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Jessica Schwenk, Pharm.D. September 14, 2013
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Review pharmacologic treatment of hypertension, including drug combinations and management of hypertension with other disease states Discuss updates in the use of antihypertensive drugs Describe medications used for hypertensive urgencies and emergencies
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How many people in the US have hypertension?
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58 to 65 million adults (estimated in 2008) 29-31% of US adults Treatment of hypertension #1 reason for doctor visits (non-pregnant adults) #1 reason for use of prescription drugs
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Definitions Normal blood pressure: systolic <120 mmHg and diastolic <80 mmHg Prehypertension: systolic 120-139 mmHg or diastolic 80-89 mmHg Hypertension: Stage 1: systolic 140-159 mmHg or diastolic 90-99 mmHg Stage 2: systolic ≥160 or diastolic ≥100 mmHg
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Definitions Isolated systolic hypertension: systolic ≥140 mmHg and diastolic <90 mmHg Isolated diastolic hypertension: systolic <140 mmHg and diastolic ≥90 mmHg
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Definitions continued Malignant hypertension: hypertension with retinal hemorrhages, exudates, or papilledema Hypertensive encephalopathy Acute renal failure Hypertensive urgency: Diastolic blood pressure > 120 mmHg without symptoms
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Primary (essential) hypertension Pathogenesis Increased sympathetic neural activity (beta-adrenergic) Increased angiotensin II activity Mineralocorticoid excess Genetics Reduced adult nephron mass
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Risk Factors Ethnicity Genetics Diet Sodium intake Alcohol Obesity Tobacco use Decreased physical activity Hyperlipidemia Age > 65 years Personality Traits Vitamin D Deficiency
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Complications Risk factor for other disease states Heart failure Left ventricular hypertrophy Stroke Intra-cerebral hemorrhage Kidney disease Malignant hypertension
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Treatment benefits Reduce risk of cardiovascular events, kidney disease, eye damage, morbidity and mortality Only 46-51%have blood pressure under control Poor access to healthcare, medications Lack of adherence Side effects, disadvantages of therapy Benefits not obvious to patients
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Lifestyle Modifications Treatment Algorithm Treatment Goal Medication Classes
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Lifestyle Modification ModificationSystolic BP reduction Sodium restriction4.8 mmHg (2.5 mm HG diastolic) Weight loss0.5-2 mmHg per 1 kg weight loss Diet (DASH)2-8 mm Hg Physical activity4-8 mmHg Moderation of alcohol consumption2-4 mmHg
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JNC7 blood pressure goals Generally <140/<90 mmHg Complications or increased risk factors <130/<90 Diabetes Chronic kidney disease
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Medications Monitor Blood pressure Side effects: hypotension, orthostatic hypotension, dizziness
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Chlorthalidone (generic) 12.5-25 mg daily Hydrochlorothiazide (Microzide, HydroDIURIL) 12.5-50 mg daily Indapamide (Lozol) 1.25-2.5 mg daily Metolazone (Zaroxolyn) 2.5-5 mg daily
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Side effects Hypokalemia Hypomagnesemia Hypercalcemia Hyperuricemia Hyperglycemia Hyperlipidemia Sexual dysfunction Monitoring Fluid status Electrolytes Renal function Loses efficacy with ClCr < 40 mL/min Dose-related side effects Limiting dose to chlorthalidone or HCTZ 25- 50 mg greatly reduces risk of metabolic side effects
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Bumetanide (Bumex) 0.5-2 mg daily-BID Furosemide (Lasix) 20-80 mg daily-BID Torsemide (Demadex) 2.5-10 mg daily
