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Hypertension Chapter 15

Hypertension Chapter 15. Pharmacotherapy: A Pathophysiologic Approach The McGraw-Hill Companies. Abbreviations. Overview. Definition, classification of hypertension (HTN) Goals of therapy Compelling indications Lifestyle modifications Hypertension in pregnancy Treatment

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Hypertension Chapter 15

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  1. Hypertension Chapter 15 Pharmacotherapy: A Pathophysiologic Approach The McGraw-Hill Companies

  2. Abbreviations

  3. Overview • Definition, classification of hypertension (HTN) • Goals of therapy • Compelling indications • Lifestyle modifications • Hypertension in pregnancy • Treatment • Orthostatic hypotension • Hypertensive crisis • Monitoring antihypertensive drug therapy

  4. Hypertension • Persistent elevation of arterial blood pressure (BP) • National Guideline • 7th Report of the Joint National Committee on the Detection, Evaluation, and Treatment of High Blood Pressure (JNC7) • ~72 million Americans (31%) have BP > 140/90 mmHg • Most patients asymptomatic • Cardiovascular morbidity & mortality risk directly correlated with BP; antihypertensive drug therapy reduces cardiovascular & mortality risk Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42(6):1206–1252.

  5. Target-Organ Damage • Brain: stroke, transient ischemic attack, dementia • Eyes: retinopathy • Heart: left ventricular hypertrophy, angina • Kidney: chronic kidney disease • Peripheral Vasculature: peripheral arterial disease

  6. Etiology • Essential hypertension: • > 90% of cases • hereditary component • Secondary hypertension: • < 10% of cases • common causes: chronic kidney disease, renovascular disease • other causes: Rx drugs, street drugs, natural products, food, industrial chemicals

  7. Causes of 2˚ Hypertension • Diseases • chronic kidney disease • Cushing's syndrome • coarctation of the aorta • obstructive sleep apnea • parathyroid disease • pheochromocytoma • primary aldosteronism • renovascular disease • thyroid disease

  8. Causes of 2˚ Hypertension • Prescription drugs:   • prednisone, fludrocortisone, triamcinolone • amphetamines/anorexiants: phendimetrazine, phentermine, sibutramine • antivascular endothelin growth factor agents • estrogens: usually oral contraceptives • calcineurin inhibitors: cyclosporine, tacrolimus • decongestants: phenylpropanolamine & analogs • erythropoiesis stimulating agents: erythropoietin, darbepoietin

  9. Causes of 2˚ Hypertension • Prescription drugs: • NSAIDs, COX-2 inhibitors • venlafaxine • bupropion • bromocriptine • buspirone • carbamazepine • clozapine • ketamine • metoclopramide

  10. Causes of 2˚ Hypertension • Situations: • β-blocker or centrally acting α-agonists • when abruptly discontinued • β-blocker without α-blocker first when treating pheochromocytoma • Food substances:   • sodium • ethanol • licorice

  11. Causes of 2˚ Hypertension • cocaine • cocaine withdrawal • ephedra alkaloids (e.g., ma-huang) • “herbal ecstasy” • phenylpropanolamine analogs • nicotine withdrawal • anabolic steroids • narcotic withdrawal • methylphenidate • phencyclidine • ketamine • ergot-containing herbal products • St. John's wort • Street drugs, other natural products:  

  12. Mechanisms of Pathogenesis • Increased cardiac output (CO): • increased preload: • increased fluid volume • excess sodium intake • renal sodium retention • venous constriction: • excess RAAS stimulation • sympathetic nervous system overactivity

  13. Mechanisms of Pathogenesis • Increased peripheral resistance (PR): • functional vascular constriction: • excess RAAS stimulation • sympathetic nervous system overactivity • genetic alterations of cell membranes • endothelial-derived factors • structural vascular hypertrophy: • excess RAAS stimulation • sympathetic nervous system overactivity • genetic alterations of cell membranes • endothelial-derived factors • hyperinsulinemia due to obesity, metabolic syndrome

  14. Arterial Blood Pressure • Sphygmomanometry: indirect BP measurement • MAP = 1/3 (SBP) + 2/3 (DBP) • BP = CO x TPR MAP: Mean Arterial Pressure SBP: Systolic Blood Pressure DBP: Diastolic Blood Pressure BP: Blood Pressure CO: Cardiac Output TPR: Total Peripheral Resistance

  15. Arterial Pressure Determinants

  16. Adult Classification Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42(6):1206–1252.

  17. Clinical Controversy • White coat hypertension: elevated BP in clinic followed by normal BP reading at home • Aggressive treatment of white coat hypertension is controversial • Patients with white coat hypertension may have increased CV risk compared to those without such BP changes

  18. Classification for Adults • Classification based on average of > 2 properly measured seated BP measurements from > 2 clinical encounters • If systolic & diastolic blood pressure values give different classifications, classify by highest category • > 130/80 mmHg: above goal for patients with diabetes mellitus or chronic kidney disease • Prehypertension: patients likely to develop hypertension

  19. Clinical Controversy • Ambulatory BP measurements may be more accurate & better predict target-organ damage than manual BP measurements using a sphygmomanometer in a clinic setting (gold standard) • many patients may be misdiagnosed, misclassified • poor technique, daily BP variability, white coat HTN • Validated ambulatory BP monitoring: role in the routine HTN management unclear

  20. Treatment Goals • Reduce morbidity & mortality • Select drug therapy based on evidence demonstrating risk reduction Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42(6):1206–1252.

