L10 - Cardiovascular Pharmacology PDF

PHAR-20030 Pharmacology Cardiovascular Pharmacology Teaching Block Ass. Prof. Monica de Gaetano, PhD Pharmacology  My Background Classical High School (Latin & Greek) BSc in Pharmaceutical Chemistry MSc in Environmental Toxicology PhD...

PHAR-20030 Pharmacology Cardiovascular Pharmacology Teaching Block Ass. Prof. Monica de Gaetano, PhD Pharmacology  My Background Classical High School (Latin & Greek) BSc in Pharmaceutical Chemistry MSc in Environmental Toxicology PhD in Biomolecular & Biomedical Science (SBBS, Belton Lab) Post Doc in Medicinal Chemistry (SoM, Godson Lab) Ass Prof in Cell Biology & Genetics (SBES) Ass Prof in Pharmacology (SBBS, Ad Astra Fellow) My Research My Teaching Resolution of CV & Renal Pharmacology Inflammation Advanced Immunology ▪ PHAR20030 ▪ PHAR20040 Macrovascular ▪ PHAR30020 Diabetes Complications ▪ PHAR30110 ▪ PHAR40030 Drug ▪ BMOL40410 Discovery CV teaching block Schedule  CV teaching block Syllabus Lecture 1 - Regulation of Cardiovascular (CV) function Lecture 2 - Anti-hypertensive Lecture 3 - Angina & Dyslipidemia Lecture 4 - Anti-platelets & Anti-coagulants Lecture 5 - Renal System & Diuretics Lecture 6 – Mid-Term Review Session Lecture7 – End-of-Term Review Session WHY A TEACHING BLOCK ON CVD PHARMACOLOGY? CARDIOVASCULAR DISEASE (CVD): a Global Pandemic no longer concentrated in Western countries involved in the majority of deaths worldwide Dai H, Much AA, Maor E, et al. Global, regional, and national burden of ischaemic heart disease and its attributable risk factors, 1990-2017: results from the Global Burden of Disease Study 2017. Eur Heart J Qual Care Clin Outcomes. 2022;8(1):50-60.  CVD Pharmacology Milestones ▪ Discovery of  adrenergic & ACE receptors, as blood pressure checkpoints - 50’s ▪ Development of anti-hypertensives: − -blockers (i.e. propranolol, James Black) - 60’s - ACE inhibitors (i.e. Captopril) - 70’s ▪ Discovery of the LDL metabolic pathway - 70’s ▪ Development of statins to tackle LDL metabolic pathway - 80’s ▪ Discovery of PCSK9 gene as molecular mediator of LDL metabolism - 2003 ▪ Development of PCSK9 inhibitors, reducing LDL & rate of MI/stroke - 2017 What will be next-generation therapy ???  CV teaching block Overview Which Diseases ? How to treat ? ▪ Hypertension (HTN) ▪ Atherosclerosis Drug classes (Dyslipidemia) ▪ Targeted sites ▪ Heart Disease (Angina) ▪ Main Uses ▪ Elective drugs Which Systems? (targeted by drugs) ▪ Most prescribed Sympathetic Nervous System (SNS) How to study ? Renin-Angiotensin-Aldosterone System (RAAS) Coagulation system N. A. C. (Haemostasis) (Pharm Learning Tool) Haemodynamics & heart ❑ Nature Renal System ❑ Action Liver/RCT (brief mention) ❑ Consequences (include S/E)  How to perform well at EXAM ? N. A. C. (Pharm Learning Tool) ❑ Nature ❑ Action ❑ Consequences (include S/E) Nature: Is the drugs a - receptor agonist/antagonist (surface or nuclear receptor)? - enzyme inhibitor or stimulator? - channel blocker or stimulator? Action:What receptor/enzyme/channel do they target? Consequence: What is the effect of blocking the receptor/enzyme? What are the side effects? PHAR20030 – CV PHARMACOLOGY TEACHING BLOCK 3rd October 2024 LECTURE 1 CARDIOVASCULAR SYSTEM: STRUCTURE, FUNCTION & REGULATION Dr Monica de Gaetano Ass. Prof. in Pharmacology School of Biomolecular & Biomedical Science UCD Conway Institute (F070) [email protected]  Learning Outcome Today’s Learning Outcome By the end of today’s lecture, you should be able to… 1. Describe the anatomo-physio-pathology of CV system 2. Define the role of Adrenergic Nervous System (ANS) and adrenergic receptors in CV system 3. Provide examples of where