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Side Effects Hypokalemia Hypomagnesemia Hypocalcemia Hyperuricemia Sexual dysfunction Monitoring Fluid status Weight loss/gain Electrolytes Usually need electrolyte supplementation Renal function Hearing (high doses)
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Amiloride (Midamor) 5-10 mg daily-BID Triamterene (Dyrenium) 50-100 mg daily-BID Eplerenone (Inspra) 50-100 mg daily Spironolactone (Aldactone) 25-50 mg daily
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Side effects Similar to thiazide diuretics: hypomagnesemia, hypercalcemia, hyperuricemia, sexual dysfunction Hyperkalemia Especially eplerenone (contraindicated in impaired renal function or DM II with proteinuria) Gynecomastia (10% with spironolactone) Monitoring Electrolytes, fluid status, renal function
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Benazepril (Lotensin) 10-40 mg daily Captopril (Capoten) 25-100 mg BID Enalapril (Vasotec) 5-40 mg daily-BID Fosinopril (Monopril) 10-40 mg daily Lisinopril (Prinivil, Zestril) 10-40 mg daily Moexipril (Univasc) 7.5-30 mg daily Perindopril (Aceon) 4-8 mg daily Quinapril (Accupril) 10-80 mg daily Ramipril (Altace) 2.5-20 mg daily Trandolapril (Mavik) 1-4 mg daily
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Side effects Hyperkalemia Dry cough (20%) Increased serum creatinine/kidney insufficiency Angioedema (2%) Rare (<1%) Neutropenia and agranulocytosis, proteinuria, glomerulonephritis, acute kidney failure Monitoring: potassium, kidney function Absolute contraindication in pregnancy
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Candesartan (Atacand) 8-32 mg daily Eprosartan (Teveten) 400-800 mg daily-BID Irbesartan (Avapro) 150-300 mg daily Losartan (Cozaar) 25-100 mg daily-BID Olmesartan (Benicar) 20-40 mg daily Telmisartan (Micardis) 20-80 mg daily Valsartan (Diovan) 80-320 mg daily-BID
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Side effects Hyperkalemia Increased serum creatinine/kidney insufficiency Possible angioedema (cross-reactivity with ACEIs reported) No bradykinin-induced dry cough Monitoring: potassium, kidney function Should not be used in pregnancy
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Non-Dihydropyridines Diltiazem Extended release (Cardizem CD, Dilacor XR, Tiazac) 180- 420 mg daily Extended release (Cardizem LA) 120-540 mg dialy Verapamil Immediate release (Calan, Isoptin † ) 80-320 mg BID Long acting (Calan SR, Isoptin SR † ) 120-480 mg daily-BID, (Coer, Covera HS, Verelan PM) 120-360 mg daily
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Dihydropyridines Amlodipine (Norvasc) 2.5-10 mg daily Felodipine (Plendil) 2.5-20 mg daily Isradipine (Dynacirc CR) 2.5-10 mg daily Nicardipine sustained release (Cardene SR) 60-120 mg BID Nifedipine long-acting (Adalat CC, Procardia XL) 30-60 mg daily Nisoldipine (Sular) 10-40 mg daily
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Side effects Flushing, headache, gingival hyperplasia, peripheral edema Non-dihydropyridines: bradycardia, AV block (high doses), heart failure, anorexia Precautions/Contraindications Contraindicated in heart failure Multiple drug interactions due to CYP450 3A4 inhibition Combination of non-dihydropyridine with beta blocker increases chance of heart block
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Beta-1 selective (cardioselective) Atenolol (Tenormin) 25-100 mg daily Metoprolol (Lopressor, Toprol XL) 50-100 mg daily-BID Betaxolol (Kerlone) 5-10 mg daily Bisaprolol (Zebeta) 2.5-20 mg daily Non-selective Nadolol (Corgard) 40-120 mg daily Propranolol (Inderal, Inderal LA) 40-160 mg BID (60-180 mg daily for LA) Timolol (Blocadren) 20-40 mg BID
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Intrinsic sympathomimetic activity Acebutolol (Sectral) 200-800 mg BID Penbutolol (Levatol) 10-40 mg daily Pindolol (generic) 10-40 mg BID Combined alpha-1 and beta blockers Carvedilol (Coreg) 12.5-50 mg BID Labetalol (Normodyne, Trandate † ) 200-800 mg BID Nebivolol (Bystolic) 5-40 mg daily
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Side effects Bradycardia, heart block, heart failure Monitoring: HR Increased blood glucose Sexual dysfunction (impotence) Abrupt cessation: rebound hypertension, unstable angina/myocardial infarction Specific groups More CNS effects (dizziness/drowsiness ) with more lipophylic agents (propranolol) Non-selective agents: β2-receptor activation, bronchospasm Non-ISA agents: increased triglycerides
