CHRONOPHARMACOLOGY

Dr.Jeevan JacobJR, Pharmacology

Introduction History Definitions Circadian rhythm Applications of Chronopharmacology Future Directions

Overview

The physiological parameters shows a rhythmic change, mostly synchronized with the periodic changes in the environment. biological rhythm.

The ‘Milieu intérieur ’ do not behave constantly in time, but varies with changing external cues like day-night cycle.

Cues- environmental signals/ synchronizers /Entraining Factors/Zeitgebers

Introduction

Circadian: Lasting for about 24 hours. -Sleep wake cycles

Infradian: Cycles longer than 24 hours. -Menstrual cycle

Ultradian: Cycles shorter than a day. -Neuronal firing time

Seasonal: Seasonal affective disorders.

Biological rhythms

Ultraradian

Circadia

nInfra

radianCircaSepta

n

CircaDi

Septan

CircaVi

gintan

CircaTri

gintanCirca

Annual

Biorhythms

T<24 h T h T = 7 d

T>24 h T = 1 y

T = 30 d

T = 21 d

T = 14 d

Jean-Jaques d’Ortous de Mairan : described circadian rhythms of plants in the 18th century.

History

Franz Halberg coined the term ‘Circadian’ in 20th century.

(circa – about or approximately; dies-day, or about 24 hour).

Considered as one of the founders of Modern Chronobiology.

Chronobiology The branch of science focusing on

biological rhythms and their mechanisms. Chronos (time),

Bios (life),

Logos (study).

Definitions

Chronopharmacology Science dealing with optimization of drug effects & minimization of adverse effects by timing medications in relation to biological rhythm. It is concerned with the effects of drugs upon the timing of biological events and rhythms.

Chronokinetics

Subdivision of chronopharmacology which deals with the study of the temporal changes in the pharmacokinetics of the drugs with respective time.

Study of absorption, distribution, metabolism, and excretion of drug according to the time of the day or year.

Definitions

ChronoPharmacodynamics Chronesthesy The rhythmic changes in susceptibility or

sensitivity of a target system to a drug.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

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

Chronergy Rhythmic changes of both the desired

[effectiveness] and undesired [toxicity, tolerance] effects on the organism as a whole.

Definitions

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.

Refers to concept of matching timing of treatment with intrinsic timing of illness.

Advantages Prevents over dosage Appropriate usage of drug Reduce side effects

ChronoPharmaceutics- Branch which designs and develops a drug delivery system in accordance with biological rhythm to optimize the treatment of disease.

Clock genes Supra chiasmatic nucleus

Sleep and activityHormone levelsAppetiteOther bodily functions with 24 hr cycles

Circadian rhythm

Supra chiasmatic nucleus

Zeitgeber

Input pathway -retinohypothalamic tract

Central oscillator [SCN]

Output pathway -manifesting as circadian physiology and behavior

Circadian clock

Per1, Per2, Per3,cry1, cry2,frq,clock,tau

Rhythmically expressed in SCN.

Clock genes

`

E Box

PER 1

PER 3

PER 2

CRY 1

CRY 2RORα

CK1

BMAL 1

LH846 and longdaysin are CK1 inhibitors while indirubin is a GSK3b inhibitor. SR9009 is a REV-ERB agonist and KL001 is an activator of CRY.

Physiological / biochemical parameters showing diurnal variation

Diseases with diurnal pattern of exacerbation

Applications of Chronopharmacology

Increased bronchoconstriction at night.

↑Parasympathetic tone↓ Adrenaline↓ Cortisol at midnight

↑Sensitivity to irritants and allergens at night

-exacerbations of allergic rhinitis & asthma

Respiratory system

Acute attack of asthma- more common between midnight and 6 am.

Theophylline and Beta 2 agonist is timed at evening

1. CONTIN- Complex formed between cellulose polymer and non polar solid aliphatic alcohol which act as matrix

Asthma

BP peaks between 6am and 9am, and 6pm and 7 pm.

BP dips at night, decreases slightly afternoon.

Diastolic BP varies more than systolic.

Cardiovascular system

Night time dip

Morning rise

Myocardial infarctionSudden cardiac deathAngina pectorisTransient ischemic attacks / Stroke

High incidence between 6am and 12 noon. ↑ Vascular tone ↑ Platelet aggregation ↓ Intrinsic thrombolytic activity.

Cardiovascular Disorders

Aspirin – maximum antiplatelet effect in the morning.

Thrombolytics and Heparin – ↓ benefit during early morning hours.

Atenolol – more effective during day time.

Labetalol – more effective in early morning hours.

Cardiovascular drugs

Enalapril Peak effect in the afternoon after morning

dose, Early morning after evening dose.

