Transcript No Slide Title - Vanderbilt University Medical Center

Treatment of Hypertension
Nancy J. Brown, M.D.
Division of Clinical Pharmacology
Vanderbilt University Medical Center
Classification of Blood Pressure
for Adults
Category
SBP
DBP
Optimal
<120
and
<80
Normal
High Normal
<130
130-139
and
or
<85
85-89
Hypertension
-Stage 1
-Stage 2
-Stage 3
140-159
160-179
>180
or
or
or
90-99
100-109
>110
When SBP and DBP fall into different categories, use the higher category.
Examples of Identifiable
Causes of Hypertension
Renal Causes
Renovascular disease
• Polycystic kidneys
 Renal parenchymal disease

Endocrine Causes
Pheochromocytoma
 Primary aldosteronism

• Cushing syndrome
• Hyperparathyroidism
Exogenous causes

OTC sympathomimetics, NSAIDs, cocaine,
alcohol, etc.
Treatment Strategies and
Risk Stratification
Blood Pressure
Stages (mm Hg)
Risk Group A
High-normal
(130-139/85-89)
Lifestyle modification
Stage 1
(140-159/90-99)
Lifestyle modification
(up to 12 months)
Stages 2 and 3
(>160/>100)
Risk Group B
Risk Group C
Lifestyle modification
Drug therapy*
Lifestyle modification
Lifestyle modification
Drug therapy
(up to 6 months)** Lifestyle modification
Drug therapy
Drug therapy
Lifestyle modification
Lifestyle modification
Drug therapy
Lifestyle modification
* For those with heart failure, renal insufficiency, or diabetes.
** For those with multiple risk factors, clinicians should consider drugs as initial therapy plus lifestyle modification
Predicting physiology in HTN
patients
Renin-dependent
Volume-dependent
Younger
Older
White
Black
JNC recommendations
b-blockers
diuretics (thiazide-type)
Anti-hypertensive agents
Renin-dependent
Volume-dependent
ACE inhibitors
Diuretics
AT1RA
CCBs
b-blockers
vasodilators
Central-acting
agonists
Age-race subgrouping as
prediction of BP response
Older Blacks
Younger Whites
60
70
60
50
40
30
20
10
0
50
40
30
20
10
A
PL
PR
AZ
DI
LT
H
CT
Z
N
CL
O
N
AT
E
PT
CA
PT
C
A
A
PL
PR
A
Z
A
TE
N
N
C
LO
C
TZ
H
D
IL
T
0
Materson et al NEJM, 1993
What physicians prescribe
1992
1998
b-blockers 18%
11%
Diuretics
16%
8%
ACEI
25%
33%
CCBs
33%
38%
Siegel and Lopez, JAMA, 1997
Thiazide Diuretics
Advantages
• Proven morbidity and mortality benefits
• Effective for many patient groups – esp older, salt-sens
• Reduces edema and heart failure symptoms
• Protects against osteoporosis
• Increases efficacy of other antihypertensives
• Inexpensive
Disadvantages
• Electrolyte imbalances (K+, Mg+,  uric acid)
• Ineffective in advanced renal disease (SrCr > 2.4)
• Adverse effect on lipid profile
Thiazide diuretics and risk of cardiac
arrest
0
 100
1
2
mg thiazide
 50
mg thiazide
 25
mg thiazide
 50
mg thiazide + K-sparing
 25
mg thiazide + K-sparing
Siscovick et al, NEJM, 1994
Systolic Hypertension in the
Elderly (SHEP)
Cumulative risk
stroke/100
10
8
6
*
4
2
0
1
2
3
4
5
6
Years
*chlorthalidone 12.5mg + 12.5mg + atenolol 25 mg
JAMA 1991
% coronary events
MRC
10
8
6
4
2
0
0
1
2
3
4
5
6
7
Years
Placebo
beta-blocker
diuretic
Atenolol
Hctz + amiloride
Loop Diuretics
Similar to thiazides except:
• Less effective in treating hypertension
except…
• Effective in advanced renal disease
• More potent effects on edema
• No osteoporosis benefit
• Wider dosing range (high ceiling)
• May cause ototoxicity
Other Diuretics
Metolazone
• Higher ceiling than other thiazides
• Additive effects with loop diuretics
Triamterene and Amiloride
• Weak diuretics used in combinations
• Maintains serum K+ and Mg+
Spironolactone
• Weak diuretic, often combined with thiazide
• May cause gynecomastia (7-10%)
• Maintains serum K+
• High doses used in liver disease for ascites
• Low doses beneficial in heart failure
• Drug of choice in primary hyperaldosteronism
b- Blockers
Advantages
• Proven morbidity and mortality benefits
• Reduces mortality rate post-MI (non-ISA)
• Benefit in chronic stable angina
• Available generics are inexpensive
Disadvantages
• Bronchospasm in asthmatics
• Potential for excessive bradycardia
• Adverse effects of lipid profile
• Masks symptoms of hypoglycemia
• Relatively high incidence of impotence
ACE Inhibitors
(ACE-I)
Advantages:
• Minimal adversities on quality of life.
• Protects against hypokalemia
• Prevents LV remodeling post-MI
• Protects against diabetic renal insufficiency