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Doxazosin (Cardura) 1-16 mg daily Prazosin (Minipress) 2-20 mg BID-TID Terazosin (Hytrin) 1-20 mg daily-BID Side effects 1 st dose phenomenon: dizziness, palpitations, syncope Orthostatic hypotension CNS effects: vivid dreams, depression Sodium and water retention
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Clonidine (Catapres) 0.1-0.8 mg BID Clonidine patch (Catapres-TTS) 0.1-0.3 weekly Clonidine (Catapres) 0.1-0.8 mg BID Methyldopa (Aldomet † ) 250-1,000 mg BID Reserpine (generic) 0.1-0.25 mg daily Guanfacine (Tenex † ) 0.5-2 mg daily
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Side effects Sodium and water retention Orthostatic hypotension CNS side effects: depression Anticholinergic: dry mouth, sedation, constipation, urinary retention, blurred vision Reserpine: parasympathetic activity (increased secretions, bradycardia) Abrupt cessation: rebound hypertension Clonidine often used for resistant hypertension Methyldopa is a first-line agent in pregnancy
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Hydralazine (Apresoline) 25-100 mg BID Minoxidil (Loniten) 2.5-80 mg daily-BID Side effects Sodium and water retention Tachyphylaxis (use with beta blocker) Hydralazine Lupus-like syndrome, dermatitis, drug fever, peripheral neuropathy, hepatitis, vascular HA Minoxidil Hypertrichosis (hirsutism of face, arms, back, chest), pericardial effusion, nonspecific T-wave change
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Treatment of hypertension with concurrent disease states or compelling indications Choice of medication for hypertension Treatment of hypertensive urgency & emergency New Recommendations
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Stable angina Beta blocker, or CCB Acute coronary syndrome Beta blocker (without ISA), ACEI Post-MI Beta blocker, ACEI, aldosterone antagonist
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Asymptomatic heart failure ACEI (or ARB), beta blocker Symptomatic ventricular dysfunction or end- stage heart disease Beta blocker, ACEI or ARB, aldosterone antagonist, loop diuretic
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ACEI or ARB Reduce diabetic nephropathy and albuminuria ARBs reduce progression to macroalbuminuria Thiazide diuretics, BBs, ACEIs, ARBs, and CCBs Prevent CVD and stroke incidence Caution with beta blockers Mask signs of hypoglycemia
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ACEI or ARB Slow progression of renal disease Limited rise in Scr acceptable (up to 35% increase) Advanced CKD Loop diuretics (volume control) Thiazide diuretics lose efficacy with ClCr < 40
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Combination of thiazide diuretic and ACEI Reduce recurrent stroke rate
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All classes of antihypertensive agents except the direct vasodilators hydralazine and minoxidil Regression of LVH Severe hypertension with ECG evidence of LVH ARB Only indication where ARB has proven benefit over ACEI
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African-American Monotherapy: thiazide diuretic or CCB Reduced BP responses with BBs, ACEIs, or ARBs Caution: ACEI-induced angioedema occurs 2–4 times more frequently Heart failure Hydralazine/Isosorbide dinitrate (Bidil)
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Follow same principles of therapy Start at lower doses, increase more slowly Avoid side effects Classes to avoid Alpha-1 blockers, alpha-2 agonists, centrally acting agents, direct vasodilators Treatment of HTN may slow progression of cognitive impairment and dementia
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Preferred agents Methyldopa, beta blockers, and vasodilators Contraindicated: ACEIs and ARBs
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Atrial tachyarrythmias/fibrillation Beta blockers or calcium channel blockers (rate control) Migraine, tremor Beta blockers BPH Alpha-1 blockers Asthma, reactive airway disease, second or third degree heart block Avoid beta-blockers (especially non-selective) Gout, hyponatremia Avoid thiazide diuretics Hyperkalemia Avoid potassium-sparing diuretics, aldosterone antagonists
