Cardiovascular Pharmacology

1
Cardiovascular Pharmacology

• Review of Cardiovascular Form and Function

2
Introduction and Background

• Cardiovascular disease is the major cause of
  death in the US (gt50 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

3
Major Cardiovascular Pathologies Requiring
Pharmacological Intervention

• Hypertension
• Arrhythmia
• Heart failure
• Reduced vascular blood flow

4
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)

5
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 (a1,
  a2 receptors)
• Vascular volume depends on
• Intake of fluids (thirst)
• Output of fluids (urine, sweat, etc)
• Distribution of fluids (Starlings law)
• Myocardial contractility (MC proportional to
  sympathetic tone ß1 receptors)

6
Characteristics of some adrenoceptors
(sympathetic nerves)
Tissues and effects
receptors
a1 a2 ß1 ß2
Smooth muscle
Arteries/ veins constrict constrict/ dilate dilate
Skeletal muscle dilate
Heart
Rate (increase)
Force of contraction increase
7
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

8
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)

9
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

10
II. Background to Arrhythmia - Rhythm of the Heart

• Human heart is four-chambered
• 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)

11
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

12
Sequential Discharge of SA and AV nodes
13
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

14
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

15
Quantification of Total Peripheral Resistance

• TPR _L ?_ for sum of all blood vessels
• r4 (Poiseuilles equation)
• Where r radius of blood vessel
• L length of blood vessel
• ? 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

16
Relationship between blood flow and radius of a
blood vessel
0.063
0.5
17
Relationship between blood pressure, velocity and
total area of vasculature
18
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

19
Autonomic regulation of the vasculature

• Increased sympathetic activity ? reduction in
  blood vessel opening (caliber) ? increase in
  vascular resistance ? etc. ? etc ? increase blood
  pressure

20
Stop talking now and let them go!
Im outta here!