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Evidence Based Treatment of Hypertension Harleen Singh Pharm.D., Assistant Professor Ted D. Williams Pharm.D. Candidate OSU/OHSU College of Pharmacy P3 Year – Investing in your Education Objectives 1. 2. Describe the epidemiology of hypertension Identify various physiologic systems that can contribute to the development of elevated blood pressure. 3. Identify the complications of untreated hypertension. 4. Describe the classification of blood pressure in adults. 5. Identify appropriate blood pressure goals for patients with hypertension. 6. Know the disease states and other factors that increase the risk of cardiovascular complications for a patient with hypertension. 7. Be able to identify secondary causes of hypertension, including drugs. 8. Summarize our current knowledge on the relative effectiveness of antihypertensive therapy in preventing complications of hypertension. 9. Describe the role of non-pharmacologic management of hypertension and various lifestyle changes that can be recommended. 10. Describe when drug therapy for hypertension is indicated. Objectives 11. Be able to articulate the advantages, disadvantages, effectiveness as monotherapy, side effects, contraindications, relative cost, and monitoring parameters for the following classes of antihypertensives: A. Diuretics (Loop, Thiazide, Potassium Sparing) B. Beta-blockers C. Angiotensin-converting enzyme (ACE) inhibitors D. Calcium blockers E. Centrally-acting sympatholytics F. Peripheral sympatholytics and arteriolar dilators G. Alpha blockers H. Angiotensin receptor blockers (ARBs) I. Direct rennin inhibitors Objectives 11. Describe differences among various agents in the same antihypertensive class. 12. Identify antihypertensives that should not be abruptly discontinued. 13. Taking into consideration demographics, socio-economic factors, and medical disorders for a given hypertensive patient, be able to develop an appropriate therapeutic plan (recommend appropriate agent, patient education, and monitoring). 14. Identify factors that can lead to a poor response to antihypertensive therapy. 15. Describe the factors that can influence compliance with antihypertensive therapy. 16. Be able to distinguish between true hypertensive emergency and hypertensive urgency. The Road Ahead • Evidence Based Medicine (EBM) Primer • Hypertension Defined, Epidemiology, Complications • Goals of Hypertension Therapy • Hypertension Treatment Guidelines • Non-Pharmacological Treatments of Hypertension • Pharmacology Review • 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 : A patient is taking 25mg HCTZ QDay with BP 140/95. What should the next step be? • 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 • Express and Full Version Case • JD is a pleasant 56 yo female with – Hypertension (HTN) – type 2 diabetes – occasional gout attacks. • Her last three home BP readings were 145/95mmHg, 153/98mmHg, and 143/92mmHg. • Today in the clinic she had a BP of 142/89mmHg. • Her last Lipid panel was 2 months ago: LDL 153mg/dL, HDL 63mg/dL, triglycerides 121 • Lisinopril 40mg once daily • Metformin 1000mg BID Hypertension (HTN) Defined • Elevated Blood Pressure (BP) – Systolic Blood Pressure (SBP) >=140mmHg – Diastolic Blood Pressure (DBP) >=90mmHg • Why these values will be discussed later The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. 