Cvi fall 2011


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  • Porth pg. 319-320
  • Porth pg 320
  • Lehne pg. 455
  • Porth pg 321
  • Porth pg 322-324
  • Porth pg 320-321; Compliance, distensibility, porth pg 325.
  • Porth pg 337
  • Porth 340-341
  • Pg 342
  • Porth pg 342
  • Poarth pg 326
  • Porth pg 326
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  • Porth pg 328
  • Porth 328
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  • Porth pg 333
  • Porth 334-335
  • Porth 334
  • Porth pg 335.
  • Porth pg 335.
  • Porth 335
  • Lehne pg 456, Porth 326
  • Porth pg 322-324
  • Porth pg 361
  • Lehne pg 457
  • Porth pg 364; Lehne pg 492
  • Porth pg 343, 364
  • Porth pg 344
  • Porth pg 365
  • Porth pg 364
  • Porth pg 365
  • Lehne pg 457 “regulation of arterial pressure”
  • Porth pg 374
  • Porth pg 374-5
  • Porth pg 375
  • Porth pg 375-376
  • Porth pg 366
  • Porth pg 366
  • Porth pg 366
  • Porth pg 366-367
  • Porth pg 367
  • Porth pg 368
  • Porth pg 368, Lehne pg 490-491
  • Lehne pg 492-494 : Re-iterate that thiazides do not affect VSM!
  • Lehne pg 500
  • Lehne 501 - 502
  • Lehne pg 439
  • Lehne pg 441
  • Lehne pg 443
  • Lehne 439: mechanism of action
  • Lehne pg 439
  • Lehne p 440 - incorporate pt/family teaching into these adverse effects
  • Lehne pg 443; compare mechanism of action here for Aladatone and triamterone (p.443 and 444)
  • Lehne pg 443
  • Lehne pg 444
  • Lehne pg 444
  • Lehne pg 444
  • Porth pg 364
  • Lehne pg 464
  • Lehne pg 464-466
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  • Lehne pg 468
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  • Lehne pg 469
  • Lehne 495
  • Lehne pg 495-496
  • Lehne pg 498
  • Lehne pg 498;include pt teaching about sedation and no driving, don’t stop med quickly
  • Lehne pg 474
  • Lehne p475
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  • Lehne pg 478
  • Lehne 484-5
  • Lehne pg 485
  • Porth pg 347
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  • Porth pg 348
  • Lehne pg 558
  • Porth 349, 350
  • Porth pg 350
  • Porth pg 352
  • Porth 352
  • N98-305 Pathophys ACS 11/02/11 12:10 PM Histologic studies have characterized the progression of atherosclerotic lesion types. The earliest lesions (from the first decade on) are characterized histologically by isolated foam cells or fatty streaks in the vessel wall. Lesion growth at this stage occurs mainly by lipid accumulation. Intermediate lesions, which may be associated with small extracellular lipid pools, progress to atheroma, which has a core of extracellular lipid. These lesions may be seen starting in the third decade. Starting in the fourth decade, lesions may progress to the fibrous plaque stage, which is characterized by accelerated increases in smooth muscle and collagen. Complicated lesions are characterized by thrombosis, fissure, and hematoma formation. 2 Atherosclerosis Timeline 2 Stary HC, Chander AB, Dinsmore RE, et al. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. Circulation. 1995;92:1355–1374. Slide 2
  • Porth 352, robbins pg 517
  • Porth pg 323
  • Porth pg 352
  • Porth 352-3
  • Porth 355
  • Porth 350 - 351.
  • Porth pg 351
  • Porth pg 351
  • Proth 351
  • Lehne pg 557
  • Lehne pg 557-8
  • Lehne pg 558
  • Lehne pg 558
  • Lehne pg 559-60
  • Lehne pg 560
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  • Lehne 562
  • Lehne pg 562-563
  • Lehne pg 563
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  • Lehne pg 564
  • Lehne 562
  • Lehne 562
  • Lehne pg 562
  • Lehne pg 563
  • Cvi fall 2011

    1. 1. Control of Cardiovascular Function, Disorders of Blood Flow & Blood Pressure, Hyperlipidemia & Artherosclerosis
    2. 2. <ul><li>Review of Hemodynamics </li></ul><ul><ul><li>Blood vessel structure, function </li></ul></ul><ul><ul><li>Regulation of cardiac output </li></ul></ul><ul><ul><li>Mechanisms of blood pressure regulation </li></ul></ul><ul><li>Disorders of blood pressure </li></ul><ul><ul><li>Hypertension </li></ul></ul><ul><ul><li>Orthostatic hypotension </li></ul></ul><ul><li>Drugs that affect blood pressure </li></ul><ul><li>Disorders of arterial circulation </li></ul><ul><ul><li>Hyperlipidemia, atherosclerorosis </li></ul></ul><ul><li>Drugs that lower LDL cholesterol </li></ul>
    3. 3. Pulmonary and Systemic Circulation Baxter Corp. (1999)
    4. 4. Differences in the Two Systems <ul><li>PULMONARY </li></ul><ul><li>Low pressure system (MPAP 12 mmHg) </li></ul><ul><li>Good for gas exchange </li></ul><ul><li>SYSTEMIC </li></ul><ul><li>High pressure system (MAP 90-100 mmHg) </li></ul><ul><li>Good for distant transport, against gravity </li></ul>
    5. 5. How does blood get back to the heart? Lehne, 2009, Pharmacology for Nursing Care, 7 th ed., Elsevier, p 461
    6. 6. Principles of Blood Flow <ul><li>Hemodynamics </li></ul><ul><li>Heart is an intermittent pump, blood flow is pulsatile </li></ul><ul><li>Factors governing the function of the CV system </li></ul><ul><ul><li>Volume </li></ul></ul><ul><ul><li>Pressure </li></ul></ul><ul><ul><li>Resistance </li></ul></ul><ul><ul><li>Flow </li></ul></ul>
    7. 7. Determinants of Blood Pressure <ul><li>BP = CO X Peripheral vascular resistance </li></ul><ul><li>CO = SV X HR </li></ul><ul><li>What determines peripheral vascular resistance? </li></ul>
    8. 8. Resistance of a Tube Porth, Pathophysiology, Concepts of Altered Health States, 7 th ed., 2005, Lippincott, p. 452. Also see p 322, point 2 in Porth, Essentials Big factor!
    9. 9. Volume & Pressure Distribution Porth, 2007, Essentials of Pathophysiology, 2 nd ed., Lippincott, p. 321. Arteriolar tone determines systemic vascular resistance
    10. 10. Same concept from Lehne Lehne, 2009, Pharmacology for Nursing Care, 7 th ed., Elsevier, p 461
    11. 11. All Blood Vessels Have 3 Layers <ul><li>Intima - elastic layer </li></ul><ul><li>Media - smooth muscle for diameter control (innervated by the SNS with alpha receptors) </li></ul><ul><li>Externa - fibrous and connective tissue for support </li></ul>Porth, 2007, Essentials of Pathophysiology, 2 nd ed., Lippincott, p. 338
    12. 12. Resistance Arterioles Maintain Blood Pressure Porth, 2007, Essentials of Pathophysiology, 2 nd ed., Lippincott, p. 338 Arteries have abundant smooth muscle. The diameter of the artery/arteriole is determined by the degree of contraction of the smooth muscle, which is mediated by the SNS (alpha receptors).
    13. 13. Blood Vessels and the Peripheral Circulation <ul><li>Blood vessels are dynamic structures </li></ul><ul><li>They constrict and relax to adjust blood flow to meet varying needs of tissues/organs </li></ul><ul><li>The heart, brain, liver, and kidney require large continuous flow </li></ul><ul><li>Skin, skeletal muscle require varying flow </li></ul>
    14. 14. Arteries, Arterioles <ul><li>Elasticity allows for stretching during systole </li></ul><ul><li>Arterioles have abundant smooth muscle </li></ul><ul><li>Arterioles are the major resistance vessels for circulatory system and basically determine the systemic vascular resistance </li></ul><ul><li>Sympathetic fibers innervate arterioles cause them to constrict/relax as needed to maintain BP (alpha receptors) </li></ul>
    15. 15. Veins, Venules <ul><li>Collect blood from capillaries, carry back to heart </li></ul><ul><li>Enlarge and store large quantities of blood </li></ul><ul><li>Contract/expand to accommodate varying amounts </li></ul><ul><li>Innervated by SNS (alpha receptors) </li></ul><ul><li>Venous constriction can increase the preload to the heart by conducting stored blood into the vena cava </li></ul>
    16. 16. Veins <ul><li>Valves prevent retrograde flow </li></ul><ul><ul><li>Incompetent valves in venous varicosities </li></ul></ul><ul><li>Skeletal muscles help compress veins in “milking manner” up to heart </li></ul><ul><li>Low pressure system – Pressure in venules is ~10 mm Hg and in the vena cava ~0 mmHg </li></ul>Porth, 2007, Essential of Pathophysiology, 2 nd ed., Lippincott, p. 339.
    17. 17. Endothelial Cells Endothelial cells line all blood vessels. They are normally quite smooth and permit laminar blood flow. They also form a tight barrier in larger vessels, but in capillaries are more permissive of small molecules exiting and entering the vascular system.
    18. 18. Capillaries <ul><li>Single cell-thick vessels that connect arterial and venous segments </li></ul><ul><li>Wall composed of a single layer of endothelial cells surrounded by a basement membrane </li></ul><ul><li>In most vascular beds, capillaries have fenestrations that allow passage of water and small molecules but not large proteins. </li></ul>Porth, 2007, Essentials of Pathophysiology, 2 nd ed., Lippincott, p. 341.
