Chronopharmacology

Chronopharmacology

Chronos in greek means time. Chronopharmacology is the investigative science concerned with the effects of drugs upon the timing of biological events and rhythms. It also links effects of drugs on biological timing to get the dynamic activity.

Biorhythms

• A daily cycle or periodicity affects biochemical, physiological, or behavioral process of living being is known as circadian rhythm. (20h>T<28 h)
• The rhythms that have period shorter than 24 h are known as ultradian rhythm, for example eye blink, heartbeat, sleep pattern, every 4-hourly rhythm of awakening of babies for feeding.
• A rhythm of 7 days period is circaseptan rhythm, for example road traffic accidents peak at weekends.
• Synchronized rhythms to waxing and waning of moon that forms a lunar month are referred as circalunar rhythm. They last approximately 29.5 days, for example menstrual cycle.

The Biological Clock

Circadian Rhythm

• All light-sensitive organisms, including mammals, possess a master circadian clock that regulates physiological and behavioral processes in alignment with the 24-h day.
• Optimizing and coordinating metabolic processes, cellular functions and the organism’s behavior including the sleepwake cycle can be viewed as the main tasks of the circadian timing system (CTS).
• CTS is hierarchical in structure à master pacemaker à superchiasmatic nucleus (SCN) of the hypothalamus.
• This master pacemaker coordinates countless peripheral clocks within various tissue and cell types. The SCN is entrained by light received by the retina while the peripheral oscillators are often adjusted by chemical signals or by feeding.
• These include (a) direct signals such as innervation by the autonomous nervous system and hormones such as glucocorticoids and (b) indirect signals emanating from SCN-controlled rhythmic behavior, such as timing of food intake and small rhythmic changes in body temperature from activity.

Zeitgeber

• from German: „time-giver”, „synchronizer”
• The biological clocks are reset and calibrated (τ=24 h) by environmental signals that also have τ=24 h, such as dawn/dusk (photic signals), activity/rest, or noise/silence (nonphotic signals).These periodic environmental factors are called synchronizers, zeitgebers, or entraining agents.

• Environmental time cues, termed synchronizers or zeitgebers, the strongest one being the daily light-dark cycle occurring in conjunction with the wake-sleep routine, set the inherited pacemaker circadian timekeeping systems to 24 hr each day.
• The change in glucocorticoid rhythmicity appears to play an important role in physiological rhythmicity by the manipulation of the feeding schedule, because plasma corticosterone levels show anticipatory increases preceding the time of feeding, and the continuous administration of corticosterone disturbed the rhythmicity of behavior, physiological function and cyclic gene expression.
• The manipulation of the feeding schedule can modify the chronopharmacological action and chronopharmacokinetics of drugs.
• Disruption of circadian rhythms is often observed in individuals involved with shift-work or sudden changes in time schedule from traveling (jet-lag), and often contribute to fluctuations in sleep patterns, behaviors, and metabolic patterns.
• leading to an increased incidence of gastrointestinal, cardiovascular, and metabolic diseases, as well as menstrual problems in women, and increased cancer risks.

Molecular Basis of Circadian Rhythm

• In addition to playing a key role in normal physiology and behavior, aberrations in the circadian rhythm are associated with the pathophysiology of diseases including diabetes, cardiovascular disease, psychological disorders and various autoimmune diseases/inflammation.

• Additionally, the potency and efficacy of many drugs is associated with the circadian rhythmicity of expression of their molecular targets and cellular biochemical signals.

• Applying the knowledge of circadian function and regulation to the relevance of disease has enabled a chronotherapy approach in the timing of administration of conventional drugs in order to synchronize the rhythms in disease activity with the efficacy of the drug.

• The basic unit of circadian timekeeping is the cell. Feedback regulation on a transcriptional and posttranscriptional level creates and maintains the circadian oscillations in the context of a single cell.

• In mammals, the principal activators within this system are the CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein-1) proteins and their homologs, which dimerize and bind to cis-acting E-box elements (with the simple consensus DNA sequence CAANTG) to activate the transcription of a large number of circadian genes. Among these genes are loci encoding the PERIOD and CRYPTOCHROME families of repressor proteins (PER1–3 and CRY1–2).

• Three mammalian clock genes (Per1, Per2 and Per3) are rhythmically expressed in the SCN. Per1 and Per2 are induced in response to light.

