Pharmacology of Hypertension Vicki Groo, Pharm.d. Clinical Associate Professor Clinical pharmacist, heart center vjust@uic.edu 413-0928

objectives Classify hypertension and define treatment goals Be able to describe the pharmacology of oral antihypertensives with considerations in drug choice and compelling indications Be able to describe the pharmacology of intravenous antihypertensives used in the treatment of hypertensive emergency

CLASSIFICATION SBP DBP Normal < 120 and < 80 Prehypertension 120-139 or 80-89 Hypertension Stage 1 140-159 90-99 Stage 2 ≥ 160 ≥ 100 **Adults (18 yo) **Avg of 2 readings, 2 mins apart, on 2 occasions Secondary HTN only accounts for 5-10% of population JAMA 2003;289:2560-2572

epidemiology 31% of US population with HTN 30% of US population with pre-HTN Present in: 69% of patients who present with 1st MI 77% of patients who present with 1st stroke 74% of patients with heart failure Only 47% have BP under control http://www.cdc.gov/bloodpressure/facts.htm

National Health & Nutrition Examination Survey 2007-2008 81% 73% 50%

TREATMENT GOALS JNC-7 REDUCE MORBIDITY AND MORTALITY Measurable goal: Prehypertension: <120/80 HTN w/ diabetes or renal disease: <130/80 Others: <140/90 Minimize/ control other CV risk factors Reduce/ minimize adverse drug effects JAMA 2003;289:2560-2572

AHA BP targets 2007: For prevention and management of ischemic heart disease: *Don’t worry about learning these for now. They may change Circulation 2007:115:2761-88

Algorithm for Treatment of Hypertension Lifestyle Modifications Not at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those with diabetes or chronic kidney disease) Initial Drug Choices Stage 2 Hypertension (SBP >160 or DBP >100 mmHg) 2-drug combination for most (usually thiazide-type diuretic and ACEI, or ARB, or BB, or CCB) Stage 1 Hypertension (SBP 140–159 or DBP 90–99 mmHg) Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination. Without Compelling Indications Drug(s) for the compelling indications Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed. With Compelling Indications Not at Goal Blood Pressure Optimize dosages or add additional drugs until goal blood pressure is achieved. Consider consultation with hypertension specialist. JNC VII JAMA 2003;289:2560-2572

Drug Therapy Considerations Clinical trial data Over 2/3 of patients will require ≥2 drugs Cost/ adverse effects JAMA 2003;289:2560-2572

Lifestyle Modifications Limit salt intake Physical activity DASH eating Plan Lose weight Limit alcohol intake

Pharmacology of Antihypertensives Diuretics: Deplete sodium thereby decreasing blood volume Agents that block production or action of angiotensin Reduce peripheral vascular resistance Potentially ↓ blood volume Sympathoplegic agents: ↓ peripheral vascular resistance Inhibit cardiac function ↑ venous pooling in capacitance vessels Direct vasodilators: Relax vascular smooth muscle, thus dilating resistance vessels

Diuretic moa

Diuretic Comparison HCTZ CTD Indapamide benzothiadiazine thiazide-like Non-thiazide sulfonamide VD 2.5 L 3-13 L 25 L T ½ 8-15 hours 45-60 hours 14 hours duration 16-24 hours 48-72 hours 24 hr SBP (-) 7.4 ± 1.7 (-) 12.4 ± 1.8 PM BP (-)6.4 ± 1.8 (-) 13.5 ± 1.9 P = 0.054 and 0.009 for 24 hr and pm BP respectively Indapamide Hypertension 2004;43:4-9,

Diuretic Considerations K Dose Other Thiazides: 1st line choice Hydrochlorothiazide ↓ 12.5-50 mg/d Chlorthalidone ↓↓ 12.5-25 mg/d Metolazone ↓↓↓ 2.5-10 mg/d Reserve for resistant edema Indapamide --- 1.25-2.5 mg/d 1st line choice elderly Aldosterone Antag Reserve for resistant HTN or HF Spironolactone ↑ avoid K > 5.0 or CrCl < 30 Eplerenone 25-100 mg/d K sparing Caution, ACE/ARB, renal failure Amiloride 5- 20 mg/d Use in combo to counteract K loss Triamterene 37.5-50 mg/d Combo product with HCTZ available Loop Reserve for HF or resistant edema Furosemide 20-80 mg/d Bioavailability 60% or less Bumetanide 0.5-4 mg/d Bioavailability 80% Torsemide 5-10 mg/d Goodman and Gilmans: The Pharmacologic Basis of Therapeutic 12th edition: http://www.accesspharmacy.com

diuretics Compelling Indications: Heart Failure High CAD risk Diabetes Recurrent Stroke Prevention Monitoring Electrolytes after initiation or dose increases Every 6-12 months K sparing, every 3 months if also on RAAS inhibitor Side Effects Increase glucose Increase uric acid — precipitate gout dehydration — orthostatic hypotension Spironolactone — gynecomastia