    19. 19. Vascular Smooth Muscle and Sympathetic Nervous System <ul><li>Norepinephrine-activated alpha receptors cause calcium channels in vascular smooth muscle to open, which produces vasoconstriction </li></ul><ul><li>In some vascular beds, beta-2 receptors promote vasodilation by decreasing calcium. </li></ul><ul><li>C alcium C auses C ontraction in vascular smooth muscle </li></ul><ul><li>Calcium channel blockers prevent vasoconstriction </li></ul>
    20. 20. Perfusion of Organs <ul><li>Tissue blood flow to a given organ is regulated on minute-to-minute basis in relation to tissue needs </li></ul><ul><li>Neural mechanisms regulate CO and systemic vascular resistance (BP) to support local mechanisms </li></ul><ul><li>Local control includes preferential vasoconstriction or vasodilation mediated by the SNS or by intrinsic mechanisms within the organ. </li></ul>
    21. 21. Tissue Factors Contributing to Local Control of Blood Flow <ul><li>Factors are released from an organ when it has too much or too little blood flow. </li></ul><ul><li>Increase blood flow </li></ul><ul><ul><li>Histamine </li></ul></ul><ul><li>Decrease blood flow </li></ul><ul><ul><li>Serotonin </li></ul></ul>
    22. 22. Endothelial Control of Vascular Smooth Muscle <ul><li>The endothelium produces factors that act on smooth muscle to produce vasoconstriction or vasodilation </li></ul><ul><li>Vasodilating substances </li></ul><ul><ul><li>Nitric Oxide </li></ul></ul><ul><li>Vasoconstricting substances </li></ul><ul><ul><li>Angiotensin II, Prostaglandins, Endothelins </li></ul></ul>
    23. 23. Functional Anatomy of the Heart Pericardium: Sac around heart Porth, 2007, Essential of Pathophysiology, 2 nd ed., Lippincott, p. 328. A “virtual space” which can become fluid or blood-filled (pericardial effusion).
    24. 24. Contraction: Actin & Myosin Binding Spirito et al., NEJM 336, pg 775, 1997
    25. 25. Heart Valves Keep Blood Flow Unidirectional Semilunar valves: Control blood flow out of ventricles A ortic valve P ulmonic valve A-V valves : Control blood flow between atria & ventricles T ricuspid valve M itral valve Major function of heart valves: Forward direction of blood flow Porth, 2007, Essentials of Pathophysiology, 2 nd ed., Lippincott, p. 329.
    26. 26. Cardiac Conduction System <ul><li>The conduction system stimulates the myocardium to contract & pump blood </li></ul><ul><li>The conduction system controls the rhythm of the heart. </li></ul><ul><li>Heart has two conduction systems </li></ul><ul><ul><li>One controls atrial activity </li></ul></ul><ul><ul><li>One that controls ventricular activity </li></ul></ul><ul><ul><li>The two systems communicate when the impulse that causes atrial contraction travels to the ventricular system via the A-V node </li></ul></ul>
    27. 27. SA Node <ul><li>Pacemaker of the heart </li></ul><ul><li>Impulses originate here </li></ul><ul><li>Located in posterior wall RA </li></ul><ul><li>Fires at 60 -100 bpm </li></ul><ul><li>Rate is determined by the autonomic nervous system (beta-1 receptors increase HR and muscarinic receptors decrease it). </li></ul>Porth, 2007, Essentials of Pathophysiology, 2 nd ed., Lippincott, p. 331.
    28. 28. AV Node <ul><li>Connects the atria & ventricles, provides one way conduction </li></ul><ul><li>Speed of conduction is determined by the ANS </li></ul><ul><li>Can assume pacemaker function if SA fails to discharge </li></ul><ul><ul><li>Fires at 40 -60 bpm </li></ul></ul>Porth, 2007, Essentials of Pathophysiology, 2 nd ed., Lippincott, p. 331.
    29. 29. Purkinje Fibers <ul><li>Supply the ventricles </li></ul><ul><li>Large fibers, rapid conduction for swift & efficient ejection of blood from heart </li></ul><ul><li>Assume pacemaker of ventricles if AV fails </li></ul><ul><ul><li>Intrinsic rate is 15-40 bpm </li></ul></ul>Porth, 2007, Essentials of Pathophysiology, 2 nd ed., Lippincott, p. 331.
    30. 30. ECG <ul><li>Electrical events recorded </li></ul><ul><li>Electrical events precede mechanical events; know what they represent! </li></ul><ul><ul><li>P </li></ul></ul><ul><ul><li>QRS </li></ul></ul><ul><ul><li>T </li></ul></ul>Porth, 2007, Essentials of Pathophysiology, 2 nd ed., Lippincott, p.331 & 333.
    31. 31. Cardiac Cycle <ul><li>Term used to describe the rhythmic pumping action of heart </li></ul><ul><li>Cycle divided into 2 parts </li></ul><ul><ul><li>Systole : period during which ventricles are contracting </li></ul></ul><ul><ul><li>Diastole : period during which ventricles are relaxed, filling with blood </li></ul></ul><ul><li>Simultaneous changes occur in pressure (LA,LV, aorta), ventricular volume, ECG, heart sounds during cardiac cycle </li></ul>
    32. 32. Porth, 2007, Essential of Pathophysiology, 2 nd ed., Lippincott, p. 334. The Wiggers diagram
    33. 33. Ventricular Systole Porth, 2007, Essentials of Pathophysiology, 2 nd ed., Lippincott, p. 334. Isovolumic (isometric) contraction Closure of AV valves (S1), all valves closed. No change in ventricular volume, ventricles contract. When ventricular pressures > aortic & pulmonary pressures, semilunar valves open, leading to the - Ejection period . Stroke volume ejected. Ventricles contract, then relax. Intraventricular pressures  and become less than pressures in aorta & pulm. artery. Blood from large arteries flows back toward ventricles and aortic/pulmonic valves shut (S2).
    34. 34. Ventricular Diastole Porth, 2007, Essentials of Pathophysiology, 2 nd ed., Lippincott, p. 334. Ventricular relaxation & filling. Isovolumic (isometric) relaxation: Semilunar valves closed, ventricles relax. No change in ventricular volume, but  ventricular pressure until it’s less than atrial pressures. AV valves open, blood from atria enters ventricles -> Rapid filling period . Most ventricular filling in first third of diastole.(S3) During the last third, atria contract (atrial kick).
    35. 35. Atrial Contraction <ul><li>Last third of ventricular diastole </li></ul><ul><li>Gives additional thrust to ventricular filling </li></ul><ul><li>Important during tachycardia or when heart disease impairs ventricular filling </li></ul><ul><ul><li>May not be important in a person with a normal heart, especially at physiologic heart rates. </li></ul></ul><ul><li>Fourth heart sound (S4), when present, occurs when atria contract </li></ul>
    36. 36. Definitions <ul><li>Cardiac output (CO) </li></ul><ul><ul><li>Amount of blood the heart pumps/minute </li></ul></ul><ul><ul><li>3.5 - 8.0 L/minute </li></ul></ul><ul><li>Stroke volume (SV) </li></ul><ul><ul><li>Amount of blood the heart pumps each beat </li></ul></ul><ul><ul><li>70 ml/beat </li></ul></ul><ul><li>CO = SV x HR </li></ul><ul><li>CO varies with body activities. </li></ul><ul><li>CO varies by changes in SV and/or HR </li></ul>
    37. 37. Heart Rate <ul><li>Frequency with which blood is ejected from heart </li></ul><ul><li>As HR  ->  CO </li></ul><ul><li>HR is increased by activation of beta-1 receptors and decreased by activation of muscarinic receptors on the SA node. </li></ul><ul><li>BUT as HR  ->  diastolic filling time </li></ul><ul><li> diastolic filling time may  SV &  CO </li></ul><ul><li>Tachycardia can be dangerous because the heart may not have time to fill adequately ->  CO </li></ul>
    38. 38. Cardiac Output = Stroke Volume x Heart Rate Preload Contractility Afterload
    39. 39. Stroke Volume Components <ul><li>Preload </li></ul><ul><ul><li>Ventricular filling (volume) </li></ul></ul><ul><li>Afterload </li></ul><ul><ul><li>Resistance to ejection of blood from heart </li></ul></ul><ul><li>Contractility </li></ul><ul><ul><li>Pumping function of heart </li></ul></ul>
    40. 40. Preload (“Volume”) <ul><li>Represents the volume of blood the heart must pump with each beat </li></ul><ul><li>Largely determined by venous return and stretch of muscle fibers </li></ul><ul><li>Venous return </li></ul><ul><ul><li>64% of blood volume in veins </li></ul></ul><ul><ul><li>Venous constriction mediated by alpha-1 receptors </li></ul></ul>
    41. 41. <ul><li>Preload: Frank-Starling Law of the Heart </li></ul><ul><li>Actin, myosin filaments that overlap and create cross bridge attachments leads to contraction of cardiac muscle </li></ul>Porth, 2007, Essentials of Pathophysiology, 2 nd ed., Lippincott, p. 336.
    42. 42. Implications of the Frank-Starling Law <ul><li>At normal volumes, as preload increases, stretch increases, which increases contractility. </li></ul><ul><ul><li>CO goes up both because of the increased volume and increased contractility </li></ul></ul><ul><ul><li>The increase in contractility is independent of the SNS – it is an intrinsic property of the heart. </li></ul></ul><ul><li>At high volumes, the cardiac muscle is overstretched and contractility decreases. </li></ul><ul><ul><li>This is usually seen only in patients with heart failure (covered in CVII) who have fluid overload. </li></ul></ul>
    43. 43. Afterload (“Resistance”) <ul><li>The amount of pressure the heart must develop during the period of isovolumic contraction to open the aortic and pulmonic valves. </li></ul><ul><li>Arterial pressures are the major sources of resistance </li></ul><ul><ul><li>Right ventricle: </li></ul></ul><ul><ul><ul><li>pulmonary arterial pressure (low) </li></ul></ul></ul><ul><ul><li>Left ventricle: </li></ul></ul><ul><ul><ul><li>systemic arterial pressure (high – equal to the diastolic BP in the absence of valve disease) </li></ul></ul></ul><ul><li>Disease of the aortic or pulmonic valves   resistance </li></ul><ul><ul><li>Stenosis/narrowing of the valve </li></ul></ul><ul><ul><li>This means that the heart has to develop an increased pressure to open the diseased valve. </li></ul></ul><ul><ul><li>Diastolic hypertension also increases the pressure necessary to open the aortic valve. </li></ul></ul>
    44. 44. Effect of Afterload on CO Guyton, 2006, Textbook of Medical Physiology, 11th ed.,Saunders, p. 114.
