Treatment of Hypertension Nancy J. Brown, M.D. Division of Clinical Pharmacology Vanderbilt University Medical Center.

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