  21. 2007 AHA Recommendations • More aggressive BP lowering for high risk patients Rosendorff C, Black HR, Cannon CP, et al. Treatment of hypertension in the prevention and management of ischemic heart disease: A scientific statement from the American Heart Association Council for High Blood Pressure Research and the Councils on Clinical Cardiology and Epidemiology and Prevention. Circulation 2007;115(21):2761–2788.

  22. ALLHAT • Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) • Primary endpoints • fatal CHD • nonfatal MI • Secondary endpoints • other hypertension-related complications • HF • stroke ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288(23):2981–2997.

  23. ALLHAT • Prospective, double-blind trial • randomized patients to: • chlorthalidone • amlodipine • doxazosin • lisinopril-based therapy • 42,418 patients: age > 55 yr with HTN + 1 additional CV risk factor (mean subject participation 4.9 years) • Thiazide-type diuretics remain unsurpassed for reducing CV morbidity & mortality in most patients ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288(23):2981–2997.

  24. JNC7 Recommendations • Thiazide-like diuretics preferred 1st line therapy based on clinical trials showing morbidity & mortality reductions • ALLHAT confirms 1st line role of thiazide diuretics • Compelling indications: comorbid conditions where specific drug therapies provide unique long-term benefits based on clinical trials • drug therapy recommendations are in combination with or in place of a thiazide diuretic Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42(6):1206–1252.

  25. Clinical Controversy • Avoiding Cardiovascular Events through COMbination Therapy in Patients LIving with Systolic Hypertension (ACCOMPLISH) • Endpoint: composite of death from CV causes, hospitalization for angina, nonfatal MI or stroke, coronary revascularization, & resuscitation after cardiac arrest • Prospective, double-blind, industry sponsored trial • randomized patients to benazepril + amodipdine or benazepril + HCTZ • 11,506 patients with HTN & high CV risk • Combination benazepril + amlodipine superior to benazepril + HCTZ for reducing CV events in high risk patients Jamerson KA, Weber MA, Bakris GL, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension. N Engl J Med. 2009;359(23):2417-2428.

  26. Compelling Indications • Heart Failure • Post Myocardial Infarction • High Coronary Disease Risk • Diabetes Mellitus • Chronic Kidney Disease • Recurrent Stroke Prevention

  27. Recommendations & Evidence • Strength of recommendations • A: good, B: moderate, C: poor • Quality of evidence • 1: more than 1 properly randomized, controlled trial • 2: at least 1 well-designed clinical trial with randomization; cohort or case-controlled analytic studies; dramatic results from uncontrolled experiments or subgroup analyses • 3: opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert communities

  28. ACE: angiotensin-converting enzyme; ARB: angiotensin receptor blocker; CCB: calcium channel blocker; • DBP: diastolic blood pressure; SBP: systolic blood pressure

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  30. Lifestyle Modifications DASH, Dietary Approaches to Stop Hypertension. aEffects of implementing these modifications are time and dose dependent and could be greater for some patients. DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy:APathophysiologic Approach, 7th Edition: http://www.accesspharmacy.com/

  31. Clinical Controversy • Prehypertension: patients do not have HTN but at risk for developing it • Trial of Preventing Hypertension (TROPHY) showed treating prehypertension with candesartan decreased progression to stage 1 hypertension • Unknown whether managing prehypertension with drug therapy and lifestyle modifications decreases CV events or if this approach is cost-effective Julius S, Nesbitt SD, Egan BM, et al. Feasibility of treating prehypertension with an angiotensin-receptor blocker. N Engl J Med 2006;354(16):1685–1697.

