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Introduction of current development and concept cardiovascular physiology and pharmacology

Introduction of current development and concept cardiovascular physiology and pharmacology . Mohammad Saifur Rohman , MD. PhD. FIHA Lab. Cardiology and Vascular Medicine Faculty of Medical, Brawijaya University. Outline. Physiology of CV Pathogenesis of CV

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Introduction of current development and concept cardiovascular physiology and pharmacology

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  1. Introduction of current development and concept cardiovascular physiology and pharmacology Mohammad SaifurRohman, MD. PhD. FIHA Lab. Cardiology and Vascular Medicine Faculty of Medical, Brawijaya University

  2. Outline • Physiology of CV • Pathogenesis of CV • Current development and concepts of CV drugs

  3. Blood Flow Through Heart

  4. Blood Flow Through and Pump Action of the Heart

  5. Coronary Arteries • Originates from the aorta just beyond the aortic valve • Coronary blood flow to the myocardium occurs primarily during diastole * To maintain adequate blood flow through the coronaries, mean arterial pressure (MAP) must be at least 60 mmHg

  6. Intrinsic Cardiac Conduction System Approximately 1% of cardiac muscle cells are autorhythmic rather than contractile 70-80/min 40-60/min 20-40/min

  7. Type of Cells in The Heart • Pacemaker cells • – 5 – 10 um in length; • Sinoatrial and atrioventricular nodes • – Spontaneous depolarization • – Action Potential • Electrical conducting cells • – Long thin cells • Atrial conducting system • Ventricular conducting system • Myocardial cells • – Contractile units in the heart, most are myocardial cells • – Calcium is responsible for contractile process after initiation of action potential

  8. Physiology of the Heart • Electrophysiologic properties (regulates heart rate & rhythm) - Automaticity – ability of all cardiac cells to initiate an impulse spontaneously & repetitively - Excitability – ability of cardiac cells to respond to stimulus by initiating an impulse (depolarization) - Conductivity – cardiac cells transmit the electrical impulses they receive - Contractility – cardiac cells contract in response to an impulse - Refractoriness – cardiac cells are unable to respond to a stimulus until they’ve recovered (repolarized)

  9. Ion movement and channels • The movement of specific ions across the cell membrane serve as action potentials depends on : • 1. Energetic favorability; concentration gradient and transmembrane potential • 2. Permeability of the membrane for the ion: channels which is selective and gated • Selective: manifestation of size and structure of its pore • Gated: pass through it specific channels only at certain times; voltage sensitive gating (fast sodium channel)

  10. Action potential in autorhythmic cells

  11. Action Potential in contractile cells

  12. Different pattern of Membrane potential at different cells

  13. Action Potential in contractile cells and ECG

  14. P wave: atrial depolarization START P The end R PQ or PR segment: conduction through AV node and A-V bundle T P P QS Atria contract. T wave: ventricular Repolarization ELECTRICAL EVENTS OF THE CARDIAC CYCLE Repolarization R T P QS Q wave P Q ST segment R R wave P R Q S P R Ventricles contract. Q P S wave QS Heart Excitation Related to ECG

  15. Cardiac Cycle - Filling of Heart Chambers • Heart is two pumps that work together, right and left half • Repetitive contraction (systole) and relaxation (diastole) of heart chambers • Blood moves through circulatory system from areas of higher to lower pressure. • Contraction of heart produces the pressure

  16. Late diastole: both sets of chambers are relaxed and ventricles fill passively. 1 START Isovolumic ventricular relaxation: as ventricles relax, pressure in ventricles falls, blood flows back into cups of semilunar valves and snaps them closed. 5 Atrial systole: atrial contraction forces a small amount of additional blood into ventricles. 2 Isovolumic ventricular contraction: first phase of ventricular contraction pushes AV valves closed but does not create enough pressure to open semilunar valves. 3 Ventricular ejection: as ventricular pressure rises and exceeds pressure in the arteries, the semilunar valves open and blood is ejected. 4 Cardiac Cycle - Mechanical Events Figure 14-25: Mechanical events of the cardiac cycle

