NUR1125 - Pathophysiology, Pharmacology & Nursing Practice I - Cardiovascular Pharmacology Consolidation Session.pdf

NUR1125 – Pathophysiology, Pharmacology & Nursing Practice I Cardiovascular Pharmacology Consolidation Session Dr. David Fann [email protected] Department of Pharmacology, Yong Loo Lin School of Medicine National Univ...

NUR1125 – Pathophysiology, Pharmacology & Nursing Practice I Cardiovascular Pharmacology Consolidation Session Dr. David Fann [email protected] Department of Pharmacology, Yong Loo Lin School of Medicine National University of Singapore, Singapore  Objectives  Revise major concepts of each lecture.  Identify what to focus on for your Examination.  Opportunity to ask questions, if you have any? NUR1125 – Pathophysiology, Pharmacology & Nursing Practice I Diuretic Drug Therapy Dr. David Fann [email protected] Department of Pharmacology, Yong Loo Lin School of Medicine National University of Singapore, Singapore  Diuretic Drugs What are Diuretic Drugs? Diuretic drugs increase the production and excretion of urine, which decreases the amount of fluid (i.e. water) in the body. How do Diuretics Work? Fundamental Principle: Decrease Na+ ions moving from the tubule lumen back into interstitium/blood stream ↑[Na+] ions in the tubular lumen, which creates a hypertonic environment (i.e. high solutes/low water) Due to osmosis, water flows from the interstitium/blood stream (i.e. low solutes/high water) into the tubular lumen ↑Urine production and excretion Overall, diuretic drugs increase natriuresis (i.e. Na+ excretion), which drives diuresis (i.e. water excretion) to varying degrees. Tip: Water will follow where Na+ goes.  Diuretic Drugs: Loop Diuretics (Most Efficacious) A. Loop/High-Ceiling Diuretics: Furosemide, Torsemide & Bumetanide Mechanism(s) of Action: Loop diuretics inhibit the Na+/K+/2Cl- Co-transporter/symporter in the thick ascending limb of the Loop of Henle. Lumen TAL Loop of Henle Tubule Cell Interstitium/ (Urine) Blood Na+ Na+ ↑[Na+] K+ ATP Collecting ↑[Cl-] 2Cl- K+ K+ Cl- H2 O K+ Cl- Na+ Cl- Basolateral ↓[Na+] Luminal Na+ Collecting Tubule Cell Interstitium/ ↓[Cl-] Blood Osmosis Aquaporins Aquaporins Hypertonic ↑[Na+] H 2O H2 O H 2O Environment ↑[Cl-] Interstitium/ Blood ↑[H2O] ↓[H2O] ↑Urination ↓Blood Volume https://classnotes123.com/describe-the-structure-and-functioning-of-nephron-class-10/ ↑Urine  Diuretic Drugs: Thiazide Diuretics (Most Widely Used) B. Thiazide/Thiazide-Like Diuretics: Hydrochlorothiazide, Chlorthalidone, Indapamide & Metolazone Mechanism(s) of Action: Thiazide diuretics inhibit the Na+/Cl- Symporter/Co-transporter in the distal convoluted tubules of the nephron. Distal Convoluted Tubule Cell Lumen Interstitium/ (Urine) Blood Na+ Na+ ↑[Na+] ATP ↑[Cl-] Na+ Collecting Cl- K+ Cl- Na+ Cl- H2 O Ca2+ Na+ Ca2+ Basolateral ↓[Na+] Luminal Interstitium/ Collecting Tubule Cell ↓[Cl-] Blood Osmosis Aquaporins Aquaporins Hypertonic ↑[Na+] H2 O H2 O H2O Environment ↑[Cl-] Interstitium/ Blood ↑[H2O] ↓[H2O] https://classnotes123.com/describe-the-structure-and-functioning-of-nephron-class-10/ ↑Urine ↑Urination ↓Blood Volume  Diuretic Drugs: Potassium (K+)-Sparing Diuretics C. Potassium(K+)-Sparing