Lecture 1 cvs function, regulation of the heart and overview of therapeutic goals in cv disorders

DRUGS USED IN DISORDERS OF THE CARDIOVASCULAR SYSTEM Lecture 1:

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

Purpose of Presentation:

CVS Pharmacology Lecture 1

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 eNotes: Cardiovascular Pharmacology Textbook Reading: Section III. Cardiovascular and Renal Drugs.

In: Katzung BG, ed. Basic & Clinical Pharmacology. 12th ed.

Marc Imhotep Cray, M.D.

2

Classification Schema: CARDIOVASCULAR & RENAL AGENTS Direct Vasodilators Nitroglycerin Nitroprusside Nesiritide Hydralazine ACE Inhibitors, ARBs, & Renin Inhibitors Captopril Losartan Alisklren Calcium Channel Blockers Nifedipine Verapamil Other antianginals Ranolazine Marc Imhotep Cray, M.D.

Inotropes & Pulmonary Arterial Vasodilators Digoxin Milrinone Sildenafil Epoprostenol Bosentan Diuretics Furosemide Hydrochlorothiazide Spironolactone Acetazolamide Mannitol

CVS Pharmacology Lecture 1

Antiarrhythmics Procamamide Lidocaine Flecainide Amiodarone Ibutilide Adenosine

3 See: Most Common Drugs (Classes) with Phonetic Pronunciations

CVS Pharmacology Lecture 1

To best understand pharmacological approaches to management of cardiovascular disorders, an overview of regulation of cardiovascular function is warranted.

Marc Imhotep Cray, M.D.

4

CVS Pharmacology Lecture 1

Overview ď ą The heart and circulatory system must provide continuous, efficient, and reliable operation while adapting to short and long-term physiologic changes ď ą Drugs that are used to treat cardiovascular disorders constitute one of the largest categories of prescription drugs used

Marc Imhotep Cray, M.D.

5

CVS Pharmacology Lecture 1

Overview (2)  Two factors suggest that the use of CV drugs will continue to increase:  An aging population and  increasing use of drugs as prevention against future CVD

 These 2 factors work synergistically:  As preventive care increases average lifespan, the population has a greater risk of cardiovascular disease, and  As life expectancy increases, greater emphasis is placed on earlier preventive intervention

Marc Imhotep Cray, M.D.

6

Overview (3)

CVS Pharmacology Lecture 1

 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 because they were average (age-appropriate mean) are now widely considered to fall into hypertension category and are now routinely treated with medication  Cholesterol levels that were once deemed normal (or were even thought to be so insignificant that they went unmeasured) are now routinely treated with medications Marc Imhotep Cray, M.D.

7

Overview (4) U.S. Epidemiology*

CVS Pharmacology Lecture 1

 Dysfunction of the CVS is the principal cause of death and disability in middle-aged and elderly men and women in the industrialized world  In the United States in 2004, there were nearly 1 million deaths from cardiovascular disease, representing approximately 36% of all deaths  Estimates of the 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 Marc Imhotep Cray, M.D.

8

CVS Pharmacology Lecture 1

Overview (5) 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 the heart is principally via the vagus nerve (cranial nerve X) and is mediated by the action of acetylcholine (ACh) at muscarinic cholinergic receptors  Sympathetic innervation of the heart is mediated principally by the action of norepinephrine (NE) on β adrenoceptors (β1 subtype)

Marc Imhotep Cray, M.D.

9

CVS Pharmacology Lecture 1

Overview (6)  The vasculature is controlled in a site-dependent manner  By the parasympathetic subdivision mediated by ACh, which usually causes vasodilation*, and  By the 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.

Marc Imhotep Cray, M.D.

10

Overview (7)

CVS Pharmacology Lecture 1

 A major advance in treatment strategies for cardiovascular disorders occurred as a result of recognition of the significant contributions made by other neurotransmitter and hormone systems to normal and pathologic cardiovascular function  Targeting these systems, such as the renin-angiotensinaldosterone system (RAAS) , has led to a broader variety of treatment options  Cardiovascular drugs include some of the 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 Marc Imhotep Cray, M.D.

11

Cardiovascular function: Anatomy

CVS Pharmacology Lecture 1

 The heart muscle pumps blood through the circulatory system.  Each day, the heart beats 100,000 times and pumps 2000 gal of blood.  The heart is composed of 4 chambers (divisions): the upper two, the right and left atria; the lower two, the right and left ventricles.  Blood is pumped through the chambers, in only 1 direction, via 4 valves: the tricuspid, located between the right atrium and the right ventricle; the pulmonary, between the right ventricle and the pulmonary artery; the mitral, between the left atrium and the left ventricle; and the aortic, between the left ventricle and the aorta.

Marc Imhotep Cray, M.D.

12

CV function: Anatomy cont.

CVS Pharmacology Lecture 1

 Dark blood, low in oxygen, returns from body tissues through veins, enters the right atrium, and then flows to the right ventricle, the pulmonary artery, and the lungs, where it is oxygenated.  Blood returns by pulmonary veins to the left atrium and goes through the mitral valve into the left ventricle, which pumps oxygen-rich, bright-red blood through the aortic valve into the aorta and then into the circulation.

Marc Imhotep Cray, M.D.

13

Cardiovascular function: Definition of Terms and Regulation

CVS Pharmacology Lecture 1

 Cardiac output (CO) is total blood volume pumped by ventricles per minute  (CO=heart rate × stroke volume)  Stroke volume (SV) is the blood pumped by the 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 the contraction phase of the cardiac cycle, when ventricles pump stroke volumes  Diastole is the resting phase of the cycle, which occurs between heartbeats  End-diastolic volume (EDV) is the blood volume in each ventricle at the end of diastole: 120 mL at rest  End-systolic volume(ESV) is the blood volume in each ventricle after contraction: 50 mL at rest Marc Imhotep Cray, M.D.

