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CVS Function, Regulation of the Heart and Overview of Therapeutic Goals in CV Disorders

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DRUGS USED IN DISORDERS OF THE
CARDIOVASCULAR SYSTEM
CVS Function, Regulation of the Heart
and Overview of Therapeutic Goa...

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Marc Imhotep Cray, M.D.
Purpose of Presentation:
2
To provide an overview/review of the function of the
cardiovascular sys...

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Marc Imhotep Cray, M.D.
Classification Schema:
CARDIOVASCULAR & RENAL AGENTS
3
Direct Vasodilators
Nitroglycerin
Nitroprus...

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CVS Function, Regulation of the Heart and Overview of Therapeutic Goals in CV Disorders

  1. 1. DRUGS USED IN DISORDERS OF THE CARDIOVASCULAR SYSTEM CVS Function, Regulation of the Heart and Overview of Therapeutic Goals in CV Disorders Marc Imhotep Cray, M.D. Photo: Photograph of chordae tendineae attached to papillary muscles of a ventricle. Seeley’s anatomy & physiology. 10th ed. New York, NY: McGraw-Hill 2010.
  2. 2. Marc Imhotep Cray, M.D. Purpose of Presentation: 2 To provide an overview/review of the function of the cardiovascular system, the regulation of the heart, the pathophysiology of the most common cardiovascular diseases and the therapeutic goals of each treatment strategy as a prerequisite to learning and understanding each drug class. Companion Notes: Core Principles in Cardiovascular Therapeutics.pdf
  3. 3. Marc Imhotep Cray, M.D. Classification Schema: CARDIOVASCULAR & RENAL AGENTS 3 Direct Vasodilators Nitroglycerin Nitroprusside Nesiritide Hydralazine ACE Inhibitors, ARBs, & Renin Inhibitors Captopril Losartan Aliskiren Inotropes & Pulmonary Arterial Vasodilators Digoxin Milrinone Sildenafil Epoprostenol Bosentan Diuretics Furosemide Hydrochlorothiazide Spironolactone Eplerenone Acetazolamide Antiarrhythmics Procamamide Lidocaine Flecainide Amiodarone Ibutilide Adenosine Calcium Channel Blockers Nifedipine Verapamil Diltiazem Other antianginals RanolazineMost Common Drugs (Classes) with Phonetic Pronunciations. pdf
  4. 4. Marc Imhotep Cray, M.D. 4 N.B. To best understand pharmacological approaches to management of cardiovascular disorders, an overview of the regulation of cardiovascular function is warranted.
  5. 5. Marc Imhotep Cray, M.D. Overview of cardiovascular system 5  The heart and circulatory system must provide continuous, efficient, and reliable operation while adapting to short and long-term physiologic changes  Drugs that are used to treat cardiovascular disorders constitute one of the largest categories of prescription drugs used
  6. 6. Marc Imhotep Cray, M.D. Overview of CVS (2) 6  Two factors suggest that use of CV drugs will continue to increase:  An aging population and  increasing use of drugs as prevention against future CVD  Above 2 factors work synergistically:  As preventive care increases average lifespan, population has a greater risk of cardiovascular disease, and  As life expectancy increases, greater emphasis is placed on earlier preventive intervention
  7. 7. Marc Imhotep Cray, M.D. Overview CVS (3) 7 Certain cardiovascular disorders, such as cardiac arrhythmias and congestive heart failure (CHF), produce symptoms that are readily apparent to person affected and have consequences long known to necessitate treatment Other conditions do not produce obvious symptoms  have become recognized as health problems only as a result of epidemiologic studies in relatively recent years  For example, blood pressures that had been considered normal b/c they were average (age-appropriate mean) are now widely considered to fall into hypertension category and are now routinely treated w medication  Cholesterol levels that were once deemed normal (or were even thought to be so insignificant that they went unmeasured) are now routinely treated w medications
  8. 8. Marc Imhotep Cray, M.D. Overview of CVS (4) U.S. Epidemiology* 8 Dysfunction of CVS is the principal cause of death and disability in middle-aged and elderly men and women in industrialized world In United States in 2004, there were nearly 1 million deaths from cardiovascular disease, representing approximately 36% of all deaths Estimates of prevalence of cardiovascular disease in 2005 indicated that more than  70 million individuals had hypertension,  16 million had coronary heart disease, and  5 million had congestive heart failure *Data from the American Heart Association
  9. 9. Marc Imhotep Cray, M.D. Overview of CVS (5) 9 For many years, treatment of cardiovascular disorders primarily targeted innervation of the heart and blood vessels by the 2 subdivisions of the ANS:  Parasympathetic innervation of heart is principally via vagus nerve (cranial nerve X) and is mediated by action of acetylcholine (ACh) at muscarinic cholinergic receptors  Sympathetic innervation of heart is mediated principally by action of norepinephrine (NE) on β adrenoceptors (β1 subtype)
  10. 10. Marc Imhotep Cray, M.D. Overview of CVS (6) 10 The vasculature is controlled in a site-dependent manner  By parasympathetic subdivision mediated by ACh, which usually causes vasodilation*, and  By sympathetic subdivision mediated by NE, which generally causes vasoconstriction Hormones and local factors also contribute to overall vascular tone *Remember: There are no cholinergic receptors in vascular smooth muscle, however vascular smooth muscle nonetheless responses to Ach causing vasodilation.