Mechanism of Action

ACE Inhibitors ARBs Drug Dose Captopril 12.5-50 mg tid Enalapril 2.5-40 mg/day Lisinopril 5-40 mg/day Benazepril 5-80 mg/day Fosinopril* 10-80 mg/day Moexipril 7.5-30 mg/day Quinapril Ramipril 1.25-20 mg/day Perindopril 2-16 mg/day Trandolapril 1-8 mg/day Drug Dose Candesartan (Atacand)* 4-32 mg/d Eprosartan (Tevetan)* 400-800 mg/d Irbesartan (Avapro)* 75-300 mg/d Losartan (Cozaar)* 25-100 mg/d Omelsartan (Benicar) 20-40 mg/d Telmisartan (Micardis) 40-80 mg/d Valsartan (Diovan) 80-320 mg/d * generic Combining with thiazide usually more effective than dose increase Direct Renin Inhibitors Aliskiren (Tekturna) 150-300 mg/day As effective as ACE or ARB in HTN * Dual elimination: liver & kidney Goodman and Gilmans: The Pharmacologic Basis of Therapeutic 12th edition: http://www.accesspharmacy.com

ACE Inhibitors and ARB Compelling Indications Systolic Heart Failure DM CKD with Proteinuria CAD Monitoring 1-2 weeks after initiation or dose change for K & Cr Every 6 months on stable doses Side Effects Dry Cough  Switch to ARB Angioedema: ARB likely okay, consider severity Hyperkalemia: supplements, diet, worsening renal fxn Combining RAAS inhibitors is generally not recommended No added benefit CV or renal outcomes / Increased toxicity ACE or ARB + aldosterone antagonist is the exception Avoid in Pregnancy

Beta Blockers MOA: Sympatholytic  ↓ HR and CO / ↓ release of renin Receptor Affinity Lipid Solubility Renal Elimination Dose Atenolol β1 Low Yes 25-100 mg/d Bisoprolol No 2.5-10 mg/d Carvedilol β1, β2, α Mod 3.125-25 mg bid Labetalol 100-400 mg bid Metoprolol tartrate Metoprolol succinate 50-200 mg bid 25-200 mg/d Nebivolol 5-40 mg/d Propranolol β1, β2 High 40-120 mg bid Avoid sudden discontinuation Rebound HTN d/t up regulation of ᵦ receptors Goodman and Gilmans: The Pharmacologic Basis of Therapeutic 12th edition: http://www.accesspharmacy.com

Beta Blockers Compelling Indications CAD Systolic Heart Failure Monitoring ECG if bradycardic- AV block Avoid combining with other AV nodal blocking agents Side Effects Bronchoconstriction—Reactive Airway Disease Choose B1 selective agent and keep at lower doses Metabolic—↓HDL, ↑ LDL and triglycerides Diabetes—↓ insulin sensitivity Mask symptoms of hypoglycemia, delay recovery Carvedilol may have advantage as it ↑’s insulin sensitivity Peripheral Vascular Disease—↑ symptoms, use B1 selective Depression—Choose agent with low lipid solubility Fatigue

Calcium channel blockers http://www.accesspharmacy.com/content.aspx?aID=6543820 http://www.drugdevelopment-technology.com/projects/istaroxime/istaroxime4.html

CCB Considerations AV Node SA Node Contractility Vasodilation DHP Nifedipine^ 1 5 Amlodipine Felodipine Nicardipine Non-DHP# Diltiazem^ 4 2 3 Verapamil^ ^ Do not use short acting agents in treatment of HTN # Do not combine with beta-blockers: increased risk of bradycardia Doses provided in Dr DiDomenico’s lecture on angina Goodman and Gilmans: The Pharmacologic Basis of Therapeutic 12th edition: http://www.accesspharmacy.com

Calcium channel blockers Compelling Indications High CAD risk Diabetes Monitoring / Side Effects Dihydropyridine (DHP) peripheral edema reflex tachycardia dizziness Non DHP Bradycardia Contra-indicated in heart failure Constipation (especially verapamil)

Vasodilators: alpha-1 blockers Doxazosin: start 1 mg daily: max 8 mg daily Prazosin: start 1 mg bid-tid: max 15 mg/day Terazosin: start 1 mg qhs: max 20 mg/day http://cvpharmacology.com/vasodilator/alpha.htm