Diuretics: (I). Amiloride, Triamterene (II). Spironolactone & Eplerenone Mechanism(s) of Action: (I). Amiloride and Triamterene inhibit the epithelial Na+ channels in the luminal membrane of the collecting tubules and ducts of the nephron. Basolateral Luminal Lumen Interstitium/ (Urine) Collecting Tubule/Duct Cell Blood Na+ Hypertonic Na+ (-) ↑[Na+] ATP Environment Collecting K+ Na+ K+ ↑[K+] ↓[Na+] Na+ Cl- H2 O Cl- Aquaporins ↑[K+] Osmosis Aquaporins Na+ ↑[H2O] H2O H2O H 2O Cl- Interstitium/ Blood ↑Urination ↓[H2O] H2 O Note: Decreasing the reabsorption of Na+ ions back into the tubule cell will cause the inside of the cell to become more negative, which will stop K+ Interstitium/ Blood ions from being secreted into the lumen. Therefore, increasing the concentration of K+ ions in the tubule cell and ultimately in the blood. https://classnotes123.com/describe-the-structure-and-functioning-of-nephron-class-10/ ↑Urine  Diuretic Drugs: Potassium (K+)-Sparing Diuretics C. Potassium(K+)-Sparing Diuretics: (I). Amiloride, Triamterene (II). Spironolactone & Eplerenone Mechanism(s) of Action: (II). Spironolactone & Eplerenone blocks aldosterone from binding onto the mineralocorticoid/aldosterone receptor in the cytosol. Therefore, decreases expression of epithelial Na+ channels & Na+/K+-ATPase pumps in the collecting tubules and ducts. Lumen Collecting Tubule/Duct Cell Interstitium/ Aldosterone (Urine) Blood Na+ Na+ ↓[Na+] (+) ATP ↑[Na+] Na+ K+ Hypertonic Na+ Environment ↑[K+] K+ ATP Collecting K+ ↓[K+] Na+ Aquaporins Osmosis Aquaporins Cl- Cl- H2O H2 O H2 O H2O ↑[H2O] Na+ ↑Blood Basolateral Luminal Na+ Spironolactone & Eplerenone Collecting Tubule/Duct Cell Volume Cl- H2O Na+ Hypertonic Na+ (-) ATP ↓[Na+] ↑[Na+] Environment K+ ↓[K+] K+ ↑[K+] ↑[K+] ↑[H2O] Aquaporins Osmosis Aquaporins H2 O H2 O H2 O https://classnotes123.com/describe-the-structure-and-functioning-of-nephron-class-10/ ↑Urine ↑Urination  Diuretic Drugs Classes of Common Therapeutically Used Diuretics : A. Loop/High-Ceiling Diuretics: furosemide, torsemide & bumetanide B. Thiazide/Thiazide-Like Diuretics: hydrochlorothiazide, chlorthalidone, indapamide & metolazone C. Potassium(K+)-Sparing Diuretics: (I). amiloride, triamterene (II). spironolactone & eplerenone Questions? Dr. David Fann [email protected] NUR1125 – Pathophysiology, Pharmacology & Nursing Practice I Pharmacological Treatment of Hypertension Dr. David Fann [email protected] Department of Pharmacology, Yong Loo Lin School of Medicine National University of Singapore, Singapore  Major Factors Influencing Arterial Blood Pressure Mean Arterial Cardiac Output Total Peripheral Blood Pressure = (CO; L/min) x Resistance (TPR) (MAP; mmHg) A or NA binds ⍺1-adrenoreceptor = VSMCs Contract = Arteriole Vasoconstriction = ↑TPR A or NA binds β2-adrenoreceptor = VSMCs Relax = Arteriole Vasodilation = ↓TPR Cardiac Output Stroke Volume Heart Rate (CO; L/min) = (SV; ml/beat) x (HR; beats/min) A or NA binds β1-adrenoreceptor = ↑Heart Rate Ach binds Muscarinic 2 (M2)-Receptor = ↓Heart Rate A: Adrenaline NA: Noradrenaline A or NA binds β1-adrenoreceptor = ↑Force of Contraction of Heart = ↑SV Ach: Acetylcholine Ach binds Muscarinic 2 (M2)-Receptors = ↓Force