1. Hypertension Hypertension Hypertension: A Pharmacological Approach Robert J. DiDomenico, Pharm.D

2. Hypertension Hypertension Hypertension

3. JNC 7 Express. NIH publication No 03-5233. http://www.nhlbi.nih.gov/guidelines/hypertension/express.pdf. May, 2003.http://www.nhlbi.nih.gov/guidelines/hypertension/express.pdf

4. Hypertension Hypertension Percent Decline in Age-Adjusted Mortality Rates for Stroke by Sex and Race: U.S. 1972-1994 The decline in age-adjusted mortality for stroke in the total population is 59.0%. Age-adjusted to the 1940 U.S. census population.

5. Hypertension Hypertension Percent Decline in Age-Adjusted Mortality Rates for CHD by Sex and Race: U.S. 1972-1994 The decline in age-adjusted mortality for stroke in the total population is 59.0%. Age-adjusted to the 1940 U.S. census population.

6. Hypertension Hypertension Incidence of Reported End-Stage Renal Disease Therapy, 1982-1995 253* *Provisional data. Adjusted for age, race, and sex.

7. Hypertension Hypertension Prevalence of Heart Failure, by Age, 1976-80 and 1988-91 1988-91 1976-80

8. Hypertension Hypertension Hypertension & Blood Pressure  Hypertension is a condition in which the blood pressure is persistently higher than normal Measurement is indirect Measurement is indirect Blood pressure is silent Blood pressure is silent  Hypertensive crisis: acute, life threatening rise in blood pressure associated with acute end-organ damage.

9. Hypertension Hypertension Risk Stratification Major Cardiovascular Risk Factors Hypertension Hypertension Smoking Smoking Obesity (BMI > 30) Obesity (BMI > 30) Physical inactivity Physical inactivity Dyslipidemia Dyslipidemia Diabetes mellitus Diabetes mellitus Microalbuminuria or GFR < 60ml/min Microalbuminuria or GFR < 60ml/min Advanced age Advanced age –Men > 55, women > 65 Family history of premature CV disease Family history of premature CV disease Target Organ Disease Heart Heart –Left ventricular hypertrophy –CAD –Angina and/or prior MI –Prior coronary revascularization –Heart failure Brain Brain –Stroke or TIA Chronic renal insufficiency Chronic renal insufficiency Peripheral arterial disease Peripheral arterial disease Retinopathy Retinopathy NHBPEP Coordinating Committee. The JNC 7 Report. JAMA 2003;289:2560-72.

10. JNC 7 Treatment Recommendations Initial Drug Therapy JNC 7 Express. NIH publication No 03-5233. http://www.nhlbi.nih.gov/guidelines/hypertension/express.pdf. May, 2003.http://www.nhlbi.nih.gov/guidelines/hypertension/express.pdf

11. Hypertension Hypertension Hypertension  Therapeutic Treatment Options Diuretics Diuretics Beta blockers Beta blockers ACE inhibitors ACE inhibitors Angiotensin II receptor blockers Angiotensin II receptor blockers Calcium channel blockers Calcium channel blockers Alpha blockers Alpha blockers Centrally acting alpha agonists Centrally acting alpha agonists Direct vasodilators Direct vasodilators Peripheral adrenergic blockers Peripheral adrenergic blockers

12. Hypertension Hypertension Arch Inter Med 1997 Hypertension  Selection of Initial Therapy Demographics Demographics Concomitant Diseases and Therapies Concomitant Diseases and Therapies Quality of Life Quality of Life Cost Cost Drug Interactions Drug Interactions

13. Hypertension Hypertension Hypertension Nervous System Somatic NS Autonomic NS Parasympathetic NS Sympathetic NS

14. Hypertension Hypertension Functional Aspects of the Sympathetic NS OrganSympathetic Response Heart Increased contractility (beta-1) Increased HR (beta-1) Arterioles Vasoconstriction (skin/viscera) (alpha-1) Vasodilation (skeletal muscle/liver) (beta-2) Lung Bronchodilation (beta-2) Kidney Increased renin (alpha-1, beta-1) Hypertension

15. Hypertension Hypertension Hypertension  Therapeutic Options: Beta Blockers Inhibit sympathetic stimulation Inhibit sympathetic stimulation –Beta-1 receptors  heart –Beta-2 receptors  blood vessels, lungs Cardioselective vs. Nonselective Cardioselective vs. Nonselective Intrinsic sympathomimetic activity (ISA) Intrinsic sympathomimetic activity (ISA)

