Hypertension: A Pharmacological Approach

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

2. Hypertension

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

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

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

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

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

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

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

10. Hypertension Functional Aspects of the Sympathetic NS Organ Sympathetic 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)

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

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

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

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

15. 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. • Carvedilol: alpha-1 + beta-1+ beta-2 blockade • Labetalol: alpha-1 + beta-1 + beta-2 blockade

16. Hypertension

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

18. Hypertension

19. Hypertension

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

21. Hypertension • Diuretics: Pharmacodynamics • Decreased intravascular (blood) fluid volume • Decreased extravascular (edema) fluid volume • Decreased blood pressure

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

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

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

25. Hypertension • Therapeutic Options: ACE Inhibitors • 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

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

27. X X Aldosterone secretion ARB Vasoconstriction X Renal tubular reabsorption of sodium and water X AT1 receptors Catecholamine secretion X Antidiuretic hormone (vasoprressin)secretion X Stimulation of thirst center  BP Hypertension Renin Angiotensinogen Angiotensin I Non-ACE alternate pathways (eg, chymase) ACE Angiotensin II

28. Hypertension

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

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

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

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

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

34. 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 • Dihydropyridine • Non-dihydropyridine

35. Hypertension Calcium Channel Blocking Agents

36. Hypertension Calcium Channel Blocking Agents

37. Hypertension • Calcium Channel Blockers: Pharmacodynamics • 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

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

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

40. Hypertension: The Diagnosis and Treatment Process

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

42. 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.

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

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

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

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

48. Algorithm for Treatment of HTN NHBPEP Coordinating Committee. The JNC 7 Report. JAMA 2003;289:2560-72.

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

50. Algorithm for Treatment (continued) Initial Drug Choices 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)