14

Definition of Terms and Regulation cont.

CVS Pharmacology Lecture 1

 To maintain equal flow through pulmonary and systemic circuits, the left and right ventricles maintain the same cardiac output  The 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

Marc Imhotep Cray, M.D.

15

CVS Pharmacology Lecture 1

Functional Regulation of the CVS:  The function of the cardiovascular system involves:  the autonomic nervous system (ANS)  the kidneys(RAAS)  the heart  the vasculature, and  the blood  Because these systems represent an integrated network, cardiovascular function can be affected by alterations at any point Marc Imhotep Cray, M.D.

16

CVS Pharmacology Lecture 1

ANS  The ANS innervates the heart, blood vessels, kidney, and adrenal medulla and has the potential to modify cardiovascular function in a number of different ways  (See cardiovascular physiology, Unit 4 string of MedPharm Digital Guidebook and NIP-associated graphics.)  The CO is the amount of blood pumped by the ventricles per unit time  As stated previously, it is determined by the volume of blood ejected during each ventricular contraction (stroke volume [SV]) and how frequently the heart beats (heart rate [HR] ), expressed as CO = HR x SV.  The HR can be affected by a variety of factors but is principally under the control of the ANS  Beta blockers can reduce CO by decreasing HR and contractility

Marc Imhotep Cray, M.D.

17

CVS Pharmacology Lecture 1

The kidneys (RAAS) ď ą The kidneys adjust the excretion of Na+, other ions and H2O to maintain extracellular fluid and volume; fluid retention by the kidney is a modifiable physiological parameter that can result in changes in blood pressure.  (See renal physiology, Unit 4 string of MedPharm Digital Guidebook and NIPassociated graphics.)

Marc Imhotep Cray, M.D.

18

CVS Pharmacology Lecture 1

The heart ď ą The heart, including the rhythmic nature of its electrical signals, force of contraction, and magnitude of the discharge pressure, is responsible for pumping the blood through the pulmonary system for oxygenation and delivering it through the vasculature to organs throughout the body.  (See cardiovascular physiology, Unit 4 string of MedPharm Digital Guidebook and NIP-associated graphics.)

Marc Imhotep Cray, M.D.

19

CVS Pharmacology Lecture 1

The circulation ď ą The circulation (both blood volume and composition), including H2O, electrolyte and iron balances, cholesterol, lipid composition and capabilities for clot formation and lysis, delivers O2 and nutrients to and carries away CO2 and waste from all tissues.  (See cardiovascular physiology, Unit 4 string of MedPharm Digital Guidebook and NIP-associated graphics.)

Marc Imhotep Cray, M.D.

20

Mathematical determinants of the arterial blood pressure

CVS Pharmacology Lecture 1

 The mean arterial pressure (MAP) is determined by:  How much blood the heart pumps into the arterial system in a given time (CO) and  How much resistance the arteries have to this input (total peripheral resistance [TPR])  Mathematically, this is expressed as MAP = CO x TPR  Consequently, all drugs that lower blood pressure work by affecting either the 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  Because approximately one third of the cardiac cycle is spent in systole and two thirds in diastole, the MAP can be calculated as MAP= 1/3 SBP + 2/3 DBP

Marc Imhotep Cray, M.D.

21

Strategies for Treating Cardiovascular Diseases: Hypertension Therapeutic Goal

CVS Pharmacology Lecture 1

Pharmacologic Strategies

Reduce volume overload

Diuretics decrease blood volume by increasing volume of water excreted in the urine.

Reduce sympathetic outflow from the brain

Clonidine is an agonist at α2 receptors. It inhibits release of NE and inhibits sympathetic outflow from the brain

Block adrenergic receptors in the 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

Marc Imhotep Cray, M.D.

22

Strategies for Treating Cardiovascular Diseases: Angina Therapeutic Goal Reduce work of the heart and improve cardiac circulation = Decrease myocardial O2 demand Increase myocardial O2 supply

CVS Pharmacology Lecture 1

Pharmacologic Strategies 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

Marc Imhotep Cray, M.D.

23

Strategies for Treating Cardiovascular Diseases: Myocardial Infarction Therapeutic Goal Reperfuse ischemic tissue

CVS Pharmacology Lecture 1

Pharmacologic Strategies 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 the setting of acute myocardial infarction

Marc Imhotep Cray, M.D.

24

Strategies for Treating Cardiovascular Diseases: Heart Failure Therapeutic Goal Reduce workload

CVS Pharmacology Lecture 1

Pharmacologic Strategies 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 the heart)

Improve myocardial contractility

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

Marc Imhotep Cray, M.D.

25

Strategies for Treating Cardiovascular Diseases: Arrhythmias Therapeutic Goal Restore synchronous myocardial contraction

Marc Imhotep Cray, M.D.

CVS Pharmacology Lecture 1

Pharmacologic Strategies Several classes of agents described in a subsequent lecture, including: Na Channel Blockers K Channel Blockers Ca Channel Blockers β-Blockers Others agents

26

Strategies for Treating Cardiovascular Diseases: Vascular Occlusion 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

Marc Imhotep Cray, M.D.

CVS Pharmacology Lecture 1

27

THE END

Marc Imhotep Cray, M.D.

CVS Pharmacology Lecture 1

28

CVS Pharmacology Lecture 1

Further study (SDL): Online resource center: Medical Pharmacology Cloud Folder

Lectures/discussions to follow: 2. Hypercholesterolemia and Atherosclerosis 3. Angina 4. Heart Failure 5. Arrhythmias 6. Hypertension 7. Peripheral Vascular Disease

Marc Imhotep Cray, M.D.

29