Cardiovascular drugs

Highest secretion of cortisol early morning. Lowest at midnight. GH peaks during sleep. Testosterone peaks early morning. TSH peaks at mid night. Corticosteroids given as single morning

dose cause less pituitary adrenal suppression

Endocrine system

Insulin – regular pulses every 5 – 15 min. Non diabetics: ↓ glucose tolerance in the

later part of the day.- ↓ utilization-↓ insulin sensitivity

T2 DM: progressive glucose tolerance from morning to evening.- higher dose of insulin in the morning.

Diabetes

Acid secretion peaks between 10 pm and 2 am.

Ulcer pain is worst at this time.

Ulcer healing is directly related to acid secretion inhibition at night.

Evening dosage of H2 receptor antagonists

Gastrointestinal tract

Melatonin – secreted at night by pineal gland.

Function – synchronizes sleep wake cycle with circadian rhythm.

Melatonin agonist[Ramelteon] – hypnotic for sleep onset insomnia.

Reduces Jet lag symptoms. Bedtime administration of hypnotics- more effective.

CNS

Rheumatoid Arthritis

Symptoms more severe - 8am & 11am.

Long acting NSAIDS at bed time

Musculoskeletal system

Osteoarthritis

Pain more intense between 2 pm and 8 pm.

Morning dose for afternoon worsening, evening dose for night time worsening.

Cholesterol synthesis more at night.

Evening dose of HMG CoA reductase inhibitors is more effective than morning dose.

Hypercholesterolemia

Cancer cells are considered to have lost internal time keeping mechanism.

Tumor cells and normal cells differ in their chronobiological cycles.The basis for the chronopharmacotherapy of

cancers.

Cancer

The DNA synthesis in the normal human bone marrow cells has a peak around noon while the peak of DNA synthesis in lymphoma cells is near midnight.

So, an s-phase active cytotoxic therapy at late nights should be more advantageous

Lymphoma

A comparison study* included 118 children received maintenance chemotherapy of mercaptopurine and methotrexate around the period from 1976 to 1984

It was found that the risk of relapse was 2.56 times higher in children who received chemotherapy in the morning than in those receiving in the evening.

*Circadian time dependent response of childhood lymphoblastic leukemia to chemotherapy: A long-term follow-up study of survival. Chronobiology International, 10(3): 201-4.

Acute lymphoblastic leukemia

Continuous infusion over 24 hrs

Oxaliplatin during day time, Folinic acid & Flurouracil at night.(chronotherapy group )

Statistically significant differences in complete and partial remission rates between the constant-infusion group (29%) and chronotherapy group (51%) were found

Colorectal cancer

Doxorubicin – last stage of sleep / before normal waking time.

Cisplatin: Maximum toxicity and kidney damage in the morning.

Psoriasis: cell proliferation rate peaks between 9pm & 3am.

-Inflammatory activity highest at night, least in the morning.

Atopic dermatitis: sensitivity to histamine highest at night.

Skin Disorders

Lignocaine: Skin penetration at 11am twice that at 8am.

Topical corticosteroids: activity in the afternoon higher than that in the morning.

Skin Medications

Chrono Drug Delivery Systems (Chrono-DDS)

OROS, CODAS, CEFORM, TIMERx, POLYMERS, MICROCHIPS

Design and development of ChrDDS:

Chronopharmaceutical technologies:

1. CONTIN technology 2. Physico-chemical modification of the API 3. OROS technology 4. CODAS technology 5. CEFORM technology 6. DIFFUCAPS technology 7. Chronomodulating infusion pumps 8. TIMERx technology 9. Other CR erodible polymers 10. Controlled-release microchip

MARKETED DRUGSFDA

approval date

API Propriatory name;dosage

form

Chronopharmaceutical tchnology

Indication

Sept. 01, 1982

Theophylline Uniphyl CONTIN ASTHMA

Oct. 15, 1986

Famotidine PepcidR; tablets

Physico-chemical

modification of API

Ulcer

Dec. 23, 1991

Simvastatin ZocorR; Tablets

Physico-chemical

modification of API

Hypercholesterolemia

Feb. 26, 1996

Verapamil HCl Covera-HSRTablet

OROS Hypertension

Nov. 25, 1998

Verapamil HCl VerelanRPM; Capsule

CODAS Hypertension

Feb. 06, 2003

Diltiazem HClverapamil HCl

CardizemR LA;Tablet

CEFORM Hypertension

Mar. 12, 2003

Propranolol HClverapamil HCl

InnoPranR XLCapsule

DIFFUCAPS Hypertension

One of the major challenges in Chronopharmacology is the Identification of Circadian Oscillations at the protein level.

Future directions

Effectiveness and toxicity of a drug are not constant over 24 hr period.

Understanding the biological rhythms can optimize and individualize drug therapy to a great extent.

Thus it can help to decrease the drug related toxicity and enhance effectiveness

Conclusion

THANK YOU