  11. 11. Marc Imhotep Cray, M.D. Overview of CVS (7) 11 A major advance in treatment strategies for cardiovascular disorders occurred as a result of recognition of significant contributions made by other neurotransmitter and hormone systems to normal and pathologic cardiovascular function  Targeting these systems, such as renin-angiotensin-aldosterone system (RAAS) , has led to a broader variety of treatment options Cardiovascular drugs include some of oldest medications, discovered by serendipity, and some of the newest, discovered by molecular modeling and screening technology  They include a wide variety of receptor agonists, receptor antagonists, and enzyme inhibitors
  12. 12. Marc Imhotep Cray, M.D. Cardiovascular function: Cardiac cycle 12  To understand how cardiac function is regulated, one must know the sequence of mechanical events during a complete cardiac cycle and how these mechanical events relate to electrical activity of heart  Cardiac cycle diagram in next slide (sometimes called the Wiggers diagram) depicts changes in left side of heart (left ventricular pressure and volume, left atrial pressure, and aortic pressure) as a function of time
  13. 13. Cardiac cycle / Wiggers diagram Seven phases of cardiac cycle: (1) atrial systole (2) Isovolumetric contraction (3) rapid ejection (4) reduced ejection (5) isovolumetric relaxation (6) rapid filling (7) reduced filling
  14. 14. 14 Cardiovascular function: Anatomy  Heart muscle pumps blood through circulatory system  Each day, heart beats 100,000 times and pumps 2000 gal of blood  Heart is composed of 4 chambers (divisions): o upper two, right and left atria o lower two, the right and left ventricles  Blood is pumped through chambers, in only 1 direction, via 4 valves: o tricuspid, located between right atrium and right ventricle o pulmonary, between right ventricle and pulmonary artery o mitral, between left atrium and left ventricle and o aortic, between left ventricle and aorta
  15. 15. 15 CV function: Anatomy cont.  Dark blood, low in oxygen, returns from body tissues through veins enters right atrium then flows to right ventricle pulmonary artery and lungs where it is oxygenated  Blood returns by pulmonary veins to left atrium and goes through mitral valve into left ventricle which pumps oxygen-rich, bright-red blood  through aortic valve into aorta and then into systemic circulation
  16. 16. Marc Imhotep Cray, M.D. CV function: Definitions and Regulation 16  Cardiac output (CO) is total blood volume pumped by ventricles per minute  (CO=heart rate × stroke volume)  Stroke volume (SV) is blood pumped by left or right ventricle per beat  In a resting adult, SV averages 60 to 80 mL of blood  The 3 determinates of SV are preload, contractility and afterload  Systole is contraction phase of cardiac cycle ventricles pump stroke volumes  Diastole is resting phase of cardiac cycle occurs between heartbeats  End-diastolic volume (EDV) is blood volume in each ventricle at end of diastole:  120 mL at rest  End-systolic volume(ESV) is blood volume in each ventricle after contraction:  50 mL at rest
  17. 17. Marc Imhotep Cray, M.D. Definition of Terms and Regulation cont. 17 To maintain equal flow through pulmonary and systemic circuits, left and right ventricles maintain same cardiac output  resting CO is 4.8 to 6.4 L/min CO increases (20-85%) during intense exercise to transport more oxygen to muscles  This greater blood flow is caused by higher blood pressure and arteriolar vasodilation in muscles, which is due to smooth muscle relaxation
  18. 18. Marc Imhotep Cray, M.D. Functional Regulation of CVS: 18  Function of cardiovascular system involves:  autonomic nervous system (ANS)  kidneys(RAAS)  heart  vasculature, and  blood N.B. B/C these systems represent an integrated network, cardiovascular function can be affected by alterations at any point A review of each system’s main contribution follows.