    45. 45. Implications of the Afterload/CO Curve <ul><li>At normal afterloads, in people with normal hearts, afterload is not an important factor in cardiac output. </li></ul><ul><ul><li>Normally, preload is a much more important determinant of CO. </li></ul></ul><ul><ul><li>The normal heart pumps what it gets from the venous system. </li></ul></ul><ul><li>In people with heart failure (CVII), afterload becomes an important determinant of CO. </li></ul>
    46. 46. Contractility <ul><li>Ability of the heart to change its force of contraction </li></ul><ul><li>Strongly influenced by number of calcium ions that are available to participate in the contractile process. </li></ul><ul><ul><li>Determined by biochemical and biophysical properties that govern actin and myosin interactions in myocardial cells (Frank-Starling mechanism). </li></ul></ul><ul><ul><li>Activation of beta-1 receptors in the ventricles by norepinephrine increases the availability of calcium ions and increases contractility. </li></ul></ul>
    47. 47. Determinants of Blood Pressure <ul><li>BP = CO X Peripheral vascular resistance </li></ul><ul><li>CO = SV X HR </li></ul>
    48. 48. Mechanisms of BP Regulation <ul><li>Arterial pressure must remain relatively constant as blood flow shifts from one area of body to another </li></ul><ul><li>Method by which arterial pressure is regulated depends on whether short-term or long-term adaptation is needed </li></ul>
    49. 49. Mechanisms of BP Regulation <ul><li>Autonomic nervous system – short-term regulation </li></ul><ul><li>RAAS (Renin-angiotensin-aldosterone system) – longer term regulation </li></ul><ul><li>Kidneys – control blood volume as well as the RAAS – a long-term mechanism of blood pressure control. </li></ul>
    50. 50. The Baroreceptor Reflex Baroreceptors in the aortic arch and carotid artery Autonomic centers in the brainstem Cardiac muscle, cardiac conduction system, and vascular smooth muscle.
    51. 51. The Sensory Components of the Baroreceptor Reflex – Chemo and Stretch Receptors Porth, 2007, Essentials of Pathophysiology, 2 nd ed., Lippincott, p. 364.
    52. 52. ANS Regulation of BP – the Baroreceptor Reflex Be sure you know which receptors are where!!! McCance & Heuther, 2002, Pathophysiology: The Biologic Basis for Disease in Adults & Children, Mosby, p.961
    53. 53. Neurotransmitters Porth, Pathophysiology, Concepts of Altered Health States, 7 th ed., 2005, Lippincott, p. 1151.
    54. 54. Long-term Regulation of BP <ul><li>Primarily controlled by kidneys </li></ul><ul><li>Neural mechanisms act rapidly, but can’t maintain their effectiveness over time </li></ul><ul><li>Kidneys’ control in long term is thru regulation of Na + and H 2 0 balance </li></ul><ul><ul><li>RAAS </li></ul></ul><ul><ul><li>Vasopressin </li></ul></ul>
    55. 55. Humoral Mechanisms: Renin-angiotensin-aldosterone system Porth, 2007, Essentials of Pathophysiology, 2 nd ed., Lippincott, p. 365. MUST KNOW THIS!
    56. 56. Vasopressin (Antidiuretic Hormone (ADH)) Porth, Pathophysiology, Concepts of Altered Health States, 7 th ed., 2005, Lippincott, p. 756.
    57. 57. Porth, Pathophysiology, Concepts of Altered Health States, 7 th ed., 2005, Lippincott, p. 756. The ANS and RAAS systems work in concert.
    58. 58. Which of the following is an important determinant of cardiac output in a normal person? <ul><li>Afterload. </li></ul><ul><li>Heart rate. </li></ul><ul><li>Venous return (preload) </li></ul><ul><li>Total peripheral resistance. </li></ul>
    59. 59. You assess a patient’s pulse to be 40 bpm. He is not an athlete. Given this HR, the electrical impulses in the heart are probably originating from: <ul><li>SA Node </li></ul><ul><li>AV Node </li></ul><ul><li>An ectopic atrial focus </li></ul><ul><li>Purkinje Fibers </li></ul>
    60. 60. Angiotensin II causes: <ul><li>Release of aldosterone </li></ul><ul><li>Vasoconstriction of arterioles </li></ul><ul><li>Increased arterial blood pressure </li></ul><ul><li>All of the above </li></ul>
    61. 61. Disorders of Blood Pressure Regulation: Hypertension and Orthostatic Hypotension
    62. 62. Orthostatic Hypotension <ul><li>Abnormal drop in BP on assumption of the standing position </li></ul><ul><li>Defined as a drop in systolic pressure > 20 mm Hg or drop in diastolic pressure > 10 mm Hg when going from lying to standing </li></ul><ul><li>In absence of normal circulatory reflexes and/or if blood volume is decreased, blood pools in lower part of the body when the standing position is assumed (decreased venous return), CO  and blood flow to the brain is inadequate  dizziness, syncope (fainting), or both </li></ul>
    63. 63. Porth, 2007, Essentials of Pathophysiology, 2 nd ed., Lippincott, p. 374 Orthostatic Hypotension
    64. 64. Causes <ul><li>Reduced blood volume (dehydration) (reduced preload) </li></ul><ul><ul><li>This is the most common cause of dizziness and fainting, especially in young, health people. </li></ul></ul><ul><li>Drug-induced orthostatic hypotension </li></ul><ul><ul><li>Impairment of venous return (reduced preload) (Ca 2+ channel blockers) </li></ul></ul><ul><ul><li>Impairment of the baroreceptor reflex (beta blockers, alpha-1 blockers) </li></ul></ul><ul><ul><li>Diuretics (reduced preload) </li></ul></ul><ul><li>Aging – sluggish reflexes, including the baroreceptor reflex </li></ul><ul><li>Bedrest – deconditioning </li></ul><ul><li>Disorders of the autonomic nervous system </li></ul>
    65. 65. Treatment <ul><li>Alleviating cause </li></ul><ul><ul><li>Rehydrate, change meds </li></ul></ul><ul><li>Help cope with disorder, prevent falls, injury </li></ul><ul><ul><li>Gradual ambulation (sit on edge of bed, move legs) </li></ul></ul><ul><ul><li>Avoid venodilation (drinking ETOH; exercise in warm environment) </li></ul></ul><ul><ul><li>Maintain hydration </li></ul></ul>
    66. 66. Hypertension <ul><li>Common health problem in adults </li></ul><ul><li>A leading risk factor for cardiovascular disorders (myocardial infarction, heart failure, stroke, vascular disease) </li></ul><ul><li>More common in young men than young women, blacks compared with whites, in persons from lower socioeconomic groups, and with increasing age </li></ul><ul><li>Diabetics are more likely to have hypertension and it is more likely to lead to cardiovascular disease than in nondiabetics. </li></ul>
    67. 67. Hypertension <ul><li>PRIMARY </li></ul><ul><li>“ Essential hypertension” </li></ul><ul><li>Chronic elevation of BP occurs without evidence of other disease </li></ul><ul><li>90-95% of hypertension </li></ul><ul><li>SECONDARY </li></ul><ul><li>Elevation of BP occurs from some other disorder </li></ul><ul><ul><li>Kidney disease </li></ul></ul><ul><ul><li>Chronic renal failure </li></ul></ul><ul><ul><li>disorders of adrenocorticoid hormones (pheochromocytoma) </li></ul></ul>
    68. 68. Hypertension Definitions <ul><li>JNC-VII * (June 2003) </li></ul><ul><ul><li>“ Prehypertension” (120-139/80-89) </li></ul></ul><ul><ul><li>Stage I (140-159/90-99) </li></ul></ul><ul><ul><li>Stage II (160-179/100-109) </li></ul></ul><ul><ul><li>Stage III (>180/>110) </li></ul></ul><ul><ul><li>* 7th Report of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure </li></ul></ul>
    69. 69. Constitutional Risk Factors <ul><li>Family history </li></ul><ul><ul><li>Hereditary pattern unclear, genes not identified </li></ul></ul><ul><li>Age related changes </li></ul><ul><ul><li>BP higher with advancing age </li></ul></ul><ul><li>Insulin resistance, metabolic syndrome, diabetes (especially type II) </li></ul><ul><li>Race </li></ul><ul><ul><li>African Americans more prevalent, early onset, more severe; greater renal, CV damage </li></ul></ul><ul><ul><li>Less known about other races </li></ul></ul>
    70. 70. Lifestyle Risk Factors <ul><li>Diet high in Na + & saturated fats </li></ul><ul><li>Obesity </li></ul><ul><li>Physical inactivity </li></ul><ul><li>Excessive alcohol consumption </li></ul><ul><li>Oral contraceptives in predisposed women </li></ul>
    71. 71. Consequences of HTN <ul><li>Usually related to long term effects of HTN on other organs, “ target organ damage ”. </li></ul><ul><li>HTN seems to accelerate atherosclerotic vascular disease (covered later today) </li></ul><ul><ul><li>Heart </li></ul></ul><ul><ul><ul><li>Left ventricular hypertrophy, coronary artery disease (angina, myocardial infarction), heart failure </li></ul></ul></ul><ul><ul><li>Brain </li></ul></ul><ul><ul><ul><li>Stroke or transient ischemic attack </li></ul></ul></ul><ul><ul><li>Chronic kidney disease </li></ul></ul><ul><ul><li>Peripheral vascular disease </li></ul></ul><ul><ul><li>Retinopathy </li></ul></ul>