2004 Hypertensive Crisis • Less than 1% of all hypertensive patients 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 White Coat Hypertension • Elevated blood pressure in a clinical setting • Believed to be tied to anxiety • Documented lower blood pressures at home Epidemiology of Hypertension • Approximately 50 million people in the U.S. have hypertension. • The risk of CVD beginning at 115/75 mmHg doubles with each increment of 20/10 mmHg • 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 • While 70% of hypertensives are aware of their condition and 59% are being treated; only 34% are controlled. Epidemiology of Hypertension Prevalence Doubles From 40s to 60s Epidemiology of Hypertension The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. 2004 Definitions - 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. Schematic of the 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 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 be surprised if you don’t 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 (Stable and Unstable) – Heart Failure (HF) – Left Ventricular Hypertrophy or Dysfunction (LVH, LVD) – Cerebrovascular Disease • Stroke • Transient Ischemic Attack (TIA) – Chronic Kidney Disease (CKD) – Retinopathy 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 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) – Weight – Exercise – Diet – Smoking – Caffeine • Pharmacotherapy 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 EBM • Trials of Hypertension Prevention, Phases I and II (TOHP I, TOHP II) Late 1980s, early 1990s – Evaluated Multiple Non-Pharmacological Methods of weight loss (weight reduction, sodium restriction, mineral supplementation) in pre-hypertensive (DBP 83-89mmHg female, 80-89mmHg male) and BMI approximately 25-35 – Sodium Restriction and Weight Loss were the most effective methods for reducing both SBP and DBP More Weight Reduction EBM Rate(%) of Hypertension Comparison of the 7 year cumulative incidence of hypertension between active intervention and control groups for weight loss and sodium reduction interventions. 45 40 35 30 25 20 15 10 5 0 Active Control Weight Loss p = 0.02 Sodium Reduction p=0.19 He, J et. al Long-Term Effects of Weight Loss and Dietary Sodium Reduction on Incidence of Hypertension. Hypertension 2000;35:544-549 DASH Diet & Sodium Restriction DASH Diet & Sodium Restriction • • • • • • Restricted Sodium Low Fat High Fiber Emphasis on Fruits and Vegetables High Potassium High Calcium EBM of DASH Diet & Sodium Restriction • 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 EBM of DASH Diet & Sodium Restriction • Controlling for sodium content, the DASH diet provides significant BP reductions • Add sodium restrictions and further reductions in BP are obtained 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 Exercise 30 minutes most days • A 2002 systematic Meta-analysis of Randomized Control Trials (RCTs) showed the following results – BP reductions appear to be independent of weight loss – Method of aerobic activity (biking, walking, etc) did not show a statistically significant link to BP reductions – Neither frequency nor intensity of exercise showed statistically significant reductions in BP Whelton SP, Chin A, Xin X, He J. Effect of aerobic exercise on blood pressure: A metaanalysis of randomized, controlled trials. Ann Intern Med 2002;136:493-503. M 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 • Acute vs. Chronic Effects • Surrogate endpoints vs. Primary Endpoints Caffeine increases BP – Acute elevations in Systolic and Diastolic BP – But what about Morbidity and Mortality ? Hartley, et al Hypertension Risk Status and Effect of Caffeine on Blood Pressure. Hypertension 2000;36:137-141 Caffeine’s effects on morbidity and mortality – No controlled trials have demonstrated an increased risk of cardiovascular endpoints – Several studies have demonstrated no linear relationship between caffeine consumption and hypertension rates • MacDonald, TM, et al. Caffeine Restriction: effect on mild hypertension BMJ 1991(303)1235-8 • Winkelmayer, WC, et al. Habitual