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 Describe the epidemiology of hypertension Identify various physiologic systems that can contribute to the development of elevated blood pressure. Identify the complications of untreated hypertension. Describe the classification of blood pressure in adults. Identify appropriate blood pressure goals for patients with hypertension. Know the disease states and other factors that increase the risk of cardiovascular complications for a patient with hypertension. Be able to identify secondary causes of hypertension, including drugs. Summarize our current knowledge on the relative effectiveness of antihypertensive therapy in preventing complications of hypertension. Describe the role of non-pharmacologic management of hypertension and various lifestyle changes that can be recommended. Describe when drug therapy for hypertension is indicated.

Objectives Be able to articulate the advantages, disadvantages, effectiveness as monotherapy, side effects, contraindications, relative cost, and monitoring parameters for the following classes of antihypertensives: Diuretics (Loop, Thiazide, Potassium Sparing) Beta-blockers Angiotensin-converting enzyme (ACE) inhibitors Calcium blockers Centrally-acting sympatholytics Peripheral sympatholytics and arteriolar dilators Alpha blockers Angiotensin receptor blockers (ARBs) Direct rennin inhibitors

Objectives Describe differences among various agents in the same antihypertensive class. Identify antihypertensives that should not be abruptly discontinued. 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). Identify factors that can lead to a poor response to antihypertensive therapy. Describe the factors that can influence compliance with antihypertensive therapy. 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 Clinical 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 Peripheral Resistance Cardiac Output HR Stroke Volume Renin AT II Aldosterone Blood Pressure Plasma Adapted from APhA’s Completed Review for Pharmacy. Gourley, DR. 2004

Pathophysiology of Hypertension Increased Sympathetic Activation Excessive vascular volume Activation of the Renin Anginotensin Aldosterone System 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 Chronic Kidney Disease Peripheral Vascular Disease Retinopathy HTN Whenever working with a patient, check for signs of end organ damage (e.g. Retinopathy, Heart sounds, Chest Pain, unilateral weakness, Edema, increased urniation) Run baseline labs (Chem 7, EKG, Lipid Panel, Uric Acid) Ischemic Heart Disease Cerebrovascular Disease Heart Failure

Hypertension as a Risk Factor Hypertension is a primary risk factor for multiple co-morbidities 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 A sustained 12mmHg reduction over 10 years prevents 1 death for 11 patients treated (Haxby Lecture) Benefits of HTN treatment are so profound and well documented, no large placebo control trials have been done in over 10 years, as it is viewed as unethical (Saseen, JJ. Essential Hypertension. Applied Therapeutics: The Clinical Use of Drugs 10th edition. 2008) 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 Blood Pressure Goal Framingham Risk Score <10% Primary Prevention <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 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) Pharmacotherapy 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 77% Reduction in HTN Rate 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 meta-analysis 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 5-15 years, the rate approaches that of a never smoker Annual Smoking Related Deaths 1995-1999 from Center for Disease Control and Prevention Data from Dr Haxby’s Spring Smoking Lecture

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)18:2330-2335 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 Peripheral Resistance Cardiac Output Blood Pressure 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 Peripheral Resistance Cardiac Output Blood Pressure 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 Peripheral Resistance Cardiac Output Blood Pressure 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 Peripheral Resistance Cardiac Output Blood Pressure ACEI do not completely block conversion of AT-1 to AT-2 Aldosterone HR Stroke Volume Plasma Volume AT II ACE Renin

Angiotensin Receptor Blockers– Mechanism of Action Sympathetic Activation Peripheral Resistance Cardiac Output Blood Pressure Aldosterone HR Stroke Volume Plasma Volume AT II Renin

Renin Inhibitors – Mechanism of Action Sympathetic Activation Peripheral Resistance Cardiac Output Blood Pressure 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 Peripheral Resistance Cardiac Output Blood Pressure Aldosterone HR Stroke Volume Plasma Volume AT II Renin

Non-DHP CCB– Mechanism of Action Sympathetic Activation Peripheral Resistance Cardiac Output Blood Pressure 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 Peripheral Resistance Cardiac Output Blood Pressure Aldosterone HR Stroke Volume Plasma Volume AT II Renin

DHP CCB– Mechanism of Action Sympathetic Activation Peripheral Resistance Cardiac Output Blood Pressure 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 Surrogate end points are frequently used in studies and marketing, but are not substitutes for studies of clinical outcomes (stroke, MI, etc.). Examples of surrogate endpoints include:

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. In general, the strongest predictor of reduced complications is control of BP (Lancet 2003;363:1527-35). The greatest absolute benefit is in patients at highest risk. For patients with stage 1 hypertension and additional CVD risk factors, a sustained 12 mmHg reduction in SBP for 10 years prevents 1 death for every 11 treated The NNT is 9 for patients with target organ damage

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 (0.91-1.08) 0.81 Amlodipine 11.3 0.98 (0.90-1.07) 0.65 ALLHAT Cooperative Research Group. JAMA 2002; 288:2981-2997

Secondary outcomes: Amlodipine vs chlorthalidone End point Amlodipine (%) Chlorthalidone (%) Relative risk (95% CI) p 6-year rate of heart failure 10.2 7.7 1.38 (1.25-1.52) <0.001 ALLHAT Cooperative Research Group. JAMA 2002; 288:2981-2997