    72. 72. Consequences of HTN <ul><li>Heart: LV Hypertrophy </li></ul><ul><ul><li> workload of LV (  afterload); LV tries to compensate for  workload. </li></ul></ul><ul><ul><li>LV hypertrophy is major risk factor for ischemic heart disease, dysrhythmias, heart failure, sudden death </li></ul></ul>
    73. 73. Consequences of HTN <ul><li>Vascular damage </li></ul><ul><ul><li>Coronary arteries – myocardial infarction (CVII) </li></ul></ul><ul><ul><li>Peripheral blood vessels – peripheral vascular disease </li></ul></ul><ul><ul><li>Kidney – renal failure </li></ul></ul><ul><ul><li>Cerebral blood vessels – stroke </li></ul></ul>
    74. 74. Diagnosis of Hypertension <ul><li>Repeated BP measurements </li></ul><ul><ul><li>Average of > 2 readings taken at > 2 visits after an initial screening visit; over several months </li></ul></ul><ul><li>Laboratory tests, x-rays looking for target organ damage </li></ul><ul><ul><li>ECG, Urinalysis, Hb, Hct, Na + , K + , Cr, glucose, triglycerides, cholesterol </li></ul></ul>
    75. 75. Treatment of Hypertension <ul><li>Lifestyle modification is the first line of treatment </li></ul><ul><ul><li>Weight reduction, regular physical exercise, DASH eating plan, reduction of dietary sodium intake, moderation of alcohol intake </li></ul></ul><ul><li>Pharmacologic treatment </li></ul><ul><li>Goal: To achieve and maintain systolic BP below 140 mm Hg and diastolic BP below 90 mm Hg </li></ul>
    76. 76. Lehne, 2009, Pharmacology for Nursing Care, 6 7h ed., Elsevier, p. 500 Sites of Action
    77. 77. Pharmacologic Treatment <ul><li>Diuretics </li></ul><ul><li>Sympatholytics </li></ul><ul><ul><li>Beta-adrenergic blockers </li></ul></ul><ul><ul><li>Alpha-1 adrenergic blockers </li></ul></ul><ul><ul><li>Centrally-acting alpha-2 agonists </li></ul></ul><ul><ul><li>Drugs that block norepinephrine release </li></ul></ul><ul><li>Act on RAAS </li></ul><ul><ul><li>Renin inhibitor </li></ul></ul><ul><ul><li>ACE inhibitors </li></ul></ul><ul><ul><li>Angiotensin II receptor blockers </li></ul></ul><ul><ul><li>Aldosterone antagonists </li></ul></ul><ul><li>Others </li></ul><ul><ul><li>Ca +2 channel blockers </li></ul></ul><ul><ul><li>Direct-acting vasodilators </li></ul></ul>Adapted from Lehne, 2009, Pharmacology for Nursing Care, 7 th ed., Elsevier, Table 46-5, p. 502
    78. 78. Pharmacologic Treatment <ul><li>Compliance is a huge issue </li></ul><ul><ul><li>Lifetime treatment </li></ul></ul><ul><ul><li>Many of the drugs have unpleasant side effects </li></ul></ul><ul><ul><li>Many are expensive </li></ul></ul>
    79. 79. Algorithm for Treating Hypertension Lifestyle modifications Goal BP not met Stage 1 – thiazide diuretic /consider ACEI,ARB, beta blocker, CCB or combination Stage 2 – 2-drug combo (usually a thiazide + ACEI, ARB, beta blocker or CCB Goal BP not met Optimize dosage or add a drug from a different class Continue adding drugs from other classes until goal is achieved Goal BP not met Adapted from Lehne, 2009, Pharmacology for Nursing Care, 7 th ed., Elsevier, p. 507
    80. 80. Classes of Antihypertensive Drugs Recommended for Initial Therapy in Patients with High-Risk Comorbid Conditions Adapted from Lehne, 2009, Pharmacology for Nursing Care, 7 th ed., Elsevier, p. 508 Condition Drug Classes Recommended for Initial Therapy of HTN Diuretic Beta Blocker ACEI ARB CCB Aldosterone Antagonist Heart Failure X X X X X Post MI X X X Coronary Artery Disease Risk X X X X Diabetes X X X X X Chronic Kidney Disease X X Recurrent Stroke Prevention X X
    81. 81. Drugs That Affect BP: Diuretics Lehne, 2009, Pharmacology for Nursing Care, 7 th ed., Elsevier, p. 500
    82. 82. Classification of Diuretics <ul><li>Thiazide diuretics – Hydrochlorothiazide (HCTZ ® ) & chlorthalidone </li></ul><ul><li>High-ceiling (loop)– Furosemide (Lasix ® ) </li></ul><ul><li>K + sparing: </li></ul><ul><ul><li>Non-aldosterone antagonists - Triamterene (Dyrenium ® ) </li></ul></ul><ul><ul><li>Aldosterone receptor antagonists – Spironolactone (Aldactone) </li></ul></ul><ul><li>Osmotic diuretics – Mannitol </li></ul><ul><li>All diuretics indirectly prevent the re-absorption of water in the kidneys! </li></ul>
    83. 83. Thiazides Lehne, 2009, Pharmacology for Nursing Care, 7 th ed., Elsevier, p. 445 Prevent re-absorption of sodium in the distal tubule.
    84. 84. Thiazides: hydrochlorthiazide & chlorthalidone <ul><li>Uses: </li></ul><ul><li>Essential hypertension </li></ul><ul><ul><li>Often first drug used </li></ul></ul><ul><ul><li>May be part of multiple-drug therapy </li></ul></ul><ul><li>Edema </li></ul><ul><ul><li>Preferred drugs for mobilizing edema associated with mild, moderate heart failure </li></ul></ul>
    85. 85. Thiazide Diuretics <ul><li>Adverse Effects </li></ul><ul><ul><li>Hypokalemia </li></ul></ul><ul><ul><li>Hyponatremia, hypochloremia, dehydration </li></ul></ul><ul><ul><li>Orthostatic hypotension </li></ul></ul><ul><ul><li>Avoid in pregnancy if possible </li></ul></ul><ul><ul><ul><li>May reduce placental perfusion (not for routine use in pregnancy) </li></ul></ul></ul><ul><ul><li>Nocturia if taken at night </li></ul></ul><ul><li>Drug Interactions </li></ul><ul><ul><li>Digoxin -> digoxin toxicity (ALL K + -LOSING DIURETICS) </li></ul></ul><ul><ul><li>Lithium -> lithium toxicity (ALL DIURETICS!!!) </li></ul></ul><ul><ul><li>NSAIDS -> Reduced natriuresis/diuresis </li></ul></ul>
    86. 86. Loop Diuretics Lehne, 2009, Pharmacology for Nursing Care, 7 th ed., Elsevier, p. 445 Prevent the re-absorption of sodium from the ascending Loop of Henle.
    87. 87. Furosemide (Lasix ®) <ul><li>A second-line diuretic for hypertension but has many other uses. </li></ul><ul><li>Used for pulmonary edema associated with congestive heart failure </li></ul><ul><li>Edema of hepatic, cardiac, or renal origin unresponsive to less efficacious diuretics </li></ul><ul><ul><li>Promotes diuresis in renal impairment </li></ul></ul>
    88. 88. Loop Diuretics: Adverse Effects <ul><li>Hypokalemia </li></ul><ul><li>Hyponatremia, hypochloremia, dehydration </li></ul><ul><li>Orthostatic hypotension </li></ul><ul><li>Ototoxicity </li></ul><ul><li>Avoid in pregnancy if possible </li></ul><ul><li>Nocturia if taken at night </li></ul>
    89. 89. Loop Diuretics: Drug Interactions <ul><li>Digoxin – hypokalemia is dangerous with digoxin </li></ul><ul><li>Nitrates/other antihypertensives – increased hypotensive effects </li></ul><ul><li>Other ototoxic drugs (aminoglycoside antibiotics) </li></ul><ul><li>Lithium – lithium toxicity </li></ul><ul><li>NSAIDS can attenuate the diuretic effect of furosemide </li></ul>
    90. 90. Potassium-Sparing Diuretics Lehne, 2009, Pharmacology for Nursing Care, 7 th ed., Elsevier, p. 445 Prevent the re-absorption of sodium from the collecting tubule and duct.
    91. 91. Spironolactone - Aldactone ® <ul><li>Hypertension </li></ul><ul><li>Edema </li></ul><ul><li>Commonly used in combination with thiazide or loop diuretics </li></ul><ul><li>Effects are delayed </li></ul>
    92. 92. Spironolactone (Aldactone ®) <ul><li>Adverse effects </li></ul><ul><ul><li>Hyperkalemia </li></ul></ul><ul><ul><ul><li>Avoid use of potassium supplements </li></ul></ul></ul><ul><ul><ul><li>Synergistic with ACE inhibitors and ARBs </li></ul></ul></ul><ul><ul><li>Endocrine effects </li></ul></ul><ul><ul><ul><li>Spironolactone has a steroid structure and can cause a variety of effects similar to steroid hormones, such as gynecomastia and impotence in men, menstrual irregularities, hirsutism, and deepening of the voice in women </li></ul></ul></ul>
    93. 93. Spironolactone (Aldactone ®) <ul><li>Drug interactions </li></ul><ul><ul><li>Potassium supplements and salt substitutes are contraindicated </li></ul></ul><ul><ul><li>ACE inhibitors or ARBs may exacerbate the tendency to hyperkalemia </li></ul></ul><ul><ul><li>Pregnancy category D because of steroid-like effects on the fetus </li></ul></ul>
    94. 94. Triamterene <ul><li>Often given in combination with a thiazide </li></ul><ul><ul><li>Dyazide = hydrochlorothiazide + triamterene </li></ul></ul><ul><li>Adverse Effect </li></ul><ul><ul><li>Hyperkalemia – AVOID K + supplements </li></ul></ul><ul><li>Drug Interactions </li></ul><ul><ul><li>ACE Inhibitors/ARBs: Hyperkalemia potential </li></ul></ul><ul><ul><li>NSAIDS may blunt diuretic effect and indomethacin may precipitate renal failure </li></ul></ul><ul><ul><li>Take after meals in AM </li></ul></ul><ul><ul><li>Avoid potassium rich diet items -- bananas, orange juice, salt substitutes (which are likely to be KCl) </li></ul></ul>
    95. 95. Osmotic Diuretics -Mannitol Lehne, 2009, Pharmacology for Nursing Care, 7 th ed., Elsevier, p. 445 Prevents re-absorption of water from the proximal tubule.