Caffeine Intake and the Risk of Hypertension in Women. JAMA 2005:(294)18:23302335 – JNC-7 only mentions caffeine in the context of abstention 30 minutes before taking a BP reading 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 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 Initial Evaluation Goals • Identify target organ damage • Identify secondary causes • Identify other CVD risk factors and assess overall CVD risk • Identify lifestyle contributory factors • Identify factors or conditions that influence therapy decisions (contraindications, indications, etc.) Ideal Antihypertensive Drugs • Prevents all complications of hypertension (all cause mortality, CVD mortality, CVD events, renal failure, etc.) • Effective as monotherapy • Favorable quality of life profile • Does not worsen other conditions, safe • Once a day dosing • Inexpensive Examples Surrogate end • • • • • Blood pressure Glucose, lipids Carotid artery thickening Fasting insulin levels Hemodynamic effects Benefits of Drug Therapy • Pharmacotherapy has been associated with the following benefits: • 35-40% reduced risk of stroke • 20-25% decrease in MI • > 50% decrease in CHF • Several drug classes are proven to prevent complications, and a majority of patients will require combination therapy. • However, there are important advantages and disadvantages of the various drugs and drug classes used to treat hypertension. Thiazide diuretics • Place in therapy :“gold standard”. • More recent studies using low doses of thiazide diuretics have found reductions in all CVD events and they are “virtually unsurpassed” in preventing complications (JNC-7). Overall, they have the strongest body of evidence to support their use as a first line agent. Antihypertensive and lipid lowering treatment to prevent heart attack trial ALLHAT • Most robust prospective randomized controlled clinical trial • Primary end point: Incidence of fatal CHD or fatal MI • Secondary outcomes were all-cause mortality , stroke , combined CHD ( fatal CHD, non-fatal MI, Coronary revasularization , or angina with hospitalizations) ALLHAT: Primary end point Drug 6-year rate of events (%) Relative risk (95% CI) p vs chlorthalidone Chlorthalidone 11.5 -- -- Lisinopril 11.4 0.99 (0.911.08) 0.81 Amlodipine 11.3 0.98 (0.901.07) 0.65 ALLHAT Cooperative Research Group. JAMA 2002; 288:2981-2997 Secondary outcomes: Amlodipine vs chlorthalidone End point Amlodipine (%) 6-year 10.2 rate of heart failure Chlorthalidone (%) Relative p risk (95% CI) 7.7 1.38 (1.251.52) ALLHAT Cooperative Research Group. JAMA 2002; 288:2981-2997 <0.001 Secondary outcomes: Lisinopril vs chlorthalidone End point Lisinopril (%) Chlorthalidone (%) Relative risk (95% CI) p 6-year 33.3 rate of combined CVD 30.9 1.10 (1.051.16) <0.001 6-year rate of stroke 6.3 5.6 1.15 (1.021.30) 0.02 6-year rate of heart failure 8.7 7.7 1.19 (1.071.31) <0.001 ALLHAT Cooperative Research Group. JAMA 2002; 288:2981-2997 ALLHAT subgroup analysis: Relative risk of heart failure with amlodipine vs chlorthalidone by race Comparison Relative 95% CI risk p Overall 1.37 1.24-1.51 <0.001 Blacks 1.46 1.24-1.73 <0.001 Nonblacks 1.32 1.17-1.49 <0.001 Wright JT Jr et al. JAMA 2005; 293:1595-1608. ALLHAT subgroup analysis: Relative risk of stroke, combined CVD outcomes, and heart failure by race with lisinopril vs chlorthalidone Comparison Relative 95% CI risk Stroke •Black participants •Nonblack participants Combined CVD 1.40 1.17-1.68 1.00 0.85-1.17 •Black 1.19 1.09-1.30 •Nonblack Heart failure 1.06 1.00-1.13 •Black 1.30 1.10-1.54 •Nonblack 1.13 1.00-1.28 Wright JT Jr et al. JAMA 2005; 293:1595-1608. ALLHAT • -The ALLHAT study found no advantage of amlodipine or lisinopril over chlorthalidone in preventing HTN complications