at mealtimes.

During night, in the absence of food, intragastric pH remains low and
as a result gastric mucosa is vulnerable to damage and also most
susceptible to acid inhibiting treatment strategies.

• The gastric acid secretion is more during early morning and late
night based on the circadian rhythm, so in order to get proper result
drugs can be given at late night.

Gastric mucosal defence

• The major therapeutic aim in most peptic ulcer regimens is to reduce

gastric acidity. A significant % of patients (10-20%) fail to respond
acid suppressing medical or surgical treatments.

• That attention has been directed to alteration in mucosal defence

factors in the pathogenesis of acid peptic disorders.

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• These factors include gastric epithelial cell mucous and bicarbonate
secretion, PG production and gastric mucosal blood flow.

• Circadian alteration in gastric emptying rates may result in delayed

absorption of many oral medications administered in the evening.
The delay is reflected by lower Cmax and longer Tmax showed lower
when administered during the evening, compared to morning.

H2 blockers

• A constant infusion of ranitidine over a period of 24 h does not lead

to a constant effect, the increase in gastric pH by ranitidine was less
during night than day hours of drug infusion indicating a partial
nocturnal resistance to H2-receptor blockade.

• H2- blockers should be administered after the final meal of the day
to achieve optimum protection during the nocturnal time period.

Proton pump inhibitors

• The PPIs provide superior 24- h acid suppression when compared

with the H2-blockers .

• PPIs are more effective if administered during the morning hours as

compared with evening dosing.

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