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John B. Crider, M.D. Family Medical Clinic Arab, AL

Managing High-Risk CV Patients: Understanding the Neuronal Hormonal Mechanisms and End-Organ Protection. Improving Cardiovascular Risk: Effective Therapy. John B. Crider, M.D. Family Medical Clinic Arab, AL. A ’- Rab , AL. No Pharmaceutical Industry Affiliations. Learning Objectives.

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John B. Crider, M.D. Family Medical Clinic Arab, AL

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  1. Managing High-Risk CV Patients: Understanding the Neuronal Hormonal Mechanisms and End-Organ Protection Improving Cardiovascular Risk: Effective Therapy John B. Crider, M.D. Family Medical Clinic Arab, AL A’- Rab, AL No Pharmaceutical Industry Affiliations

  2. Learning Objectives • State of the Union: A Discussion of Patient Outcomes • What do the Guidelines Say About Cardiovascular Risk — JNC 7? • Defining Cardiovascular Risks in Patients with Co-morbid Conditions — Case Studies • Understanding Modes of Action of Antihypertensive Drugs

  3. The World’s Greatest Public Health Problem WHO, 2002 http://www.who.int/mdg/publications/04MDGChapter4.pdf

  4. Adults with High Blood Pressure Source: CDC, Behavioral Risk Factor Surveillance System, 2007.

  5. CHD Mortality: Missouri http://hp2010.nhlbihin.net/hrmaps/_cvdmaps.html

  6. HTN: Cardiovascular Disease Risk Kannel WB. JAMA. 1996; 275:1571-1576

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  8. HTN: Awareness, Treatment, Control NHANES: 2003-2006. Source: NCHS and NHLBI.

  9. 14.0 12.0 10.0 8.0 Population (millions) 6.0 NOT MEETING GOAL 4.0 2.0 0.0 91–100 81–90 131–140 231–240 141–150 151–160 161–170 171–180 181–190 241–250 111–120 121–130 221–230 191–200 201–210 101–110 211–220 SBP Range (mm Hg) Majority Are Not at SBP Goal Whyte JL et al. J ClinHypertens. 2001;3:211-216. Lapuerta P, L’Italien GJ. Am J Hypertens. 1999;12:92A. Adapted from Whyte JL et al. J ClinHypertens. 2001;3:211-216.

  10. Learning Objectives • State of the Union: A Discussion of Patient Outcomes • What do the Guidelines Say About Cardiovascular Risk — JNC 7? • Defining Cardiovascular Risks in Patients with Co-morbid Conditions — Case Studies • Understanding Modes of Action of Antihypertensive Drugs

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  12. JNC 7: Blood Pressure Definitions JAMA. 2003;289:(doi:10.1001/jama.289.19.2560) (JNC-7).

  13. “High-Normal” BP and CVD Risk 130-139/85-89 120-129/80-84 <120/80 VasanVasanRS et al. RS et al. N N EnglEngl J Med. J Med. 2001;345:1291 2001;345:1291- -1297. (Framingham)

  14. 8 7 6 5 4 3 2 1 0 115/75 135/85 155/95 175/105 SBP/DBP (mm Hg) CV Mortality Doubles with Each 20/10 BP Increment 8x CardiovascularMortalityRisk 4x 2x Chobanian AV et al. JAMA. 2003;289:2560-2572. LewingtonS et al. Lancet. 2002;360:1903-1913.

  15. “Lower is Better ” Diastolic BP Systolic BP CV event % RR CV event % RR Adapted from Hansson L et al. Lancet. 1998;351:1755-1762 (HOT TRIAL).

  16. Importance of Systolic BP >130/85 >120/80 SBP >160 • MRFITT Arch Int Med, 1992

  17. SBP, DBP, Age and CHD Risk Franklin SS et al. Circulation. 2001;103:1245-1249

  18. SBP, Risk Factors, & CHD JAMA. 2003;289:(doi:10.1001/jama.289.19.2560) (JNC-7).

  19. MIDAS/NICS/VHAS UKPDS C vs A NORDIL INSIGHT HOT L vs H STOP ACEIs HOT M vs H MRC1 MRC2 STOP CCBs HEP SHEP STONE HOPE EWPHE CAPPP Syst-Eur UKPDS L vs H Syst-China RCT70-80 PART 2/SCAT ATMH STOP-1 SBP Reduction & CV Mortality P = 0.003 1.50 1.25 1.00 Odds Ratio 0.75 0.50 0.25 - 5 0 5 10 15 20 25 Difference in SBP (mm Hg) Staessen JA, et al. Lancet. 2001;358:1305-15.