in type 2 diabetics or impaired fasting glucose, and chlorthalidone was better at preventing CHF, despite an increased risk of new cases of DM. (Arch Intern Med 2005;165:1401-9. • SHEP STUDY • - The SHEP study found that diabetics received the same benefit as non diabetics from low dose thiazide therapy (JAMA 1996; 276: 1886-92) • DM Non-DM • CV Events 0.66 0.66 • Stroke 0.78(ns) 0.62 • CHD Events 0.44 0.81(ns) • Death 0.74(ns) 0.85(ns) Other Benefits of thiazides include: • • • • Effective as monotherapy – no tolerance Once a day Inexpensive Adds to the effectiveness of other classes of antihypertensives • Two epidemiologic studies suggest long-term thiazide use may reduce the risk of hip fractures • They may be among the best tolerated classes of antihypertensives Adverse Effects: • • • • Increases in lipids and glucose with high dose. Decreases in K+, Mg++, and Na+. Increases in uric acid and calcium. Drug interactions: NSAIDs, corticosteroids, and lithium. • Contraindicated in GFR<30ml/min Management of Diuretic Induced Hypokalemia Prevention • Low doses of diuretic with or without potassium sparing agent. Treatment options: • Discontinue diuretic • High dose potassium chloride if continue diuretic • Add potassium-sparing diuretic if continue diuretic – – – – – Most effective regimen Spares Mg++ as well Convenient and inexpensive Positive outcome data Triamterene and amiloride have minimal BP lowering effect _ Spironolactone Potassium Sparing diuretics • Is it Okay to empirically start all patients with HTN on fixed doses of combination products to avoid hypokalemia? KEY counseling points • Increased urination when starting the medication • Taking the dose in morning to minimize nocturia • Signs and Symptoms of hypokalemia • Consumption of K rich foods • Salt substitutes Loop diuretics • More potent diuretics • Smaller decrease in PVR , and less vasodilation • Less effective as antihypertensives as compared to Thiazide diuretics • Diuretics of choice in severe CKD (GFR<30ml/min) Summary Slide ACE inhibitors • Recommended for all compelling indications • Clearly demonstrated reduction in HTN related complications • Patients who cannot take or tolerate first line agents ACE inhibitors • CHF , Diabetes and CKD have a compelling indication for ARBS • The overall efficacy appears comparable to thiazides and CCBs. • They have a higher rate of stroke and lower rate of CHF and new cases of DM than CCBs. • They also have a higher rate of stroke and lower rate of DM than diuretics. • Lack metabolic side effects such as lipid or glucose alterations. Some data suggests ACEI may reduce the onset of DM. ACE Inhibitors – Dose Conversions Generic (Brand) Typical Daily Dose (Oral) ‡ Maximum Daily Dose (Oral) ‡ Frequency Lisinopril (Prinivil,Zestril) 5-40mg 80mg ‡ Typical oral dose for use in Hypertension. Other indications may have differing doses. All doses are once daily except where noted QD ACE Inhibitors – Mechanism of Action Sympathetic Activation Cardiac Output Blood Pressure Peripheral Resistance Aldosterone HR Stroke Volume Plasma Volume AT II ACE Renin ACE Inhibitors – Side Effects • Hypotension • Cough: 5-20% of patients develop a dry nonproductive • Angioedema – 1% in general population – 4% in African Americans – Also less effective in African American as monotherapy • Hyperkalemia ACE Inhibitors – Monitoring • Efficacy – Blood Pressure • Safety – Chem 7 • K+ • SCr/BUN – Angioedema – Cough Summary slide Angiotensin Receptor Blockers(ARB) • Reserve for patients who cannot tolerate an ACEI. • Evidence to support with Type 2 Diabetes who have diabetic nephropathy with albuminuria ANGIOTENSIN RECEPTOR BLOCKERS MECHANISM OF ACTION RENIN Angiotensin I Angiotensinogen ACE Other paths ANGIOTENSIN II AT1 