  17. Wiggers Diagram Time (msec) 0 100 200 300 400 500 600 700 800 QRS complex QRS complex Electro- cardiogram (ECG) Cardiac cycle P T P 120 90 Aorta Dicrotic notch Pressure (mm Hg) Left ventricular pressure 60 Left atrial pressure 30 S2 S1 Heart sounds EDV 135 Left ventricular volume (mL) ESV 65 Atrial systole Ventricular systole Atrial systole Ventricular diastole Atrial systole Isovolumic ventricular contraction Ventricular systole Late ventricular diastole Atrial systole Early ventricular diastole

  18. Modulation of Cardiac Contractions

  19. Regulation of Cardiac Output Figure 18.23

  20. Normal Endothelial Function

  21. Endothelial Dysfunction :

  22. Atherogenesis

  23. Atorvastatin calcium Extensively Studied in Large Trials Atorvastatin effectively reduces LDL-C Across a Broad Range of Patients 10 mg 80 mg* 10,305 patientswithout CHDin ASCOT-LLA 2838 patientswith diabetesin CARDS 10,001 patientswith CHDin TNT 654 patientswith CHDin REVERSAL 4162 patientswith CHDin PROVE IT LDL-C level at randomisation 133mg/dL 116mg/dL <130mg/dL 150mg/dL 106mg/dL 90mg/dL 77mg/dL 77mg/dL 79mg/dL 62mg/dL Follow-upLDL-C level Significantly impacted atherosclerotic disease progression; pravastatin was associated with further disease progression • 37% RRR of death andmajor CV events • 48% RRof stroke Outcomes • 36% RRRof nonfatal MIand fatal CHD • 27% RRR of stroke • 22% RR of major CV events • 25% RR of stroke • 16% RR ofmajor CV eventsversuspravastatin *80 mg is nota starting dose.RR=risk reduction.Nissen et al. JAMA. 2004;291:1071-1080; Cannon et al. N Engl J Med. 2004;350:1495-1504; LaRosa et al. N Engl J Med. 2005;352:1425-1435; Sever et al, for the ASCOT Investigators. Lancet. 2003;361:1149-1158; Colhoun et al. Lancet. 2004;364:685-696.

  24. Atherosclerosis  ACS

  25. STEACS vs. NSTACS

  26. Occluded artery

  27. ECG featured of Ischemic cell

  28. Arrhythmias Detected on ECG continued • In third-degree or complete AV node block, no atrial activity passes to ventricles • Ventricles are driven slowly by bundle of His or Purkinjes

  29. Therapeutic Options in Acute Coronary Syndromes • Anti-ischemictreatment • Antiplatelet agents • Anticoagulants • Revascularization/Reperfusion/Thrombolysis • Long termtreatment/secondaryprevention

  30. Targets for anti thrombotics Tissue factor Collagen Aspirin Plasma clotting cascade ADP Direct Xa inhib Thromboxane A2 Clopidogrel Prasugrel AZD 6140 LMWH Heparin Prothrombin AT Factor Xa Conformational activation of GPIIb/IIIa GPIIb/IIIa inhibitors Thrombin Platelet aggregation Bivalirudin Hirudin Dabigatran Fibrinogen Fibrin Thrombus

  31. NSTE-ACS : Antiplatelets What, when and How? Invasive 1,2 Conservative 2 Aspirin Ticagrelor* / Clopidogrel‡ Aspirin Ticagrelor* / Clopidogrel‡ What? Loading dose ASAP When? Aspirin: started at a dose of 150–300 mg and at a maintenance dose of 75–100 mg, plus Ticagrelor: 180 mg LD, 90 mg twicedaily, or Clopidogrel: 300 or 600 mg LD, 75 mg daily UpstreamGPIIbIIIa are not recommended in patients with high ischaemic risk Aspirin: startedat150–300 mg and at a maintenance dose of 75–100 mg, plus Ticagrelor 180 mg LD, 90 mg twicedaily, or Clopidogrel: an immediate 300 mg LD, 75 mg daily dose How ? ‡All patient receivedclopidogrel LD before PCI in CURRENT * Ticagrelor has limitedexperience for prePCIloading 1. Wijns W et al Eur Heart J 2010;31:2501-55 2. Hamm CW et al ESC NSTE-ACS Guidelines EHJ 2011; doi:10.1093/eurheartj/ehr236 3. Anderson JL et al Circulation 2007;116:148-304