adrenergic receptor agonists and antagonists are used 4. Understand the hemodynamics controlling the heart (ie heart rate) 5. Define the Renin-Angiotensin-Aldosterone-System and its role in CV disease 6. Define the role of Nitric Oxide (NO) and other important mediators in the CV system  Today’s Lecture Lecture 1 Structure PART I. CARDIOVASCULAR SYSTEM Definition Components (anatomy) Functions (physio-pathology) PART II. ADRENERGIC SYSTEM Neurotransmitters Receptors distribution and function Agonist and Antagonists PART III. HAEMODYNAMICS and the HEART Renin-Angiotensin-System (RAS) RAS Antagonists Vasodilators: Calcium Blockers & Nitric Oxide PART IV. Summary & Conclusion o MCQ & T/F Summary Take home message  Today’s Lecture PART I. CARDIOVASCULAR SYSTEM PART I. CARDIOVASCULAR SYSTEM Definition Components (anatomy) Functions (physio-pathology) PART II. ADRENERGIC SYSTEM Neurotransmitters Receptors distribution and function Agonist and Antagonists PART III. HAEMODYNAMICS and the HEART Renin-Angiotensin-System (RAS) RAS Antagonists Vasodilators: Calcium Blockers & Nitric Oxide PART IV. Summary & Conclusion o MCQ & T/F Summary Take home message  Cardiovascular system The circulatory system or cardiovascular [CV] system delivers oxygen & nutrients throughout the body by way of a complex network of vessels (arteries, arterioles, capillaries, veins and venules) David Darling, Year in Review 2020, NEJM  CV Physiology Functions of CV System Maintain homeostasis and favorable cellular environment Provide continuous and controlled flow of blood through capillaries to every cell Deliver O2 and nutrients to cells Remove and transport waste for elimination (transport & exchange)  CV Anatomo-Physiology Components of the CV System: Heart (i) Physiology (ii)Electrophysiology Blood Vessels (i) Arteries (ii) Veins (iii) Capillaries Blood Cells (i) Erythrocytes (ii) Leukocytes (iii) Platelets  Structure of components Heart Physiology: - Deoxygenated blood via pulmonary artery to lungs - Re-oxygenated blood from pulmonary vein to body via aorta Electrophysiology: The heart is electric! Co-ordination of contraction by a conducting system  Structure of components Vasculature Arteries Tunica media- smooth muscle thickest layer providing support and changing vessel diameter to regulate blood flow and pressure Veins Less smooth muscle and connective tissue Thinner walls - less pressure than in the arteries Valves- blood flowing toward the heart (unidirectional flow) Both lined by endothelial cells → which releases vasoactive substances that affect diameter and flow  Structure of components Blood cells Erythrocytes anuclear contain Hb transport O2 to lungs Leukocytes defense cells Platelets form “plugs” to stop leaks from blood vessels  CV Anatomo-Physiology Functions based on components: ✓ Heart [i.e. Cardiac pumping ability] Pace-making electrical signals Force of contraction ✓ Blood Vessels [i.e. Integrity of vasculature] Presence of blockage Muscular tone/structural integrity Pressure drop needed to move blood to and through capillary beds ✓ Blood [i.e. Volume / Composition] Water, electrolyte, iron balances Lipid and protein composition  CV Pathology Cardiovascular Disease (CVD): the Big Umbrella CVD is a term for all types of diseases affecting heart or blood vessels: 1) Coronary Artery Disease (CAD) 2) Peripheral Artery Disease (PAD) 3) Heart Diseases (HD) {ie Angina, Heart Failure, Myocardial Infarction} Careful with terminology !!! “Heart disease” is a ‘catch-all phrase’ for a variety of conditions affecting the heart …All heart diseases are CVD, but not all CVD are heart disease…  Today’s Lecture PART II. ADRENERGIC SYSTEM