of Contraction of Heart = ↓SV VSMCs: Vascular Smooth Muscle Cells  Major Factors Influencing Arterial Blood Pressure The Renin-Angiotensin-Aldosterone System (RAAS) is a complex endogenous system that regulates arterial blood pressure by controlling vascular tone, cardiovascular growth and blood volume, which is primarily controlled by the kidneys. ↑Sympathetic Nervous Angiotensinogen release System Activity (globulin) Liver A or NA β1-Receptor release converts Kidneys Renin ↓Renal Blood Flow → ↓Renal Perfusion Pressure Angiotensin I Lungs contain ACE converts ACE (endothelial cell) degrades Angiotensin II Bradykinin A: Adrenaline binds NA: Noradrenaline ACE: Angiotensin Converting Enzyme Inactive Metabolites AT1-Receptor AT1: Angiotensin II Type 1  Renin-Angiotensin-Aldosterone System (RAAS) When Angiotensin II binds onto the AT1-receptor: 1. Arterioles VSMCs Contract Vasoconstriction ↑TPR ↑MAP Note: MAP = CO x TPR VSMCs: Vascular Smooth Muscle Cells 2. β1-R ↑Contractile Force ↑SV Sympathetic (Heart) ↑HR ↑CO Nerve Terminals NA ↑MAP (Peripheral) ⍺1-R VSMCs Contract Vasoconstriction ↑TPR (Arterioles) Note: CO = SV x HR Note: MAP = CO x TPR 3. β2-R (Arterioles) VSMCs Relax Vasodilation ↓TPR A Adrenal (Blood) β1-R ↑Contractile Force ↑SV ↑MAP glands (Heart) NA ↑HR ↑CO (Medulla) (Blood) ⍺1-R VSMCs Contract Vasoconstriction Note: CO = SV x HR ↑TPR Note: MAP = CO x TPR (Arterioles)  Renin-Angiotensin-Aldosterone System (RAAS) When Angiotensin II binds onto the AT1-receptor: 4. Adrenal Distal Tubule & ↑Na+ Reabsorption ↑H2O Reabsorption ↑VR ↑SV Aldosterone glands Collecting Ducts * ↑MAP (Blood) ↑K+ Secretion ↑Blood Volume ↑Contractile ↑CO (Cortex) (Kidney) (Veins) Force Note: MAP = CO x TPR *Frank-Starling Mechanism VR: Venous Return 5. Cardiac Hypertrophy Cardiac Fibrosis Heart & Cardiovascular ↑TPR ↑MAP Arteries Remodeling VSMCs Hypertrophy VSMCs Hyperplasia Note: MAP = CO x TPR  Treatment of Hypertension Overall Aim: To decrease arterial blood pressure in hypertensive patients to significantly reduce their risk of cardiovascular disease (e.g. myocardial infarction, stroke, heart failure and peripheral arterial disease), which is the leading of morbidity and mortality. Classes of First Line Anti-Hypertensive Drugs: A. Angiotensin Converting Enzyme (ACE) Inhibitors: E.g. captopril, enalapril, lisinopril & perindopril. B. Angiotensin II Type 1 (AT1)-Receptor Antagonists/Blockers (ARBs/Sartans): E.g. candesartan, irbesartan, losartan, telmisartan & valsartan C. Beta(β)-Adrenoreceptor Antagonists/Blockers: E.g. atenolol, bisoprolol, metoprolol, carvedilol & propranolol. D. Calcium Channel Antagonists/Blockers: E.g. diltiazem, verapamil, amlodipine, felodipine & nicardipine. E. Diuretics (Thiazide): E.g. chlorthalidone, hydrochlorothiazide, indapamide & metalozone. Questions? Dr. David Fann [email protected] NUR1125 – Pathophysiology, Pharmacology & Nursing Practice I Pharmacological Treatment of Hyperlipidemia Dr. David Fann [email protected] Department of Pharmacology, Yong Loo Lin School of Medicine National University of Singapore, Singapore  How are Lipids Transported in the Body? Conceptual Understanding  Lipids are not soluble in the plasma of the blood. (Analogy: Oil and Water). Therefore, the way the body transports lipids in the blood stream is via Lipoproteins. What are Lipoproteins?  