New Frontiers in Devices to Treat Refractory Hypertension Scope of the Problem: the Pharm Approach John Somberg, M.D.

U.S. Hypertension Statistics 76,400,000 U.S. Population Hypertensive (equally distributed between men & women) 33.5% of adults > 20 years have hypertension (NHANES 2005-2008) African American adults 44% hypertensive Among hypertensive adults 80% aware of their condition 71% are using antihypertensive medication 48% aware of being hypertensive controlled with meds Resistant hypertension (BP > 140/90 on BP meds 3 different categories) 8-9% of population Estimated cost (direct & indirect 2008) 50.6 billion (NHLBI)

Hypertension Treatment & Control in Europe, Canada & U.S. Prevalence of age-adjusted hypertension (140/90) age 35-64 U.S. 28% Canada 27% Sweden 38% Italy 38% England 42% Spain 47% Germany 55%

Drugs to Treat Hypertension Class Toxicity Diuretics hypokalemia ↑ lipids fatigue Centrally Acting methyldopa CNS – sedation clonidine rebound quanfacine Ganglion-blocking guanethine OH reserpine sympathoplegia depression Beta-blockers bronchial constriction bradycardia Alpha-blockers prazosin, terazosin, doxazosin 1st dose CNS tachycardia Vasodilators hydralazine CNS, tachycardia minoxidil hypertrichosis fenolapam Ca++ Blockers peripheral edemia constipation ACE Inhibitors cough angioedemia hyperkalemia renal failure ARBs angioedemia Renin Inhibitors hyperkalemia aliskiren renal impairment

Downsides of Chronic Pharmacologic Therapy   Toxicity Cost Tolerance Drug Interactions

Resistant Hypertension BP > 140/90 mmHg Using antihypertensive from 3 different drug classes or drugs from > 4 antihypertensive drug classes regardless of BP This represents 12.8% of population taking antihypertensive therapy (NHWES 2003-2008)

Resistant Hypertension & Medication 53% of NHANES surveyed patients were controlled at <140/90 BP Framingham only 48% of treated participants were controlled at 140/90 & less than 40% of elderly participants (>75 year) were controlled NHAMES surveyed patients with chronic kidney disease, only 37% were controlled to <130/80 and only 25% of patients with diabetes were controlled at <130/85 ALLHAT after 5 years 34% remained uncontrolled on average of 2 meds 50% on 3 meds for control 16% not controlled AASK study an average of 3 agents was needed to achieve a mean arterial BP goal of <95 mmHg.

Pharmacologic Causes of Hypertension Glucocorticoids Mineralcorticoids Licorice, carbenoxolone, fluoroprednisolone, ketoconazol Sex hormones Estrogen, progesterone, androgens, danazol Sympathomametics phenylephrine, dipiralyl, phenylpropanolamine, pseudoephedrine, caffine, deongestants (oxymetazoline), ephedra, cocaine, methylphenidate, siburtamine, clozapine, venlafaxine, selegiline, tricyclics, buspirone, fluoxetine, thioridazine, disulfiram Renin angiotensin activation lead, torcetrapid Vasoconstrictors cyclosporine A tacrolimus Volume load NSAID’s erythropoietin alcohol, bevacizumab, sorafenib Unknown Mechanisms acetaminophen, scopolamine, naloxone, metoclopramide, alizapride, prochlorperazine, lithium, paclitaxel, cadmium, arsenic, bromocriptine, amphotericine B

New Pharmacologic Therapy   Aliskiren added to an ACE (or ARB) and a ß blocker can be effective in hypertension DORADO trial suggests that ET-a receptor antagonist darusentan is effective in refractory hypertension Cicletanine – more natriuresis and less kaliuresis and effective new thiazide diuretic

Nonpharmacologic Therapy of Hypertension 1. Are there safe, cost-effective nonpharmacologic therapies for the treatment of drug resistant hypertension? 2. If nonpharmacologic therapies are safe and cost effective in treating resistant hypertension, can they be considered for nonresistant hypertension?