evidence based treatment of hypertension harleen singh pharm.d., assistant professor ted d. williams...

Evidence Based Treatment of Hypertension

Harleen SinghPharm.D., Assistant Professor

Ted D. WilliamsPharm.D. Candidate

OSU/OHSU College of Pharmacy

P3 Year – Investing in your Education

Objectives1. Describe the epidemiology of hypertension 2. 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.

Objectives11. 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

Objectives11. 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


• While 70% of hypertensives are aware of their condition and 59% are being treated; only 34% are controlled.


Prevalence Doubles From 40s to 60s

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 StrokeVolume

Renin

AT II

Aldosterone

Blood Pressure

PlasmaVolume

Adapted from APhA’s Completed Review for Pharmacy. Gourley, DR. 2004

Pathophysiology of Hypertension

1. Increased Sympathetic Activation2. Excessive vascular volume3. Activation of the Renin Anginotensin

Aldosterone System4. 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

RETINOPATHY

HEART FAILURE

ISCHEMIC HEART

DISEASECEREBROVASCULAR

DISEASE

PERIPHERAL VASCULAR

DISEASE

CHRONIC KIDNEY DISEASE

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


Hypertension and Stroke


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

Primary Prevention

Past Medical History Blood Pressure Goal

Diabetes Melitus

Chronic Kidney Disease

CAD

Left Ventricular Dysfunction

FraminghamRisk Score <140/90 mmHg

<130/80 mmHg

<10%

>10%

<120/80 mmHg

Adapted From Saseen, JJ. Essential Hypertension. Applied Therapeutics: The Clinical Use of Drugs 10 th edition. 2008

CAD Risk Equivalents

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

He, J et. al Long-Term Effects of Weight Loss and Dietary Sodium Reduction on Incidence of Hypertension. Hypertension 2000;35:544-549

Weight Loss p = 0.02 Sodium Reduction p=0.1905

1015202530354045

Comparison of the 7 year cumulative incidence of hyperten-sion between active intervention and control groups for weight

loss and sodium reduction interventions.

ActiveControl

Rat

e(%

) of

Hyp

erte

nsio

n

77% Reduction in HTN Rate

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

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

Loop Diuretics – Mechanism of ActionSympathetic Activation


Cardiac Output

HR StrokeVolume

Renin

AT II

Aldosterone

Blood Pressure

PlasmaVolume

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



Cardiac Output

HR StrokeVolume

Renin

AT II

Aldosterone

Blood Pressure

PlasmaVolume

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



Cardiac Output

HR StrokeVolume

Renin

AT II

Aldosterone

Blood Pressure

PlasmaVolume

Potassium Sparing Diuretics– Mechanism of Action

• Mild Diuretic Effects

• Usually used for synergistics effects

Na↑ K↓

ACE Inhibitors – Mechanism of ActionSympathetic Activation


Cardiac Output

HR StrokeVolume

Renin

AT II

Aldosterone

Blood Pressure

PlasmaVolume

ACE

Angiotensin Receptor Blockers– Mechanism of Action



Cardiac Output

HR StrokeVolume

Renin

AT II

Aldosterone

Blood Pressure

PlasmaVolume

Renin Inhibitors – Mechanism of ActionSympathetic Activation


Cardiac Output

HR StrokeVolume

Renin

AT II

Aldosterone

Blood Pressure

PlasmaVolume

Beta Blockers – Mechanism of ActionSympathetic Activation


Cardiac Output

HR StrokeVolume

Renin

AT II

Aldosterone

Blood Pressure

PlasmaVolume

Non-DHP CCB– Mechanism of ActionSympathetic Activation


Cardiac Output

HR StrokeVolume

Renin

AT II

Aldosterone

Blood Pressure

PlasmaVolume

Alpha Blockers – Mechanism of ActionSympathetic Activation


Cardiac Output

HR StrokeVolume

Renin

AT II

Aldosterone

Blood Pressure

PlasmaVolume

DHP CCB– Mechanism of ActionSympathetic Activation


Cardiac Output

HR StrokeVolume

Renin

AT II

Aldosterone

Blood Pressure

PlasmaVolume

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 (0.91-1.08)

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 (%)


p

6-year rate of heart failure

10.2 7.7 1.38 (1.25-1.52)

<0.001


Secondary outcomes: Lisinopril vs chlorthalidone


End point Lisinopril (%)

Chlorthalidone (%)


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)

<0.001

Wright JT Jr et al. JAMA 2005; 293:1595-1608.

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 <0.001

Nonblacks 1.32 1.17-1.49 <0.001

ALLHAT subgroup analysis: Relative risk of stroke, combined CVD outcomes, and heart failure by race with lisinopril vs

chlorthalidone

Wright JT Jr et al. JAMA 2005; 293:1595-1608.

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

•Black 1.30 1.10-1.54

•Nonblack 1.13 1.00-1.28

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 ConversionsGeneric (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.

All doses are once daily except where noted

ACE Inhibitors – Mechanism of ActionSympathetic Activation


Cardiac Output

HR StrokeVolume

Renin

AT II

Aldosterone

Blood Pressure

PlasmaVolume

ACE

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

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

Angiotensinogen Angiotensin I

ANGIOTENSIN II

ACEOther paths

Vasoconstriction Proliferative Action

Vasodilatation Antiproliferative Action

AT1 AT2

AT1 RECEPTOR BLOCKERS

RECEPTORS

ARB Costs

GENERIC BRAND DOSE COST/YR $

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

NifedipineNicardipine

Verapamil Diltiazem Isradipine Felodipine Amlodipine

Systemic vasodilation

+++ ++ + +++ +++ +++

Coronary vasodilation

+++ ++ +++ +++ +++ +++

Myocardial contractility

↓/0 ↓↓ ↓ ↓/0 0 0

Heart rate ↑ ↓ ↓ ↑/0 ↑ 0

AV node conduction

0 ↓↓ ↓ 0 0 0

Calcium Antagonists CostsGENERIC BRAND DOSE COST/YR

$

diltiazem ER DILTIA XT DILACOR XR

240mg qd257

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

240mg qd 432

nifedipine ER PROCARDIA XL

60mg qd 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

DrugCardiosele

ctivity ISA

Alpha-

Blockers

Water Solubi

lity

Lipid Solubi

lityBioavailability

T ½ (Hour

s)Atenolol + - - + - 50 6-9Nadolol - - - + - 40 17-22Acebutolol

+ + - + + 40 3-6

Pindolol - +++ - + + 90 2-5Metoprolol

+ - - + + 40 3-4

Timolol - - - + + 75 2-5Labetolol - - + - + 40 3-4Propranolol

- - - - + 30 2-5

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 CostsGENERIC 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 CommentsHypertension 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 + ACEIAngina Beta Blockers or CCB Consider adding ACEI to

decrease CVD riskNephropathy (diabetic and nondiabetic)

ACEI ARB if ACEI cough or angioedema

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 orACEI + CCB

ARB can replace ACEI if intolerance to cough or angioedema.

Combination therapy is usually required.

Wiysonge CS et al. Cochrane Database Syst Rev 2007;1:CD002003.

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


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


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


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

evidence based treatment of hypertension harleen singh pharm.d., assistant professor ted d. williams...

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