    96. 96. Mannitol <ul><li>Must be given parenterally </li></ul><ul><li>Therapeutic uses </li></ul><ul><ul><li>Prophylaxis of renal failure </li></ul></ul><ul><ul><li>Reduction of intracranial pressure </li></ul></ul><ul><ul><li>Increased intra-ocular pressure </li></ul></ul><ul><li>When mannitol is in the bloodstream, before it gets into the renal tubules, it increases the osmotic pressure of the blood and draws edema fluid into the vascular system. </li></ul><ul><li>Mannitol is filtered into the glomerulus, drawing the excess water with it and holding it in the renal tubules for excretion. </li></ul>
    97. 97. Osmotic Diuretics <ul><li>Adverse Effects </li></ul><ul><ul><li>Edema (caused by mannitol leaving the circulation and drawing water into the tissues with it) </li></ul></ul><ul><ul><ul><li>Administer with extreme caution in heart failure because of its ability to increase vascular volume and overload the heart. </li></ul></ul></ul><ul><ul><li>Dehydration </li></ul></ul><ul><ul><li>Orthostatic hypotension </li></ul></ul><ul><li>Drug Interactions </li></ul><ul><ul><li>Mannitol is not metabolized, very inert. </li></ul></ul><ul><ul><li>It has no significant drug interactions </li></ul></ul>
    98. 98. Drugs Acting on RAAS Lehne, 2009, Pharmacology for Nursing Care, 7 th ed., Elsevier, p. 500 Renin inhibitor
    99. 99. Renin inhibition
    100. 100. Renin Inhibitor <ul><li>Renin inhibition should prevent all activation of the renin-angiotensin aldosterone system. </li></ul><ul><li>Only one such drug, aliskiren (Tekturna), is approved for use as monotherapy or in combination with hydrochlorothiazide. </li></ul><ul><li>Like other drugs that target the RAAS, aliskiren is pregnancy category D because of evidence of fetal harm. </li></ul>
    101. 101. Porth, 2007, Essential of Pathophysiology, 2 nd ed., Lippincott, p. 365. ACE Inhibitors (ACEI) Captopril, lisinopril, enalapril, and others
    102. 102. Lehne, 2009, Pharmacology for Nursing Care, 7 th ed., Elsevier, p. 469
    103. 103. Therapeutic Uses of ACEI <ul><li>Hypertension </li></ul><ul><li>Heart failure </li></ul><ul><li>Protective effects in diabetic nephropathy </li></ul><ul><li>Post MI prophylaxis </li></ul><ul><li>Prevention of MI, stroke, and death in patients at risk </li></ul>
    104. 104. Therapeutic Uses of ACEIs: HTN <ul><li>Initial responses: reduced formation of angiotensin II </li></ul><ul><li>Prolonged therapy: additional reduction in BP </li></ul><ul><li>Do not interfere with cardiovascular reflexes </li></ul><ul><li>Do not cause hypokalemia but may contribute to the tendency to hyperkalemia if given with potassium-sparing diuretics. </li></ul><ul><li>Do not induce lethargy, weakness, sexual dysfunction as other antihypertensives may. </li></ul><ul><li>REDUCE THE RISK OF CV MORTALITY CAUSED BY HEART FAILURE </li></ul><ul><li>REDUCE THE RISK OF RENAL FAILURE IN DIABETICS </li></ul>
    105. 105. ACE Inhibitors: Adverse Effects <ul><li>Bilateral renal artery stenosis is a contraindication because these drugs can precipitate acute renal failure in these patients </li></ul><ul><li>Dry cough – an effect of increased bradykinin </li></ul><ul><li>First dose hypotension – Most prominent in patients with very high BP or those on diuretics. </li></ul><ul><li>Teratogenic – contraindicated in pregnancy </li></ul><ul><li>Angioedema – due to increased bradykinin, may be very serious </li></ul>
    106. 106. Westra S and de Jager C. N Engl J Med 2006;355:295 A 75-year-old man presented to the emergency department with diffuse swelling of his tongue that had begun a few hours earlier. He had been taking 25 mg of captopril twice daily for the past 3 years because of hypertension. He was treated with epinephrine, corticosteroids, and antihistamines and the swelling resolved over a three-hour period. The angioedema was likely due to the angiotensin-converting enzyme inhibitor.
    107. 107. ACE Inhibitors: Drug Interactions <ul><li>Digoxin  Increased digoxin levels </li></ul><ul><li>Lithium  Increased lithium levels/toxicity </li></ul><ul><li>K + sparing diuretics  hyperkalemia </li></ul><ul><li>Potassium supplements  hyperkalemia </li></ul>
    108. 108. ACE Inhibitors <ul><li>Can be combined with a thiazide diuretic </li></ul><ul><li>All are oral except for enalaprilat, which is IV only </li></ul><ul><li>Patients with renal impairment may need dosage reduction </li></ul>
    109. 109. Porth, 2007, Essential of Pathophysiology, 2 nd ed., Lippincott, p. 365. Angiotensin II Receptor Blockers (ARBs) Losartan, valsartan, candesartan, and others
    110. 110. ARB Therapeutic Uses <ul><li>Hypertension </li></ul><ul><ul><li>Reductions in BP = ACEI </li></ul></ul><ul><li>Heart failure – prevent the progression and improve outcomes </li></ul><ul><li>Diabetic nephropathy – prevents progression </li></ul><ul><li>Post-MI prophylaxis </li></ul><ul><li>Stroke prevention </li></ul>
    111. 111. ARBs <ul><li>Adverse effects </li></ul><ul><ul><li>Well tolerated </li></ul></ul><ul><ul><li>Do not cause cough </li></ul></ul><ul><ul><li>Angioedema </li></ul></ul><ul><ul><li>Fetal harm – contraindicated in pregnancy </li></ul></ul><ul><ul><li>Renal failure </li></ul></ul><ul><li>Drug interactions </li></ul><ul><ul><li>Hypotensive effects are additive with other anti-HTN drugs </li></ul></ul><ul><ul><li>Do not cause hyperkalemia but may contribute if given with potassium-sparing diuretics </li></ul></ul>
    112. 112. Porth, 2007, Essential of Pathophysiology, 2 nd ed., Lippincott, p. 365. Aldosterone Antagonists Spironolactone Eplerenone (Inspra) Potassium-sparing diuretics (covered previously as diuretics) Promote Na + & H 2 0 excretion in the collecting tubule & duct
    113. 113. Drugs That Affect BP: Sympatholytics (Antiadrenergics) <ul><li>Beta blockers </li></ul><ul><li>Alpha-1 blockers </li></ul><ul><li>Alpha/beta blockers </li></ul><ul><li>Centrally acting alpha-2 agonists </li></ul><ul><li>Adrenergic neuron blockers (inhibit synthesis or release of norepinephrine) </li></ul><ul><li>Ganglionic blockers (not used, we will not cover) </li></ul>
    114. 114. Drugs That Affect BP: Sympatholytics (Antiadrenergics) Lehne, 2009, Pharmacology for Nursing Care, 7 th ed., Elsevier, p. 500 Sites of Action
    115. 115. Beta-Adrenergic Blockers* <ul><li>Widely used anti-hypertensive drugs </li></ul><ul><li>Actions in hypertension </li></ul><ul><ul><li>Blockade of cardiac beta-1 receptors ->↓ HR, contractility -> ↓ CO </li></ul></ul><ul><ul><li>Suppress reflex tachycardia caused by vasodilators </li></ul></ul><ul><ul><li>Blockade of beta-1 receptors in JG cells in kidney -> ↓ renin release -> ↓ RAAS mediated vasoconstriction (angiotensin II) and volume expansion (aldosterone) </li></ul></ul><ul><ul><li>Long-term use   peripheral vascular resistance </li></ul></ul>*Recall from Dr McPherson’s lecture; Lehne Chapter 18
    116. 116. Beta-Adrenergic Blockers <ul><li>Some block both beta-1 and beta-2 receptors (nonselective) </li></ul><ul><li>Some have greater affinity for beta-1 than beta-2 (“cardioselective”) – but the selectivity is not absolute </li></ul><ul><li>Some are partial agonists – they are said to have “intrinsic sympathomimetic activity” or ISA </li></ul>
    117. 117. Clinical Pharmacology of Some Beta Blockers Adapted from Lehne, 2009, Pharmacology for Nursing Care, 7 th ed., Elsevier, p. 167 Generic/trade name ISA Cardioselective (beta 1 > beta 2 ) Acebutolol/Sectal ® + Atenolol/Tenormin ® 0 Esmolol/Brevibloc ® 0 Metolprolol/Lopressor ® Slow release/Toprol XL 0 Nonselective (beta 1 = beta 2 ) Pindolol/Visken ® +++ Propranolol/Inderal ® Slow release/Inderal LA® 0 Nonselective alpha/beta blockers Carvedilol/Coreg ® 0 Labetolol/Normodyne ® or Trandate ® 0
    118. 118. Therapeutic Uses Adapted from Lehne, 2009, Pharmacology for Nursing Care, 7 th ed., Elsevier, p.168 A – approved; I - investigational Drug HTN Angina Dysrrhy-thmias MI Migraine Stage Fright Heart Failure Cardioselective Acebutolol A I A Atenolol A A I A I I Esmolol I A Metolprolol A A I A I A Nonselective Pindolol A I I Propranolol A A A A A I Nonselective alpha/beta blockers Carvedilol A I A A Labetolol A
