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Angiotensin Receptor Blockade: Applications to Clincal Care

Angiotensin Receptor Blockade: Applications to Clincal Care. Timothy A. Denton, M.D. Divisions of Cardiology and Cardiothoracic Surgery Cedars-Sinai Medical Center Los Angeles. Outline. JNC VI “Undertreatment” Physiology HTN drugs ARB’s. JNC VI. JNC VI.

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Angiotensin Receptor Blockade: Applications to Clincal Care

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  1. Angiotensin Receptor Blockade: Applications to Clincal Care Timothy A. Denton, M.D. Divisions of Cardiology and Cardiothoracic Surgery Cedars-Sinai Medical Center Los Angeles

  2. Outline • JNC VI • “Undertreatment” • Physiology • HTN drugs • ARB’s

  3. JNC VI

  4. JNC VI Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure JNC VI -- Arch Int Med 1997;157:2413

  5. Why do we need blood pressure?

  6. Why do we need blood pressure? • Get blood to the scalp • Distribute flow quickly

  7. Classification of HTN JNC VI -- Arch Int Med 157:2413, 1997

  8. Risk Classification JNC VI -- Arch Int Med 157:2413, 1997

  9. Approach to HTN Therapy JNC VI -- Arch Int Med 157:2413, 1997

  10. Etiology of HTN Normal Pulse Pressure • Renal Chronic pyelonephritis Glomerulonephritis Polycystic kidney Renovascular Other renal • Endocrine Oral contraceptives Adrenocortical (Cushing, hyperaldo, 17 hydroxylase, 11-hydroxylase) Pheochromocytoma Myxedema Acromegaly • Neurogenic Psychogenic Familial dysautonomia Polyneuritis Increased intracranial pressure Spinal cord section • Misc Coarctation Intravascular volume Polyarteritis nodosa Hypercalcemia Acute intermittent porphyria Pre-eclampsia

  11. Etiology of HTN Wide Pulse Pressure • Decreased aortic compliance • Increased stroke volume AI Thyrotoxicosis Hyperkinetic heart syndrome Fever AV fistula / PDA

  12. Physiology of HTN • Primary Hypertension • ? central/peripheral adrenergic • ? renal • ? hormonal • ? vascular

  13. Physiology of HTN • Secondary • Wide Pulse Pressure Aortic compliance Stroke volume • Normal Pulse Pressure Renal Endocrine Neurogenic Misc

  14. Epidemiology of HTN Harrison’s Principles of Internal Medicine, 12th Edition

  15. Classes of Anti-Hypertensives (1999 PDR) Adrenergic blockers Alpha/Beta adrenergic blockers ACE inhibitors ACE + Ca blockers ACE + diuretics ARB’s ARB’s with diuretics Beta blockers Beta blockers with diuretics Calcium blockers Diuretics Rauwolfia derivatives Vasodilators

  16. Preparations of Anti-Hypertensives by Class (1999 PDR) Adrenergic blockers Alpha/Beta adrenergic blockers ACE inhibitors ACE + Ca blockers ACE + diuretics ARB’s ARB’s with diuretics Beta blockers Beta blockers with diuretics Calcium blockers Diuretics Rauwolfia derivatives Vasodilators 6 5 11 4 5 4 2 15 6 25 24 2 18 Total = 127

  17. Special Considerations In African-Americans: -- low probability of success with Beta blockers or ACE or ARB’s -- higher probability of success with diuretics or Ca blockers

  18. Compelling Indications JNC VI -- Arch Int Med 157:2413, 1997

  19. “The committee recognizes that the responsible clinician’s judgment of the individual patient’s needs remains paramount.” JNC VI -- Arch Int Med 1997;157:2413

  20. Undertreatment

  21. Undertreatment of Hypertension Berlowitz, NEJM 1998;339:1957

  22. Undertreatment of Hypertension Berlowitz, NEJM 1998;339:1957

  23. Undertreatment of Hypertension Berlowitz, NEJM 1998;339:1957

  24. If you have not achieved goal, you must change your therapy

  25. You push a medication’s dose to EFFECT or SIDE EFFECT or maximal recommended dose

  26. Patient Example

  27. Combination Drugs: A Different Animal • Beta blocker + diuretic • ACE + diuretic • ACE + calcium blocker • ARB + diuretic • Diuretic + diuretic • “other” + diuretic

  28. Pressure/Volume Relation Pressure = 150 mmHg Pressure = 120 mmHg Fluid Flux Fluid Flux Vasculature

  29. Physiology

  30. Goodfriend TL, New Engl J Med 1996 334(25):1649-54

  31. Goodfriend TL, New Engl J Med 1996 334(25):1649-54

  32. Angiotensinogen Inactive products Renin Inhibitor Renin increase nitric oxide, prostacyclin (improved endothelial function ? anti-atherosclerotic?) non-ACE alternative pathways (chymase, cathepsin G, chymostatin ATII generation) Angiotensin I ACE Inhibitor ACE ACE hypotension Angiotensin II Bradykinin ? angioedema AT1 receptor Inhibitor cough Vaso- constriction Vaso- dilatation Vasopressin Endothelin-1 Adapted, Bonn, D. Lancet 1998;352:378

  33. Hypothesized Atherosclerotic Effects of Angiotensin II • Causes SMC growth and migration • Activates macrophages • Increases platelet aggregation • Stimulation of PAI1 • Made directly by SMCs & macrophages • A-II stimulation causes endothelial dysfunction Gibbons, G.H. et al, NEJM, 330(20):1431-1438.

  34. Angiotensin II FormationAlternate Pathways* Angiotensinogen Renin Angiotensin I • t-PA • Cathepsin G • Tonin • CAGE • Cathepsin G • Chymase ACE Angiotensin II Angiotensin II Receptors * The clinical significance of the alternate pathway is unknown Dzau, V.J. et al, J of Hypertension, 11(suppl 3):1993.

  35. AT Receptors AT1 AT2 Heart Vasculature Brain Adrenal Fetus Vasculature

  36. Proposed Pathophysiologic Effects of Angiotensin II Angiotensin II AT1 Receptor Aldosterone Production Vasoconstriction Cell Growth Sodium/Water Retention TVR LVH Vascular Remodeling BP BP Hypertension, 23(2):258, 1994.

  37. AT Receptors AT1 AT2 Hypertrophy Proliferation Thirst Aldosterone Proliferation anti-proliferation

  38. AT Receptors ATII 1000x losartan AT1 AT2 decreased Proliferation

  39. ARB’s Angiotensin Receptor Blockers

  40. Angiotensin II Receptor Blocking Agents 1/6/2000

  41. Angiotensin II Receptor Blocking Agents

  42. ELITE • Evaluation of Losartan In The Elderly • Losartan vs captopril • Primary endpoint Increase of creat >0.3 mg% • Secondary endpoints All cause mortality Hospital admit for CHF Death + admit for CHF Bertram, Lancet 1997;349:747

  43. ELITE • Age > 65 years • CHF NYHA class II-IV • EF < 40% • No prior ACE therapy • Double-blind, randomized, placebo • losartan-352 pts, captopril-370 pts • 48 weeks of follow-up Bertram, Lancet 1997;349:747

  44. ELITE Bertram, Lancet 1997;349:747

  45. ELITE P=0.42 Bertram, Lancet 1997;349:747

  46. ELITE P=0.075 Bertram, Lancet 1997;349:747

  47. ELITE P=0.035 *primarily SCD Bertram, Lancet 1997;349:747

  48. ELITE P=0.035 Bertram, Lancet 1997;349:747

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