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Chronopharmacology in
Cardiovascular Diseases
Presentation by
Payaam Vohra
M.S. (Pharm.) Pharmacology and Toxicology
23PCM3895
Supervisor
Prof. Shyam .S. Sharma
1
FLOW OF PRESENTATION
• INTRODUCTION
• TERMINOLOGIES
• EPIDEMIOLOGY AND STATISTICS
• CHRONOPHARMACOLOGY AND CVS
• CONNECTION BETWEEN CIRCADIAN CLOCK GENES AND CVS
• NOVEL INSIGHTS
• SUMMARY
• REFERENCES 2
TERMINOLOGIES
3
DEFINITIONS
Buurma, Marleen et al Frontiers in Cardiovascular Medicine 84 (6),2019
Chronobiology
Chronopharmacology
Rhythm-dependent differences in the absorption, distribution, metabolism, and
elimination of medications
Refers to treatment method in which drug availability is timed to
match rhythms of disease to optimize therapeutic outcomes and
minimize side effects
The scientific study of biological rhythm
The study of extent to which the kinetics and dynamics of medications are affected
by endogenous biological rhythms, along with dosing time of medications and the
features (period, level, amplitude) of biological rhythms
Chronotherapeutics
Chronokinetics
4
INTRODUCTION
Mia S, Sonkar et al The FASEB Journal.;35(3), 2021
Biological System Disease/ Syndrome Biological rhythmicity
Respiratory Allergic rhinitis Worse in morning/upon rising
Asthma Exacerbation more common during sleep period
Inflammatory Rheumatoid arthritis Symptoms are more intense upon awakening
Osteoarthritis Symptoms worse in the middle/later portion of the day
Cardiovascular Hypertension Incidence greatest in the early morning between 4-6 am
Myocardial infarction Incidence greatest in the early morning
Strokes Incidence higher in the morning
Sudden Cardiac Death Incidence higher in the morning after awakening
Angina Pectoris Chest pain and ECG changes more common in early morning
Gastrointestinal Peptic ulcer disease Worse in late evening and early morning hours
Endocrinology Hormonal deficiency, Diabetes Glucose level is highest at night time, insulin secretion highest at week hours of morning
5
Epidemiology
Every year, an estimated 17 million
people globally die of cardiovascular
diseases (CVD), particularly heart
attacks and strokes. CVDs occur
almost equally in men and women.
In Asia CVDs accounts
18% of the deaths
Deaths from cardiovascular disease (CVD)
jumped globally from 12.1 million in 2016
to 20.5 million in 2022, according to a new
report from the World Heart Federation
(WHF). CVD was the leading cause of
death worldwide in 2021
6
STATISTICS
Among cardiovascular diseases, Hypertension, Angina Pectoris, Acute Myocardial Infarction and Ischemic
stroke present a circadian pattern with a greater incidence of unfavourable events between awakening and noon..
Chai, Ruoning et al. 2023,European Journal of Medical Research, 28(1):194
7
CLOCK: Circadian Locomotor Output Clock Katput
BMAL:Brain and Muscle Arnt Like genes
Cry: Circadian Cryptochrome
Regulation of Circadian Rhythms
8
Circadian clock and Cell Death associated with cardiomyocytes
Crnko S, Du et al ,Nature Reviews Cardiology 16(7):437-47. 9
CONNECTION BETWEEN CIRCADIAN CLOCK GENES AND CVS
Mia S., Kane et al. Am J Physiol Heart Circ Physiology 318:6: H1487-H1508,2020,
Alignments of
extrinsic (ie, behavior control of blood
pressure)
intrinsic (ie, clock control of PAI-1)
Regulated by
(eg, PAI-1 is a direct BMAL1/CLOCK
target gene),
fluctuate in response to behaviors (eg,
blood pressure)
Adverse Ischemic events during late night is majorly due to
Shear stress, clotting factors and platelet
aggregability
Neurohumoral factors (eg, cortisol).
