Transcript Cardiovascular Pharmacology

Cardiovascular Pharmacology
Review of Cardiovascular Form
and Function
Introduction and Background
Cardiovascular disease is the major cause
of death in the US (>50% of all deaths)
Cardiovascular function based on
– Cardiac pumping ability
Pace-making electrical signals
Force of contraction
Height of ventricle discharge pressure
– Integrity of vasculature
Presence of blockage
Muscular tone/structural integrity
Pressure drop needed to move blood to and through
capillary beds
– Blood volume/composition
Water, electrolyte, iron balances
Lipid and protein composition
Major Cardiovascular Pathologies
Requiring Pharmacological Intervention
Hypertension
Arrhythmia
Heart failure
Reduced vascular blood flow
I. Background to Hypertension Regulation of Blood Pressure
Arterial blood pressure due to combination
of cardiac output (CO) and total peripheral
resistance (TPR)
CO – regulated by heart rate and stroke
volume (CO = HR x SV)
TPR function of
– Viscosity of blood (hematocrit)
– Length of blood vessels
– Blood vessel luminal diameter (especially
precapillary arterioles)
Cardiac Output
Heart rate
– Function of
sympathetic, vagal nervous activity
Neuro-hormonal substances
– 1° angiotensin II
– 2º vasopression (anti-diuretic hormone = ADH)
Stroke volume
– Function of
Venous return (function of venous tone [contractile state]
and circulating blood (vascular) volume)
– Venous tone function of sympathetic activity (α1, α2 receptors)
– Vascular volume depends on
Intake of fluids (thirst)
Output of fluids (urine, sweat, etc)
Distribution of fluids (Starling’s law)
Myocardial contractility (MC proportional to sympathetic
tone [β1 receptors])
Characteristics of some adrenoceptors
(sympathetic nerves)
Tissues
receptors
and effects
α1
α2
constrict
constrict/
dilate
β1
β2
Smooth
muscle
Arteries/
veins
dilate
Skeletal
muscle
dilate
Heart
Rate
(increase)
Force of
contraction
increase
Beat-to-Beat Modulation of Blood
Pressure
Controlled by baroreceptor reflex arch
– Baroreceptors located in aortic arch
– Increased stretching due to higher aortic arch
pressure  increased vagal nerve activity 
decreased heart rate decreased cardiac
output  decreased blood pressure
– Fast acting
Autonomic Regulation of Blood Pressure
Coordinates and integrates all
regulators of cardiovascular function
Can regulate both cardiac output and
blood vessel size via sympathetic and
parasympathetic innervation of
cardiovascular end-organs (heart,
vasculature, kidneys, adrenal glands,
etc)
Autonomic Regulation of the Heart
Heart Rate
– Parasympathetic input via vagus nerve
causes decrease in HR (dominates)
– Sympathetic input to sino-atrial node
causes increase in HR (usually minor)
Heart contractility
– Increased by sympathetic activity
causing release of epinephrine,
norepinephrine from adrenal gland
II. Background to Arrhythmia Rhythm of the Heart
Human heart is fourchambered
Chambers need to contract
sequentially (atria, then
ventricles) and in
synchronicity
Also need relaxation
between contractions to
allow refilling of chambers
Above controlled
electrically (Purkinje fibers
allow rapid, organized
spread of activation)
Regulation of Heart Rate
– Primarily accomplished by sinoatrial node (SA)
Located on right atrium
Receives autonomic input
When stimulated, SA signals atrial contractile fibers
 atria depolarization and contraction (primes
ventricles with blood)
– Depolarization picked up by atrioventricular
node (AV node)  depolarizes ventricles 
blood discharged to pulmonary artery and
dorsal aorta  eventually rest of body
Sequential Discharge of SA and AV nodes
III. Background to Congestive Heart Failure
Maintenance of Normal Heart Function
Normal cardiac output needed to adequately perfuse
peripheral organs
– Provide O2, nutrients, etc
– Remove CO2, metabolic wastes, etc
– Maintain fluid flow from capillaries into interstitium and back
into venous system  if flow reduced or pressure increased in
venous system  build up of interstitial fluid = edema
Because CO is a function of
– Heart Rate – determined by pacemaker cells in the sinoatrial
node
– Stroke volume – determined by fill rate and contractile force
– Atrial/ventricular/valvular coordination
Any negative change on above can lead to inadequate
perfusion and development of the syndrome of heart failure
IV. Background to Reduced Vascular Blood
Flow: Blood Vessel Anatomy and Function
Arterial blood vessels
– Smooth muscle (slow, steady contraction)
– elastic tissue (stretch on systole, recoil on diastole)
– Contain about 10% of blood volume
– Arterioles have sphincters which regulate 70% of blood pressure
Venous blood vessels
– Highly distensible, some contractility
– Contain over 50% of blood volume
Capillaries
– Tiny but contain greatest cross-sectional area to allow high exchange
rate
– Contain precapillary sphincters to regulate blood flow
– 5% of blood volume
All vasculature under ANS and humeral control
Quantification of Total Peripheral Resistance
TPR =
_L · η_ for sum of all blood vessels
r4
(Poiseuille’s equation)
Where
r = radius of blood vessel
L = length of blood vessel
η = viscosity of blood (function of
hematocrit) hematocrit =
Therefore: change in blood vessel radius has
greatest effect on TPR
Note: 70% of TPR produced/controlled by
arterioles  target of drug treatment
Relationship between blood flow
and radius of a blood vessel
0.063
0.5
Relationship between blood pressure,
velocity and total area of vasculature
Humeral Regulation of Blood Pressure:
Renin-Angiotensin-Aldosterone System
Renin: secreted by the kidney in response to reduced blood pressure
or blood volume
Angiotensin: Renin converts Angiotensinogen  Angiotensin I
Angiotensin Converting-Enzyme (ACE): converts Angiotensin I 
Angiotensin II in lung
Angiotensin II:
– Actions:
Intense vasoconstriction  increase TPR
Causes release of Aldosterone from adrenal gland  promotes Na+ and
water reabsorption in kidney  cause increased blood volume.
Regulatory negative feedback on the release of Renin.
CNS: Stimulate thirst in hypothalamus, stimulate sympathetic outflow.
- All above designed to bring arterial blood pressure
back up to normal set-point
Autonomic regulation
of the vasculature
Increased sympathetic activity 
reduction in blood vessel opening
(caliber)  increase in vascular
resistance  etc.  etc  increase
blood pressure
Stop talking now and
let them go!
I’m outta’
here!