RECEPTOR BLOCKERS AT1 Vasoconstriction RECEPTORS Proliferative Action AT2 Vasodilatation Antiproliferative Action ARB Costs GENERIC BRAND DOSE Telmisarten MICARDIS 40mg qd COST/Y R$ 676 Losartan COZAAR 50mg QD 588 Valsartan DIOVAN 160mg qd 647 Irbesartan AVAPRO 150mg qd 542 Olmisartan BENICAR 20mg qd 538 Adverse effects • Similar to ACEI’s • Angiedema • Both ACE and ARBs contraindicated in pregnancy and bilateral renal artery stenosis Summary slide Calcium channel Blockers(CCB) • Elderly and Black patients have greater BP reductions • Used in Combination with diuretics • Do not alter Lipids , glucose or electrolyte Types of CCB • Dihyropyridines • Non-dihydropyridines Calcium Antagonists Nifedipine Nicardipine +++ Verapamil Diltiazem Isradipine Felodipine Amlodipine ++ + +++ +++ +++ Coronary vasodilation +++ ++ +++ +++ +++ +++ Myocardial contractility Heart rate ↓/0 ↓↓ ↓ ↓/0 0 0 ↑ ↓ ↓ ↑/0 ↑ 0 AV node conduction 0 ↓↓ ↓ 0 0 0 Systemic vasodilation Calcium Antagonists Costs GENERIC diltiazem ER BRAND DOSE COST/YR $ DILTIA XT 240mg qd DILACOR XR 257 verapamil SR CALAN SR 240mg qd 142 verapamil ER COVERA HS 240mg qd 268 Nifedipine ER ADALAT CC 60mg qd 563 felodipine ER PLENDIL 5mg qd 312 amlodipine NORVASC 5mg qd 110 diltiazem ER CARDIZEM CD PROCARDIA XL 240mg qd 432 60mg qd 545 nifedipine ER CCB • Recommended to treat HTN in patients with diabetes • Nondihyropyridines CCB slow the progression of CKD • Add on therapy after an ACEI or ARB and thaizide diuretic • Additional anti -ischemic effects with BB or when alternatives to BB are needed Adverse effects • Dihydopyridines (nifedipine, nicardipine, isradipine, amlodipine and felodipine): headache, dizziness, flushing, peripheral edema, and reflex tachycardia. • Verapamil – constipation, dizziness, fatigue, peripheral edema, heart failure and depressed A-V conduction. • Diltiazem—similar to verapamil but less likely to cause constipation Beta Blockers • All the approved beta blockers for hypertension appear to have similar effectiveness in lowering BP. • Long-term studies have shown that beta blockers can reduce the morbidity and mortality from hypertension, notably stroke and CHF. • Beta-blockers are effective for treating other conditions including certain tachyarrhythmia’s and migraine prophylaxis Beta blockers • Several studies suggest beta blocker based regimens increase the risk of new onset diabetes (especially when combined with thiazides) as compared to other drug classes (Lancet 2005;366:895-906). Beta –Blockers • However, meta-analyses suggest that beta-blockers may be less effective as compared to other antihypertensive drugs in older patients when used as initial therapy for primary prevention (Lancet 2005;366:1545-53, CMAJ 2006;174:1737-42). • Based on the above, beta-blockers are not recommended as a first-line agents in older patients without another indication for beta-blocker use. They also are not the best control treatment in hypertension primary prevention clinical trials. Beta blockers • Use post-myocardial infarction has demonstrated clear benefit in reducing fatal and non-fatal recurrent MIs (for non-ISA beta blockers and acebutolol). Strong clinical benefit has also been demonstrated for patients with CHF and angina Beta Blockers Alpha- Water Lipid T½ Cardiosele Block Solubi Solubi Bioavail (Hour Drug ctivity ISA ers lity lity ability s) Atenolol + + 50 6-9 Nadolol + 40 17-22 Acebutol + + + + 40 3-6 ol Pindolol +++ + + 90 2-5 Metoprol + + + 40 3-4 ol Timolol + + 75 2-5 Labetolol + + 40 3-4 Propranol + 30 2-5 ol ISA = intrinsic sympathomimetic activity: T ½ = elimination half-life. Beta-Blockers • Reduce morbidity and mortality in patient with compelling indication s • (LVD, CAD and diabetes) • Elderly and black patients may have