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

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.

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

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

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.

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

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

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

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

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)

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.

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

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

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
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
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

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

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

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.

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

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

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

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

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

Cardiac output (CO) variables
24
 Stroke volume
 Contractility
 Myocardial oxygen demand
 Preload
 Afterload
 Ejection fraction

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)

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)

CO variables: Myocardial oxygen demand
27
Myocardial O2 demand is↑ by:
 ↑ Contractility
 ↑ Afterload (proportional to arterial pressure)
 ↑ Heart Rate
 ↑ Diameter of ventricle (↑ wall tension)

CO variables: Preload
28
 Preload approximated by ventricular EDV depends
on venous tone and circulating blood volume
 Venodilators (e.g., nitroglycerin) ↓preload

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

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)

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

Strategies for Treating CV Diseases: Angina
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

Strategies for Treating CV Diseases:
Myocardial Infarction
33
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

Strategies for Treating CV Diseases: Heart Failure
34
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

Strategies for Treating Cardiovascular
Diseases: Arrhythmias
35
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

Strategies for Treating Cardiovascular
Diseases: Vascular Occlusion
36
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

THE END
37

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

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

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