Secondary outcomes: Lisinopril vs chlorthalidone End point Lisinopril (%) Chlorthalidone (%) Relative risk (95% CI) p 6-year rate of combined CVD 33.3 30.9 1.10 (1.05-1.16) <0.001 6-year rate of stroke 6.3 5.6 1.15 (1.02-1.30) 0.02 6-year rate of heart failure 8.7 7.7 1.19 (1.07-1.31) The incidence of combined CVD was higher with lisinopril VS CH and the incidence of stroke 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 risk 95% CI p Overall 1.37 1.24-1.51 <0.001 Blacks 1.46 1.24-1.73 Nonblacks 1.32 1.17-1.49 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 risk 95% CI Stroke   Black participants 1.40 1.17-1.68 Nonblack participants 1.00 0.85-1.17 Combined CVD Black 1.19 1.09-1.30 Nonblack 1.06 1.00-1.13 Heart failure 1.30 1.10-1.54 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 Not an optimal choice in patients with gout. Caution is warranted with ventricular arrhythmias, and careful monitoring is required. Metabolic abnormalities directly related to dose. With low dose diuretics about <25 % patient sdevelop Hypokalemia

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 Start low Metabolic abnormalities not at lower doses DM and gout not contrindications Do

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 QD ‡ Typical oral dose for use in Hypertension. Other indications may have differing doses. Produgs , bezapril lis, enalapril ramiprol renally Mixed All doses are once daily except where noted

ACE Inhibitors – Mechanism of Action Sympathetic Activation Peripheral Resistance Cardiac Output Blood Pressure Aldosterone HR Stroke Volume Plasma Volume AT II ACE Renin

ACE Inhibitors – Side Effects Hypotension Cough: 5-20% of patients develop a dry non-productive Angioedema 1% in general population 4% in African Americans Also less effective in African American as monotherapy Hyperkalemia Bradikinin >30 % jump Firstt dose response to an ACEI , OH , diziness, syncope . The incresed pre activity of RAAS and then coupled with acute block Concurrant diuretic therap Conceptt of stopping HCTZ or reducing th edose of HCTZ unnecessary, unless th epatient I shemodynamically unstable or elderly Renal artery stenosis

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 Angiotensin I ANGIOTENSIN II MECHANISM OF ACTION RENIN Angiotensinogen Angiotensin I ANGIOTENSIN II ACE Other paths AT1 RECEPTOR BLOCKERS Treatment of congestive heart failure. Angiotensin II inhibitors Angiotensin II has different effects mediated via specific receptors. There are two types of tissue receptors for angiotensin: AT1 and AT2. Stimulation of AT1 receptors has a proliferative and vasoconstrictor effect, while stimulation of AT2 receptors has the opposite effects, that is, vasodilatory and antiproliferative. In the treatment of heart failure, specific blockade of the AT1 receptors is desirable. Drugs which create a selective and competitive block of the AT1 receptors include:losartan, valsartan, irbersartan and candersartan. RECEPTORS AT1 AT2 Vasoconstriction Proliferative Action Vasodilatation Antiproliferative Action

ARB Costs GENERIC BRAND DOSE COST/Y R $ Telmisarten MICARDIS 40mg qd 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 Systemic vasodilation +++ ++ + Coronary vasodilation Myocardial contractility ↓/0 ↓↓ ↓ Heart rate ↑ ↑/0 AV node conduction

Calcium Antagonists Costs GENERIC BRAND DOSE COST/YR $ diltiazem ER DILTIA XT DILACOR XR 240mg qd 257 verapamil SR CALAN SR 142 verapamil ER COVERA HS 268 Nifedipine ER ADALAT CC 60mg qd 563 felodipine ER PLENDIL 5mg qd 312 amlodipine NORVASC 110 CARDIZEM CD 432 nifedipine ER PROCARDIA XL 545

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 Drug Cardioselectivity ISA Alpha-Blockers Water Solubility Lipid Solubility Bioavailability T ½ (Hours) Atenolol + - 50 6-9 Nadolol 40 17-22 Acebutolol 3-6 Pindolol +++ 90 2-5 Metoprolol 3-4 Timolol 75 Labetolol Propranolol 30 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 $ atenolol TENORMIN 50mg qd 46 propranolol INDERAL 80mg bid 76 metoprolol LOPRESSOR 50mg bid 59 pindolol VISKIN 10mg bid 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 First Choice Alternate Comments Hypertension without compelling indication Low dose chlorthalidone or HCTZ or Amlodipine or ACEI 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 ACEI not recommended for initial therapy but can be used as add on therapy Isolated systolic hypertension Low dose chlorthalidone or HCTZ or amlodipine ARB Beta-blockers are not recommended for initial therapy CHF ACEI + beta-blockers +/- spironolactone (severe CHF) ARB if ACEI cough or angioedema Diuretics usually needed as additive therapy Prior MI Beta-blockers + ACEI Angina Beta Blockers or CCB Consider adding ACEI to decrease CVD risk Nephropathy (diabetic and nondiabetic) ACEI Diuretics often needed as additive therapy. Goal BP < 130/80 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. Combination therapy often required. Goal BP < 130/80. Some guidelines recommend ACEI Post-stroke Thiazide + ACEI Not much data to guide selection of alternative regimens Stage 2 hypertension Thiazide + ACEI or ACEI + CCB ARB can replace ACEI if intolerance to cough or angioedema. 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.