• The clock genes are expressed not only in the SCN, but also in other brain regions and various peripheral tissues. The liver is a biological clock capable of generating its own circadian rhythms. Since the liver is a major organ of metabolism and detoxification, knowledge of circadian effects on transcriptional activities that govern daily biochemical and physiological processes in the liver may play a key role in toxicology.

• There is a significant circadian rhythm in cytochrome P-450 4a3 (Cyp4a3) and putative N-acetyltransferase camello 4 (Clm4) of phase I and phase II of drug metabolism.

Circadian rhythm modulators

• Synthetic agonists for REV-ERB, SR9009, demonstrated the ability to modulate circadian behavior as well as metabolism.
• when administered to diet-induced obese mice, REV-ERB agonist SR9009 induced significant weight loss (fat mass) and reduced plasma triglycerides and cholesterol levels. Clearly, these data suggest that targeting the clock may hold utility in the treatment of metabolic disorders.
• Longdaysin, an inhibitor of CK1a, à ability to lengthen the circadian period. Administration of longdaysin to zebrafish resulted in a lengthened circadian period.

• In contrast to the CK1d inhibitors, inhibitors of glycogen synthase kinase b (GSK3b), such as indirubin, appear to shorten the circadian period.

Physiologic variations in relation to Circadian changes

• Variations in gene expression due to circadian changes often have effects on the absorption, distribution, metabolism and elimination. These effects result from the rhythmic changes in liver metabolism, membrane viscosity, blood flow in the periphery as well as through organs, renal filtration rates, and various other rhythmic physiological properties. Clearly, efficacy and tolerability of a drug can be severely impacted by circadian pharmacokinetics and pharmacodynamics of drugs.

• The peak in serum cortisol, aldosterone, testosterone, platelet adhesiveness, blood viscosity and NK-cell activity is observed during the initial hours of daytime.

• Hematocrit is greatest and airway caliber (FEV1) best around the middle and afternoon hours, respectively.

• Insulin, cholesterol, triglycerides, platelet numbers, and uric acid peak later during the day and evening.

• The rhythms of basal gastric acid secretion, white blood cells (WBC), lymphocytes, prolactin, melatonin, eosinophils, adrenal corticotrophic hormone (ACTH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) shows a peak at specific times during the night-time.

Disease pattern due to circadian changes

• 24 hr rhythms in the processes that make up the pathophysiology of diseases cause prominent day-night patterns in the manifestation and severity of many medical conditions.

• The onset of migraine headache is most frequent in the morning around the time of awakening from nighttime. The sneezing, runny nose, and stuŠy nose in allergic and infectious rhinitis are worst in the morning upon arising from nighttime. The symptoms of rheumatoid arthritis are worst when awaking from nighttime, while those of osteoarthritis are worst later in the day. The morbid and mortal events of myocardial infarction are greatest during the initial hours of daytime. The incidence of thrombotic and hemorrhagic stroke is greatest in the morning around the time of commencing diurnal activity. Ischemic events, chest pain, and ST-segment depression of angina are strongest during the initial three to ˆve hours of daytime.

• Pain and gastric distress at the onset and acute exacerbation of peptic ulcer disease are most likely in the late evening and early morning.

• Epilepsy seizures are common around sleep onset at night and oŠset in the morning.

• The symptoms of congestive heart failure are worse nocturnally. The manifestation of ST-segment elevation in Prinzmetal’s angina is most frequent during the middle to latter half of the nighttime. The risk of asthma attack is greatest during nighttime.

Divisions of Chronopharmacology

ChronoPK

Chronopharmacokinetics is subdivision of chronopharmacology which deals with the study of the temporal changes in the pharmacokinetics of the drugs with respective time.

Time-dependent changes in pharmacokinetics may proceed from 24 hr rhythms in each process, e.g. absorption, distribution, metabolism and elimination.

Thus, 24 hr rhythms in gastric acid secretion and pH, motility, gastric emptying time, gastrointestinal blood flow, drug protein binding, liver enzyme activity and/or hepatic blood flow, glomerular filtration, renal blood flow, urinary pH and tubular resorption may play a role in such pharmacokinetic variations.

Absorption:

Circadian patterns of absorption are most pronounced in lipophilic drugs, with greater absorption occurring during the day than at night eg. Propanolol.