    119. 119. Sympatholytics - Alpha-1 antagonists Sites of Action Lehne, 2009, Pharmacology for Nursing Care, 7 th ed., Elsevier, p. 500
    120. 120. Alpha-1 Antagonists* <ul><li>Doxazosin, terazosin, prazosin and others </li></ul><ul><li>Block alpha-1 receptors on arterioles and veins  prevent SNS-mediated vasoconstriction  vasodilation   peripheral resistance,  venous return to heart </li></ul><ul><li>Not used as first line therapy for hypertension </li></ul><ul><ul><li>Orthostatic hypotension is a big problem </li></ul></ul><ul><ul><li>Sexual side effects are big reasons for noncompliance </li></ul></ul><ul><li>Doxazosin, terazosin and tamsulosin (Flomax) used for BPH. </li></ul>*Recall Dr McPherson’s lecture; Lehne Chapter 18
    121. 121. Centrally Acting Alpha-2 Agonists Sites of Action Lehne, 2009, Pharmacology for Nursing Care, 7 th ed., Elsevier, p. 500
    122. 122. Centrally Acting Alpha-2 Agonists <ul><li>Clonidine, methyldopa (agent of choice for chronic hypertension in pregnancy – not for pre-eclampsia) </li></ul><ul><li>Act within brainstem (alpha-2 receptors) to suppress sympathetic outflow to the heart and blood vessels -> vasodilation,  CO   BP </li></ul><ul><li>Cause dry mouth, sedation, hemolytic anemia, liver disorders </li></ul><ul><li>Rebound hypertension if abruptly stopped </li></ul>
    123. 123. Calcium Channel Blockers <ul><li>Dihydropyridines </li></ul><ul><ul><li>Nifedipine </li></ul></ul><ul><ul><li>Amlodipine (Norvasc) </li></ul></ul><ul><ul><li>Promote dilation of arterioles, little effect on veins </li></ul></ul><ul><li>Non-dihydropyridines </li></ul><ul><ul><li>Verapamil, diltiazem </li></ul></ul><ul><ul><li>Promote dilation of arterioles, little effect on veins </li></ul></ul><ul><ul><li>Also act on heart to slow conduction and decrease contractility </li></ul></ul>
    124. 124. Lehne, 2009, Pharmacology for Nursing Care, 7 th ed., Elsevier, p. 481 Calcium Channels in the Heart
    125. 125. Verapamil <ul><li>Blocks Ca +2 channels in arterioles, heart </li></ul><ul><ul><li>Dilation of peripheral vessels   BP </li></ul></ul><ul><ul><li>Dilation of coronary arteries   coronary perfusion </li></ul></ul><ul><ul><li>Blockade at SA node   HR </li></ul></ul><ul><ul><li>Blockade at AV node   nodal conduction </li></ul></ul><ul><ul><li>Blockade in myocardium   contractile force </li></ul></ul><ul><li>Indications </li></ul><ul><ul><li>Angina pectoris, hypertension, dysrhythmias </li></ul></ul>
    126. 126. Verapamil: Adverse Effects <ul><li>Constipation (why?) </li></ul><ul><li>Dizziness, facial flushing, headache, edema of ankles, feet (why?) </li></ul><ul><li>Bradycardia, conduction defects (why?) </li></ul>
    127. 127. Nifedipine and amlodipine (dihydropyridines) <ul><li>Block Ca +2 channels in arterioles </li></ul><ul><ul><li>Dilation of peripheral vessels ->  BP </li></ul></ul><ul><ul><li>Dilation of coronary arteries ->  coronary perfusion </li></ul></ul><ul><li>Do NOT block cardiac Ca +2 channels at therapeutic doses </li></ul>
    128. 128. Nifedipine & Amlodipine:Indirect (reflex) Effects <ul><li>Lowering BP  baroreceptor reflex ->  firing of SNS to beta receptors in the heart </li></ul><ul><li>But, nifedipine lacks direct cardiosuppressant actions, cardiac stimulation is unopposed ->  HR,  contractility </li></ul><ul><li>Net effect is the sum of the direct effect (vasodilation) and the indirect effect (reflex cardiac stimulation) </li></ul>
    129. 129. Nifedipine & amlodipine: Uses <ul><li>Angina pectoris </li></ul><ul><ul><li>Vasospastic angina, angina of effort </li></ul></ul><ul><li>Hypertension </li></ul><ul><ul><li>Essential hypertension </li></ul></ul><ul><ul><li>Nifedipine – only use sustained-release formulation for hypertension </li></ul></ul><ul><ul><ul><li>Take whole, do not crush or chew </li></ul></ul></ul><ul><ul><li>Amlodipine has a longer half-life than nifedipine and does not have a sustained-release formulation </li></ul></ul>
    130. 130. Nifedipine & Amlodipine: Adverse Effects <ul><li>Flushing, dizziness, headache, edema </li></ul><ul><li>Gingival hyperplasia </li></ul><ul><li>Constipation </li></ul><ul><li>Do not exacerbate conduction abnormalities </li></ul><ul><li>Do cause reflex tachycardia ->  cardiac oxygen demand -> angina </li></ul><ul><ul><li>Give with a beta blocker to counteract this in patients with angina </li></ul></ul>
    131. 131. Nifedipine blocks Ca +2 channels in arterioles. This results in: <ul><li>Vasoconstriction of peripheral vessels </li></ul><ul><li>Vasoconstriction of coronary arteries </li></ul><ul><li>Decrease in HR </li></ul><ul><li>Dilation of peripheral vessels </li></ul>
    132. 132. Hypertensive Emergencies <ul><li>(SBP >200 mm Hg or DBP >120 mm Hg) </li></ul><ul><li>Symptoms of actual or impending end-organ damage </li></ul><ul><li>Neurological </li></ul><ul><ul><li>Hypertensive encephalopathy </li></ul></ul><ul><ul><li>Cerebral vascular accident/cerebral infarction </li></ul></ul><ul><ul><li>Subarachnoid hemorrhage </li></ul></ul><ul><ul><li>Intracranial hemorrhage </li></ul></ul><ul><li>Cardiovascular </li></ul><ul><ul><li>Myocardial ischemia/infarction </li></ul></ul><ul><ul><li>Acute left ventricular dysfunction </li></ul></ul><ul><ul><li>Acute pulmonary edema </li></ul></ul><ul><ul><li>Aortic dissection </li></ul></ul><ul><li>Other </li></ul><ul><ul><li>Acute renal failure/insufficiency </li></ul></ul><ul><ul><li>Retinopathy </li></ul></ul><ul><ul><li>Eclampsia </li></ul></ul><ul><ul><li>Microangiopathic hemolytic anemia </li></ul></ul>
    133. 133. Sodium nitroprusside-Nitropress ® <ul><li>A very powerful arterial vasodilator </li></ul><ul><li>No reflex tachycardia </li></ul><ul><li>Overshoot hypotension is possible but can be correctly quickly by stopping or slowing the infusion </li></ul><ul><li>Titrate to blood pressure </li></ul><ul><ul><li>An infusion pump is essential. An arterial line or an automatic blood pressure cuff must be used to check BP continuously. </li></ul></ul>
    134. 134. Adverse Effects <ul><li>Cyanide poisoning </li></ul><ul><ul><li>Likely in pts with liver disease </li></ul></ul><ul><ul><li>Avoid prolonged rapid infusion </li></ul></ul><ul><li>Thiocyanate Toxicity </li></ul><ul><ul><li>Likely when drug given over days </li></ul></ul><ul><ul><li>CNS effects (disorientation, delirium) </li></ul></ul><ul><ul><li>Avoid infusions > 3 days; monitor plasma thiocyanate </li></ul></ul>Lehne, 2009, Pharmacology for Nursing Care, 7 th ed., Elsevier, p. 492
    135. 135. IV Calcium Channel Blockers <ul><li>Fenoldepam – long half-life </li></ul><ul><li>Nicardipine – long half life </li></ul><ul><li>Clevidipine – short half-life, easy to titrate </li></ul><ul><li>Titrate similarly to sodium nitroprusside </li></ul><ul><li>All can cause reflex tachycardia and hypotension. </li></ul>
    136. 136. How do diuretics decrease blood pressure? <ul><li>Block beta adrenergic receptors </li></ul><ul><li>Inhibit angiotensin converting enzyme </li></ul><ul><li>Act on renal tubules to promote water excretion </li></ul><ul><li>Act as a vasodilator </li></ul>
    137. 137. Disorders of Arterial Circulation Hyperlipidemia Leading to Atherosclerosis
    138. 138. Hyperlipidemia <ul><li>Triglycerides, phospholipids, cholesterol classified as lipids; chemical substances insoluble in water but soluble in alcohol. </li></ul><ul><li>Three types of biological lipids </li></ul><ul><li>Triglycerides </li></ul><ul><ul><li>Used as sources for energy metabolism </li></ul></ul><ul><li>Phospholipids </li></ul><ul><ul><li>Structural components of lipoproteins, clotting components, myelin sheath, cell membranes </li></ul></ul><ul><li>Cholesterol </li></ul><ul><ul><li>Basis of steroid hormones and an important cell membrane component </li></ul></ul>
    139. 139. Lipoproteins <ul><li>Lipids (cholesterol, triglycerides) insoluble in plasma </li></ul><ul><li>Encapsulated in lipid transport particles (lipoproteins) composed of phospholipids and embedded proteins </li></ul><ul><li>Apoproteins are large proteins contained within the phospholipid coat of the lipoprotein </li></ul>Porth, 2007, Essentials of Pathophysiology, 2 nd ed., Lippincott, p. 348.