16. Hypertension Hypertension Hypertension  Beta Blockers: CV Pharmacodynamics Reduced heart rate Reduced heart rate Reduced force of heart contraction Reduced force of heart contraction Reduced cardiac output Reduced cardiac output Reduced blood pressure Reduced blood pressure Decreased renin Decreased renin

17. Hypertension Hypertension Hypertension  Beta Blockers: Potential Adverse Effects Glucose intolerance, masked hypoglycemia Glucose intolerance, masked hypoglycemia Bradycardia, dizziness Bradycardia, dizziness Bronchospasm Bronchospasm Increased triglycerides and decreased HDL Increased triglycerides and decreased HDL CNS: Depression, fatigue, sleep disturbances CNS: Depression, fatigue, sleep disturbances Reduced C.O., exacerbation of heart failure Reduced C.O., exacerbation of heart failure Impotence Impotence Exercise intolerance Exercise intolerance

18. Hypertension Hypertension Hypertension  Beta Blockers: Precautions Bronchospastic disease Bronchospastic disease Heart Block Heart Block Sick sinus syndrome Sick sinus syndrome Diabetes Diabetes Dyslipidemia Dyslipidemia Depression Depression

19. Hypertension Hypertension Hypertension  Beta Blockers: Specific Indications Myocardial Infarction  Myocardial Infarction  Congestive Heart Failure  Congestive Heart Failure  Essential Tremors Essential Tremors Hyperthyroidism Hyperthyroidism Angina Angina Supraventricular tachycardias Supraventricular tachycardias Perioperative Hypertension Perioperative Hypertension Migraine Headaches Migraine Headaches Beta blockers are underused!!!  Compelling indications

20. Hypertension Hypertension Hypertension  Therapeutic Options: Alpha-Beta Blockers Work by binding to both alpha-1 and beta-1 and/or beta-2 adrenergic receptors consequently preventing their activation by sympathetic neurotransmitters. Work by binding to both alpha-1 and beta-1 and/or beta-2 adrenergic receptors consequently preventing their activation by sympathetic neurotransmitters. –Carvedilol: alpha-1 + beta-1+ beta-2 blockade –Labetalol: alpha-1 + beta-1 + beta-2 blockade

21. Hypertension Hypertension Hypertension

22. Hypertension  Therapeutic Options: Diuretics Promote sodium and water excretion at various sites of the nephron Promote sodium and water excretion at various sites of the nephron –Loop diuretics –Thiazide/Thiazide-like diuretics diuretics –Potassium-sparing diuretics –Carbonic Anhydrase Inhibitors

23. Hypertension Hypertension Hypertension

24. Hypertension

25. Hypertension Loop diuretics Thiazide diuretics Potassium-sparing diuretics Carbonic anhydrase inhibitors

26. Hypertension Hypertension Hypertension  Diuretics: Pharmacodynamics Decreased intravascular (blood) fluid volume Decreased intravascular (blood) fluid volume Decreased extravascular (edema) fluid volume Decreased extravascular (edema) fluid volume Decreased blood pressure Decreased blood pressure

27. Hypertension Hypertension Hypertension  Diuretics: Potential Adverse Effects Electrolyte disturbances Electrolyte disturbances –potassium, magnesium, sodium, calcium Hyperglycemia Hyperglycemia Hypotension, orthostasis Hypotension, orthostasis Lipid abnormalities Lipid abnormalities Photosensitivity Photosensitivity Ototoxicity Ototoxicity Hyperuricemia, gout flare Hyperuricemia, gout flare

28. Hypertension Hypertension  Unless contraindicated Hypertension  Diuretics: Compelling Indications* Isolated Systolic Hypertension Isolated Systolic Hypertension Congestive Heart Failure Congestive Heart Failure  Diuretics: Possible Favorable Effects Osteoporosis (thiazides) Osteoporosis (thiazides)  Diuretics: Possible Unfavorable Effects Diabetes Diabetes Gout Gout Renal Insufficiency Renal Insufficiency

29. Hypertension Hypertension Hypertension  Diuretics: Considerations Useful for patients with ISH, African Americans, CHF Useful for patients with ISH, African Americans, CHF Different diuretic classes can be combined for additive, or possible synergistic effects Different diuretic classes can be combined for additive, or possible synergistic effects Work well in combination with other antihypertensives Work well in combination with other antihypertensives Efficacy drops when renal function becomes seriously impaired Efficacy drops when renal function becomes seriously impaired

