1. Jessica Schwenk, Pharm.D. September 14, 2013

2.  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

4.  How many people in the US have hypertension?

5.  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

6.  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

7.  Definitions  Isolated systolic hypertension: systolic ≥140 mmHg and diastolic <90 mmHg  Isolated diastolic hypertension: systolic <140 mmHg and diastolic ≥90 mmHg

8.  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

9.  Primary (essential) hypertension  Pathogenesis  Increased sympathetic neural activity (beta-adrenergic)  Increased angiotensin II activity  Mineralocorticoid excess  Genetics  Reduced adult nephron mass

10.  Risk Factors  Ethnicity  Genetics  Diet  Sodium intake  Alcohol  Obesity  Tobacco use  Decreased physical activity  Hyperlipidemia  Age > 65 years  Personality Traits  Vitamin D Deficiency

11.  Complications  Risk factor for other disease states  Heart failure  Left ventricular hypertrophy  Stroke  Intra-cerebral hemorrhage  Kidney disease  Malignant hypertension

12.  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

13. Lifestyle Modifications Treatment Algorithm Treatment Goal Medication Classes

14.  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

16.  JNC7 blood pressure goals  Generally <140/<90 mmHg  Complications or increased risk factors <130/<90  Diabetes  Chronic kidney disease

17.  Medications  Monitor  Blood pressure  Side effects: hypotension, orthostatic hypotension, dizziness

18.  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

19.  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

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

21.  Side Effects  Hypokalemia  Hypomagnesemia  Hypocalcemia  Hyperuricemia  Sexual dysfunction  Monitoring  Fluid status  Weight loss/gain  Electrolytes  Usually need electrolyte supplementation  Renal function  Hearing (high doses)

22.  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

23.  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

24.  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

25.  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

26.  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

27.  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

28.  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

29.  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

30.  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

31.  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

32.  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

33.  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

34.  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

35.  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

36.  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

37.  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

38. Treatment of hypertension with concurrent disease states or compelling indications Choice of medication for hypertension Treatment of hypertensive urgency & emergency New Recommendations

40.  Stable angina  Beta blocker, or CCB  Acute coronary syndrome  Beta blocker (without ISA), ACEI  Post-MI  Beta blocker, ACEI, aldosterone antagonist

41.  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

42.  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

43.  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

44.  Combination of thiazide diuretic and ACEI  Reduce recurrent stroke rate

45.  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

46.  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)

47.  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

48.  Preferred agents  Methyldopa, beta blockers, and vasodilators  Contraindicated:  ACEIs and ARBs

49.  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

51.  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

52.  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)

53.  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

54.  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

55.  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

56.  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

57.  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

59.  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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