Lect1 CVS Function, Regulation of 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

CVS Pharmacology
Lecture 1
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 eNotes: Cardiovascular Pharmacology
Textbook Reading: Section III. Cardiovascular and Renal Drugs.
In: Katzung BG, ed. Basic & Clinical Pharmacology. 12th ed.

CVS Pharmacology
Lecture 1Classification Schema:
CARDIOVASCULAR & RENAL AGENTS
3
Direct Vasodilators
Nitroglycerin
Nitroprusside
Nesiritide
Hydralazine
ACE Inhibitors, ARBs,
& Renin Inhibitors
Captopril
Losartan
Alisklren
Calcium Channel Blockers
Nifedipine
Verapamil
Other antianginals
Ranolazine
Inotropes & Pulmonary
Arterial Vasodilators
Digoxin
Milrinone
Sildenafil
Epoprostenol
Bosentan
Diuretics
Furosemide
Hydrochlorothiazide
Spironolactone
Acetazolamide
Mannitol
Antiarrhythmics
Procamamide
Lidocaine
Flecainide
Amiodarone
Ibutilide
Adenosine
See: Most Common Drugs (Classes) with Phonetic Pronunciations

CVS Pharmacology
Lecture 1
4
To best understand pharmacological approaches to
management of cardiovascular disorders, an overview of
regulation of cardiovascular function is warranted.

CVS Pharmacology
Lecture 1
Overview
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

CVS Pharmacology
Lecture 1
Overview (2)
6
 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

CVS Pharmacology
Lecture 1
Overview (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 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

CVS Pharmacology
Lecture 1
Overview (4) U.S. Epidemiology*
8
 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

CVS Pharmacology
Lecture 1
Overview (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 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)

CVS Pharmacology
Lecture 1
Overview (6)
10
 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.

CVS Pharmacology
Lecture 1
Overview (7)
11
 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-angiotensin-
aldosterone 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

CVS Pharmacology
Lecture 1
12
 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.
Cardiovascular function:
Anatomy

CVS Pharmacology
Lecture 1
13
 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.
CV function: Anatomy cont.

CVS Pharmacology
Lecture 1
Cardiovascular function: Definition of
Terms and Regulation
14
 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

CVS Pharmacology
Lecture 1
Definition of Terms and Regulation
cont.
15
 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

CVS Pharmacology
Lecture 1
Functional Regulation of the CVS:
16
 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

CVS Pharmacology
Lecture 1
ANS
17
 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

CVS Pharmacology
Lecture 1
The kidneys (RAAS)
18
 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 NIP-
associated graphics.)

CVS Pharmacology
Lecture 1
The heart
19
 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.)

CVS Pharmacology
Lecture 1
The circulation
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 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.)

CVS Pharmacology
Lecture 1
Mathematical determinants of the
arterial blood pressure
21
 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

CVS Pharmacology
Lecture 1Strategies for Treating Cardiovascular
Diseases: Hypertension
22
Therapeutic Goal 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

CVS Pharmacology
Lecture 1
Strategies for Treating Cardiovascular
Diseases: Angina
23
Reduce work of the 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

CVS Pharmacology
Lecture 1
Diseases: Myocardial Infarction
24
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 the setting of acute
myocardial infarction

CVS Pharmacology
Lecture 1
Diseases: Heart Failure
25
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 the 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

CVS Pharmacology
Lecture 1
Diseases: Arrhythmias
26
Restore synchronous myocardial
contraction
Several classes of agents described in a
subsequent lecture, including:
Na Channel Blockers
K Channel Blockers
Ca Channel Blockers
β-Blockers
Others agents

CVS Pharmacology
Lecture 1
Diseases: Vascular Occlusion
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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

CVS Pharmacology
Lecture 1
THE END
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CVS Pharmacology
Lecture 1
29
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

Lect1 CVS Function, Regulation of Heart and Overview of Therapeutic Goals in CV Disorders

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Lect1 CVS Function, Regulation of Heart and Overview of Therapeutic Goals in CV Disorders