Transcript Hypertension - Dr Ted Williams

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