less BP control with BB Beta Blocker Costs GENERIC BRAND DOSE COST/YR $ 46 atenolol TENORMIN 50mg qd propranolol INDERAL 80mg bid 76 metoprolol pindolol LOPRESSOR 50mg bid VISKIN 10mg bid 59 111 acebutolol SECTRAL 400mg qd 200 labetalol NORMODYNE 200mg bid 201 nadolol CORGARD 80mg qd 190 metoprolol ext. rel. TOPROL XL 100mg qd 410 carvedilol Coreg 12.5mg bid 1249 Which BB should be used? • • • • Selective vs non –selective Intrinsic sympathomatic activity Lipid solubility Comorbidities Side effects • • • • fatigue Depression Metabolic side effects Hypogycemia Beta-Blockers • These agents can cause problems for patients with asthma, COPD, heart block, brittle diabetes, and peripheral vascular disease (nonCS) and may worsen the lipid profile short-term (decrease HDL, increase TG-non ISA beta blockers Monitoring • • • • HR ( no less than 60beats/min ) Glucose /lipids Discontinuation Exercise intolerance, fatigue, insomnia, cold extremities can occur. Postural hypotension with labetalol due to alpha-blocking effects. Suggestions for selecting pharmacotherapy factoring in Cost Condition/Status Hypertension without compelling indication First Choice Low dose chlorthalidone or HCTZ or Alternate Amlodipine or ACEI Comments British guidelines recommend ACEI if age < 55 and diuretic or CCB age 55+ African American Low dose chlorthalidone or HCTZ Amlodipine if at risk for diabetes Isolated systolic hypertension Low dose chlorthalidone or HCTZ or amlodipine ARB CHF ACEI + beta-blockers +/spironolactone (severe CHF) ARB if ACEI cough or angioedema ACEI not recommended for initial therapy but can be used as add on therapy Beta-blockers are not recommended for initial therapy Diuretics usually needed as additive therapy Prior MI Angina Beta-blockers + ACEI Beta Blockers or CCB Nephropathy (diabetic and nondiabetic) ACEI ARB if ACEI cough or angioedema Diabetes without nephropathy ACEI or thiazide or amlodipine ARB if ACEI cough or angioedema. Beta-blocker can be used if first line agents can’t be used. Post-stroke Thiazide + ACEI Stage 2 hypertension Thiazide + ACEI or ACEI + CCB ARB can replace ACEI if intolerance to cough or angioedema. Consider adding ACEI to decrease CVD risk Diuretics often needed as additive therapy. Goal BP < 130/80 Combination therapy often required. Goal BP < 130/80. Some guidelines recommend ACEI Not much data to guide selection of alternative regimens Combination therapy is usually required. Relative risk of all-cause mortality for beta blockers vs placebo or other treatments Comparative drug RR of all-cause mortality for beta blockers 95% CI Placebo 0.99 0.88–1.11 Diuretics 1.04 0.91–1.19 ACE inhibitors/ ARBs 1.10 0.98–1.24 Calcium blockers 1.07 1.00–1.14 Wiysonge CS et al. Cochrane Database Syst Rev 2007;1:CD002003. Relative risk of total cardiovascular disease for beta blockers vs placebo or other treatments Comparative drug RR of total CV disease for beta blockers 95% CI Placebo 0.88 0.79–0.97 Diuretics 1.13 0.99–1.13 ACE inhibitors/ ARBs 1.00 0.72–1.38 Calcium blockers 1.18 1.08–1.29 Wiysonge CS et al. Cochrane Database Syst Rev 2007;1:CD002003. Relative risk of stroke for beta blockers vs placebo or other treatments Comparative drug RR of stroke for beta blockers 95% CI Placebo 0.80 0.66–0.96 Diuretics 1.17 0.65–2.09 ACE inhibitors/ ARBs 1.30 1.11–1.53 Calcium blockers 1.24 1.11–1.40 Wiysonge CS et al. Cochrane Database Syst Rev 2007;1:CD002003. Relative risk of discontinuing treatment for beta blockers vs placebo or other treatments Comparative drug RR of stopping treatment for beta blockers 95% CI Placebo 2.34 0.84–6.52 Diuretics 1.86 1.39–2.50 ACE inhibitors/ ARBs 1.41 1.29–1.54 Calcium blockers 1.20 0.71–2.04 Wiysonge CS et al. Cochrane Database Syst Rev 2007;1:CD002003.