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Evidence Based Treatment of Hypertension Harleen Singh, Pharm.D. Ted D. Williams, Pharm.D. Candidate OSU/OHSU College of Pharmacy P4 Year – Investing in your Education Lab Lecture Learning Objectives 1. 2. 3. 4. 5. 6. 7. 8. Demonstrate an understanding of the different roles of pharmacology, pathophysiology, and evidence based medicine as they apply to patient therapy Demonstrate understanding of pathological disorders caused by chronic, poorly controlled hypertension Identify signs and symptoms of end-organ damage due to hypertension Demonstrate an understanding of sites of action and most likely side effects of various antihypertensive drug classes and differences between drugs in the same class Classify patients by JNC-7 Hypertension levels Assign blood pressure goals according to AHA 2007 Scientific Statement for patients based on comorbidities Select most appropriate therapy for patients based on Evidence Based Medicine Compelling Indications Apply outcomes of landmark hypertension studies to selecting patient therapy The Road Ahead • Evidence Based Medicine (EBM) Primer • Hypertension Defined, Epidemiology, Complications • Goals of Hypertension Therapy • Hypertension Treatment Guidelines • Non-Pharmacological Treaments of Hypertension • Pharmacology Review – By Drug Class – Assessing Drug Interactions • EBM for pharmacological treatment selection Evidence Based Medicine • Evidence-based medicine (EBM) – EBM is the conscientious, explicit, and judicious use of the current best evidence in making decisions about the care of individual patients.(Sackett 1998) Pathophysiology, Pharmacology and EBM • Pathophysiology suggests where we can intervene to improve outcomes • Pharmacology helps predict likely targets – Therapeutic Effects – Adverse Effects • Clinical Trials show what happens when we treat 10,000 patients – Evidence Based Medicine lives here Types of Significance • Statistical Significance – Can we detect any difference • Clinical Significance – Do we care if there is a difference • Patient Significance – Blood Glucose level differences with Thiazide Diuretics are significantly higher vs. placebo – Increase in Blood Glucose 3-5mg/dL in non-diabetics – Is this clinically significant? EBM In Real Life • Question for PharmD: Recommend a therapy for a patient on 25mg HCTZ QDay with BP 140/95 • Answer from PharmD: “Continue HCTZ 25mg Q Day and add Lisinopril 10mg Q Day, titrating to 40mg Q Day” • Response: “Why not increase HCTZ to 50mg Q Day. Micromedex says the max daily dose is 100mg” • PharmD: ??? JNC-7 • The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure • Gold Standard EBM in Hypertension diagnosis and treatment Case More Cases Hypertension Defined • Elevated Blood Pressure (BP) – Systolic Blood Pressure (SBP) >=140mmHg – Diastolic Blood Pressure (DBP) >=90mmHg Epidemiology of Hypertension • Approximately 50 million people in the U.S. have hypertension. • The incidence of hypertension increases steadily with age and prevalence is higher in blacks than in whites. Prevalence exceeds 60% in people over age 60. • There is a strong correlation between blood pressure and cardiovascular morbidity and mortality. – Systolic BP has a stronger correlation than diastolic BP, but both are important Epidemiology of Hypertension • The higher the pressure, the greater the risk of myocardial infarction, angina, stroke, heart failure, renal failure, peripheral vascular disease and retinopathy. – For each 20mm increase in