10
MORNING SURGE
This is majorly
due to high
amount of
Catecholamine
release
This is known as
Morning Surge
BP is at its
lowest during
sleep stage and
rises steeply
during early
morning and
late night
Superahiasmatic
nucleus (SCN) is the
main pacemaker for
endogenous biological
rhythms
Chong, Nelson et al, Frontiers in Pharmacology , 13;14:1132735, 2023 11
REASONS FOR MORNING SURGE
Supe
Morning Hours
Enhanced Nor
Epinephrine
activity ,Cortisol
and Renin Activity
Increased
Sympathetic tone
Boosted Platelet
aggregability and
decreased
fibrinolytic activity
Capillary
resistance and
Vascular Reactivity
Sandra, et al, Nature Reviews Cardiology 16(7),437-47
12
CHRONO GENES ASSOCIATED WITH CVD
Genes Effects References
BMAL Loss of physiological rhythms in heart rate and
blood pressure
(Rigamonti et al., 2022)
CLOCK Bradycardia, disruption of normal heart rate
and rhythm
(Scheiermann et al.,
2018)
PER2 Endothelial dysfunction (Tampakakis et al.,
2021)
CRY Cardiomyopathy, cardiac fibrosis, impaired
cardiac contractility
(Buurma et al., 2019)
13
VARIABILITY IN EFFECTS OF ANTIHYPERTENSIVE MEDICATIONS
Smolensky et al. Current Opinion in Pharmacology 1;57:41-8,2021
14
DOSING ACCORDING TO CHRONOPHARMACOLOGY
Yuan, et al Frontiers in Immunology 14(11),102 2019.
Medication Treatment times Comparison of morning vs. evening dosing
Valsartan Awakening bedtime Significant reduction in asleep SBP/DBP with evening dosing
Olmesartan Awakening bedtime Significant reduction in asleep SBP/DBP with evening dosing
Telmisartan Awakening bedtime Significant reduction in asleep SBP/DBP with evening dosing
Trandolapril Awakening bedtime Significant reduction in 24-h BP mean with evening dosing
Ramipril Awakening bedtime Significant reduction in 48-h SBP/DBP mean with evening dosing
Spirapril Awakening bedtime Significant reduction in asleep SBP/DBP with evening dosing
Nifedipine Awakening bedtime Significant reduction in 48-h SBP/DBP mean with evening dosing
Torasemide Awakening bedtime Significant reduction in 48-h SBP/DBP mean with evening dosing
15
RESEARCH STUDIES ON CARDIOPROTECTIVE ACTIVITY
Supe
Tampakakis, Emmanouil et al.Science Advances 7(49), 2021. 16
Technology API used References
Ceform Technology Verapamil (Gowthami,
Krishna, and
Rao 2021)
Chronomodulating Infusion
Pumps
Felodipine (Ballesta et al.
2017)
TIMERx Technology Losartan (Gangadhar et al.
2022)
Diffu Caps Technology Nifedipine (Amit and Sonam
2012; Battu et
al. 2018)
Chronotherapeutics Oral Drug
Absorption System
(CODAS):-
Verapamil (Prisant, Devane,
and Butler
2019)
OROSOR Verapamil (Syed mujtaba
pasha et al.
2019)
NOVEL INSIGHTS
Gangadhar, B et al International Journal of Research in Ayurveda and Pharmacy 13(6),2019
PULSATILE DRUG
DELIVERY SYSTEMS
CIRCADIOMICS
17
NOVEL INSIGHTS
18
SUMMARY
1
2
3
Revolutionize drug
development
Develop more effective
and safer medications for a
wide range of diseases
with minimized side
effects
Interventions designed with
chronobiology in optimizing
chronotherapeutics
Modulating drug delivery
systems for maintenance of
cardiovascular functioning
4
19
• Battu, Sowjanya et al. 2018. “Design and Assessment of Pulsatile Technology Based Chronomodulated Delivery Systems of Nifedipine.” Beni-Suef University
Journal of Basic and Applied Sciences 7(4).
• Benjamin, Emelia J. et al. 2017. “Heart Disease and Stroke Statistics’2017 Update: A Report from the American Heart Association.” Circulation 135(10).
• Brzezińska, Agnieszka, Aleksandra Skorupa, Aleksandra Nowińska, and Justyna Nowaczek. 2022. “Circadian Rhythm and Heart Disease - What Is the Link? A
Review.” Journal of Education, Health and Sport 12(12).