Lipoproteins are round particles that carry lipids (i.e. triglycerides and cholesterol esters) in the central core surrounded by a phospholipid membrane that is embedded with free cholesterol and certain types of apolipoproteins. Structure of Lipoprotein Apolipoprotein https://my.clevelandclinic.org/health/articles/23229-lipoprotein  Classification of Lipoproteins  The classification of lipoproteins is based on the density of lipoproteins by ultracentrifugation, which is primarily determined by the amount of lipids (in particular triglycerides) and proteins (i.e. apolipoproteins) that it contains. There are 5 main types of Lipoproteins IDL (βVLDL) General Rule: 1). If the amount of lipids (i.e. triglycerides) in the lipoprotein is high, then the density of the lipoprotein is low and vice versa. 2). If the amount of proteins (i.e. apolipoprotein) in the lipoprotein is high, then https://www.amboss.com/us/knowledge/lipids-and-their-metabolism the density of the lipoprotein is high and vice versa.  Each lipoprotein has a specific role in transporting lipids (i.e. Triglycerides and Cholesterol esters) in the body via the exogenous and endogenous pathways. VLDL: Very-Low Density Lipoprotein; IDL: Intermediate Density Lipoprotein; LDL: Low-Density Lipoprotein; HDL: High-Density Lipoprotein  Exogenous and Endogenous Pathway in Lipid Transport Dietary 1 Lipids Endogenous Pathway Exogenous Pathway 1 HMG-CoA 1 HDL HMG-CoA Reductase Mevalonic Acid Secreted Bile Duct 2 Cholesterol Bile Acids Enterohepatic Circulation Bile Acids (Production) (Production) HDL Reabsorbed Cholesterol (Uptake) Portal Vein Triglyceride 1 FFA Remnant Receptor 2 (Production) 5 Small Intestine Chylomicrons 3 VLDL Chylomicrons Triglyceride LDL Remnants T>>CE T>CE Cholesterol CE>T CE>T IDL T>CE Blood HDL 4 3 4 2 Lipoprotein Lipase Lipoprotein Lipase Endothelial Cells Cholesterol Capillaries FFA FFA Deposited Peripheral Tissues Cholesterol (Adipose and Skeletal Muscle) Uptake Promotes Atherosclerosis CE: Cholesterol Esters; FFA: Free Fatty Acids; T: Triglycerides https://www.lifespan.io/topic/liver/  Pharmacological Treatment of Hyperlipidemia Overall Aim: To decrease LDL particles in the blood in patients with hyperlipidemia to significantly reduce their risk of developing atherosclerosis and eventually cardiovascular disease (e.g. myocardial infarction & stroke), which is the leading of morbidity and mortality. Classes of Anti-Hyperlipidemic Drugs: A. HMG-CoA Reductase Inhibitors (Statins): simvastatin, lovastatin, pravastatin, atorvastatin, rosuvastatin, B. PCSK9 Inhibitors: alirocumab, evolocumab C. Fibric Acid Derivatives/Analogues (Fibrates): clofibrate, gemfibrozil, fenofibrate, bezafibrate, ciprofibrate D. Ezetimibe E. Bile-Acid Binding Resins (Sequestrants): colestyramine, colestipol, colesevelam Questions? Dr. David Fann [email protected]  NUR1125 – Pathophysiology, Pharmacology & Nursing Practice I Pharmacological Treatment of Coronary Artery Disease/ Angina Dr. David Fann [email protected] Department of Pharmacology, Yong Loo Lin School of Medicine National University of Singapore, Singapore  Definition: Angina Pectoris  Angina pectoris (i.e. acute chest pains) is usually caused by atherosclerosis where the coronary arteries are partially occluded or narrowed due to a build-up of fatty plaque within the coronary arteries causing coronary artery disease (CAD).  