30. Hypertension Hypertension Hypertension  Therapeutic Options: ACE Inhibitors ACE inhibitors inhibit the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor ACE inhibitors inhibit the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor  Therapeutic Options: Angiotensin II Receptor Blockers (ARB’s) ARB’s block the effects of angiotensin II by competing for binding sites at the receptor ARB’s block the effects of angiotensin II by competing for binding sites at the receptor

31. Hypertension Hypertension Hypertension Renin ARB site of action Angiotensin II receptors Angiotensin II Angiotensin I Angiotensinogen ACE Low Blood Pressure (liver) (kidney) Vasoconstriction +  PVR  Aldosterone   Na retention ACE inhibitor site of action  Blood Pressure bradykinin

32. Hypertension Hypertension Renin Angiotensinogen ACE Angiotensin I Angiotensin II Non-ACE alternate pathways (eg, chymase ) ARB AT 1 receptors Vasoconstriction Aldosterone secretion Renal tubular reabsorption of sodium and water Antidiuretic hormone (vasoprressin) secretion Stimulation of thirst center Catecholamine secretion X X X X X X  BP Hypertension

33. Hypertension Hypertension Hypertension

34. Hypertension  ACE inhibitors and ARB’s: Pharmacodynamics Vasodilation Vasodilation Reduced peripheral resistance Reduced peripheral resistance Increased diuresis Increased diuresis Reduced BP Reduced BP No change in HR No change in HR No reduction in cardiac output No reduction in cardiac output

35. Hypertension Hypertension Hypertension  ACE Inhibitors/ARB’s: Potential Adverse Effects  ACE inhibitors Hyperkalemia Hyperkalemia Cough Cough Hypotension, dizziness Hypotension, dizziness Headache Headache Angioedema Angioedema  ARB’s Same as ACE inhibitors but cough is uncommon Same as ACE inhibitors but cough is uncommon

36. Hypertension Hypertension Hypertension  ACE inhibitors and ARB’s: Potential Drug Interactions Medications which promote hyperkalemia Medications which promote hyperkalemia Medications that have activity which is sensitive to changes in serum K+ Medications that have activity which is sensitive to changes in serum K+ Medications that may cause additive antihypertensive effects Medications that may cause additive antihypertensive effects NSAIDs NSAIDs

37. Hypertension Hypertension Hypertension  Therapeutic Options: ACE inhibitors  Compelling Indications Diabetes Mellitus (Type 1) with proteinuria Diabetes Mellitus (Type 1) with proteinuria Heart Failure Heart Failure Post MI with systolic dysfunction Post MI with systolic dysfunction  Possible Favorable Effects Diabetes Mellitus (Type 1 or 2) with proteinuria Diabetes Mellitus (Type 1 or 2) with proteinuria Renal Insufficiency Renal Insufficiency

38. Hypertension Hypertension Hypertension  ACE inhibitors/ARB’s should be carefully considered: Pre-existing kidney dysfunction (degree of impairment, response to therapy) Pre-existing kidney dysfunction (degree of impairment, response to therapy) Renal artery stenosis (degree of stenosis) Renal artery stenosis (degree of stenosis)  ACE inhibitors/ARB’s are contraindicated: Pregnancy Pregnancy History of angioedema History of angioedema Hyperkalemia Hyperkalemia

39. Hypertension Hypertension Hypertension  Therapeutic Options: Calcium Channel Blockers (CCB’s) Calcium channel blockers work by blocking calcium channels through which calcium ions enter muscle fibers, controlling hypertension. Calcium channel blockers work by blocking calcium channels through which calcium ions enter muscle fibers, controlling hypertension.  Calcium Channel Blockers Dihydropyridine Dihydropyridine Non-dihydropyridine Non-dihydropyridine

40. Hypertension Hypertension Calcium Channel Blocking Agents Hypertension

41. Hypertension Hypertension Hypertension Calcium Channel Blocking Agents

42. Hypertension Hypertension Hypertension  Calcium Channel Blockers: Pharmacodynamics The activation of calcium channels can increase: The activation of calcium channels can increase: – blood pressure by increasing heart rate – stroke volume – cardiac output – total peripheral resistance Calcium channel blocking reduces these parameters Calcium channel blocking reduces these parameters

43. Hypertension Hypertension Hypertension  CCB’s: Potential Side Effects Dihydropyridines Dihydropyridines –Peripheral edema –reflex tachycardia –flushing/headache –hypotension Nondihydropyridines Nondihydropyridines –constipation –conduction abnormalities