  19. 19. Marc Imhotep Cray, M.D. CVS and the Autonomic Nervous System 19  ANS innervates heart, blood vessels, kidney, and adrenal medulla and has potential to modify cardiovascular function in a number of different ways (See CV physiology, Unit 4 string of MedPharm Digital Guidebook and NIP-associated graphics) CO is amount of blood pumped by ventricles per unit time  As stated previously, it is determined by volume of blood ejected during each ventricular contraction (stroke volume [SV]) and how frequently heart beats (heart rate [HR] ), expressed as CO = HR x SV HR can be affected by a variety of factors but is principally under control of ANS  Beta blockers can reduce CO by decreasing HR and contractility
  20. 20. Marc Imhotep Cray, M.D. The kidneys (RAAS) 20  The kidneys adjust excretion of Na+, other ions and H2O to maintain extracellular fluid and volume fluid retention by kidney is a modifiable physiological parameter that can result in changes in blood pressure
  21. 21. Marc Imhotep Cray, M.D. The heart 21 The heart, including  rhythmic nature of its electrical signals  force of contraction, and  magnitude of discharge pressure is responsible for pumping blood through pulmonary system for oxygenation and delivering it through vasculature to organs throughout body
  22. 22. Marc Imhotep Cray, M.D. The circulation 22  The circulation (both blood volume and composition) including  H2O and electrolyte balances  iron balances  cholesterol and lipid composition  capabilities for clot formation and lysis  delivers O2 and nutrients to and carries away CO2 and waste from all tissues
  23. 23. Marc Imhotep Cray, M.D. Mathematical determinants of arterial blood pressure (MAP) 23 Mean arterial pressure (MAP) is determined by:  How much blood heart pumps into arterial system in a given time (CO) and  How much resistance arteries have to this input (total peripheral resistance [TPR]) Mathematically, this is expressed as MAP = CO x TPR o Consequently all drugs that lower blood pressure work by affecting either CO or TPR (or both) NB:  The primary determinant of systolic blood pressure (SBP) is CO, whereas  The primary determinant of diastolic blood pressure (DBP) is TPR  b/c approximately one third of cardiac cycle is spent in systole and two thirds in diastole, MAP can be calculated as MAP= 1/3 SBP + 2/3 DBP
  24. 24. Marc Imhotep Cray, M.D. Cardiac output (CO) variables 24  Stroke volume  Contractility  Myocardial oxygen demand  Preload  Afterload  Ejection fraction
  25. 25. Marc Imhotep Cray, M.D. CO variables: Stroke volume 25  Stroke Volume is affected by Contractility, Afterload, and Preload ↑SV with:  ↑ Contractility (e.g., anxiety, exercise)  ↑ Preload (e.g., early pregnancy)  ↓ Afterload  A failing heart has ↓SV (systolic dysfunction)
  26. 26. Marc Imhotep Cray, M.D. CO variables: Contractility 26 Contractility (and SV) ↑ with:  Catecholamines (inhibition of phospholamban  ↑ Ca2+ entry into sarcoplasmic reticulum ↑ Ca2+-induced Ca2+ release)  ↑intracellular Ca2+  ↓ extracellular Na+ (↓activity of Na+/Ca2+ exchanger)  Digitalis (blocks Na+/K+ pump ↑intracellular Na+  ↓Na+/Ca2+ exchanger activity ↑Intracellular Ca2+) Contractility (and SV) ↓with:  β1-blockade (↓ cAMP)  HF with systolic dysfunction  Acidosis  Hypoxia/hypercapnia (↓ pO2/ ↑ pCO2)  Non-dihydropyridine Ca2+ channel blockers (verapamil & diltiazem)
  27. 27. Marc Imhotep Cray, M.D. CO variables: Myocardial oxygen demand 27 Myocardial O2 demand is↑ by:  ↑ Contractility  ↑ Afterload (proportional to arterial pressure)  ↑ Heart Rate  ↑ Diameter of ventricle (↑ wall tension)
  28. 28. Marc Imhotep Cray, M.D. CO variables: Preload 28  Preload approximated by ventricular EDV depends on venous tone and circulating blood volume  Venodilators (e.g., nitroglycerin) ↓preload
  29. 29. Marc Imhotep Cray, M.D. CO variables: Afterload 29  Afterload approximated by MAP  ↑ afterload ↑ pressure  ↑wall tension per Laplace’s law o LV compensates for ↑ afterload by thickening (hypertrophy) in order to ↓wall tension  Vasodilators (e.g., hydralazine) ↓Afterload (arterial)  ACE inhibitors and ARBs ↓ both preload and afterload  Chronic hypertension (↑MAP)  LV hypertrophy