    140. 140. Five Types of Lipoproteins Porth, 2007, Essentials of Pathophysiology, 2 nd ed., Lippincott, p. 348. -Of the five, LDLs and HDLs are the most important - As the density of the lipoprotein increases, the proportion of triglycerides decreases and the proportion of cholesterol increases
    141. 141. Lipoprotein Synthesis & Transport Porth, 2007, Essentials of Pathophysiology, 2 nd ed., Lippincott, p. 349. Synthesis in small intestine, liver Liver important in LDL metabolism; removes LDL via LDL receptors
    142. 142. HDL <ul><li>“ Good cholesterol” </li></ul><ul><li>Carries cholesterol FROM tissues TO liver </li></ul><ul><li>High HDL prevents atherosclerosis </li></ul><ul><ul><li>HDLs are scavengers, picking up cholesterol from deposits in the arteries and bringing it back to the liver for disposal </li></ul></ul><ul><li>HDL inhibits uptake of LDLs into cells </li></ul><ul><li>Exercise, moderate ETOH  HDLs </li></ul><ul><li>Smoking, diabetes or metabolic syndrome (sort of a diabetic prodrome)  HDLs </li></ul>
    143. 143. LDL <ul><li>Familial defects in LDL receptor – “familial hypercholesterolemia” </li></ul><ul><ul><li>Inadequate, or defective hepatic uptake of LDL  circulating LDL </li></ul></ul><ul><li>“ Receptor disease” </li></ul>
    144. 144. LDL Receptors in Liver Remove LDLs from the Blood Robbins & Cotran Pathologic Basis of Disease (7th ed), 2005, Elsevier, p.158
    145. 145. Hypercholesterolemia <ul><li>Primary </li></ul><ul><ul><li>Develops independent of other causes; defective synthesis of apoproteins, lack of receptors, defective receptors, defects in handling of cholesterol in cell that are genetically determined </li></ul></ul><ul><li>Secondary </li></ul><ul><ul><li>Associated with other health problems & behaviors (high fat diet, obesity, diabetes mellitus) </li></ul></ul>Porth, 2007, Essentials of Pathophysiology, 2 nd ed., Lippincott, p. 350. Xanthomas (deposits of cholesterol) develop in certain areas, including the knuckles.
    146. 146. Diagnosis, Screening <ul><li>All adults 20 years of age and older should have a fasting lipoprotein profile done every 5 years </li></ul><ul><ul><li>Total cholesterol, LDL, HDL, TG </li></ul></ul>See Porth, text on page 350-351 for specific recommendations Also Table 49.4 in Lehne
    147. 147. Classification of LDL, Total, and HDL Cholesterol Cholesterol Level (mg/dL) Classification Total <200 Optimal 200-239 Borderline high > 240 High LDL cholesterol <100 Optimal 100-129 Above optimal 130-159 Borderline high 160-189 High > 190 Very high Adapted from Porth, 2007, Essentials of Pathophysiology, 2 nd ed., Lippincott, p. 350. Cholesterol Level (mg/dL) Classification HDL cholesterol <40 Low > 60 High
    148. 148. Why are increased blood lipids so bad? <ul><li>Increased blood lipids, particularly cholesterol, increase the risk of a vascular disease called atherosclerosis. </li></ul><ul><ul><li>Fatty deposits form in arterial walls </li></ul></ul><ul><ul><li>This increases the risk of clot formation and occlusion of an artery. </li></ul></ul><ul><ul><li>Occluded arteries cause myocardial infarctions, stroke, and peripheral vascular disease. </li></ul></ul><ul><li>Atherosclerosis leads to arteriosclerosis (hardening of the arteries) which increases the risk of aneurysms and other vessel wall problems. </li></ul>
    149. 149. Atherosclerosis <ul><li>Atheros (glue/paste) </li></ul><ul><li>Sclerosis (hardening) </li></ul><ul><li>Formation of fibrofatty lesions (atheromas) in the intimal lining of large and medium sized arteries (aorta, coronaries, carotids, and many others) </li></ul>
    150. 150. Atherosclerotic Lesions <ul><li>Fatty streak </li></ul><ul><ul><li>Thin, flat, yellow discolorations that progressively enlarge by becoming thicker and more elevated. Present in children. Precursors to atheromata? </li></ul></ul><ul><li>Fibrous atheromatous plaque </li></ul><ul><li>Complicated lesions </li></ul>
    151. 151. Atheromatous Plaque Porth, 2007, Essential of Pathophysiology, 2 nd ed., Lippincott, p. 353 Plaque Complicated Lesion
    152. 152. Definitions <ul><li>Thrombus = clot </li></ul><ul><li>Embolus = a clot that breaks off from its initial location and travels through the vascular system. </li></ul><ul><li>Stenosis = narrowing or closing off of a vessel (or a heart valve). </li></ul><ul><li>Mural = wall (a mural thrombus is a clot in the wall of a vessel or a chamber of the heart) </li></ul>
    153. 153.
    154. 154. Robbins & Cotran Pathologic Basis of Disease (7th ed), Elsevier, 2005, p.517
    155. 155.
    156. 156. Porth, 2007, Essentials of Pathophysiology, 2 nd ed., Lippincott, p. 352. Atheromas tend to develop at sites of turbulent flow – near branch points As the artheroma develops, it creates more of a constriction, which produces more turbulent flow. See Figure 17.8 in Porth!
    157. 157. Laminar & Turbulent Flow Porth, 2007, Essentials of Pathophysiology, 2 nd ed., Lippincott, p. 323.
    158. 158. Risk Factors for Atherosclerosis <ul><li>Age </li></ul><ul><ul><li>Men > 45 y.o.; women > 55 y.o. (or premature menopause) </li></ul></ul><ul><li>Family History </li></ul><ul><ul><li>MI before 55 y.o. in father or before 65 y.o. mother </li></ul></ul><ul><li>Current cigarette smoking </li></ul><ul><li>Hypertension (BP > 140/90) </li></ul><ul><li>Hyperlipidemia </li></ul><ul><ul><li>Low HDL (< 40 mg/dL) </li></ul></ul><ul><ul><li>High LDL </li></ul></ul><ul><li>Diabetes mellitus </li></ul>
    159. 159. Risk Factors <ul><li>C-reactive protein (CRP) </li></ul><ul><ul><li>Marker of inflammation; better than LDL? </li></ul></ul><ul><li>Homocysteine </li></ul><ul><ul><li>Inhibits coagulation, causes endothelial damage, important in initial phases? </li></ul></ul><ul><li>Serum lipoprotein (a) </li></ul><ul><ul><li>Part of the LDL; promotes foam cells </li></ul></ul><ul><li>Infectious agents </li></ul><ul><ul><li>Chlamydia pneumoniae </li></ul></ul>
    160. 160. Clinical Manifestations of Vascular Disease Cotran (1999) pg. 499
    161. 161. Management <ul><li>Reduction in LDL is primary target for cholesterol-lowering therapy, particularly for people at risk for CHD* </li></ul><ul><ul><li>Age, family history of premature CHD, cigarette smoker, hypertension, low HDL, diabetes mellitus </li></ul></ul><ul><li>Some evidence that when lipids are lowered, at least with statin drugs, that atheromatous changes regress. </li></ul>*See Porth, Table 17-1, page 351 and Lehne, Table 49-4, p. 551
    162. 162. Management <ul><li>Dietary changes* </li></ul><ul><ul><li> calories,  saturated fats,  cholesterol </li></ul></ul><ul><li>Lifestyle changes </li></ul><ul><ul><li> physical activity, smoking cessation, weight loss </li></ul></ul><ul><li>Pharmacologic treatment </li></ul>* See Lehne, Table 49-6, pg. 556
    163. 163. Lipid-Lowering Drugs Porth, 2007, Essentials of Pathophysiology, 2 nd ed., Lippincott, p. 349. <ul><li>Mechanisms: </li></ul><ul><li>Affect cholesterol production by liver </li></ul><ul><li>Remove cholesterol from bloodstream </li></ul><ul><li> LDL receptors </li></ul><ul><li> Cholesterol absorption from intestine </li></ul><ul><li> intravascular conversion of VLDL and IDL to LDL </li></ul>
    164. 164. Classes of Drugs Used in Treatment of Hypercholesterolemia <ul><li>HMG-CoA reductase inhibitors (statins) </li></ul><ul><li>Bile acid-binding resins </li></ul><ul><li>Cholesterol absorption inhibitor agents </li></ul><ul><li>Niacin and its congeners </li></ul><ul><li>Fibric acid derivatives </li></ul>
    165. 165. Statins <ul><li>Atorvastatin [Lipitor] </li></ul><ul><li>Fluvastatin [Lescol] </li></ul><ul><li>Lovastatin [Mevacor] </li></ul><ul><li>Provastatin [Pravachol] </li></ul><ul><li>Rosuvastatin [Crestor] </li></ul><ul><li>Simvastatin [Zocor] </li></ul>
    166. 166. Statins <ul><li>Beneficial Actions: </li></ul><ul><ul><li>Reduce cholesterol synthesis in liver </li></ul></ul><ul><ul><li> LDL receptors (most important) </li></ul></ul><ul><ul><li> LDLs </li></ul></ul><ul><ul><li> HDLs </li></ul></ul><ul><ul><li> TG </li></ul></ul><ul><li>Timing: </li></ul><ul><ul><li>Results within 2 weeks; maximal 4-6 weeks </li></ul></ul><ul><ul><li>If drug is stopped, serum cholesterol returns to pretreatment levels (lifelong treatment) </li></ul></ul>
