ANTIHYPERTENSIVE DRUG UPDATE

Jessica Schwenk, Pharm.D.September 14, 2013

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 Hypertension

Review of Hypertension How many people in the US have

hypertension?

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 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 Hypertension Definitions

Isolated systolic hypertension: systolic ≥140 mmHg and diastolic <90 mmHg

Isolated diastolic hypertension: systolic <140 mmHg and diastolic ≥90 mmHg

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 Hypertension Primary (essential) hypertension

Pathogenesis  Increased sympathetic neural activity (beta-

adrenergic) Increased angiotensin II activity

Mineralocorticoid excess Genetics

Reduced adult nephron mass

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 Hypertension Complications

Risk factor for other disease states Heart failure Left ventricular hypertrophy Stroke Intra-cerebral hemorrhage Kidney disease Malignant hypertension

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 HypertensionLifestyle ModificationsTreatment AlgorithmTreatment GoalMedication Classes

Treatment of Hypertension Lifestyle Modification

Modification Systolic BP reduction

Sodium restriction 4.8 mmHg(2.5 mm HG diastolic)

Weight loss 0.5-2 mmHgper 1 kg weight loss

Diet (DASH) 2-8 mm Hg

Physical activity 4-8 mmHg

Moderation of alcohol consumption

2-4 mmHg

Treatment Goal JNC7 blood pressure goals

Generally <140/<90 mmHg Complications or increased risk factors

<130/<90 Diabetes Chronic kidney disease

Treatment of Hypertension Medications

Monitor Blood pressure Side effects: hypotension, orthostatic

hypotension, dizziness

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 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 Bumetanide (Bumex) 0.5-2 mg daily-BID Furosemide (Lasix) 20-80 mg daily-BID Torsemide (Demadex) 2.5-10 mg daily

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 Amiloride (Midamor) 5-10 mg daily-BID Triamterene (Dyrenium) 50-100 mg

daily-BIDAldosterone Antagonists Eplerenone (Inspra) 50-100 mg daily Spironolactone (Aldactone) 25-50 mg

daily

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 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) 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) 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 (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 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 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 Nifedipine long-acting (Adalat CC,

Procardia XL) 30-60 mg daily Nisoldipine (Sular) 10-40 mg daily

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-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 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 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 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 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 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 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 HypertensionTreatment of hypertension with

concurrent disease states or compelling indications

Choice of medication for hypertensionTreatment of hypertensive urgency &

emergencyNew Recommendations

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 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 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 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 Combination of thiazide diuretic and

ACEI Reduce recurrent stroke rate

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 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)

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 Preferred agents

Methyldopa, beta blockers, and vasodilators Contraindicated:

ACEIs and ARBs

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 medication

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

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 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 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 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 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 Hypertension 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

What’s to come?

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 Chobanian AV, Bakris GL, Black HR et al. The Seventh Report of the Joint

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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.

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