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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