44. Hypertension Hypertension Hypertension  Calcium Channel Blockers: Specific Indications  CCB’s: Compelling Indications Isolated Systolic Hypertension (long-acting) Isolated Systolic Hypertension (long-acting)  CCB’s: Possible Favorable Effects angina angina atrial tachyarhythmias atrial tachyarhythmias Cyclosporine-induced HTN Cyclosporine-induced HTN Diabetes Mellitus Type 1 and 2 with proteinuria Diabetes Mellitus Type 1 and 2 with proteinuria

45. Hypertension Hypertension Hypertension: The Diagnosis and Treatment Process

46. JNC 7 Express. NIH publication No 03-5233. http://www.nhlbi.nih.gov/guidelines/hypertension/express.pdf. May, 2003.http://www.nhlbi.nih.gov/guidelines/hypertension/express.pdf

47. Hypertension Hypertension Why the More Aggressive BP Classifications? High-Normal BP as CV Risk Factor Vasan RS, et al. N Eng J Med 2001;345:1291-7.

48. Hypertension Hypertension Outcomes Studies in High-Risk Patients ALLHAT Study: Optimal 1st Line Agent ALLHAT Investigators. JAMA 2002;288:2981-7.

49. Hypertension Hypertension Outcomes Studies in High-Risk Patients HOPE Study: Ramipril vs Placebo HOPE Investigators. N Eng J Med 2000;342:145-53.

50. Hypertension Hypertension Outcomes Studies in High-Risk Patients LIFE Study: Losartan vs Atenolol LIFE Investigators. Lancet 2002;359:995-1003.

51. Hypertension Hypertension EUROPA Investigators. Lancet 2003;362:782-8. Outcomes Studies in High-Risk Patients EUROPA Study: Perindopril vs Placebo

52. Hypertension Hypertension

53. Algorithm for Treatment of HTN Compelling Indications DiureticB-Blocker ACE Inhibitor ARBCCB Aldosterone antagonisst Heart Failure XXXXX Post-MIXXX High CAD risk XXXXNon-DHP DiabetesXXXXXNon-DHP Chronic renal disease XX 2° Stroke prevention XX NHBPEP Coordinating Committee. The JNC 7 Report. JAMA 2003;289:2560-72.

54. Hypertension Treatment Costs Patient Perspective www.walgreens.com. Accessed 4/8/05 * Most patients require ~ 2 antihypertensive drugs ALLHAT Investigators. JAMA 2002;288:2981-7.

55. Hypertension Hypertension Algorithm for Treatment (continued) Not at Goal Blood Pressure (< 140/90 mm Hg) No response or troublesome side effects Inadequate response but well tolerated Substitute drug from different class Add second agent from different class (diuretic if not already used) Initial Drug Choices

56. Hypertension Hypertension Drug Therapy  Dose-effect curve Variation in a population Variation in a population Length of therapy Length of therapy Counter-regulation Counter-regulation  Absorption  Elimination Effect Dose Toxic No Effect

57. Hypertension Hypertension Special Populations  African Americans Response to diuretics & CCB > response to ACEI, ARB, beta-blockers Response to diuretics & CCB > response to ACEI, ARB, beta-blockers Angioedema 2 – 4-fold higher Angioedema 2 – 4-fold higher  Left ventricular hypertrophy Aggressive BP control regresses LVH Aggressive BP control regresses LVH …but hydralazine & minoxidil DO NOT! …but hydralazine & minoxidil DO NOT!  Elderly (Isolated Systolic HTN) (Isolated Systolic HTN) Same general principles Same general principles Thiazide or CCB may be better tolerated Thiazide or CCB may be better tolerated  Pregnancy Methyldopa, beta-blockers, vasodilators (hydralazine) Methyldopa, beta-blockers, vasodilators (hydralazine) Avoid ACEI & ARBs Avoid ACEI & ARBs  Children/adolescents Avoid ACEI & ARBs in pregnant or sexually active girls Avoid ACEI & ARBs in pregnant or sexually active girls NHBPEP Coordinating Committee. The JNC 7 Report. JAMA 2003;289:2560-72.

58. Hypertension Hypertension Finally: Quality of Life  Hypertension is often silent Depression Depression Urinary frequency Urinary frequency Sexual dysfunction Sexual dysfunction –Male –Female Fatigue Fatigue Cough Cough  Cost