PART I. CARDIOVASCULAR SYSTEM Definition Components (anatomy) Functions (physio-pathology) PART II. ADRENERGIC SYSTEM Neurotransmitters Receptors distribution and function Agonist and Antagonists PART III. HAEMODYNAMICS and the HEART Renin-Angiotensin-System (RAS) RAS Antagonists Vasodilators: Calcium Blockers & Nitric Oxide PART IV. Summary & Conclusion o MCQ & T/F Summary Take home message  Adrenergic Nervous System (ANS) regulation of CV system ❖ Adrenergic or Autonomous or Sympathetic nervous system (ANS/SNS) controls – Exocrine excretion – Metabolic processes – Smooth muscle cells activity (contraction or relaxation) – Rate and force of heart ❖ Main neurotransmitters (endogenous agonists) Catecholamines (CAs) o Adrenaline (or Epinephrine) o Noradrenaline (or Norepinephrine) Sympathetic – taking action in emergency situations: fight or flight ! SNS releases CAs → to INCREASE HEART RATE Acetylcholine (ACh) Parasympathetic – restoring equilibrium after a sympathetic action PNS releases Ach → to DECREASE HEART RATE  Distribution of Adrenergic Receptors Adrenergic receptors -adrenergic receptors -adrenergic receptors 1 2 1 2 Effects on Heart & Blood Vessels Blood vessels - Smooth muscle & calcium influx lead to increased concentration  Adrenergic agonists and the heart Adrenaline (or Epinephrine) Activates all adrenergic receptor subtypes – Cardiac muscle 1 receptor → Increases force and rate of contraction (adrenalin used for cardiac arrest) – Vascular Smooth Muscle 1 receptor → contract vSMC in arterioles 2 receptor→ relaxes (dilate) vSMC in skeletal muscle, liver, GI Alters cerebral and coronary blood flow – Other Muscles 2 receptors localised on lung epithelium →Bronchodilator (2-mediated) → used for Acute asthma attacks Decreases uterine contractions  Use of Adrenaline in Anaphylaxis What is Anaphylaxis? Benefit of Adrenaline Causes Peripheral Vasodilation Increase in peripheral vascular Smooth muscle contraction Bronchoconstriction resistance Improvement in blood Symptoms pressure Flushing (red and hot) Increased capillary permeability (swelling) Reduction in angio-oedema → angio-, laryngeal, pulmonary oedema Hypotension Reduced consciousness Abdominal cramps Urticaria Bradycardia Time to cardiac or respiratory arrest: 30 minutes for food allergens 15 minutes for insect venom 5 minutes for medications  ANS and CV System - Main Effects Effects on the Heart of Catecholamines ❖ Physiological effects 1 (cardio) receptors increase cAMP Increase Ca2+ channel opening Increase intracell calcium Increase heart rate & force of contraction Increase cardiac efficiency ❖ Pathological effects: Hypertension Cardiac failure Myocardial infarction  Adreno-blockers Catecholamine antagonists ❖ Endogenous (natural) (ie Adenosine) ❖ Exogenous (drugs) (ie B-blockers)  -adrenergic receptor antagonists ( blockers) Cardio-selective (1) and Non-selective (1 and 2) receptor antagonists Used in: ▪ angina - reduce cardiac work ▪ hypertension - reduce cardiac output, renin release ▪ post MI - inhibit the increase in SNS activity S/E’s o Non-selective (ie propranolol) - nightmares, depression, insomnia (central effects as it crosses BBB) - Bronchoconstriction (contraindicated in asthmatics:  blockers can block 2 adrenoreceptors in the lungs, which normally cause bronchodilation) - Hyperglycaemia (contraindicated in diabetics → inhibits insulin release) o Cardio-selective (ie Atenolol) Higher Theraputic dosage only target Beta 1 dose may also effext everywhere else - do not have “central” effects - *less risk of bronchoconstriction (*selective rather than specific → less risk rather than no risk)  Today’s Lecture PART III. HAEMODYNAMICS and