• Effective in treating/preventing CHF (decreases LVH)
Disadvantages:
• May induce cough after several weeks (3-30%)
• May induce hyperkalemia (4-5%)
• May cause rash, taste dysgeusia; rare angioedema
• Avoid in renal artery stenosis
• Contraindicated in pregnancy (2nd & 3rd trimesters)
Primary outcomes in HOPE
Ramipril Placebo
Relative Risk
P value
MI, stroke, 653 (14.1) 824 (17.7) 0.78 (0.70-0.86) 0.000001
CV death
CV death 282 (6.1) 375 (8.1) 0.75 (0.64-0.87) 0.0002
MI
460 (9.9) 567 (12.2) 0.80 (0.71-0.91) <0.001
Stroke
157 (3.4) 226 (4.9)
0.69 (0.56-0.84) 0.0002
Non-CV
death
200 (4.3) 193 (4.1)
1.03 (0.84-1.25) 0.78
Any death 482 (10.4) 568 (12.2) 0.84 (0.75-0.95) 0.006
Angiotensin II Receptor Blockers
(ARB)
Advantages
• Similar benefits to ACE-I (CHF, HTN)
• ACE-I cough not observed
• Angioedema extremely rare
Disadvantages
• Contraindicated in pregnancy
• Hyperkalemia possible
• Fewer clinical trials
• Relatively expensive (no generics)
Calcium Channel Blockers
A Diverse Class of Drugs
Dihydropyridines
• Short half-life associated with increased risk of
mortality
• Several sustained-release products are available
• One agent (amlodipine) has a long half-life
• Used following subarachnoid hemorrhage
Diltiazem and Verapamil
• Sustained release products are acceptable
Short acting
Dihydropyridines
• not recommended for use in blood
pressure control due to increased
mortality
Sustained release products
• Procardia XL®, Adalat CC®, Cardene SR®,
Plendil®, DynaCirc CR®, Sular®
• Dosage forms should not be split/crushed
• GI transit limits value with 24 hour dosage forms
One agent with a long half-life is recommended
• Amlodipine
• Crushing/splitting does not affect bioavailability
Side effects of
Dihydropyridines
• Reflex tachycardia
• May precipitate angina
• Peripheral edema
• Dizziness
• Flushing
• Headache
• Gingival hyperplasia (rare)
Rate Lowering
Calcium Antagonists
Verapamil and diltiazem
Advantages
• Rate control in supraventricular tachyarrhythmias
• May be beneficial in hypertrophic cardiomyopathy
Disadvantages
• Negative inotropic effects (may unmask CHF)
• Constipation (particularly with verapamil)
•Significant bradycardia possible in some patients
Antihypertensive drugs to avoid in
patients with a low resting heart rate
• Beta Blocker drugs
• Rate lowering CCB drugs
•
•
•
•
•
•
•
• Diltiazem
• Mibefradil
• Verapamil
Acebutolol
Atenolol
Betaxolol
Metoprolol
Nadolol
Propranolol
Timolol
• Central alpha-2 drugs
• Clonidine
• Methyldopa
CCBs and CAD: summary
 Short-acting
CCBs should not be used.
 Long-acting dihydopyridines are
appropriate in elderly patients who don't
tolerate thiazide diuretics.
 ACEI are drug-of-choice in diabetes
mellitus.
 CCBs should be used like vasodilators in
combination therapy.
1- Receptor Blockers
Prazosin, doxazosin, and terazosin
(tamsulosin not indicated for HTN)
Advantages
• Beneficial in BPH (prostatism)
• Favorable trend in lipid profile
Disadvantages
• Orthostatic hypotension
• First dose syncope
• Increased risk of heart failure in patients on
doxazosin in ALLHAT
www.nhlbi.nih.gov/new/press/mar08-00.htm
JAMA 2000;283:1967-75
Central a2-Agonists
Clonidine, guanabenz, guanfacine, and methyldopa
Advantage
• Lowers heart rate
Disadvantages
• Sedation
• Depression
• Dry mouth
• Clonidine - rebound hypertension
• Methyldopa - autoimmune hepatitis and drug fever
• Relatively high incidence of impotence
Direct Vasodilators
Hydralazine
Advantage
• Useful in CHF (with concurrent ISSDN)
Disadvantages
• Lupus syndrome
• Headache (~10%) and reflex tachycardia
Minoxidil
Advantage
• Most potent oral agent
Disadvantages
• Reflex tachycardia and edema
• (Can precipitate MI due to increased oxygen demand)
• Hirsutism
• Pericardial effusion
JNC and other recommendations
Initial drug choice
Not at goal BP
No response/side effects
Substitute drug from
Opposite arm
Partial response
Add agent from
opposite arm
Not at Goal BP
Combination Rx/ Secondary HTN
Anti-hypertensive agents
Renin-dependent
Volume-dependent
ACE inhibitors
Diuretics
AT1RA
CCBs
b-blockers
vasodilators
Central-acting
agonists
Combination Therapies
• Beta-blockers and diuretics
• ACE inhibitors and diuretics
• Angiotensin II antagonists and diuretics
• Calcium antagonists and ACE inhibitors
• Other combinations