Vasodilators: alpha-1 blockers Compelling Indications: None Second line therapy Also used to treat BPH (benign prostatic hypertrophy) Monitoring: Na and H20 retention with high doses Side Effects: Dizziness — Orthostatic hypotension, first dose syncope Headaches Reflex tachycardia Fatigue

Vasodilators: direct MOA: vascular smooth muscle relaxation Compelling Indications: None Second line therapy: Resistant HTN Hydralazine 10 – 50 mg qid; max 300 mg /day Often dosed bid or tid to improve adherence Rare but serious SE: Lupus erythematosus, blood dyscrasias, peripheral neuritis Headaches, tachycardia, angina, nausea, diarrhea, rash Minoxidil Start 5 mg daily; usual 10-40 mg daily; max 100 mg daily Rare but serious SE: Stevens-Johnson syndrome Hypertrichosis — used topically to promote hair growth Headache, edema, tachycardia, paresthesia

Vasodilators: direct Caution: Increased myocardial work Use in combination with B-blocker / diuretic to combat these effects

Central alpha 2 agonists Bind to and activate α2 receptors in the brain ↓ sympathetic outflow to the heart → CO and HR ↓ sympathetic outflow to vasculature → ↓ vascular tone http://www.cvpharmacology.com/vasodilator/Central-acting.htm

Central alpha 2 agonists Compelling Indications: None Second line therapy: Resistant HTN Clonidine Start 0.1 mg bid, titrate up weekly: max 2.4 mg/day Available as a transdermal patch changed weekly Severe rebound HTN if stopped abruptly Side Effects: sedation, depression, bradycardia + many more Methyldopa Start 250-500 mg bid-tid, adjust every 2-3 days, max 3gm/day Can be used in pregnancy Serious but uncommon SE: blood dyscrasias, myocarditis, pancreatitis Side effects: sedation, orthostatic hypotension + many more

Hyperkalemia, dry cough Antihypertensives: α 1 blocker: Prazosin, Doxazosin, Terazosin Dizziness, edema Centrally Acting: Methlydopa Clonidine Sedation, dry mouth Vascular Smooth Muscle: Hydralazine, Minoxidil CCBs Headache, Dizziness, edema, B-blockers: Atenolol Carvedilol Metoprolol Propranolol Bradycardia Diuretics: Thiazide Loop Other hypokalemia Renin ACE Angiotensinogen Angiotensin I Angiotensin II ARBs Aliskiren ACE Inhibitors Hyperkalemia, dry cough

Algorithm for Treatment of Hypertension Lifestyle Modifications Not at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those with diabetes or chronic kidney disease) Initial Drug Choices Stage 2 Hypertension (SBP >160 or DBP >100 mmHg) 2-drug combination for most (usually thiazide-type diuretic and ACEI, or ARB, or BB, or CCB) Stage 1 Hypertension (SBP 140–159 or DBP 90–99 mmHg) Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination. Without Compelling Indications Drug(s) for the compelling indications Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed. With Compelling Indications Not at Goal Blood Pressure Optimize dosages or add additional drugs until goal blood pressure is achieved. Consider consultation with hypertension specialist. JNC VII JAMA 2003;289:2560-2572

Inadequate BP Response with Initial Agent Increase dose Substitute new drug from different class Little to no response to initial drug No compelling indication for the drug Troublesome SE Add a new drug from a different class Initial drug produces some response and is well tolerated Compelling indication for the initial drug Add thiazide if not used initially

HTN: Special Populations Elderly Isolated systolic HTN common SBP rises and DPB declines with aging Generally salt sensitive Use lower initial drug doses and slower dose titration Avoid 1-blockers, labetalol, central 2 agonists JNC-8 – higher BP goal? AHA Consensus Statement on the Elderly 2011 Goal SBP < 140 mm Hg Age > 80, goal SBP < 150 mmHg No evidence for lower BP goals for elderly patients at high risk, eg DM, CAD, CKD. Maintain DBP > 65 mmHg --- coronary perfusion Circulation 2011;123:2434-2506

HTN Elderly Guidelines Canada 2013 In the very elderly (age ≥ 80), the target for SBP should be < 150 (grade C) No changes for those age 65-79; ie goal remains at < 140/90 Europe 2013 In elderly < 80 years old with SBP ≥160 mmHg there is solid evidence to reducing SBP to 150 and 140 mmHg (IA) In fit elderly patients < 80 years old SBP values <140 mmHg may be considered, whereas in the fragile elderly population SBP goals should be adapted to individual tolerability (IIb C) If > 80 years and with initial SBP ≥160 mmHg, it is recommended to reduce SBP to between 150 and 140 mmHg provided they are in good physical and mental conditions (IB) Benefit in treating elderly, ↓ stroke, CV events, heart failure Canadian Journal of Cardiology 2013;29:528-542