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First line options Thiazide diuretic Calcium channel blocker (long acting) ACEI or ARB If treatment with second medication likely (ACCOMPLISH trial) Calcium channel blocker (long acting) ACEI or ARB
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Hypertensive urgency Severe hypertension: SBP ≥180 mmHg and/or DBP ≥120 mmHg Asymptomatic (other than headache) No evidence of acute end-organ damage Hypertensive emergency Malignant hypertension Marked hypertension with retinal hemorrhages, exudates, or papilledema Hypertensive encephalopathy Acute renal failure (malignant nephrosclerosis)
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Treatment Goal: gradual reduction of BP to < 160/100 Previously: rapid reduction of BP, but no proven benefit Cerebral or myocardial ischemia or infarction can be induced Sublingual nifedipine now contraindicated
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Treatment: oral medications Previously treated HTN Increase dose of existing medication or add new medications Previously untreated HTN Furosemide 20 mg PO(or higher if renal insufficiency) Clonidine 0.2 mg PO Captopril 6.25-12.5 mg PO Monitor until BP decreases 20-30 mmHg (or < 160/100) Prescribe longer acting agent(s), follow-up with provider
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Goal: rapidly reduce DBP to 100-105 mmHg in 2-6 hours (25% reduction) Treatment: IV medications Nitroprusside (Nitropress) Arteriolar and venous dilator IV infusion 0.25-0.5 mcg/kg/min Max 8-10 mcg/kg /min. Onset: seconds. Duration of action: 2-5 minutes Cyanide toxicity possible with prolonged use Nicardipine IV infusion 5 mg/hr; max 15 mg/hr
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Treatment: IV medications Clevidipine Dihydropyridine calcium channel blocker IV infusion 1 mg/hr; max 21 mg/hr Labetalol IV bolus 20 mg initially, followed by 20-80 mg every 10 min Infusion: 0.5-2 mg/min Max dose 300 mg in 24 hours Fenoldopam Peripheral dopamine-1 receptor agonist, IV infusion 0.1 mcg/kg/min, titrate as needed every 15 minutes
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Treatment: oral medications Not recommended unless IV meds not available Uncontrolled hypotensive response Sublingual nifedipine 10 mg Sublingual captopril 25 mg Monitoring When BP controlled, switch to oral therapy Decrease DBP to 85-90 mmHg over 2-3 months
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Chlorthalidone preferred over HCTZ More potent Longer acting Potential lower risk of cardiovascular events Beta blockers should NOT be used as 1 st line therapy In absence of compelling indications Especially for patient’s > 60 years old Higher SBP goals may be more appropriate Elderly: <150/<60 Diabetes: SBP < 130 may not improve CV risk
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Chobanian AV, Bakris GL, Black HR et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42(6):1206-52. Cupp M. Antihypertensives. Pharmacist’s Letter 2013; 29(4):290401. [Electronic version]. Available at: http://www.pharmacistsletter.com. Accessed April 14, 2013. DRUGDEX® System [Internet database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically. Kaplan NM. Malignant hypertension and hypertensive encephalopathy in adults. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2013. Kaplan NM, Domino FJ. Overview of hypertension in adults. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2013. Lacy CF, Armstrong LL, Goldman MP, Lance LL. Lexi-Comp’s Drug Information Handbook. 17th ed. Hudson (OH): Lexi-Comp;2008. Saseen JJ, Carter BL. Hypertension. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, editors. Pharmacotherapy. A Pathophysiologic Approach. 6th ed. New York (NY): McGraw Hill;2005:185-218. Systematic Evidence Reviews in Development: Cardiovascular Disease Risk Reduction in Adults (June 2013). National Institutes of Health Web site. Available at: http://www.nhlbi.nih.gov/guidelines/indevelop.htm#status. Accessed August 14, 2013.
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