Treatment of HypertensionTreatment of Hypertension
Nancy J. Brown, M.D.
Division of Clinical Pharmacology
Vanderbilt University Medical Center
Classification of Blood Pressure Classification of Blood Pressure for Adultsfor Adults
Category SBP DBP
Optimal <120 and <80
Normal <130 and <85
High Normal 130-139 or 85-89
Hypertension -Stage 1 140-159 or 90-99-Stage 2 160-179 or 100-109-Stage 3 >180 or >110
When SBP and DBP fall into different categories, use the higher category.
Examples of Identifiable Examples of Identifiable Causes of HypertensionCauses of Hypertension
Renal Causes Renovascular disease • Polycystic kidneys Renal parenchymal disease
Endocrine Causes Pheochromocytoma • Cushing syndrome Primary aldosteronism •
Hyperparathyroidism
Exogenous causesOTC sympathomimetics, NSAIDs, cocaine,
alcohol, etc.
Treatment Strategies andTreatment Strategies andRisk StratificationRisk Stratification
Blood PressureStages (mm Hg) Risk Group A Risk Group B Risk Group C
High-normal Lifestyle modification Lifestyle modification Drug therapy* (130-139/85-89) Lifestyle modification
Stage 1 Lifestyle modification Lifestyle modification Drug therapy (140-159/90-99) (up to 12 months) (up to 6 months)** Lifestyle modification
Stages 2 and 3 Drug therapy Drug therapy Drug therapy(>160/>100) Lifestyle modification Lifestyle modification 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 Predicting physiology in HTN patientspatients
Renin-dependent Volume-dependent
Younger Older
White Black
JNC recommendationsJNC recommendations
blockers
diuretics (thiazide-type)
Anti-hypertensive agentsAnti-hypertensive agents
Renin-dependent Volume-dependent
ACE inhibitors Diuretics
AT1RA CCBs
-blockers vasodilators
Central-acting agonists
Age-race subgrouping as Age-race subgrouping as prediction of BP responseprediction of BP response
0
10
20
3040
50
60
70
DILT
HCTZ
CLON
PRAZ
ATENPLA
CAPT0
10
20
30
40
50
60
Older Blacks Younger Whites
Materson et al NEJM, 1993
What physicians prescribeWhat physicians prescribe
1992 1998
-blockers 18% 11%
Diuretics 16% 8%
ACEI 25% 33%
CCBs 33% 38%
Siegel and Lopez, JAMA, 1997
Thiazide DiureticsThiazide DiureticsAdvantages
• 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 Thiazide diuretics and risk of cardiac arrestarrest
100 mg thiazide
50 mg thiazide
25 mg thiazide
50 mg thiazide + K-sparing
25 mg thiazide + K-sparing
Siscovick et al, NEJM, 1994
0 1 2
Systolic Hypertension in the Systolic Hypertension in the Elderly (SHEP) Elderly (SHEP)
0
2
4
6
8
10
1 2 3 4 5 6
Years
Cum
ulat
ive
risk
st
roke
/100
*
*chlorthalidone 12.5mg + 12.5mg + atenolol 25 mg
JAMA 1991
MRCMRC
0
2
4
6
8
10
0 1 2 3 4 5 6 7
Years
% c
oron
ary
even
ts
Placebo beta-blocker diuretic
Atenolol Hctz + amiloride
Loop DiureticsLoop 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 DiureticsOther DiureticsMetolazone
• Higher ceiling than other thiazides• Additive effects with loop diuretics
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
• Weak diuretics used in combinations• Maintains serum K+ and Mg+
Triamterene and Amiloride
- Blockers- BlockersAdvantages
• 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 Inhibitors (ACE-I)(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 HOPEPrimary outcomes in HOPE
Ramipril Placebo Relative Risk P value
MI, stroke, CV death
653 (14.1) 824 (17.7) 0.78 (0.70-0.86) 0.000001
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 BlockersAngiotensin II Receptor Blockers(ARB)(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 BlockersA 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
DihydropyridinesDihydropyridinesShort acting
• 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 Side effects of DihydropyridinesDihydropyridines
• Reflex tachycardia• May precipitate angina• Peripheral edema• Dizziness • Flushing• Headache • Gingival hyperplasia (rare)
Rate LoweringRate Lowering Calcium Antagonists 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 Antihypertensive drugs to avoid in
patients with a low resting heart ratepatients with a low resting heart rate • Beta Blocker drugs• Acebutolol• Atenolol• Betaxolol• Metoprolol• Nadolol• Propranolol• Timolol
• Rate lowering CCB drugs• Diltiazem• Mibefradil• Verapamil
• Central alpha-2 drugs• Clonidine• Methyldopa
CCBs and CAD: summaryCCBs 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.
11- Receptor Blockers- Receptor Blockers
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
Prazosin, doxazosin, and terazosin(tamsulosin not indicated for HTN)
www.nhlbi.nih.gov/new/press/mar08-00.htm JAMA 2000;283:1967-75
Central Central aa22-Agonists-AgonistsClonidine, guanabenz, guanfacine, and methyldopaAdvantage
• Lowers heart rate
Disadvantages• Sedation• Depression• Dry mouth• Clonidine - rebound hypertension• Methyldopa - autoimmune hepatitis and drug fever• Relatively high incidence of impotence
Direct VasodilatorsDirect VasodilatorsHydralazine
Advantage• Useful in CHF (with concurrent ISSDN)
Disadvantages• Lupus syndrome• Headache (~10%) and reflex tachycardia
MinoxidilAdvantage
• Most potent oral agentDisadvantages
• Reflex tachycardia and edema• (Can precipitate MI due to increased oxygen demand)• Hirsutism• Pericardial effusion
JNC and other recommendationsJNC and other recommendations
Initial drug choice
Not at goal BP
No response/side effects Partial response
Substitute drug from Opposite arm
Add agent fromopposite arm
Not at Goal BP
Combination Rx/ Secondary HTN
Anti-hypertensive agentsAnti-hypertensive agents
Renin-dependent Volume-dependent
ACE inhibitors Diuretics
AT1RA CCBs
-blockers vasodilators
Central-acting agonists
Combination TherapiesCombination 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: Think secondary causes: Hyperaldosteronism in resistant Hyperaldosteronism in resistant hypertensionhypertension
Resistant HTN3 or more agents at adequate doses
PRA< 1.0 ng/ml/hr andurine aldosterone >12g/24 hours
3 excluded 2 probable renovascular HTN
1 transplant patient
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 10/8 34/36
BMI, kg/M2 33.8±8.2 32.18±.2
SBP, mmHg 158±17.9 159±25.8
DBP, mmHg 92±11.7 89±16.9
# anti-htn 4.2±0.9 3.8±0.9
K<3.6mEq/L or suppl 13 (72%)† 14 (20%)
PAC, ng/dL 19.2±10.7† 10.8±7.7
PRA, mg/ml/hr 0.3±0.2† 3.2±5.4
Ratio 80.6±53.0† 22.9±32.8
Urine aldosterone g 21.0±10.3† 7.9±4.8
Effect of spironolactone in resistant Effect of spironolactone in resistant hypertensionhypertension
Initial Drug ChoicesInitial 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