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  21. Targets in HTN Treatment Treating BP ≤140-160/90-100 does not reduce mortality or morbidity — Systematic reviews regarding recommendations for lower targets in DM and CKD are in progress Arguedas JA, Perez MI, Wright JM. Treatment blood pressure targets for hypertension. Cochrane Database of Systematic Reviews 2009, Issue 3. Art. No.: CD004349. DOI: 10.1002/14651858.CD004349.pub2.

  22. Achieving Target BP Bakris GL et al. Am J Kidney Dis. 2000;36:646-661. Cushman WC et. al J ClinHypertens 2002; 4:393-404

  23. JNC 7: Key Messages • Optimal BP is ≤120/80 • CVD risk doubles for every 20/10 increase over 115/75 • SBP more important than DBP in predicting risk after age 50 • Most patients require 2 or more anti-hypertensives to achieve BP goal JAMA. 2003;289:(doi:10.1001/jama.289.19.2560) (JNC-7).

  24. Learning Objectives • State of the Union: A Discussion of Patient Outcomes • What do the Guidelines Say About Cardiovascular Risk — JNC 7? • Defining Cardiovascular Risks in Patients with Co-morbid Conditions — Case Studies • Understanding Modes of Action of Antihypertensive Drugs

  25. Case Study: “Pre-hypertension” • 40-year-old male presents for routine examination. • No complaints or problems. • ROS: CV, Neuro unremarkable. • PMSH: Unremarkable. • BP 136/86, P 72 • PE: Normal • U/A: Protein (-), Renal Panel: WNL, Lipid: WNL • EKG: NSR What are the patient’s risks based on the blood pressure?

  26. Case Study: “Pre-hypertension” “Pre-hypertension”: (120-139) / (80-90) Does not increase Stroke risk Triples the risk of MI 1. Mohammad Y, Qureshi AI, Suri MFK, et al. Is pre-hypertension a risk factor for stroke and myocardial infarction? Program and abstracts from the 29th International Stroke Conference; February 5-7, 2004; San Diego, California. Abstract P326. 2. M. Fareed K. Suri, M.D.; Jawad F. Kirmani, M.D.; Afshin A. Divani, Ph.D.; and Yousef Mohammad, M.D. American Heart Association (2005, August 6).

  27. Case Study: Hypertension • 50-year-old male presents for routine examination. • No complaints or problems. • ROS: CV, Neuro unremarkable • PMSH: Unremarkable. • BP 150/94, P 80 • PE: Normal • U/A: Protein (-), Renal Panel: WNL, Lipid: WNL • EKG: NSR What are the patient’s risks based on the blood pressure?

  28. HTN & Stroke Odds ratios and95% confidence intervals 0.63(0.55 to 0.72) 0 2 0.5 1.5 1 Active treatment worse than placebo Active treatment better than placebo Reprinted from He J, et al. Am Heart J. 1999; 138:211-219.

  29. HTN & MI Odds ratios and95% confidence intervals 0.79(0.69 to 0.90) 0 2 0.5 1.5 1 Active treatment worse than placebo Active treatment better than placebo Reprinted from He J, et al. Am Heart J. 1999; 138:211-219.

  30. HTN & CV Risk HTN confers >50% lifetime risk of Stroke vs. “Optimal BP” (120/80) 2 separate BP factors impact the 10-year CVD Risk Calculator (SBP & Treatment of HTN) • Seshadri S, Beiser A, Wolf PA. Lifetime risk of stroke: results from the Framingham Study. Program and abstracts from the 29th • International Stroke Conference; February 5-7, 2004; San Diego, California. Abstract 43. 2. NCEP ATP III JAMA. 2001;285:2486-2497 (Framingham Point Scores).

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  32. 20 10 0 -10 -20 -30 -40 -50 HTN & DM Any DM Endpoint Death fromDM Microvascular Complications Stroke 11 Risk Reduction (%) 10 12 24* 25 32* 37* 44* Tight glucose control (HgbA1c7.0%) Tight BP control (<150/85 mm Hg) *P<0.05 vs tight glucose control. BakrisGL et al. Am J Kidney Dis. 2000;36:646-661. (UKPDS)

  33. HTN & DM 75% of CVD in DM may be attributableto HTN — Therefore, reduce BP <130/85 in DM and HTN Hypertension. 2001;37:1053.

  34. HTN &End-stage Renal Disease JAMA. 2003;289:(doi:10.1001/jama.289.19.2560) (JNC-7).

  35. HTN & Mortality Overall life expectancy at age 50 with High Blood Pressure: Reduced by ~5 years Hypertension. 2001;37:1053.