  32. Hypertension in Pregnancy • Important to differentiate preeclampsia from chronic, transient, & gestational hypertension • Preeclampsia: >140/90 mmHg after 20 weeks’ gestation with proteinuria • restricted activity, bed rest, close monitoring beneficial • definitive treatment: delivery • Methyldopa: drug of choice

  33. Chronic HTN in Pregnancy DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy:APathophysiologic Approach, 7th Edition: http://www.accesspharmacy.com/

  34. Diuretics • Exact hypotensive mechanism unknown • Initial BP drop caused by diuresis • reduced plasma & stroke volume decreases CO and BP • causes compensatory increase in peripheral vascular resistance • Extracellular & plasma volume return to near pretreatment levels with chronic use • peripheral vascular resistance becomes lower than pretreatment values • results in chronic antihypertensive effects

  35. Diuretics • Thiazide • chlorthalidone, hydrochlorothiazide (HCTZ), indapamide, metolazone • Loop • bumetanide, furosemide, torsemide • Potassium-sparing • amiloride, triamterene • Aldosterone antagonists • eplerenone, spironolactone

  36. Thiazide Diuretics • Dose in morning to avoid nocturnal diuresis • Adverse effects: • hypokalemia, hypomagnesemia, hypercalcemia, hyperuricemia, hyperuricemia, hyperglycemia, hyperlipidemia, sexual dysfunction • lithium toxicity with concurrent administration • More effective antihypertensives than loop diuretics unless CrCl < 30 mL/min • Chlorthalidone 1.5 to 2 times as potent as HCTZ 37

  37. Loop Diuretics • Dose in AM or afternoon to avoid nocturnal diuresis • Higher doses may be needed for patients with severely decreased glomerular filtration rate or heart failure • Adverse effects: • hypokalemia, hypomagnesemia, hypocalcemia, hyperuricemia, hyperuricemia

  38. Potassium-sparing Diuretics • Dose in AM or afternoon to avoid nocturnal diuresis • Generally reserved for diuretic-induced hypokalemia patients • Weak diuretics, generally used in combination with thiazide diuretics to minimize hypokalemia • Adverse effects: • may cause hyperkalemia especially in combination with an ACE inhibitor, angiotensin-receptor blocker or potassium supplements • avoid in patients with CKD or diabetes

  39. Aldosterone antagonists • Dose in AM or afternoon to avoid nocturnal diuresis • Due to increased risk of hyperkalemia, eplerenone contraindicated in CrCl < 50 mL/min & patients with type 2 diabetes & proteinuria • Adverse effects: • may cause hyperkalemia especially in combination with ACE inhibitor, angiotensin-receptor blocker or potassium supplements • avoid in CKD or DM patients • Gynecomastia: up to 10% of patients taking spironolactone

  40. ACE Inhibitors • 2nd line to diuretics for most patients • Block angiotensin I to angiotensin II conversion • ACE (AngiotensinConverting Enzyme) distributed in many tissues • primarily endothelial cells • blood vessels: major site for angiotensin II production • Block bradykinin degradation; stimulate synthesis of other vasodilating substances such as prostaglandin E2 & prostacyclin • Prevent or regress left ventricular hypertrophy by reducing angiotensin II myocardial stimulation

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  42. ACE Inhibitors • Monitor serum K+ & SCr within 4 weeks of initiation or dose increase • Adverse effects: • cough • up to 20% of patients • due to increased bradykinin • angioedema • hyperkalemia: particularly in patients with CKD or DM • neutropenia, agranulocytosis, proteinuria, glomerulonephritis, acute renal failure

  43. ARBs • Angiotensin II Receptor Blockers • Angiotensin II generation • renin-angiotensin-aldosterone pathway • alternative pathway using other enzymes such as chymases • Inhibit angiotensin II from all pathways • directly block angiotensin II type 1 (AT1) receptor • ACE inhibitors partially block effects of angiotensin II

  44. ARBs • Do not block bradykinin breakdown • less cough than ACE Inhibitors • Adverse effects: • orthostatic hypotension • renal insufficiency • hyperkalemia

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  46. ACE Inhibitor/ARB Warnings • Reduce starting dose 50% in some patients due to hypotension risk • patients also taking diuretic • volume depletion • elderly patients • May cause hyperkalemia in: • CKD patients • patients on other K+ sparing medications • K+ sparing diuretics • aldosterone antagonists

  47. ACE Inhibitor/ARB Warnings • Can cause acute kidney failure in certain patients • severe bilateral renal artery stenosis • severe stenosis in artery to solitary kidney • Pregnancy category C in 1st trimester • Pregnancy category D in 2nd & 3rd trimester

  48. Clinical Controversy • CV events risk further reduced when ARB combined with an ACE inhibitor for patients with left ventricular dysfunction • Data supports ACE/ARB combination therapy for patients with severe forms of nephrotic syndrome • Combination ACE/ARB therapy not well studied as standard treatment for HTN • Significantly higher risk of adverse effects such as hyperkalemia

  49. Clinical Controversy • ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) • Endpoint: composite of death, dialysis, SCr doubling • Prospective, randomized, multicenter, double-blind trial; patients randomized patients to ramipril, telmisartan, combination of both • 25,620 patients > age 55 yr with diabetes & end-organ damage or established atherosclerotic vascular disease • Combination therapy reduces proteinuria more than monotherapy but worsens major renal outcomes Mann JF, Schmieder RE, McQueen M, et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet 2008;372:547-543.

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