SBP or 10mm increase in DBP over 115/75, risk doubles – Complication rates increase with each additional CVD risk factor that is present – Hypertension accounts for 2/3 of strokes and about 25% of MIs • Preventing and controlling hypertension is a major strategy for reducing CVD morbidity and mortality. • While 70% of hypertensives are aware of their condition and 59% are being treated; only 34% are controlled. Determinants of Blood Pressure • Arterial blood pressure is generated by the interplay of cardiac output and total peripheral resistance: BP = CO x TPR • It reaches a peak during cardiac contraction (systolic pressure) and a nadir at the end of cardiac relaxation (diastolic pressure). • Blood pressure is measured in millimeters of mercury and recorded as systolic (SBP) over diastolic pressure (DBP). • The difference between the systolic and the diastolic pressure is the pulse pressure (PP) • Mean arterial pressure (MAP) = 1/3 PP + DBP. Pathophysiology of Hypertension Sympathetic Activation Cardiac Output Blood Pressure Peripheral Resistance Aldosterone HR Stroke Volume Adapted from APhA’s Completed Review for Pharmacy. Gourley, DR. 2004 Plasma Volume AT II Renin Pathophysiology of Hypertension(HTN) 1. Increased Sympathetic Activation 2. Excessive vascular volume 3. Activation of the Renin Anginotensin Aldosterone System 4. Peripheral Resistance Causes of Hypertension • Idiopathic – 90-95% of cases have no known etiology • Secondary – – – – – – – – Renal Insufficiency Coarcation of the aorta Primary Aldosteronism Thyroid/parathyroid disease Cushing’s Syndrome Pheochromocytoma Sleep Apnea Increased Intracranial pressure • Look for secondary causes, but don’t expect to find them Hypertension as a Risk Factor HTN Hypertension as a Risk Factor • Hypertension is a primary risk factor for multiple comorbidities – Ischemic Heart Disease (IHD) • aka Carotid Artery Disease (CAD), Coronary Heart Disease(CHD) • Myocardial Infarction (MI) • Angina – Heart Failure (HF) – Left Ventricular Hypertrophy or Dysfunction (LVH, LVD) – Cerebrovascular Disease • Stroke • Transient Ischemic Attack (TIA) – Chronic Kidney Disease (CKD) – Retinopathy Types of Hypertension • Chronic – What we will focus on today and what we will call Hypertension • Hypertensive Crisis – Hypertensive Emergency – Hypertensive Urgency – Dr Marrs will discuss this in detail in subsequent lectures Hypertensive Crisis • Less than 1% of all hypertensives will ever have a hypertensive crisis. • Hypertensive crisis is defined as a diastolic pressure above 120mm Hg. • There are 2 types of hypertensive crisis: – hypertensive emergency – hypertensive urgency Goals of Hypertensive Therapy • Long Term • Short Term Long Term Goals of Hypertension Therapy • Direct Measures – Reduced Mortality – Reduced incidence of end organ damage • • • • Cardiovascular Cerebrovascular Renal Retinopathy – Trailing indicators Short Term Goals of Hypertension Therapy • Surrogate markers – Blood Pressure – Leading indicator • Why is blood pressure a good surrogate marker? Hypertension and Ischemic Heart Disease The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. 2004 Hypertension and Stroke The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. 2004 Hypertension and Cardiovascular Disease • High Normal = 130-139/85-89mmHg • Normal = 120-129/80-84mmHg • Optimal <120/<80mmHg The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. 