Therefore, this decreases the supply of oxygenated blood and nutrients (i.e. glucose) to the cardiac muscle causing ischemia, which then causes angina/angina pectoris (i.e. acute chest pains). Hypertension Hyperlipidemia Obesity Atherosclerosis Angina Pectoris CAD (Plaque Build-Up) (Acute Chest Pains) Diabetes Smoking Age https://www.cardiovascularconsultantspc.com/services-specialties/tests-and-procedures/atherosclerotic-heart-disease/  What causes Angina Pectoris? Angina pectoris (acute chest pains) is usually caused when Cardiac Oxygen Demand is greater than Cardiac Oxygen Supply. ↑Heart Rate ↑Force of Contraction ↑Cardiac Workload ↑Cardiac Oxygen (O2) Demand > ↓Cardiac Oxygen (O 2) Supply ↓Coronary Blood Flow ↑Preload ↑Afterload Ischemia Angina Pectoris (Acute Chest Pains) Preload: mechanical stress on the right ventricular walls during diastole (relaxation), which is directly regulated by venous return. Afterload: mechanical stress on the left ventricular walls during systole (contraction), which is directly regulated by arterial blood pressure.  SVC A PV PV PA PV PV LA RA LV IVC RV (A) Preload: mechanical stress on the right ventricular walls during diastole (relaxation), which is directly regulated by venous return. Venous Return → Preload → Workload on the Heart → Cardiac Oxygen Demand Afterload: mechanical stress on the left ventricular walls during systole (contraction), which is directly regulated by arterial blood pressure. Systemic Arterial Blood Pressure → Afterload → Workload on the Heart → Cardiac Oxygen Demand https://www.ezmedlearning.com/blog/heart-blood-flow-diagram  How to treat Angina Pectoris? There are 2 main strategies that can be used to treat angina pectoris: 1). Decrease Cardiac Oxygen Demand – Decreasing Cardiac Workload (Decreasing heart rate, force of contraction, preload or afterload) 2). Increase Cardiac Oxygen Supply - Increasing blood flow through the coronary arteries ↓Heart Rate Balance ↓Force of Contraction ↓Cardiac Workload ↓Cardiac Oxygen (O2) Demand = ↑Cardiac Oxygen (O 2) Supply ↑Coronary Blood Flow ↓Preload ↓Afterload Ischemia Angina Pectoris (Acute Chest Pains) Preload: mechanical stress on the right ventricular walls during diastole (relaxation), which is directly regulated by venous return. Afterload: mechanical stress on the left ventricular walls during systole (contraction), which is directly regulated by arterial blood pressure.  Treatment of Angina Pectoris Classes of First Line Anti-Anginal Drugs: A. Organic Nitrates: E.g. glyceryl trinitrate (nitroglycerin), isosorbide mononitrate B. Beta(β)-Adrenoreceptor Antagonists/Blockers: E.g. atenolol, bisoprolol, metoprolol, carvedilol C. Calcium Channel Antagonists/Blockers: E.g. diltiazem, verapamil, amlodipine, felodipine & nicardipine D. HCN4 Ion Channel Blocker: E.g. ivabradine Questions? Dr. David Fann [email protected]