Transcript Antihypertensive Drug Update

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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How many people in the US have hypertension?
 58 to 65 million adults (estimated in 2008)
 29-31% of US adults
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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
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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
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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
Lifestyle Modifications
Treatment Algorithm
Treatment Goal
Medication Classes
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Lifestyle Modification
Modification
Systolic BP reduction
Sodium restriction
4.8 mmHg
(2.5 mm HG diastolic)
Weight loss
0.5-2 mmHg
per 1 kg weight loss
Diet (DASH)
2-8 mm Hg
Physical activity
4-8 mmHg
Moderation of alcohol consumption
2-4 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
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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 2550 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
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Hypokalemia
Hypomagnesemia
Hypocalcemia
Hyperuricemia
Sexual dysfunction
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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)
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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
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Hyperkalemia
Dry cough (20%)
Increased serum creatinine/kidney insufficiency
Angioedema (2%)
Rare (<1%)
 Neutropenia and agranulocytosis, proteinuria,
glomerulonephritis, acute kidney failure
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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
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Monitoring: potassium, kidney function
Should not be used in pregnancy
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Non-Dihydropyridines
 Diltiazem
 Extended release (Cardizem CD, Dilacor XR, Tiazac) 180420 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
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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
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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)
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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
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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
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Side effects
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1st 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
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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
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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)
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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
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Side effects
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 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
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
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Acute coronary syndrome
 Beta blocker (without ISA), ACEI
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Post-MI
 Beta blocker, ACEI, aldosterone antagonist
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Asymptomatic heart failure
 ACEI (or ARB), beta blocker
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Symptomatic ventricular dysfunction or endstage 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
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Thiazide diuretics, BBs, ACEIs, ARBs, and CCBs
 Prevent CVD and stroke incidence
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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)
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Advanced CKD
 Loop diuretics (volume control)
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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
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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
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Classes to avoid
 Alpha-1 blockers, alpha-2 agonists, centrally acting
agents, direct vasodilators
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Treatment of HTN may slow progression of
cognitive impairment and dementia
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Preferred agents
 Methyldopa, beta blockers, and vasodilators
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Contraindicated:
 ACEIs and ARBs
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Atrial tachyarrythmias/fibrillation
 Beta blockers or calcium channel blockers (rate control)
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Migraine, tremor
 Beta blockers
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BPH
 Alpha-1 blockers
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Asthma, reactive airway disease, second or third degree heart
block
 Avoid beta-blockers (especially non-selective)
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Gout, hyponatremia
 Avoid thiazide diuretics
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Hyperkalemia
 Avoid potassium-sparing diuretics, aldosterone antagonists
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First line options
 Thiazide diuretic
 Calcium channel blocker (long acting)
 ACEI or ARB
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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
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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
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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
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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
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Beta blockers should NOT be used as 1st line therapy
 In absence of compelling indications
 Especially for patient’s > 60 years old
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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.