2004 JNC-7 Hypertension Classifications 2 Agent Initial Therapy DBP = Diastolic Blood Pressure, SBP = Systolic Blood Pressure *Treatment should be determined by the highest blood pressure ‡Treat patients with chronic kidney disease or diabetes to BP goal of <130/80mmHg JNC-7 Express: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. 2004 From JNC-7 to 2007 AHA Guidelines Past Medical History Primary Prevention Blood Pressure Goal Framingham Risk Score <10% <140/90 mmHg >10% Diabetes Melitus Chronic Kidney Disease <130/80 mmHg CAD Risk Equivalents CAD Left Ventricular Dysfunction <120/80 mmHg Adapted From Saseen, JJ. Essential Hypertension. Applied Therapeutics: The Clinical Use of Drugs 10th edition. 2008 Framingham Risk Factors and CAD Equivalents • Framingham Risk Factors – – – – – – Age > 45 Total Cholesterol Smoking HDL Cholesterol Systolic Blood Pressure See ATP III Guidelines for scoring algorithm • CAD Equivalents – – – – Ischemic Stroke Transient Ischemic Attack Peripheral Arterial Disease Abdominal Aortic Aneurysm Therapy • Therapeutic Lifestyle Changes (TLC) • Pharmacological Therapy Therapeutic Lifestyle Changes vs. Pharmacotherapy Therapeutic Intervention Approximate SBP Reduction Weight Reduction (5-10% or 10kg) 5-20mmHg DASH Diet (Low sodium, low fat) 8-14mmHg Single Antihypertensive 10mmHg (10 over 5 rule) 30 minutes exercise most days 4-9mmHg Dietary Sodium Reduction 2-8mmHg Reduce alcohol to <=2 drinks/day 2-4mmHg Adapted From: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. 2004 Weight Reduction Dash Diet 30 Minutes of Exercise Sodium Restriction Trial • 412 subjects randomized to typical American diet (control) or DASH diet and to three different sodium levels for 30 days with a 2 week run in period – High 3.5g – Intermediate 2.3g (Recommended DASH) – Low 1.2g • Typical American diet is 4,100 mg per day for men and 2,750 for women (JNC-7) Sacks, et al. Effects on Blood Pressure of Reduced Dietary Sodium and the Dietary Approaches to Stop Hypertension (DASH) Diet. NEJM 2001(1);344:3-10 Sodium Restriction Trial Sacks, et al. Effects on Blood Pressure of Reduced Dietary Sodium and the Dietary Approaches to Stop Hypertension (DASH) Diet. NEJM 2001(1);344:3-10 Smoking • Smoking – In the first year after quitting, excess risk of a cardiovascular event is cut in half, and after 515 years, the rate approaches that of a never smoker Annual Smoking Related Deaths 1995-1999 from Center for Disease Control and Prevention Caffeine • Caffeine JNC-7 Recommendations by Hypertension Stage JNC-7 Recommendations by Compelling Indication The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. 2004 2007 AHA Scientific Statement Recommendations First Line Therapy ACEI/ARB or CCB or Thiazide Diuretic Past Medical History Primary Prevention Blood Pressure Goal Framingham Risk Score <10% <140/90 mmHg >10% ACEI/ARB or CCB or Thiazide Diuretic Diabetes Melitus Chronic Kidney Disease CAD Risk Equivalents BB‡ and ACEI/ARB CAD (ACEI/ARB or BB) And Diuretic And Aldosterone Antagonist And Hydralazine/Isosorbide Dinitrate¥ Left Ventricular Dysfunction ‡ Only use BB in patients who are hemodynamically stable ¥ African American <130/80 mmHg <120/80 mmHg Adapted From Saseen, JJ. Essential Hypertnesion. Applied Therapeutics: The Clinical Use of Drugs 10th edition. 2008 and Rosendorff, C., et. Al. AHA Scientific Statement. Treatment of Hypertnesion in the Prevention and Management of Ischemic Heart Disease. Circulation. 2007;115:2761-2788. 2007 AHA Scientific Statement Recommendations Rosendorff, C., et. Al. AHA Scientific Statement. Treatment of Hypertnesion in the Prevention and Management of Ischemic Heart Disease. Circulation. 