the HEART PART I. CARDIOVASCULAR SYSTEM Definition Components (anatomy) Functions (physio-pathology) PART II. ADRENERGIC SYSTEM Neurotransmitters Receptors distribution and function Agonist and Antagonists PART III. HAEMODYNAMICS and the HEART Renin-Angiotensin-System (RAS) RAS Antagonists Vasodilators: Calcium Blockers & Nitric Oxide PART IV. Summary & Conclusion o MCQ & T/F Summary Take home message  Haemodynamics and the heart Bloos pressure  Haemodynamics and the heart CO = HR x SV Cardiac output = heart rate x stroke volume Heart rate (HR) (number of beat/minute) Stroke volume (SV) (volume of blood pumped out of the left ventricle during each systolic cardiac contraction) Venous return or ‘preload’= Determines the volume in ventricle at each beat Peripheral resistance or ‘afterload’= determines the arterial pressure that must be overcome by the pumping system Renin-Angiotensin-System Renin-Angiotensin-System Inhibitors  Renin-Angiotensin-Aldosterone-System Inhibitors RAAS in disease Increase RAAS activity in: – hypertension Long-term activation contributes to cardiac and vascular remodeling → hallmarks of cardiac failure Drugs: – Angiotensin Converting Enzyme (ACE) inhibitors (ACEi) – Angiotensin II receptor (AT1 receptor) antagonists (ARAs / ARBs) - Aldosterone antagonists (K+ sparing diuretics) – Renin inhibitors RAAS blockers used in: - hypertension - Heart failure Vascular Tone Regulation  Vasodilators (i): Calcium channel Blockers Influx of Ca++ causes Ca++ channel blockers cause vasoconstriction vasodilation Ca channel blocker Calcium ions channel blockers used in: - hypertension - angina  Vasodilators: Nitric Oxide (NO) ▪ Biosynthesis: Synthesized in endothelial cells from L-arginine by the endothelial Nitric oxide synthase (eNOS) ▪ Effect: Causes relaxation of vascular smooth muscle cells ▪ How? Mechanism of Action of NO  Vasodilators: Nitrates - NO has a very short half life - Nitrates are pro-drugs, when metabolised release Nitric Oxide (NO)  Today’s Lecture PART IV. Summary & Conclusion PART I. CARDIOVASCULAR SYSTEM Definition Components (anatomy) Functions (physio-pathology) PART II. ADRENERGIC SYSTEM Neurotransmitters Receptors distribution and function Agonist and Antagonists PART III. HAEMODYNAMICS and the HEART Renin-Angiotensin-System (RAS) RAS Antagonists Vasodilators: Calcium Blockers & Nitric Oxide PART IV. Summary & Conclusion o MCQ & T/F Summary Take home message Use Poll Everywhere to participate to Quizzes Please scan QR code PollEv.com/monicadegaetano244  SUMMARY – part I ANS and the vasculature variety of receptors with different effects specific to vascular beds vasoconstrictive b1 adrenoceptors most important 1 antagonists used in hypertension ANS and the heart 1 adrenergic receptors increase rate and rhythm ANS activity in diseases – hypertension, heart failure, myocardial infarction -blockade useful in many disorders 1-cardio-selective agents usually preferred Adrenergic agonists Adrenaline used in anaphylaxis  TAKE HOME MESSAGE ❖ In order to maintain homeostasis, controlling blood flow, providing O2 and nutrients to cells, by also removing waste, the CV system has 3 main components to regulate its functions: heart, vessel and blood ❖ The CV system is also controlled by the adrenergic system (ANS) composed by 2 main neurotransmitters (adrenaline and acetylcholine) and their receptors ❖ To treat most of CVDs (i.e. heart diseases and hypertension) drugs can act on: - adrenergic receptors (mainly controlling heart rate) - RAAS (mainly controlling blood volume) - NO formation (controlling vascular tone) THANKS FOR YOUR ATTENTION !!! 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