rate-controlling drug (usually β-blocker)
diuretic (loop if minoxidil)
potent vasodilator
Variations
 + ACE I or ARB (to minimize vasodilator)
 + α-blocker (to complement β-blocker)
 + thiazide (to enhance anti-hypertensive effect of
minoxidil)
Think secondary causes:
Hyperaldosteronism in resistant
hypertension
Resistant HTN
3 or more agents
at adequate doses
3 excluded
2 probable renovascular HTN
1 transplant patient
PRA< 1.0 ng/ml/hr and
urine aldosterone >12mg/24 hours
Calhoun et al. Hypertension 2000
Characteristic
PA (n=18)
20%!
Est Htn (n=70)
Age, y
51.2±10.5*
57.91±1.7
Black/White
BMI, kg/M2
SBP, mmHg
DBP, mmHg
10/8
33.8±8.2
158±17.9
92±11.7
34/36
32.18±.2
159±25.8
89±16.9
# anti-htn
K<3.6mEq/L or suppl
PAC, ng/dL
4.2±0.9
13 (72%)†
19.2±10.7†
3.8±0.9
14 (20%)
10.8±7.7
PRA, mg/ml/hr
Ratio
0.3±0.2†
80.6±53.0†
21.0±10.3†
3.2±5.4
22.9±32.8
7.9±4.8
Urine aldosterone mg
Effect of spironolactone in resistant
hypertension
Initial Drug Choices
Compelling Indications
(Based on randomized controlled trials)
• Heart failure
- ACE inhibitors
- Diuretics (spironolactone)
• Myocardial Infarction
- Beta-blockers (non-ISA)
- ACE inhibitors (with systolic dysfunction)
• Diabetes mellitus (type 1) with proteinuria
- ACE inhibitors
• Isolated systolic hypertension (older person)
- Diuretics preferred
- Long-acting DHP calcium antagonists