    167. 167. Statins  LDL Receptors in Liver ->  LDLs Robbins & Cotran Pathologic Basis of Disease (7th ed), 2005, Elsevier, p.158
    168. 168. Statins <ul><li>Cardiovascular actions </li></ul><ul><ul><li>Reduce inflammation at plaque sites </li></ul></ul><ul><ul><li>Improve endothelial cell function </li></ul></ul><ul><ul><li>Enhance blood vessel dilation </li></ul></ul><ul><ul><li>Reduce risk of thrombosis </li></ul></ul><ul><li>Increased bone formation </li></ul><ul><ul><li>Enhance osteoblast activity   risk of osteoporosis, fractures </li></ul></ul>
    169. 169. Statins: Therapeutic Uses <ul><li>Hypercholesterolemia </li></ul><ul><li>Prevention of cardiovascular events </li></ul><ul><ul><li>MI, stroke, angina </li></ul></ul><ul><li>Diabetes </li></ul><ul><ul><li>ADA: Pts > 40 y.o. with total cholesterol > 135 mg/dL- regardless of LDL </li></ul></ul><ul><ul><li>ACP: All pts with type 2 diabetes with coronary artery disease, even if they don’t have high cholesterol; all adults with type 2 diabetes plus one CV risk factor - even if they don’t have high cholesterol </li></ul></ul>
    170. 170. Statins: Side Effects <ul><li>Myopathy/rhabdomyolysis </li></ul><ul><ul><li>Report unexplained muscle weakness, tenderness </li></ul></ul><ul><ul><li>Rosuvastatin higher risk </li></ul></ul><ul><li>Hepatotoxicity </li></ul><ul><ul><li>Monitor liver enzymes every 6-12 months </li></ul></ul><ul><ul><li>Avoid use for pts with viral, alcoholic hepatitis </li></ul></ul>
    171. 171. Statins: Drug Interactions <ul><li>Fibrates and ezetimibe </li></ul><ul><ul><li>Also  cholesterol, so their activity might be additive to statins </li></ul></ul><ul><ul><li>Can also cause myopathy, so the danger from that would also be increased </li></ul></ul><ul><li>Inhibitors of cytochrome P450 like ketoconazole, erythromycin, HIV protease inhibitors, etc., inhibit the metabolism of statins and raise blood levels   risk of adverse effect </li></ul>
    172. 172. Bile Acid Sequestrants <ul><li>Cholestyramine, colestipol, and colesevelam </li></ul><ul><li>Biologically inert, insoluble in water, cannot be absorbed from GI tract, simply pass through intestine, excreted in feces </li></ul><ul><li>Absorb bile acids in the intestine and keep them from being reabsorbed into the bloodstream. </li></ul><ul><ul><li>New bile acids must be synthesized, which requires cholesterol. </li></ul></ul><ul><ul><li>LDLs are internalized into liver cells as a source of cholesterol. </li></ul></ul><ul><ul><li>This lowers LDLs. </li></ul></ul><ul><li>Reduce LDL cholesterol </li></ul><ul><ul><li>Maximal reduction within one month (20%) </li></ul></ul><ul><ul><li>LDL levels return to pre-treatment levels when drug is discontinued </li></ul></ul>
    173. 173. Bile Acid Sequestrants Porth, 2007, Essentials of Pathophysiology, 2 nd ed., Lippincott, p. 349. Prevent the absorption of cholesterol in the intestine
    174. 174.  Bile acid reabsorption (GI)  synthesis in liver   need for cholesterol   LDL receptors Robbins & Cotran Pathologic Basis of Disease (7th ed), 2005, Elsevier, p.158
    175. 175. Therapeutic Use <ul><li>Reduce LDL cholesterol </li></ul><ul><ul><li>Drug plus diet ->  LDL by 15-30% </li></ul></ul><ul><li>Usually combined with statin </li></ul><ul><ul><li> LDL by 50% </li></ul></ul>
    176. 176. Adverse effects <ul><li>Devoid of systemic effects </li></ul><ul><li>GI symptoms (except colesevelam) </li></ul><ul><ul><li>Constipation </li></ul></ul><ul><ul><li>Bloating </li></ul></ul><ul><ul><li>Indigestion </li></ul></ul><ul><ul><li>Nausea </li></ul></ul>
    177. 177. Bile Acid Sequestrants Drug Interactions <ul><li>Decreased absorption of: </li></ul><ul><ul><li>Warfarin -Acetaminophen </li></ul></ul><ul><ul><li>Thiazides -Beta blockers </li></ul></ul><ul><ul><li>Digoxin -Corticosteroids </li></ul></ul><ul><ul><li>Iron -Thyroid hormones </li></ul></ul><ul><ul><li>Fat-soluble vitamins A, D, E, and K (except colesevelam) </li></ul></ul><ul><ul><li>Take oral medications 1 hour before or 4 hours after the bile acid sequestrant. </li></ul></ul>
    178. 178. Cholesterol Absorption Inhibitors Ezetimibe (Zetia ® )
    179. 179. Ezetimibe (Zetia ® ) <ul><li>Mechanism of action </li></ul><ul><ul><li>Acts on cells in the brush border of the intestine and inhibits cholesterol absorption </li></ul></ul><ul><ul><li>Blocks absorption of dietary cholesterol and cholesterol secreted in bile </li></ul></ul><ul><li>Lowers total cholesterol, LDLs, TG and raises HDLs </li></ul><ul><li>Used as adjunct to diet modification </li></ul><ul><li>Can be used as monotherapy or with a statin </li></ul><ul><ul><li>Recent evidence that the combo of ezetimibe and simvastin (Vytorin) actually worsened plaques rather than making them better . </li></ul></ul>
    180. 180. Ezetimibe (Zetia): Drug Interactions <ul><li>Statins -  risk of liver damage </li></ul><ul><li>Fibrates – both  the concentration of cholesterol in the bile   the risk of gallstones </li></ul><ul><li>Bile-acid sequestrants- impair the absorption of ezetimibe </li></ul><ul><li>Cyclosporine- inhibits metabolism of ezetimibe   its concentration. </li></ul>
    181. 181. Nicotinic Acid (Niacin) [Niacor, Niaspan] Porth, 2007, Essentials of Pathophysiology, 2 nd ed., Lippincott, p. 349. Decreases production of VLDLs by inhibiting lipolysis in adipose tissue   LDL
    182. 182. Nicotinic acid (Niacin) <ul><li>Effect on plasma lipoproteins: </li></ul><ul><ul><li>Reduces triglycerides (20 – 50%) and LDLs (5-25%) </li></ul></ul><ul><ul><li>Raises HDLs (15-35%) </li></ul></ul><ul><ul><li>Drug of choice to lower triglyceride levels in patients at risk for pancreatitis. </li></ul></ul><ul><ul><li>More effective when combined with statin </li></ul></ul><ul><ul><li>Triple therapy (nicotinic acid, statin, bile-acid sequestrant)  LDL 70% </li></ul></ul><ul><li>Nicotinic acid is also a B-vitamin, but doses as a vitamin are much smaller than as a lipid-lowering drug. </li></ul>
    183. 183. Nicotinic Acid: Adverse Effects <ul><li>Intense flushing of the head & neck in nearly all pts– diminishes in several weeks, attenuated with aspirin </li></ul><ul><li>GI upset – take with food </li></ul><ul><li>Hepatotoxic – follow liver enzymes </li></ul><ul><li>Raises blood levels of homocyteine, a substance thought to increase cardiovascular risk. To counteract this, add folic acid supplements. </li></ul><ul><li>Hyperglycemia – use with caution in diabetics </li></ul>
    184. 184. Fibric Acid Derivatives (Fibrates) Porth, 2007, Essentials of Pathophysiology, 2 nd ed., Lippincott, p. 349. <ul><li>Gemfibrozil [Lopid] </li></ul><ul><li>Fenofibrate [Tricor] </li></ul><ul><li>Increase lipoprotein lipase ->  VLDLs and  TG storage in adipose tissue (  serum TG) </li></ul><ul><li>Also  HDL </li></ul><ul><li>No effect on LDL </li></ul>
    185. 185. Fibric acid derivatives Adverse effects <ul><li>Gallstones – Increase biliary cholesterol saturation -> increase risk of gallstones </li></ul><ul><li>Myopathy – like the statins, can cause myopathy </li></ul><ul><li>Heptatotoxicity – like the statins, fibric acid derivatives are hepatotoxic; Monitor liver enzymes </li></ul><ul><li>Because of overlapping adverse effects, the combo of a statin and a fibric acid derivative should be used with great caution. </li></ul><ul><li>Pregnancy category C </li></ul>
    186. 186. Fibric acid derivatives Drug interactions <ul><li>Warfarin – Gemfibrozil increases the efficacy of warfarin by displacing it from protein binding sites. </li></ul><ul><ul><li>Follow INR closely </li></ul></ul><ul><li>Use with caution in statins because of the increase in risk of myopathy </li></ul>
    187. 187. Which of the following drugs are insoluble in water, cannot be absorbed from the GI tract and pass through the intestine? <ul><li>Bile acid sequestrants </li></ul><ul><li>HMG Co-A reductase inhibitors </li></ul><ul><li>Fibric acid derivatives </li></ul><ul><li>Nicotinic acid </li></ul>
    188. 188. Which of the following drug classes has been shown to reverse athrosclerotic changes? <ul><li>Statins </li></ul><ul><li>Fibric acid derivatives </li></ul><ul><li>Bile acid sequestrants </li></ul><ul><li>Niacin </li></ul>
    189. 189. Questions?