jessica schwenk pharm d september 14 2013
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Jessica Schwenk, Pharm.D. September 14, 2013. Antihypertensive Drug Update. Objectives. Review pharmacologic treatment of hypertension, including drug combinations and management of hypertension with other disease states Discuss updates in the use of antihypertensive drugs

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objectives
Objectives
  • 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
review of hypertension1
Review of Hypertension
  • How many people in the US have hypertension?
review of hypertension2
Review of Hypertension
  • How many people in the US have hypertension?
    • 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
review of hypertension3
Review of Hypertension
  • 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
review of hypertension4
Review of Hypertension
  • Definitions
    • Isolated systolic hypertension: systolic ≥140 mmHg and diastolic <90 mmHg
    • Isolated diastolic hypertension: systolic <140 mmHg and diastolic ≥90 mmHg
review of hypertension5
Review of Hypertension
  • 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
review of hypertension6
Review of Hypertension
  • Primary (essential) hypertension
    • Pathogenesis 
      • Increased sympathetic neural activity (beta-adrenergic)
      • Increased angiotensin II activity
        • Mineralocorticoid excess
      • Genetics
        • Reduced adult nephron mass
review of hypertension7
Review of Hypertension
  • Risk Factors
    • Ethnicity
    • Genetics
    • Diet
      • Sodium intake
      • Alcohol
    • Obesity
    • Tobacco use
  • Decreased physical activity
  • Hyperlipidemia
  • Age > 65 years
  • Personality Traits
  • Vitamin D Deficiency
review of hypertension8
Review of Hypertension
  • Complications
    • Risk factor for other disease states
      • Heart failure
      • Left ventricular hypertrophy
      • Stroke
      • Intra-cerebral hemorrhage
      • Kidney disease
      • Malignant hypertension
review of hypertension9
Review of Hypertension
  • 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
treatment of hypertension
Treatment of Hypertension

Lifestyle Modifications

Treatment Algorithm

Treatment Goal

Medication Classes

treatment of hypertension1
Treatment of Hypertension
  • Lifestyle Modification
treatment goal
Treatment Goal
  • JNC7 blood pressure goals
    • Generally <140/<90 mmHg
    • Complications or increased risk factors <130/<90
      • Diabetes
      • Chronic kidney disease
treatment of hypertension2
Treatment of Hypertension
  • Medications
    • Monitor
      • Blood pressure
      • Side effects: hypotension, orthostatic hypotension, dizziness
thiazide diuretics
Thiazide Diuretics
  • 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
thiazide diuretics1
Thiazide Diuretics
  • 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
loop diuretics
Loop Diuretics
  • Bumetanide (Bumex) 0.5-2 mg daily-BID
  • Furosemide (Lasix) 20-80 mg daily-BID
  • Torsemide (Demadex) 2.5-10 mg daily
loop diuretics1
Loop Diuretics
  • Side Effects
    • Hypokalemia
    • Hypomagnesemia
    • Hypocalcemia
    • Hyperuricemia
    • Sexual dysfunction
  • Monitoring
    • Fluid status
      • Weight loss/gain
    • Electrolytes
      • Usually need electrolyte supplementation
    • Renal function
    • Hearing (high doses)
potassium sparing diuretics
Potassium-Sparing Diuretics
  • Amiloride (Midamor) 5-10 mg daily-BID
  • Triamterene (Dyrenium) 50-100 mg daily-BID

Aldosterone Antagonists

  • Eplerenone (Inspra) 50-100 mg daily
  • Spironolactone (Aldactone) 25-50 mg daily
potassium sparing diuretics aldosterone antagonists
Potassium-Sparing Diuretics/Aldosterone Antagonists
  • 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
angiotensin converting enzyme ace inhibitors
Angiotensin Converting Enzyme (ACE) Inhibitors
  • 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
angiotensin converting enzyme ace inhibitors1
Angiotensin Converting Enzyme (ACE) Inhibitors
  • 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
angiotensin ii receptor blockers arbs
Angiotensin II Receptor Blockers (ARBs)
  • 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
angiotensin ii receptor blockers arbs1
Angiotensin II Receptor Blockers (ARBs)
  • 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
calcium channel blockers
Calcium Channel Blockers
  • 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
calcium channel blockers1
Calcium Channel Blockers
  • 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
    • Nifedipinelong-acting (Adalat CC, Procardia XL) 30-60 mg daily
    • Nisoldipine (Sular) 10-40 mg daily
calcium channel blockers2
Calcium Channel Blockers
  • 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
beta blockers
Beta Blockers
  • 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
beta blockers1
Beta Blockers
  • 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
beta blockers2
Beta Blockers
  • 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
alpha 1 blockers
Alpha-1 Blockers
  • Doxazosin (Cardura) 1-16 mg daily
  • Prazosin (Minipress) 2-20 mg BID-TID
  • Terazosin (Hytrin) 1-20 mg daily-BID
  • Side effects
    • 1st dose phenomenon: dizziness, palpitations, syncope
    • Orthostatic hypotension
    • CNS effects: vivid dreams, depression
    • Sodium and water retention
central alpha 2 agonists and other centrally acting drugs
Central alpha-2 agonists and Other centrally acting drugs
  • 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
central alpha 2 agonists and other centrally acting drugs1
Central alpha-2 agonists and Other centrally acting drugs
  • 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
direct vasodilators
Direct vasodilators
  • 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
treatment of hypertension3
Treatment of Hypertension

Treatment of hypertension with concurrent disease states or compelling indications

Choice of medication for hypertension

Treatment of hypertensive urgency & emergency

New Recommendations

ischemic heart disease
Ischemic Heart Disease
  • Stable angina
    • Beta blocker, or CCB
  • Acute coronary syndrome
    • Beta blocker (without ISA), ACEI
  • Post-MI
    • Beta blocker, ACEI, aldosterone antagonist
heart failure
Heart Failure
  • 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
diabetes
Diabetes
  • 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
chronic kidney disease
Chronic Kidney Disease
  • 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
cerebrovascular disease
Cerebrovascular Disease
  • Combination of thiazide diuretic and ACEI
    • Reduce recurrent stroke rate
left ventricular hypertrophy
Left ventricular hypertrophy
  • 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
ethnicity
Ethnicity
  • 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/Isosorbidedinitrate (Bidil)
elderly
Elderly
  • 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
pregnancy
Pregnancy
  • Preferred agents
    • Methyldopa, beta blockers, and vasodilators
  • Contraindicated:
    • ACEIs and ARBs
other indications
Other indications
  • 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
choice of initial medication1
Choice of initial medication
  • 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
hypertensive urgency vs emergency
Hypertensive Urgency vs. Emergency
  • 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)
hypertensive urgency
Hypertensive Urgency
  • 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
hypertensive urgency1
Hypertensive Urgency
  • 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
malignant hypertension
Malignant Hypertension
  • 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
malignant hypertension1
Malignant Hypertension
  • 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
malignant hypertension2
Malignant Hypertension
  • Treatment: oral medications
    • Not recommended unless IV meds not available
      • Uncontrolled hypotensive response
    • Sublingual nifedipine10 mg
    • Sublingual captopril 25 mg
  • Monitoring
    • When BP controlled, switch to oral therapy
    • Decrease DBP to 85-90 mmHg over 2-3 months
new recommendations
New Recommendations
  • Chlorthalidone preferred over HCTZ
    • More potent
    • Longer acting
    • Potential lower risk of cardiovascular events
  • Beta blockers should NOT be used as 1st 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
references
References
  • 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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