• Buurma, Marleen et al. 2019. “Circadian Rhythm of Cardiovascular Disease: The Potential of Chronotherapy With Aspirin.” Frontiers in Cardiovascular
Medicine 6.
• Man, Andy W.C., Huige Li, and Ning Xia. 2021. “Circadian Rhythm: Potential Therapeutic Target for Atherosclerosis and Thrombosis.” International Journal of
Molecular Sciences 22(2).
• Marjot, Thomas, David W. Ray, and Jeremy W. Tomlinson. 2022. “Is It Time for Chronopharmacology in NASH?” Journal of Hepatology 76(5).
• Pagel, René et al. 2017. “Circadian Rhythm Disruption Impairs Tissue Homeostasis and Exacerbates Chronic Inflammation in the Intestine.” FASEB Journal
31(11).
• Potucek, P., and J. Klimas. 2020. “Chronopharmacology of High Blood Pressure - a Critical Review of Clinical Evidence.” European Pharmaceutical Journal.
• Chai, Ruoning et al. 2023. “Circadian Rhythm in Cardiovascular Diseases: A Bibliometric Analysis of the Past, Present, and Future.” European Journal of
Medical Research 28(1).
• Crnko, Sandra, Bastiaan C. Du Pré, Joost P.G. Sluijter, and Linda W. Van Laake. 2019. “Circadian Rhythms and the Molecular Clock in Cardiovascular Biology
and Disease.” Nature Reviews Cardiology 16(7).
• Gangadhar, B., B. Sai Bhanu Sree, PV Swamy, and M. Aruna Devi. 2022. “PULSATILE DRUG DELIVERY SYSTEM: A REVIEW.” International Journal of
Research in Ayurveda and Pharmacy 13(6).
• Gowthami, Buduru, S. V.Gopala Krishna, and D. Subba Rao. 2021. “Application of Coating Technology to Chronotherapeutic Drug Delivery Systems: Recent
Publications and Patents.” Current Research in Pharmacology and Drug Discovery 2.
REFERENCES
20
THANK YOU !
The rhythm of the body along with melody of mind
and harmony of soul creates the symphony of life
21

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ChronoPharmacology in Body Functioning and in Cardiovascular Diseases.ppt

  • 1. Chronopharmacology in Cardiovascular Diseases Presentation by Payaam Vohra M.S. (Pharm.) Pharmacology and Toxicology 23PCM3895 Supervisor Prof. Shyam .S. Sharma 1
  • 2. FLOW OF PRESENTATION • INTRODUCTION • TERMINOLOGIES • EPIDEMIOLOGY AND STATISTICS • CHRONOPHARMACOLOGY AND CVS • CONNECTION BETWEEN CIRCADIAN CLOCK GENES AND CVS • NOVEL INSIGHTS • SUMMARY • REFERENCES 2
  • 4. DEFINITIONS Buurma, Marleen et al Frontiers in Cardiovascular Medicine 84 (6),2019 Chronobiology Chronopharmacology Rhythm-dependent differences in the absorption, distribution, metabolism, and elimination of medications Refers to treatment method in which drug availability is timed to match rhythms of disease to optimize therapeutic outcomes and minimize side effects The scientific study of biological rhythm The study of extent to which the kinetics and dynamics of medications are affected by endogenous biological rhythms, along with dosing time of medications and the features (period, level, amplitude) of biological rhythms Chronotherapeutics Chronokinetics 4
  • 5. INTRODUCTION Mia S, Sonkar et al The FASEB Journal.;35(3), 2021 Biological System Disease/ Syndrome Biological rhythmicity Respiratory Allergic rhinitis Worse in morning/upon rising Asthma Exacerbation more common during sleep period Inflammatory Rheumatoid arthritis Symptoms are more intense upon awakening Osteoarthritis Symptoms worse in the middle/later portion of the day Cardiovascular Hypertension Incidence greatest in the early morning between 4-6 am Myocardial infarction Incidence greatest in the early morning Strokes Incidence higher in the morning Sudden Cardiac Death Incidence higher in the morning after awakening Angina Pectoris Chest pain and ECG changes more common in early morning Gastrointestinal Peptic ulcer disease Worse in late evening and early morning hours Endocrinology Hormonal deficiency, Diabetes Glucose level is highest at night time, insulin secretion highest at week hours of morning 5