  32. ST-ACS: Oral antiplatelet What, when and how ? Primary PCI1 Thrombolysis2 Aspirin Clopidogrel / Prasugrel* / Ticagrelor* Aspirin Clopidogrel What? ASAP When? Aspirin: mulai150–300mg per oral or 250–500mg bolus iv dilanjutkandengan 75-100mg/hari Prasugrel: 60mg Loadingdilanjutkan 10mg /hariatau Ticagrelor: 180mg Loadingdilanjutkan 2x90mg/ hariatau Clopidogrel: 600mg Loadingdilanjutkan 75mg /hari Aspirin: 150-325mg per oral or i.v. 250mg iikatidakmungkin per oral. Clopidogrel: loading 300mg jikausia ≤75 tahun; 75mg jikausia >75tahun How? 1. Wijns W et al Eur Heart J 2010;31:2501-55 2. Van de Werf F et al Eur Heart J 2008;29:2909-45

  33. ESC Guidelines

  34. Doses of antiplatelet and antithrombin co-therapies ESC Guidelines for the management of AMI in patients presentingwith ST-segment elevation, 2012

  35. Contractile Dysfunction in IHD

  36. Myocardial ischaemia Oxygen Supply and Demand Are Mismatched During Ischaemia , Leading to Impaired Diastolic Relaxation X X Vasospasm Afterload X Heart rate O O Thrombus X 2 2 Contractility Supply Demand Atherosclerosis Preload • Diltiazem, Amlodipine, Nicorandil, Nitrates • β-Blockers, Verapamil/Diltiazem Ischaemia • β-Blockers, Verapamil/Diltiazem, Ivabradine • β-Blockers, Calcium Antagonists Diastolic Wall Sodium - Induced Microvascular Flow Calcium Overload Tension Relaxation Impaired Diastolic Adapted from Chaitman BR. Circulation 2006;113:2462 - 72. Adapted from Belardinelli L et al. Eur Heart J 2004;6(Suppl I):I3 - 7.

  37. New Approach of Ischemic Heart Disease Traditionally, ischemic heart disease is treated by pharmacological or mechanical means that act primarily either to increase oxygen supply to the heart or to decrease oxygen demand of the heart muscle Recently, an additional approach to treating ischemic heart disease is by means of metabolic modulation, whereby optimizing energetics in the myocardium can improve cardiac efficiency of the heart muscle 1. Ussher JR. et al. Basic Res Cardiol. 2009;104:203–10. 2. Stanley WC et al. Physiol Rev. 2005;85:1093–129. 3. Lam A et al. CurrOpinPharmacol. 2007;7:179–85.

  38. CH3 N CH3 O O H O N CH3 SO2 N N NH H CH3 OH OCH3 H N N N O O CH3 New mechanistic approaches to chronic stable angina Rho kinase inhibition (fasudil) Metabolic modulation (trimetazidine) Sinus node inhibition (ivabradine) Preconditioning (nicorandil) O NO2 O H H3C O O CH3 N N N H3C O N CH3 O CH3 O Late INa inhibition (ranolazine)

  39. NEW CONCEPT IN CARDIAC METABOLISM  Former concept (in past decades):  Chronic heart failure associated with chronic coronary artery disease (CAD) is irreversible  It should be treated with hemodynamic agents  New concept (progress in cardiac imaging techniques):  CHF associated with chronic CAD is reversible  Cause of reversible left ventricle dysfunction is Hibernation and Stunning  It highlights the impact of metabolic changes