As a result of these diurnal variations in physiologic parameters and transporters/efflux pumps, the absorption on many drugs, including diazepam, acetaminophen, theophylline, digoxin, propranolol, nitrates, nifedipine, and amitriptyline is sensitive to the time of day of administration. The absorption of most drugs is greater in the morning, paralleling morning increases in gut perfusion and gastric pH.

Distribution:

It depends mainly on drug’s lipophilicity and plasma protein binding affinity.

The degree of protein binding of several drugs, including the antiepileptic agents valproic acid and carbamazepine, and the chemotherapeutic cisplatin, varies in a diurnal manner which correlates appropriately with changes in plasma albumin level. a variety of drug transporters which are critical for drug distribution in tissues are regulated by circadian mechanisms.

Metabolism:

Diurnal variation in the levels and activity of various phase I metabolic enzymes specially CYP450 in the liver of rodents has been long appreciated.

Phase II metabolism is also regulated by circadian mechanisms. Initial studies in mice demonstrated diurnal variation in hepatic glutathione-S-transferase (GST) activity, with greatest activity being present during the dark (active) phase.

Excretion:

diurnal variation in renal parameters including glomerular filtration rate, renal plasma flow, and urine output have been described, it is not surprising that diurnal variation in the urinary excretion of several drugs has been observed.

Circadian regulation of urinary pH could also contribute to variations in drug excretion, as many drugs become protonated at high pH which enhances excretion.

Affecting the route of administration

alternative routes of drug administration, including oral, cutaneous/transdermal, and intravenous, have differences in drug absorption rates influenced by circadian rhythms.

It has been demonstrated previously that local anesthetic agents have varying penetration rates through the skin in a circadian time-dependent manner. Therefore, drug formulation, route of administration and circadian rhythms influences should all be taken into account when treating a disease.

ChronoPD

Rhythmic alterations in the expression of target receptors, transporters and enzymes, intracellular signaling systems, and gene transcription all have been reported, and have the potential to impact the efficacy of therapeutics.

PR prolongation was significantly greater when verapamil is given in morning than evening.

Chronesthesy

Biological rhythms at the cellular and subcellular level can give rise to significant dosing-time differences in the pharmacodynamics of medications that are unrelated to their pharmacokinetics. This phenomenon is termed chronesthesy.

Chronotherapeutics

Discipline of medical treatment which allows for the consideration of a patient’s biological rhythm, changes in the severity of a disease state during the day, and the synchronizing of dosing and delivery of a particular drug to allow for the optimal efficacy in the patient.

Many studies have shown that cardiovascular related events, such as myocardial infarction and stroke, often occur in the early morning due to circadian changes regulating blood pressure, heart rate, vasodilating hormones, etc.

Dihydropyridine calcium channel blockers, have been shown that time of day dosing, particularly evening, is the most advantageous for efficacy of the treatment and normalizing changes in blood pressure rhythms to reduce early morning cardiac events.

Chronotoxicity

predictable- in-time variation in patient vulnerability to the side effects of medications due to biological rhythm determinants.

Chronotoxicities are known especially with antitumor agents. For example, the body weight loss with irinotecan hydrochloride (CPT-11) of nocturnally active mice is more serious in the late active phase and the early rest phase and milder in the late rest phase and the early active phase.

Chrono Drug Delivery Systems (Chrono-DDS)

The technologies in chronopharmaceutics includes:

1. CONTIN – controlled release formulation of Morphine, physicochemical modification of the active pharmaceutical ingredient,
2. chronomodulating infusion pumps, TIMERx, three-dimensional printing, controlled-release erodible polymer and controlled release microchip strategies and Chronotopic, Egalet, CODAS, Geoclock, PORT technologies.
3. As examples of Chrono- DDS on the market, there are compounds such as theophylline (Uniphyl}), famotidine (Pepcid}), simvastatin (Zocor}), COER-verapamil, diltiazem (Cardizem} LA)

Applied Chronopharmacology

Morning daily or alternate day dosing strategy for methylprednisolone that was introduced during the 1960sconstitutes the first chronotherapy to be incorporated into clinical practice.

Asthma

One of the most extensively studied examples of time-dependent dosing on drug effect and toxicity is glucocorticoid receptor (GR) agonists.

