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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

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Cardiovascular Pharmacology

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  1. Cardiovascular Pharmacology Review of Cardiovascular Form and Function

  2. 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

  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 (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])

  6. Characteristics of some adrenoceptors (sympathetic nerves) Tissues and effects receptors

  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 · 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

  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! I’m outta’ here!

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