2007;115:2761-2788. Antihypertensive Therapies • Volume Management – Loop Diuretics – Thiazide Diuretics – Potassium Sparing Diuretics • Including Aldosterone Antagonists (Aldo Ant) • RAAS Agents – Angiotensin Converting Enzyme Inhibitors (ACEI) – Angiotensin II Receptor Blockers (ARB) – Renin Inhibitors • Direct Cardiac Agents – Beta Blockers (BB) – Non-Dihydropyridine Calcium Channel Blockers (Non-DHP CCB) • Vasodilators – Dihydropyridine Calcium Channel Blockers (DHP CCB) – Alpha 1 Antagonists Antihypertensive Therapies • Volume Management – Loop Diuretics – Thiazide Diuretics – Potassium Sparing Diuretics • Including Aldosterone Antagonists (Aldo Ant) • RAAS Agents – Angiotensin Converting Enzyme Inhibitors (ACEI) – Angiotensin II Receptor Blockers (ARB) – Renin Inhibitors • Direct Cardiac Agents – Beta Blockers (BB) – Non-Dihydropyridine Calcium Channel Blockers (Non-DHP CCB) • Vasodilators – Dihydropyridine Calcium Channel Blockers (DHP CCB) – Alpha 1 Antagonists Loop Diuretics – Mechanism of Action Sympathetic Activation Cardiac Output Blood Pressure Peripheral Resistance Aldosterone HR Stroke Volume Plasma Volume AT II Renin Loop Diuretics – Mechanism of Action • Act mainly in ascending loop of Henle to decrease sodium reabsorption • Action is shorter but more intense than other diuretics • Preferred for edema vs. BP management Na↑ Ca↑ Mg↑ K↑ Thiazide Diuretics – Mechanism of Action Sympathetic Activation Cardiac Output Blood Pressure Peripheral Resistance Aldosterone HR Stroke Volume Plasma Volume AT II Renin Thiazide Diuretics– Mechanism of Action • Increase urinary excretion • Works at the distal convoluted renal tubules • Increase urinary excretion of potassium • Additional MOA – May cause peripheral vasodilation, but this is unclear Na Cl↑ + K↑ Potassium Sparing Diuretics – Mechanism of Action Sympathetic Activation Cardiac Output Blood Pressure Peripheral Resistance Aldosterone HR Stroke Volume Plasma Volume AT II Renin Potassium Sparing Diuretics– Mechanism of Action • Mild Diuretic Effects • Usually used for synergistics effects Na↑ K↓ Antihypertensive Therapies • Volume Management – Loop Diuretics – Thiazide Diuretics – Potassium Sparing Diuretics • Including Aldosterone Antagonists (Aldo Ant) • RAAS Agents – Angiotensin Converting Enzyme Inhibitors (ACEI) – Angiotensin II Receptor Blockers (ARB) – Renin Inhibitors • Direct Cardiac Agents – Beta Blockers (BB) – Non-Dihydropyridine Calcium Channel Blockers (Non-DHP CCB) • Vasodilators – Dihydropyridine Calcium Channel Blockers (DHP CCB) – Alpha 1 Antagonists ACE Inhibitors – Mechanism of Action Sympathetic Activation Cardiac Output Blood Pressure Peripheral Resistance Aldosterone HR Stroke Volume Plasma Volume AT II ACE Renin Angiotensin Receptor Blockers– Mechanism of Action Sympathetic Activation Cardiac Output Blood Pressure Peripheral Resistance Aldosterone HR Stroke Volume Plasma Volume AT II Renin Renin Inhibitors – Mechanism of Action Sympathetic Activation Cardiac Output Blood Pressure Peripheral Resistance Aldosterone HR Stroke Volume Plasma Volume AT II Renin Antihypertensive Therapies • Volume Management – Loop Diuretics – Thiazide Diuretics – Potassium Sparing Diuretics • Including Aldosterone Antagonists (Aldo Ant) • RAAS Agents – Angiotensin Converting Enzyme Inhibitors (ACEI) – Angiotensin II Receptor Blockers (ARB) – Renin Inhibitors • Direct Cardiac Agents – Beta Blockers (BB) – Non-Dihydropyridine Calcium Channel Blockers (Non-DHP CCB) • Vasodilators – Dihydropyridine Calcium Channel Blockers (DHP CCB) – Alpha 1 Antagonists Beta Blockers – Mechanism of Action Sympathetic Activation Cardiac Output Blood Pressure Peripheral Resistance Aldosterone HR Stroke Volume Plasma Volume AT II Renin Non-DHP CCB– Mechanism of Action Sympathetic Activation Cardiac Output Blood Pressure Peripheral Resistance Aldosterone HR Stroke Volume Plasma Volume AT II Renin Antihypertensive Therapies • Volume Management – Loop Diuretics – Thiazide Diuretics – Potassium Sparing Diuretics • Including Aldosterone Antagonists (Aldo Ant) • RAAS Agents – Angiotensin Converting Enzyme Inhibitors (ACEI) – Angiotensin II Receptor Blockers (ARB) – Renin Inhibitors • Direct Cardiac Agents – Beta Blockers (BB) – Non-Dihydropyridine Calcium Channel Blockers (Non-DHP CCB) • Vasodilators – Dihydropyridine Calcium Channel Blockers (DHP CCB) – Alpha 1 Antagonists Alpha Blockers – Mechanism of Action Sympathetic Activation Cardiac Output Blood Pressure Peripheral Resistance Aldosterone HR Stroke Volume Plasma Volume AT II Renin DHP CCB– Mechanism of Action Sympathetic Activation Cardiac Output Blood Pressure Peripheral Resistance Aldosterone HR Stroke Volume Plasma Volume AT II Renin Other CVD Risk Reducing Agents • Aspirin • Statins Combination Therapy – Stepped, Sequential, Concurrent • Stepped Care – Select one agent initially and titrate to effect – If BP control is not achieved, add-on another agent – Standard approach • Sequential – Select one agent initially and titrate to effect – If BP control is not achieved, switch to another agent – Use when medication is poorly tolerated or sub-optimal efficacy • Concurrent – Start two or more agents simultaneously and titrate in parallel – Reserved for special needs patient (e.g. JNC-7 Stage 2 HTN) Combination Therapy Recommendations • 2 Drug ACEI/BB + (Diuretic or CCB) • 3 Drug ACEI/BB + Diuretic + CCB • Remember, don’t combine CCB and BB without extreme caution and compelling indications Thiazide OR CCB ACEI/BB Supplemental Foundation Adapted from Williams, B, Poulter, NR, Morris, JP, et al. British Hypertension Society Guidelines for Hypertension Management 2004 (BHS-IV). BMJ 2004;328;634-640 Drug Interactions • Physiological – e.g. Non-DHP CCB and BB • Pharmacological – e.g. Non-Selective BB and Beta Agonists in COPD • Metabolic – e.g. Statins (3A4 Substrates) and Non-DHP CCB (3A4 Inhibitors) Drug Interaction Dictionary • • • • • • • • • • • • • • • Corticosteroids Anorectics (e.g., phenylporpanolamine, sibutramine, amphetamines) Cocaine Buproprion plus nicotine replacement Cyclosporine, tacrolimus Decongestants Erythropoeitin and analogues Licorice Ma huang, ephedra, bitter orange Monoamine oxidase inhibitors Nonsteroidal anti-inflammatory drugs/ Cox 2 inhibitors Oral contraceptives Thyroid hormone excess Venlafaxine Anabolic steroids Don’t Panic Approach to Drug Interactions • Consider site of action and molecular structure – NSAIDs • Prostaglandin Synthesis Inhibitor – Lithium (Na) • Competitive – Steroids (Na) • Aldosterone Analogs Drug Interaction Dictionary Revisited • • • • • • • • • • • • • • • Corticosteroids Anorectics (e.g., phenylporpanolamine, sibutramine, amphetamines) Cocaine Buproprion plus nicotine replacement Cyclosporine, tacrolimus Decongestants Erythropoeitin and analogues Licorice Ma huang, ephedra, bitter orange Monoamine oxidase inhibitors Nonsteroidal anti-inflammatory drugs/ Cox 2 inhibitors Oral contraceptives Thyroid hormone excess Venlafaxine Anabolic steroids Compelling Indications HTN