HTN: Special Populations African Americans Prevalence, severity and impact increased compared to other populations Onset at younger age More Na+ sensitive, lower plasma renin activity Good response to Na restriction and diuretic therapy  response to ACE inhibitors, ARBs, and -blockers as monotherapy HOWEVER, can be overcome by adding a diuretic Still indicated if compelling indication exists! ACE inhibitor angioedema 2-4 x more frequent

Hypertensive crisis

HYPERTENSION CRISES EMERGENCY BP >180/120 Acute Target Organ Damage Life threatening GOAL:  BP now IV therapy URGENCY BP >180/120 No Target Organ Damage Not life-threatening GOAL:  BP over days Oral therapy

HYPERTENSIVE EMERGENCIES Heart Acute coronary syndrome Acute heart failure with pulmonary edema Dissecting aortic aneurysm CNS Intra-cerebral hemorrhage / CVA Encephalopathy Eclampsia Acute Renal Failure Eyes: Papilledema, hemorrhage

Treatment for Hypertensive Emergencies Goal: Lower MAP no greater than 20-25% in a few hours Maintain DBP 100-110 mmHg Too rapid or too much  cerebral hypoperfusion Continuous BP monitoring IV Vasodilators Sodium Nitroprusside Nicardipine Nitroglycerin Enalaprilat Fenoldopam Hydralazine IV Adrenergic Inhibitors Labetalol Esmolol Phentolamine

IV vasodilators MOA Indication Nitroprusside Vasodilator* Most HTN emergencies Caution high ICP or azotemia Nicardipine CCB Except acute heart failure Caution coronary ischemia Nitroglycerin Coronary Ischemia Enalaprilat ACE inhibitor Acute heart failure Avoid in acute MI Fenoldopam Dopamine 1 agonist* Caution glaucoma Hydralazine Direct vasodilator Eclampsia * See next slide

IV vasodilators: MOA Fenoldopam D1 receptor agonist moderate affinity α2 vasodilation Release Pro drug Nitroprusside: arteriole and venous No tolerance Less effect on HR Nitroglycerin 1° venodilator Arteriole dilator at high doses + tolerance http://cvpharmacology.com/vasodilator/nitrodilator%20mech.gif http://www.drugabuse.gov/sites/default/files/imagecache/content_image_landscape/images/colorbox/dopamine.gif

IV vasodilators Dose Onset Adverse Effects Nitroprusside 0.25-10 ug/min immediate Thiocyanate Cyanide toxicity Nicardipine 5-15 mg/hr 5-10 min ↑ HR, HA, flushing Nitroglycerin 5-100 ug/min 2-5 min HA, vomiting Tolerance with prolonged use Enalaprilat 1.25-5 mg q6h 15-30 min High renin states: ↓↓↓ BP Variable response Fenoldopam 0.1-0.3 ug/kg/min < 5 min ↑ HR, HA, flushing, nausea Hydralazine 10-20 mg IV 10-50 mg IM 10-20 min 20-30 min ↑ HR, HA, flushing, vomiting, angina Duration of action varies from 1-2 min to 6 hours

Nitroprusside Toxicity Metabolism releases Cyanide Increased Risk if: Rate at ≥ 5 ug/kg/min 2 ug/kg/min for prolonged use (24-48 hours) Renal insufficiency Can administer Na Thiosulfate to enhance metabolism of cyanide Cyanide Toxicity Weakness Headaches Vertigo Confusion / giddiness Perceived difficulty breathing Thiocyanate Toxicity Anorexia / nausea Fatigue Toxic psychosis http://www.biomedcentral.com/content/figures/1471-2253-13-9-1-l.jpg

IV adrenergic blockers MOA Indication Labetalol B1, B2, α blocker Most HTN emergencies Except acute heart failure Esmolol B1 blocker Aortic dissection Perioperative Phentolamine α antagonist Catecholamine excess Dose Onset (min) Adverse Effects Labetalol 20-80 mg q 10 min 0.5-2.0 mg/min 5-10 Heart block Esmolol 250-500 ug/kg/min x 1 min 50-100 ug/kg/min x 4 min 1-2 Hypotension, nausea Phentolamine 5-15 mg ↑ HR, HA, flushing Duration of action varies from 3-10 min to 6 hours