  40. Energy Utilization in Ischemia

  41. Classification of Blood Pressure ESC-ESH 2007 JNC-VII Optimal : <120 and < 80 Normal : 120-129 and/or 80 - 84 High Normal : 130-139 and/or 85-89 Normal Pre-hypertension HYPERT ENS ION Stage 1 Grade 1 : 140-159 and/or 90-99 Grade 2 : 160-179 and/or 100-109 Grade 3 : > 180 and/or > 110 Stage 2 JNC VII committee, JAMA 2003: 289;2560-2572

  42. History of Hypertension Management • Hypertension: entered the language of medicine in the 19th and early 20th centuries. • The history of hypertension can be divided into two eras: 1. Pre-treatment Era (before 1967) 2. Treatment era (established the benefit of drug therapy for hypertension) Krakoff LR. Et al. Boca Raton; Taylor & Francis Group, 2005: 3-14.

  43. Pretreatment • During the first 120 years of hypertension research (from the 1840s to 1965) basic and clinical research defined the following (1): 1. The mechanisms of increased BP 2. The natural history of untreated HTN to CVD 3. Causes of secondary HTN 4. Set the stage for recognizing potential therapy through drug treatment • Non farmacological treatments: Phlebotomy, purgatives Loss of Water and sodium (2) • Krakoff LR. Et al. Boca Raton; Taylor & Francis Group, 2005: 3-14. • 2. Hoobler SW. Hoeber-Harper Book, N York 1959

  44. Diet for HTN Krakoff LR. Et al. Boca Raton; Taylor & Francis Group, 2005: 3-14.

  45. Surgical (Sympathectomy) for HTN Krakoff LR. Et al. Boca Raton; Taylor & Francis Group, 2005: 3-14.

  46. Farmacotherapy for HTN Krakoff LR. Et al. Boca Raton; Taylor & Francis Group, 2005: 3-14.

  47. Fluid Volume Regulation of BP Excess sodium intake Reduced Nephron number Stress Genetic Alteration Endothelium derived factors Obesity Blood Pressure = Cardiac Output (CO) X Peripheral Resistance (PR) Hypertension Increased CO and/or Increased PR Sympathetic nervous overactivity Renal Sodium retention Renin Angiotensin Excess Decreased Filtration surface Hyperinsulinemia Cell membrane alteration Venous Constriction Preload Contractility Functional Constriction Structural Hypertrophy Autoregulation Kaplan NM, Clinical Hypertension 7th ed. 2002; 63

  48. Krakoff LR. Et al. Boca Raton; Taylor & Francis Group, 2005: 3-14.

  49. LIFESTYLE MODIFICATIONS Not Goal BP INITIAL DRUG CHOICES Without Compelling Indications With Compelling Indications Stage 1 Thiazide-Type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination Stage 2 Two –Drug combination for most (usually thiazide-type diuretic and ACEI, or ARB, or BB, or CCB Drug(s) for the compelling indications. Other antiHT Drugs (Diuretics, ACEI, ARB, , CCB) as needed US-JNC VII Report

  50. Aldo Ant Diuretic ACEI ARB CCB BB Clinical Trial and Guideline Basis for Compelling Indications (JNC VII 2003) Compelling Indication* Recommended Drugs Clinical trial basis Heart Failure ACC/AHA Heart Failure Guideline, MERITHF, COPERNICUS, CIBIS, SOLVD, AIRE, TRACE, ValHEFT, RALES, CHARM Postmyocardial Infarction ACC/AHA Post-MI Guideline, BHAT, SAVE, Capricorn, EPHESUS High Coronary Disease Risk ALLHAT, HOPE, ANBP2, LIFE, CONVINCE, EUROPA, INVEST Diabetes NKF-ADA Guideline, UKPDS, ALLHAT Chronic Kidney Disease NKF Guideline, Captopril Trial, RENAAL, IDNT, REIN, AASK Recurrent Stroke Prevention PROGRESS

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