  36. Learning Objectives • State of the Union: A Discussion of Patient Outcomes • What do the Guidelines Say About Cardiovascular Risk — JNC 7? • Defining Cardiovascular Risks in Patients with Co-morbid Conditions — Case Studies • Understanding Modes of Action of Antihypertensive Drugs

  37. Without Compelling Indications With Compelling Indications Drug(s) for the compelling indications Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed. Stage 1 Hypertension(SBP 140–159 or DBP 90–99 mmHg) Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination. Stage 2 Hypertension(SBP >160 or DBP >100 mmHg) 2-drug combination for most (usually thiazide-type diuretic and ACEI, or ARB, or BB, or CCB) Not at Goal Blood Pressure Optimize dosages or add additional drugs until goal blood pressure is achieved.Consider consultation with hypertension specialist. JNC 7 Treatment Algorithm Lifestyle Modifications Not at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those with diabetes or chronic kidney disease) Initial Drug Choices JAMA. 2003;289:(doi:10.1001/jama.289.19.2560) (JNC-7).

  38. Ways to Lower Pressure Vasodilators • Reduce Cardiac Output — ß-Bs, CCBs • Reduce Plasma Volume — Diuretics • Reduce Peripheral Vascular Resistance — Vasodilators (RASI, ß-Bs, CCBs, α-Bs, Diuretics) ß-Bs CCBs Vasodilators Diuretics MAP = CO X TPR

  39. Modes of Action: DIURETICS • Inhibit Na+/CL- reabsorption • in the nephron Reabsorption Na+ H2O DistalTubule Blood Urine Distal Tubular Cell Clˉ ATP Na+ Na+ K+ Na+/ClˉCotransporter Na+/K+ Pump • Hyperosmolar renal tubules pull water • into the urine for excretion Brater DC. In: Principles of Pharmacology: Basic Concepts and Clinical Applications. 1995;657-672.

  40. β-Blockers in HTN Block β receptors  Sympathetic tone  CO: (-) ionotropic & chronotropic effect  Renin release  Vasoconstriction (mild) 1)http://www.mc.uky.edu/Pharmacology/instruction/decor/ar/bhkbbl.jpg. 2)Cleveland Clinic Journal of Medicine. February 2010, 77 (2)

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  42. RAS in HTN Bradykinin-----//----- AT II http://upload.wikimedia.org/wikipedia/commons/a/a2/Renin-angiotensin-aldosterone_system.png

  43. RAS in HTN Angiotensin II Stimulates ADH H20 retension Superstimulates sympathetic response  Myocardial norepinephine  Arterial & venous vasoconstriction  Renin Stimulates Thirst  Blood volume Potent venous vasocontricter  SBP Potent arterial vasoconstricter  DBP Stimulates Aldosterone Na+ & H20 retension Stimulates Myocardial Growth Factor Cardiac Remodeling Am Fam Physician 1999;60:1185-90

  44. RASIs in HTN Medication Effects • ARBs: •  Prevent AT II • from acting on • target tissue • β-Bs: •  Block Renin • formation in the • kidney DRIs:  Prevent formation of AT I (“upstream”)  No Bradykinin effect ACEIs:  Prevent formation of AT II Augment Bradykinin Vasodilation

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  46. HTN &Renin • 15% High Renin • 60% Normal Renin • 25% Low Renin • — Elderly • — African American • — More salt-sensitive, • Less weight-sensitive • — More responsive to Diuretic &CCB’s 1.) Am J Med 1984 Aug 20;77(2A):36-4. 2.) J Hum Hypertens. 2001 Jan;15(1):17-25. 3.) Kidney IntSuppl 1988 Sep;25:S162-74. 4.) JAMA 1992 Mar 4;267(9):1221-5. 5.) Kidney IntSuppl 1988 Sep;25:S162-74.

  47. CCBs in HTN Blocks Ca++ transport into arterial wall & myocardium Nitric Oxide Bradykinin  CO: (-) ionotropic & chronotropic effect  Dilate coronary arteries Vasodilate arterioles Reduce PVR (?) Pleomorphic effect CCB Action Non-dihydropyridines Dihydropyridines Myocardium Arterioles 1) Int J Diabetes & Metabolism (2005) 13: 76-82. 2) http://www.heartonline.org/images/bloodpressure.jpg.

  48. CCBs and RASIs Arterial HTN Vasoconstriction ------------------------------------------------------- CCB Arteriodilation without Venodilation  BP stimulates RAS Proteinuria ------------------------------------------------------- CCB + RASI Venodilation  Additional BP, Edema Messerli. Am J Hypertens2001;14:978–9

  49. Questions ?

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