  • 6. Epidemiology Every year, an estimated 17 million people globally die of cardiovascular diseases (CVD), particularly heart attacks and strokes. CVDs occur almost equally in men and women. In Asia CVDs accounts 18% of the deaths Deaths from cardiovascular disease (CVD) jumped globally from 12.1 million in 2016 to 20.5 million in 2022, according to a new report from the World Heart Federation (WHF). CVD was the leading cause of death worldwide in 2021 6
  • 7. STATISTICS Among cardiovascular diseases, Hypertension, Angina Pectoris, Acute Myocardial Infarction and Ischemic stroke present a circadian pattern with a greater incidence of unfavourable events between awakening and noon.. Chai, Ruoning et al. 2023,European Journal of Medical Research, 28(1):194 7
  • 8. CLOCK: Circadian Locomotor Output Clock Katput BMAL:Brain and Muscle Arnt Like genes Cry: Circadian Cryptochrome Regulation of Circadian Rhythms 8
  • 9. Circadian clock and Cell Death associated with cardiomyocytes Crnko S, Du et al ,Nature Reviews Cardiology 16(7):437-47. 9
  • 10. CONNECTION BETWEEN CIRCADIAN CLOCK GENES AND CVS Mia S., Kane et al. Am J Physiol Heart Circ Physiology 318:6: H1487-H1508,2020, Alignments of extrinsic (ie, behavior control of blood pressure) intrinsic (ie, clock control of PAI-1) Regulated by (eg, PAI-1 is a direct BMAL1/CLOCK target gene), fluctuate in response to behaviors (eg, blood pressure) Adverse Ischemic events during late night is majorly due to Shear stress, clotting factors and platelet aggregability Neurohumoral factors (eg, cortisol). 10
  • 11. MORNING SURGE This is majorly due to high amount of Catecholamine release This is known as Morning Surge BP is at its lowest during sleep stage and rises steeply during early morning and late night Superahiasmatic nucleus (SCN) is the main pacemaker for endogenous biological rhythms Chong, Nelson et al, Frontiers in Pharmacology , 13;14:1132735, 2023 11
  • 12. REASONS FOR MORNING SURGE Supe Morning Hours Enhanced Nor Epinephrine activity ,Cortisol and Renin Activity Increased Sympathetic tone Boosted Platelet aggregability and decreased fibrinolytic activity Capillary resistance and Vascular Reactivity Sandra, et al, Nature Reviews Cardiology 16(7),437-47 12
  • 13. CHRONO GENES ASSOCIATED WITH CVD Genes Effects References BMAL Loss of physiological rhythms in heart rate and blood pressure (Rigamonti et al., 2022) CLOCK Bradycardia, disruption of normal heart rate and rhythm (Scheiermann et al., 2018) PER2 Endothelial dysfunction (Tampakakis et al., 2021) CRY Cardiomyopathy, cardiac fibrosis, impaired cardiac contractility (Buurma et al., 2019) 13
  • 14. VARIABILITY IN EFFECTS OF ANTIHYPERTENSIVE MEDICATIONS Smolensky et al. Current Opinion in Pharmacology 1;57:41-8,2021 14
  • 15. DOSING ACCORDING TO CHRONOPHARMACOLOGY Yuan, et al Frontiers in Immunology 14(11),102 2019. Medication Treatment times Comparison of morning vs. evening dosing Valsartan Awakening bedtime Significant reduction in asleep SBP/DBP with evening dosing Olmesartan Awakening bedtime Significant reduction in asleep SBP/DBP with evening dosing Telmisartan Awakening bedtime Significant reduction in asleep SBP/DBP with evening dosing Trandolapril Awakening bedtime Significant reduction in 24-h BP mean with evening dosing Ramipril Awakening bedtime Significant reduction in 48-h SBP/DBP mean with evening dosing Spirapril Awakening bedtime Significant reduction in asleep SBP/DBP with evening dosing Nifedipine Awakening bedtime Significant reduction in 48-h SBP/DBP mean with evening dosing Torasemide Awakening bedtime Significant reduction in 48-h SBP/DBP mean with evening dosing 15