  30. 30. Marc Imhotep Cray, M.D. CO variables: Ejection fraction 30  Left ventricular EF is an index of ventricular Contractility normal EF is ≥ 55%  EF ↓ in systolic HF(HFrEF)  EF normal in diastolic HF(HFpEF)
  31. 31. Marc Imhotep Cray, M.D. Strategies for Treating CV Diseases: Hypertension 31 Therapeutic Goal Pharmacologic Strategies Reduce volume overload Diuretics decrease blood volume by increasing volume of water excreted in the urine. Reduce sympathetic outflow from brain Clonidine is an agonist at α2 receptors. It inhibits release of NE and inhibits sympathetic outflow from the brain Block adrenergic receptors in heart Atenolol is a β1 adrenergic receptor antagonist that reduces heart rate and myocardial work Dilate blood vessels Prazosin blocks α1 adrenergic receptors causing vasodilation Nifedipine blocks calcium entry into smooth into smooth cells of arterial walls, preventing contraction Captopril reduces production of AT2 causing vasodilation
  32. 32. Marc Imhotep Cray, M.D. Strategies for Treating CV Diseases: Angina Therapeutic Goal Pharmacologic Strategies Reduce work of heart and improve cardiac circulation = Decrease myocardial O2 demand Increase myocardial O2 supply Stable Angina Nitroglycerin reduces preload by venodilation Atenolol decreases myocardial work (β1 antagonists) Diltiazem decreases BP through vasodilation by blocking calcium entry Unstable Angina β-Blockers reduce rate and myocardial work Aspirin prevents platelet aggregation in myocardial arteries Heparin inhibits clotting in myocardial arteries Nitroglycerin reduces preload Eptifibatide or Tirofiban inhibit platelet aggregation
  33. 33. Marc Imhotep Cray, M.D. Strategies for Treating CV Diseases: Myocardial Infarction 33 Therapeutic Goal Pharmacologic Strategies Reperfuse ischemic tissue Streptokinase converts plasminogen to plasmin Plasmin digest fibrin and fibrinogen, thus dissolving clots Antianginals (see previous slide). But not calcium channel blockers, which are dangerous in setting of acute myocardial infarction
  34. 34. Marc Imhotep Cray, M.D. Strategies for Treating CV Diseases: Heart Failure 34 Therapeutic Goal Pharmacologic Strategies Reduce workload Improve myocardial contractility Diuretics decrease blood volume Captopril causes vasodilation Atenolol (β-blocker) reduces heart rate and work load Nitroglycerin reduces venous tone (It also dilates coronary arteries, enhancing blood delivery to heart) Hydralazine and Nitroprusside relax arterioles Digoxin increases calcium influx into myocardial cells Amrinone inhibits cAMP degradation (cAMP is a biochemical messenger that stimulates the heart) Dobutamine increases cAMP production by stimulating adrenergic receptors
  35. 35. Marc Imhotep Cray, M.D. Strategies for Treating Cardiovascular Diseases: Arrhythmias 35 Therapeutic Goal Pharmacologic Strategies Restore synchronous myocardial contraction Several classes of agents described in a subsequent lecture, including: Na+ Channel Blockers K+ Channel Blockers Ca+2 Channel Blockers β-Blockers Others agents
  36. 36. Marc Imhotep Cray, M.D. Strategies for Treating Cardiovascular Diseases: Vascular Occlusion 36 Therapeutic Goal Pharmacologic Strategies Prevent coagulation Heparin and Warfarin inhibit coagulation pathway Prevent clot formation Aspirin inhibits platelet aggregation Ticlopidine inhibits platelet binding to fibrinogen Destroy clots that have already formed Streptokinase converts plasminogen to plasmin
  37. 37. Marc Imhotep Cray, M.D. THE END 37
  38. 38. Marc Imhotep Cray, M.D. 38 Lectures/discussions to follow: 2. Hypercholesterolemia and Atherosclerosis 3. Angina 4. Heart Failure 5. Arrhythmias 6. Hypertension 7. Peripheral Vascular Disease Further study (SDL): Online resource center: Medical Pharmacology Cloud Folder Companion Notes: Cardiovascular Pharmacology

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