The natural ligands for GR are glucocorticoids, predominantly cortisol, and are synthesized from cholesterol precursors in the adrenal cortex under tight regulation from hypothalamo-pituitary axis.

Circulating levels of glucocorticoids fluctuate in a circadian manner, with the highest levels observed in the morning and the lowest levels in the late evening in diurnal animals.

the timing of prednisone was absolutely critical for the relief of the nocturnal worsening of the symptoms and the 1500 h administration of prednisone was effective while dosing at either 0800 h or 2000 h was ineffective.

Asthma- The risk of asthmatic attack is almost 70 times higher in patients at 04:00-05:00.

Theophylline chronotherapy – Evening, once daily dosing of specially formulated theophylline tablets for nocturnal asthma. Therapeutic drug concentrations during the night and avoiding toxic levels during the day.

Oral prednisone (3 pm) is much more effective in improving nocturnal asthma rather than 8 am and 8 pm dose barely better than placebo.

Allergic rhinitis

The major symptomes are usually worst in the morning and evening.

Chronotherapy: non-sedating antihistamine once daily before bedtime to control overnight exacerbations morning oral corticosteroid therapy for severe allergic rhinitis.

Arthritis

symptoms of rheumatoid arthritis are always worse in the morning.

Taking long-acting NSAIDs like flubiprofen, ketoprofen and indomethacin at bedtime optimizes their therapeutic effect and minimizes or averts their side effects.

osteoarthritis, the most common form of the disease, tend to have less pain in the morning and more at night. The optimal time for a NSAIDs such as ibuprofen would be around noon or mid-afternoon.

Circadian changes in the pH levels of the stomach.

Acidity (H+) reaches its peak in the evening in both the healthy and patients affected by gastric ulcers. In peptic ulcer patients, there will be a maximum acid secretion, ulcer pain, and exacerbation during night.

Administration of H antagonists drugs at bedtime is more effective in reducing acid secretion and promoting ulcer healing. Evening administration of ranitidine is justified from the point of view of chronopharmacology.

Congenital adrenal hyperplasia –

Bedtime corticosteroid dosing controls excessive hormone secretion Bedtime ADH analogue dosing helps to alleviate nocturnal bedwetting in children and nocturia in adults.

Morning application of testosterone drug-delivery patch systems to achieve physiologic androgen-replacement therapy.

Myocardial infarction

A 40% increase in risk of myocardial infarction occurs between 6 am and noon. A 29% of increase in sudden cardiac death in early morning hours and 49% increase in stroke risk between 6 am and noon have been noted.

faster reduction in BP with morning dose of enalapril, maximum vasodilatation occurs with morning dose of nitrates, 3hydroxy3methylglutarylcoenzyme A (HMGCoA) reductase inhibitor being more effective when administered in the evening with exception of atorvastatin.

Before-bedtime administration of verapamil HCL as a unique controlled onset extended-release 24 hr dosage form to optimize the treatment of patients with ischemic heart disease and/or essential hypertention.

Evening administration of HMG-CoA-reductase antagonists for the management of hyperlipidemia.

Anticancer

Many anticancer therapeutics have been shown to exhibit differing effects and toxicity based on administration time

Colorectal cancer- Oxaliplatin is given in during daytime & flurouracil at night.

Chronopharmacology in Ayurveda

Altered chronobiology (study of alterations of each organisms temporal structure under various situations) manifested as vitiated dosas because of change of seasons or altered habits does decrease the performance, that’s why Ayurveda suggests avoidance of sahasa (stress) and observance of regular habits in the form of dinacarya. Ayurveda recommends the consumption of preparations at specific times during the day

Abhakta	Drugs in morning absorption is maximum and more efficient
Pragbhakta	Just before food. For diseases of apana vayu – for strengthening and preventing the disease of lower half of body and treating obesity.
Madhyabhakta	In between foods. For diseases of samana vayu, disease of koshtas and for paittic diseases.
Sanya Pscadbhakta	In evenings after food. For diseases of udana vayu.
Muhurmuhuh	Drugs given repeatedly for treating swasa (dyspnoea), kasa (cough), hikka (hiccoughs), chardi (vomitting), visa (poisoning) and pipasa (Thirst).
Samudga	Before and after light food in hikka, akepsa(convulsions) and in diseases of head and neck.
Sabhakta	Drugs as appetizers with food, in children with weak constitution.