  • 16. RESEARCH STUDIES ON CARDIOPROTECTIVE ACTIVITY Supe Tampakakis, Emmanouil et al.Science Advances 7(49), 2021. 16
  • 17. Technology API used References Ceform Technology Verapamil (Gowthami, Krishna, and Rao 2021) Chronomodulating Infusion Pumps Felodipine (Ballesta et al. 2017) TIMERx Technology Losartan (Gangadhar et al. 2022) Diffu Caps Technology Nifedipine (Amit and Sonam 2012; Battu et al. 2018) Chronotherapeutics Oral Drug Absorption System (CODAS):- Verapamil (Prisant, Devane, and Butler 2019) OROSOR Verapamil (Syed mujtaba pasha et al. 2019) NOVEL INSIGHTS Gangadhar, B et al International Journal of Research in Ayurveda and Pharmacy 13(6),2019 PULSATILE DRUG DELIVERY SYSTEMS CIRCADIOMICS 17
  • 19. SUMMARY 1 2 3 Revolutionize drug development Develop more effective and safer medications for a wide range of diseases with minimized side effects Interventions designed with chronobiology in optimizing chronotherapeutics Modulating drug delivery systems for maintenance of cardiovascular functioning 4 19
  • 20. • Battu, Sowjanya et al. 2018. “Design and Assessment of Pulsatile Technology Based Chronomodulated Delivery Systems of Nifedipine.” Beni-Suef University Journal of Basic and Applied Sciences 7(4). • Benjamin, Emelia J. et al. 2017. “Heart Disease and Stroke Statistics’2017 Update: A Report from the American Heart Association.” Circulation 135(10). • Brzezińska, Agnieszka, Aleksandra Skorupa, Aleksandra Nowińska, and Justyna Nowaczek. 2022. “Circadian Rhythm and Heart Disease - What Is the Link? A Review.” Journal of Education, Health and Sport 12(12). • Buurma, Marleen et al. 2019. “Circadian Rhythm of Cardiovascular Disease: The Potential of Chronotherapy With Aspirin.” Frontiers in Cardiovascular Medicine 6. • Man, Andy W.C., Huige Li, and Ning Xia. 2021. “Circadian Rhythm: Potential Therapeutic Target for Atherosclerosis and Thrombosis.” International Journal of Molecular Sciences 22(2). • Marjot, Thomas, David W. Ray, and Jeremy W. Tomlinson. 2022. “Is It Time for Chronopharmacology in NASH?” Journal of Hepatology 76(5). • Pagel, René et al. 2017. “Circadian Rhythm Disruption Impairs Tissue Homeostasis and Exacerbates Chronic Inflammation in the Intestine.” FASEB Journal 31(11). • Potucek, P., and J. Klimas. 2020. “Chronopharmacology of High Blood Pressure - a Critical Review of Clinical Evidence.” European Pharmaceutical Journal. • Chai, Ruoning et al. 2023. “Circadian Rhythm in Cardiovascular Diseases: A Bibliometric Analysis of the Past, Present, and Future.” European Journal of Medical Research 28(1). • Crnko, Sandra, Bastiaan C. Du Pré, Joost P.G. Sluijter, and Linda W. Van Laake. 2019. “Circadian Rhythms and the Molecular Clock in Cardiovascular Biology and Disease.” Nature Reviews Cardiology 16(7). • Gangadhar, B., B. Sai Bhanu Sree, PV Swamy, and M. Aruna Devi. 2022. “PULSATILE DRUG DELIVERY SYSTEM: A REVIEW.” International Journal of Research in Ayurveda and Pharmacy 13(6). • Gowthami, Buduru, S. V.Gopala Krishna, and D. Subba Rao. 2021. “Application of Coating Technology to Chronotherapeutic Drug Delivery Systems: Recent Publications and Patents.” Current Research in Pharmacology and Drug Discovery 2. REFERENCES 20
  • 21. THANK YOU ! The rhythm of the body along with melody of mind and harmony of soul creates the symphony of life 21